Latest revision as of 17:48, 23 June 2024

Back to Top

Page editor		Section editor
	Michael J. Glover, MD Stanford University Palo Alto, CA, USA LinkedIn		Ali Raza Khaki, MD Stanford University Palo Alto, CA, USA LinkedIn

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: this page has recently been renamed from "Bladder cancer" to "Urothelial carcinoma" to reflect the fact that most regimens here are generic to urothelial cancer. For now, the page also has adjuvant and perioperative regimens specific to bladder cancer, but these will be moved to a dedicated bladder cancer page soon.

See the bladder cancer page for regimens specific to bladder cancer.

See the upper tract urothelial carcinoma page for regimens specific to UTUC.

31 regimens on this page 47 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

2022: Powles et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
2019: eUpdate – Bladder Cancer Treatment Recommendations
2019: eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy

2014: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines PubMed

NCCN

NCCN Guidelines - Bladder Cancer

2017: Spiess et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
2009: Montie et al. Bladder cancer PubMed

SITC

2021: Galsky et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer PubMed
- 2017: Kamat et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma PubMed

Adjuvant therapy

Nivolumab monotherapy

Regimen variant #1, q2wks

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bajorin et al. 2021 (CheckMate 274)	2016-2020	Phase 3 (E-RT-esc)	Placebo	Superior DFS (co-primary endpoint) Median DFS: 20.8 vs 10.8 mo (HR 0.70, 98.22% CI 0.55-0.90)

Preceding treatment

CheckMate 274: Radical surgery

Immunotherapy

Nivolumab (Opdivo) 240 mg IV over 30 minutes once on day 1

14-day cycle for up to 26 cycles (1 year)

Regimen variant #2, q4wks

FDA-recommended dose

Note: this is not the dose that was used in the registration study, CheckMate 274.

Preceding treatment

CheckMate 274: Radical surgery

Immunotherapy

Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycle for up to 13 cycles (1 year)

References

CheckMate 274: Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02632409
1. HRQoL analysis: Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol. 2022 Oct;5(5):553-563. Epub 2022 Mar 11. link to original article link to PMC article PubMed
VOLGA: NCT04960709

Locally advanced or metastatic disease, first-line, platinum-ineligible

Gemcitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Heinzelbecker et al. 2023 (AUO-AB 22/00)	2000-07 to 2008-12	Phase 3 (C)	Gemcitabine; adjuvant	Did not meet primary endpoint of OS

Chemotherapy

Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

AUO-AB 22/00: Heinzelbecker J, Spieler N, Kuehn M, Fischer C, Volkmer B, von Rundstedt F, Albers P, Becht E, Bannowsky A, Weber HM, Hofmann R, Müller M, Langbein S, Steiner G, Retz M, Kamradt J, Wagenpfeil G, Wellek S, Lehmann J, Stoeckle M. Adjuvant vs progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial. Urol Oncol. 2023 Aug;41(8):356.e19-356.e30. Epub 2023 May 16. link to original article contains dosing details in manuscript PubMed NCT00146276

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Balar et al. 2017 (KEYNOTE-052)	2015-2016	Phase 2 (RT)	ORR: 24% (95% CI 20-29)

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article contains dosing details in abstract PubMed NCT02335424
1. Update: Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. Epub 2020 Jun 17. link to original article PubMed
2. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
LEAP-011: NCT03898180

Locally advanced or metastatic disease, first-line, platinum-eligible

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin

Regimen variant #1, AUC 4.5/1000 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	1. Durvalumab	Did not meet co-primary endpoint of OS	More toxic
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	2. Durvalumab & Tremelimumab	Might have inferior OS	Not more toxic
Powles et al. 2024 (EV-302)	2020-2023	Phase 3 (C)	Enfortumab vedotin & Pembrolizumab	Inferior PFS/OS

Note: this was the lower bound of AUC specified by DANUBE & EV-302.

Chemotherapy

Carboplatin (Paraplatin) AUC 4.5 IV over 60 minutes once on day 1, given second
Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8, given first

21-day cycle for up to 6 cycles

Regimen variant #2, AUC 4.5/1000, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
De Santis et al. 2009 (EORTC 30986)	2001-2005	Randomized Phase 2/3 (E-de-esc)	M-CAVI	Did not meet primary endpoint of ORR¹ ORR: 30.3% vs 41.2%	Lower toxicity than M-CAVI
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (C)	1. Atezolizumab	Did not meet co-primary endpoint of OS
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (C)	2a. GCb & Atezolizumab 2b. GC & Atezolizumab	Might have inferior OS²

¹Reported efficacy for EORTC 30986 is based on the 2011 update.
²Reported efficacy for IMvigor130 is based on the 2023 update.
Note: Patients in EORTC 30986 who achieved complete response were given two additional cycles of treatment.

Chemotherapy

Carboplatin (Paraplatin) AUC 4.5 IV over 60 minutes once on day 1, given second
Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8, given first

21-day cycles

Regimen variant #3, AUC 5/1000 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carles et al. 2000	1997-1998	Phase 2, fewer than 20 pts
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	1. Durvalumab	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	2. Durvalumab & Tremelimumab	Might have inferior OS
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (C)	1a. GC & Pembrolizumab 1b. GCb & Pembrolizumab	Might have inferior OS
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (C)	2. Pembrolizumab	Not reported
Powles et al. 2024 (EV-302)	2020-2023	Phase 3 (C)	Enfortumab vedotin & Pembrolizumab	Inferior PFS/OS

Note: this was the upper bound of AUC specified by DANUBE & EV-302.

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1
Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #4, AUC 5/1250

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Dogliotti et al. 2006	2000-2002	Randomized Phase 2 (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of reduced toxicity

ORR for this arm: Intention to treat: 40% (95% CI NR)
Evaluable patients only: 56%
(95% CI: 40–72)
ORR for control arm: Intention to treat: 49% (95% CI NR)
Evaluable patients only: 66%
(95% CI: 49–80)

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 2
Gemcitabine (Gemzar) 1250 mg/m² IV over 30 to 60 minutes once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. link to original article contains dosing details in abstract PubMed
Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains dosing details in manuscript PubMed
EORTC 30986: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00111787
1. Update: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. Epub 2011 Dec 12. link to original article link to PMC article contains dosing details in manuscript PubMed
IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed
DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article PubMed NCT02516241
KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305
EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856
NILE: NCT03682068
RC48-C016: NCT05302284

Carboplatin & Gemcitabine (GCb) & Pembrolizumab

GCb & Pembrolizumab: Gemcitabine, Carboplatin, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (E-RT-esc)	1a. GC 1b. GCb	Might have superior OS (co-primary endpoint) Median OS: 17 vs 14.3 mo (HR 0.86, 95% CI 0.72-1.02) Might have superior PFS¹ (co-primary endpoint) Median PFS: 8.3 vs 7.1 mo (HR 0.78, 95% CI 0.65-0.3)
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (E-RT-esc)	2. Pembrolizumab	Not reported

¹Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Carboplatin (Paraplatin) as follows:
- Cycles 1 up to 6: AUC 5 IV once on day 1
Gemcitabine (Gemzar) as follows:
- Cycles 1 up to 6: 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles

References

KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305

Carboplatin & Paclitaxel (CP)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Vaughn et al. 2002 (ECOG E2896)	1996-1999	Phase 2		ORR: 24% (95% CI 12-42)
Dreicer et al. 2004 (ECOG E4897)	1998-2001	Phase 3 (E-de-esc)	MVAC	Did not meet primary endpoint of OS

Note: ECOG E4897 was closed early due to poor accrual.

Chemotherapy

Carboplatin (Paraplatin) AUC 6 IV once on day 1
Paclitaxel (Taxol) 225 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

References

ECOG E2896: Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. link to original article contains dosing details in abstract PubMed
ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article contains dosing details in manuscript PubMed NCT00003376

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

AIM pathway regimen 2022-08-01

Regimen variant #1, 70/2000; q3wk x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601)	2009-2014	Phase 3 (C)	GC & Bevacizumab	Might have inferior OS
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	1. Durvalumab	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	2. Durvalumab & Tremelimumab	Might have inferior OS
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (C)	1a. GC & Pembrolizumab 1b. GCb & Pembrolizumab	Might have inferior OS
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (C)	2. Pembrolizumab	Not reported
van der Heijden et al. 2023 (CheckMate 901 part 1)	2018-01-30 to 2022-09-28	Phase 3 (C)	GC & Nivolumab	Seems to have inferior OS (co-primary endpoint)
Powles et al. 2024 (EV-302)	2020-2023	Phase 3 (C)	Enfortumab vedotin & Pembrolizumab	Inferior PFS/OS

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV over 30 to 60 minutes once on day 1
Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Supportive therapy

2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

21-day cycle for 6 cycles

Regimen variant #2, 70/2000; q3wk, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Soto Parra et al. 2002	1998-2000	Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc)	Cisplatin & Gemcitabine; q4wk	Not reported
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (C)	1. Atezolizumab	Did not meet co-primary endpoint of OS
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (C)	2a. GCb & Atezolizumab 2b. GC & Atezolizumab	Might have inferior OS¹

¹Reported efficacy for IMvigor130 is based on the 2023 update.

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV over 30 to 60 minutes once on day 1 or 2
Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Supportive therapy

2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

21-day cycles

Regimen variant #3, 70/2500; q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Dogliotti et al. 2006	2000-2002	Randomized Phase 2 (C)	Carboplatin & Gemcitabine		Did not meet primary endpoint of reduced toxicity
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	1. Durvalumab	Did not meet co-primary endpoint of OS	More toxic
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	2. Durvalumab & Tremelimumab	Might have inferior OS	Not more toxic

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV once on day 1 or 2
Gemcitabine (Gemzar) 1250 mg/m² IV over 30 to 60 minutes once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #4, 70/3000; q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von der Maase et al. 2000	1996-1998	Phase 3 (E-de-esc)	MVAC	Did not meet primary endpoint of OS
Soto Parra et al. 2002	1998-2000	Randomized Phase 2, fewer than 20 pts in this subgroup (E-de-esc)	Cisplatin & Gemcitabine; q3wk	Not reported
Bellmunt et al. 2012 (EORTC 30987)	2001-2004	Phase 3 (C)	PCG	Might have inferior OS
Sternberg et al. 2013 (CILAB)	2008-2010	Phase 3 (C)	Cisplatin & Larotaxel	Did not meet primary endpoint of OS
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	1. Durvalumab	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE)	2015-2017	Phase 3 (C)	2. Durvalumab & Tremelimumab	Might have inferior OS

Note: Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had non-small cell lung cancer.

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV over 30 to 60 minutes once on day 2
Gemcitabine (Gemzar) 1000 mg/m² IV over 30 to 60 minutes once per day on days 1, 8, 15

Supportive therapy

Per Soto Parra et al. 2002:
2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

28-day cycle for up to 6 cycles

References

von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains dosing details in manuscript PubMed
1. Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. link to original article contains dosing details in manuscript PubMed
Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains dosing details in manuscript PubMed
EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00022191
CILAB: Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. link to original article contains dosing details in abstract PubMed NCT00625664
IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed
DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article PubMed NCT02516241
KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305
CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00942331
CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article contains dosing details in supplement PubMed NCT03036098
EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856
NILE: NCT03682068
RC48-C016: NCT05302284

Cisplatin & Gemcitabine (GC) & Bevacizumab

GCB: Gemcitabine, Cisplatin, Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601)	2009-2014	Phase 3 (E-esc)	GC	Might have superior OS (primary endpoint) Median OS: 14.5 vs 14.3 mo (HR 0.87, 95% CI 0.72-1.05)

Chemotherapy

Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 70 mg/m² IV over 30 to 60 minutes once on day 1 or 2
Gemcitabine (Gemzar) as follows:
- Cycles 1 to 6: 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00942331

Cisplatin & Gemcitabine (GC) & Nivolumab

GC & Nivolumab: Gemcitabine, Cisplatin, Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van der Heijden et al. 2023 (CheckMate 901 part 1)	2018-01-30 to 2022-09-28	Phase 3 (E-RT-esc)	GC x 6	Seems to have superior OS (co-primary endpoint) Median OS: 21.7 vs 18.9 mo (HR 0.78, 95% CI 0.63-0.96) Superior PFS (co-primary endpoint) Median PFS: 7.9 vs 7.6 mo (HR 0.72, 95% CI 0.59-0.88)

Chemotherapy

Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 70 mg/m² IV once on day 1
Gemcitabine (Gemzar) as follows:
- Cycles 1 to 6: 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

Nivolumab (Opdivo) as follows:
- Cycles 1 to 6: 360 mg IV once on day 1
- Cycle 7 up to 28: 480 mg IV once on day 1

21-day cycle for 6 cycles, then 28-day cycle for up to 22 cycles (2 years)

References

CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article contains dosing details in supplement PubMed NCT03036098

Cisplatin & Gemcitabine (GC) & Pembrolizumab

GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (E-RT-esc)	1a. GC 1b. GCb	Might have superior OS (co-primary endpoint) Median OS: 17 vs 14.3 mo (HR 0.86, 95% CI 0.72-1.02) Might have superior PFS¹ (co-primary endpoint) Median PFS: 8.3 vs 7.1 mo (HR 0.78, 95% CI 0.65-0.3)
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (E-RT-esc)	2. Pembrolizumab	Not reported

¹Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Cisplatin (Platinol) as follows:
- Cycles 1 up to 6: 70 mg/m² IV once on day 1
Gemcitabine (Gemzar) as follows:
- Cycles 1 up to 6: 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305

Enfortumab vedotin & Pembrolizumab

Regimen variant #1, q3wk pembrolizumab

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 2024 (EV-302)	2020-2023	Phase 3 (E-RT-switch-ooc)	1a. GC 1b. GCb	Superior OS (co-primary endpoint) Median OS: 31.5 vs 16.1 mo (HR 0.47, 95% CI 0.38-0.58) Superior PFS (co-primary endpoint) Median PFS: 12.5 vs 6.3 mo (HR 0.45, 95% CI 0.38-0.54)

Antibody-drug conjugate therapy

Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1 & 8

Immunotherapy

Pembrolizumab (Keytruda) as follows:
- Cycles 1 to 35: 200 mg IV once on day 1

21-day cycles

Regimen variant #2, q6wk pembrolizumab

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 2024 (EV-302)	2020-2023	Phase 3 (E-RT-switch-ooc)	1a. GC 1b. GCb	Superior OS (co-primary endpoint) Median OS: 31.5 vs 16.1 mo (HR 0.47, 95% CI 0.38-0.58) Superior PFS (co-primary endpoint) Median PFS: 12.5 vs 6.3 mo (HR 0.45, 95% CI 0.38-0.54)

Note: Dosing is as described in the FDA approval announcement; this dosing was not reported in Powles et al. 2024.

Antibody-drug conjugate therapy

Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 22, 29

Immunotherapy

Pembrolizumab (Keytruda) as follows:
- Cycles 1 to 17: 200 mg IV once on day 1

42-day cycles

References

EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856

Gemcitabine & Paclitaxel

Regimen variant #1

Study	Dates of enrollment	Evidence	Efficacy
Calabrò et al. 2009	2003-2005	Phase 2	ORR: 37%

Chemotherapy

Gemcitabine (Gemzar) 2500 mg/m² IV over 30 minutes once on day 1, given second
Paclitaxel (Taxol) 150 mg/m² IV over 3 hours once on day 1, given first

14-day cycle for 6 to 12 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Efficacy
Meluch et al. 2001	1997-1999	Phase 2	ORR: 54% (95% CI 40-67)

Chemotherapy

Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

References

Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. link to original article contains dosing details in manuscript PubMed

MVAC

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen variant #1, standard

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Loehrer et al. 1992 (ECOG E5886)	1984-1989	Phase 3 (E-esc)	Cisplatin	Superior OS
Logothetis et al. 1990	1985-1989	Phase 3 (E-switch-ic)	CISCA	Superior OS
Siefker-Radtke et al. 2002	1992-1999	Phase 3 (C)	FAP	Did not meet primary endpoint of OS50%
Sternberg et al. 2001 (EORTC 30924)	1993-1998	Phase 3 (C)	Dose-dense MVAC	Seems to have inferior OS¹
von der Maase et al. 2000	1996-1998	Phase 3 (C)	GC	Did not meet primary endpoint of OS
Dreicer et al. 2004 (ECOG E4897)	1998-2001	Phase 3 (C)	CP	Did not meet primary endpoint of OS

¹Reported efficacy for EORTC 30924 is based on the 2005 update.

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV once per day on days 1, 15, 22
Vinblastine (Velban) 3 mg/m² IV once per day on days 2, 15, 22
Doxorubicin (Adriamycin) 30 mg/m² IV once on day 2
Cisplatin (Platinol) 70 mg/m² IV once over 120 minutes on day 1 or 2

28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)

Regimen variant #2, with G-CSF support

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bamias et al. 2003	1997-2002	Phase 3 (C)	Cisplatin & Docetaxel	Seems to have superior OS

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV once per day on days 1, 15, 22
Vinblastine (Velban) 3 mg/m² IV once per day on days 1, 15, 22
Doxorubicin (Adriamycin) 30 mg/m² IV once on day 1
Cisplatin (Platinol) 70 mg/m² IV over 60 minutes once on day 1

Supportive therapy

Filgrastim (Neupogen) (dose not specified) SC once per day on days 7, 8, 9, 25, 26

28-day cycles

References

Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains dosing details in manuscript PubMed
ECOG E5886: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. link to original article contains dosing details in manuscript PubMed
1. Update: Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. link to original article PubMed
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains dosing details in manuscript PubMed
1. Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article contains dosing details in manuscript PubMed
1. Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article contains dosing details in manuscript PubMed
Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. link to original article contains dosing details in manuscript PubMed
Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. link to original article contains dosing details in manuscript PubMed
ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article contains dosing details in manuscript PubMed NCT00003376

MVAC, dose-dense

ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sternberg et al. 2001 (EORTC 30924)	1993-1998	Phase 3 (E-esc)	MVAC	Seems to have superior OS¹
Bamias et al. 2012 (HE 16/03)	2003-2008	Phase 3 (C)	DD-GC	Did not meet primary endpoint of OS

¹Reported efficacy for EORTC 30924 is based on the 2005 update.
Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. ORR for this arm of EORTC 30924 was 62% (95% CI 54-70) versus 50% (95% CI 42-59) in the control arm.

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV once on day 1
Vinblastine (Velban) 3 mg/m² IV once on day 2
Doxorubicin (Adriamycin) 30 mg/m² IV once on day 2
Cisplatin (Platinol) 70 mg/m² IV once on day 2

Supportive therapy

G-CSF (type not specified) 240 mcg/m² SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/μL.
- In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.

14-day cycles

References

EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article contains dosing details in manuscript PubMed
1. Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article contains dosing details in manuscript PubMed
HE 16/03: Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. link to original article contains dosing details in abstract PubMed ACTRN12610000845033

PGC

PGC: Paclitaxel, Gemcitabine, Cisplatin
PCG: Paclitaxel, Cisplatin, Gemcitabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2012 (EORTC 30987)	2001-2004	Phase 3 (E-esc)	Cisplatin & Gemcitabine	Might have superior OS (primary endpoint) Median OS: 15.8 vs 12.7 mo (HR 0.85, 95% CI 0.72-1.02)

Note: ORR for this arm of EORTC 30987 was 56% vs 44% in the control arm.

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV once on day 1
Gemcitabine (Gemzar) 1000 mg/m² IV over 30 to 60 minutes once per day on days 1 & 8
Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8, given first

21-day cycle for up to 6 cycles

References

EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00022191

Locally advanced or metastatic disease, maintenance after platinum chemotherapy

Avelumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Powles et al. 2020 (JAVELIN Bladder 100)	2016-2019	Phase 3 (E-RT-esc)	Best supportive care	Superior OS¹ (primary endpoint) Median OS: 23.8 vs 15 mo (HR 0.76, 95% CI 0.63-0.91)	More toxic

¹Reported efficacy is based on the 2023 update.

Preceding treatment

First-line GC x 4 to 6 or GCb x 4 to 6

Immunotherapy

Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once per day on days 1 & 15

Supportive therapy

Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:

Diphenhydramine (Benadryl) 25 to 50 mg IV or PO equivalent
Acetaminophen (Tylenol) 500 to 650 mg IV or PO equivalent

28-day cycles

References

JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article contains dosing details in manuscript PubMed NCT02603432
1. PRO analysis: Grivas P, Kopyltsov E, Su PJ, Parnis FX, Park SH, Yamamoto Y, Fong PC, Tournigand C, Climent Duran MA, Bamias A, Caserta C, Chang J, Cislo P, di Pietro A, Wang J, Powles T. Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma. Eur Urol. 2023 Apr;83(4):320-328. Epub 2022 May 30. link to original article PubMed
2. Update: Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullén A, Loriot Y, Sridhar SS, Sternberg CN, Bellmunt J, Aragon-Ching JB, Wang J, Huang B, Laliberte RJ, di Pietro A, Grivas P. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023 Jul 1;41(19):3486-3492. Epub 2023 Apr 18. link to original article link to PMC article PubMed
MAIN-CAV: NCT05092958

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Galsky et al. 2020 (HCRN GU14-182)	2015-2018	Randomized Phase 2 (E-esc)	Placebo	Seems to have superior PFS (primary endpoint) Median PFS: 5.4 vs 3 mo (HR 0.65, 95% CI 0.43-0.97)	More toxic

Preceding treatment

First-line platinum-based combination chemotherapy for up to 8 cycles, without progression of disease

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

HCRN GU14-182: Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02500121

Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy

Avelumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Apolo et al. 2017 (JAVELIN Solid Tumor)	2014-2016	Phase 1b (RT)	ORR: 17% (95% CI 11-24)¹

¹Reported efficacy is based on the 2017 update.

Immunotherapy

Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once on day 1

Supportive therapy

Per Apolo et al. 2017:

"All patients were premedicated with an antihistamine and acetaminophen (doses and routes not given)
The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."

14-day cycles

References

JAVELIN Solid Tumor: Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01772004
1. Update: Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. Epub 2017 Dec 5. Erratum in: Lancet Oncol. 2018 Jul;19(7):e335. link to original article link to PMC article PubMed

Docetaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
McCaffrey et al. 1997	1993-1995	Phase 2
Choueiri et al. 2011 (DFCI 06-116)	2007-2010	Phase 3 (C)	Docetaxel & Vandetanib	Did not meet primary endpoint of PFS
Petrylak et al. 2016 (JCDC)	2011-2014	Randomized Phase 2 (C)	1. Docetaxel & Icrucumab	Did not meet primary endpoint of PFS
Petrylak et al. 2016 (JCDC)	2011-2014	Randomized Phase 2 (C)	2. Docetaxel & Ramucirumab	Inferior PFS
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-01-13 to 2016-02-15	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of OS
Petrylak et al. 2017 (RANGE)	2015-2017	Phase 3 (C)	Docetaxel & Ramucirumab	Inferior PFS¹
Powles et al. 2021 (EV-301)	2018-2020	Phase 3 (C)	Enfortumab vedotin	Inferior OS
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to NR	Phase 3 (C)	Erdafitinib	Inferior OS

¹Reported efficacy for RANGE is based on the 2019 update.
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Biomarker eligibility criteria

THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

KEYNOTE-045: Exposure to platinum-based chemotherapy
EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycles

References

McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. link to original article link to PMC article PubMed NCT00880334
JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article PubMed NCT01282463
KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains dosing details in manuscript PubMed NCT02426125
1. Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article PubMed
IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
SWOG S1937: NCT04579224
TROPiCS-04: NCT04527991

Docetaxel & Ramucirumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Petrylak et al. 2016 (JCDC)	2011-2014	Randomized Phase 2 (E-esc)	1. Docetaxel	Superior PFS (primary endpoint) Median PFS: 5.4 vs 2.8 mo (sHR 0.39, 95% CI 0.235-0.64)
Petrylak et al. 2016 (JCDC)	2011-2014	Randomized Phase 2 (E-esc)	2. Docetaxel & Icrucumab	Not reported
Petrylak et al. 2017 (RANGE)	2015-2017	Phase 3 (E-esc)	Docetaxel	Superior PFS¹ (primary endpoint) (HR 0.70, 95% CI 0.57-0.85)

¹Reported efficacy for RANGE is based on the 2019 update.

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

21-day cycles

References

JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article contains dosing details in manuscript PubMed NCT01282463
RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains dosing details in manuscript PubMed NCT02426125
1. Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article PubMed

Enfortumab vedotin & Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Hoimes et al. 2022 (EV-103)	2017-2020	Phase 1b/2 (RT)	ORR: 73.3% CR: 15.6%

Antibody-drug conjugate therapy

Enfortumab vedotin (Padcev) 1.25 mg/kg IV once per day on days 1 & 8

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

EV-103: Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. Epub 2022 Aug 30. link to original article PubMed NCT03288545

Erdafitinib monotherapy

Regimen variant #1

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Loriot et al. 2019 (BLC2001)	2015-2018	Phase 2 (RT)	ORR 40% (95% CI 31-50)

Biomarker eligibility criteria

Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion

Targeted therapy

Erdafitinib (Balversa) as follows:
- Cycle 1: 8 mg PO once per day on days 1 to 21, then 9 mg PO once per day on days 22 to 28 if serum phosphorus level and tolerability are acceptable
- Cycle 2 onwards: 9 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to NR	Phase 3 (E-RT-switch-ooc)	1a. Docetaxel 1b. Vinflunine	Superior OS (primary endpoint) Median OS: 12.1 vs 7.8 mo (HR 0.64, 95% CI 0.47-0.88)

Note: The details of pharmacodynamic guidance were not described in the manuscript.

Biomarker eligibility criteria

Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Targeted therapy

Erdafitinib (Balversa) as follows:
- Cycle 1: 8 mg PO once per day on days 1 to 13, then 9 mg PO once per day on days 14 to 21, guided by pharmacodynamics
- Cycle 2 onwards: 9 mg PO once per day on days 1 to 21

21-day cycles

References

BLC2001: Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. link to original article PubMed NCT02365597
1. Update: Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. Epub 2022 Jan 11. link to original article PubMed
THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article PubMed NCT03390504

Gemcitabine monotherapy

AIM pathway regimen 2022-08-01

Regimen

Study	Dates of enrollment	Evidence
Lorusso et al. 1998	NR in abstract	Phase 2

Chemotherapy

Gemcitabine (Gemzar) 1200 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. link to original article PubMed

Gemcitabine & Paclitaxel

GP: Gemcitabine & Paclitaxel

Regimen variant #1, gemcitabine 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Albers et al. 2010 (AUO AB 20/99)	2001-2005	Phase 3 (C)	GP; prolonged	Did not meet primary endpoint of OS

Chemotherapy

Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8
Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

Regimen variant #2, weekly gemcitabine

Study	Dates of enrollment	Evidence	Efficacy
Meluch et al. 2001	1997-1999	Phase 2, fewer than 20 pts in this subgroup	ORR: 47%

Chemotherapy

Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

References

Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
AUO AB 20/99: Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. link to original article contains dosing details in manuscript PubMed

MVAC

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Han et al. 2008	2002-2006	Phase 2	ORR: 30%

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV once per day on days 1, 15, 22
Vinblastine (Velban) 3 mg/m² IV once per day on days 2, 15, 22
Doxorubicin (Adriamycin) 30 mg/m² IV once on day 2
Cisplatin (Platinol) 70 mg/m² IV once on day 2

28-day cycles

References

Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. link to original article contains dosing details in manuscript link to PMC article PubMed

Nivolumab monotherapy

Regimen variant #1, weight-based

Study	Dates of enrollment	Evidence	Efficacy
Sharma et al. 2017 (CheckMate 275)	2015	Phase 2 (RT)	19.6% overall PD-L1 expression at least 5%: 28.4% PD-L1 expression at least 1%: 23.8% PD-L1 expression less than 1%: 16.1%

Note: this is the dosing used in the study but is not the FDA-recommended dose.

Prior treatment criteria

At least one platinum-based therapy, with progression

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

Regimen variant #2, flat dosing

FDA-recommended dose

Immunotherapy

Nivolumab (Opdivo) 240 IV over 60 minutes once on day 1

14-day cycles

References

CheckMate 275: Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. link to original article contains dosing details in abstract PubMed NCT02387996
1. Update: Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Oct 1;26(19):5120-5128. Epub 2020 Jun 12. link to original article link to PMC article PubMed

nab-Paclitaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Ko et al. 2013 (ABX207-GU07CA)	2008-2010	Phase 2	ORR: 28% (95% CI 17-44)

Chemotherapy

Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV once on day 1

21-day cycles

Dose and schedule modifications

"Two dose reductions were permitted, to 240 mg/m² and then to 180 mg/m². When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/μL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."

References

ABX207-GU07CA: Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. Epub 2013 May 22. link to original article contains dosing details in abstract PubMed NCT00683059

Paclitaxel monotherapy

AIM pathway regimen 2022-08-01

Regimen variant #1, q3wks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-01-13 to 2016-02-15	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of OS
Powles et al. 2021 (EV-301)	2018-2020	Phase 3 (C)	Enfortumab vedotin	Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.

Prior treatment criteria

KEYNOTE-045: Exposure to platinum-based chemotherapy
EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression

Chemotherapy

Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycles

Regimen variant #2, 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Efficacy
Vaughn et al. 2002	NR	Phase 2	ORR: 10% (95% CI 0-20)

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, weekly

Study	Dates of enrollment	Evidence
Sideris et al. 2016	2004-2014	Retrospective

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

21-day cycles

References

Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article contains dosing details in abstract PubMed
Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to original article link to PMC article PubMed
KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
TROPiCS-04: NCT04527991

Pembrolizumab monotherapy

AIM pathway regimen 2022-08-01

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. Docetaxel 1b. Paclitaxel 1c. Vinflunine	Superior OS (co-primary endpoint) Median OS: 10 vs 7 mo (HR 0.73, 95% CI 0.59-0.91)
Siefker-Radtke et al. 2023 (THOR cohort 2)	2018-04-26 to NR	Phase 3 (C)	Erdafitinib	Did not meet primary endpoint of OS

Biomarker eligibility criteria

THOR cohort 2: Susceptible FGFR2 or FGFR3 alterations

Eligibility criteria

KEYNOTE-045: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

Prior treatment criteria

KEYNOTE-045: Exposure to platinum-based chemotherapy
THOR cohort 2: Exposure to one prior treatment that did NOT include an anti-PD-1 antibody or anti-PD-L1 antibody (anti-PD-(L)1-naive).

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1

21-day cycles

References

KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article cotains dosing details in manuscript PubMed NCT03390504

Pemetrexed monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Sweeney et al. 2006	2001-2004	Phase 2	ORR: 28% (95% CI 16-43)

Chemotherapy

Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

21-day cycles

References

Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. link to original article contains dosing details in abstract PubMed

Tislelizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (RATIONALE-204)	2017-NR	Phase 2

Immunotherapy

Tislelizumab (Baizean) 200 mg IV once on day 1

21-day cycles

References

RATIONALE-204: NCT04004221

Toripalimab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (Junshi-JS001-009)	2017-NR	Phase 2

Immunotherapy

Toripalimab (Loqtorzi) 3 mg/kg IV once on day 1

14-day cycles

References

Junshi-JS001-009: contains dosing details on CT.gov NCT03113266

Vinflunine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2009 (CA183004)	2003-2006	Phase 3 (E-esc)	Best supportive care	Superior OS¹ (primary endpoint) Median OS: 6.9 vs 4.6 mo (aHR 0.72, 95% CI 0.57-0.91)
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-01-13 to 2016-02-15	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of OS Median OS: 10.6 vs 11.1 mo (HR 1.15, 95% CI 0.83-1.59)
Powles et al. 2021 (EV-301)	2018-2020	Phase 3 (C)	Enfortumab vedotin	Inferior OS
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to NR	Phase 3 (C)	Erdafitinib	Inferior OS

¹Reported efficacy for CA183004 is based on the 2013 update.

Biomarker eligibility criteria

THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

KEYNOTE-045: Exposure to platinum-based chemotherapy
EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Chemotherapy

Vinflunine (Javlor) 320 mg/m² IV over 20 minutes once on day 1

21-day cycles

References

CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article contains dosing details in abstract PubMed NCT00315237
1. Update: Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. link to original article PubMed
KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
TROPiCS-04: NCT04527991

Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor

Enfortumab vedotin monotherapy

AIM pathway regimen 2022-08-01

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 2018 (EV-201)	2017-10-08 to 2018-07-02	Phase 2 (RT)		ORR: 44% (95% CI 35.2-53.2)
Powles et al. 2021 (EV-301)	2018-2020	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. Docetaxel 1b. Paclitaxel 1c. Vinflunine	Superior OS¹ (primary endpoint) Median OS: 12.91 vs 8.94 mo (HR 0.70, 95% CI 0.58-0.85)

¹Reported efficacy for EV-301 is based on the 2023 update.
Note: ORR in this arm of EV-301 (ITT) was 40.6% vs 17.9 % in the control arm (ITT).

Prior treatment criteria

Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression

Antibody-drug conjugate therapy

Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

EV-201: Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03219333
1. Update: Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, Necchi A, Kojima T, Harrison MR, Hoon Park S, Quinn DI, Heath EI, Rosenberg JE, Steinberg J, Liang SY, Trowbridge J, Campbell M, McGregor B, Balar AV. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. Epub 2021 May 12. Erratum in: Lancet Oncol. 2021 Jun;22(6):e239. link to original article PubMed
EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03474107
1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed

Sacituzumab govitecan monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Tagawa et al. 2021 (TROPHY-U-01)	2018-2019	Phase 2 (RT)	ORR: 27% (95% CI 19.5-37)

Prior treatment criteria

Exposure to platinum-based therapy and checkpoint inhibitor, with progression

Antibody-drug conjugate therapy

Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8

21-day cycles

References

TROPHY-U-01: Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. Epub 2021 Apr 30. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03547973
1. Update: Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthélémy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. Epub 2024 Jan 18. link to original article PubMed
TROPiCs-04: NCT04527991

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:100%;"
+<span id="BackToTop"></span>
-! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''
+[[#top|Back to Top]]
-|-
+</div>
-| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]
+{{#lst:Editorial board transclusions|bladder}}
-| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/arkhaki arkhaki]
+''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Urothelial_carcinoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Urothelial carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
-| style="background-color:#F0F0F0" |[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]
+<br><big>'''Note: this page has recently been renamed from "Bladder cancer" to "Urothelial carcinoma" to reflect the fact that most regimens here are generic to urothelial cancer. For now, the page also has adjuvant and perioperative regimens specific to bladder cancer, but these will be moved to a dedicated bladder cancer page soon.'''
-|<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Massachusetts General Hospital<br>Boston, MA</big>
+*See the [[Bladder cancer|'''bladder cancer page''']] for regimens specific to bladder cancer.
-|-
+*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big>
-|}
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 15: / Line 14: @@
 |}
 {{TOC limit|limit=3}}
 =Guidelines=
-==AUA, ASCO, ASTRO, SUO==
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
+==[https://www.esmo.org/ ESMO]==
+*'''2022:''' Powles et al. [https://doi.org/10.1016/j.annonc.2021.11.012 Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/34861372/ PubMed]
+*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]
+*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]
-*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/28456635 PubMed]
+*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417 NCCN Guidelines - Bladder Cancer]
-*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/25096609 PubMed]
+*'''2017:''' Spiess et al. [https://doi.org/10.6004/jnccn.2017.0156 Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28982750/ PubMed]
+*'''2009:''' Montie et al. [https://doi.org/10.6004/jnccn.2009.0002 Bladder cancer] [https://pubmed.ncbi.nlm.nih.gov/19176203/ PubMed]
+==SITC==
+*'''2021:''' Galsky et al. [https://dx.doi.org/10.1136/jitc-2021-002552 Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer] [https://pubmed.ncbi.nlm.nih.gov/34266883/ PubMed]
+**'''2017:''' Kamat et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5557323/ Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma] [https://pubmed.ncbi.nlm.nih.gov/28807024/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+=Adjuvant therapy=
-*[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]
+==Nivolumab monotherapy {{#subobject:23ugd2|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-=Intravesical chemotherapy=
+===Regimen variant #1, q2wks {{#subobject:gu17g8|Variant=1}}===
-==Bacillus Calmette-Guérin (BCG) monotherapy==
+{| class="wikitable" style="color:white; background-color:#404040"
-{{:Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer}}
+|<small>'''FDA-recommended dose'''</small>
-==Doxorubicin monotherapy {{#subobject:8034b6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Regimen {{#subobject:49ccdb|Variant=1}}===
+! style="width: 20%" |Study
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Study
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
-| style="background-color:#d73027" |Inferior RFS
 |-
-|2. [[#Thiotepa_monotherapy|Thiotepa]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ Bajorin et al. 2021 (CheckMate 274)]
-| style="background-color:#d3d3d3" |Not reported
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-324-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 |-
-|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]
+|} -->
-| style="background-color:#1a9851" |Phase III (C)
+|2016-2020
-|[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-| style="background-color:#fc8d59" |Seems to have inferior DFS
+|[[Urothelial_carcinoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior DFS (co-primary endpoint)<br>Median DFS: 20.8 vs 10.8 mo<br>(HR 0.70, 98.22% CI 0.55-0.90)
 |-
 |}
-''Inferior to BCG, included for reference purposes only.''
+<div class="toccolours" style="background-color:#cbd5e8">
-====Chemotherapy====
+====Preceding treatment====
+*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
-*[[Doxorubicin (Adriamycin)]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-'''15 or more treatments'''
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 240 mg IV over 30 minutes once on day 1
-===References===
+'''14-day cycle for up to 26 cycles (1 year)'''
+</div></div><br>
-#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2106041 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1922207 PubMed]
+===Regimen variant #2, q4wks {{#subobject:hy27g8|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
-==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==
+|<small>'''FDA-recommended dose'''</small>
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]
-| style="background-color:#1a9851" |Phase III (E)
-|Placebo (saline)
-| style="background-color:#1a9850" |Superior TTR
 |-
 |}
+''Note: this is not the dose that was used in the registration study, CheckMate 274.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
-*[[Surgery#TURBT|TURBT]], up to 3 hours prior
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
-*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
+'''28-day cycle for up to 13 cycles (1 year)'''
+</div></div>
-'''One treatment'''
-===Variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 Addeo et al. 2009]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Mitomycin_monotherapy|Mitomycin]]
-| style="background-color:#1a9850" |Superior DFS
-|-
-|}
-====Chemotherapy====
-*[[Gemcitabine (Gemzar)]] 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
-'''6-week course'''
 ===References===
+#'''CheckMate 274:''' Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. [https://doi.org/10.1056/nejmoa2034442 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34077643/ PubMed] [https://clinicaltrials.gov/study/NCT02632409 NCT02632409]
+##'''HRQoL analysis:''' Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol. 2022 Oct;5(5):553-563. Epub 2022 Mar 11. [https://doi.org/10.1016/j.euo.2022.02.003 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062393/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35288066/ PubMed]
+#'''VOLGA:''' [https://clinicaltrials.gov/study/NCT04960709 NCT04960709]
-#Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19841330 PubMed]
+=Locally advanced or metastatic disease, first-line, platinum-ineligible=
-#'''SWOG S0337:''' Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. [https://jamanetwork.com/journals/jama/fullarticle/2680547 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29801011 PubMed]
+==Gemcitabine monotherapy {{#subobject:7fgei3|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==
+===Regimen {{#subobject:oasdvc|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/j.urolonc.2023.04.016 Heinzelbecker et al. 2023 (AUO-AB 22/00)]
-|}
+|2000-07 to 2008-12
-===Variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[Bladder_cancer#Gemcitabine_monotherapy_999|Gemcitabine]]; adjuvant
-! style="width: 25%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext Ojea et al. 2007 (CUETO study 95011)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|Low-dose BCG]]
-| style="background-color:#d73027" |Inferior DFS
-|-
-|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|Very-low-dose BCG]]
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Surgery#TURBT|TURBT]], 14 to 21 days prior
 ====Chemotherapy====
+*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Mitomycin (Mutamycin)]] as follows:
+'''21-day cycle for up to 6 cycles'''
-**Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
+</div></div>
-**Cycles 4 to 9: 30 mg intravesicularly once on day 1
-'''14-day cycle for 9 cycles'''
-===Variant #2, 40 mg x 11 {{#subobject:531377|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 Lammers et al. 2012]
-| style="background-color:#1a9851" |Phase III (C)
-|Keyhole limpet hemocyanin
-| style="background-color:#1a9850" |Superior RFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#TURBT|TURBT]]
-====Chemotherapy====
-*[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1
-'''7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles'''
 ===References===
+#'''AUO-AB 22/00:''' Heinzelbecker J, Spieler N, Kuehn M, Fischer C, Volkmer B, von Rundstedt F, Albers P, Becht E, Bannowsky A, Weber HM, Hofmann R, Müller M, Langbein S, Steiner G, Retz M, Kamradt J, Wagenpfeil G, Wellek S, Lehmann J, Stoeckle M. Adjuvant vs progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial. Urol Oncol. 2023 Aug;41(8):356.e19-356.e30. Epub 2023 May 16. [https://doi.org/10.1016/j.urolonc.2023.04.016 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37198025/ PubMed] [https://clinicaltrials.gov/study/NCT00146276 NCT00146276]
-#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO Group (Club Urológico Español De Tratamiento Oncológico). A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17485161 PubMed]
+==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
-#Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. [https://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22585689 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:946aec|Variant=1}}===
-==Observation==
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/S1470-2045(17)30616-2 Balar et al. 2017 (KEYNOTE-052)]
-|}
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-===Regimen===
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-277-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]
+|} -->
-| style="background-color:#1a9851" |Phase III (C)
+|2015-2016
-|[[#Pirarubicin_monotherapy|Pirarubicin]]
+| style="background-color:#91cf61" |Phase 2 (RT)
-| style="background-color:#fc8d59" |Seems to have inferior RFS
+| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)
 |-
 |}
-''No active antineoplastic treatment after surgery.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-*[[Surgery#Nephroureterectomy|Nephroureterectomy]]
+'''21-day cycles'''
+</div></div>
 ===References===
+#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://doi.org/10.1016/S1470-2045(17)30616-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28967485/ PubMed] [https://clinicaltrials.gov/study/NCT02335424 NCT02335424]
+##'''Update:''' Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. Epub 2020 Jun 17. [https://doi.org/10.1200/jco.19.01213 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32552471/ PubMed]
+##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
+#'''LEAP-011:''' [https://clinicaltrials.gov/study/NCT03898180 NCT03898180]
-#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]
+=Locally advanced or metastatic disease, first-line, platinum-eligible=
+==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==
-==Pirarubicin monotherapy {{#subobject:d9be78|Regimen=1}}==
+GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, AUC 4.5/1000 x 6 {{#subobject:5f00b7|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[[#top|back to top]]
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
-|}
+| rowspan="2" |2015-2017
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-===Regimen {{#subobject:dfdcd9|Variant=1}}===
+|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
-! style="width: 25%" |Study
+| style="background-color:#d73027" |More toxic
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]
+|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
-| style="background-color:#1a9851" |Phase III (E)
+| style="background-color:#fee08b" |Might have inferior OS
-|[[#Observation|Observation]]
+| style="background-color:#ffffbf" |Not more toxic
-| style="background-color:#91cf60" |Seems to have superior RFS
 |-
-|}
+|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
-''Pirarubicin was given within 48 hours after nephroureterectomy.''
+|2020-2023
-====Preceding treatment====
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
-*[[Surgery#Nephroureterectomy|Nephroureterectomy]]
+| style="background-color:#d73027" |Inferior PFS/OS
+|
-====Chemotherapy====
-*[[Pirarubicin (THP)]] 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes
-'''1 dose'''
-===References===
-#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]
-==Thiotepa monotherapy {{#subobject:5b9d6c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:97d2e7|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
-| style="background-color:#d73027" |Inferior RFS
-|-
-|2. [[#Doxorubicin_monotherapy|Doxorubicin]]
-| style="background-color:#d3d3d3" |Not reported
 |-
 |}
-''Inferior to BCG, included for reference purposes only.''
+''Note: this was the lower bound of AUC specified by DANUBE & EV-302.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
+'''21-day cycle for up to 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments
+===Regimen variant #2, AUC 4.5/1000, indefinite {{#subobject:5f0in7|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===References===
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
-#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2106041 PubMed]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
-==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]
-|}
+|2001-2005
+| style="background-color:#1a9851" |Randomized Phase 2/3 (E-de-esc)
-===Regimen {{#subobject:74j2e7|Variant=1}}===
+|[[#M-CAVI_999|M-CAVI]]
-{| class="wikitable" style="color:white; background-color:#404040"
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup><br>ORR: 30.3% vs 41.2%
-|<small>'''FDA-recommended dose'''</small>
+| style="background-color:#1a9851" |Lower toxicity than M-CAVI
 |-
-|}
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
-{| class="wikitable" style="width: 50%; text-align:center;"
+| rowspan="2" |2016-2018
-! style="width: 50%" |Study
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|1. [[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy_2|Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
+|
 |-
-|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]
+|2a. [[Urothelial_carcinoma_-_historical#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br>2b. [[Urothelial_carcinoma_-_historical#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
-| style="background-color:#91cf61" |Non-randomized (RT)
+| style="background-color:#fee08b" |Might have inferior OS<sup>2</sup>
+|
 |-
 |}
+''<sup>1</sup>Reported efficacy for EORTC 30986 is based on the 2011 update.''<br>
+''<sup>2</sup>Reported efficacy for IMvigor130 is based on the 2023 update.''<br>
+''Note: Patients in EORTC 30986 who achieved complete response were given two additional cycles of treatment.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
+===Regimen variant #3, AUC 5/1000 x 6 {{#subobject:4gua36|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-'''6-week course'''
+!style="width: 20%"|Study
-===References===
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; The Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10687972 PubMed]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-=Neoadjuvant chemotherapy=
-==Cisplatin & Gemcitabine {{#subobject:d08e11|Regimen=1}}==
-{{#subobject:be43aa|Variant=1}}
-{{#subobject:dc99d5|Variant=1}}
-{{:Cisplatin & Gemcitabine for bladder cancer, neoadjuvant}}
-==MCV {{#subobject:553fe2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1159/000012132 Carles et al. 2000]
-|}
+|1997-1998
-CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts
-<br>MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine
-===Variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]
-| style="background-color:#91cf61" |Phase II
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
-| style="background-color:#91cf61" |Phase II
+| rowspan="2" |2015-2017
-| style="background-color:#d3d3d3" |
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d3d3d3" |
+|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 |-
-|[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]
+|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
-| style="background-color:#1a9851" |Phase III (E)
+| style="background-color:#fee08b" |Might have inferior OS
-|[[#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|}
+|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
-====Chemotherapy====
+|rowspan=2|2016-2018
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_333|GC & Pembrolizumab]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Pembrolizumab_333|GCb & Pembrolizumab]]
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
+| style="background-color:#fee08b" |Might have inferior OS
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
-'''28-day cycle for 2 cycles'''
-====Subsequent treatment====
-*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
-*RTOG 88-02 & 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT induction]]
-===Variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]
+|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
-| style="background-color:#1a9851" |Phase III (E)
+| style="background-color:#d3d3d3" |Not reported
-|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
 |-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
+|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
-| style="background-color:#91cf61" |Non-randomized
+|2020-2023
-| style="background-color:#d3d3d3" |
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d3d3d3" |
+|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
+| style="background-color:#d73027" |Inferior PFS/OS
 |-
 |}
-''Patients in '''Zapatero et al. 2000''' had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.''
+''Note: this was the upper bound of AUC specified by DANUBE & EV-302.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration
+'''21-day cycle for up to 6 cycles'''
-*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-====Supportive medications====
+===Regimen variant #4, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*'''BA06 30894:''' [[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of [[Methotrexate (MTX)]] (total dose per cycle: 120 mg/m<sup>2</sup>)
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
-'''21-day cycle for 3 cycles'''
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
-====Subsequent treatment====
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT
-**Patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT consolidation]] which begins 4 to 6 weeks after completion of chemotherapy
-**Otherwise, patients proceeded to [[Surgery#Cystectomy|cystectomy]]
-===References===
-#Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. [https://www.nejm.org/doi/10.1056/NEJM199311043291903 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8413433 PubMed]
-#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8558186 PubMed]
-#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9817278 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10470696 PubMed]
-##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502557 PubMed]
-#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11091353 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19362865 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-==MVAC {{#subobject:701fbe|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/j.eururo.2006.12.029 Dogliotti et al. 2006]
-|}
+|2000-2002
-MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-===Variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+|
-! style="width: 25%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-| style="background-color:#d9ef8b" |Might have superior OS
 |-
 |}
+''ORR for this arm: Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)''<br>
+''ORR for control arm: Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
+*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
+'''21-day cycle for up to 6 cycles'''
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
+</div></div>
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
-'''28-day cycle for 2 cycles'''
-====Subsequent treatment====
-*[[Surgery#Radical_cystectomy|Radical cystectomy]]
-===Variant #2, 3 cycles {{#subobject:dc2c80|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
-'''28-day cycle for 3 cycles'''
-====Subsequent treatment====
-*[[Surgery#Radical_cystectomy|Radical cystectomy]]
 ===References===
+#Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. [https://doi.org/10.1159/000012132 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10895062/ PubMed]
+#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://doi.org/10.1016/j.eururo.2006.12.029 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17207911/ PubMed]
+#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19786668/ PubMed] [https://clinicaltrials.gov/study/NCT00111787 NCT00111787]
+##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. Epub 2011 Dec 12. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22162575/ PubMed]
+#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416780/ PubMed] [https://clinicaltrials.gov/study/NCT02807636 NCT02807636]
+##'''Update:''' Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. [https://doi.org/10.1016/s1470-2045(23)00540-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38101433/ PubMed]
+#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005/ PubMed] [https://clinicaltrials.gov/study/NCT02516241 NCT02516241]
+#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
+#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
+#'''NILE:''' [https://clinicaltrials.gov/study/NCT03682068 NCT03682068]
+#'''RC48-C016:''' [https://clinicaltrials.gov/study/NCT05302284 NCT05302284]
-#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12944571 PubMed]
+==Carboplatin & Gemcitabine (GCb) & Pembrolizumab {{#subobject:88gic5|Regimen=1}}==
-#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 PubMed]
+GCb & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Pembrolizumab
+<div class="toccolours" style="background-color:#eeeeee">
-==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==
+===Regimen {{#subobject:4iggca|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
-|}
+|rowspan=2|2016-2018
-ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-<br>AMVAC: '''<u>A</u>'''ccelerated '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
-===Variant #1, 3 cycles {{#subobject:c4bf38|Variant=1}}===
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 17 vs 14.3 mo<br>(HR 0.86, 95% CI 0.72-1.02)<br><br>Might have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 8.3 vs 7.1 mo<br>(HR 0.78, 95% CI 0.65-0.3)
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014]
+|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#d3d3d3" |Not reported
 |-
 |}
+''<sup>1</sup>Reported efficacy did not meet the prespecified boundary for statistical significance.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] as follows:
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+**Cycles 1 up to 6: AUC 5 IV once on day 1
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2
+*[[Gemcitabine (Gemzar)]] as follows:
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2
+**Cycles 1 up to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2
+====Immunotherapy====
-**Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m<sup>2</sup>: 35 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for up to 35 cycles'''
-====Supportive medications====
+</div></div>
-*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, 24 to 48 hours after completion of chemotherapy
-*Antiemetics used often included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Dexamethasone (Decadron)]] but were not specified by the trial.
-'''14-day cycle for 3 cycles'''
-====Subsequent treatment====
-*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy
-===Variant #2, 4 cycles {{#subobject:7ae9e3|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://jco.ascopubs.org/content/32/18/1889.long Choueiri et al. 2014]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2
-====Supportive medications====
-*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)
-'''14-day cycle for 4 cycles'''
-====Subsequent treatment====
-*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy
 ===References===
-<!-- # Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri. Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). 2013 ASCO Annual Meeting abstract 4530. [http://meetinglibrary.asco.org/content/117233-132 link to abstract] -->
+#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
+==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==
-#Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. [http://jco.ascopubs.org/content/32/18/1889.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24821883 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 Jun 20;32(18):1895-901. Epub 2014 May 12. [http://jco.ascopubs.org/content/32/18/1895.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24821881 PubMed]
+===Regimen {{#subobject:5d481c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-==Immune checkpoint inhibitors {{#subobject:3cb963|Regimen=1}}==
+! style="width: 20%" |Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1002/cncr.10782 Vaughn et al. 2002 (ECOG E2896)]
-|}
+|1996-1999
-===Variant #1, Pembrolizumab {{#subobject:c4bf38|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| class="wikitable" style="width: 50%; text-align:center;"
+| style="background-color:#d3d3d3" |
-! style="width: 25%" |Study
+| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pubmed/30343614 Necchi et al. 2018 (PURE-01)]
+|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004 (ECOG E4897)]
-| style="background-color:#91cf61" |Phase II
+|1998-2001
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|[[#MVAC_2|MVAC]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+''Note: ECOG E4897 was closed early due to poor accrual.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
-*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200mg IV over 30 minutes once on day 1
+*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
+'''21-day cycle for up to 6 cycles'''
-'''21-day cycle for 3 cycles'''
+</div></div>
-====Subsequent treatment====
-*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy
-===Variant #2, Atezolizumab {{#subobject:7ae9e3|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pubmed/31686036 Powles et al. 2019]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Atezolizumab (Tecentriq)|Atezolizumab]] 1200mg IV over 60 minutes on day 1
-'''21-day cycle for 2 cycles'''
-====Subsequent treatment====
-*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy
 ===References===
-<!-- # Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri. Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). 2013 ASCO Annual Meeting abstract 4530. [http://meetinglibrary.asco.org/content/117233-132 link to abstract] -->
+#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://doi.org/10.1002/cncr.10782 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12209686/ PubMed]
+#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] [https://clinicaltrials.gov/study/NCT00003376 NCT00003376]
-#Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. [https://ascopubs.org/doi/suppl/10.1200/JCO.18.01148 Link to original article] '''contains verified protocol'''. [https://www.ncbi.nlm.nih.gov/pubmed/30343614 PubMed]
+==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==
-#Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. [https://www.ncbi.nlm.nih.gov/pubmed/31708296 PubMed]
+GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin
-#Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma  in the ABACUS trial. Nat Med. 2019 Nov 4. [https://www.nature.com/articles/s41591-019-0628-7 Link to original article.] [https://www.ncbi.nlm.nih.gov/pubmed/31686036 PubMed]
+<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)
+{| class="wikitable" style="color:white; background-color:#9e4244"
-==No neoadjuvant therapy==
+|<small>'''AIM pathway regimen 2022-08-01'''</small>
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen===
+===Regimen variant #1, 70/2000; q3wk x 6 {{#subobject:69fea8|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 Martinez-Piñeiro et al. 1995]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ Rosenberg et al. 2021 (CALGB 90601)]
-| style="background-color:#1a9851" |Phase III (C)
+|2009-2014
-|Cisplatin
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Bevacizumab|GC & Bevacizumab]]
+| style="background-color:#fee08b" |Might have inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
-| style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" |2015-2017
-|[[#MCV|CMV]]
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
+|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#MVAC|MVAC]]
 | style="background-color:#fee08b" |Might have inferior OS
 |-
-|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]
+|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
-| style="background-color:#1a9851" |Phase III (C)
+|rowspan=2|2016-2018
-|[[#MVAC|MVAC]]
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_333|GC & Pembrolizumab]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Pembrolizumab_333|GCb & Pembrolizumab]]
 | style="background-color:#fee08b" |Might have inferior OS
 |-
-|}
+|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
-''No preoperative treatment; used as a comparator arm and here for reference purposes only. Reported efficacy for BA06 30894 is based on the 2011 update.''
+| style="background-color:#d3d3d3" |Not reported
-====Subsequent treatment====
-*[[Surgery#Bladder_cancer_surgery|Surgery]]
-===References===
-#Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol. 1995 Mar;153(3 Pt 2):964-73. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7853584 PubMed]
-#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10470696 PubMed]
-##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502557 PubMed]
-#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12944571 PubMed]
-#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 PubMed]
-=Induction chemoradiotherapy=
-==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/nejmoa2309863 van der Heijden et al. 2023 (CheckMate 901 part 1)]
-|}
+|2018-01-30 to 2022-09-28
-Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Nivolumab|GC & Nivolumab]]
-===Variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===
+| style="background-color:#fc8d59" |Seems to have inferior OS (co-primary endpoint)
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
-| style="background-color:#91cf61" |Phase I/II
 |-
-|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]
+|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
-| style="background-color:#91cf61" |Non-randomized
+|2020-2023
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
+| style="background-color:#d73027" |Inferior PFS/OS
 |-
 |}
-''Patients in '''Zapatero et al. 2000''' had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero, et al. 2010), '''given first'''
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Supportive therapy====
-'''7-day cycle for 3 cycles'''
+*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
-====Radiotherapy====
+*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
+'''21-day cycle for 6 cycles'''
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
+</div></div><br>
-**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.
+<div class="toccolours" style="background-color:#eeeeee">
-**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.
+===Regimen variant #2, 70/2000; q3wk, indefinite {{#subobject:69find|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Subsequent treatment====
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
+! style="width: 20%" |Comparator
-**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-===Variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]
+|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
-| style="background-color:#91cf61" |Phase II
+|1998-2000
-|-
+| style="background-color:#ffffbe" |Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc)
-|}
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk
-====Preceding treatment====
+| style="background-color:#d3d3d3" |Not reported
-*[[#MCV|MCV]] x 2
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
-'''4.5-week course'''
-====Subsequent treatment====
-*Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."
-**Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
-**Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]
-===Variant #3, cisplatin 100 mg/m<sup>2</sup> q3wk x 2 {{#subobject:9a3fd0|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
-| style="background-color:#91cf61" |Non-randomized
+| rowspan="2" |2016-2018
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy_2|Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 |-
-|[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]
+|2a. [[Urothelial_carcinoma_-_historical#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br>2b. [[Urothelial_carcinoma_-_historical#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
 |-
 |}
-====Preceding treatment====
+''<sup>1</sup>Reported efficacy for IMvigor130 is based on the 2023 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*RTOG 89-03: [[#MCV|MCV]] versus [[#No_neoadjuvant_therapy|no neoadjuvant therapy]]
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Supportive therapy====
-'''21-day cycle for 2 cycles'''
+*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
-====Radiotherapy====
+*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
+'''21-day cycles'''
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''4.5-week course'''
+===Regimen variant #3, 70/2500; q3wk {{#subobject:44c03b|Variant=1}}===
-====Subsequent treatment====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
-*RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology."
+! style="width: 15%" |Dates of enrollment
-**Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-**Patients in complete remission usually proceeded to: [[#Cisplatin_.26_RT_2|cisplatin & RT consolidation]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-===References===
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-#Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. [https://jamanetwork.com/journals/jama/article-abstract/367764 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3613023 PubMed]
-#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8558186 PubMed]
-#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9817278 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14529770 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19362865 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-==Cisplatin, Fluorouracil, RT {{#subobject:b5e26|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/j.eururo.2006.12.029 Dogliotti et al. 2006]
-|}
+|2000-2002
-===Variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-{| class="wikitable" style="width: 50%; text-align:center;"
+|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]
-! style="width: 25%" |Study
+|
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity
 |-
-|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
-| style="background-color:#91cf61" |Phase I/II
+| rowspan="2" |2015-2017
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
+| style="background-color:#d73027" |More toxic
 |-
-|}
+|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
-''Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>.''
+| style="background-color:#fee08b" |Might have inferior OS
-====Chemotherapy====
+| style="background-color:#ffffbf" |Not more toxic
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second, before radiation'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''
-====Supportive medications====
-*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]
-'''14-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes
-'''17-day course'''
-====Dose modifications====
-*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.
-====Subsequent treatment====
-*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
-**Patients with complete response: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]] in week 9
-**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]
-===Variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |Comparator
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#Gemcitabine_.26_RT|Gemcitabine & RT]]
 |-
 |}
-''Note: this trial was not statistically powered to compare regimens.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1 or 2
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17
+*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17
+'''21-day cycle for up to 6 cycles'''
+</div></div><br>
-====Radiotherapy====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 70/3000; q4wk {{#subobject:53ad73|Variant=1}}===
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
+! style="width: 20%" |Study
-**1.5 Gy fractions to the bladder every evening on days 1 to 5
+! style="width: 20%" |Dates of enrollment
-**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-'''17-day course'''
-====Subsequent treatment====
-*Treatment followed by repeat cystoscopy & biopsy
-**Patients with complete response: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]]
-**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
-===Variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |Comparator
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
+|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+|1996-1998
-|[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|[[#MVAC_2|MVAC]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|}
+|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
-====Chemotherapy====
+|1998-2000
+| style="background-color:#ffffbe" |Randomized Phase 2, fewer than 20 pts in this subgroup (E-de-esc)
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3
+| style="background-color:#d3d3d3" |Not reported
-'''7-day cycle for 3 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
-**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
-**1.5 Gy fractions to the bladder every evening on days 1 to 5
-**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
-**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
-'''3-week course'''
-====Subsequent treatment====
-*On week 7, patients under reevaluation for response.
-**Patients with less than stage T1 disease: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]]
-**Patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]
-===References===
-#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11110598 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://ascopubs.org/doi/full/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]
-==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
-|}
+|2001-2004
-===Variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 50%; text-align:center;"
+|[[#PGC_2|PCG]]
-! style="width: 25%" |Study
+| style="background-color:#fee08b" |Might have inferior OS
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
+|[https://doi.org/10.1159/000354085 Sternberg et al. 2013 (CILAB)]
-| style="background-color:#91cf61" |Phase I/II
+|2008-2010
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin_.26_Larotaxel_999|Cisplatin & Larotaxel]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|}
+| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
-''Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease.''
+| rowspan="2" |2015-2017
-====Preceding treatment====
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
-*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycle for 3 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:
-**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
-**1.5 Gy fractions to the bladder every evening on days 1 to 5
-**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
-**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
-'''3-week course'''
-====Subsequent treatment====
-*On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology
-**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]
-**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then [[#Cisplatin_.26_Gemcitabine_2|adjuvant cisplatin & gemcitabine]]
-===Variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
+|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+| style="background-color:#fee08b" |Might have inferior OS
-|[[#Cisplatin.2C_Fluorouracil.2C_RT|Cisplatin, Fluorouracil, RT]]
 |-
 |}
+''Note: Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
+====Supportive therapy====
+*Per Soto Parra et al. 2002:
-'''7-day cycle for 3 cycles'''
+*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
-====Radiotherapy====
+*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
+'''28-day cycle for up to 6 cycles'''
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
+</div></div>
-**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
-**1.5 Gy fractions to the bladder every evening on days 1 to 5
-**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
-**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
-'''3-week course'''
-====Subsequent treatment====
-*On week 7, patients under reevaluation for response
-**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]
-**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]
-===References===
-#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19100600 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Regimen {{#subobject:6a18dc|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Radiation_therapy_2|Radiation therapy]]
-| style="background-color:#91cf60" |Seems to have superior locoregional DFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion for 10 total days (total dose: 5000 mg/m<sup>2</sup>) during radiation fractions 1 to 5, 16 to 20
-*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1
-====Radiotherapy====
-*[[External beam radiotherapy]] given according to one of the following plans:
-**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
-**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 32 fractions (total dose: 64 Gy)
-'''4- to 6.5-week course'''
-===References===
-#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1106106/suppl_file/nejmoa1106106_appendix.pdf link to supplementary index] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]
-==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:6333a7|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |Comparator
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]
-|-
-|}
-''Note: this trial was not statistically powered to compare regimens.''
-====Chemotherapy====
-*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
-'''14-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20
-**Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy
-'''3-week course'''
-====Subsequent treatment====
-*Treatment followed by repeat cystoscopy & biopsy
-**Patients with complete response: Gemcitabine & RT consolidation
-**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
-===References===
-#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://ascopubs.org/doi/full/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]
-==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:6222a7|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]
-| style="background-color:#ffffbe" |Non-randomized, <20 pts
-|-
-|}
-''Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, '''given 6 hours before radiation therapy'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
-**Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.
-**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
-'''One course'''
-====Subsequent treatment====
-*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]
-**Patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT consolidation]]
-**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
-===References===
-#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-==Radiation therapy {{#subobject:1103c0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:e0ed54|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]
-| style="background-color:#fc8d59" |Seems to have inferior locoregional DFS
-|-
-|}
-====Preceding treatment====
-*Depending on response, treatment in '''Zapatero et al. 2000''' preceded by [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]
-====Radiotherapy====
-*[[External beam radiotherapy]] as follows:
-**CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.
-**Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.
-===References===
-#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11091353 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19362865 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]
-=Consolidation chemoradiotherapy=
-==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2 {{#subobject:dc2b84|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
-| style="background-color:#91cf61" |Phase I/II
-|-
-|}
-====Preceding treatment====
-*Depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero et al. 2010), '''given first'''
-'''7-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
-**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
-**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.
-====Subsequent treatment====
-*RTOG 97-06: [[#MCV_2|Adjuvant MCV]]
-===Variant #2, cisplatin 70 mg/m<sup>2</sup> x 1 {{#subobject:314189|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Preceding treatment====
-*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
-'''3-week course'''
-===Variant #3, cisplatin 100 mg/m<sup>2</sup> x 1 {{#subobject:7afeca|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
-'''3-week course'''
 ===References===
+#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11001674/ PubMed]
+##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041/ PubMed]
+#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12176787/ PubMed]
+#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://doi.org/10.1016/j.eururo.2006.12.029 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17207911/ PubMed]
+#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319/ PubMed] [https://clinicaltrials.gov/study/NCT00022191 NCT00022191]
+#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://doi.org/10.1159/000354085 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24080920/ PubMed] [https://clinicaltrials.gov/study/NCT00625664 NCT00625664]
+#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416780/ PubMed] [https://clinicaltrials.gov/study/NCT02807636 NCT02807636]
+##'''Update:''' Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. [https://doi.org/10.1016/s1470-2045(23)00540-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38101433/ PubMed]
+#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005/ PubMed] [https://clinicaltrials.gov/study/NCT02516241 NCT02516241]
+#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
+#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] [https://clinicaltrials.gov/study/NCT00942331 NCT00942331]
+#'''CheckMate 901 part 1:''' van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. [https://doi.org/10.1056/nejmoa2309863 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/37870949/ PubMed] [https://clinicaltrials.gov/study/NCT03036098 NCT03036098]
+#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
+#'''NILE:''' [https://clinicaltrials.gov/study/NCT03682068 NCT03682068]
+#'''RC48-C016:''' [https://clinicaltrials.gov/study/NCT05302284 NCT05302284]
-#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8558186 PubMed]
+==Cisplatin & Gemcitabine (GC) & Bevacizumab {{#subobject:5ig13|Regimen=1}}==
-#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9817278 PubMed]
+GCB: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, '''<u>B</u>'''evacizumab
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
+===Regimen {{#subobject:u5fea8|Variant=1}}===
-#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11091353 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19362865 PubMed]
-##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14529770 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-==Cisplatin, Fluorouracil, RT {{#subobject:fe2538|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]
-|-
-|}
-''Consolidation starts starts on week 8.''
-====Preceding treatment====
-*[[#Cisplatin.2C_Fluorouracil.2C_RT|Cisplatin, 5-FU, RT induction]]
-====Chemotherapy====
-''Starts on week 8.''
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3
-'''7-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
-'''2-week course'''
-====Subsequent treatment====
-*[[#PGC|Adjuvant PGC]]
-===Variant #2, 45/1200 x 2 + 44 Gy {{#subobject:904a96|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]
-| style="background-color:#91cf61" |Phase I/II
-|-
-|}
-''Treatment starts on week 9.''
-====Preceding treatment====
-*Depending on response, treatment preceded by [[#Cisplatin.2C_Fluorouracil.2C_RT|cisplatin, fluorouracil, RT induction]] or [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''
-'''14-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.
-====Dose modifications====
-*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.
-====Supportive medications====
-*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]
-'''17-day course'''
-===References===
-#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11110598 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-==Cisplatin, Paclitaxel, RT {{#subobject:4bc0dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, 5-FU, RT]]
-|-
-|}
-''Consolidation starts starts on week 8.''
-====Preceding treatment====
-*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
-'''2-week course'''
-====Subsequent treatment====
-*[[#PGC|Adjuvant PGC]]
-===Variant #2, 40/50 x 2 + 64.3 Gy {{#subobject:6bec62|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
-| style="background-color:#91cf61" |Phase I/II
-|-
-|}
-''Consolidation starts starts on week 8.''
-====Preceding treatment====
-*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycle for 2 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
-'''2-week course'''
-====Subsequent treatment====
-*[[#Cisplatin_.26_Gemcitabine_2|Adjuvant cisplatin & gemcitabine]]
-===References===
-#'''RTOG 99-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19100600 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-==Paclitaxel & RT {{#subobject:039b5c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:de252a|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]
-| style="background-color:#ffffbe" |Non-randomized, <20 pts
-|-
-|}
-====Preceding treatment====
-*Depending on response, treatment preceded by [[#Paclitaxel_.26_RT|paclitaxel & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, given 6 hours before radiation therapy
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
-**Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
-**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
-'''One course'''
-===References===
-#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]
-=Adjuvant chemotherapy=
-==Cisplatin & Gemcitabine {{#subobject:684e48|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:72a413|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
-| style="background-color:#91cf61" |Phase I/II
-|-
-|}
-====Preceding treatment====
-*Depending on response to induction, treatment starts 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT consolidation]], or 8 weeks after [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-'''28-day cycle for 4 cycles'''
-===References===
-#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19100600 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-==Cisplatin & Methotrexate {{#subobject:684e48|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:72a413|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.11.094 Lehmann et al. 2005 (AUO-AB 05/95)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ Rosenberg et al. 2021 (CALGB 90601)]
-| style="background-color:#1a9851" |Phase III (E)
+|2009-2014
-|M-VEC x 3
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
-| style="background-color:#1a9850" |Less toxic
+| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 14.5 vs 14.3 mo<br>(HR 0.87, 95% CI 0.72-1.05)
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Surgery#Cystectomy|Radical cystectomy]]
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
-*[[Cisplatin (Platinol)]]
+**Cycles 1 to 6: 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2
-*[[Methotrexate (MTX)]]
+*[[Gemcitabine (Gemzar)]] as follows:
+**Cycles 1 to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
+'''21-day cycles'''
+</div></div>
 ===References===
+#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] [https://clinicaltrials.gov/study/NCT00942331 NCT00942331]
-#'''AUO-AB 05/95:''' Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO-AB 05/95 Study Group. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol. 2005 Aug 1;23(22):4963-74. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.11.094 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15939920 PubMed]
+==Cisplatin & Gemcitabine (GC) & Nivolumab {{#subobject:igniv5|Regimen=1}}==
+GC & Nivolumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Nivolumab
-==MCV {{#subobject:8e6bb8|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:jo4c2a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/nejmoa2309863 van der Heijden et al. 2023 (CheckMate 901 part 1)]
-|}
+|2018-01-30 to 2022-09-28
-MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]] x 6
-===Regimen {{#subobject:ca6708|Variant=1}}===
+| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>Median OS: 21.7 vs 18.9 mo<br>(HR 0.78, 95% CI 0.63-0.96)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 7.9 vs 7.6 mo<br>(HR 0.72, 95% CI 0.59-0.88)
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
-| style="background-color:#91cf61" |Phase I/II
 |-
 |}
-''Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
-*[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
-*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
+**Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once on day 1
-*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4
+*[[Gemcitabine (Gemzar)]] as follows:
-*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
+**Cycles 1 to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Immunotherapy====
-'''28-day cycle for 3 cycles'''
+*[[Nivolumab (Opdivo)]] as follows:
+**Cycles 1 to 6: 360 mg IV once on day 1
+**Cycle 7 up to 28: 480 mg IV once on day 1
+'''21-day cycle for 6 cycles, then 28-day cycle for up to 22 cycles (2 years)'''
+</div></div>
 ===References===
+#'''CheckMate 901 part 1:''' van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. [https://doi.org/10.1056/nejmoa2309863 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/37870949/ PubMed] [https://clinicaltrials.gov/study/NCT03036098 NCT03036098]
-#Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14529770 PubMed]
+==Cisplatin & Gemcitabine (GC) & Pembrolizumab {{#subobject:igccc5|Regimen=1}}==
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
+GC & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Pembrolizumab
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:jx642a|Variant=1}}===
-==Observation==
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
-|}
+|rowspan=2|2016-2018
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-===Regimen===
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 17 vs 14.3 mo<br>(HR 0.86, 95% CI 0.72-1.02)<br><br>Might have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 8.3 vs 7.1 mo<br>(HR 0.78, 95% CI 0.65-0.3)
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]
+|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#d3d3d3" |Not reported
-|[[#PGC|PGC]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ Stadler et al. 2011]
-| style="background-color:#1a9851" |Phase III (C)
-|MVAC
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://academic.oup.com/annonc/article/23/3/695/227146 Cognetti et al. 2011]
-| style="background-color:#1a9851" |Phase III (C)
-|Cisplatin & Gemcitabine
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext Sternberg et al. 2014 (EORTC 30994)]
-| style="background-color:#1a9851" |Phase III (C)
-|MVAC
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). This arm underwent cystectomy and no further treatment. The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions. In Stadler et al. 2011, only patients with positive p53 staining were randomized.''
+''<sup>1</sup>Reported efficacy did not meet the prespecified boundary for statistical significance.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Surgery#Cystectomy|Cystectomy]]
+*[[Cisplatin (Platinol)]] as follows:
+**Cycles 1 up to 6: 70 mg/m<sup>2</sup> IV once on day 1
-====Subsequent treatment====
+*[[Gemcitabine (Gemzar)]] as follows:
+**Cycles 1 up to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*EORTC 30994, upon relapse: [[#MVAC_2|MVAC]] x 6
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div>
 ===References===
+#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
-#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [http://meetinglibrary.asco.org/content/51401-74 link to abstract] '''contains verified protocol'''
+==Enfortumab vedotin & Pembrolizumab {{#subobject:dbopfd|Regimen=1}}==
-#Stadler WM, Lerner SP, Groshen S, Stein JP, Shi SR, Raghavan D, Esrig D, Steinberg G, Wood D, Klotz L, Hall C, Skinner DG, Cote RJ. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol. 2011 Sep 1;29(25):3443-9. Epub 2011 Aug 1. [https://ascopubs.org/doi/full/10.1200/JCO.2010.34.4028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21810677 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, Massidda B, Rubagotti A, Giannarelli D, Boccardo F; Study Group. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012 Mar;23(3):695-700. Epub 2011 Aug 22. [https://academic.oup.com/annonc/article/23/3/695/227146 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21859900 PubMed]
+===Regimen variant #1, q3wk pembrolizumab {{#subobject:1cc557|Variant=1}}===
-#'''EORTC 30994:''' Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, Dumez H, de Santis M, Théodore C, Leahy MG, Chester JD, Verbaeys A, Daugaard G, Wood L, Witjes JA, de Wit R, Geoffrois L, Sengelov L, Thalmann G, Charpentier D, Rolland F, Mignot L, Sundar S, Symonds P, Graham J, Joly F, Marreaud S, Collette L, Sylvester R; European Organisation for Research and Treatment of Cancer Genito-Urinary Cancers Group; Groupe d'Etude des Tumeurs Urogénitales; National Cancer Research Institute Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; German Association of Urologic Oncology. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):76-86. Epub 2014 Dec 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25498218 PubMed]
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
-==PGC {{#subobject:22e1d2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
-<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine
-===Variant #1 {{#subobject:ad1bc8|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Observation|Observation]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |}
-''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions.''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Preceding treatment====
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-====Chemotherapy====
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*[[Paclitaxel (Taxol)]] 80 mg mg/2 IV once per day on days 1 & 8
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 4 cycles'''
-===Variant #2 {{#subobject:29bee9|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
+|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|2020-2023
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 31.5 vs 16.1 mo<br>(HR 0.47, 95% CI 0.38-0.58)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 12.5 vs 6.3 mo<br>(HR 0.45, 95% CI 0.38-0.54)
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Antibody-drug conjugate therapy====
+*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1 & 8
-*Depending on response, adjuvant chemotherapy began 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT]] versus [[#Cisplatin.2C_Fluorouracil.2C_RT_2|cisplatin, 5-FU, RT]] or 8 weeks after [[Surgery#Cystectomy|cystectomy]]
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
-'''21-day cycle for 4 cycles'''
-===References===
-#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [http://meetinglibrary.asco.org/content/51401-74 link to abstract] '''contains verified protocol'''
-#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 PubMed]
-##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19636019 PubMed]
-##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]
-=Locally advanced or metastatic disease, first-line=
-==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:764948|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext Balar et al. 2016 (IMvigor210 Cohort 2)]
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#88419d; color:white " |ORR: 23% (95% CI 16-31)
-|-
-|}
-<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing IMVIGOR-130 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big>
 ====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] as follows:
-*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
+**Cycles 1 to 35: 200 mg IV once on day 1
 '''21-day cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q6wk pembrolizumab {{#subobject:1c7637|Variant=1}}===
-#'''IMvigor210 Cohort 2:''' Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. [http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27939400 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02951767 IMvigor210 at ClinicalTrials.gov]
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
-==Carboplatin & Gemcitabine {{#subobject:8855e5|Regimen=1}}==
-{{#subobject:5f00b7|Variant=1}}
-{{#subobject:4f0596|Variant=1}}
-{{:Carboplatin & gemcitabine for unresectable or metastatic bladder cancer}}
-==Carboplatin & Paclitaxel {{#subobject:b33fe7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:5d481c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 75%; text-align:center;"
+!style="width: 20%"|Study
-! style="width: 33%" |Study
+!style="width: 20%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]
+|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
-| style="background-color:#91cf61" |Phase II
+|2020-2023
-| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 31.5 vs 16.1 mo<br>(HR 0.47, 95% CI 0.38-0.58)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 12.5 vs 6.3 mo<br>(HR 0.45, 95% CI 0.38-0.54)
 |-
 |}
+''Note: Dosing is as described in the FDA approval announcement; this dosing was not reported in Powles et al. 2024.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Antibody-drug conjugate therapy====
+*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 22, 29
-====Chemotherapy====
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] as follows:
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
+**Cycles 1 to 17: 200 mg IV once on day 1
-*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
-'''21-day cycle for up to 6 cycles'''
-===References===
-#Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12209686 PubMed]
-==CISCA {{#subobject:b60f2a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CISCA: '''<u>CIS</u>'''platin, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin)
-===Regimen {{#subobject:2d0b5e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-![[Overall response rate|'''ORR''']]
-!Comparator [[Overall response rate|'''ORR''']]
-|-
-|[https://jamanetwork.com/journals/jama/article-abstract/356753 Sternberg et al. 1977]
-| style="background-color:#ffffbe" |Non-randomized, <20 pts
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
-|
-|-
-|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#MVAC_2|MVAC]]
-| style="background-color:#d73027" |Inferior OS
-|46% (95% CI 32-62)
-|65% (95% CI 52-77)
-|-
-|}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 2
-====Supportive medications====
-*Forced mannitol diuresis with [[Cisplatin (Platinol)]]
-'''21-day cycle for up to 6 cycles'''
-===References===
-#Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. [https://jamanetwork.com/journals/jama/article-abstract/356753 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/578848 PubMed]
-#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2189954 PubMed]
-==Cisplatin monotherapy {{#subobject:1af7a9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:71bd05|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P Soloway et al. 1983]
-| style="background-color:#1a9851" |Randomized (C)
-|Cisplatin & Cyclophosphamide
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]
-| style="background-color:#1a9851" |Randomized (C)
-|CAD
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://www.sciencedirect.com/science/article/pii/S002253471744167X Troner et al. 1987]
-| style="background-color:#1a9851" |Phase III (C)
-|CAD
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]
-| style="background-color:#1a9851" |Phase III (C)
-|Cisplatin & Methotrexate
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#MVAC_2|MVAC]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|}
-''For historic reference. To our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
-====Chemotherapy====
-*[[Cisplatin (Platinol)]]
-===References===
-#Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J. A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer: a National Bladder Cancer Collaborative Group A study. Cancer. 1983 Sep 1;52(5):767-72. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6347356 PubMed]
-#Khandekar JD, Elson PJ, DeWys WD, Slayton RE, Harris DT. Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract. J Clin Oncol. 1985 Apr;3(4):539-45. [https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3884746 PubMed]
-#Troner M, Birch R, Omura GA, Williams S. Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial. J Urol. 1987 Apr;137(4):660-2. [https://www.sciencedirect.com/science/article/pii/S002253471744167X link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/3550148 PubMed]
-#Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G, Levi J, Abbott RL, Aroney R, Gill PG, McLennan R. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol. 1989 Jun;7(6):706-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2654329 PubMed]
-#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 PubMed]
-==Cisplatin & Gemcitabine {{#subobject:5cbd83|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
-<br>GP: '''<u>G</u>'''emcitabine, '''<u>P</u>'''latinol (Cisplatin)
-===Variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]
-| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E)
-|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine q4wk]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
-====Supportive medications====
-*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]
-*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
-'''21-day cycle for up to 6 cycles'''
-===Variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#MVAC_2|MVAC]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]
-| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E)
-|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine q3wk]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#PGC_2|PCG]]
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|[https://www.karger.com/Article/Abstract/354085 Sternberg et al. 2013 (CILAB)]
-| style="background-color:#1a9851" |Phase III (C)
-|Cisplatin & Larotaxel
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2
-*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15
-====Supportive medications====
-*Per Soto Parra et al. 2002:
-*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]
-*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
-'''28-day cycle for up to 6 cycles'''
-===Variant #3, 70/1250, q3wk {{#subobject:44c03b|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-![[Overall response rate|'''ORR''']]
-!Comparator [[Overall response rate|'''ORR''']]
-|-
-|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#Carboplatin_.26_Gemcitabine|Carboplatin & Gemcitabine]]
-| style="background-color:#ffffbf" |Seems not superior
-|Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)
-|Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)
-|-
-|}
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
-*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
-'''21-day cycle for up to 6 cycles'''
+'''42-day cycles'''
+</div></div>
 ===References===
+#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
-#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11001674 PubMed]
-##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16034041 PubMed]
-#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [http://annonc.oxfordjournals.org/content/13/7/1080.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12176787 PubMed]
-#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17207911 PubMed]
-#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://ascopubs.org/doi/full/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]
-#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://www.karger.com/Article/Abstract/354085 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24080920 PubMed]
 ==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1002/cncr.24313 Calabrò et al. 2009]
-|}
+|2003-2005
-===Variant #1 {{#subobject:af7c37|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full Calabrò et al. 2009]
-| style="background-color:#91cf61" |Phase II
 | style="background-color:#5e5e5e; color:white" |ORR: 37%
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''
 *[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 '''14-day cycle for 6 to 12 cycles'''
+</div></div><br>
-===Variant #2 {{#subobject:b840fe|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 75%; text-align:center;"
+===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===
-! style="width: 33%" |Study
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/19/12/3018.long Meluch et al. 2001]
+|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]
-| style="background-color:#91cf61" |Phase II
+|1997-1999
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#8a8a8a" |ORR: 54% (95% CI 40-67)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 *[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 '''21-day cycle for up to 6 cycles'''
+</div></div>
 ===References===
+#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496/ PubMed]
-#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11408496 PubMed]
+#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://doi.org/10.1002/cncr.24313 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19396817/ PubMed]
-#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19396817 PubMed]
 ==MVAC {{#subobject:d2ea09|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
-===Variant #1, standard {{#subobject:33db41|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]
+|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992 (ECOG E5886)]
-| style="background-color:#1a9851" |Phase III (E)
+|1984-1989
-|[[#CISCA|CISCA]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Urothelial_carcinoma_-_historical#Cisplatin_monotherapy|Cisplatin]]
 | style="background-color:#1a9850" |Superior OS
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]
+|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]
-| style="background-color:#1a9851" |Phase III (E)
+|1985-1989
-|[[#Cisplatin_monotherapy|Cisplatin]]
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Urothelial_carcinoma_-_historical#CISCA|CISCA]]
 | style="background-color:#1a9850" |Superior OS
 |-
-|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]
+|[https://doi.org/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]
-| style="background-color:#1a9851" |Phase III (C)
+|1992-1999
-|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[Stub#FAP|FAP]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
-|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]
+|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]
-| style="background-color:#1a9851" |Phase III (C)
+|1993-1998
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#MVAC.2C_dose-dense_2|Dose-dense MVAC]]
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]
+|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]
-| style="background-color:#1a9851" |Phase III (C)
+|1996-1998
-|FAP
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004 (ECOG E4897)]
+|1998-2001
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: reported efficacy for EORTC 30924 is based on the 2005 update.''
+''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on either day 1 or 2
+*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2
 '''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)
+</div></div><br>
-===Variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 Bamias et al. 2003]
+|[https://doi.org/10.1200/JCO.2004.02.152 Bamias et al. 2003]
-| style="background-color:#1a9851" |Phase III (C)
+|1997-2002
-|Cisplatin & Docetaxel
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cisplatin_.26_Docetaxel_.28DC.29_999|Cisplatin & Docetaxel]]
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1
 *[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+====Supportive therapy====
-====Supportive medications====
 *[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26
 '''28-day cycles'''
+</div></div>
 ===References===
+#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2189954/ PubMed]
-#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2189954 PubMed]
+#'''ECOG E5886:''' Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1607913/ PubMed]
-#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 PubMed]
+##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826/ PubMed]
-#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11001674 PubMed]
+#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11001674/ PubMed]
-##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16034041 PubMed]
+##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041/ PubMed]
-#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11352955 PubMed]
+#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11352955/ PubMed]
-##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16330205 PubMed]
+##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://doi.org/10.1016/j.ejca.2005.08.032 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330205/ PubMed]
-#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11870180 PubMed]
+#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11870180/ PubMed]
-#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665607 PubMed]
+#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14665607/ PubMed]
+#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] [https://clinicaltrials.gov/study/NCT00003376 NCT00003376]
 ==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:daeb1c|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-!Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
-![[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!Comparator [[Overall response rate|'''ORR''']]
 |-
-|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]
+|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]
-| style="background-color:#1a9851" |Phase III (E)
+|1993-1998
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#MVAC_2|MVAC]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup>
-|62% (95% CI 54-70)
-|50% (95% CI 42-59)
 |-
-|[https://academic.oup.com/annonc/article/24/4/1011/259546 Bamias et al. 2012 (HE 16/03)]
+|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]
-| style="background-color:#1a9851" |Phase III (C)
+|2003-2008
-|DD-GC
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Dose-dense_Gemcitabine_.26_Cisplatin_.28GC.29_999|DD-GC]]
-|
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|
 |-
 |}
-''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. Reported efficacy for EORTC 30924 is based on the 2005 update.''
+''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br>
+''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. ORR for this arm of EORTC 30924 was 62% (95% CI 54-70) versus 50% (95% CI 42-59) in the control arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1
 *[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once on day 2
 *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 *[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
+====Supportive therapy====
-====Supportive medications====
+*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/μL.
-*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/uL.
 **''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''
 '''14-day cycles'''
+</div></div>
 ===References===
+#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11352955/ PubMed]
-#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11352955 PubMed]
+##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://doi.org/10.1016/j.ejca.2005.08.032 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330205/ PubMed]
-##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16330205 PubMed]
+#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23136231/ PubMed] ACTRN12610000845033
-#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://academic.oup.com/annonc/article/24/4/1011/259546 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23136231 PubMed]
 ==PGC {{#subobject:393eb6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
 <br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:837446|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-!Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
-![[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!Comparator [[Overall response rate|'''ORR''']]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
-| style="background-color:#1a9851" |Phase III (E)
+|2001-2004
-|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#d9ef8b" |Might have superior OS
+|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]
-|56% (95% CI NR)
+| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 15.8 vs 12.7 mo<br>(HR 0.85, 95% CI 0.72-1.02)
-|44% (95% CI NR)
 |-
 |}
+''Note: ORR for this arm of EORTC 30987 was 56% vs 44% in the control arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
 *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''
 '''21-day cycle for up to 6 cycles'''
+</div></div>
 ===References===
+#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319/ PubMed] [https://clinicaltrials.gov/study/NCT00022191 NCT00022191]
-#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://ascopubs.org/doi/full/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]
+=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=
+==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==
-==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:913o9g|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]
-|}
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-===Regimen {{#subobject:946aec|Variant=1}}===
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-220-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]
+|} -->
-| style="background-color:#91cf61" |Phase II (RT)
+|2016-2019
-| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Urothelial_carcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
+| style="background-color:#1a9851" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 23.8 vs 15 mo<br>(HR 0.76, 95% CI 0.63-0.91)
+| style="background-color:#d73027" |More toxic
 |-
 |}
-<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big>
+''<sup>1</sup>Reported efficacy is based on the 2023 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*First-line [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]] x 4 to 6 or [[Urothelial_carcinoma#Carboplatin_.26_Gemcitabine_.28GCb.29 |GCb]] x 4 to 6
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+====Supportive therapy====
+Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:
-'''21-day cycles'''
+*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO equivalent
+*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or PO equivalent
+'''28-day cycles'''
+</div></div>
 ===References===
-<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract]
+#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://doi.org/10.1056/NEJMoa2002788 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32945632/ PubMed] [https://clinicaltrials.gov/study/NCT02603432 NCT02603432]
-# '''Abstract:''' Dean F. Bajorin, Elizabeth R. Plimack, Arlene O. Siefker-Radtke, Toni K. Choueiri, Ronald De Wit, Guru Sonpavde, Adrianna Gipson, Holly Brown, Yabing Mai, Lei Pang, Rodolfo F. Perini, Joaquim Bellmunt. KEYNOTE-052: Phase 2 study of pembrolizumab (MK-3475) as first-line therapy for patients (pts) with unresectable or metastatic urothelial cancer ineligible for cisplatin-based therapy. 2015 ASCO Annual Meeting abstract TPS4572. [http://meetinglibrary.asco.org/content/146071-156 link to abstract]
+##'''PRO analysis:''' Grivas P, Kopyltsov E, Su PJ, Parnis FX, Park SH, Yamamoto Y, Fong PC, Tournigand C, Climent Duran MA, Bamias A, Caserta C, Chang J, Cislo P, di Pietro A, Wang J, Powles T. Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma. Eur Urol. 2023 Apr;83(4):320-328. Epub 2022 May 30. [https://doi.org/10.1016/j.eururo.2022.04.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35654659/ PubMed]
-# '''Abstract:''' A. Balar, J. Bellmunt, P.H. O'Donnell, D. Castellano, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R. Perini, S. Keefe, D. Bajorin. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol (2016) 27 (suppl_6): LBA32_PR. [https://academic.oup.com/annonc/article-abstract/27/suppl_6/LBA32_PR/2800534/Pembrolizumab-pembro-as-first-line-therapy-for?redirectedFrom=fulltext link to abstract] -->
+##'''Update:''' Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullén A, Loriot Y, Sridhar SS, Sternberg CN, Bellmunt J, Aragon-Ching JB, Wang J, Huang B, Laliberte RJ, di Pietro A, Grivas P. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023 Jul 1;41(19):3486-3492. Epub 2023 Apr 18. [https://doi.org/10.1200/jco.22.01792 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10306435/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37071838/ PubMed]
+#'''MAIN-CAV:''' [https://clinicaltrials.gov/study/NCT05092958 NCT05092958]
-#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967485 PubMed]
+==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-=Maintenance after first-line therapy=
+===Regimen {{#subobject:9gia9g|Variant=1}}===
-==Placebo==
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 17%" |Study
-|-
+! style="width: 15%" |Dates of enrollment
-|[[#top|back to top]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|}
+! style="width: 17%" |Comparator
-===Regimen===
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 Powles et al. 2016 (LaMB)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ Galsky et al. 2020 (HCRN GU14-182)]
-| style="background-color:#1a9851" |Phase III (C)
+|2015-2018
-|Lapatinib
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Placebo_888|Placebo]]
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 5.4 vs 3 mo<br>(HR 0.65, 95% CI 0.43-0.97)
+| style="background-color:#d73027" |More toxic
 |-
 |}
-''No active antineoplastic treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
-===References===
+====Preceding treatment====
+*First-line [[Regimen_classes#Platinum-based_regimen|platinum-based combination chemotherapy]] for up to 8 cycles, without progression of disease
-#'''LaMB:''' Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, Hussain S, Crabb S, Jagdev S, Chester J, Hilman S, Beresford M, Macdonald G, Santhanam S, Frew JA, Stockdale A, Hughes S, Berney D, Chowdhury S. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol. 2017 Jan;35(1):48-55. Epub 2016 Oct 28. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28034079 PubMed]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-=Locally advanced or metastatic disease, subsequent lines=
-==Atezolizumab monotherapy {{#subobject:451e68|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:feb2e2|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nature.com/articles/nature13904 Powles et al. 2014]
-| style="background-color:#ffffbe" |Phase 1
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext Rosenberg et al. 2016 (IMvigor210)]
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#88419d; color:white" |ORR: 15% (95% CI 11-20)
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
-| style="background-color:#1a9851" |Phase III (E)
-|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.''
 ====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div>
-'''21-day cycles'''
 ===References===
+#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32271672/ PubMed] [https://clinicaltrials.gov/study/NCT02500121 NCT02500121]
-#'''Phase 1:''' Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. [https://www.nature.com/articles/nature13904 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25428503 PubMed]
+=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy=
-#'''IMvigor210:''' Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. Epub 2016 Mar 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480242/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26952546 PubMed]
-#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]
 ==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==
-{{#subobject:D9FB6C|Variant=1}}
+<div class="toccolours" style="background-color:#eeeeee">
-{{:Avelumab (Bavencio) for metastatic bladder cancer}}
+===Regimen {{#subobject:D9FB6C|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-==Best supportive care==
+!style="width: 25%"|Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN Solid Tumor)]
-|}
+|2014-2016
-===Regimen===
+| style="background-color:#91cf61" |Phase 1b (RT)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|ORR: 17% (95% CI 11-24)<sup>1</sup>
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Vinflunine_monotherapy|Vinflunine]]
-| style="background-color:#d73027" |Inferior OS (*)
 |-
 |}
-''No active antineoplastic treatment. Reported efficacy is based on the 2013 update.''
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1
+====Supportive therapy====
+''Per Apolo et al. 2017:''
+*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)
+*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."
+'''14-day cycles'''
+</div></div>
 ===References===
+#'''JAVELIN Solid Tumor:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787/ PubMed] [https://clinicaltrials.gov/study/NCT01772004 NCT01772004]
-#Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]
+##'''Update:''' Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. Epub 2017 Dec 5. Erratum in: Lancet Oncol. 2018 Jul;19(7):e335. [https://doi.org/10.1016/s1470-2045(17)30900-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7984727/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29217288/ PubMed]
-##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23419284 PubMed]
 ==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:b840fe|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-!Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
-![[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!Comparator [[Overall response rate|'''ORR''']]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]
+|[https://doi.org/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]
-| style="background-color:#91cf61" |Phase II
+|1993-1995
-| style="background-color:#d3d3d3" |
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
-| style="background-color:#88419d; color:white " |13% (95% CI 4-31)
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2011 (DFCI 06-116)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2010
-|Docetaxel & Vandetanib
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Docetaxel_.26_Vandetanib_999|Docetaxel & Vandetanib]]
-| style="background-color:#6e016b; color:white" |11% (95% CI NR)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-| style="background-color:#6e016b; color:white" |7% (95% CI NR)
 |-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016]
+| rowspan="2" |[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
+| rowspan="2" |2011-2014
-|1. Docetaxel & Icrucumab
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|1. [[#Docetaxel_.26_Icrucumab_999|Docetaxel & Icrucumab]]
-|
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|
 |-
 |2. [[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
 | style="background-color:#d73027" |Inferior PFS
-|
-|
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
-| style="background-color:#1a9851" |Phase III (C)
+|2014-11-05 to 2015-11-13
-|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
 | style="background-color:#d73027" |Inferior OS
-|
-|
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]
+|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
-| style="background-color:#1a9851" |Phase III (C)
+|2015-01-13 to 2016-02-15
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1016/S0140-6736(17)32365-6 Petrylak et al. 2017 (RANGE)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+| style="background-color:#d73027" |Inferior PFS<sup>1</sup>
-|
+|-
-|
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
+|2018-2020
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
+| style="background-color:#d73027" |Inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
-| style="background-color:#1a9851" |Phase III (C)
+|2018-08-06 to NR
-|[[#Atezolizumab_monotherapy_2|Atezolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Erdafitinib_monotherapy|Erdafitinib]]
-|
+| style="background-color:#d73027" |Inferior OS
-|
 |-
 |}
+''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br>
 ''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
+====Prior treatment criteria====
+*KEYNOTE-045: Exposure to platinum-based chemotherapy
+*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
+*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===References===
+#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195/ PubMed]
-#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9164195 PubMed]
+#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381/ PubMed] [https://clinicaltrials.gov/study/NCT00880334 NCT00880334]
-#Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. [http://jco.ascopubs.org/content/30/5/507.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22184381 PubMed]
+#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681/ PubMed] [https://clinicaltrials.gov/study/NCT01282463 NCT01282463]
-#Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26926681 PubMed]
+#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
-<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] -->
+##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
-#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]
+##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
-##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31050707 PubMed]
+##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
-#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]
+#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://doi.org/10.1016/S0140-6736(17)32365-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28916371/ PubMed] [https://clinicaltrials.gov/study/NCT02426125 NCT02426125]
-#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]
+##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://doi.org/10.1016/S1470-2045(19)30668-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727/ PubMed]
+#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
+#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
+##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
+##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
+#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
+#'''SWOG S1937:''' [https://clinicaltrials.gov/study/NCT04579224 NCT04579224]
+#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
 ==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:b840fe|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|rowspan=2|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]
-|}
+|rowspan=2|2011-2014
-===Regimen {{#subobject:b840fe|Variant=1}}===
+|rowspan=2 style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|1. [[#Docetaxel_monotherapy|Docetaxel]]
-! style="width: 25%" |Study
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.4 vs 2.8 mo<br>(sHR 0.39, 95% CI 0.235-0.64)
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016]
+|2. [[#Docetaxel_.26_Icrucumab_777|Docetaxel & Icrucumab]]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+| style="background-color:#d3d3d3" |Not reported
-|[[#Docetaxel_monotherapy|Docetaxel]]
-| style="background-color:#1a9850" |Superior PFS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]
+|[https://doi.org/10.1016/S0140-6736(17)32365-6 Petrylak et al. 2017 (RANGE)]
-| style="background-color:#1a9851" |Phase III (E)
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#Docetaxel_monotherapy|Docetaxel]]
-| style="background-color:#91cf60" |Seems to have superior PFS
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>(HR 0.70, 95% CI 0.57-0.85)
 |-
 |}
+''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
 *[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===References===
+#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26926681/ PubMed] [https://clinicaltrials.gov/study/NCT01282463 NCT01282463]
+#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://doi.org/10.1016/S0140-6736(17)32365-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28916371/ PubMed] [https://clinicaltrials.gov/study/NCT02426125 NCT02426125]
+##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://doi.org/10.1016/S1470-2045(19)30668-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727/ PubMed]
-#Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26926681 PubMed]
+==Enfortumab vedotin & Pembrolizumab {{#subobject:dbi8bd|Regimen=1}}==
-#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:jeq057|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.22.01643 Hoimes et al. 2022 (EV-103)]
+|2017-2020
+| style="background-color:#91cf61" |Phase 1b/2 (RT)
+|ORR: 73.3%<br>CR: 15.6%
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Antibody-drug conjugate therapy====
+*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg IV once per day on days 1 & 8
-==Durvalumab monotherapy {{#subobject:7ae7fb|Regimen=1}}==
+====Immunotherapy====
-{{#subobject:b2af36|Variant=1}}
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-{{:Durvalumab (Imfinzi) for metastatic bladder cancer}}
+'''21-day cycles'''
+</div></div>
+===References===
+#'''EV-103:''' Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. Epub 2022 Aug 30. [https://doi.org/10.1200/jco.22.01643 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36041086/ PubMed] [http://clinicaltrials.gov/show/NCT03288545 NCT03288545]
 ==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:473057|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:473057|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-{| class="wikitable" style="color:white; background-color:#404040"
+!style="width: 25%"|Study
-|<small>'''FDA-recommended dose'''</small>
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-276-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
+|-
+|} -->
+|2015-2018
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#8c96c6" |ORR 40% (95% CI 31-50)
 |-
 |}
-{| class="wikitable" style="width: 50%; text-align:center;"
+<div class="toccolours" style="background-color:#fdcdac">
-! style="width: 25%" |Study
+====Biomarker eligibility criteria====
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Erdafitinib (Balversa)]] as follows:
+**Cycle 1: 8 mg PO once per day on days 1 to 21, then 9 mg PO once per day on days 22 to 28 if serum phosphorus level and tolerability are acceptable
+**Cycle 2 onwards: 9 mg PO once per day on days 1 to 28
+'''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:47gh17|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]
+|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
-| style="background-color:#91cf61" |Phase II (RT)
+|2018-08-06 to NR
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1a. [[#Docetaxel_monotherapy|Docetaxel]]<br>1b. [[#Vinflunine_monotherapy|Vinflunine]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.1 vs 7.8 mo<br>(HR 0.64, 95% CI 0.47-0.88)
 |-
 |}
-====Chemotherapy====
+''Note: The details of pharmacodynamic guidance were not described in the manuscript.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Susceptible FGFR2 or FGFR3 alterations
+====Prior treatment criteria====
+*Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Erdafitinib (Balversa)]] as follows:
+**Cycle 1: 8 mg PO once per day on days 1 to 13, then 9 mg PO once per day on days 14 to 21, guided by pharmacodynamics
+**Cycle 2 onwards: 9 mg PO once per day on days 1 to 21
+'''21-day cycles'''
+</div></div>
-*[[Erdafitinib (Balversa)]] 8 mg PO once per day
+===References===
-**If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day
+#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://doi.org/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094/ PubMed] [https://clinicaltrials.gov/study/NCT02365597 NCT02365597]
-**Additional dose adjustments per package insert
+##'''Update:''' Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00660-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35030333/ PubMed]
+#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
+#'''THOR cohort 2:''' Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.10.003 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37871702/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
+==Gemcitabine monotherapy {{#subobject:ec25gd|Regimen=1}}==
+{| class="wikitable" style="color:white; background-color:#9e4244"
+|<small>'''AIM pathway regimen 2022-08-01'''</small>
+|-
+|}
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:3gaen7|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/s0959-8049(98)00030-6 Lorusso et al. 1998]
+|NR in abstract
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 '''28-day cycles'''
+</div></div>
 ===References===
-<!-- # '''Abstract:''' Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Peter De Porre, Yohann Loriot, on behalf of the BLC2001 Study Group. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). 2018 ASCO Annual Meeting abstract 4503 [https://meetinglibrary.asco.org/record/160559/abstract link to abstract] '''contains verified protocol'''
+# Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. [https://doi.org/10.1016/s0959-8049(98)00030-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9849481/ PubMed]
-# '''BLC2001:''' [https://clinicaltrials.gov/ct2/show/NCT02365597 CT.gov] -->
-#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31340094 PubMed]
 ==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel
-===Variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://academic.oup.com/annonc/article/22/2/288/171507 Albers et al. 2010 (AUO AB 20/99)]
+|[https://doi.org/10.1093/annonc/mdq398 Albers et al. 2010 (AUO AB 20/99)]
-| style="background-color:#1a9851" |Phase III (C)
+|2001-2005
-|Prolonged [[#Gemcitabine_.26_Paclitaxel_2|GP]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Gemcitabine_.26_Paclitaxel_2|GP]]; prolonged
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
 *[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 '''21-day cycle for up to 6 cycles'''
+</div></div><br>
-===Variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 75%; text-align:center;"
+===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===
-! style="width: 33%" |Study
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/19/12/3018.long Meluch et al. 2001]
+|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]
-| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup
+|1997-1999
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts in this subgroup
 | style="background-color:#8c96c6" |ORR: 47%
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 *[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 '''21-day cycle for up to 6 cycles'''
+</div></div>
 ===References===
+#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496/ PubMed]
-#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11408496 PubMed]
+#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20682548/ PubMed]
-#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://academic.oup.com/annonc/article/22/2/288/171507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20682548 PubMed]
 ==MVAC {{#subobject:373ed3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:af2e64|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ Han et al. 2008]
-| style="background-color:#91cf61" |Phase II
+|2002-2006
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#8c6bb1" |ORR: 30%
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 *[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
+'''28-day cycles'''
-'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)
+</div></div>
 ===References===
+#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289/ PubMed]
-#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://www.nature.com/bjc/journal/v98/n1/full/6604113a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18087289 PubMed]
 ==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==
-{{#subobject:beb7fa|Variant=1}}
+<div class="toccolours" style="background-color:#eeeeee">
-{{:Nivolumab (Opdivo) for unresectable or metastatic bladder cancer}}
+===Regimen variant #1, weight-based {{#subobject:beb7fa|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(17)30065-7 Sharma et al. 2017 (CheckMate 275)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-240-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
+|-
+|} -->
+|2015
+| style="background-color:#91cf61" |Phase 2 (RT)
+|19.6% overall<br>PD-L1 expression at least 5%: 28.4%<br>PD-L1 expression at least 1%: 23.8%<br>PD-L1 expression less than 1%: 16.1%
+|-
+|}
+''Note: this is the dosing used in the study but is not the FDA-recommended dose.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, flat dosing {{#subobject:beb6ea|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 240 IV over 60 minutes once on day 1
+'''14-day cycles'''
+</div></div>
+===References===
+#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://doi.org/10.1016/S1470-2045(17)30065-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28131785/ PubMed] [https://clinicaltrials.gov/study/NCT02387996 NCT02387996]
+##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Oct 1;26(19):5120-5128. Epub 2020 Jun 12. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8166422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32532789/ PubMed]
+==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:7dc525|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(13)70162-1 Ko et al. 2013 (ABX207-GU07CA)]
+|2008-2010
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/μL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
+</div></div>
+===References===
+#'''ABX207-GU07CA:''' Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. Epub 2013 May 22. [https://doi.org/10.1016/S1470-2045(13)70162-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23706985/ PubMed] [https://clinicaltrials.gov/study/NCT00683059 NCT00683059]
 ==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable" style="color:white; background-color:#9e4244"
+|<small>'''AIM pathway regimen 2022-08-01'''</small>
 |-
-|[[#top|back to top]]
 |}
-===Regimen, q3wks {{#subobject:9fddc0|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
-| style="background-color:#1a9851" |Phase III (C)
+|2014-11-05 to 2015-11-13
-|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
 | style="background-color:#d73027" |Inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
-| style="background-color:#1a9851" |Phase III (C)
+|2015-01-13 to 2016-02-15
-|[[#Atezolizumab_monotherapy_2|Atezolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
+|2018-2020
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
+''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*KEYNOTE-045: Exposure to platinum-based chemotherapy
+*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div><br>
-===Variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 75%; text-align:center;"
+===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===
-! style="width: 33%" |Study
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/20/4/937.long Vaughn et al. 2002]
+|[https://doi.org/10.1200/jco.2002.20.4.937 Vaughn et al. 2002]
-| style="background-color:#91cf61" |Phase II
+|NR
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#6e016b; color:white" |ORR: 10% (95% CI 0-20)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
 '''28-day cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, weekly {{#subobject:525ggf|Variant=1}}===
-#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [http://jco.ascopubs.org/content/20/4/937.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11844814 PubMed]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27284445 PubMed]
+!style="width: 33%"|Study
-<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] -->
+!style="width: 33%"|Dates of enrollment
-#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31050707 PubMed]
-#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]
-==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ Sideris et al. 2016]
-|}
+|2004-2014
-===Regimen {{#subobject:7dc525|Variant=1}}===
+| style="background-color:#ffffbe" |Retrospective
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext Ko et al. 2013]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
-====Dose modifications====
-*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
 ===References===
+#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11844814/ PubMed]
-#Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23706985 PubMed]
+#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445/ PubMed]
+#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
+##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
+##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
+##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
+#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
+#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
+##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
+##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
+#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
 ==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable" style="color:white; background-color:#9e4244"
+|<small>'''AIM pathway regimen 2022-08-01'''</small>
 |-
-|[[#top|back to top]]
 |}
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:8aec07|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-278-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2014-11-05 to 2015-11-13
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|Investigator's choice of:<br>1a. [[#Docetaxel_monotherapy|Docetaxel]]<br>1b. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1c. [[#Vinflunine_monotherapy|Vinflunine]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 10 vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+|[https://doi.org/10.1016/j.annonc.2023.10.003 Siefker-Radtke et al. 2023 (THOR cohort 2)]
-| style="background-color:#1a9851" |Phase III (E-RT)
+|2018-04-26 to NR
-|Investigator's choice of:<br> [[#Docetaxel_monotherapy|Docetaxel]]<br> [[#Paclitaxel_monotherapy|Paclitaxel]]<br> [[#Vinflunine_monotherapy|Vinflunine]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#1a9850" |Superior OS
+|[[#Erdafitinib_monotherapy|Erdafitinib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*THOR cohort 2: Susceptible FGFR2 or FGFR3 alterations
+====Eligibility criteria====
+*KEYNOTE-045: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
+====Prior treatment criteria====
+*KEYNOTE-045: Exposure to platinum-based chemotherapy
+*THOR cohort 2: Exposure to one prior treatment that did NOT include an anti-PD-1 antibody or anti-PD-L1 antibody (anti-PD-(L)1-naive).
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV over 30 minutes once on day 1
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===References===
+#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
-#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]
+##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
-##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31050707 PubMed]
+##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
+##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
+#'''THOR cohort 2:''' Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.10.003 link to original article] '''cotains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37871702/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 ==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:7dc525|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 25%"|Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/24/21/3451.long Sweeney et al. 2006]
+|[https://doi.org/10.1200/jco.2005.03.6699 Sweeney et al. 2006]
-| style="background-color:#91cf61" |Phase II
+|2001-2004
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#8c6bb1" |ORR: 28% (95% CI 16-43)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1
 '''21-day cycles'''
+</div></div>
+===References===
+#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16849761/ PubMed]
+==Tislelizumab monotherapy {{#subobject:13vc7d|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:6klcv5|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://clinicaltrials.gov/study/NCT04004221 Awaiting publication (RATIONALE-204)]
+|2017-NR
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Tislelizumab (Baizean)]] 200 mg IV once on day 1
+'''21-day cycles'''
+</div></div>
 ===References===
+# '''RATIONALE-204:''' [https://clinicaltrials.gov/study/NCT04004221 NCT04004221]
-#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [http://jco.ascopubs.org/content/24/21/3451.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16849761 PubMed]
+==Toripalimab monotherapy {{#subobject:8ivc7d|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==
+===Regimen {{#subobject:6klko5|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://clinicaltrials.gov/study/NCT03113266 Awaiting publication (Junshi-JS001-009)]
+|2017-NR
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#top|back to top]]
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Toripalimab (Loqtorzi)]] 3 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div>
+===References===
+#'''Junshi-JS001-009:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03113266 NCT03113266]
+==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:b5b9b9|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009 (CA183004)]
+|2003-2006
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Urothelial_carcinoma_-_null_regimens#Best_supportive_care_2|Best supportive care]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 6.9 vs 4.6 mo<br>(aHR 0.72, 95% CI 0.57-0.91)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
+|2014-11-05 to 2015-11-13
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
+| style="background-color:#d73027" |Inferior OS
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]
+|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
-| style="background-color:#1a9851" |Phase III (E)
+|2015-01-13 to 2016-02-15
-|[[#Best_supportive_care|Best supportive care]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#1a9850" |Superior OS (*)
+|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 10.6 vs 11.1 mo<br>(HR 1.15, 95% CI 0.83-1.59)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
-| style="background-color:#1a9851" |Phase III (C)
+|2018-2020
-|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
 | style="background-color:#d73027" |Inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
-| style="background-color:#1a9851" |Phase III (C)
+|2018-08-06 to NR
-|[[#Atezolizumab_monotherapy_2|Atezolizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Erdafitinib_monotherapy|Erdafitinib]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: reported efficacy for Bellmunt et al. 2009 is based on the 2013 update.''
+''<sup>1</sup>Reported efficacy for CA183004 is based on the 2013 update.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
+====Prior treatment criteria====
+*KEYNOTE-045: Exposure to platinum-based chemotherapy
+*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
+*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV over 20 minutes once on day 1
+'''21-day cycles'''
+</div></div>
+===References===
+#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19687335/ PubMed] [https://clinicaltrials.gov/study/NCT00315237 NCT00315237]
+##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284/ PubMed]
+#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
+##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
+##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
+##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
+#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
+#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
+##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
+##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
+#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
+#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
-*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1
+=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor=
+==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==
+{| class="wikitable" style="color:white; background-color:#9e4244"
+|<small>'''AIM pathway regimen 2022-08-01'''</small>
+|-
+|}
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:415bc7|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-275-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2017-10-08 to 2018-07-02
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#d3d3d3" |
+|ORR: 44% (95% CI 35.2-53.2)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-286-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2018-2020
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|Investigator's choice of:<br>1a. [[Urothelial_carcinoma#Docetaxel_monotherapy | Docetaxel]]<br>1b. [[Urothelial_carcinoma#Paclitaxel_monotherapy | Paclitaxel]]<br>1c. [[Urothelial_carcinoma#Vinflunine_monotherapy | Vinflunine]]
+| style="background-color:#1a9851" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 12.91 vs 8.94 mo<br>(HR 0.70, 95% CI 0.58-0.85)
+|}
+''<sup>1</sup>Reported efficacy for EV-301 is based on the 2023 update.''<br>
+''Note: ORR in this arm of EV-301 (ITT) was 40.6% vs 17.9 % in the control arm (ITT).''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Antibody-drug conjugate therapy====
+*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
+'''28-day cycles'''
+</div></div>
+===References===
+#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31356140/ PubMed] [https://clinicaltrials.gov/study/NCT03219333 NCT03219333]
+##'''Update:''' Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, Necchi A, Kojima T, Harrison MR, Hoon Park S, Quinn DI, Heath EI, Rosenberg JE, Steinberg J, Liang SY, Trowbridge J, Campbell M, McGregor B, Balar AV. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. Epub 2021 May 12. Erratum in: Lancet Oncol. 2021 Jun;22(6):e239. [https://doi.org/10.1016/s1470-2045(21)00094-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33991512/ PubMed]
+#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
+##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
+##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
+==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:417gu7|Variant=1}}===
+{| class="wikitable sortable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+! style="width: 25%" |Study
+! style="width: 25%" |Dates of enrollment
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8315301/ Tagawa et al. 2021 (TROPHY-U-01)]
+|2018-2019
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#8c96c6" |ORR: 27% (95% CI 19.5-37)
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Exposure to platinum-based therapy and checkpoint inhibitor, with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Antibody-drug conjugate therapy====
+*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8
 '''21-day cycles'''
+</div></div>
 ===References===
+#'''TROPHY-U-01:''' Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. Epub 2021 Apr 30. [https://doi.org/10.1200/jco.20.03489 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8315301/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33929895/ PubMed] [https://clinicaltrials.gov/study/NCT03547973 NCT03547973]
-#Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]
+##'''Update:''' Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthélémy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. Epub 2024 Jan 18. [https://doi.org/10.1016/j.annonc.2024.01.002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38244927/ PubMed]
-##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23419284 PubMed]
+#'''TROPiCs-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
-#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]
+[[Category:Urothelial carcinoma regimens]]
-##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31050707 PubMed]
-#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]
-=Links=
-*[http://www.eortc.be/tools/bladdercalculator/ EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer] - predicts probability of recurrence and progression in 1 to 5 years
-=Urine assays=
-''These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.''
-*[https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347921 Cxbladder (uRNA-2)], a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
-*[http://www.scimedx.com/products/bladder_cancer/bladder_cancer.php ImmunoCyt™/uCyt+™], a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."<ref>Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751037/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17192798 PubMed]</ref>
-*[http://www.abbottmolecular.com/us/products/oncology/fish/bladder-cancer-urovysion.html UroVysion] (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."
-=References=
-<references />
-[[Category:Bladder cancer regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Genitourinary cancers]]

Difference between revisions of "Urothelial carcinoma"

Latest revision as of 17:48, 23 June 2024

Guidelines

ESMO

NCCN

SITC

Adjuvant therapy

Nivolumab monotherapy

Regimen variant #1, q2wks

Preceding treatment

Immunotherapy

Regimen variant #2, q4wks

Preceding treatment

Immunotherapy

References

Locally advanced or metastatic disease, first-line, platinum-ineligible

Gemcitabine monotherapy

Regimen

Chemotherapy

References

Pembrolizumab monotherapy

Regimen

Immunotherapy

References

Locally advanced or metastatic disease, first-line, platinum-eligible

Carboplatin & Gemcitabine (GCb)

Regimen variant #1, AUC 4.5/1000 x 6

Chemotherapy

Regimen variant #2, AUC 4.5/1000, indefinite

Chemotherapy

Regimen variant #3, AUC 5/1000 x 6

Chemotherapy

Regimen variant #4, AUC 5/1250

Chemotherapy

References

Carboplatin & Gemcitabine (GCb) & Pembrolizumab

Regimen

Chemotherapy

Immunotherapy

References

Carboplatin & Paclitaxel (CP)

Regimen

Chemotherapy

References

Cisplatin & Gemcitabine (GC)

Regimen variant #1, 70/2000; q3wk x 6

Chemotherapy

Supportive therapy

Regimen variant #2, 70/2000; q3wk, indefinite

Chemotherapy

Supportive therapy

Regimen variant #3, 70/2500; q3wk

Chemotherapy

Regimen variant #4, 70/3000; q4wk

Chemotherapy

Supportive therapy

References

Cisplatin & Gemcitabine (GC) & Bevacizumab

Regimen

Chemotherapy

Targeted therapy

References

Cisplatin & Gemcitabine (GC) & Nivolumab

Regimen

Chemotherapy

Immunotherapy

References

Cisplatin & Gemcitabine (GC) & Pembrolizumab

Regimen

Chemotherapy

Immunotherapy

References

Enfortumab vedotin & Pembrolizumab

Regimen variant #1, q3wk pembrolizumab

Antibody-drug conjugate therapy

Immunotherapy

Regimen variant #2, q6wk pembrolizumab

Antibody-drug conjugate therapy

Immunotherapy

References