Key Trials Warrant Consideration in Early-Stage Pancreatic Cancer Paradigm

Partner | Cancer Centers | <b>Johns Hopkins Cancer Center</b>

Nilofer Saba Azad, MD, discusses data from 3 recent pivotal trials have influenced practice and/or warrant consideration when treating patients with localized pancreatic cancer.

Nilofer S. Azad, M

The incidence of pancreatic cancer is on the rise—a phenomenon that can only be counteracted by better diagnostics and therapeutic strategies, explained Nilofer Saba Azad, MD, an associate professor of oncology at Johns Hopkins Medicine.

If a patient is diagnosed with localized disease, it is termed resectable, borderline resectable, or locally advanced, prefaced Azad in a presentation during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Cancers.

However, only 20% of pancreatic cancer cases are considered resectable at time of diagnosis. As such, many trials have been conducted to see if there are ways to enhance the resection rates for patients with borderline resectable tumors or to improve responses to chemotherapy and radiation in those who are ineligible for surgery. Moreover, investigators are also examining ways to convert patients with unresectable disease into candidates for resection.

Several trials have examined the use of neoadjuvant chemotherapy and radiation in borderline resectable and locally advanced cancers, said Azad, but as single-center, nonrandomized studies, they have had little impact on the field.


However, data from 3 recent pivotal trials have influenced practice and/or warrant consideration when treating patients with localized disease, said Azad.Historically, the standard of care for patients with resectable or borderline resectable tumors has been surgery followed by adjuvant chemotherapy. Although prior studies that have suggested the benefit of neoadjuvant therapy have been mainly observational in nature, the data were enough to warrant further exploration, explained Azad.

The phase III PREOPANC-1 trial took patients who were eligible for surgery at the time of enrollment and randomized them to receive surgery upfront and 6 months of adjuvant chemotherapy (n = 127) or neoadjuvant chemoradiotherapy followed by surgery and 4 months of adjuvant chemotherapy (n = 119).

In the experimental arm, patients received 1 cycle of gemcitabine prior to and following 15 fractions of 2.4 Gy radiation therapy in combination with 1000 mg/m2 of gemcitabine on days 1, 8, and 15. Overall survival (OS) served as the primary endpoint among the intent-to-treat population.

Baseline characteristics were well balanced between the 2 arms in terms of age, performance status, and resectability, said Azad.

At the time of data cutoff, 72% (n = 91) of patients in the control arm underwent resection compared with 60% (n = 72) of patients in the experimental arm (P = .065).1 Serious adverse events (AEs) occurred in 39% (n = 49) and 46% (n = 55) of patients in the control and experimental arms, respectively (P = .28). The rate of R0 resection was more than doubled in the experimental arm compared with the control arm (63% [n = 45] vs 31% [n = 28], respectively; P <.001), said Azad.

Although neoadjuvant therapy resulted in a 3.4-month extension in median OS compared with upfront surgery, it failed to demonstrate statistical significance (HR, 0.74; P = .74).

In the subset analysis, investigators noted a benefit with neoadjuvant therapy with regard to the secondary endpoints of metastasis-free survival (MFS; HR, 0.71; P = .013) and the locoregional recurrence-free interval (HR, 0.55; P = .002). Moreover, if patients achieved an R0 resection, they experienced a dramatic improvement in median OS at 42.2 months versus 16.8 months (P <.001).


Now that FOLRINOX has become the optimal regimen in pancreatic cancer, the question of whether or not it can replace gemcitabine in combination with chemoradiation remains unknown, said Azad. Nonetheless, this study provides clinicians with preliminary phase III data to support giving chemoradiation preoperatively.In 2013, the combination of gemcitabine and nab-paclitaxel (Abraxane) showed a survival benefit compared with single-agent gemcitabine in patients with advanced disease. As such, the nonrandomized phase II LAPACT trial2 was designed to assess the safety and efficacy of 6 cycles of induction therapy with the combination in patients with locally advanced treatment-naïve disease.

In the induction phase of the trial, 106 patients received 125 mg/m2 of nab-paclitaxel in combination with 1000 mg/m2 of gemcitabine days 1, 8, and 15 of each 28-day cycle for up to 6 cycles, after which patients were able to continue on the prespecified treatment, begin chemoradiation, or undergo surgical resection, if eligible. Of the 61 patients who completed induction therapy, 45 went on to receive investigator’s choice of nab-paclitaxel/gemcitabine (n = 12), chemoradiation (n = 17), or surgery (n = 16).

“No matter which approach you take, you have preserved quality of life (QoL),” said Azad.

Time to treatment failure (TTF) served as the primary endpoint of the study, with secondary endpoints of disease-control rate (DCR), objective response rate (ORR), progression-free survival (PFS), OS, safety, and QoL.

TTF exceeded the prespecified target expectation of 6.6 months; the TTF was 8.8 months (90% CI, 6.67-9.82). Moreover, the median PFS was 10.8 months (90% CI, 9.26-11.63) with the combination, and the 12-month OS rate was 72% (90% CI, 64.5%-78.9%). The combination also resulted in an ORR of 33% and a DCR of 78%.


Of the 16 patients who underwent surgery, approximately 44% (n = 7) achieved an R0 resection. Moreover, the combination was tolerable and in line with the known safety profile, and as such, can be considered an appropriate treatment regimen for these patients.Presented at the 2018 ASCO Annual Meeting, the PRODIGE 24/CCTG PA.6 trial had an immediate impact on practice, challenging the standard at the time, gemcitabine and capecitabine, said Azad.

The multicenter international phase III trial randomized patients with resected pancreatic cancer to receive adjuvant therapy with either modified FOLFIRINOX (mFOLFIRINOX) or gemcitabine monotherapy based on the combination’s success in the metastatic setting.

To be eligible for the trial, patients had to achieve an R0 or R1 resection, be ≥18 and ≤79 years of age, have a World Health Organization performance status score of ≤1, and a CA 19-9 radio-immunoassay level of <180 μ/mL within 12 weeks after surgery.

Following surgery, 493 patients were randomized 1:1 to receive mFOLFIRINOX or gemcitabine for a total of 6 months. In the investigational arm, patients received intravenous (IV) oxaliplatin, leucovorin, and irinotecan on day 1, followed by continuous infusion with 5-fluorouracil over 46 hours every 2 weeks for 12 cycles. Gemcitabine was administered via IV infusion on days 1, 8, and 15 every 28 days for 6 cycles.

The primary endpoint of the study was disease-free survival (DFS), with secondary endpoints of OS, cancer-specific survival, MFS, and toxicity.

The median DFS was 21.6 months with mFOLFIRINOX and 12.8 months with gemcitabine, resulting in a 42% reduction in the risk of disease progression or death (HR, 0.58; 95% CI, 0.46-0.73; P <.0001).3 The 3-year DFS rates were 39.7% and 21.4% with mFOLFIRINOX and gemcitabine, respectively.

Median OS was also superior with mFOLFIRINOX compared with gemcitabine at 54.4 months and 35.0 months, respectively (HR, 0.64; 95% CI, 0.48-0.86; P = .003).

“This is the best survival [benefit] that has been seen in any randomized trial of pancreatic cancer,” said Azad. “Compared with the ESPAC-4 trial, which showed a 28.0-month median OS...the magnitude of benefit is quite compelling.”

In terms of toxicity, mFOLFIRINOX resulted in higher rates of grade 3/4 diarrhea, fatigue, vomiting, and mucositis with the exception of thrombocytopenia, which occurred in 1.3% of patients who received mFOLFIRINOX and 4.5% of those who received gemcitabine (P <.03).

The most common grade 3/4 hematologic AEs across arms included neutropenia and febrile neutropenia, resulting in a higher need for G-CSF in the mFOLFIRINOX arm (59.9%) compared with the gemcitabine arm (3.7%; P <.001).

Notably, over half of the patients on mFOLFIRINOX received a dose reduction over the 6-month course of therapy, added Azad.

“This is very reassuring for those of us who treat patients with FOLFIRINOX and are regularly having to dose reduce patients,” concluded Azad. “With this trial, the standard of care has changed, particularly for the fit patient.”


  1. Van Tienhoven G, Versteijne E, Suker M, et al; Dutch Pancreatic Cancer Group. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial. J Clin Oncol. 2018;36(suppl 18, abstr LBA4002). doi: 10.1200/2018.36.18_suppl.LBA4002.
  2. Hammel P, Lacy J, Portales F, et al. Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC). J Clin Oncol. 2018;36(suppl 4; abstr 204). doi: 10.1200/JCO.2018.36.4_suppl.204.
  3. 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.LBA4001.