Bladder cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main bladder cancer page for regimens that include active anticancer treatment.
=Nonmuscle invasive bladder cancer/Intravesical chemotherapy=
==Observation==
===Regimen===
Study 	Dates 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 shorter 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 EuroPMC UMIN000004039
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Messing et al. 2018 (SWOG S0337)	2008-2012 	Phase 3 (C)	Gemcitabine	Shorter time to recurrence (primary endpoint)Recurrence at 48 mo: 47% vs 35%(HR 1.52, 95% CI 1.11-2.08)
====Preceding treatment====
*TURBT, up to 3 hours prior
===References===
#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 link to PMC article EuroPMC NCT00445601
=Neoadjuvant chemotherapy=
==No neoadjuvant therapy==
===Regimen===
Study 	Dates 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 shorter OS
Griffiths et al. 1999 (BA06 30894)	1989-1995 	Phase 3 (C)	CMV 	Seems to have shorter OS1Median OS: 37 vs 44 mo(HR 1.19, 95% CI 1.01-1.39)
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 shorter OSMedian OS: 82 vs 102 mo(HR 1.54, 99.99% CI 0.46-5.26)
1Reported efficacy for BA06 30894 is based on the 2011 update.
No preoperative treatment.
====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 EuroPMC
#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 EuroPMC
##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. Epub 2009 Jul 27. link to original article link to PMC article EuroPMC
##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 link to PMC article EuroPMC
#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 EuroPMC ISRCTN82694463
##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 link to PMC article EuroPMC
#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 EuroPMC
#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. Epub 2014 Mar 24. link to original article EuroPMC UMIN C000000093
#KEYNOTE-905: NCT03924895
=Adjuvant chemotherapy=
==Observation==
===Regimen===
Study 	Dates 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 	Shorter 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
Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl more 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
====Subsequent treatment====
*EORTC 30994, upon relapse: First-line 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
#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 EuroPMC NCT00005047
#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 EuroPMC NCT00054626
#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 EuroPMC NCT00028756
==Placebo==
===Regimen===
Study 	Dates 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 time to response
No active antineoplastic therapy.
====Preceding treatment====
*TURBT
===References===
#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 EuroPMC NCT00004154
=Maintenance after first-line therapy=
==Placebo==
===Regimen===
Study 	Dates 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 time to response
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 EuroPMC NCT00949455
#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 EuroPMC ISRCTN84681538
Category:Bladder cancer regimens
Category:Disease-specific pages
Category:Urothelial carcinomas
Category:Null regimens