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|WebCafé report by Wendy Sheridan|
index of the presentations
Session 1: Diagnosis of bladder cancer
MRI of urinary bladder cancer
Tumor Markers in Bladder Cancer: Where are we?
Analyzing p53 status and other markers to determine management strategies
Flourescence in Situ Hybridization as a tool for early detection of bladder cancer P.F. Bassi, MD, Clinica Urologica, Universita di Padova, Italy
Session 2: How to Treat Low-Risk Tumors
Chemoresection for superficial bladder cancer
A meta-analysis of randomized trials investigating transurethral resection plus one immediate instillation of chemotherapy
Observation of TaGI bladder tumors: Acceptable?
Results from Finn bladder group in low risk Tumors,
Chemotherapy for intermediate risk and BCG for high risk
Which patients treated with BCG do better: Those with or without side-effects? A.P.M. van der Meijden, MD, PhD Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands
New Agents in the Treatment of superficial bladder cancer M.A. O’Donnell, MD, University of Iowa Health Care, Iowa, United States
Session 4: Advanced Bladder Cancer
What to do when radical cystectomy is not radical
Current treatment approaches in advanced bladder cancer
Adjuvant chemotherapy in muscle invasive bladder cancer: Current concepts D.F. Bajorin,MD, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
Overview of novel agents
Future management of advanced bladder cancer
Chemotherapy for intermediate risk and BCG for high risk E.Solsona, MD, Valencia Institute of Oncology, Spain
In a review of six randomized series looking at intermediate risk patients, only one BCG trial showed superiority over chemo in decreasing recurrence, with the remaining series showing no significant difference between the two treatments;
The data suggest that the objectives of each group should differ. In the intermediate group the first priority is to reduce the high recurrence rate and secondly to decrease progression rate, while the high risk group’s main objective should be to decrease progression.
There is compelling evidence that early instillation of chemotherapy after TUR reduces recurrence rate in intermediate risk groups compared with late instillation (after 24 hrs). There is not enough evidence to claim that BCG is superior to MMC in the intermediate risk group, but toxicity is clearly higher in the BCG group.
BCG induction therapy and/or BCG + maintenance has never been compared to TUR + immediate instillation of chemotherapy. A better definition of intermediate risk is needed along with specific trials comparing the two approaches.
For those with high risk bladder tumors, BCG + maintenance (as in the SWOG protocol) is the treatment of choice, although the exact number of induction courses, maintenance schedules and BCG’s association with intravesical chemo is still unclear.
BCG is considered the conservative treatment of choice for those in the high risk category; in the absence of randomized trials comparing it to cystectomy, a literature review reveals only one out of seven series showing that immediate cystectomy gives a significant survival benefit when compared to delayed cystectomy after treatment failure. The cause-specific survival of these series showed no difference between both approaches:
Controversy remains over the best time to resort to salvage cystectomy in case of BCG failure. In cases on non-response of high risk tumors to BCG, the progression rate is high, with mortality at five years ranging from 40-66%. Clinical non-response to BCG at 3 months was a good predictive factor for progression.
High risk patients who do not respond to BCG at 3 months should be offered cystectomy.
The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. Tolley DA, Parmar MK, Grigor KM, Lallemand G, Benyon LL, Fellows J, Freedman LS, Grigor KM, Hall RR, Hargreave TB, Munson K, Newling DW, Richards B, Robinson MR, Rose MB, Smith PH, Williams JL, Whelan P. Medical Research Council Cancer Trials Office, Cambridge, United Kingdom. J Urol. 1996 Apr;155(4):1233-8. PMID: 8632538
The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer. Solsona E, Iborra I, Dumont R, Rubio-Briones J, Casanova J, Almenar S. Departments of Urology and Pathology, Instituto Valenciano de Oncologia, Valencia, Spain. J Urol. 2000 Sep;164(3 Pt 1):690-1. PMID:10953125
OBJECTIVES: Previous publications have suggested that patients developing local and/or systemic side effects to Bacillus Calmette-Guerin (BCG) have a better clinical result, however it is necessary to determine if toxicity is responsible for improved efficacy.
The side effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do not predict its efficacy: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Sylvester RJ, van der Meijden AP, Oosterlinck W, Hoeltl W, Bono AV; EORTC Genito-Urinary Tract Cancer Group.European Organisation for Research and Treatment of Cancer Data Center, 83 avenue E Mounier, Bte 11, 1200, Brussels, Belgium. Eur Urol. 2003 Oct;44(4):423-8. PMID:14499675
New intravesical treatments and modifications of older protocols have recently emerged which deserve to be considered in the adjuvant treatment of superficial bladder cancer.
Optimization of Mitomycin C
Using these techniques, the improvement of clinical response at 4 years went from 23% to 42%
Advances in depth of penetration of Mitomycin C
Intravesical Gemcitabine-now entering phase II trials 7,8
Optimization of BCG therapy
Whether this is the optimal schedule is still uncertain; two large meta-analyses have shown that a minimum of one year of BCG maintenance provides both significant protection from progression and superiority over intravesical chemotherapy.10,11 Also, reduced dose BCG regimens are emerging which show efficacy with the added benefit of reduced toxicity. 12
Other active agents in BCG failures are mycobacterial DNA cell wall extracts, in trials now for CIS. 14
The potential for combining chemotherapy and immunotherapy seems attractive based on trails using sequential treatments.17,18 It may prove worthwhile to use one dose of chemo after TUR, followed by optimized BCG treatments 2-3 weeks later.
2.Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study.Di Stasi SM, Giannantoni A, Stephen RL, Capelli G, Navarra P, Massoud R, Vespasiani G.Departments of Urology and Clinical Biochemistry, Tor Vergata University, Via Torrice n. 4, 00189 Rome, Italy. J Urol. 2003 Sep;170(3):777-82. PMID: 12913696
3. Combination of intravesical chemotherapy and hyperthermia for the treatment of superficial bladder cancer: preliminary clinical experience. Colombo R, Salonia A, Da Pozzo LF, Naspro R, Freschi M, Paroni R, Pavone-Macaluso M, Rigatti P.Department of Urology, Vita-Salute University, Ospedale San Raffaele, Via Olgettina, 60, Milan 20132, Italy. Crit Rev Oncol Hematol. 2003 Aug;47(2):127-39. PMID: 12900006
4.The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. Tolley DA, Parmar MK, Grigor KM, Lallemand G, Benyon LL, Fellows J, Freedman LS, Grigor KM, Hall RR, Hargreave TB, Munson K, Newling DW, Richards B, Robinson MR, Rose MB, Smith PH, Williams JL, Whelan P. Medical Research Council Cancer Trials Office, Cambridge, United Kingdom. J Urol. 1996 Apr;155(4):1233-8. PMID: 8632538
5. Expression of DT-diaphorase and cytochrome P450 reductase correlates with mitomycin C activity in human bladder tumors.Gan Y, Mo Y, Kalns JE, Lu J, Danenberg K, Danenberg P, Wientjes MG, Au JL.College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA. Clin Cancer Res. 2001 May;7(5):1313-9. PMID:11350900
7.Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study. Laufer M, Ramalingam S, Schoenberg MP, Haisfield-Wolf ME, Zuhowski EG, Trueheart IN, Eisenberger MA, Nativ O, Egorin MJ. Department of Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA. J Clin Oncol. 2003 Feb 15;21(4):697-703. PMID: 12586808
8. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. Dalbagni G, Russo P, Sheinfeld J, Mazumdar M, Tong W, Rabbani F, Donat MS, Herr HW, Sogani P, dePalma D, Bajorin D.Department of Urology, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Comment in: J Clin Oncol. 2002 Aug 1;20(15):3185-6. PMID:12149290
10. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. Sylvester RJ, van der MEIJDEN AP, Lamm DL. European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium. J Urol. 2002 Nov;168(5):1964-70. PMID:12394686
11.ntravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. Bohle A, Jocham D, Bock PR. Department of Urology, Medical University of Lubeck, Lubeck, Germany. J Urol. 2003 Jan;169(1):90-5. PMID: 12478111
12.Improving the efficacy of BCG immunotherapy by dose reduction. Pagano F, Bassi P, Piazza N, Abatangelo G, Drago Ferrante GL, Milani C.Istituto di Urologia, Universita degli Studi, Monoblocco Ospedaliero, Padova, Italia. Eur Urol. 1995;27 Suppl 1:19-22. Review. PMID: 7750527
13. Modified induction course: a solution to side-effects? Bassi P, Spinadin R, Carando R, Balta G, Pagano F.Department of Urology, University of Padova, Padova, Italy.Eur Urol. 2000;37 Suppl 1:31-2. PMID:10575270
14. Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder. Morales A, Chin JL, Ramsey EW. Department of Urology, Queen's University, Kingston, Canada. J Urol. 2001 Nov;166(5):1633-7; discussion 1637-8. PMID:11586191
17.Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study. Kaasinen E, Wijkstrom H, Malmstrom PU, Hellsten S, Duchek M, Mestad O, Rintala E; Nordic Urothelial Cancer Group. Department of Surgery, Hyvinkaa Hospital, Sairaalakatu 1, FIN-05850 Hyvinkaa, Finland Eur Urol. 2003 Jun;43(6):637-45. PMID: 12767365
18.The effects of intravesical chemoimmunotherapy with epirubicin and bacillus Calmette-Guerin for prophylaxis of recurrence of superficial bladder cancer: a preliminary report. Uekado Y, Hirano A, Shinka T, Ohkawa T. Department of Urology, Wakayama Medical College 27, Japan. Cancer Chemother Pharmacol. 1994;35 Suppl:S65-8. PMID: 7994790
The year 2003 saw approximately 57,400 new cases of bladder cancer in the U.S. Cystectomy remains the gold standard for those with muscle invasive bladder cancer, but the 5 year survival rates are low when lymph nodes or perivesical fat have been invaded, ranging from 5-30%. Lymph nodes are involved in 13% of T1 tumors, 20% of T2, 24% of T3a, 42% T3b and 45% of T4 tumors.
The integration of either neoadjuvant or adjuvant chemotherapy with cystectomy has not yet been clearly defined. Of 8 randomized trials comparing chemo+cystectomy to cystectomy alone, 6 trials showed no statistical benefit, while two trials showed a survival benefit. A randomized trial comparing cystectomy alone to cystectomy+M-VAC demonstrated an improved survival for the chemotherapy arm, especially for those who had a complete response (stage P0).2 A recent European trial achieved a 6% survival advantage using CMV (cisplatin, methotrexate and vinblastine).3
The role of adjuvant therapy is less clear. Past trials have not provided sufficient statistical power or efficiently designed drug protocols. Currently, an EORTC/SWOG trial is comparing adjuvant M-VAC or gemcitabine to treatment at time of progression.
Bladder sparing approaches are designed to integrate chemotherapy and radiation therapy with TUR. The 'combined modality' approach may be appropriate for the elderly and/or those with serious co-morbidities who may not be able to withstand radical surgery [or those who refuse cystectomy].
Sternberg's team in Rome evaluated pre-operative M-VAC in 104 patients with T2-T4 disease; of the 94 people who were restaged, 49% achieved P0 status [complete response of tumor], 51% of those who had a complete response are still alive with an intact bladder. 4,5
The Southwest Oncology Group studied the efficacy of 5FU and cisplatin+radiotherapy for those with muscle invasive bladder cancer; unfortunately the 5 year survival rate was only 32%.7
The EGF [epidermal growth factor] receptor is present in up to 70% of invasive bladder cancers, while the Her-2 gene is over expressed in up to 25% of primary tumors and 50% of metastatic tumors. At the present there are no molecular markers (or standard way to test them) or imaging techniques sensitive enough to predict which patients are appropriate for bladder preservation. SWOG is currently evaluating biomarkers [p53, RB, MDR, EGF, Her-2] and imaging techniques such as PET scanning to predict who will obtain a complete response to neoadjvant carboplatin, gemcitabine and Taxol.
Those with T2 tumors were the best responders to the combined modality approaches, with a 5 year survival of 45-63%. A superficial relapse occurred in 26-43%. Squamous cell tumors or adenocarcinoma of the bladder were contra-indicative to multi-modality treatment [with cystectomy most often advised].
2. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED.M.D. Anderson Cancer Center, Houston, USA.N Engl J Med. 2003 Aug 28;349(9):859-66. PMID:12944571
3. Radical transurethral resection and chemotherapy in the treatment of muscle-invasive bladder cancer: a long-term follow-up. Thomas DJ, Roberts JT, Hall RR, Reading J.Department of Urology, Freeman Hospital, Newcastle upon Tyne, UK. BJU Int. 1999 Mar;83(4):432-7. PMID: 10210567
5. Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder. Sternberg CN, Pansadoro V, Calabro F, Marini L, van Rijn A, Carli PD, Giannarelli D, Platania A, Rossetti A. San Raffaele Scientific Institute, Rome, Italy Ann Oncol. 1999 Nov;10(11):1301-5. PMID: 10631456
6.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. Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Department of Radiation Oncology, Massachusetts General Hospital, Boston 02114, USA. J Clin Oncol. 1998 Nov;16(11):3576-83.
7.Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study. Hussain MH, Glass TR, Forman J, Sakr W, Smith DC, Al-Sarraf M, Jones J, Balcerzak SP, Crawford ED, Grossman HB.Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA. J Urol. 2001 Jan;165(1):56-60; discussion 60-1. PMID: 11125363
Metastatic bladder TCC (transitional cell carcinoma) has an aggressive course, with survival of 3-6 months without treatment. The addition of chemotherapy after cystectomy using cisplatin-containing combination chemotherapy-with M-VAC as the gold standard these last 15 years-has extended survival to 12-16 months, with a response rate ranging from 40-70%. However, long term surival is low (3.7% at six years) with toxicity and number of visits per cycle remaining problematic. 1,2,3
Newer drugs are in trails in an effort to improve outcome and quality of life; these include gemcitabine/Gemzar, paclitaxel/Taxol, docetaxel/Taxotere and ifosfamide.4-10
Von der Masse and colleagues compared gemcitabine + cisplatin with M-VAC in a large, randomized phase III trial; median survival was 13.8 for the GC arm and 14.8 for the M-VAC arm, survival at 18 months was 37% vs 38%, with GC having a significantly better safety profile/tolerability. On the basis of this trial, Gemcitabine+cisplatin has now become the new gold standard treatment for metastatic bladder cancer.8
Phase I and II trials are now comparing gemcitabine plus taxane(s) with or without a cisplatin analogue (related drug) to M-VAC. 11-14 Cisplatin+Taxol and Cisplatin+Taxotere are also under investigation; a recent phase III trial showed that M-VAC was more effective than cisplatin+Taxotere.15
For people who co-morbidities or renal insufficiency, Carboplatin based combinations may be considered; ongoing trials suggest that although the G/cisplatin combination scores better, gemcitabin+Carboplatin is a less toxic, effective regimen for this population. 16 Taxol+Carboplatin has been tested in several trials but had a substandard survival rate (9.5 months).17
The stratification of patients according to risk factor are needed to avoid bias in the results of future trials. The use of novel prognostic markers in future trials will define their role in clinical outcome, and could potentially help to design individualized chemotherapy regimens. One ongoing trial is randomizing people with postive, over-expressed p53 [thought to be a risk factor for recurrence] to observation after cystectomy or cystectomy followed by M-VAC.18 Monclonal antibody therapies are new, targeted approaches with Trastuzumab (Herceptin) and gefitinib (Iressa) currently being investigated for use in metastatic bladder cancer. A recent phase I trial demonstrated that the use of adenovirus-mediated p53 transfer [gene therapy] is safe, feasible and biologically active. 19
Although there have been no concrete advances in 15 years, newer therapies with less toxicity may begin replacing M-VAC without compromising survival.
Phase II Study of Trastuzumab (Herceptin), Paclitaxel, Carboplatin, and Gemcitabine in Patients With Locally Recurrent or Metastatic Urothelial Carcinoma Overexpressing HER2 recruiting
2.A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG.Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston 77030. J Clin Oncol. 1990 Jun;8(6):1050-5. PMID: 2189954
3.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. Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D.Indiana University School of Medicine, Indianapolis 46202, USA J Clin Oncol. 1997 Jul;15(7):2564-9. PMID: 9215826
4.Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. Roth BJ, Dreicer R, Einhorn LH, Neuberg D, Johnson DH, Smith JL, Hudes GR, Schultz SM, Loehrer PJ. Division of Hematology/Oncology, Indiana University Medical Center, Indianapolis. J Clin Oncol. 1994 Nov;12(11):2264-70. PMID: 7525883
5.Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA J Clin Oncol. 2002 Feb 15;20(4):937-40. PMID: 11844814
6.Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: a multicenter phase II study of the Hellenic Cooperative Oncology Group. Dimopoulos MA, Bakoyannis C, Georgoulias V, Papadimitriou C, Moulopoulos LA, Deliveliotis C, Karayannis A, Varkarakis I, Aravantinos G, Zervas A, Pantazopoulos D, Fountzilas G, Bamias A, Kyriakakis Z, Anagnostopoulos A, Giannopoulos A, Kosmidis P. Department of Clinical Therapeutics, Urology and Radiology, University of Athens School of Medicine, Greece. Ann Oncol. 1999 Nov;10(11):1385-8. PMID: 10631471
7.Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients.
9.Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract. Dodd PM, McCaffrey JA, Hilton S, Mazumdar M, Herr H, Kelly WK, Icasiano E, Boyle MG, Bajorin DF.Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, New York, New York, USA. J Clin Oncol. 2000 Feb;18(4):840-6. PMID: 10673526
10.Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer. Garcia del Muro X, Marcuello E, Guma J, Paz-Ares L, Climent MA, Carles J, Parra MS, Tisaire JL, Maroto P, Germa JR. Institut Catala d'Oncologia, Department of Medical Oncology, Avda Gran Via km 2.7, 08907 L'Hospitalet, Barcelona, Spain Br J Cancer. 2002 Feb 1;86(3):326-30. PMID: 11875692
11.Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A. Vincenzo Pansadoro Foundation, Rome, Italy Cancer. 2001 Dec 15;92(12):2993-8. PMID: 11753976
12.Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group. Bellmunt J, Guillem V, Paz-Ares L, Gonzalez-Larriba JL, Carles J, Batiste-Alentorn E, Saenz A, Lopez-Brea M, Font A, Nogue M, Bastus R, Climent MA, de la Cruz JJ, Albanell J, Banus JM, Gallardo E, Diaz-Rubio E, Cortes-Funes H, Baselga J.Hospital General Universitari Vall d'Hebron, Bacelona, Spain J Clin Oncol. 2000 Sep 15;18(18):3247-55. PMID: 10986057
13.Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Sarah Cannon Cancer Center, Nashville, TN, USA. J Clin Oncol. 2001 Jun 15;19(12):3018-24. PMID: 11408496
14.Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Division of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, USA J Clin Oncol. 2001 May 1;19(9):2527-33. PMID: 11331332
15.Docetaxel and cisplatin versus M-VAC in advanced urothelial carcinoma: A multicenter, randomized, phase III study conducted by the Hellenic Cooperative Oncology Group A. Bamias, G. Aravantinos, D. Bafaloukos, C. Kalofonos, D. Pektasides, N. Xiros, P. Papakostas, C. Kourousis, P. Kosmidis, M. A. Dimopoulos; Dept of Clinical Therapeutics, University of Athens, Athens, Greece; Agii Anargiri Hospital, Athens, Greece; Metaxa Hospital, Athens, Greece; Ongology Department, Rio University, Patra, Greece; Evangelismos Hospital, Athens, Greece; Ippokratio Hospital, Athens, Greece; University Hospital, Oncology Dept, Hiraklio, Greece; Hygeia Hospital, Athens, Greec Citation: Proc Am Soc Clin Oncol 22: page 384, 2003 (abstr 1541)
18.Current understanding of the biology of advanced bladder cancer. Al-Sukhun S, Hussain M.Division of Hematology/Oncology, Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan 48109, USA. Cancer. 2003 Apr 15;97(8 Suppl):2064-75. PMID: 12673698
19.Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy. Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P, Slaton JW, Merritt JA, Grossman HB, Dinney CP.Department of Genitourinary Medical Oncology, Box 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA J Clin Oncol. 2003 Jun 15;21(12):2247-53. PMID: 12805322
Therapy for muscle invasive bladder cancer can be divided roughly into bladder-sparing and non-bladder-sparing approaches, with the gold standard being cystectomy+lymphadenectomy. Peri-operative chemotherapy is still evolving; the most recent data show a survival advantage with neo-adjuvant (pre-op) chemotherapy.
Rationale behind the use of pre-or post-operative chemotherapy include:
Multiple randomized trials of neo-adjuvant chemotherapy have investigated a spectrum of drug regimens; the largest randomized trial in the literature , conducted by The Medical Research Council/European Organization for the Research and Treatment of Cancer (MRC/EORTC) compared neoadjuvant CMV (cisplatin,methotrexate, vinblastine) to a control group that received no chemo before treatment; time to progression was improved by 8%, the 3 year survival rate was improved by 5.5%; the median survival was 44 months with treatment vs. 37.5 for those who received no chemotherapy. However, when the trail was updated in 2002 after a median of seven years, a statistically significant improvement in survival was seen (p=0.048, hazard ratio of 0.85,CI 0.72-1.0).1
A second large, co-operative group study from the Southwest Oncololgy Group (SWOG) showed superior survival with neo-adjuvant M-VAC for 3 cycles vs. cystectomy alone for muscle-invasive disease, with median survivals of 6.2 years for the chemotherapy group vs. 3.8 years for cystectomy alone, and 5 year survivals of 57% and 42% respectively. 2 *Several other randomized trials failed to show a benefit for neo-adjuvant chemotherapy, however these studies had shortcomings such as inadequate number of enrollments, premature closure or sub-standard drug regimens.
A recent world-wide meta-analysis examined the use of neo-adjuvant chemo; a significant survival benefit was seen in those who underwent cisplatin-containing regimens (HR 0.87,p=p016), with no benefit observed in those who had single-agent cisplatin.3
Adjuvant (post-operative) chemotherapy has been studied in five randomized trials, with two of these suggesting a survival benefit for adjuvant chemotherapy over cystectomy alone. 4-6 Although there is insufficient data available about the efficacy of adjuvant chemo, it is assumed that adjuvant treatment is equally effective as neo-adjuvant treatment with M-VAC or GC.
There is sufficient evidence from the MRC/EORTC and SWOG trials, along with the meta-analysis, to support the use of neo-adjuvant chemotherapy in the treatment of muscle invasive bladder cancer for those who are candidates for cisplatin-based therapies.
Ongoing clinical trials are evaluating the use of adjuvant chemotherapy in the US and Europe, and will hopefully give some clearer answers about this approach in the near future.
1Updated results of a randomised controlled trial of neoadjuvant cisplatin (C), methotrexate (M) and vinblastine (V) chemotherapy for muscle-invasive bladder cancer. RR Hall Year: 2002 International collaboration of trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle invasive bladder cancer: a randomised controlled trial. The Lancet 1999, 354, p533-40. Abstract No: 710
2.Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED.M.D. Anderson Cancer Center, Houston, USA. N Engl J Med. 2003 Aug 28;349(9):859-66. Erratum in: N Engl J Med. 2003 Nov 6;349(19):1880. PMID: 12944571
3.Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis.Advanced Bladder Cancer Meta-analysis Collaboration. Lancet. 2003 Jun 7;361(9373):1927-34. PMID:12801735
4.The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, Kern W, Sakamoto J, Krailo M, Groshen S.Department of Urology, University of Southern California School of Medicine, Kenneth Norris, Jr. Cancer Hospital, Los Angeles. J Urol. 1991 Mar;145(3):459-64; discussion 464-7. PMID: 1997689
5.Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. Stockle M, Meyenburg W, Wellek S, Voges G, Gertenbach U, Thuroff JW, Huber C, Hohenfellner R.Department of Urology, University of Mainz Medical School, Wuppertal, Germany. J Urol. 1992 Aug;148(2 Pt 1):302-6; discussion 306-7. PMID: 1635123
6.Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. Stockle M, Meyenburg W, Wellek S, Voges GE, Rossmann M, Gertenbach U, Thuroff JW, Huber C, Hohenfellner R. Department of Urology, University of Mainz Medical School, Germany J Urol. 1995 Jan;153(1):47-52. PMID: 7966789
Thanks to advancements in the understanding of molecular biology and the new drugs which have resulted from this, a new era is emerging with new anti-cancer agents that inhibit many of the 'hallmarks of cancer."1
Epidermal Growth Factor
COX-2: Eicosanoid metabolism
Frequent, low daily doses of IFN (interferon) have also been shown to lower micro-vessel density (MVD).
Nuclear Factor kappa (NF-kappa B)
New chemotherapeutic agents
1.The hallmarks of cancer. Hanahan D, Weinberg RA.Department of Biochemistry, Hormone Research Institute, University of California at San Francisco, 94143, USA.Cell. 2000 Jan 7;100(1):57-70. Review. No abstract available. PMID: 10647931
2.Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX. Cedars-Sinai Prostate Cancer Center, Los Angeles, California 90048, USA. Cancer Cell. 2002 Aug;2(2):127-37. PMID: 12204533
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new paradigm of molecular prediction
Glutathione expression has been correlated to chemo response; DPD overexpression predicts tumor non-response; a mutated p53+an absent p21=10% survival at ten years, regardless of the original stage.
Phase III Randomized Study of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Versus Observation Alone Based on p53 Gene Status in Patients With Organ Confined Transitional Cell Carcinoma of the Bladder Who Have Undergone Radical Cystectomy and Bilateral Pelvic Lymphadenectomy
The combination of chemotherapy with novel biological agents targeting cell surface growth regulators such as EGFR and erb-B2 are also in clinical trials. The intitial results of the combination of trastuzumab+chemotherapy has not shown improved outcome, but this study is the first to evaluate such an approach; in the next generation of clinical trials, molecular typing of bladder cancers along with innovative clinical trials will help to clarify the use of such novel agents. In the near future it will become crucial for clinicians to understand and integrate molecular biology into trial design and clinical practice.
Clonal analysis of a bladder cancer cell line: an experimental model of tumour heterogeneity. Brown JL, Russell PJ, Philips J, Wotherspoon J, Raghavan D.Urological Cancer Research Unit, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Br J Cancer. 1990 Mar;61(3):369-76.
Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cote RJ, Dunn MD, Chatterjee SJ, Stein JP, Shi SR, Tran QC, Hu SX, Xu HJ, Groshen S, Taylor CR, Skinner DG, Benedict WF Department of Pathology, University of Southern California School of Medicine/Norris Comprehensive Cancer Center, Los Angeles 90033, USA. Cancer Res. 1998 Mar 15;58(6):1090-4.
Pharmacogenetics and cancer chemotherapy.Iyer L, Ratain MJ.Committee on Clinical Pharmacology, University of Chicago, Illinois 60637, USA. Eur J Cancer. 1998 Sep;34(10):1493-9. Review. PMID: 9893619
The significance of dihydropyrimidine dehydrogenase (DPD) activity in bladder cancer. Mizutani Y, Wada H, Fukushima M, Yoshida O, Ukimura O, Kawauchi A, Miki T.Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan Eur J Cancer. 2001 Mar;37(5):569-75. PMID: 11290431
Biology and management of bladder cancer. Raghavan D, Shipley WU, Garnick MB, Russell PJ, Richie JP. Department of Clinical Oncology, Royal Prince Alfred Hospital, Sydney, N.S.W., Australia.N Engl J Med. 1990 Apr 19;322(16):1129-38. Review. PMID: 2181313
Translational studies of glutathione in bladder cancer cell lines and human specimens.Pendyala L, Velagapudi S, Toth K, Zdanowicz J, Glaves D, Slocum H, Perez R, Huben R, Creaven PJ, Raghavan D.Departments of Investigational Therapeutics, Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.Clin Cancer Res. 1997 May;3(5):793-8. PMID: 9815751
Two molecular pathways to transitional cell carcinoma of the bladder. Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, Lerner SP, Schmutte C, Yang AS, Cote R, et al. Kenneth Norris Jr. Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Southern California, School of Medicine, Los Angeles 90033. Cancer Res. 1994 Feb 1;54(3):784-8. PMID: 8306342
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