Revision as of 08:06, 13 November 2019

Page editor		Section editor
	Ali Raza Khaki, MD University of Washington Seattle, WA arkhaki		Eddy J. Chen, MD Massachusetts General Hospital Boston, MA

31 regimens on this page 47 variants on this page

Guidelines

AUA, ASCO, ASTRO, SUO

2017: Chang et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline PubMed

ESMO

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

Intravesical chemotherapy

Bacillus Calmette-Guérin (BCG) monotherapy

Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer

Doxorubicin monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Martínez-Piñeiro et al. 1990	Phase III (C)	1. BCG	Inferior RFS
Martínez-Piñeiro et al. 1990	Phase III (C)	2. Thiotepa	Not reported
Lamm et al. 1991 (SWOG 8216)	Phase III (C)	BCG	Seems to have inferior DFS

Inferior to BCG, included for reference purposes only.

Chemotherapy

Doxorubicin (Adriamycin)

15 or more treatments

References

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. link to SD article contains partial protocol PubMed
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. link to original article PubMed

Gemcitabine monotherapy

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Variant #1, 1 treatment

Study	Evidence	Comparator	Comparative Efficacy
Messing et al. 2018 (SWOG S0337)	Phase III (E)	Placebo (saline)	Superior TTR

Preceding treatment

TURBT, up to 3 hours prior

Chemotherapy

Gemcitabine (Gemzar) 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes

One treatment

Variant #2, 6 treatments

Study	Evidence	Comparator	Comparative Efficacy
Addeo et al. 2009	Phase III (E)	Mitomycin	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

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. link to original article contains verified protocol PubMed
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. link to original article contains verified protocol PubMed

Mitomycin monotherapy

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Variant #1, 30 mg x 12

Study	Evidence	Comparator	Comparative Efficacy
Ojea et al. 2007 (CUETO study 95011)	Phase III (C)	1. Low-dose BCG	Inferior DFS
Ojea et al. 2007 (CUETO study 95011)	Phase III (C)	2. Very-low-dose BCG	Seems not superior

Preceding treatment

TURBT, 14 to 21 days prior

Chemotherapy

Mitomycin (Mutamycin) as follows:
- Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
- Cycles 4 to 9: 30 mg intravesicularly once on day 1

14-day cycle for 9 cycles

Variant #2, 40 mg x 11

Study	Evidence	Comparator	Comparative Efficacy
Lammers et al. 2012	Phase III (C)	Keyhole limpet hemocyanin	Superior RFS

Preceding treatment

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

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. link to original article contains verified protocol PubMed
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. link to original article contains verified protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial)	Phase III (C)	Pirarubicin	Seems to have inferior RFS

No active antineoplastic treatment after surgery.

Preceding treatment

Nephroureterectomy

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. link to original article contains verified protocol PubMed

Pirarubicin monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial)	Phase III (E)	Observation	Seems to have superior RFS

Pirarubicin was given within 48 hours after nephroureterectomy.

Preceding treatment

Nephroureterectomy

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. link to original article contains verified protocol PubMed

Thiotepa monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Martínez-Piñeiro et al. 1990	Phase III (C)	1. BCG	Inferior RFS
Martínez-Piñeiro et al. 1990	Phase III (C)	2. Doxorubicin	Not reported

Inferior to BCG, included for reference purposes only.

Chemotherapy

Thiotepa (Thioplex) 50 mg intravesicularly x 15 treatments

References

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. link to SD article contains partial protocol PubMed

Valrubicin monotherapy

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Regimen

FDA-recommended dose

Study	Evidence
Steinberg et al. 2000	Non-randomized (RT)

Chemotherapy

Valrubicin (Valstar) 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36

6-week course

References

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. link to original article contains protocol PubMed

Neoadjuvant chemotherapy

Cisplatin & Gemcitabine

Cisplatin & Gemcitabine for bladder cancer, neoadjuvant

MCV

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CMV: Cisplatin, Methotrexate, Vinblastine
MCV: Methotrexate, Cisplatin, Vinblastine

Variant #1, 2 cycles

Study	Evidence	Comparator	Comparative Efficacy
Kaufman et al. 1993	Phase II
Tester et al. 1996 (RTOG 88-02)	Phase II
Shipley et al. 1998 (RTOG 89-03)	Phase III (E)	No neoadjuvant chemotherapy	Seems not superior

Chemotherapy

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

28-day cycle for 2 cycles

Subsequent treatment

Kaufman et al. 1993, CR: Cisplatin & RT consolidation
RTOG 88-02 & 89-03: Cisplatin & RT induction

Variant #2, 3 cycles

Study	Evidence	Comparator	Comparative Efficacy
Griffiths et al. 1999 (BA06 30894)	Phase III (E)	No neoadjuvant therapy	Seems to have superior OS (*)
Zapatero et al. 2000	Non-randomized

Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV bolus once per day on days 1 & 8
Cisplatin (Platinol) 100 mg/m² IV once on day 2, before hydration
Vinblastine (Velban) 4 mg/m² IV bolus once per day on days 1 & 8

Supportive medications

BA06 30894: Folinic acid (Leucovorin) 15 mg/m² 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/m²)

21-day cycle for 3 cycles

Subsequent treatment

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: RT consolidation which begins 4 to 6 weeks after completion of chemotherapy
- Otherwise, patients proceeded to 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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. link to original article PubMed
1. 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol PubMed
1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article PubMed

MVAC

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MVAC: Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin

Variant #1, 2 cycles

Study	Evidence	Comparator	Comparative Efficacy
Kitamura et al. 2014 (JCOG0209)	Phase III (E)	No neoadjuvant therapy	Might 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 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 cycle for 2 cycles

Subsequent treatment

Radical cystectomy

Variant #2, 3 cycles

Study	Evidence	Comparator	Comparative Efficacy
Grossman et al. 2003 (SWOG S8710)	Phase III (E)	No neoadjuvant therapy	Might 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 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 cycle for 3 cycles

Subsequent treatment

Radical cystectomy

References

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. link to original article contains verified protocol 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. link to original article PubMed

MVAC, dose-dense

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ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
AMVAC: Accelerated Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin

Variant #1, 3 cycles

Study	Evidence
Plimack et al. 2014	Phase II

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV over 30 minutes once on day 1
Vinblastine (Velban) 3 mg/m² IV push once on day 2
Doxorubicin (Adriamycin) 30 mg/m² IV push once on day 2
Cisplatin (Platinol) 70 mg/m² IV in 1 liter normal saline once on day 2
- Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m²: 35 mg/m² IV once per day on days 1 & 2

Supportive medications

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

Radical cystectomy with bilateral lymphadenectomy, within 4 to 8 weeks after the last cycle of chemotherapy

Variant #2, 4 cycles

Study	Evidence
Choueiri et al. 2014	Phase II

Chemotherapy

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

Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy

References

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. link to original article contains verified protocol PubMed
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. link to original article contains verified protocol link to PMC article PubMed

Immune checkpoint inhibitors

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Variant #1, Pembrolizumab

Study	Evidence
Necchi et al. 2018 (PURE-01)	Phase II

Chemotherapy

Pembrolizumab 200mg IV over 30 minutes once on day 1

21-day cycle for 3 cycles

Subsequent treatment

Radical cystectomy, within 1 to 3 weeks after the last cycle of chemotherapy

Variant #2, Atezolizumab

Study	Evidence
Powles et al. 2019	Phase II

Chemotherapy

Atezolizumab 1200mg IV over 60 minutes on day 1

21-day cycle for 2 cycles

Subsequent treatment

Cystectomy to be performed 4 to 8 weeks after completion of chemotherapy

References

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. Link to original article contains verified protocol. PubMed
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. PubMed
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. Link to original article. PubMed

No neoadjuvant therapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Martinez-Piñeiro et al. 1995	Phase III (C)	Cisplatin	Seems not superior
Griffiths et al. 1999 (BA06 30894)	Phase III (C)	CMV	Seems to have inferior OS (*)
Grossman et al. 2003 (SWOG S8710)	Phase III (C)	MVAC	Might have inferior OS
Kitamura et al. 2014 (JCOG0209)	Phase III (C)	MVAC	Might have inferior OS

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.

Subsequent treatment

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. link to original article 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. link to original article PubMed
1. 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol 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. link to original article PubMed

Induction chemoradiotherapy

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Variant #1, cisplatin 40 mg/m² qwk x 3

Study	Evidence
Hagan et al. 2003 (RTOG 97-06)	Phase I/II
Zapatero et al. 2009	Non-randomized

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.

Chemotherapy

Cisplatin (Platinol) 20 mg/m² 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 3 cycles

Radiotherapy

Concurrent radiation therapy according to one of the following:
- 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.
- 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

3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- Patients with complete regression (R0): Cisplatin & RT consolidation
- Nonresponders: Cystectomy

Variant #2, cisplatin 70 mg/m² q3wk x 2

Study	Evidence
Tester et al. 1996 (RTOG 88-02)	Phase II

Preceding treatment

MCV x 2

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV once on day 1

21-day cycle for 2 cycles

Radiotherapy

Concurrent 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 & RT consolidation
- Patients without CR proceeded immediately to: cystectomy

Variant #3, cisplatin 100 mg/m² q3wk x 2

Study	Evidence
Shipley et al. 1988	Non-randomized
Shipley et al. 1998 (RTOG 89-03)	Non-randomized portion of RCT

Preceding treatment

RTOG 89-03: MCV versus no neoadjuvant therapy

Chemotherapy

Cisplatin (Platinol) 100 mg/m² IV once on day 1

21-day cycle for 2 cycles

Radiotherapy

Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)

4.5-week course

Subsequent treatment

RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology."
- Patients not in CR usually proceeded to: cystectomy
- Patients in complete remission usually proceeded to: cisplatin & RT consolidation

References

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. link to original article 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol PubMed
1. 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. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, RT

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Variant #1, 90/2400/24

Study	Evidence
Kaufman et al. 2000 (RTOG 95-06)	Phase I/II

Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m².

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV over 60 minutes once per day on days 1 to 3, given second, before radiation
Fluorouracil (5-FU) 400 mg/m² 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 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 10⁹/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 10⁹/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: CF & RT consolidation in week 9
- Incomplete responders were recommended to undergo radical cystectomy

Variant #2, 135/2400/40.3

Study	Evidence	Comparator
Coen et al. 2018 (RTOG 0712)	Randomized Phase II (C)	Gemcitabine & RT

Note: this trial was not statistically powered to compare regimens.

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV once per day on days 1 to 3, 8 to 10, 15 to 17
Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 3, 15 to 17

Radiotherapy

Concurrent 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.

17-day course

Subsequent treatment

Treatment followed by repeat cystoscopy & biopsy
- Patients with complete response: CF & RT consolidation
- Incomplete responders: Radical cystectomy

Variant #3, 135/3600/40.3

Study	Evidence	Comparator
Mitin et al. 2013 (RTOG 02-33)	Randomized Phase II (E)	Cisplatin, Paclitaxel, RT

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV once per day on days 1 to 3
Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 3

7-day cycle for 3 cycles

Radiotherapy

Concurrent 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: CF & RT consolidation
- Patients with at least stage T1 disease: Radical cystectomy on week 9, then 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT

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Variant #1, 40/50 x 3 + 40.3 Gy

Study	Evidence
Kaufman et al. 2009 (RTOG 99-06)	Phase I/II

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.

Preceding treatment

TURBT, within 4 to 6 weeks

Chemotherapy

Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 & 2
Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 3 cycles

Radiotherapy

Concurrent 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, paclitaxel, RT consolidation
- Patients with at least stage ypT1 disease: Radical cystectomy, then adjuvant cisplatin & gemcitabine

Variant #2, 45/50 x 3 + 40.3 Gy

Study	Evidence	Comparator
Mitin et al. 2013 (RTOG 02-33)	Randomized Phase II (E)	Cisplatin, Fluorouracil, RT

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV once per day on days 1 to 3
Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 3 cycles

Radiotherapy

Concurrent 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 ypT1 disease: Cisplatin, paclitaxel, RT consolidation
- Patients with at least stage ypT1 disease: Radical cystectomy on week 9, then 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Fluorouracil, Mitomycin, RT

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Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
James et al. 2012 (BC2001)	Phase III (E)	Radiation therapy	Seems to have superior locoregional DFS

Chemotherapy

Fluorouracil (5-FU) 500 mg/m²/day IV continuous infusion for 10 total days (total dose: 5000 mg/m²) during radiation fractions 1 to 5, 16 to 20
Mitomycin (Mutamycin) 12 mg/m² IV bolus once on day 1

Radiotherapy

External beam radiotherapy given according to one of the following plans:
- Concurrent radiation therapy, 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
- Concurrent 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. link to original article link to supplementary index contains verified protocol PubMed

Gemcitabine & RT

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Regimen

Study	Evidence	Comparator
Coen et al. 2018 (RTOG 0712)	Randomized Phase II (E)	CF & RT

Note: this trial was not statistically powered to compare regimens.

Chemotherapy

Gemcitabine (Gemzar) 27 mg/m² IV once per day on days 1, 4, 8, 11

14-day cycle for 2 cycles

Radiotherapy

Concurrent 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: 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. link to original article contains verified protocol link to PMC article PubMed

Paclitaxel & RT

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Regimen

Study	Evidence
Zapatero et al. 2012	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/m² IV once per week, given 6 hours before radiation therapy

Radiotherapy

Concurrent 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 TURBT
- Patients with complete regression (R0): Paclitaxel & RT consolidation
- Nonresponders: 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. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Zapatero et al. 2000	Non-randomized
James et al. 2012 (BC2001)	Phase III (C)	Fluorouracil, Mitomycin, RT	Seems to have inferior locoregional DFS

Preceding treatment

Depending on response, treatment in Zapatero et al. 2000 preceded by MCV x 3 or 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. link to original article contains verified protocol PubMed
1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article 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. link to original article contains verified protocol PubMed

Consolidation chemoradiotherapy

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Variant #1, cisplatin 40 mg/m²/wk x 2

Study	Evidence
Zapatero et al. 2000	Non-randomized
Hagan et al. 2003 (RTOG 97-06)	Phase I/II

Preceding treatment

Depending on response: Cisplatin & RT induction or cystectomy

Chemotherapy

Cisplatin (Platinol) 20 mg/m² 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 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: Adjuvant MCV

Variant #2, cisplatin 70 mg/m² x 1

Study	Evidence
Tester et al. 1996 (RTOG 88-02)	Phase II

Preceding treatment

Depending on response, treatment preceded by cisplatin & RT induction or cystectomy

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV once on day 1

Radiotherapy

Concurrent 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/m² x 1

Study	Evidence
Shipley et al. 1998 (RTOG 89-03)	Non-randomized portion of RCT

Preceding treatment

Depending on response, treatment preceded by cisplatin & RT induction or cystectomy

Chemotherapy

Cisplatin (Platinol) 100 mg/m² IV once on day 1

Radiotherapy

Concurrent 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

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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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. link to original article PubMed
1. 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. link to original article contains verified protocol PubMed
2. 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Fluorouracil, RT

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Variant #1, 30/1200 x 2 + 64.3 Gy

Study	Evidence	Comparator
Mitin et al. 2013 (RTOG 02-33)	Randomized Phase II (E)	Cisplatin, Paclitaxel, RT

Consolidation starts starts on week 8.

Preceding treatment

Cisplatin, 5-FU, RT induction

Chemotherapy

Starts on week 8.

Cisplatin (Platinol) 15 mg/m² IV once per day on days 1 & 2
Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 3

7-day cycle for 2 cycles

Radiotherapy

Concurrent 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

Adjuvant PGC

Variant #2, 45/1200 x 2 + 44 Gy

Study	Evidence
Kaufman et al. 2000 (RTOG 95-06)	Phase I/II

Treatment starts on week 9.

Preceding treatment

Depending on response, treatment preceded by cisplatin, fluorouracil, RT induction or cystectomy

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV over 60 minutes once per day on days 1 to 3, given second
Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 3, given first

14-day cycle for 2 cycles

Radiotherapy

Concurrent 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 10⁹/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 10⁹/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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT

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Variant #1, 30/50 x 2 + 64.3 Gy

Study	Evidence	Comparator
Mitin et al. 2013 (RTOG 02-33)	Randomized Phase II (E)	Cisplatin, 5-FU, RT

Consolidation starts starts on week 8.

Preceding treatment

Cisplatin, Paclitaxel, RT induction

Chemotherapy

Cisplatin (Platinol) 15 mg/m² IV once per day on days 1 & 2
Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 2 cycles

Radiotherapy

Concurrent 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

Adjuvant PGC

Variant #2, 40/50 x 2 + 64.3 Gy

Study	Evidence
Kaufman et al. 2009 (RTOG 99-06)	Phase I/II

Consolidation starts starts on week 8.

Preceding treatment

Cisplatin, Paclitaxel, RT induction

Chemotherapy

Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 & 2
Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 2 cycles

Radiotherapy

Concurrent 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

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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Paclitaxel & RT

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Regimen

Study	Evidence
Zapatero et al. 2012	Non-randomized, <20 pts

Preceding treatment

Depending on response, treatment preceded by paclitaxel & RT induction or cystectomy

Chemotherapy

Paclitaxel (Taxol) 50 mg/m² IV once per week, given 6 hours before radiation therapy

Radiotherapy

Concurrent 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. link to original article contains verified protocol PubMed

Adjuvant chemotherapy

Cisplatin & Gemcitabine

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Regimen

Study	Evidence
Kaufman et al. 2009 (RTOG 99-06)	Phase I/II

Preceding treatment

Depending on response to induction, treatment starts 12 weeks after cisplatin, paclitaxel, RT consolidation, or 8 weeks after cystectomy

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV once on day 1
Gemcitabine (Gemzar) 1000 mg/m² 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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Methotrexate

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Regimen

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Lehmann et al. 2005 (AUO-AB 05/95)	Phase III (E)	M-VEC x 3	Seems not superior	Less toxic

Preceding treatment

Radical cystectomy

Chemotherapy

References

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. link to original article PubMed

MCV

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MCV: Methotrexate, Cisplatin, Vinblastine

Regimen

Study	Evidence
Hagan et al. 2003 (RTOG 97-06)	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.

Preceding treatment

Cisplatin & RT consolidation

Chemotherapy

Methotrexate (MTX) 30 mg/m² IV once per day on days 1, 15, 22
Cisplatin (Platinol) 25 mg/m² IV once per day on days 2 to 4
Vinblastine (Velban) 3 mg/m² IV once per day on days 2, 15, 22

28-day cycle for 3 cycles

References

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. link to original article contains verified protocol PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01)	Phase III (C)	PGC	Inferior OS
Stadler et al. 2011	Phase III (C)	MVAC	Seems not superior
Cognetti et al. 2011	Phase III (C)	Cisplatin & Gemcitabine	Seems not superior
Sternberg et al. 2014 (EORTC 30994)	Phase III (C)	MVAC	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/1.73m²). 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.

Preceding treatment

Cystectomy

Subsequent treatment

EORTC 30994, upon relapse: MVAC x 6

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. link to abstract contains verified protocol
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. link to original article link to PMC article PubMed
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. link to original article PubMed
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. link to original article PubMed

PGC

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

Variant #1

Study	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01)	Phase III (E)	Observation	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/1.73m²). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions.

Preceding treatment

Cystectomy; the median time treatment started post-cystectomy was 48 days

Chemotherapy

Paclitaxel (Taxol) 80 mg mg/2 IV once per day on days 1 & 8
Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
Cisplatin (Platinol) 70 mg/m² IV once on day 1

21-day cycle for 4 cycles

Variant #2

Study	Evidence
Mitin et al. 2013 (RTOG 02-33)	Non-randomized portion of RCT

Preceding treatment

Depending on response, adjuvant chemotherapy began 12 weeks after cisplatin, paclitaxel, RT versus cisplatin, 5-FU, RT or 8 weeks after cystectomy

Chemotherapy

Cisplatin (Platinol) 35 mg/m² IV once per day on days 1 & 8
Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
Paclitaxel (Taxol) 50 mg/m² 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. 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 link to PMC article PubMed
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. link to original article link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed

Locally advanced or metastatic disease, first-line

Atezolizumab monotherapy

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Regimen

Study	Evidence	Efficacy
Balar et al. 2016 (IMvigor210 Cohort 2)	Phase II (RT)	ORR: 23% (95% CI 16-31)

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.

Immunotherapy

Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

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. link to original article contains protocol PubMed IMvigor210 at ClinicalTrials.gov

Carboplatin & Gemcitabine

Carboplatin & gemcitabine for unresectable or metastatic bladder cancer

Carboplatin & Paclitaxel

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Regimen

Study	Evidence	Efficacy
Vaughn et al. 2002 (ECOG E2896)	Phase II	ORR: 24% (95% CI 12-42)

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

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 protocol PubMed

CISCA

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CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Sternberg et al. 1977	Non-randomized, <20 pts
Logothetis et al. 1990	Phase III (E)	MVAC	Inferior OS	46% (95% CI 32-62)	65% (95% CI 52-77)

Chemotherapy

Cyclophosphamide (Cytoxan) 650 mg/m² IV once on day 1
Cisplatin (Platinol) 100 mg/m² IV once on day 2
Doxorubicin (Adriamycin) 50 mg/m² 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. link to original article 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. link to original article contains verified protocol PubMed

Cisplatin monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Soloway et al. 1983	Randomized (C)	Cisplatin & Cyclophosphamide	Seems not superior
Khandekar et al. 1985	Randomized (C)	CAD	Seems not superior
Troner et al. 1987	Phase III (C)	CAD	Seems not superior
Hillcoat et al. 1989	Phase III (C)	Cisplatin & Methotrexate	Seems not superior
Loehrer et al. 1992	Phase III (C)	MVAC	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. link to original article 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. link to original article 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. link to SD article 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. link to original article 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. link to original article contains verified protocol PubMed

Cisplatin & Gemcitabine

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

Variant #1, 70/1000, q3wk

Study	Evidence	Comparator	Comparative Efficacy
Soto Parra et al. 2002	Randomized Phase II, <20 pts in this subgroup (E)	Cisplatin & Gemcitabine q4wk	Not reported

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV over 30 to 60 minutes once on day 2
Gemcitabine (Gemzar) 1000 mg/m² 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

Study	Evidence	Comparator	Comparative Efficacy
von der Maase et al. 2000	Phase III (E)	MVAC	Seems not superior
Soto Parra et al. 2002	Randomized Phase II, <20 pts in this subgroup (E)	Cisplatin & Gemcitabine q3wk	Not reported
Bellmunt et al. 2012 (EORTC 30987)	Phase III (C)	PCG	Might have inferior OS
Sternberg et al. 2013 (CILAB)	Phase III (C)	Cisplatin & Larotaxel	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/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 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

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Dogliotti et al. 2006	Randomized Phase II (C)	Carboplatin & Gemcitabine	Seems not superior	Intention to treat: 49% (95% CI NR) Evaluable patients only: 66% (95% CI: 49–80)	Intention to treat: 40% (95% CI NR) Evaluable patients only: 56% (95% CI: 40–72)

Chemotherapy

Cisplatin (Platinol) 70 mg/m² IV 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

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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol link to PMC article 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. link to original article contains protocol PubMed

Gemcitabine & Paclitaxel

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Variant #1

Study	Evidence	Efficacy
Calabrò et al. 2009	Phase II	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

Variant #2

Study	Evidence	Efficacy
Meluch et al. 2001	Phase II	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 verified protocol PubMed

MVAC

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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Variant #1, standard

Study	Evidence	Comparator	Comparative Efficacy
Logothetis et al. 1990	Phase III (E)	CISCA	Superior OS
Loehrer et al. 1992	Phase III (E)	Cisplatin	Superior OS
von der Maase et al. 2000	Phase III (C)	Cisplatin & Gemcitabine	Seems not superior
Sternberg et al. 2001 (EORTC 30924)	Phase III (C)	Dose-dense MVAC	Seems to have inferior OS (*)
Siefker-Radtke et al. 2002	Phase III (C)	FAP	Seems not superior

Note: reported 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 on either day 1 or 2

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

Variant #2, with G-CSF support

Study	Evidence	Comparator	Comparative Efficacy
Bamias et al. 2003	Phase III (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 medications

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 verified protocol 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. link to original article contains verified protocol 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 verified protocol 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; 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. link to original article contains verified protocol 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 verified protocol 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 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 verified protocol PubMed

MVAC, dose-dense

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

Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Sternberg et al. 2001 (EORTC 30924)	Phase III (E)	MVAC	Seems to have superior OS (*)	62% (95% CI 54-70)	50% (95% CI 42-59)
Bamias et al. 2012 (HE 16/03)	Phase III (C)	DD-GC	Seems not superior

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.

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 medications

G-CSF 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/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

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; 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. link to original article contains verified protocol 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 verified protocol 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. 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 protocol PubMed

PGC

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

Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Bellmunt et al. 2012 (EORTC 30987)	Phase III (E)	Cisplatin & Gemcitabine	Might have superior OS	56% (95% CI NR)	44% (95% CI NR)

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 verified protocol link to PMC article PubMed

Pembrolizumab monotherapy

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Regimen

Study	Evidence	Efficacy
Balar et al. 2017 (KEYNOTE-052)	Phase II (RT)	ORR: 24% (95% CI 20-29)

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.

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 PubMed

Maintenance after first-line therapy

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Powles et al. 2016 (LaMB)	Phase III (C)	Lapatinib	Seems not superior

No active antineoplastic treatment.

References

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. link to original article PubMed

Locally advanced or metastatic disease, subsequent lines

Atezolizumab monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Powles et al. 2014	Phase 1
Rosenberg et al. 2016 (IMvigor210)	Phase II (RT)		ORR: 15% (95% CI 11-20)
Powles et al. 2017 (IMvigor211)	Phase III (E)	1. Docetaxel 2. Paclitaxel 3. Vinflunine	Seems not superior

Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.

Immunotherapy

Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

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. link to original article PubMed
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. link to original article link to PMC article contains protocol 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 protocol PubMed

Avelumab monotherapy

Avelumab (Bavencio) for metastatic bladder cancer

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2009	Phase III (C)	Vinflunine	Inferior OS (*)

No active antineoplastic treatment. Reported efficacy is based on the 2013 update.

References

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 protocol PubMed
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

Docetaxel monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
McCaffrey et al. 1997	Phase II			13% (95% CI 4-31)
Choueiri et al. 2012	Phase III (C)	Docetaxel & Vandetanib	Seems not superior	11% (95% CI NR)	7% (95% CI NR)
Petrylak et al. 2016	Randomized Phase II (C)	1. Docetaxel & Icrucumab	Seems not superior
Petrylak et al. 2016	Randomized Phase II (C)	2. Docetaxel & Ramucirumab	Inferior PFS
Bellmunt et al. 2017 (KEYNOTE-045)	Phase III (C)	Pembrolizumab	Inferior OS
Petrylak et al. 2017 (RANGE)	Phase III (C)	Docetaxel & Ramucirumab	Seems to have inferior PFS
Powles et al. 2017 (IMvigor211)	Phase III (C)	Atezolizumab	Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV 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
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. link to original article link to PMC article 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. 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 verified protocol PubMed
1. 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] 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 verified protocol 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 protocol PubMed

Docetaxel & Ramucirumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Petrylak et al. 2016	Randomized Phase II (E)	Docetaxel	Superior PFS
Petrylak et al. 2017 (RANGE)	Phase III (E)	Docetaxel	Seems to have superior PFS

Chemotherapy

Docetaxel (Taxotere) 75 mg/m² IV once on day 1
Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

21-day cycles

References

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 verified protocol 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 verified protocol PubMed

Durvalumab monotherapy

Durvalumab (Imfinzi) for metastatic bladder cancer

Erdafitinib monotherapy

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Regimen

FDA-recommended dose

Study	Evidence
Loriot et al. 2019 (BLC2001)	Phase II (RT)

Chemotherapy

Erdafitinib (Balversa) 8 mg PO once per day
- If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day
- Additional dose adjustments per package insert

28-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

Gemcitabine & Paclitaxel

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GP: Gemcitabine & Paclitaxel

Variant #1, gemcitabine 2 out of 3 weeks

Study	Evidence	Comparator	Comparative Efficacy
Albers et al. 2010 (AUO AB 20/99)	Phase III (C)	Prolonged GP	Seems not superior

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

Variant #2, weekly gemcitabine

Study	Evidence	Efficacy
Meluch et al. 2001	Phase II, <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 verified protocol PubMed

MVAC

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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study	Evidence	Efficacy
Han et al. 2008	Phase II	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 (number of cycles and criteria to continue therapy varies depending on reference)

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 verified protocol link to PMC article PubMed

Nivolumab monotherapy

Nivolumab (Opdivo) for unresectable or metastatic bladder cancer

Paclitaxel monotherapy

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Regimen, q3wks

Study	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	Phase III (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	Phase III (C)	Atezolizumab	Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Chemotherapy

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

21-day cycles

Variant #2, 3 out of 4 weeks

Study	Evidence	Efficacy
Vaughn et al. 2002	Phase II	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

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 protocol 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 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 verified protocol PubMed
1. 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] 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 protocol PubMed

nab-Paclitaxel monotherapy

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Regimen

Study	Evidence	Efficacy
Ko et al. 2013	Phase II	ORR: 28% (95% CI 17-44)

Chemotherapy

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

21-day cycles

Dose 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/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

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. link to original article contains protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	Phase III (E-RT)	Investigator's choice of: Docetaxel Paclitaxel Vinflunine	Superior OS

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV 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 verified protocol PubMed
1. 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] link to original article PubMed

Pemetrexed monotherapy

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Regimen

Study	Evidence	Efficacy
Sweeney et al. 2006	Phase II	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 protocol PubMed

Vinflunine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2009	Phase III (E)	Best supportive care	Superior OS (*)
Bellmunt et al. 2017 (KEYNOTE-045)	Phase III (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	Phase III (C)	Atezolizumab	Seems not superior

Note: reported efficacy for Bellmunt et al. 2009 is based on the 2013 update.

Chemotherapy

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

21-day cycles

References

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 protocol PubMed
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 verified protocol PubMed
1. 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] 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 protocol PubMed

Links

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.

Cxbladder (uRNA-2), a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
ImmunoCyt™/uCyt+™, a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."^[1]
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

↑ Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. link to PMC article PubMed

[1] Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. link to PMC article PubMed

[1]

@@ Line 3: / Line 3: @@
 ! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''
 |-
-|style="background-color:#F0F0F0"|[[File:Alikhaki.jpg|frameless|upright=0.3|center]]
+| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]
-|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]
+| 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]
-|style="background-color:#F0F0F0"|[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]
+| style="background-color:#F0F0F0" |[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]
 |<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Massachusetts General Hospital<br>Boston, MA</big>
 |-
@@ Line 18: / Line 18: @@
 =Guidelines=
 ==AUA, ASCO, ASTRO, SUO==
 *'''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]
 ==[http://www.esmo.org/ ESMO]==
 *'''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]
 ==[https://www.nccn.org/ NCCN]==
 *[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]
@@ Line 36: / Line 41: @@
 ===Regimen {{#subobject:49ccdb|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[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" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 |1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
-|style="background-color:#d73027"|Inferior RFS
+| style="background-color:#d73027" |Inferior RFS
 |-
 |2. [[#Thiotepa_monotherapy|Thiotepa]]
-|style="background-color:#d3d3d3"|Not reported
+| style="background-color:#d3d3d3" |Not reported
 |-
 |[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]
-| style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
 | style="background-color:#fc8d59" |Seems to have inferior DFS
@@ Line 57: / Line 62: @@
 ''Inferior to BCG, included for reference purposes only.''
 ====Chemotherapy====
 *[[Doxorubicin (Adriamycin)]]
@@ Line 62: / Line 68: @@
 ===References===
-# 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]
-# '''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]
+#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]
+#'''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]
 ==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==
@@ Line 72: / Line 79: @@
 ===Variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |Placebo (saline)
-|style="background-color:#1a9850"|Superior TTR
+| style="background-color:#1a9850" |Superior TTR
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#TURBT|TURBT]], up to 3 hours prior
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
@@ Line 92: / Line 102: @@
 ===Variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Mitomycin_monotherapy|Mitomycin]]
-|style="background-color:#1a9850"|Superior DFS
+| 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
@@ Line 109: / Line 120: @@
 ===References===
-# 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]
-# '''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]
+#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]
+#'''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]
 ==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==
@@ Line 119: / Line 131: @@
 ===Variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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" |[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)
+| 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
+| style="background-color:#d73027" |Inferior DFS
 |-
 |2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|Very-low-dose BCG]]
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#TURBT|TURBT]], 14 to 21 days prior
 ====Chemotherapy====
 *[[Mitomycin (Mutamycin)]] as follows:
 **Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
@@ Line 144: / Line 159: @@
 ===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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (C)
 |Keyhole limpet hemocyanin
-|style="background-color:#1a9850"|Superior RFS
+| style="background-color:#1a9850" |Superior RFS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#TURBT|TURBT]]
 ====Chemotherapy====
 *[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1
@@ Line 163: / Line 181: @@
 ===References===
-# '''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]
-# 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]
+#'''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]
+#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]
 ==Observation==
@@ Line 173: / Line 192: @@
 ===Regimen===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Pirarubicin_monotherapy|Pirarubicin]]
-|style="background-color:#fc8d59"|Seems to have inferior RFS
+| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
 |}
 ''No active antineoplastic treatment after surgery.''
 ====Preceding treatment====
 *[[Surgery#Nephroureterectomy|Nephroureterectomy]]
 ===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]
+#'''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]
 ==Pirarubicin monotherapy {{#subobject:d9be78|Regimen=1}}==
@@ Line 198: / Line 220: @@
 ===Regimen {{#subobject:dfdcd9|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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 (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Observation|Observation]]
-|style="background-color:#91cf60"|Seems to have superior RFS
+| style="background-color:#91cf60" |Seems to have superior RFS
 |-
 |}
 ''Pirarubicin was given within 48 hours after nephroureterectomy.''
 ====Preceding treatment====
 *[[Surgery#Nephroureterectomy|Nephroureterectomy]]
 ====Chemotherapy====
 *[[Pirarubicin (THP)]] 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes
@@ Line 218: / Line 243: @@
 ===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]
+#'''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}}==
@@ Line 228: / Line 254: @@
 ===Regimen {{#subobject:97d2e7|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[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" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 |1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
-|style="background-color:#d73027"|Inferior RFS
+| style="background-color:#d73027" |Inferior RFS
 |-
 |2. [[#Doxorubicin_monotherapy|Doxorubicin]]
-|style="background-color:#d3d3d3"|Not reported
+| style="background-color:#d3d3d3" |Not reported
 |-
 |}
 ''Inferior to BCG, included for reference purposes only.''
 ====Chemotherapy====
 *[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments
 ===References===
-# 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]
+#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]
 ==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==
@@ Line 261: / Line 289: @@
 |}
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 50%"|Study
+! style="width: 50%" |Study
-!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]
@@ Line 269: / Line 297: @@
 |}
 ====Chemotherapy====
 *[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
 '''6-week course'''
 ===References===
-# 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]
+#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]
 =Neoadjuvant chemotherapy=
@@ Line 290: / Line 320: @@
 ===Variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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:#91cf61" |Phase II
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
 |-
 |[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
 |-
 |[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
@@ Line 318: / Line 349: @@
 '''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]]
@@ Line 323: / Line 355: @@
 ===Variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-|style="background-color:#91cf60"|Seems to have superior OS (*)
+| 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]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#91cf61" |Non-randomized
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
 |-
 |}
 ''Patients in '''Zapatero et al. 2000''' had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.''
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
 *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration
@@ Line 346: / Line 379: @@
 ====Supportive medications====
 *'''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>)
@@ Line 351: / Line 385: @@
 ====Subsequent treatment====
 *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]
+#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 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]
+#'''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]
-## '''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]
+#'''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:''' 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]
+##'''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]
-# '''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]
+##'''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]
-## '''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]
+#'''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]
-# 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:''' 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]
-## '''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]
+#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, 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]
+##'''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}}==
@@ Line 374: / Line 411: @@
 ===Variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-|style="background-color:#d9ef8b"|Might have superior OS
+| 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
@@ Line 393: / Line 431: @@
 '''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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]
-|style="background-color:#d9ef8b"|Might have superior OS
+| 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
@@ Line 416: / Line 456: @@
 '''28-day cycle for 3 cycles'''
 ====Subsequent treatment====
 *[[Surgery#Radical_cystectomy|Radical cystectomy]]
 ===References===
-# '''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]
+#'''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]
 ==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==
@@ Line 430: / Line 473: @@
 ===Variant #1, 3 cycles {{#subobject:c4bf38|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014]
-|style="background-color:#91cf61"|Phase II
+| 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
@@ Line 445: / Line 489: @@
 ====Supportive medications====
 *[[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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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
@@ Line 469: / Line 516: @@
 ====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] -->
-# 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]
-# 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]
-==No neoadjuvant therapy==
+#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]
+#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]
+==Immune checkpoint inhibitors {{#subobject:3cb963|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
+===Variant #1, Pembrolizumab {{#subobject:c4bf38|Variant=1}}===
-===Regimen===
+{| class="wikitable" style="width: 50%; text-align:center;"
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 25%" |Study
-!style="width: 25%"|Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[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/pubmed/30343614 Necchi et al. 2018 (PURE-01)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#91cf61" |Phase II
-|Cisplatin
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#MCV|CMV]]
-|style="background-color:#fc8d59"|Seems to have inferior OS (*)
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
-|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)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#MVAC|MVAC]]
-|style="background-color:#fee08b"|Might have inferior OS
 |-
 |}
-''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.''
+====Chemotherapy====
+*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200mg IV over 30 minutes once on day 1
+'''21-day cycle for 3 cycles'''
+====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#Bladder_cancer_surgery|Surgery]]
+*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy
 ===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]
+<!-- # 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] -->
-# '''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=
+#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]
+#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]
+#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]
-==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==
+==No neoadjuvant therapy==
 {| 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> qwk x 3 {{#subobject:f782c3|Variant=1}}===
+===Regimen===
-{| class="wikitable" style="width: 50%; text-align:center;"
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Comparator
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
+|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 Martinez-Piñeiro et al. 1995]
-|style="background-color:#91cf61"|Phase I/II
+| style="background-color:#1a9851" |Phase III (C)
+|Cisplatin
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]
+| style="background-color:#1a9851" |Phase III (C)
+|[[#MCV|CMV]]
+| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+|-
+|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
+| style="background-color:#1a9851" |Phase III (C)
+|[[#MVAC|MVAC]]
+| style="background-color:#fee08b" |Might have inferior OS
 |-
-|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]
+|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#1a9851" |Phase III (C)
+|[[#MVAC|MVAC]]
+| style="background-color:#fee08b" |Might have inferior 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.''
+''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.''
-====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 3 cycles'''
-====Radiotherapy====
-*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
-**'''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.
-**'''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====
-*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
-**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
-**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
-===Variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===
+*[[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]]
+|}
+Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+===Variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]
+|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Non-randomized
 |-
 |}
-====Preceding treatment====
+''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.''
-*[[#MCV|MCV]] x 2
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 2 cycles'''
+*[[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 3 cycles'''
 ====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
+**'''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.
+**'''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====
+*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
+**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
+**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
+===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)]
+| style="background-color:#91cf61" |Phase II
+|-
+|}
+====Preceding treatment====
+*[[#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]]
@@ Line 583: / Line 696: @@
 ===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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#91cf61" |Non-randomized
 |-
 |[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
+| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
 |}
 ====Preceding treatment====
 *RTOG 89-03: [[#MCV|MCV]] versus [[#No_neoadjuvant_therapy|no neoadjuvant therapy]]
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 100 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====
 *RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology."
 **Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]
@@ Line 607: / Line 727: @@
 ===References===
-# 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]
+#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 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]
+#'''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]
-## '''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]
+#'''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:''' 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]
+##'''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]
-# '''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:''' 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]
-## '''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]
+#'''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:''' 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]
+##'''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]
-# 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]
+##'''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]
-## '''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]
+#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}}==
@@ Line 625: / Line 746: @@
 ===Variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| style="background-color:#91cf61" |Phase I/II
 |-
 |}
 ''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>.''
 ====Chemotherapy====
 *[[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
@@ Line 652: / Line 781: @@
 ===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%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|Comparator
+! 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)
+| style="background-color:#1a9851" |Randomized Phase II (C)
 |[[#Gemcitabine_.26_RT|Gemcitabine & RT]]
 |-
@@ Line 663: / Line 792: @@
 ''Note: this trial was not statistically powered to compare regimens.''
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17
 ====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
@@ Line 671: / Line 803: @@
 **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.
 '''17-day course'''
 ====Subsequent treatment====
 *Treatment followed by repeat cystoscopy & biopsy
 **Patients with complete response: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]]
@@ Line 679: / Line 813: @@
 ===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%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|Comparator
+! style="width: 33%" |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)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]
 |-
 |}
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3
 '''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
@@ Line 701: / Line 838: @@
 '''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]]
@@ Line 706: / Line 844: @@
 ===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]
+#'''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:''' 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]
+##'''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]
-# '''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:''' 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]
-## '''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]
+#'''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:''' 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]
+##'''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]
-# '''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]
+##'''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}}==
@@ Line 721: / Line 860: @@
 ===Variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| style="background-color:#91cf61" |Phase I/II
 |-
 |}
 ''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.''
 ====Preceding treatment====
 *[[Surgery#TURBT|TURBT]], within 4 to 6 weeks
 ====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
@@ Line 744: / Line 888: @@
 '''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]]
@@ Line 755: / Line 900: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-|style="background-color:#1a9851"|Randomized Phase II (E)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#Cisplatin.2C_Fluorouracil.2C_RT|Cisplatin, Fluorouracil, RT]]
 |-
 |}
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
 *[[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, 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
@@ Line 772: / Line 920: @@
 '''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]]
@@ Line 777: / Line 926: @@
 ===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]
+#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:''' 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]
+##'''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]
-# '''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:''' 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]
-## '''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]
+#'''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:''' 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]
+##'''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}}==
@@ Line 792: / Line 942: @@
 ===Regimen {{#subobject:6a18dc|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Radiation_therapy_2|Radiation therapy]]
-|style="background-color:#91cf60"|Seems to have superior locoregional DFS
+| 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)
@@ Line 813: / Line 966: @@
 '''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]
+#'''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}}==
@@ Line 822: / Line 976: @@
 ===Regimen {{#subobject:6333a7|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|Comparator
+! 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)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]
 |-
@@ Line 833: / Line 987: @@
 ''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
@@ Line 845: / Line 1,004: @@
 ===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]
+#'''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}}==
@@ Line 854: / Line 1,014: @@
 ===Regimen {{#subobject:6222a7|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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.
@@ Line 871: / Line 1,034: @@
 '''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]]
@@ Line 876: / Line 1,040: @@
 ===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]
+#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}}==
@@ Line 886: / Line 1,051: @@
 ===Regimen {{#subobject:e0ed54|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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:#91cf61" |Non-randomized
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|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)
+| 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
+| 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.
@@ Line 910: / Line 1,078: @@
 ===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]
+#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, 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]
+##'''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]
-# '''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]
+##'''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=
@@ Line 924: / Line 1,093: @@
 ===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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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
+| 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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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)
@@ Line 966: / Line 1,147: @@
 ===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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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)
@@ Line 983: / Line 1,169: @@
 ===References===
-# '''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]
+#'''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]
-## '''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]
+#'''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:''' 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]
+##'''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]
-# 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]
+##'''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]
-## '''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]
+#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]
-## '''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]
+##'''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]
-# '''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]
+##'''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]
-## '''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]
+#'''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:''' 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]
+##'''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}}==
@@ Line 1,006: / Line 1,193: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-|style="background-color:#1a9851"|Randomized Phase II (E)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]
 |-
@@ Line 1,012: / Line 1,199: @@
 ''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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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)]]
@@ Line 1,053: / Line 1,253: @@
 ===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]
+#'''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:''' 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]
+##'''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]
-# '''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:''' 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]
-## '''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]
+#'''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:''' 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]
+##'''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}}==
@@ Line 1,072: / Line 1,273: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-|style="background-color:#1a9851"|Randomized Phase II (E)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, 5-FU, RT]]
 |-
@@ Line 1,078: / Line 1,279: @@
 ''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%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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]
+#'''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:''' 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]
+##'''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]
-# '''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:''' 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]
-## '''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]
+#'''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:''' 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]
+##'''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}}==
@@ Line 1,128: / Line 1,342: @@
 ===Regimen {{#subobject:de252a|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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.
@@ Line 1,146: / Line 1,365: @@
 '''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]
+#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=
@@ Line 1,156: / Line 1,376: @@
 ===Regimen {{#subobject:72a413|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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
@@ Line 1,172: / Line 1,395: @@
 ===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]
+#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:''' 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]
+##'''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}}==
@@ Line 1,183: / Line 1,407: @@
 ===Regimen {{#subobject:72a413|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+! 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)]
@@ Line 1,197: / Line 1,421: @@
 |}
 ====Preceding treatment====
 *[[Surgery#Cystectomy|Radical cystectomy]]
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]]
 *[[Methotrexate (MTX)]]
 ===References===
-# '''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]
+#'''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]
 ==MCV {{#subobject:8e6bb8|Regimen=1}}==
@@ Line 1,213: / Line 1,442: @@
 ===Regimen {{#subobject:ca6708|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! 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
+| 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.''
 ====Preceding treatment====
 *[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 ====Chemotherapy====
 *[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 *[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4
@@ Line 1,231: / Line 1,463: @@
 ===References===
-# 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]
+#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:''' 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]
+##'''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]
 ==Observation==
@@ Line 1,243: / Line 1,476: @@
 ===Regimen===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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 (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#PGC|PGC]]
-|style="background-color:#d73027"|Inferior OS
+| 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)
+| 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)
+| 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)
+| style="background-color:#1a9851" |Phase III (C)
 |MVAC
 | style="background-color:#ffffbf" |Seems not superior
@@ Line 1,271: / Line 1,504: @@
 ''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.''
 ====Preceding treatment====
 *[[Surgery#Cystectomy|Cystectomy]]
 ====Subsequent treatment====
 *EORTC 30994, upon relapse: [[#MVAC_2|MVAC]] x 6
 ===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'''
-# 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]
+#'''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'''
-# 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]
+#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]
-# '''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]
+#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]
+#'''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]
 ==PGC {{#subobject:22e1d2|Regimen=1}}==
@@ Line 1,289: / Line 1,527: @@
 ===Variant #1 {{#subobject:ad1bc8|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Observation|Observation]]
-|style="background-color:#1a9850"|Superior OS
+| 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.''
 ====Preceding treatment====
 *[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days
 ====Chemotherapy====
 *[[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
@@ Line 1,312: / Line 1,553: @@
 ===Variant #2 {{#subobject:29bee9|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
 |}
 ====Preceding treatment====
 *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
@@ Line 1,329: / Line 1,573: @@
 ===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]
+#'''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'''
-## '''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]
+#'''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:''' 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]
+##'''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=
@@ Line 1,342: / Line 1,587: @@
 ===Regimen {{#subobject:764948|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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:#91cf61" |Phase II (RT)
-| style="background-color:#88419d; color:white |ORR: 23% (95% CI 16-31)
+| 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====
 *[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
@@ Line 1,358: / Line 1,604: @@
 ===References===
-# '''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]
+#'''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]
 ==Carboplatin & Gemcitabine {{#subobject:8855e5|Regimen=1}}==
@@ Line 1,372: / Line 1,619: @@
 ===Regimen {{#subobject:5d481c|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#3d3d3d; color:white"|ORR: 24% (95% CI 12-42)
+| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)
 |-
 |}
 ====Chemotherapy====
 *[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
 *[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
@@ Line 1,389: / Line 1,637: @@
 ===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]
+#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}}==
@@ Line 1,414: / Line 1,663: @@
 |-
 |[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#MVAC_2|MVAC]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |46% (95% CI 32-62)
 |65% (95% CI 52-77)
@@ Line 1,422: / Line 1,671: @@
 |}
 ====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
@@ Line 1,427: / Line 1,677: @@
 ====Supportive medications====
 *Forced mannitol diuresis with [[Cisplatin (Platinol)]]
@@ Line 1,432: / Line 1,683: @@
 ===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]
+#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}}==
@@ Line 1,442: / Line 1,694: @@
 ===Regimen {{#subobject:71bd05|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| 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)
+| 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)
+| 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)
+| 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)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#MVAC_2|MVAC]]
-|style="background-color:#d73027"|Inferior OS
+| 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]
+#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]
-# 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]
+#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]
-# 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]
+#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]
-# 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]
+#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}}==
@@ Line 1,492: / Line 1,747: @@
 ===Variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| 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
+| 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"
@@ Line 1,515: / Line 1,772: @@
 ===Variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#MVAC_2|MVAC]]
-|style="background-color:#ffffbf"|Seems not superior
+| 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)
+| 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
+| 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)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#PGC_2|PCG]]
-|style="background-color:#fee08b"|Might have inferior OS
+| 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)
+| style="background-color:#1a9851" |Phase III (C)
 |Cisplatin & Larotaxel
-|style="background-color:#ffffbf"|Seems not superior
+| 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)]]
@@ Line 1,563: / Line 1,822: @@
 |-
 |[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]
-|style="background-color:#1a9851"|Randomized Phase II (C)
+| style="background-color:#1a9851" |Randomized Phase II (C)
 |[[#Carboplatin_.26_Gemcitabine|Carboplatin & Gemcitabine]]
-|style="background-color:#ffffbf"|Seems not superior
+| 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)
@@ Line 1,571: / Line 1,830: @@
 |}
 ====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
@@ Line 1,577: / Line 1,837: @@
 ===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. [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]
+#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]
-# 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]
+##'''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]
-# 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]
+#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]
-# '''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]
+#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]
-# '''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]
+#'''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}}==
@@ Line 1,591: / Line 1,852: @@
 ===Variant #1 {{#subobject:af7c37|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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:#91cf61" |Phase II
-|style="background-color:#5e5e5e; color:white"|ORR: 37%
+| style="background-color:#5e5e5e; color:white" |ORR: 37%
 |-
 |}
 ====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'''
@@ Line 1,608: / Line 1,870: @@
 ===Variant #2 {{#subobject:b840fe|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[http://jco.ascopubs.org/content/19/12/3018.long Meluch et al. 2001]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#8a8a8a"|ORR: 54% (95% CI 40-67)
+| style="background-color:#8a8a8a" |ORR: 54% (95% CI 40-67)
 |-
 |}
 ====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
@@ Line 1,624: / Line 1,887: @@
 ===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. [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://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]
+#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://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}}==
@@ Line 1,635: / Line 1,899: @@
 ===Variant #1, standard {{#subobject:33db41|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#CISCA|CISCA]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Cisplatin_monotherapy|Cisplatin]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (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 (*)
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |FAP
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
 ''Note: reported efficacy for EORTC 30924 is based on the 2005 update.''
 ====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
@@ Line 1,677: / Line 1,942: @@
 ===Variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 Bamias et al. 2003]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Cisplatin & Docetaxel
 | style="background-color:#91cf60" |Seems to have superior OS
@@ Line 1,689: / Line 1,954: @@
 |}
 ====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
@@ Line 1,695: / Line 1,961: @@
 ====Supportive medications====
 *[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26
@@ Line 1,700: / Line 1,967: @@
 ===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. [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]
-# 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]
+#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]
-# 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]
+#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:''' 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]
+#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]
-# '''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:''' 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:''' 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]
+#'''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]
-# 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]
+##'''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]
-# 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]
+#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]
+#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]
 ==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==
@@ Line 1,725: / Line 1,993: @@
 |-
 |[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#MVAC_2|MVAC]]
-|style="background-color:#91cf60"|Seems to have superior OS (*)
+| style="background-color:#91cf60" |Seems to have superior OS (*)
 |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)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |DD-GC
 | style="background-color:#ffffbf" |Seems not superior
@@ Line 1,741: / Line 2,009: @@
 ''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.''
 ====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
@@ Line 1,747: / Line 2,016: @@
 ====Supportive medications====
 *[[: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.''
@@ Line 1,753: / Line 2,023: @@
 ===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; 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; 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]
+#'''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]
-# '''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]
+##'''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. 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}}==
@@ Line 1,774: / Line 2,045: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]
-|style="background-color:#d9ef8b"|Might have superior OS
+| style="background-color:#d9ef8b" |Might have superior OS
 |56% (95% CI NR)
 |44% (95% CI NR)
@@ Line 1,782: / Line 2,053: @@
 |}
 ====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
@@ Line 1,789: / Line 2,061: @@
 ===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://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]
+#'''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]
 ==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
@@ Line 1,798: / Line 2,071: @@
 ===Regimen {{#subobject:946aec|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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)
+| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#88419d; color:white |ORR: 24% (95% CI 20-29)
+| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)
 |-
 |}
 <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>
 ====Immunotherapy====
 *[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
@@ Line 1,817: / Line 2,091: @@
 # '''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]
 # '''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] -->
-# '''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]
+#'''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]
 =Maintenance after first-line therapy=
@@ Line 1,827: / Line 2,102: @@
 ===Regimen===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)]
@@ Line 1,840: / Line 2,115: @@
 ''No active antineoplastic treatment.''
 ===References===
-# '''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]
+#'''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]
 =Locally advanced or metastatic disease, subsequent lines=
@@ Line 1,850: / Line 2,126: @@
 ===Regimen {{#subobject:feb2e2|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nature.com/articles/nature13904 Powles et al. 2014]
@@ Line 1,861: / Line 2,137: @@
 |-
 |[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:#91cf61" |Phase II (RT)
 | style="background-color:#d3d3d3" |
-|style="background-color:#88419d; color:white"|ORR: 15% (95% CI 11-20)
+| 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)]
@@ Line 1,873: / Line 2,149: @@
 ''Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.''
 ====Immunotherapy====
 *[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
@@ Line 1,878: / Line 2,155: @@
 ===References===
-# '''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]
-# '''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]
+#'''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]
-# '''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]
+#'''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}}==
@@ Line 1,893: / Line 2,171: @@
 ===Regimen===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Vinflunine_monotherapy|Vinflunine]]
 | style="background-color:#d73027" |Inferior OS (*)
@@ Line 1,906: / Line 2,184: @@
 ''No active antineoplastic treatment. Reported efficacy is based on the 2013 update.''
 ===References===
-# 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:''' 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]
+#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:''' 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}}==
@@ Line 1,927: / Line 2,206: @@
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-| style="background-color:#88419d; color:white |13% (95% CI 4-31)
+| 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]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Docetaxel & Vandetanib
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
-|style="background-color:#6e016b; color:white|11% (95% CI NR)
+| style="background-color:#6e016b; color:white" |11% (95% CI NR)
-|style="background-color:#6e016b; color:white|7% (95% CI NR)
+| 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://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016]
-|rowspan = 2 style="background-color:#1a9851"|Randomized Phase II (C)
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
 |1. Docetaxel & Icrucumab
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |
 |
 |-
 |2. [[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
-|style="background-color:#d73027"|Inferior PFS
+| style="background-color:#d73027" |Inferior PFS
 |
 |
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |
 |
 |-
 |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
-|style="background-color:#fc8d59"|Seems to have inferior PFS
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |
 |
@@ Line 1,966: / Line 2,245: @@
 | style="background-color:#1a9851" |Phase III (C)
 |[[#Atezolizumab_monotherapy_2|Atezolizumab]]
-|style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#ffffbf" |Seems not superior
 |
 |
@@ Line 1,973: / Line 2,252: @@
 ''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
 ====Chemotherapy====
 *[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
@@ Line 1,978: / Line 2,258: @@
 ===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://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9164195 PubMed]
-# 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]
+#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]
-# 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]
+#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]
+#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]
 <!-- # 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] -->
-# '''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]
+#'''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 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 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]
-# '''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://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]
-# '''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]
+#'''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]
 ==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==
@@ Line 1,994: / Line 2,275: @@
 ===Regimen {{#subobject:b840fe|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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]
-|style="background-color:#1a9851"|Randomized Phase II (E)
+| style="background-color:#1a9851" |Randomized Phase II (E)
 |[[#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)]
-|style="background-color:#1a9851"|Phase III (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Docetaxel_monotherapy|Docetaxel]]
-|style="background-color:#91cf60"|Seems to have superior PFS
+| style="background-color:#91cf60" |Seems to have superior PFS
 |-
 |}
 ====Chemotherapy====
 *[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 *[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1
@@ Line 2,017: / Line 2,299: @@
 ===References===
-# 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]
-# '''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]
+#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]
+#'''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]
 ==Durvalumab monotherapy {{#subobject:7ae7fb|Regimen=1}}==
@@ Line 2,035: / Line 2,318: @@
 |}
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]
@@ Line 2,043: / Line 2,326: @@
 |}
 ====Chemotherapy====
 *[[Erdafitinib (Balversa)]] 8 mg PO once per day
 **If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day
 **Additional dose adjustments per package insert
@@ Line 2,051: / Line 2,335: @@
 <!-- # '''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'''
 # '''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]
+#'''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}}==
@@ Line 2,061: / Line 2,346: @@
 ===Variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[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)]
@@ Line 2,073: / Line 2,358: @@
 |}
 ====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
@@ Line 2,080: / Line 2,366: @@
 ===Variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[http://jco.ascopubs.org/content/19/12/3018.long Meluch et al. 2001]
-|style="background-color:#ffffbe"|Phase II, <20 pts in this subgroup
+| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup
-|style="background-color:#8c96c6"|ORR: 47%
+| style="background-color:#8c96c6" |ORR: 47%
 |-
 |}
 ====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
@@ Line 2,096: / Line 2,383: @@
 ===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. [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://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]
+#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://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}}==
@@ Line 2,108: / Line 2,396: @@
 ===Regimen {{#subobject:af2e64|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ Han et al. 2008]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#8c6bb1"|ORR: 30%
+| style="background-color:#8c6bb1" |ORR: 30%
 |-
 |}
 ====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
@@ Line 2,126: / Line 2,415: @@
 ===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://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]
+#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}}==
@@ Line 2,139: / Line 2,429: @@
 ===Regimen, q3wks {{#subobject:9fddc0|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
@@ Line 2,157: / Line 2,447: @@
 ''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
@@ Line 2,163: / Line 2,454: @@
 ===Variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[http://jco.ascopubs.org/content/20/4/937.long Vaughn et al. 2002]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#6e016b; color:white|ORR: 10% (95% CI 0-20)
+| style="background-color:#6e016b; color:white" |ORR: 10% (95% CI 0-20)
 |-
 |}
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
@@ Line 2,178: / Line 2,470: @@
 ===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. [http://jco.ascopubs.org/content/20/4/937.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11844814 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27284445 PubMed]
+#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]
+#'''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]
 <!-- # 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] -->
-# '''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]
+#'''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 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 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]
+#'''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}}==
@@ Line 2,192: / Line 2,485: @@
 ===Regimen {{#subobject:7dc525|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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:#91cf61" |Phase II
-|style="background-color:#8c6bb1"|ORR: 28% (95% CI 17-44)
+| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)
 |-
 |}
 ====Chemotherapy====
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
 ====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."
+*"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===
-# 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]
+#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]
 ==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==
@@ Line 2,219: / Line 2,515: @@
 ===Regimen {{#subobject:8aec07|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
-|style="background-color:#1a9851"|Phase III (E-RT)
+| style="background-color:#1a9851" |Phase III (E-RT)
 |Investigator's choice of:<br> [[#Docetaxel_monotherapy|Docetaxel]]<br> [[#Paclitaxel_monotherapy|Paclitaxel]]<br> [[#Vinflunine_monotherapy|Vinflunine]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |}
 ====Immunotherapy====
 *[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
@@ Line 2,236: / Line 2,533: @@
 ===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://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 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]
+#'''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 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]
 ==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==
@@ Line 2,246: / Line 2,544: @@
 ===Regimen {{#subobject:7dc525|Variant=1}}===
 {| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 33%" |Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[http://jco.ascopubs.org/content/24/21/3451.long Sweeney et al. 2006]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
-|style="background-color:#8c6bb1"|ORR: 28% (95% CI 16-43)
+| style="background-color:#8c6bb1" |ORR: 28% (95% CI 16-43)
 |-
 |}
 ====Chemotherapy====
 *[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1
@@ Line 2,261: / Line 2,560: @@
 ===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. [http://jco.ascopubs.org/content/24/21/3451.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16849761 PubMed]
+#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]
 ==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==
@@ Line 2,270: / Line 2,570: @@
 ===Regimen {{#subobject:b5b9b9|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! 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 (E)
+| style="background-color:#1a9851" |Phase III (E)
 |[[#Best_supportive_care|Best supportive care]]
 | style="background-color:#1a9850" |Superior OS (*)
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
@@ Line 2,293: / Line 2,593: @@
 ''Note: reported efficacy for Bellmunt et al. 2009 is based on the 2013 update.''
 ====Chemotherapy====
 *[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
 ===References===
-# 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:''' 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]
+#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]
-# '''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:''' 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]
-## '''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]
+#'''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]
-# '''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:''' 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>
@@ Line 2,313: / Line 2,617: @@
 =References=
-<references/>
+<references />
 [[Category:Bladder cancer regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Genitourinary cancers]]

Difference between revisions of "Urothelial carcinoma"

Revision as of 08:06, 13 November 2019

Guidelines

AUA, ASCO, ASTRO, SUO

ESMO

NCCN

Intravesical chemotherapy

Bacillus Calmette-Guérin (BCG) monotherapy

Doxorubicin monotherapy

Regimen

Chemotherapy

References

Gemcitabine monotherapy

Variant #1, 1 treatment

Preceding treatment

Chemotherapy

Variant #2, 6 treatments

Chemotherapy

References

Mitomycin monotherapy

Variant #1, 30 mg x 12

Preceding treatment

Chemotherapy

Variant #2, 40 mg x 11

Preceding treatment

Chemotherapy

References

Observation

Regimen

Preceding treatment

References

Pirarubicin monotherapy

Regimen

Preceding treatment

Chemotherapy

References

Thiotepa monotherapy

Regimen

Chemotherapy

References

Valrubicin monotherapy

Regimen

Chemotherapy

References

Neoadjuvant chemotherapy

Cisplatin & Gemcitabine

MCV

Variant #1, 2 cycles

Chemotherapy

Subsequent treatment

Variant #2, 3 cycles

Chemotherapy

Supportive medications

Subsequent treatment

References

MVAC

Variant #1, 2 cycles

Chemotherapy

Subsequent treatment

Variant #2, 3 cycles

Chemotherapy

Subsequent treatment

References

MVAC, dose-dense

Variant #1, 3 cycles

Chemotherapy

Supportive medications

Subsequent treatment

Variant #2, 4 cycles

Chemotherapy

Supportive medications

Subsequent treatment

References

Immune checkpoint inhibitors

Variant #1, Pembrolizumab

Chemotherapy

Subsequent treatment

Variant #2, Atezolizumab

Chemotherapy

Subsequent treatment

Variant #1, cisplatin 40 mg/m² qwk x 3

Variant #2, cisplatin 70 mg/m² q3wk x 2

Variant #3, cisplatin 100 mg/m² q3wk x 2