BETHESDA, MD USA (UroToday.com) - In this session, Dr. Elizabeth Plimack presented data regarding neoadjuvant and adjuvant chemotherapy in bladder cancer, as well as potential new ways in which to identify patients most likely to demonstrate response to chemotherapy. Neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) results in a proven improvement in survival. Dr. Plimack presented results from the SWOG-8710 study that found a 2.6 year overall survival benefit associated with neoadjuvant chemotherapy. As a result of this and other studies confirming its survival benefit, neoadjuvant chemotherapy should be considered the standard of care in MIBC, as set out by all major association guidelines (e.g., AUA, NCCN, EAU). Dr. Plimack noted that the evidence for adjuvant therapy is not as clear-cut. She presented results from the EORTC trial of adjuvant vs deferred chemotherapy after cystectomy for pT3-pT4 and/or node positive, M0 urothelial carcinoma of the bladder which demonstrated improved progression-free survival with adjuvant chemotherapy, but was underpowered to demonstrate a difference in overall survival. Dr. Plimack noted that often these patients never make it to adjuvant chemotherapy given prolonged recovery following surgery.
Next she presented data from the Fox Chase Cancer Center experience with accelerated MVAC (AMVAC) neoadjuvant chemotherapy. This regimen involves administration of MVAC with additional growth factors and anti-emetics allowing for administration every 2 weeks, with completion of 3 cycles in 4 weeks, followed by surgery 4-8 weeks later. She noted an abbreviated time to surgery from initiation of chemotherapy at a median of 9.7 weeks. The regimen was well tolerated (18% grade 3-4 toxicity) with 84% completing all 3 cycles, and pathologic response to AMVAC was similar to other neoadjuvant regimens, with 38% of the cohort demonstrating T0 disease at time of cystectomy. In addition, 65% of patients demonstrated down-staging of disease. Increased recurrence-free survival and overall survival was seen at a median follow-up of 20 months. Dr. Plimack noted that these findings mirror those seen in prior retrospective and prospective studies examining AMVAC.
She then discussed the use of the Fox Chase prospective AMVAC study to identify biomarkers that identify patients likely to respond to chemotherapy. Utilizing pre-treatment tumor tissue, genetic mutations in known cancer-related genes were examined via the FoundationOne platform. This study demonstrated that patients who responded to chemotherapy had higher rates of genetic alterations. They found that alterations in three genes—ATM, RB1 and FANCC—were predictive of pathologic complete response, with a sensitivity of 93% and a specificity of 100% in a small cohort. A similar study comparing mutations in patients with disease downgrading to pT0 or pTis after neoadjuvant chemotherapy, vs non-responders, identified mutations in ERCC2 as predictive of response to chemotherapy. ATM, FANCC and ERCC2 are involved in DNA damage repair and RB1 is involved in chromatin remodeling and stability. Based on these functions, Dr. Plimack set forth the hypothesis that mutations of these genes, resulting in non-functioning proteins, likely results in increased tumor susceptibility to chemotherapy due to a decreased ability to cope with DNA damage induced by the chemotherapy. Dr. Plimack finished up by presenting the SWOG COXEN-directed neoadjuvant trial as an example of a prospective trial examining the ability of specific biomarkers to predict response to chemotherapy in bladder cancer.
Overall Dr. Plimack’s talk provided an excellent overview of the current state of chemotherapy use in bladder cancer as well as where research in bladder cancer chemotherapy is headed in the immediate future. The ability to identify patients likely to respond to neoadjuvant chemotherapy has the potential for significant clinical impact as it would allow for avoidance of toxicities and delays in definitive surgical treatment in those not likely to respond to standard chemotherapy regimens.
Presented by:
Elizabeth R. Plimack, MD
Fox Chase Cancer Center, Philadelphia, PA USA
Reported by:
Timothy Ito, MD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA