Chemotherapy for bladder cancer. BCAN Denver September 24, 2011

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1 Chemotherapy for bladder cancer BCAN Denver September 24, 2011

2 University of Colorado School of Medicine Founded in ,000 patients a year 100,00 cancer visits annually

3 Overview Indications for chemotherapy in bladder cancer Peri-operative chemotherapy (before or after surgery) Chemotherapy for advanced disease What to expect from chemotherapy for bladder cancer Future directions biologic agents

4 When to use chemotherapy There are different types of systemic therapy for cancer Cytotoxic chemotherapy mainstay in bladder CA Hormonal therapy (mostly breast and prostate CA) Immunotherapy/vaccines (emerging area in cancer) New generation/biologic agents Two major settings for chemotherapy in bladder CA Peri-operative Advanced/metastatic disease

5 Peri-operative chemotherapy Neo-adjuvant chemotherapy is given before surgery Adjuvant chemotherapy is given after surgery Goal to eliminate microscopic nest of cancer at a curable point (e.g. when microscopic) Curative intent Adjuvant chemotherapy is used in most cancers (colon, lung, many breast cancers) Neoadjuvant best supported in bladder cancer

6 Staging of bladder cancer Used to make decisions about the need for chemotherapy _images/bladdertstages.gif

7 Neoadjuvant chemotherapy Several studies have examined the role of neoadjuvant chemotherapy in bladder CA Many early randomized studies were inconclusive or frankly negative These used single agent cisplatin or historical doublets (two drugs used together) Modern peri-operative studies have utilized MVAC or similar regimens (MVAC is a 4 drug regimen)

8 Over 11 years, 317 patients T2-T4a Cystectomy +/- neoadjuvant MVAC X 3 Median followup of 8.7 years 78% in chemo arm received at least 1 cycle

9 Median survival Surgery along = 46 months Neoadjuvant MVAC = 77 months (p=0.06) At 5 years, 57% of chemotherapy and 43% of the surgery only group were alive. Obtain pt0 at the time of surgery Surgery alone arm = 15% Neoadjuvant MVAC = 38% (p<0.001)

10 Post-operative (adjuvant) chemotherapy

11 Post-operative chemotherapy Less evidence to support in post-operative chemotherapy in bladder cancer In all of cancer care as a whole, post-operative chemotherapy is used more often than preoperative therapy Still has a role in higher risk, chemotherapynaive patients after surgery

12 Pooled analysis 5 trials were evaluable for OS (350 patients) There was a benefit for OS (RR 0.74) Problems Skinner - chemotherapy variability Stockle no chemo with PD in surgery arm Freiha closed early with small numbers Studer/Bono all N0 patients

13 Relative risk ratio for OS

14 Summary peri-operative chemo Level I evidence for MVAC in neoadjuvant setting (included T2-T4) Adjuvant therapy is rationale, but very limited data to support (>T2 or N+) Gemcitabine + cisplatin appears equivalent to MVAC in the metastatic setting and similar pt0 rates in published series

15 Chemotherapy for advanced bladder cancer

16 Muscle-invasive disease Summary of therapeutic advancement for intravesical therapy in bladder cancer over the past 20 years:

17 Muscle-invasive disease Summary of therapeutic advancement for intravesical therapy in bladder cancer over the past 20 years: 4 drug chemotherapy 2 drug chemotherapy No improvement in efficacy

18 405 patients with locally advanced or metastatic TCC (T4b, N2, N3 or M1) Treated with MVAC vs. Gem-cis At last report, 347 patients had died OS was 14 months for Gem-cis and 15.2 months for MVAC 5 year PFS was 9% with GC vs. 11% with MVAC

19 Kaplan-Meier curve for OS

20 What to expect from chemotherapy The mainstay of medical therapy for bladder cancer remains cytotoxic chemotherapy This is traditional chemotherapy given intravenously It is not targeted therapy, that targets a particular enzyme or receptor

21 Side effects The bone marrow is significantly, but temporarily affected by chemotherapy Cisplatin is the mainstay of therapy and associated with potential kidney damage and nausea Hydration with fluids and anti-nausea medications is used. Other possible side effects include nerve damage, hair loss, fatigue and serious infections (among many others).

22 Future directions on bladder cancer Targeted agents are becoming more widely used in other cancers Renal cell has 6 recently approved drugs to treat advanced disease Prostate cancer has several new targeted agents either approved or in process However, in bladder cancer, we have moved from a 4-drug to a 2-drug combination over the last 20 years for tolerance, not efficacy

23 Systemic therapy for bladder cancer Bladder over-expresses several targets for which we have available therapies EGFR 35% of metastatic lesion ++/+++ (BJU 2005; 95:1334) associated with higher tumor grade and stage. VEGF Increased VEGF 58%, VEGFR2 50% of clinical TCC (J Urol 2006; 175: 1245) HER2/neu 31% of metastatic lesions are ++/+++ (BJU 2005; 95:1334) IGF protein expression of IGF-I and IGF-1R was increased in 74% and 59% in TCC respectively (Aizheng 2004; 223: 707) FGFR3 FGFR3 is frequently mutated (>60%) in early disease and over-expressed (>40%) in muscle invasive TCC

24 Systemic therapy for bladder cancer No targeted agents in clinical use for bladder cancer Definitive trials have not been performed CALGB Flaig SWOG coordinator

25 Thank you Questions?