ASCO 2018: Relapse-Free Survival of Clinical T2-4N0 Urothelial Bladder Carcinoma After Radical Cystectomy, with or without Perioperative Chemotherapy: Endpoints for Clinical Trial Design.

Chicago, IL (UroToday.com) Results from several prospective trials have led to neoadjuvant chemotherapy followed by radical cystectomy being considered the gold-standard treatment for patients with muscle-invasive bladder cancer (MIBC)1 2.
In a meta-analysis of 886 patients analyzed after neoadjuvant chemotherapy and radical cystectomy, the pathological complete response rate was 28.6%, leading to a relative risk for OS of 0.45 (95%CI 0.36-0.56) compared to those that did not achieve complete response3. However, data from 19 centers outside of a clinical trial suggested that pathologic complete response rates may lower in the real-world setting (23.9-24.5%) compared to clinical trials 4. As such, the full benefit of neoadjuvant therapy may not be captured via pathologic complete response rates.


Marco Bandini and colleagues presented results of their study assessing improved relapse-free survival (RFS) as a novel mechanism for identifying patients with optimal benefit from neoadjuvant chemotherapy. 

The authors used a multi-institutional cohort to identify 950 patients (1990-2016) with cT2-4N0 bladder urothelial carcinoma from 27 centers in the U.S., Europe, Israel, and Canada. A Cox-based nomogram was used to predict 12 month RFS, using gender, race, tumor characteristics (histology, pT, pN and surgical margin status), and administration of neoadjuvant or adjuvant chemotherapy in the model. For the model, multiple imputation was performed to handle missing data, and validation (2000 bootstrap resamples) was internally tested. Finally, calibration and prognostic ability were assessed comparing estimated versus observed 12 month RFS.

There were 577 (59.3%) patients with cT2 disease and 236 (24.3%) patients with cT3-T4 disease. T-stage was unknown for 160 (16.4%) patients and thus imputated. In this cohort, 125 (12.8%) patients had mixed urothelial carcinoma and other histologies, 275 (28.3%) patients received neoadjuvant chemotherapy, and 165 (17%) patients received adjuvant chemotherapy.

Overall, 405 (41.6%) patients relapsed and 375 (38.5%) patients died, with a median RFS of 44 months (95%CI 36-65) and median OS of 57 months (95%CI 50-90). On multivariable analyses, increasing pT stage (p < 0.002), increasing pN sage (p < 0.001) and positive surgical margin status (vs negative; HR 1.66, 95%CI 1.21-2.30) were associated with higher rate of recurrence.

Interestingly, use of neoadjuvant chemotherapy was associated with lower risk of recurrence on univariable analysis (HR 0.74, 95%CI 0.59-0.94), however, this association was not significant on multivariable analysis (p=0.6).

Among patients receiving perioperative chemotherapy, nomogram-predicted 12 month RFS rates were 91.6% (95%CI 87-96), 79.7% (95%CI 73-88), and 53.0% (95%CI 44-63), across the nomogram-derived tertiles. However, for patients who did not receive perioperative chemotherapy, these estimates were lower at 89.8%, 74.8%, and 47.0%, respectively. The final bootstrapped c-index of the nomogram was 78% (95%CI 74-81).

Continuing to provide new meaningful and rationale endpoints for clinical trial design is important. Based on the results presented by Marco Bandini, RFS appears to be a reasonable and evaluable endpoint and as he suggests: nomogram-predicted 12 month RFS rates may provide data to base future clinical trial designs of novel agents in the perioperative setting.

Presented by: Dr. Marco Bandini, Vita-Salute San Raffaele University, Milan, Italy

Co-Authors: Alberto Briganti, Elizabeth R. Plimack, Guenter Niegisch, Evan Y. Yu, Aristotelis Bamias, Neeraj Agarwal, Srikala S. Sridhar, Cora N. Sternberg, Ulka N. Vaishampayan, Christine Theodore, Jonathan E. Rosenberg, Joaquim Bellmunt, Matt D. Galsky, Francesco Montorsi, Andrea Necchi; Vita-Salute San Raffaele University, Milan, Italy; Vita-Salute San Raffaele University, Urological Research Institute, IRCCS San Raffaele Hospital, Milan, Italy; Fox Chase Cancer Center, Philadelphia, PA; Heinrich Heine University, Duesseldorf, Germany; Seattle Cancer Care Alliance, Seattle, WA; National and Kapodistrian University of Athens, Athens, Greece; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; San Camillo-Forlanini Hospital, Rome, Italy; Karmanos Cancer Center, Detroit, MI; Hospital Foch, Suresnes, France; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY; Universita Vita Salute San Raffaele, Milan, Italy; Istituto Nazionale dei Tumori, Milan, Italy

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:
1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
2. Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171-2177.
3. Petrelli F Coinu A, Cabiddu M, et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: A meta-analysis. Eur Urol 2014;65(2):350-357.
4. Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol  2015;67(2):241-249.
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