EAU 2017: Comparative effectiveness of selective adjuvant versus systematic neoadjuvant chemotherapy-based strategy for muscle-invasive urothelial carcinoma of the bladder

London, England (UroToday.com) Level 1 evidence supports the utilization of neoadjuvant cisplatin-based chemotherapy (NAC) prior to radical cystectomy (RC) for non-metastatic muscle-invasive bladder cancer. However, the evidence for adjuvant therapy has been mixed; though recent and upcoming studies may prove benefit of adjuvant therapy as well. The authors of this study utilized a large United States-based patient database, the National Cancer Database, to compare two different treatment strategies:
1. Selective Adjuvant chemotherapy (SelAC) - Upfront RC followed – performance status and absence of surgical contraindications permitting – by the selective delivery of AC in patients with adverse pathological features (cT3/4), while watching those with organ-confined disease.
2. Systematic NAC (SysNAC) - NAC in all eligible individuals followed by surgery if amenable

Utilizing the NCDB, the group identified 10,056 patients who underwent RC for cT2-4N0M0 bladder cancer, of which 8,312 (82.7%) vs. 1,744 (17.3%) patients underwent selAC- vs. sysNAC-based strategy, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses with time-varying covariate were used to compare OS – the Kaplan-Meier curves below demonstrate that median OS was significantly longer in the SelAC group (42.0 [95%CI, 39.5-44.6] vs. 33.7 [95%CI, 29.4-38.1] months; P=0.001). The 5-year IPTW-adjusted rates of OS was also better: 42.98% [95%CI, 41.8-44.2] vs. 37.45% [95%CI,34.8-40.1], respectively.

chart 1

Subsequently, they note that on additional analysis, the primary benefit was in cT2 (not pathologic stage, just clinical stage) patients. cT3 patients actually did worse with SelAC. Based on this, they state that randomized trials are warranted.

Limitations / Discussion Points:
This paper generated significant discussion, and had excellent input from the audience and the moderators (including Professor C.N. Sternberg). Some of the points below are my own.

1. It is uncertain from the authors if they were able to accurately determine timing of AC administration – was it truly adjuvant, or could it have been salvage?
2. The treatment regimens (chemotherapy) are unknown – cisplatin eligibility and administration may be limited after cystectomy, so knowing the AC and NAC regimens is always important.
3. To some degree, there is a component of immortal time bias – patients that die of disease or other causes soon after cystectomy (and never had opportunity to get chemotherapy in adjuvant setting) may not have been included in the study. This was unclear from their poster, and needs to be clarified. It may explain why patients getting AC appear to have done better.
4. A very important point brought up by Dr. Sternberg – the cT2 patients for the most part would not have had “poor pathologic features” such as pT3+ disease (except for the few that upstaged), so they never actually got AC. As such, they did fine without any chemotherapy at all. As this is the main group that demonstrated benefit from selAC, perhaps this study just indicates that NAC should not be administered for cT2 disease; as opposed to giving AC to cT3 disease!

Randomized prospective study in an intent-to-treat fashion would be ideal comparison.

Presented by: T. Seisen

Co-Authors: Sonpavde G., Kachroo N., Lipsitz S., Leow J., Menon M., Gild P., Von Landenberg N., Rouprêt M., Kibel A., Sun M., Pal S., Bellmunt J., Choueiri T., Trinh Q-D.

1. Brigham and Women's Hospital, Harvard Medical School, Division of Urological Surgery and Center For Surgery and Public Health, Boston, United States of America
2. University of Alabama At Birmingham, Division of Hematology-Oncology, Department of Medicine, Birmingham, United States of America
3. Henry Ford Health System, VUI Center for Outcomes Research, Analytics and Evaluation, Vattikuti Urology Institute, Detroit, United States of America
4. Brigham and Women's Hospital, Harvard Medical School and Harvard T.H. Chan School of Public Health, Center for Surgery and Public Health, Boston, United States of America
5. Pitié-Salpêtrière, APHP, University Paris VI, Dept. of Urology, Paris, France
6. City of Hope Comprehensive Cancer Center, Dept. of Medical Oncology & Experimental Therapeutics, Duarte, United States of America
7. Dana Farber Cancer Institute, Dept. of Medical Oncology, Boston, United States of America

Written by: Thenappan Chandrasekar, Clinical Fellow, University of Toronto

Twitter: @tchandra_uromd

at the #EAU17 -March 24-28, 2017- London, England