Adjuvant Treatment Strategy Shows Promise in Pancreatic Cancer

Autumn McRee, MD

Some of the most encouraging data to be read out in the pancreatic cancer space within the last decade came from the PRODIGE 24/CCTG PA.6 trial, said Autumn McRee, MD, as this was the first trial to demonstrate an overall survival (OS) benefit with an adjuvant strategy of intense chemotherapy combinations often used in the metastatic setting.

In the multicenter phase III trial, patients were randomized to receive either 28-day cycles of the standard gemcitabine on days 1, 8, and 15 for 6 cycles (arm A) or modified FOLFIRINOX every 14 days for 12 cycles (arm B). Disease-free survival (DFS) served as the primary endpoint of the trial, with OS, metastasis-free survival, and adverse events as secondary endpoints.

At a median follow-up of 33.6 months, the median DFS was 12.8 months (95% CI, 11.7-15.2) in arm A versus 21.6 months (95% CI, 17.5-26.7) in arm B.¹ Moreover, the median OS was 35.0 months (95% CI, 28.6-43.8) versus 54.4 months (95% CI, 41.5-not reached) in arms A and B, respectively.

“We saw for the first time, an OS of close to 54 months, which is incredibly promising in this patient population,” said McRee, who is an associate professor of medicine at the University of North Caroline (UNC) School of Medicine, UNC-Chapel Hill.

McRee also highlighted studies in which investigators are working to bring strategies used in the postoperative space into the neoadjuvant setting. For example, in the ongoing phase II Alliance for Clinical Oncology Trial A021501 (NCT02839343), investigators are evaluating the efficacy of mFOLFIRINOX with or without stereotactic body radiation therapy before surgery in patients who are borderline resectable. This study has an estimated primary completion date of March 2020.²

OncLive^®: What therapies are being explored in the neoadjuvant or adjuvant setting?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, McRee highlighted promising adjuvant/neoadjuvant strategies under investigation in the pancreatic cancer space and stressed the importance of using a multidisciplinary treatment approach to improve patient outcomes.McRee: One of the more promising studies that we saw come out of the pancreas space in the last decade was the PRODIGE 24/CCTG PA.6 study, data from which were reported at the 2018 ASCO Annual Meeting. This was, for the first time, an adjuvant strategy comprised of more aggressive chemotherapy combinations that we typically use in the metastatic setting. For this study, [investigators] randomized patients who had been resected to receive either gemcitabine, which is an old standard, to the 3-drug combination FOLFIRINOX. That study followed on the heels of the ESPAC-4 study, which combined gemcitabine with capecitabine.

It is nice now to have options for patients in the postoperative space. Certainly, some [responses] are going to be more robust than others. We reserve FOLFIRINOX more for the patients who come to us with a well-preserved performance status and have recovered uneventfully from their surgery.

Could you expand on these studies?

However, there are now studies looking to bring those treatments to the neoadjuvant space; [for example, work by] Matthew H.G. Katz, MD, from the Alliance for Clinical Trials in Oncology and The University of Texas MD Anderson Cancer Center.The study that Dr Katz is leading is looking at patients who are borderline resectable, meaning that we are optimistic that they are resectable, but they have certain features of their cancer that make them unlikely to have a complete resection; that is usually intimate involvement of certain blood vessels.

Could you discuss the PREOPANC-1 trial?

Are there drawbacks to the neoadjuvant chemoradiotherapy approach?

Typically, what we have done in that situation is resect them and then try to make up for positive margins or involved lymph nodes afterwards with chemotherapy. Now, what we're doing is looking at upfront chemotherapy. In this study, [patients are] randomized to either FOLFIRINOX or FOLFIRINOX plus radiation. That trial is still ongoing; it's very close to national enrollment, so we haven't seen the final results from that yet.PREOPANC-1 had a little bit of a different approach; what they did was use a combination of both gemcitabine with and without radiation in the neoadjuvant space. This trial was a little bit different [from the previous trials we discussed] in that they had some resectable patients—about 50% in each arm—and then they had a lower percentage of patients who actually went to surgery. OS in the intent-to-treat patient population was lower than what we saw with the PRODIGE 24/CCTG PA.6 trial, but if you looked at the patients who actually made it to surgery, those who received the combination of gemcitabine with chemoradiotherapy had an OS of about 42 months. Therefore, it's looking like using more aggressive combinations is moving the needle.The only potential risk to that approach is causing complications from treatment that may then render your patients ineligible for surgery. However, so far, we've seen from a safety and toxicity perspective that this has not been an issue.

Are there any exciting agents that you're waiting to hear more about?

What is the biggest challenge that still needs to be overcome in this space?

Certainly, we counsel our patients [to remind them] that chemotherapy is not perfect and that while they are on treatment, there will be a small percentage of patients who will progress, meaning their cancer spreads outside of their pancreas, and hence, they're no longer resectable. However, I tend to reassure my patients that if in that very short time of 3 to 4 months their cancer has found a way to [progress] on chemotherapy, then it's very unlikely that that their cancer would have stayed away for a significant amount of time [even with upfront surgery]. In essence, we spare them a pretty invasive and morbid operation by proving that their cancer isn't going to be one that spreads early.Pancreatic cancer is a bit challenging in the sense that we have not yet found a great targeted therapy [for these patients] and we have not seen immunotherapy really play a role in this disease. Many [approaches] are being explored in the metastatic setting, and there are some exciting trials looking at different stem cell inhibitors. Immunotherapy combinations [are under investigation], but in the neoadjuvant and adjuvant space, it has mostly been just our old “tried-and-true” chemotherapy options.If you look at the adjuvant FOLFIRINOX data, this is the most aggressive chemotherapy regimen that we have; it's arguably the most successful in the pancreas space. Despite getting this incredibly aggressive regimen, only 40% of patients are still cancer free at 3 years after their operation. We have made a lot of progress. We've moved survival from a little less than 2 years to almost 5 years.

What is your take-home to your colleagues working in the space?

Regardless, the majority of patients still have their cancer coming back. This certainly speaks to the need to be more aggressive with diagnosing these patients early so that we capture them without metastatic disease. We have a lot of room for improvement, whether that ends up being a targeted therapy or some yet-to-be-determined therapy.The big take-home message is that pancreatic cancer is now becoming a multidisciplinary tumor. These patients really benefit from seeing a medical oncologist and a surgical oncologist upfront. In the past, we received these patients as referrals from our surgeons after they've been resected, and now, we have dedicated clinic days set up to where we can see the patients in conjunction with our surgeons to explain to them that this isn't just a one-modality treatment; we've seen the best results in working together and giving dual and sometimes tri-modality therapy. The message should be that for patients diagnosed with pancreatic cancer, collaboration needs to happen. If it's not available at their center, then a referral to a tertiary care center would be in their best interest.

References

1. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIGE Group. 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 Oncol. 2018;36(suppl 18; abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA400.
2. Katz MHG, Ou FS, Herman JM, et al. Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. BMC Cancer. 2017;17(1):505. doi: 10.1186/s12885-017-3441-z.