Bladder cancer - null regimens

The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main bladder cancer page for current regimens.

Nonmuscle invasive bladder cancer/Intravesical chemotherapy

Observation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial)	2005-2008	Randomized Phase 2 (C)	Pirarubicin	Seems to have inferior RFS

No active antineoplastic treatment after surgery.

Preceding treatment

• Nephroureterectomy

References

1. 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

Neoadjuvant chemotherapy

No neoadjuvant therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martinez-Piñeiro et al. 1995	1984-1989	Phase 3 (C)	Cisplatin	Did not meet primary endpoint of OS
Grossman et al. 2003 (SWOG S8710)	1987-1998	Phase 3 (C)	MVAC	Might have inferior OS
Griffiths et al. 1999 (BA06 30894)	1989-1995	Phase 3 (C)	CMV	Seems to have inferior OS1
Shipley et al. 1998 (RTOG 89-03)	1990-1993	Phase 3 (C)	MCV	Did not meet primary endpoint of OS
Kitamura et al. 2014 (JCOG0209)	2003-2009	Phase 3 (C)	MVAC	Might have inferior OS

¹Reported efficacy for BA06 30894 is based on the 2011 update.
No preoperative treatment; used as a comparator arm and here for reference purposes only.

Subsequent treatment

• Surgery

References

1. 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
2. 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
3. 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 ISRCTN82694463
   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); EORTC 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
4. 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
5. 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 UMIN C000000093
6. KEYNOTE-905: NCT03924895

Adjuvant chemotherapy

Observation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stadler et al. 2011 (SWOG-4B951)	1997-2006	Phase 3 (C)	MVAC	Did not meet primary endpoint of RFS
Paz-Ares et al 2010 (SOGUG 99/01)	2000-2007	Phase 3 (C)	PGC	Inferior OS
Cognetti et al. 2011 (ITNRC CU02)	2001-2007	Phase 3 (C)	GC	Did not meet primary endpoint of OS
Sternberg et al. 2014 (EORTC 30994)	2002-2008	Phase 3 (C)	MVAC	Did not meet primary endpoint of OS
Bellmunt et al. 2021 (IMvigor010)	2015-2018	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of DFS Median DFS: 16.6 vs 19.4 mo (HR 1.12, 95% CI 0.93-1.35)

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.

Biomarker eligibility criteria

• SWOG-4B951: positive p53 staining

Preceding treatment

• Cystectomy
• IMvigor010: Radical cystectomy or nephroureterectomy with lymph node dissection

Subsequent treatment

• EORTC 30994, upon relapse: MVAC x 6

References

1. 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
2. SWOG-4B951: 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 NCT00005047
3. ITNRC CU02: Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, Massidda B, Rubagotti A, Giannarelli D, Boccardo F; Italian National Research Council. 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 NCT00054626
4. 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; EORTC 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 NCT00028756
5. IMvigor010: Bellmunt J, Hussain M, Gschwend JE, Albers P, Oudard S, Castellano D, Daneshmand S, Nishiyama H, Majchrowicz M, Degaonkar V, Shi Y, Mariathasan S, Grivas P, Drakaki A, O'Donnell PH, Rosenberg JE, Geynisman DM, Petrylak DP, Hoffman-Censits J, Bedke J, Kalebasty AR, Zakharia Y, van der Heijden MS, Sternberg CN, Davarpanah NN, Powles T; IMvigor010 Study Group. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):525-537. Epub 2021 Mar 12. link to original article PubMed NCT02450331

Placebo

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sabichi et al. 2008 (MDA-ID-95236)	1998-2003	Phase 3 (C)	Fenretinide	Did not meet primary endpoint of TTR
Bajorin et al. 2021 (CheckMate 274)	2016-2020	Phase 3 (C)	Nivolumab	Inferior DFS

No active antineoplastic therapy.

Preceding treatment

• MDA-ID-95236: TURBT
• CheckMate 274: Radical surgery

References

1. MDA-ID-95236: Sabichi AL, Lerner SP, Atkinson EN, Grossman HB, Caraway NP, Dinney CP, Penson DF, Matin S, Kamat A, Pisters LL, Lin DW, Katz RL, Brenner DE, Hemstreet GP 3rd, Wargo M, Bleyer A, Sanders WH, Clifford JL, Parnes HL, Lippman SM. Phase III prevention trial of fenretinide in patients with resected non-muscle-invasive bladder cancer. Clin Cancer Res. 2008 Jan 1;14(1):224-9. link to original article PubMed NCT00004154
2. CheckMate 274: Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. link to original article link to PMC article PubMed NCT02632409

Maintenance after first-line therapy

Best supportive care

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Powles et al. 2020 (JAVELIN Bladder 100)	2016-2019	Phase 3 (C)	Avelumab	Inferior OS	Less toxic

No further active antineoplastic treatment.

Preceding treatment

• Cisplatin & Gemcitabine x 4 to 6 or Carboplatin & Gemcitabine x 4 to 6 cycles

References

1. JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article PubMed NCT02603432

Placebo

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 2016 (LaMB)	2007-2013	Phase 3 (C)	Lapatinib	Did not meet primary endpoint of PFS
Kelly et al. 2019 (BOXIT)	2007-2012	Phase 3 (C)	Celecoxib	Did not meet primary endpoint of TTR

No active antineoplastic treatment.

References

1. 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 NCT00949455
2. BOXIT: Kelly JD, Tan WS, Porta N, Mostafid H, Huddart R, Protheroe A, Bogle R, Blazeby J, Palmer A, Cresswell J, Johnson M, Brough R, Madaan S, Andrews S, Cruickshank C, Burnett S, Maynard L, Hall E; BOXIT Investigators. BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004). Eur Urol. 2019 Apr;75(4):593-601. Epub 2018 Sep 29. link to original article PubMed ISRCTN84681538

Locally advanced or metastatic disease, subsequent lines

Best supportive care

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2009 (CA183004)	2003-2006	Phase 3 (C)	Vinflunine	Inferior OS1

¹Reported efficacy is based on the 2013 update.
No active antineoplastic treatment.

References

1. CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article contains 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