1. CHEMOTHERAPY AND BLADDER CANCER Walter Stadler, MD, FACP University of Chicago

2. Anatomy as a Problem

3. One score and seven years ago… The metastatic d. problem 1985 - MVAC first reported 1985 - MVAC first reported 1997 - Gemcitabine first reported to have activity 1997 - Gemcitabine first reported to have activity –GC found comparable to MVAC in 2000 Response rates: Response rates: –50-55% CR +PR –10% CR OS 14 months OS 14 months −~5% cured Sternberg et al., J Urol (1985) Stadler et al., JCO (1997) von der Maase et al., JCO (2000)

4. For the Patient Gemcitabine/cisplatin OR MVAC appropriate Gemcitabine/cisplatin OR MVAC appropriate Toxicities similar, but potential cardiac problems and mouth sores with MVAC Toxicities similar, but potential cardiac problems and mouth sores with MVAC Major toxicities of both: Major toxicities of both: –Low blood counts & risk for infection –Fatigue –Nausea –Neuropathy and hearing loss –Kidney damage

5. Carboplatin instead of Cisplatin More problems with low blood counts More problems with low blood counts Fewer kidney and neurologic problems Fewer kidney and neurologic problems Probably less effective than Cisplatin Probably less effective than Cisplatin –Significance in the metastatic setting debatable –Should not be used in peri-operative setting

6. What if Initial Therapy is not Effective No standard of care No standard of care Responses observed with paclitaxel, docetaxel, pemetrexed, etc, but not clear how meaningful these are for the patient Responses observed with paclitaxel, docetaxel, pemetrexed, etc, but not clear how meaningful these are for the patient Clinical trial participation preferred Clinical trial participation preferred

7. N=317 pts N=317 pts Enrolled from 1987 - 1998 Enrolled from 1987 - 1998 Muscle-invasive bladder cancer (stage T2 to T4a, all N0) Muscle-invasive bladder cancer (stage T2 to T4a, all N0) Primary objective: compare survival of patients treated with cystectomy alone vs treated with 3 cycles MVAC followed by cystectomy Primary objective: compare survival of patients treated with cystectomy alone vs treated with 3 cycles MVAC followed by cystectomy Randomized phase III trial Randomized phase III trial Median follow-up 8.7 years Median follow-up 8.7 years (2003)

8. Overall Survival Grossman et al., NEJM (2003) At five years, 57% alive in combination-therapy group, compared with 43% in cystectomy alone group (P=0.06) --14% survival difference

9. Poor Adoption of These Data Historical rates 5-10% Historical rates 5-10% Retrospective review of patients with bladder cancer who underwent RC between 2003 and 2008 at University of Texas Southwestern: Retrospective review of patients with bladder cancer who underwent RC between 2003 and 2008 at University of Texas Southwestern: –Among 238 patients who underwent RC for bladder cancer, 145 had a preoperative clinical stage ≥T2 –Only 17% (25 of 145) received cisplatin-based neoadjuvant chemotherapy –Renal function was adequate in 97 (67%) of these patients Raj et al., Cancer (2011)

10. Renal Function as a Hurdle Cisplatin is contraindicated in patients with significantly reduced renal function Cisplatin is contraindicated in patients with significantly reduced renal function Recent study examined prevalence of ineligibility due to poor renal function Recent study examined prevalence of ineligibility due to poor renal function –28% ineligible by the CG formula –52% by Jelliffe –24% by MDRD Concordance between formulas was low Concordance between formulas was low With all formulas the probability of ineligibility increased with age With all formulas the probability of ineligibility increased with age By the CG equation, >40% of patients age >70 years were ineligible By the CG equation, >40% of patients age >70 years were ineligible Dash et al., Cancer (2006)

11. Neoadjuvant Chemotherapy AdvantageDisadvantage Clear Survival Benefit Demonstrated Clinical Staging Information Must be Utilized to Determine Patients to be Treated; Concern for Overtreatment Patients are More Likely to Receive Intended Chemotherapy than in Post-Operative Setting Patients May be Reluctant to “Delay” Surgery Does Not Cause Increased Operative Morbidity Non-Responding Patients are Unnecessarily Delaying Definitive Surgical Intervention Patients are at Their Best Performance Status Adjuvant Chemotherapy AdvantageDisadvantage Full Pathologic Staging Information Known; Allows Best Selection of Appropriate Patients for Therapy Survival Benefit Not Clearly Established A Small Subset of Patients Ineligible for Cisplatin- Based Neoadjuvant Therapy Due to Poor Renal Function May Experience Renal Function Improvement Due to Relief of Obstruction from the Surgery Itself Patients Less Likely to Receive Intended Chemotherapy Due to Post-Operative Performance Status, Complications

12. Disadvantage With Adjuvant Survival Benefit Not Clearly Established Patients Less Likely to Receive Intended Chemotherapy Due to Post-Operative Performance Status, Complications

13. Conclusions – Bladder Cancer Peri-operative CDDP based chemotherapy improves survival Peri-operative CDDP based chemotherapy improves survival –Best data in neoadjuvant setting –Underutilized Ideal utilization rate unknown Ideal utilization rate unknown >observed 5%; observed 5%; <80% Gem/CDDP or MVAC is standard for metastatic disease Gem/CDDP or MVAC is standard for metastatic disease –Carboplatin based therapies a reasonable option –No good standard for patients in whom initial therapy is not effective Current standard is not good enough Current standard is not good enough –I don’t want to give this talk in 20 yrs again –Clinical trial participation is key