The Role of Neoadjuvant and Adjuvant Chemotherapy in

The Role of Neoadjuvant and Adjuvant Chemotherapy in Muscle Invasive Bladder TCC Scott North, MD, FRCPC, MHPE Associate Professor, Dept. of Oncology, University of Alberta Medical Oncologist, Cross Cancer Institute Edmonton, AB ACOG June 24, 2011

Disclosure • Honoraria received from Amgen, Pfizer, Novartis, Janssen-Ortho

Objectives • Discuss the scope of the problem • Discuss potential advantages and disadvantages of perioperative chemotherapy approaches • Review the pertinent literature of perioperative chemotherapy use • Discuss ongoing projects to optimally select patients for treatment • Review one center’s “real world” experience

Transitional Cell Carcinoma (TCC) in Canada • Canadian Cancer Society 2010 statistics – 7, 100 new cases – 1, 850 deaths • 75% of new cases will be superficial TCC • 25% of cases will be muscle invasive or extravesical • Patients with superficial disease can progress to muscle invasive disease over time

Peri-operative chemotherapy Rationale • TCC is really two separate disease entities – Superficial versus muscle invasive • Patients often perceive superficial disease as an “annoyance” and not a serious threat – 75% 5 y OS 1 • Once disease is muscle invasive, the stakes are much higher and mortality is significant – 30 -70% 5 y OS 1 depending on depth of invasion (T 2 versus higher) 1. US NCI, cancer. gov

Peri-operative chemotherapy Rationale • Deaths from TCC are generally not local events • Patients die as a result of metastatic disease • Local interventions will not deal with micrometastatic disease • Systemic therapy must be given to eradicate micrometastatic disease in order to improve cure rates

Peri-operative chemotherapy Rationale • For many malignancies, there is clear cut evidence for the order of therapies – colon cancer: surgery first then chemotherapy later – Inflammatory breast cancer: chemo first then local therapy • For a long time, there was little evidence to guide us in TCC as to optimal sequencing

Rationale for Adjuvant Therapy • If the bladder is the problem, deal with it immediately • Chemotherapy decisions can be based on true pathology • If perioperative treatment benefit is modest, complete the most important modality of therapy first • Surgery is a “stress test” that gives you info about tolerance for chemo

Rationale for Neoadjuvant Therapy • Give systemic therapy when the pelvic blood supply is intact • in vivo chemo-sensitivity trial • Deal with micrometastatic disease immediately • Patient is fitter and more able to tolerate chemotherapy

Adjuvant Chemotherapy • Multiple trials – Small patient numbers ranging from 49 -102 – Two trials suggest survival benefit – Skinner et al. J Urol 1991 • 91 patients • Included T 3 -4 or node positive patients • Randomized to 4 cycles of cis/doxo/cyclo or observation • Median survival – 4. 3 yrs chemo p=0. 006 – 2. 4 yrs observation • Criticized - ? selection bias: – 91 of 498 patients screened were eligible Skinner DG et al, J Urol. 1991 Mar; 145(3): 459 -64

Adjuvant Chemotherapy • Stockle et al. J Urol 19951, BJU 20062 – High risk patients randomized to: • Cystectomy + MVAC (or MVEC) – Terminated early - only 49 patients as interim analysis showed significant improved 3 yrs survival • 63% vs 13% p=0. 002 – 10 yr survival data still favours chemo group • Progression free survival 44 vs 13% • Tumour specific survival 42 vs 17% • OS 27% vs 17% 1. Stockle M et al, J Urol. 1995 Jan; 153(1): 47 -52 2. Lehmann J, et al, BJU Int. 2006 Jan; 97(1): 42 -7 p=0. 002 p=0. 007 p=0. 07 trend

Adjuvant Chemotherapy • 4 other trials – negative However…. – All small trials – Two trials only included bladder confined disease – Inferior chemotherapy - single agent cisplatin

Adjuvant chemotherapy • Meta analysis» Cochrane Collaboration 2006 – 491 pts. from 6 trials – Power limited • • Small numbers Impact of trials stopped early Patients not receiving allocated rx Patients not receiving salvage chemotherapy – Showed a relative decrease in death of 25% in favour of adjuvant chemotherapy (p=0. 02) – Absolute survival benefit: 9% Cochrane Database Syst Rev. 2006 Apr 19; (2): CD 006018

Neoadjuvant chemotherapy • MRC trial (European) – 967 patients randomized to CMV vs no chemotherapy – Definitive management of primary either cystectomy or RT – 7 yr follow shows statistically significant benefit with neoadjuvant chemotherapy – No subgroup analysis done to compare cystectomy and RT groups Lancet 354 (9178): 533 -40, 1999

Neoadjuvant Chemotherapy • INT-0800(American) study » Confirmed results of MRC study – 317 patients with T 2 to T 4 a disease – Randomized to 3 cycles of neoadjuvant MVAC prior to cystectomy or cystectomy alone – Improved median survival by almost 3 years (77 months vs 46 months) – Decreased risk of bladder cancer specific death by 25% – Improved OS by 5% (p=0. 06) Grossman et al, N Engl J Med 349 (9): 859 -66, 2003

Neoadjuvant Chemotherapy • INT-0080 continued – Of long term survivors 85% had a complete pathologic response at the time of cystectomy – c. PR rates • 38% in MVAC group • 15% in surgery alone group (post TURBT) • p=0. 001 – Patients with T 3 and T 4 disease achieved the greatest survival benefit

Neoadjuvant Chemotherapy • Meta-analyses (3) – Advanced Cancer Meta-analysis Collaboration • Included 2688 patients from 10 randomized trials (did not include INT-0080) • Showed increased overall survival benefit of 5% at 5 yrs p=0. 016 when neoadjuvant platinum based combination chemotherapy used • Not significant if only single agent cisplatin trials were included Advanced Bladder Cancer Meta-analysis Collaboration. : Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361 (9373): 1927 -34, 2003

Neoadjuvant Chemotherapy • Canadian Meta-analysis • Winquist et al – 2605 patients in 11 trials with stage II or stage III disease – 2 -4 cycles of neoadjuvant chemo – Improved OS by 6. 5% p=0. 006 – Mortality due to chemotherapy 1. 1% Winquist E, et al, J Urol. 2004 Feb; 171(2 Pt 1): 561 -9

Neoadjuvant Chemotherapy • Advanced Bladder Cancer Meta-analysis collaboration – Now included 11 trials with 3005 patients – Included 98% of all known patients in randomized trials using cisplatin based combination chemotherapy – Improved OS by 5%; p=0. 003 – Decreased risk of death by 14% Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol. 2005 Aug; 48(2): 202 -5

Compare and Contrast • • • Neoadjuvant Deals with micromets sooner Best evidence of benefit Concern re: delay in surgery ? Increased surgical complications Is benefit worth it? • • • Adjuvant Treats only the highest risk pts. No delay in local Rx Evidence of benefit is weaker Delays in healing may preclude giving therapy Is benefit worth it?

Neoadjuvant chemotherapy • Reasons for lack of wide acceptance: – Inaccuracies in staging—needless chemotherapy – Delay in definitive surgery in patients that are non-responders to chemotherapy – Is the 5% absolutely survival improvement worth it? • Patient not referred or treated

CPG’s Do they make a difference? • Data was presented at the 2009 GU ASCO meeting regarding uptake of neoadjuvant consult requests in Alberta based on our guidelines – B. Miles, B. Eigl and others • Two cohorts of muscle invasive TCC patients – Diagnosed within 18 mos. pre or post publication of our guidelines recommending neoadjuvant treatment

CPG impact • Pre-Guidelines era – 2/107 (1. 5%) of patients with presumptive >T 2 TCC undergoing cystectomy were referred – No patient was offered any therapy preoperatively • Post-Guidelines era – 23/129 (21. 5%) were referred – 18/23 were offered treatment (cis/gem) 2009 Genitourinary Cancers Symposium, Feb 26 -8, 2009, Orlando, FL, abstract #270

CPG impact • While referral rates have improved, there is still significant room for improvement • In Edmonton, our referral rate has picked up recently – Approximately 2 -3 patients/mo referred • Patient selection and discussion with Urology is critical – Not all patients are appropriate for neoadjuvant treatment • Urology comfort level with pre-op treatment is higher due to good results and lack of major perioperative complications

Can we improve patient selection for neoadjuvant therapy? • If global benefit is 5% improvement in survival, can we better target the population to treat? • Should we only treat patients with extravesical disease on CT – Patients with pure T 2 metastasize too – CT/MRI isn’t wonderful at clinical staging

Who to treat? • Pathological features – LVI? • Genetic markers – p 53 status? • Other biomarkers – Area of research • Novel markers • SNP’s • Nucleoside transporters

What’s happening in the “real world” Neoadjuvant MO survey • 30 Canadian medical oncologists were surveyed – 25 responded – 90% were academic based, 50% in practice >10 years – Half of respondents see 5 -10 muscle invasive patients/yr – 25% see >20 cases/yr • Sample is skewed towards those who see lots of TCC patients

Neoadjuvant bladder cancer survey • All but one physician offered neoadjuvant therapy • Patients who are offered neoadjuvant treatment: – Tend to be younger (<65) – Better PS (ECOG 0 -1) – Good renal function (GFR >40) • Most used GC, although 20% used HDMVAC

Neoadjuvant bladder cancer survey • Despite MO willingness to treat, referrals nationally remain low • Plan is to survey Urologists to see if they are referring or not • Explore barriers to referral • Highlights the ever increasing multidisciplinary nature of disease management and need for good communication

CCI Neoadjuvant Project • All cases sent for neoadjuvant treatment who were treated and have cystectomy path available were reviewed • 2007 to present day • TURBT info on 62 patients; cystectomy path on 61 currently available • Clinical staging info based on Urology and CT assessment available at baseline

CCI Neoadjuvant Project • Baseline TURBT (n=62): – T 2: 30 – T 3: 29 – T 4: 3 • 46 men; 16 women • No age cutoff; oldest patient is 84 • All received cisplatin based regimens

CCI Neoadjuvant Project • Cystectomy Pathology (n=61) – p. T 0: – p. Tis – p. T 1 – p. T 2 or higher 17 7 3 34 • 28% are free of all cancer after Rx • 45% have no residual invasive disease

CCI Neoadjuvant Project • No patient who was deemed operable out the outset became inoperable due to time for chemo delivery • No perioperative mortality • No anecdotal reporting of increased perioperative morbidity • DFS and OS data still being collected

CCI Neoadjuvant Project • Significant p. T 0 rates can be achieved with GC – ? comparable to MVAC – This study is observational and not randomized • “real life” experience in giving chemotherapy shows it is doable if patients are properly selected • Once a good experience has occurred with one patient, it begets further referrals

Neoadjuvant chemotherapy Lessons learned • Urologists and Med Oncs need to case conference invasive TCC patients • Recognition that not all patients are good neoadjuvant chemo candidates is key • We can’t presume to know what magnitude of benefit a patient thinks is “worth it” to proceed • Having a case go smoothly dramatically increases referrals

Conclusions • Muscle invasive bladder cancer carries a significant risk of mortality • Most deaths are due to systemic disease • Strength of evidence for perioperative chemotherapy lies with neoadjuvant therapy • Treatment should be a cisplatin-based combination therapy for a 12 week period

Conclusions • Magnitude of benefit is similar to many other oncology situations – Node negative breast cancer, high risk stage II colon cancer • Despite evidence, referrals nationally are still low • Multidisciplinary care models are critical for good outcomes • Hopefully in the future we will be able to better select patients for therapy