Trimodality Therapy for Muscle Invasive Bladder Cancer

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1 Trimodality Therapy for Muscle Invasive Bladder Cancer Brita Danielson, MD, FRCPC Radiation Oncologist, Cross Cancer Institute Assistant Professor, Department of Oncology University of Alberta Edmonton, Alberta

2 Key Learning Objectives By participating in this session, health care professionals will: Review the evidence for trimodality therapy in muscle invasive bladder cancer Understand how trimodality therapy is delivered Identify optimal candidates for a bladder-sparing approach

3 Trimodality Therapy for Muscle Invasive Bladder Cancer ICUC 2015 Brita Danielson MD FRCPC Radiation Oncology, Cross Cancer Institute

4 Bladder Preservation with Trimodality Therapy What Why How

5 Bladder Preservation with Trimodality Therapy What Why How

6 What is Trimodality Therapy (TMT)? 1) Maximal TURBT followed by 2) External beam radiation therapy combined with 3) Chemotherapy (various concurrent, neoadjuvant, and adjuvant protocols) Cystoscopic assessment During chemort: response to therapy Follow-up surveillance Radical cystectomy reserved as a salvage option: incomplete response invasive local recurrence

7 Bladder Preservation with Trimodality Therapy What Why How

8 Why consider TMT? Radical cystectomy with pelvic LN dissection is the longstanding standard of care for muscle invasive bladder cancer 5 year OS rates: 55-60% in contemporary series

9 Why consider TMT? Some patients are not surgical candidates Age Comorbidities Even in patients fit for cystectomy, removal of bladder may lead to morbidity and affect patient comfort and QOL Despite sophisticated techniques for urinary diversion and option of orthotopic neobladder with continent urinary diversion

10 Organ Preservation Organ-preserving multimodality therapies have been established in other malignancies Head and neck cancer Cervical cancer Anal canal cancer

11 TMT vs Radical Cystectomy No RCTs that have directly compared radical surgery to TMT bladder-preservation UK Phase III RCT: SPARE (Selective Bladder Preservation Against Radical Excision) failed to accrue patients Indirect comparison between two approaches is difficult Selection bias TMT patients tend to be older with more comorbidities Clinico-pathologic stage discordance Clinical under-staging in 50% of patients

12 Evidence for TMT Decades of experience with bladderpreservation approaches single institution and cooperative group studies Recent pooled analysis of 6 RTOG Trials (Mak et al, Journal of Clinical Oncology, Dec, 2014) 468 patients treated for bladder preservation (5 phase II trials, 1 phase III trial)

13 RTOG Pooled Analysis Median follow-up of 4.3 years (7.8 years among survivors) 5 year OS rate: 57% 10 year OS rate: 36% Similar to contemporary cystectomy studies

14 RTOG Pooled Analysis Complete response to chemort was 69% Local failure rate of 43% Most local failures were non muscle-invasive 80% of patients had an intact bladder at 5 years Indications for salvage cystectomy: 62%: incomplete response to chemort 36%: invasive local recurrence on follow-up 2%: other causes Distant mets develop in 1/3 of patients

15 T2 vs T3/4 disease: RTOG Subgroup Analysis Higher T-stage associated with decreased OS 5 yr OS: 62% T2 vs 49% T3/4 10 yr OS: 41% T2 vs 30% T3/4 TMT for the elderly: Patients age 75 (n= 80): no difference in rates of complete response, DSS, and bladder-intact survival

16 Common concerns regarding TMT Long Term Toxicity Pooled analysis of RTOG studies (Efstathiou et al, Journal of Clinical Oncology, 2009) Late grade 3 GU toxicity: 5.7% Late grade 3 GI toxicity: 1.9% Other series confirm low risk of toxicity, good QOL outcomes, and preservation of a functional bladder ie: cystectomy for contracted bladder: 0% in MGH series, 2% (3 patients) in Erlangen series

17 Common concerns regarding TMT Curability and Feasibility of salvage cystectomy Patients in the pooled analysis of RTOG studies who required salvage cystectomy still had a 5 yr DSS rate of 60%, and 10 year DSS rate of 47% Risk of complications from radical cystectomy after TMT is acceptable compared with upfront cystectomy 16% incidence of major complications and 2.2% rate of mortality within 90 days (Eswara et al, Journal of Urology, 2012) However, orthotopic neobladder reconstruction has a higher risk of functional complications after pelvic RT

18 Bladder Preservation with Trimodality Therapy What Why How

19 How is Trimodality Therapy delivered? Patient Selection: Ideal candidates for TMT: Small tumor (< 5 cm) Unifocal disease Absence of in situ tumors Visibly and microscopically complete TURBT Absence of hydronephrosis No pelvic lymph node metastases Good bladder function at baseline Agreeable to follow-up cystoscopy

20 How is Trimodality Therapy delivered? Maximal TURBT Start chemort within 6-8 weeks EBRT: Standard fractionation (1.8 2Gy per fraction) At least Gy to pelvic LN, 65 Gy to bladder 6-7 week course of daily treatments Use of IMRT to better target treatment volumes and avoid normal surrounding tissue In cystectomy candidates, second-look cystoscopy may be done after Gy to ensure response Salvage cystectomy is considered in patients with residual disease

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24 EBRT Side effects Acute: Fatigue Irritative voiding symptoms Loose stool, diarrhea Late: Change in bladder habits <5% risk of bladder contracture or ulceration requiring cystectomy Proctitis Rare: small bowel injury (obstruction, perforation, fistula), second malignancy

25 How is Trimodality Therapy delivered? Chemo: Concurrent cisplatin most commonly used Given q 1-3 weeks during RT (depending on dose) Weekly carboplatin for patients with poor renal function Some patients receive neoadjuvant chemo prior to chemort Cisplatin/gemcitabine x 3 cycles

26 Follow-up after Trimodality Therapy Cystoscopy ± biopsy and cytology q 3 months for 1 year, then at increasing intervals CT abdomen and pelvis q 3-6 months for 2 years, then at increasing intervals CXR q 6 months for 3 years, then at increasing intervals

27 Conclusions TMT is a safe and effective treatment approach that should be offered to good candidates with muscle invasive bladder cancer Survival rates comparable to surgery Acceptable late toxicity Vast majority of survivors preserve their bladders When counseling patients with muscle-invasive bladder cancer concerning their treatment options, organ-sparing TMT cannot be ignored. (Rödel, JCO Editorial, 2014)