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WebCafé report by Wendy Sheridan PDF Print E-mail

Organizer:

November, 2003

Padova: Sessions 3 and 4

index of the presentations

Session 1: Diagnosis of bladder cancer
Chair- Mark.S.Soloway, University of Miami School of Medicine, Florida, USA

MRI of urinary bladder cancer
J.O. Barentsz MD, PhD, University Medical Center, Nijmegen, Netherlands

Tumor Markers in Bladder Cancer: Where are we?
J.A. Witjes MD, PhD, University Medical Center, Nijmegen, The Netherlands

Review Pathology: Why it is critical
F. Algaba MD, PhD, Fundacio Puigvert Universdad Autonoma de Barcelona; Barcelona, Spain

Analyzing p53 status and other markers to determine management strategies
J. Schalken, MD, PhD, University Medical Center Nijmegen, The Netherlands

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
Chair:A.P.M. van der Meijden, MD, PhD Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

Chemoresection for superficial bladder cancer
W.Oosterlinck, MD, PhD, Ghent University Hospital, Belgium

A meta-analysis of randomized trials investigating transurethral resection plus one immediate instillation of chemotherapy
R.J. Sylvester, ScD, European Organization for Research and Treatment of Cancer, Brussels, Belgium

Observation of TaGI bladder tumors: Acceptable?
Mark.S.Soloway, University of Miami School of Medicine, Florida, USA

Results from Finn bladder group in low risk Tumors,
E. Rintala, MD, Helsinki University Central Hospital, Finland

Session 3: How Do I Treat Intermediate and High-Risk Tumors? Chair: A.P.M. van der Meijden, MD, PhD Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

Chemotherapy for intermediate risk and BCG for high risk
E.Solsona, MD, Valencia Institute of Oncology, Spain

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
Chair:P.G.Harper, MD, Guy’s Hospital, London, United Kingdom

What to do when radical cystectomy is not radical
D.P.Petrylak, MD, PhD, Colombia Uinversity, NY, NY, USA

Current treatment approaches in advanced bladder cancer
P.G.Harper, MD, Guy’s Hospital, London, United Kingdom

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
Ch.Sweeney, MD, MBBS, Indiana University, Indianapolis, Indiana, USA

Future management of advanced bladder cancer
D. Raghavan, MD, PhD, University of Southern California Norris Comprehensive Cancer Center Los Angeles, California, USA

Chemotherapy for intermediate risk and BCG for high risk E.Solsona, MD, Valencia Institute of Oncology, Spain

A review of the literature evaluating controlled trials recently showed that intravesical chemo and BCG are both effective at lowering recurrence rates, with either treatment significantly better than TUR alone. However, only BCG+ maintenance was shown to have an impact in reducing progression.1 The question is whether or not BCG remains superior throughout the three classic ‘risk groups’ of low, intermediate and high.

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;

Low risk:
recurrence-29-48%, mean of 36.5%; progression-0-7.1%, mean of 3.3%
Inter.risk:
recurrence-45-67%, mean of 57.2%; progression-1.8-17.4%, mean of 9.4%
High risk:
recurrence-54-82%, mean of 73.5%; progression-15-47.35%, mean of 31.5%

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:
BCG failure+delayed cystectomy - 78.6% survival at 5 years
Immediate cystectomy – 84.4% survival at 5 years

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:
G3 or T1, CIS or prostate involvement plus clinical non response at 3 months: progression to T2 or higher in 72.6% of cases
Intermediate Risk
G1-2 Ta, no CIS, no prostate involvement plus clinical non response: progression occurred in 35%
Any category plus clinical response at 3 months: progression occurred in 10.6%.

High risk patients who do not respond to BCG at 3 months should be offered cystectomy.

References
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

Intravesical 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

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

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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

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.
METHODS: After transurethral resection, intravesical instillations of BCG were given during a 6-week induction course followed by 3-weekly maintenance courses at 3, 6, 12, 18, 24, 30 and 36 months. The prognostic importance of delaying or stopping BCG due to local and/or systemic side effects was assessed in 487 patients.
RESULTS: Patients with local BCG side effects had a significantly longer time to first recurrence, suggesting that side effects are related to efficacy. However patients with a better outcome remain on study for a longer period of time and receive more BCG, thus increasing their risk to develop side effects. To prove whether toxicity is responsible for improved efficacy, the prognostic importance of toxicity occurring prior to the 6 month instillations was assessed using the landmark method. Neither local nor systemic BCG toxicity prior to 6 months was related to subsequent recurrence. CONCLUSIONS: While a correlation between BCG toxicity and efficacy exists, this study does not confirm that BCG toxicity is actually responsible for an improved outcome.

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

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New Agents in the Treatment of superficial bladder cancer M.A. O’Donnell, MD, University of Iowa Health Care, Iowa, United States

New intravesical treatments and modifications of older protocols have recently emerged which deserve to be considered in the adjuvant treatment of superficial bladder cancer.

Intravesical, cytotoxic chemotherapy

Optimization of Mitomycin C
Most critical aspect of clinical response is drug concentration rather than dose or indwelling time
Drug dilution can be minimized by:
-pre-treatment dehydration of the patient
-complete emptying of urine (verified by bladder scan)
-urinary alkalization
-earlier initiation of treatment administration

Using these techniques, the improvement of clinical response at 4 years went from 23% to 42%

Advances in depth of penetration of Mitomycin C
-Electromotive therapy (iontophoresis)2
-Intra-cavity microwave hyperthermia (SynergoTM)3 - this new treatment is showing impressive results as first-line chemoablation as well as for T1, G3 tumors and in cases of BCG failures.
-Upregulation of key intracellular enzyme quinone reductase - dietary modification (increased consumption of brassica vegetables such as cabbage and broccoli)5, 6

Intravesical Gemcitabine-now entering phase II trials 7,8
-used in case of BCG or previous MMC failure with favorable results, response rates exceeding 50% at 3 months (with drop off after that)
-lower toxicity profile than most commonly used agents
Strategies to maintain a complete response with re-treatment or combination with MMC are underway.

Intravesical Immunotherapy

Optimization of BCG therapy
SWOG 8507's study using post-induction maintenance therapy (see drlammsprotocol) for 3 years has shown clear improvement over the 6 round induction course, lessening both recurrence and progression.9

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
However, some high risk tumors subtypes may have less response to reduced BCG. An alternative may be to administer BCG every other week, called "slow rate" dosing.13

Other active agents in BCG failures are mycobacterial DNA cell wall extracts, in trials now for CIS. 14

BCG + Interferon-alpha (IFN-a)
-50% durable disease remissions over two years
-active against previous BCG failures15
-good tolerability and safety profiles16

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.

References
1. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III tria
l. Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, Pollifrone DL, Harbrecht JD, Chin JL, Lerner SP, Miles BJ; International Mitomycin C Consortium.Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USAJ Natl Cancer Inst. 2001 Apr 18;93(8):597-604. PMID: 11309436

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

6.Selective induction of phase II enzymes in the urinary bladder of rats by allyl isothiocyanate, a compound derived from Brassica vegetables. Munday R, Munday CM.Ruakura Agricultural Research Centre, Hamilton, New Zealand Nutr Cancer. 2002;44(1):52-9. PMID: 12672641

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

9.Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. West Virginia University Medical Center, Morgantown, USA. J Urol. 2000 Apr;163(4):1124-9. PMID: 10737480

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

15. Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette-Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed.O'Donnell MA, Krohn J, DeWolf WC.Department of Urology, University of Iowa, Iowa City, USA.J Urol. 2001 Oct;166(4):1300-4, discussion 1304-5. PMID:11547062

16.Interim results from a national multi center phase II trial of combination BCG plus interferon alpha2-B for superficial bladder cance. O'Donnell MA, Lilli K, Leopold C. J Urol.2003;169:256

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

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Session 4: Advanced Bladder Cancer
Chair:P.G.Harper, MD, Guy’s Hospital, London, United Kingdom

What to do when radical cystectomy is not radical
D.P.Petrylak, MD, PhD, Colombia Uinversity, NY, NY, USA

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

Shipley and associates used a sequential regimen of two cycles of CMV followed by radiation therapy using cisplatin as a radio-sensitizer. Those who did not respond underwent immediate cystectomy, responding patients underwent further combined chemo/radiation therapy. The 5 year survival rates was 54%, with 36% of patients achieving bladder preservation.6

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].

References
1. Cancer statistics, 2003.
Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, USA CA Cancer J Clin. 2003 Jan-Feb;53(1):5-26. PMID: 12568441 online article

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

4. Can patient selection for bladder preservation be based on response to chemotherapy?Sternberg CN, Pansadoro V, Calabro F, Schnetzer S, Giannarelli D, Emiliozzi P, De Paula F, Scarpone P, De Carli P, Pizzo M, Platania A, Amini M.Vincenzo Pansadoro Foundation, Rome, Italy Cancer. 2003 Apr 1;97(7):1644-52. PMID: 12655521

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.
PMID: 9817278

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

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Current treatment approaches in advanced bladder cancer P.G.Harper, MD, Guy’s Hospital, London, United Kingdom

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 Cisplatin, Gemcitabine, and Gefitinib in Patients With Metastatic Transitional Cell Carcinoma of the Urothelium recruiting

Phase II Study of Trastuzumab (Herceptin), Paclitaxel, Carboplatin, and Gemcitabine in Patients With Locally Recurrent or Metastatic Urothelial Carcinoma Overexpressing HER2 recruiting

Phase II trial to study the effectiveness of combining pemetrexed disodium with gemcitabine in treating patients who have advanced cancer of the urothelium not yet recruiting

References
1.A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, et al.Department of Medicine, Indiana University Medical Center, Indianapolis. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. PMID: 1607913

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.
Br J Cancer. 1998 Nov;78(10):1342-5. de Wit R, Kruit WH, Stoter G, de Boer M, Kerger J, Verweij J.Rotterdam Cancer Institute and University Hospital, The Netherlands. PMID: 9823976

8.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. 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.Aarhus University Hospital, Denmark J Clin Oncol. 2000 Sep;18(17):3068-77. PMID: 11001674

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)

16.A feasibility study of carboplatin with fixed dose of gemcitabine in "unfit" patients with advanced bladder cancer. Bellmunt J, de Wit R, Albanell J, Baselga J.University Hospital Vall d'Hebron, Barcelona, Spain Eur J Cancer. 2001 Nov;37(17):2212-5. PMID: 11677109

17.Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point. Small EJ, Lew D, Redman BG, Petrylak DP, Hammond N, Gross HM, Eastham JA, Crawford ED.University of California San Francisco, San Francisco, CA, USA J Clin Oncol. 2000 Jul;18(13):2537-44. PMID: 10893284

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

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Adjuvant chemotherapy in muscle invasive bladder cancer: Current concepts
D.F. Bajorin,MD, Memorial Sloan-Kettering Cancer Center, NY, NY, USA

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:
*TCC is chemosensitive, the complete response rate in metastatic disease ranges from 11-25% (according to phase III studies)
*Long term cure has been observed in some cases of metastatic disease
*chemotherapy benefits other cancers with similar metastatic risk and chemosensitivity (ie: breast and colon)
* Long term cure for those with lymph node involvement - incurable by surgery alone - has been seen with chemotherapy followed by cystectomy and lymphadenectomy

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.

*[see also: chemo controversy]

References

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

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Overview of novel agents
Ch.Sweeney, MD, MBBS, Indiana University, Indianapolis, Indiana, USA

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
Both tyrosine kinase inhibitors (TKI) and monoclonal antibodies have been developed to combat the malignant potential of the EGF axis; Trastuzumab [Herceptin] and gefitinib [Iressa] have been evalutad, both with limited success (the latter gave a complete response in 3% of patients). Pertuzumab, a new monoclonal antibody, has a different mechanism, blocking HER-2 association with other HER family members (HER1/EGFR, HER3 and HER4), inhibiting intracellular signaling. The over-expression of the HER-2 gene is not necessary for the anti-tumor activity of this new agent.2 HER-2 overexpression has been seen in up to 50% of metastatic tumors.

COX-2: Eicosanoid metabolism
Cyclo-oxygenase-2 (COX-2) is a known cancer promoter; inhibition of this enzyme may prove to be a successful chemo-preventative agent in the fight against TCC. COX-2 inhibitors, successful in treating familial colonic polyps, is being investigated in Phase III trials for the prevention of superficial recurrences.4,5

Angiogenesis
The developement of most cancers-including TCC- depend up the growth of new blood vessels to promote tumor growth.6 Vascular endothelial growth factors (VEGF) inhibition are a reasonable target in the fight against TCC, drugs like Bevacizumab are being tried. Angiogenesis can also be inhibitied by turning off pathways that promote angiogenesis (Nuclear factor kappa B and EGFR), however, determination of factors that give tumors the ability to grow independent of angiogenesis inhibition must be considered. 7

Frequent, low daily doses of IFN (interferon) have also been shown to lower micro-vessel density (MVD).

Nuclear Factor kappa (NF-kappa B)
NF-kappa B is a transcription factor that promotes many of the hallmarks of cancer such as invasion, evasion of apoptosis, angiogenesis and metastasis. The use of proteasome inhitors has been successful in the treatment of myeloma, 8 presumably by inhibition of NF-kappaB, and preclinical work has shown the presence of this factor in cinical specimens. 9 Ihibition of NF-kappa B has been shown to retard tumor growth in othortopic bladder cancer models.10

New chemotherapeutic agents
Any advancement in systemic therapy made thus far is thanks to this type of therapy (cytotoxic drugs). These agents impact inhibit replication. Pemetrexed [Alimta] inhibits cellular replication by impeding folate metabolism and thus RNA and DNA synthesis. This new agent has shown activity in TCC, with a 29% response.10

Phase II trial to study the effectiveness of bortezomib in treating patients who have advanced or metastatic transitional cell cancer of the bladder, renal pelvis, or ureter. recruiting

References

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

3.Cyclo-oxygenase-2 expression in primary cancers of the lung and bladder compared to normal adjacent tissue. Sweeney CJ, Marshall MS, Barnard DS, Heilman DK, Billings SD, Cheng L, Marshall SJ, Yip-Schneider MT.Department of Medicine, Indiana University, Indianapolis 46202, USA Cancer Detect Prev. 2002;26(3):238-44. PMID: 12269772

4.Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review. Pruthi RS, Derksen E, Gaston K.Division of Urologic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA J Urol. 2003 Jun;169(6):2352-9. PMID: 12771797

5.The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. University of Texas M.D. Anderson Cancer Center, Houston 77030, USA N Engl J Med. 2000 Jun 29;342(26):1946-52. PMID: 10874062

6.Angiogenesis, angiogenic factor expression and prognosis of bladder cancer. Streeter EH, Crew JP.Department of Urology, Churchill Hospital, Oxford, UK Anticancer Res. 2001 Nov-Dec;21(6B):4355-63. Review.
PMID: 11908691

7.Resistance in the anti-angiogenic era: nay-saying or a word of caution? Sweeney CJ, Miller KD, Sledge GW Jr. Indiana University, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202, USA Trends Mol Med. 2003 Jan;9(1):24-9. Review. PMID: 12524207

8.A phase 2 study of bortezomib in relapsed, refractory myeloma. A phase 2 study of bortezomib in relapsed, refractory myeloma. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. N Engl J Med. 2003 Jun 26;348(26):2609-17. PMID: 12826635

9.Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-kappaB. Mian BM, Dinney CP, Bermejo CE, Sweeney P, Tellez C, Yang XD, Gudas JM, McConkey DJ, Bar-Eli M. Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. Clin Cancer Res. 2003 Aug 1;9(8):3167-75. PMID: 12912969

10.Phase II study of pemetrexed (PEM) for second-line treatment of transitional cell cancer (TCC) of the bladder. C. Sweeney, B. J. Roth, D. S. Kaufman, S. J. Nicol; for the Hoosier Oncology Group, Indianapolis, IN; Vanderbilt-Ingram Cancer Center, Nashville, TN; Massachusetts General Hospital, Boston, MA; Eli Lilly and Company, Indianapolis, IN Year: 2003 Abstract No: 1653 Proc Am Soc Clin Oncol 22: page 411, 2003

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Future management of advanced bladder cancer
D. Raghavan, MD, PhD, University of Southern California Norris Comprehensive Cancer Center Los Angeles, California, USA

new paradigm of molecular prediction
Bladder TCC is a complex malignancy with the capacity to differentiate along different cellular pathways including transitional cell, squamous and adenocarcinoma. This makes them much more difficult to target with chemotherapy. In addition to histological heterogeneity [heterogeneous-consisting of dissimilar or diverse ingredients or constituents: m-w.com], bladder cancer also exhibits molecular heterogeneity, and variably expresses genes and oncogenes including p53, p16, p21, RB, Ras, erb-B2, and EFGR among others. Genes that code for glutathione, the metallothioneines, thymidylate synthase (TS), EGFR, and the multi-drug resistant phenotype (MDR) are all expressed in bladder cancer and have been shown to have biological activity.

Data suggests that some of these genes may confer increased responsiveness to chemotherapy; for example the studies being done with p53 at USC Norris Cancer Institute (however, data from Memorial Sloan Kettering in NYC and out of Toronto do not share the same conclusions). In addition to prediction of chemo-sensitivity, these genes could be used to devise more tailored, individual therapies for patients, stratified according to careful molecular profiling. This approach has the potential to overcome the most pressing problem in oncology today: intersubject variation of drug response and toxicity (there is evidence that African-American and Latino population responds differently to common chemo-agents).

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.

An international randomized clinical trial is testing the efficacy of post-operative M-VAC for those with T1, T2 tumors who test postive for the p53 marker. Such an approach represents a new paradigm in clinical trial design.

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

Novel Therapeutic Approaches
Several new drugs have been introduced into routine clinical use during the last decade, including gemcitabine, paclitaxel (Taxol), docetaxel (Taxotere), and isfosfamide. A number of others have been tested but failed to show sufficient benefit, including gallium nitrate and trimetrexate. Controversy arose with the use of Carboplatin, alone or in combination, due to the evidence of inadequate response and survival. SWOG is now assessing the use of ininotecan based on preliminary Japanese data. Phase II trials are also studying the the novel antimetabolite, pemetrexed.

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.

References

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.
PMID: 2328200

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.
PMID: 9515785

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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