Abstract
In two pancreatic cancer trials—the randomized phase III PRODIGE 24/CCTG PA.6 and PREOPANC-1 trials—researchers found that experimental drug regimens for patients with resectable adenocarcinomas increased overall survival or showed a trend in that direction. The findings could prompt changes in clinical practice for these patients.
People diagnosed with pancreatic cancer face long odds: According to the American Cancer Society, the 5-year relative survival rate for all stages of disease is just 8%. However, researchers recently reported improvements in survival in two trials, potentially altering clinical practice for some patients.
Gemcitabine has long been standard of care following pancreatic cancer surgery. “Yet, more than 70% of the patients still relapse within 2 years, despite this treatment,” noted Thierry Conroy, MD, of the Institut de Cancérologie de Lorraine in France. “There's obvious need for a better regimen.”
Based on data from the randomized phase III PRODIGE 24/CCTG PA.6 study, presented by Conroy at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in June, a modified FOLFIRINOX (mFOLFIRINOX) regimen should now replace standard-of-care gemcitabine for a small subset of patients who have a “successful” surgery. For the trial, Conroy's team randomly assigned 493 patients who had had all or nearly all of their tumor removed to receive mFOLFIRINOX or gemcitabine. After a median follow-up of 33.6 months, median disease-free survival was significantly longer in the mFOLFIRINOX group than in the gemcitabine group—21.6 months versus 12.8 months, respectively—as was median overall survival (OS)—54.4 months versus 35 months, respectively.
Although the regimen was considered safe, mFOLFIRINOX proved more toxic than gemcitabine, with more patients reporting diarrhea, peripheral neuropathy, fatigue, vomiting, and mucositis. The relative severity of adverse effects was borne out by rates of treatment completion: 66% of patients in the mFOLFIRINOX group finished 6 months of treatment, versus 79% of patients in the gemcitabine group. “But with gemcitabine, the [main] reason for an early stop was relapse during the treatment,” Conroy noted.
Based on OS, “it would be tempting to give this regimen to anyone after pancreas cancer surgery,” said Andrew Epstein, MD, of Memorial Sloan Kettering Cancer Center in New York, but, given the associated toxicity, physicians should recommend it only to “people who are healthy enough to withstand the rigorousness of the regimen.”
Researchers have debated whether neoadjuvant treatment might also improve OS compared with standard adjuvant chemotherapy, as some studies have suggested. However, those studies were biased, argued Geertjan van Tienhoven, MD, PhD, of the Academic Medical Center in Amsterdam, the Netherlands, because they assessed only patients who had surgical resection. To accurately compare the benefits of the regimens, he said OS needed to be assessed based on an intention-to-treat analysis.
To that end, the randomized phase III PREOPANC-1 trial enrolled 246 patients with resectable or borderline resectable pancreatic adenocarcinoma and randomly assigned them to immediately undergo surgery or to receive chemoradiotherapy for 10 weeks before having surgery. Both groups received chemotherapy following surgery, with all patients receiving the same cumulative amount of chemotherapy.
In a preliminary, overall analysis presented at the ASCO meeting by van Tienhoven, neoadjuvant chemoradiotherapy resulted in a trend in improved OS compared with standard adjuvant chemotherapy —17.1 months versus 13.7 months, respectively. The OS difference was more pronounced among patients with no signs of remaining cancer—42.2 months versus 16.8 months. Further, many more patients who received neoadjuvant therapy had no signs of cancer after surgery than those who received adjuvant therapy—63% versus 31%.
“These results are preliminary,” cautioned van Tienhoven. “We do hope that with the final results of this trial that we can settle the dispute and show, along with the circumstantial evidence in the literature, that indeed preoperative radiochemotherapy is better than postoperative chemotherapy for resectable and borderline resectable pancreatic cancer.”
Although the intention-to-treat analysis for OS hasn't yet reached statistical significance, Colin Weekes, MD, PhD, of Massachusetts General Hospital in Boston, said that overall the data demonstrate the value of preoperative chemoradiotherapy. “In this patient population, those patients receiving neoadjuvant therapy did receive a better bang for their buck.” –Suzanne Rose