Several important late-breaking abstracts on pancreatic cancer were presented at the 2018 ASCO annual meeting. In this interview, Dr. Eileen M. O’Reilly discusses key findings from two phase 3 studies that looked at adjuvant and neoadjuvant treatment approaches for different types of patients with pancreatic cancer. The Unicancer GI PRODIGE 24/CCTG PA.6 demonstrated that adjuvant mFOLFIRINOX was safe and improved survival when compared with gemcitabine in patients with resected pancreatic ductal adenocarcinomas. The PREOPANC-1 study showed that preoperative chemoradiotherapy significantly improved outcomes in resectable and borderline resectable pancreatic cancer when compared with immediate surgery. Dr. O’Reilly describes both trials in greater detail and discusses the implications of these data.
Unicancer GI PRODIGE 24/CCTG PA.6
The Unicancer GI PRODIGE 24/CCTG PA.6 (PRODIGE) trial is an important practice-changing study for clinicians managing patients who have undergone surgical resection for pancreatic cancer. In this trial, the eligibility criteria for study patients were very stringent. Participants were required to have histologically proven pancreatic ductal adenocarcinomas, had undergone successful surgery, and recovered from their operation within 12 weeks. They needed to attain an ECOG performance status score of 0 to 1 and to have otherwise good major organ function.
Participants were randomized to a control arm that received standard-of-care treatment with gemcitabine or to modified FOLFIRINOX. Patients in the control arm received single-agent gemcitabine for 3 consecutive weeks and then took 1 week off for a total of 18 doses over 6 months. For the group receiving modified FOLFIRINOX, the modifications included removal of bolus 5FU and, in about two-thirds of patients (following a Data and Safety Monitoring Board recommendation), a dose reduction of irinotecan to 150 mg/m2. The irinotecan dose restriction was performed because higher rates of grade 3-4 diarrhea had been previously seen with FOLFIRINOX. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and adverse events (AE).
Regarding the primary endpoint, patients receiving modified FOLFIRINOX had a DFS of 21.6 months, compared with 12.8 months for those receiving single-agent gemcitabine, resulting in a hazard ratio of 0.58. Secondary endpoints of OS and MFS also favored the modified FOLFIRINOX treatment group (54.4 vs 35.0 months and 30.4 vs 17.7 months, respectively). However, grade 3-4 AEs were higher for the modified FOLFIRINOX arm when compared with the gemcitabine arm (75.5% vs 51.1%, respectively). Despite the high AE rates, the overall results for outcomes are some of the best that we’ve ever seen in any setting in pancreatic cancer. Importantly, both treatment arms did better than expected because of the select patient population.
Data from PRODIGE are practice-changing, but modified FOLFIRINOX is not appropriate for every patient who has undergone pancreatic cancer resection. It’s important to note that grade 3-4 adverse events are significant for patients receiving modified FOLFIRINOX. Clinicians should follow patients carefully and monitor those who receive this regimen for toxicity. They should also be prepared to intervene and provide support with dose reductions, hydration, and early administration of antidiarrheal agents if patients are experiencing significant side effects.
Adjuvant therapy in pancreatic cancer has been an area of change over the last few years. Our current standards are gemcitabine and capecitabine, based on data from the ESPAC-4 trial, which was published in the Lancet by Dr. John Neoptolemos and colleagues. This trial supported use of two-drug combinations in pancreatic cancer, but data from PRODIGE indicate that we can now add modified FOLFIRINOX to this space and, indeed, place this regimen as the first choice for many individuals.
Another forthcoming trial that may impact options for adjuvant treatment is the phase 3 APACT study, for which data are expected soon. This trial is comparing gemcitabine plus nab-paclitaxel with gemcitabine alone as adjuvant treatment. The APACT study design is similar to PRODIGE in that it has strict patient selection criteria and DFS as the primary endpoint. Depending on the results, we may soon have a third choice for adjuvant treatment. Overall, the good news is we now have more than one alternative to better serve select patient groups and more are on the way.
PREOPANC-1, conducted by a Dutch cooperative group, was a relatively small phase 3 study involving 246 total patients. Participants with resectable pancreatic cancer or borderline resectable disease were randomized to either upfront surgery followed by standard adjuvant gemcitabine or to a neoadjuvant strategy using preoperative gemcitabine-based chemo-radiotherapy regimen followed by surgery and additional adjuvant gemcitabine. The purpose was to test if a perioperative systemic treatment delivery approach could benefit patients with pancreatic cancer that had not metastasized. The primary endpoint was OS, and secondary endpoints were (R0) resection rate, DFS, distant metastases free interval (DMFI), locoregional recurrence free interval (LRFI), and toxicity.
Preliminary data showed that OS was significantly better for patients receiving neoadjuvant therapy than those who receiving upfront surgery (17.1 vs 13.5 months). The same was true for R0 resection rate (65% vs 31%), DFS (median, 11.2 vs 7.9 months), DMFI (median, 17.1 median vs 10.2 months), and LRFI (median, not reached vs 11.8 months). No significant differences were observed in grade 3 or 4 AEs between groups. In a subgroup analysis of patients who actually received a resection, the median OS was 29.9 months for the neoadjuvant group and 16.8 months for the upfront surgery group.
Clinicians should keep in mind the small size of the PREOPANC-1 study and be aware that the data have not fully matured. In addition, the trial did not use what would be considered a modern-day combination cytotoxic approach. Furthermore, this study population was a selective group that needed to be able to tolerate surgery and neoadjuvant therapy and did not have metastatic or locally advanced disease. However, the strong trend toward superior outcomes with neoadjuvant therapy for these patients is important and supports the paradigm shift for neoadjuvant therapy. The data further support that early delivery of systemic therapy in a select group of patients can lead to better patient outcomes.
Tying it All Together
Other clinical trials and ongoing studies are underway to further assess the interventions tested in the PRODIGE and PREOPANC-1 trials as well as other combination approaches. In the meantime, clinicians should monitor progress in these studies and pay close attention to patient eligibility in the trials. Each study has very different patient populations and treatment strategies, which explains what on the surface appears to be data that is quite disparate. In addition, treatment strategies for patients with resectable and borderline resectable pancreatic cancer continue to evolve. Traditionally, upfront surgery was the standard approach for these patients, but there’s increasing interest in the potential of using neoadjuvant therapy as the initial treatment modality.
- Conroy T, Hammel P, Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Onc. 2018;36(suppl):abstract LBA4001. Available at: http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.18_suppl.LBA4001. Accessed September 19, 2018.
- Van Tienhoven G, Versteijne E, Suker M, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial.J Clin Onc. 2018;36(suppl):abstract LBA4002. Available at: http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.18_suppl.LBA4002. Accessed September 19, 2018.
- Neoptolemos JP, Palmer DH, Ghaneh P, et al; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011-1024. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28129987. Accessed September 19, 2018.
- ClinicaTrials.gov. A phase 3, multicenter, open-label, randomized study of nab-paclitaxel plus gemcitabine versus gemcitabine alone as adjuvant therapy in subjects with surgically resected pancreatic adenocarcinoma. NLM Identifier: NCT01964430. September 10, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT01964430. Accessed September 19, 2018.
This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Ipsen, and Merck & Co., Inc.