San Francisco, CA USA (UroToday.com) Dr. Nicholas James highlights that bladder cancer outcomes have not significantly improved in the past 30 years and recent discoveries have potential to change this trend. Bladder cancer is a systemic disease. There has been no plateau in survival curves. Therefore, to improve outcomes, we need improvement in systemic disease control and a better selection of patients for correct therapy.
Recently, multiple overlapping molecular stratification systems have been introduced in bladder cancer. These include UNC, MD Anderson, TCGA, and LUND schemes. Dr. James highlights TCGA Bladder Cancer stratification system, which was done on 131 chemo-naïve muscle invasive bladder cancer. The data illustrated a high-rate of DNA changes. These changes can be classified by protein expression level, RNA level or into a signaling network level. These networks can be used to identify targets for therapy. Recent potential targets identified include PI3kinase +mTOR, ERBB2 and ERBB3 pathways. The molecular stratification systems attempt to resolve profound genetic diversity. However, genetic diversity needs to be investigated as biomarkers for response to therapy such as for neoadjuvant chemotherapy so that we can triage patients into appropriate therapy. Dr. James recommends that future trials should collect data on molecular subtypes, and existing trials should try to retrospectively analyze the impact of subtypes on outcomes.
Dr. James then transitions to discussing recent interest in immunotherapy in bladder cancer. He mentions that immunotherapy has an established role in bladder cancer. BCG induces immune response. Bladder cancer has a high mutational complexity, which may allow us to identify a number of neoantigens. Dr. James then highlights several immune check-point inhibitors under investigation including Atezolizumab (antibody to PD-L1), Pembrolizumab (antibody to PD1), Nivolumab (antibody to PD1), and Ipilumimab (antibody to CTLA4). Phase I trial with MPDL3280A (anti-PDL1) showed favorable anti-tumor activity in metastatic urothelial cancer.
PD1 pathway needs to be investigated in high-risk NMIBC, neoadjuvant setting, synchronous with chemoradiotherapy in bladder conversation setting, adjuvant setting, first-line metastatic setting, or second-line metastatic setting. The race for these trials is on and next few years may allow us to identify new and effective therapeutics to improve patient outcomes.
Dr. James then highlights recent trials that brought a renewed interest in adjuvant therapy after radical cystectomy. EORTC 30994 trial illustrated an improved overall survival and progression-free survival in patients with pT3-4 or N+ M0 urothelial carcinoma. Retrospective analysis from National Cancer Database also illustrated an improved survival with adjuvant chemotherapy. Dr. James then discusses pros and cons of adjuvant therapy. Adjuvant therapy may allow us to risk stratify patients who may benefit after pathologic information is known from radical cystectomy. Additionally, AT may allow us to get the most important therapy (radical cystectomy) early. However, many patients are not fit for chemotherapy post-cystectomy and may limit the necessary treatment in many. Dr. James concludes that adjuvant chemotherapy is effective but only level 2 evidence exist. However, for neoadjuvant chemotherapy, level I evidence exist. Additionally adjuvant therapy is not as broadly applicable as neoadjuvant chemotherapy as patients may not be as fit postop as they are preop.
Dr. James then discussed recent studies in bladder preservation study. Bladder preservation leads to improved quality of life in several domains studied (physical, role, social, emotional, and cognitive functioning). Sexual HRQOL as well as body-image outlook are also improved with bladder preservation. Residual mass post TURBT in these patients is a prognostic factor and not a predictive factor. These patients have poor outcomes.
Dr. James concludes that we are living in an exciting era in bladder cancer research. Using genomics, we have identified several targets for therapeutic action. There is rapidly emerging data on immune-therapy and additional proof that chemotherapy perioperative improves outcome.
Presented By:
Nicholas D. James, BSc, MBBS, PhD
University of Warwick and Queen Elizabeth Hospital
Reported By:
Mohammed Haseebuddin, MD at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA