Urothelial carcinoma - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main urothelial carcinoma page for current regimens.

9 regimens on this page
10 variants on this page


Neoadjuvant chemotherapy

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Powles et al. 2019 (ABACUS) 2016-2018 Phase 2

Immunotherapy

21-day cycle for 2 cycles

Subsequent treatment

References

  1. ABACUS: 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;25(11):1706-1714. Epub 2019 Nov 4. link to original article PubMed NCT02662309

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

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Balar et al. 2016 (IMvigor210 untreated) 2014-2015 Phase 2 (RT) ORR: 23% (95% CI 16-31)

Immunotherapy

21-day cycles

References

  1. IMvigor210 untreated: 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 dosing details in abstract link to PMC article PubMed NCT02951767

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

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (E-switch-ooc) 1a. GCb
1b. GC 		Did not meet co-primary endpoint of OS
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Not reported

Immunotherapy

21-day cycles

References

  1. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
    1. Update: Bamias A, Davis ID, Galsky MD, Arranz JÁ, Kikuchi E, Grande E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, Panni S, Gumus M, Özgüroğlu M, Mariathasan S, Poloz Y, Bene-Tchaleu F, Lee C, Bernhard S, De Santis M. Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):46-61. Epub 2023 Dec 12. link to original article PubMed

Carboplatin & Gemcitabine (GCb) & Atezolizumab

GCb & Atezolizumab: Gemcitabine, Carboplatin, Atezolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (E-RT-esc) 1. Atezolizumab Not reported
2a. GCb
2b. GC 		Might have superior OS1 (co-primary endpoint)
Median OS: 16.1 vs 13.4 mo
(HR 0.85, 95% CI 0.73-1.00)

Seems to have superior PFS (co-primary endpoint)
Median PFS: 8.2 vs 6.3 mo
(sHR 0.82, 95% CI 0.70-0.96)

1Reported efficacy is based on the 2023 update; the p-value did not meet the predefined definition of statistical significance.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
    1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed

CISCA

CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sternberg et al. 1977 1976-1977 Non-randomized, fewer than 20 pts
Logothetis et al. 1990 1985-1989 Phase 3 (E-switch-ic) MVAC Inferior OS

Note: ORR for this arm of Logothetis et al. 1990 was 46% (95% CI 32-62) versus 65% (95% CI 52-77) in the control arm.

Chemotherapy

Supportive therapy

  • Forced mannitol diuresis with cisplatin

21-day cycle for up to 6 cycles

References

  1. 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
  2. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains dosing details in manuscript PubMed

Cisplatin monotherapy

Regimen variant #1, 70 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soloway et al. 1983 1978-NR Randomized (C) Cisplatin & Cyclophosphamide Did not meet primary endpoint of ORR
Khandekar et al. 1985 1978-1981 Randomized (C) CAD Might have inferior ORR
Troner et al. 1987 NR Phase 3 (C) CAD Did not meet endpoint of ORR
Loehrer et al. 1992 (ECOG E5886) 1984-1989 Phase 3 (C) MVAC Inferior OS

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

Chemotherapy

28-day cycle for up to 6 cycles


Regimen variant #2, 80 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hillcoat et al. 1989 1982-1986 Phase 3 (C) Cisplatin & Methotrexate Did not meet efficacy endpoints

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

Chemotherapy

28-day cycles

References

  1. Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J; National Bladder Cancer Collaborative Group A. 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
  2. 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
  3. Troner M, Birch R, Omura GA, Williams S; Southeastern Cancer Study Group. 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 original article PubMed
  4. 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 contains dosing details in abstract PubMed
  5. ECOG E5886: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. link to original article contains dosing details in manuscript PubMed
    1. Update: Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. link to original article PubMed

Cisplatin & Gemcitabine (GC) & Atezolizumab

GC & Atezolizumab: Gemcitabine, Cisplatin, Atezolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (E-RT-esc) 1. Atezolizumab Not reported
2a. GCb
2b. GC 		Might have superior OS1 (co-primary endpoint)
Median OS: 16.1 vs 13.4 mo
(HR 0.85, 95% CI 0.73-1.00)

Seems to have superior PFS (co-primary endpoint)
Median PFS: 8.2 vs 6.3 mo
(sHR 0.82, 95% CI 0.70-0.96)

1Reported efficacy is based on the 2023 update; the p-value did not meet the predefined definition of statistical significance.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
    1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed

Durvalumab & Tremelimumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (E-switch-ooc) 1a. GCb
1b. GC 		Might have superior OS (co-primary endpoint)
Median OS: 15.1 vs 12.1 mo
(HR 0.85, 95% CI 0.72-1.02)
2. Durvalumab Not reported

Immunotherapy

28-day cycles

References

  1. DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article contains dosing details in abstract PubMed NCT02516241

Metastatic disease, platinum-refractory

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2014 (PCD4989g) 2013-2014 Phase 1
Rosenberg et al. 2016 (IMvigor210 previously treated) 2014 Phase 2 (RT) ORR: 15% (95% CI 11-20)
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (E-switch-ooc) 1a. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Did not meet primary endpoint of OS

Note: this regimen did not meet its primary endpoint in phase 3; here for historical reference only.

Biomarker eligibility criteria

Patients are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering at least 5% of the tumor area), as determined by an FDA-approved test Patients are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status

Immunotherapy

21-day cycles

References

  1. PCD4989g: 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 NCT01375842
  2. IMvigor210 previously treated: 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 dosing details in abstract PubMed NCT02108652
  3. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807

Durvalumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Massard et al. 2016 (Study 1108) 2014-2015 Phase 1/2 (RT) ORR: 31% (95% CI 18 to 47)

Note: this regimen was intended for patients "who had progressed on, been ineligible for, or refused any number of prior therapies".

Immunotherapy

14-day cycle for up to 26 cycles (1 year). Patients could receive another 12 months of treatment if they experienced disease progression, had not received other anticancer treatment, and did not meet criteria for discontinuation.

References

  1. Study 1108: Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, O'Donnell PH, Drakaki A, Tan W, Kurland JF, Rebelatto MC, Jin X, Blake-Haskins JA, Gupta A, Segal NH. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016 Sep 10;34(26):3119-25. Epub 2016 Jun 6. link to original article contains dosing details in abstract link to PMC article PubMed NCT01693562
    1. Update: Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017 Sep 14;3(9):e172411. Epub 2017 Sep 14. link to original article link to PMC article PubMed
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