Surgical paradigm shifts to achieve complete cytoreduction during primary debulking surgery and the use of perioperative epidural anesthesia improve survival outcomes for ovarian cancer patients, our recently published research shows.
We collected data for all patients with stage IIIB to IV high-grade ovarian carcinoma who underwent primary debulking surgery over a 13-year period at Memorial Sloan Kettering Cancer Center and performed two retrospective analyses to examine the relationship between changes in surgical approach and patient outcomes. Both studies were published in Gynecologic Oncology.
The results of the first study confirmed that the shift in surgical protocol to more complete cytoreductive surgery has led to better outcomes. Despite higher-stage disease and greater tumor burden, rates for complete gross resection increased from 29 percent to 55 percent and were independently associated with progression-free and overall survival in our analysis of results for 978 patients. (1)
In the second study, perioperative epidural anesthesia was associated with improved progression-free survival and overall survival. The median overall survival was 62.4 months for 435 patients in the epidural group compared to 41.9 months for 213 patients in the nonepidural group (p<0.001). After controlling for confounding factors, including residual disease, epidural use was independently associated with risk of progression (HR=1.327; 95 percent CI, 1.066 to 1.653) and death (HR=1.5887; 95 percent CI, 1.224 to 2.06). (2)
Complete Gross Resection
At MSK, we implemented several significant advances in our approach to ovarian cancer debulking surgery between 2001 and 2013. These changes included a shift in the cytoreductive goal from less than 1 to 2 centimeters of residual disease to no gross residual disease, the performance of extensive upper abdominal surgery and cardiophrenic lymph node dissection, alterations in patient selection to neoadjuvant chemotherapy, and earlier operative start times.
In our recent retrospective study, we stratified patient results based on the year of their primary surgery into three groups that aligned with changes in the surgical protocol as follows. From 2001 to 2005, we incorporated extensive upper abdominal procedures into our debulking protocol. (3) Between 2006 and 2009, the goal for primary debulking surgery evolved from less than 10 millimeters of residual disease to either complete gross resection or as minimal residual tumor as possible. Finally, during the 2010 to 2013 period, we gradually adopted three additional changes: routine resection of cardiophrenic lymph nodes, selecting some patients for neoadjuvant chemotherapy, and implementing earlier start times for operations. (1)
The results showed an increase in complete gross resection rates from 29 percent to 55 percent and improved progression-free survival and overall survival, despite higher-stage disease and greater tumor burden. Five-year progression-free survival rates increased over time (15, 16, and 20 percent, respectively for each cohort, at p<0.001) and so did five-year overall survival rates (40, 44, and 56 percent, respectively, at p=<0.001). (1)
Epidural Anesthesia in Primary Debulking Surgery
Most patients with ovarian cancer are diagnosed with advanced-stage disease, often with metastases to the omentum, small and large bowel, diaphragm, and upper abdominal organs. (4)Unfortunately, five-year survival with advanced ovarian cancer is typically about 30 percent. (4)Residual disease at the time of primary debulking surgery and postoperative chemotherapy have been the only modifiable prognostic factors.
Perioperative epidural anesthesia has emerged as a potential prognostic factor for improved outcomes in solid tumors. The proposed mechanism of action involves the surgical stress response and the immune system. The use of perioperative epidural anesthesia is thought to blunt the surgical stress response, leading to decreased protumorigenic cytokine and catecholamine release while at the same time promoting antitumorigenic cell-signaling processes. Epidural anesthesia also reduces the need for general anesthesia and systemic opioid use, counteracting surgery-induced cell mediated immunity (CMI) inhibition. (2)
In our study, we identified 648 patients diagnosed with stage IIIB to IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had undergone primary debulking surgery at MSK between January 1, 2005, and December 31, 2013. Patients were divided into two groups: those who received epidural anesthesia and those who did not. All patients received intraoperative general anesthesia, regardless of epidural use. Median progression-free survival was prolonged by seven months and overall survival was extended by 20 months with epidural anesthesia use. This study was one of the largest to date investigating the association between perioperative epidural use and oncologic outcomes for solid tumor malignancies. (2)
Neoadjuvant Chemotherapy or Primary Debulking Surgery?
There is no question that complete cytoreduction during primary debulking surgery is one of the most prognostic factors in treating ovarian cancer. Our research confirms that increased complete gross resection rates are independently associated with better progression-free survival and overall survival. We will continue to strive to improve complete gross resection rates and survival outcomes while minimizing morbidity and mortality.
In the meantime, we are investigating the role of neoadjuvant chemotherapy, as the benefits need to be more clearly defined. It is difficult to compare survival rates between studies of neoadjuvant chemotherapy and primary debulking surgery in the literature since patient groups are not balanced for cancer stage. MSK is the only American cancer center participating in the Trial of Radical Upfront Surgical Therapy (TRUST), an international, multicenter, randomized, controlled trial investigating the difference in outcomes of primary debulking surgery versus neoadjuvant chemotherapy followed by interval debulking surgery.
The TRUST trial started in July 2016 and is seeking to recruit 686 participants. We hope the study will provide clinical evidence to inform the next generation of advances in ovarian cancer treatment. Until then, primary debulking surgery to achieve maximum cytoreduction followed by platinum-based chemotherapy will remain the best available approach.
Advancing Ovarian Cancer Research
MSK has a long history of continuous improvement that includes offering the latest surgical advances and conducting retrospective and prospective clinical research to inform the best ways to improve patient outcomes.
More than three years ago, we formed the Section of Ovarian Cancer Surgery within the Gynecology Service at MSK. Our dedicated ovarian cancer surgeons routinely collaborate with other members of our Gynecology Disease Management Team to develop individualized treatment plans for each patient and deliver the best care possible.
