A new study is the first to report the beneficial use of chemotherapy plus immunotherapy before surgical removal of the bladder in muscle-invasive bladder cancer (MIBC). Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center led the study, reporting that the regimen reduced the invasiveness of the cancer in 56% of patients in a phase II clinical trial.
The findings were published in the Journal of Clinical Oncology.
“Downstaging, or treating tumors so that they become less invasive prior to surgical removal, is an important tool in muscle-invasive bladder cancer,” said UNC Lineberger’s Tracy Rose, MD, MPH, assistant professor at the UNC School of Medicine and lead author of this finding. “If we can treat a tumor pre-surgically so that it regresses to a stage where it is superficial and does not invade the bladder muscle wall, the chances of long-term survival are better.”
Nearly 25% of all bladder cancers are muscle invasive. Surgical removal of the bladder is performed in many MIBC cases, but often microscopic cancer cells have already spread to lymph nodes, greatly reducing chances of a cure. In these cases, clinicians often use cisplatin chemotherapy before removal of the bladder to reduce tumor volume and kill micro-metastases. Despite this aggressive treatment, more than half of patients see their cancer return within two years.
“Optimal management of MIBC is a huge unmet need,” said UNC Lineberger’s Matthew Milowsky, MD, the paper’s corresponding author and the George Gabriel and Frances Gable Villere Distinguished Professor of Bladder and Genitourinary Cancer Research. “We think that the combination treatment used in our trial may improve outcomes compared with chemotherapy alone, with the aim of ridding micro-metastatic disease so that even a modest improvement in response rates translates to higher cure rates.”
All of the 39 patients enrolled in the trial had tumors that had grown into the muscle layer of the bladder wall. The patients intravenously received the immunotherapy drug pembrolizumab in combination with standard cisplatin-based chemotherapy before surgery. What was unique about this trial is that patients received cisplatin on the first and eighth day of their treatment cycles. This approach, known as ‘split dosing’, helped reduce toxicities compared to single, initial high doses, making the treatment more tolerable, especially in patients with borderline kidney function or other comorbidities. Pembrolizumab was continued every 21 days for four cycles. All patients except one had their bladders surgically removed after finishing their chemo- and immunotherapies.
Twenty-two patients (56%) saw their tumors regress to a less invasive stage and regress from the muscle layer of the bladder; 14 patients (36%) saw their tumors completely disappear from their bladder. The most common side effects were low blood platelet counts, anemia and several other blood and mineral-related deficiencies.
“More than a third of the patients saw a complete regression of their cancer and ultimately may not require surgical bladder removal,” Rose concluded. “More studies will need to be done to identify who can safely avoid surgery. Several ongoing trials are investigating this bladder-sparing approach.”
The researchers are now analyzing blood and tumor samples to determine which patients were likely to respond to treatment and what changes took place in the tumors, blood, and immune system during and after treatment.
Authors and disclosures
In addition to Rose and Milowsky, the paper’s other authors at UNC include Allison M. Deal, MS, Young E. Whang, MD, PhD, Blaine Brower, FNP, Mary Dunn, RN, MSN, OCN, NP-C, Chelsea K. Osterman, MD, Hillary M. Heiling, Marc A. Bjurlin, DO, MSc, Angela B. Smith, MD, MS, Matthew E. Nielsen, MD, MS, FACS. Hung-Jui Tan, MD, MSHPM, Eric Wallen, MD, FACS, Anthony Drier, and William Y. Kim, MD. Michael R. Harrison, MD, Sundhar Ramalingam, MD, Daniel George, MD, and Tian Zhang MD, are at Duke Cancer Institute, Durham, NC. Michael E. Woods, MD, is at Loyola University Medical Center, Maywood, IL.
This work was by supported by Merck & Co. Rose is supported by the Doris Duke Charitable Foundation grant 2015213 and the National Cancer Institute grant 1K08CA248967. Osterman is supported by a National Research Service Award Post-Doctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by the Cecil G. Sheps Center for Health Services Research, the University of North Carolina at Chapel Hill, grant 5T32H2000032.