Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Mahmood rasheed Hematology/oncology fellow virginia commonwealth university medical center

Briefly review the epidemiology, initial diagnostic evaluation, and staging of urothelial bladder cancer. Discuss the rationale for neo-adjuvant chemotherapy in muscle-invasive bladder cancer. Examine the data supporting chemotherapy regimens commonly used in this setting. Review society guidelines surrounding the use of neo-adjuvant chemotherapy in bladder cancer. Explore trends in utilization rates of neoadjuvant chemotherapy in bladder cancer. Consider future directions including the search for tumor markers of chemosensitivity and the use of neoadjuvant immunotherapy. Objectives

Introduction 6th most common cancer in US. 79,000 new cases, 17,000 deaths in 2017. 5:1 ratio of incidence to mortality reflects the frequency of non-invasive tumors. Median age at diagnosis – 73 years. 3:1 male to female ratio. Risk factors: Environmental exposures (“field cancerization”) Cigarette smoking, aromatic amines (industrial dyes, chemicals involved in rubber/aluminum manufacturing), cyclophosphamide, phenacetin. HNPCC (Lynch syndrome)

Extent at Diagnosis Non-muscle invasive (70%) Recur frequently. Treated with endoscopic resection (TURBT) +/- intravesical chemotherapy. Locally Advanced/ Muscle Invasive (20- 25%) High potential for metastatic recurrence. Treated with radical cystectomy and pelvic lymph node dissection. Bladder-sparing approaches Metastatic (5-10%) Systemic chemotherapy

Initial Work-up Cystoscopy, EUA/TURBT CT or MRI of abdomen/pelvis Before TURBT when muscle invasion is suspected. Urine cytology Low sensitivity Chest imaging +/- bone scan if suspected osseous disease (bone pain, elevated alkaline phosphatase).

Staging

Staging

Radical Cystectomy + Pelvic Lymph Node Dissection Clinical versus Pathologic Staging Imaging Radical Cystectomy + Pelvic Lymph Node Dissection EUA/TURBT Myonecrosis Pathologic Stage Clinical Stage

Discordance in Clinical versus Pathological Staging “Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy.” Eur Urol. 2007 Jan;51(1):137-49; discussion 149-51. Epub 2006 Jun 8.

Prognosis Pathologic stage is a key survival determinant in patients undergoing cystectomy for bladder cancer. 5-year OS: 63% pT1 , 32% pT4. Worse prognosis with lymphatic or vascular invasion in primary tumor, lymph node involvement, extracapsular extension of involved lymph node. Maderbacher et al. ”Radical Cystectomy for Bladder Cancer Today—A Homogeneous Series Without Neoadjuvant Therapy” J Clin Oncol 2003

Prognosis Metastatic recurrence by 5 years is seen in 27% of those with pT2 disease and 47% of those with pT4 disease. Distant failure is much more common than local recurrence. This suggests the presence of occult micrometastatic disease at the time of surgery. Recurrence rates are high in muscle-invasive disease even in the absence of nodal spread. Maderbacher et al. ”Radical Cystectomy for Bladder Cancer Today—A Homogeneous Series Without Neoadjuvant Therapy” J Clin Oncol 2003

Muscle-invasive bladder cancer has a high probability of systemic dissemination at the time of diagnosis, even in the absence of overt metastatic disease or nodal positivity.

Neoadjuvant Chemotherapy Rationale: Systemic chemotherapy treats occult micrometastatic disease thought to be present at time of surgery and responsible for later relapsed disease. Why neo-adjuvant? Systemic chemotherapy is better tolerated in the neoadjuvant setting than post-operatively. Potentially downstages tumor to allow for less complicated surgery. Allows in vivo assessment of tumor response to systemic treatment. Evidence for adjuvant chemotherapy not as robust.

Neoadjuvant Chemotherapy: SWOG 8710 SWOG trial with 317 patients over 126 institutions between 1987-1998. Enrolled patients with muscle-invasive (T2 to T4a) disease. Stratified by age (<65 years vs. >65) and stage (T2 vs T3-T4a). 154 patients were randomized to surgery alone and 153 to combination neoadjuvant therapy and surgery. Regimen: Three 28-day cycles of M-VAC Methotrexate (30 mg/m2) on days 1, 15 and 22 Vinblastine (3 mg/m2) on days 2, 15, and 22 Doxorubicin (30 mg/m2) Cisplatin (70 mg/m2) on day 2.

“82% of those in the chemo group and 81% of those in the surgery group proceeded with cystectomy.”

Neoadjuvant Chemotherapy: SWOG 8710 Effect on Tumor Stage: Of the 126 patients in the M-VAC group who underwent cystectomy, 48 (38%) of the surgical specimens were pathologically free of cancer (pT0) at the time of surgery. 26 (54%) of these patients initially had stage T2 disease and 22 (46%) initially had stage T3 or T4a disease. 5-year OS in this group was 85%.

Neoadjuvant Chemotherapy: SWOG 8710 First prospective trial showing efficacy in neoadjuvant chemotherapy. Prior negative neo-adjuvant studies: single- agent cisplatin or two-drug therapies. Toxicity profile and time to surgery subsequently improved upon with dose- dense MVAC: (Pilmak et al, J Clin Oncol 2014) (Choueiri et al, J Clin Oncol 2014).

Neoadjuvant Chemotherapy: EORTC/MRC BA06 30894 Multicenter, randomized trial Enrolled patients with muscle-invasive (T2 to T4a) disease. 976 patients at 102 institutions enrolled between 1989-1995. 485 patients were randomized to definitive local treatment with cystectomy or radiotherapy or both (per physician choice) and 491 to combination neoadjuvant therapy followed by definitive local treatment. Treatment Regimen: CMV x4 21-day cycles: Cisplatin 100 mg/m2 on Day 2 Methotrexate 30 mg/m2 on Days 1 and 8 Vinblastine 4 mg/m2 on Days 1 and 8 Initial analysis at 4-year median follow-up: 5.5% increase in 3- year OS (CI -0.5% to 11%)

Neoadjuvant Chemotherapy: EORTC/MRC (2011)

Neoadjuvant Chemotherapy: EORTC/MRC (2011) Median OS: ~38mo vs ~56mo

Neoadjuvant Chemotherapy: Gemcitabine/ Cisplatin Similar OS, better tolerated than MVAC in metastatic bladder cancer (von der Maase et al, J Clin Oncol 2000). Less robust data supporting its use in the neoadjuvant setting. Retrospective data: Multicenter study in J Eur Urology: 935 patients at 19 centers in North America and Europe, (64% gem/cisplatin, 20% MVAC 15% other). No significant difference in pathologic complete response between GC and MVAC (23.9% vs 24.5%).

Neoadjuvant Chemotherapy: Meta-Analysis - 3,005 patients, 11 clinical trials. Cisplatin monotherapy or cisplatin combinations (MVAC, CMV, cisplatin-methotrexate, cisplatin-adriamycin). GC was not represented. - 5% Absolute increase in 5‑year overall survival and a 14% decreased risk of death (HR 0.86) with combination chemotherapy - Single-agent cisplatin trials were not shown to provide any benefit in PFS or OS.

Neoadjuvant Chemotherapy: Society Guidelines

Neoadjuvant Chemotherapy: Commonly Used Regimens Weeks 6-8 12 9 Gemcitabine-cisplatin most commonly used. Also longest. - Some phase II data on dose-dense gemcitabine/cisplatin – effective but increased cardiac/vascular toxicity (Plimack et al 2014) Who shouldn’t receive cisplatin-based chemotherapy? Consensus criteria for ineligibility (Galsky et al 2011): - ECOG PS 2 or higher - Grade 2 or higher hearing loss or neuropathy - NYHA class III-IV heart failure - CrCl < 60

Neoadjuvant Chemotherapy: Rates of Utilization Review of SEER database, 5207 patients with non-metastatic, muscle-invasive disease from 1991-2009 who underwent radical cystectomy. Overall, 332 (6.4%) received NAC. Significantly increased over time (15% in 2009). Less likely to receive NAC: older patients, unmarried, T3 and higher disease.

Neoadjuvant Chemotherapy: Rates of Utilization Possible reasons for apparent underutilization: Actual or perceived ineligibility for chemotherapy due to age, poor performance status or renal function. Concern over risk of undue delay in surgery. Perceived modest overall benefit, especially in those without pathological response to treatment.

Neoadjuvant Chemotherapy: Rates of Utilization 117 patients with muscle-invasive disease (79% T2, 21% T3-T4a) undergoing NAC+cystectomy at Cleveland Clinic between 2006-2007. 69% gemcitabine/cisplatin, 14% MVAC, 17% other regimens. Only 7% achieved pathological CR. Median time to surgery from diagnosis: 208 days (vs 115 days in SWOG 8710, NR in EORTC/MRC).

Identifying predictors of response Avoid unnecessary toxicity/surgical delay in likely non-responders. Inactivating mutations of DNA-repair genes ERCC2, ATM, RB1, FANCC defects may confer cisplatin susceptibility (Plimack et al 2015, Van Allen et al 2014) Intrinsic subtyping by whole-genome RNA expression profiling Distinct subtypes of bladder cancer by gene expression (basal/luminal/p53-like, etc). Possible prognostic/chemosensitivity predictive value. Future Directions: Identifying predictors of response

Future Directions: SWOG 1314: “CoXEN Trial” Presently accruing (7/2014 -) Goal: ~184 patients with cT2 – cT4a, node-negative disease. Prospective assessment of the predictive power of the Co-expression Extrapolation Program (CoXEN), an mRNA expression-based algorithm, to predict tumor response to dose-dense MVAC vs GC. Estimated completion: October 2022

Anti- PD1 / PDL-1 antibodies Avelumab, durvalumab, atezolizumab, nivolumab, pembrolizumab approved for unresectable or metastatic bladder cancer that has progressed after cisplatin- containing chemotherapy. Pembrolizumab and avelumab are also approved as upfront treatment for those with unresectable or metastatic disease who are cisplatin-ineligible. Future Directions: Anti- PD1 / PDL-1 antibodies Funt and Rosenburg, Nature 2017.

A significant minority of patients with bladder cancer present with non-metastatic muscle-invasive disease and are at high risk for metastatic relapse after definitive local treatment. To treat occult metastatic disease, neo-adjuvant chemotherapy is preferred over adjuvant chemotherapy due to more robust data supporting its efficacy and better tolerability. Neoadjuvant chemotherapy does not result in increased failure to go to surgery or increased post-operative complications. Commonly used regimens include dose-dense MVAC, CMV, and GC. Cisplatin-ineligible patients with resectable disease should proceed directly to cystectomy. Non-cisplatin containing regimens have limited data to support their use in this setting. Excess delay in surgery may negate the benefit of neoadjuvant chemotherapy. Patients should proceed to surgery as early as possible following completion of chemotherapy. Tumor genetic testing and RNA expression profiling may in the future predict tumor chemosensitivity and guide who receives neoadjuvant chemotherapy. Immune checkpoint inhibitors may augment the action of neoadjuvant chemotherapy and provide a treatment options for cisplatin-ineligible patients in this setting. Take-Home Points

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