ASCO 2018: Tailoring of Chemotherapy to Fit Patients with Metastatic Urothelial Cancer

Chicago, IL (UroToday.com) At the precision therapy in the treatment of advanced urothelial cancer session, Arlene Siefker-Radtke, MD, discussed systematic chemotherapy for these patients and how it best fits into the treatment paradigm. 

Dr. Siefker-Radtke notes that there have been decades of chemotherapy for the treatment of metastatic urothelial cancer, and even early “immunotherapy”. These include cisplatin, CisCA, M-VeCarbo, FAP (5-FU, IFNa, cisplatin), gem/cis, taxol/carboplatin, escalated M-VAC, dose-dense MVAC, and taxotere + cisplatin. Gemcitabine-cisplatin is the ‘standard’ chemotherapy for metastatic bladder cancer treatment, leading to a median OS of 13 months, although it is associated with more myelosuppression as compared to MVAC. 

The current standards, according to Dr. Siefker-Radtke, for urothelial cancer are as follows:

  • Cisplatin-based chemotherapy remains the standard in the management of bladder cancer
  • In the neoadjuvant space, MVAC is still the best by prospective data, however, gemcitabine-cisplatin is used based upon metastatic data extrapolation
  • In the metastatic/incurable space, cisplatin eligible patients receive gemcitabine-cisplatin, and for cisplatin-ineligible patients, patients receive pembrolizumab or atezolizumab
  • In the second line (after progression on cisplatin-based chemotherapy), there are five immunotherapy agents approved for bladder cancer: pembrolizumab, atezolizumab, nivolumab, durvalumab, and avelumab
Despite all of the excitement for immunotherapy for bladder cancer, according to Dr. Siefker-Radtke, there are emerging concepts for chemotherapy. One such development is for dose-dense chemotherapy, the principles of which include:

  • 2 weeks of MVAC, or
  • Gemcitabine-cisplatin on a 3-week schedule
  • Improved toxicity profile
  • Modest clinical benefit
In one of the seminal trials [1], high dose MVAC on a 2-week schedule vs traditional MVAC demonstrated less mucositis and myelosuppression for the dose-dense regimen, as well as an improved complete response rate from 9% to 21%. Furthermore, this also improved 3-5 year survival, although the HR was 0.80 (95%CI 0.60-1.06). Dose-dense MVAC has also been tested in the neoadjuvant setting in combination with bevacizumab [2] (MVAC 2 weeks x 4 cycles). In high-risk patients, there was a pT0 rate of 38%, ≤pT1 rate of 53%, with a 5-year OS of 63% over a median follow-up of 49 months. This regimen was less toxic than traditional MVAC, with neutropenic fever noted in 27% and fatigue in 12%. Dr. Siefker-Radtke summarized the dose-dense therapy landscape with several important points:

  • Similar efficacy compared to traditional chemotherapy, with slightly improved response rates and slightly increased long-term survival
  • Improvement in toxicity
  • Shorter time on treatment
But, as Dr. Siefker-Radtke notes, bladder cancer is no longer just one disease. It is composed of multiple diseases, which differ in their underlying biology, and in their mutation patterns which play a role in the biology (ie. FGFR3). Gene expression profiling has differentiated tumors based on prognosis and predicting which tumors will benefit from treatment. Based on molecular subtyping, there are three intrinsic subtypes:

  • Basal – highest proliferation, with the worst clinical outcomes; however, the highest likelihood to benefit from neoadjuvant chemotherapy
  • Luminal – intermediate proliferation, often associated with FGFR3 mutations
  • p53-like – lowest proliferation, and associated with stromal markers
According to Dr. Siefker-Radtke, understanding the biology of different subtypes allows personalized medicine, in that we can choose the best treatment, understand resistance mechanisms of each, and more rationally combine and sequence different regimens. 

Dr. Siefker-Radtke concluded with an excellent final slide summarizing the paradigm shift in urothelial cancer, and once again highlighting that urothelial cancer is no longer one disease entity:

paradigm shift urothelial cancer

References:
1. Sternberg CN, de Mulder PH, Schornagel JH et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19:2638-2646.
2. McConkey DJ, Choi W, Shen Y, et al. A prognostic gene expression signature in molecular classification of chemotherapy-naïve urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: A phase 2 trial of dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in urothelial cancer. Eur Urol 2016;69(5):855-862.

Presented by: Arlene Siefker-Radke, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX


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
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