Progress Made in Locally Advanced Pancreatic Cancer

Dae Won Kim, MD

Although surgery is a therapeutic option for select patients with pancreatic cancer, many patients present with unresectable disease. Progress made in the neoadjuvant space, however, can improve the resectability of locally advanced pancreatic cancer, said Dae Won Kim, MD.

“In pancreatic cancer, even after curative surgery, the recurrence rate is quite high and prognosis is poor,” said Kim. “There are many trials [with the goal of improving] survival after surgery. Knowing the marginal status is very important; it’s one of the predictive markers of survival after surgery. Our goal with neoadjuvant chemotherapy is to improve margin status and [patient] survival.”

In a phase II randomized trial, investigators evaluated the use of neoadjuvant FOLFIRINOX followed by individualized chemoradiotherapy in patients with newly diagnosed, previously untreated, localized borderline resectable disease, who had an ECOG performance status of 0 or 1 as well as adequate hematologic, renal, and hepatic function.

Thirty-four of 43 patients who planned to receive 8 preoperative cycles of chemotherapy were able to complete all cycles of treatment. Further, 27 patients had short-course chemoradiotherapy, while 17 patients underwent long-course chemoradiotherapy. Out of the 48 patients enrolled in the trial, R0 resection was achieved in 31 patients (65%; 95% CI, 49%-78%). Of the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31).¹

Moreover, the median progression-free survival (PFS) among all patients enrolled in the trial was 14.7 months (95% CI, 10.5 to not reached), while the 2-year PFS rate was 43%. The median OS was 37.7 months (95% CI, 19.4 months to not reached), while the 2-year OS rate was 56%. In those who underwent resection, the median PFS was even higher at 48.6 months (95% CI, 14.4 to not reached), while median OS had not been reached. The 2-year PFS rate was 55%, while the 2-year OS was 72%.

As such, investigators concluded that preoperative FOLFIRINOX followed by chemoradiotherapy in patients with borderline resectable pancreatic cancer could lead to high rates of R0 resection as well as a prolonged median PFS and OS.

Meanwhile, in the adjuvant space, investigators evaluated the benefit of adjuvant mFOLFIRINOX versus gemcitabine in patients with resected disease in the phase III UNICANCER GI PRODIGE 24/CCTG PA.6 trial.

Results showed that a median follow-up of 30.5 months, the median disease-free survival (DFS) was 12.8 months in those who received gemcitabine versus 21.6 months in those given mFOLFIRINOX (HR, 0.59; 95% CI, 0.47-0.74). Further, the median OS was 34.8 months versus 54.4 months in the gemcitabine and mFOLFIRINOX arms, respectively (HR, 0.66; 95% CI, 0.49-0.89). Median metastasis-free survival (MFS) was 17.7 months in the gemcitabine arm versus 30.4 months in the mFOLFIRINOX arm (HR, 0.59; 95% CI, 0.46-0.76). Based on these data, investigators concluded that mFOLFIRINOX is not only safe but it significantly improved DFS, MFS, and OS compared with gemcitabine.²

Also in the adjuvant setting, it was reported that the combination of nab-paclitaxel (Abraxane) and gemcitabine did not improve disease-free survival (DFS) versus gemcitabine in patients with pancreatic cancer, according to results of the international, multicenter, open-label, controlled, phase III APACT study (NCT01964430).³ However, the combination did show an OS improvement, reaching nominal statistical significance.

OncLive^®: What trials support the benefit of neoadjuvant therapy in patients with localized pancreatic cancer?

In an interview during the OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Kim, a medical oncologist in the Gastrointestinal Oncology Program at Moffitt Cancer Center, highlighted recent advances in the neoadjuvant and adjuvant settings for patients with localized pancreatic cancer.Kim: In borderline resectable disease, there are several data actually showing improved survival after mFOLFIRINOX treatment and also neoadjuvant chemoradiation.

I discussed this in more detail in [my presentation at the State of the Science Summit™]. One of them is a phase II trial where the FOLFIRINOX data actually show an improved rate; it improved margin-negative surgery and was also associated with an improvement in survival.

There was also a trial [that evaluated] FOLFIRINOX and then they used gemcitabine and chemoradiation.

Previously, a phase III randomized study actually showed that around 4% of patients can have resectable disease. [In that trial], they used gemcitabine or gemcitabine plus erlotinib (Tarceva), and then patients received chemoradiation after that.

Could you discuss the recent PRODIGE 24/CCTG PA.6 trial?

Even with FOLFIRINOX, was the regimen fairly well tolerated?

Of these studies, which has had the greatest impact on practice thus far?

What are the biggest unanswered questions that remain in the space? What steps are being taken to address them?

Therefore, we are [also] using the gemcitabine plus nab-paclitaxel after that data. We don't have the data from the [trial evaluating] FOLFIRINOX in locally advanced disease yet, but we expect a conversion rate similar to or higher than [that seen with] gemcitabine plus nab-paclitaxel. PRODIGE 24/CCTG PA.6 was with adjuvant treatment. Previously, we only used gemcitabine or gemcitabine plus capecitabine after surgery to improve survival and decrease recurrence. However, the 24/CCTG PA.6 data show a significant improvement of survival compared with single-agent gemcitabine as adjuvant treatment.In that study, they used mFOLFIRINOX—not the full dose of FOLFIRINOX. There is toxicity actually that is a little bit higher—grade 3/4—than [what is observed with] gemcitabine alone. However, patients can tolerate it well; toxicity was manageable.Previous data were based on metastatic disease. We didn't have much data in borderline or locally advanced disease. Now, we have more accumulated data—the efficacy of gemcitabine plus nab-paclitaxel [in the adjuvant setting] and also with mFOLFIRINOX. Therefore, at this time, we only have 2 trials, still this is good enough to [support the] use of gemcitabine, nab-paclitaxel, and FOLFIRINOX in borderline resectable, and also, locally advanced disease.There are a couple of unanswered questions in the borderline and also the locally advanced settings. The first one is that we do not know what is the best regimen—is it gemcitabine plus nab-paclitaxel or is it FOLFIRINOX? There is an ongoing clinical trial [being conducted] to answer that question.

What intriguing data were presented at the 2019 Gastrointestinal Cancers Symposium?

In your practice, would you use neoadjuvant therapy for resectable or potentially resectable patients?

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

We also don't exactly know the role of the neoadjuvant stereotactic radiation in [patients with] borderline resectable disease. There’s another ongoing clinical trial to check out the role of neoadjuvant stereotactic radiation in [these patients].There was a phase II/III Japanese trial in resectable pancreatic cancer that used gemcitabine plus S-1, but that data actually show that even [in those with] resectable disease, neoadjuvant gemcitabine plus S-1 actually increased resection rate and also improved survival. However, we need more data of this neoadjuvant treatment in resectable pancreatic cancer.This is very controversial, because the problem is that there is still 20% to 25% of patients who receive neoadjuvant treatment and they have disease progression. If that happens, we will lose the surgical window. That is why, at this time—depending on the patient and on the situation—for most cases, we try to go to upfront surgery if it's resectable disease.[They should know] about [the latest data with] adjuvant treatment—especially with mFOLFIRINOX. That data actually show a significant improvement after surgery after gemcitabine; that's the first one.

References

1. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 4(7):963-969. doi: 10.1001/jamaoncol.2018.0329.
2. 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 Oncol. 2018;36(suppl 18; abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA4001.
3. Celgene Provides Update on ABRAXANE Combination Therapy in the Treatment of Metastatic Triple-Negative Breast Cancer and Pancreatic Cancer. Celgene. Published March 12, 2019. https://bit.ly/2HmHy2X. Accessed March 12, 2019.