Perioperative Chemotherapy Fails to Show OS Benefit in Resectable PDAC

Davendra Sohal, MD, MPH

Perioperative chemotherapy did not improve overall survival (OS) in patients with resectable pancreatic ductal adenocarcinoma (PDAC) when compared with historical data from adjuvant trials, according to the results of the phase 2 S1505 trial (NCT02562716).¹

The 2-year overall survival (OS) rate in patients who received fluorouracil, irinotecan (Onivyde), and oxaliplatin (mFOLFIRINOX) was 47% (95% CI, 31%-61%) with a median OS of 23.2 months (95% CI, 17.6-45.9). Patients who were treated with gemcitabine and nab-paclitaxel (Abraxane) had a 2-year OS rate of 48% (95% CI, 31%-63%), with a median OS of 23.6 months (95% CI, 17.8-31.7). Neither patient cohort demonstrated an estimated 2-year OS rate that was significantly higher than the prespecified threshold of 40%.

"This is the first time the 2 frontline chemotherapy regimens for pancreatic cancer have been tested in 1 study," Davendra Sohal, MD, MPH, an associate professor of medicine, experimental therapeutics director, and clinic medical director at the University of Cincinnati, stated in a press release.² "While we didn't find a patient benefit from either [regimen] prior to surgery, we did show that such a comparison can be done safely. Most of the patients who got the chemotherapy could go on to successfully have their surgery. In the end, we've created a clinical trial platform that can be used to test other presurgical chemotherapy treatments for pancreatic cancer."

Many patients with early-stage pancreatic cancer whose disease has not metastasized are considered to be good candidates for surgical resection, according to Sohal. Due to this, investigators wanted to determine whether the addition of either or both chemotherapy regimens in conjunction with surgery could help improve survival outcomes.

The primary objective of the randomized, phase 2 trial was to identify the 2-year OS of perioperative chemotherapy for patients with resectable PDAC. To be eligible for enrollment, patients had to have less than 180 degree interface between tumor and vessel wall of the portal or superior mesenteric veins and patent portal vein/splenic vein confluence. Patients could not have interface of the tumor with the celiac, common hepatic, or superior mesenteric arteries; they also could not have metastases.

Moreover, patients had to have histologically or cytologically confirmed PDAC, measurable disease, been between the ages of 18 years and 75 years, a Zubrod performance score of 0-1, and acceptable bone marrow, hepatic, and renal function.

The trial utilized a pick-the-winner design and was conducted across the National Clinical Trials Network, in both academic and community centers.

Between 2015-2017, a total of 147 patients were enrolled to the trial, 102 of whom were determined to be evaluable. Of these patients, 55 were randomized to receive mFOLFIRINOX (arm 1), while 47 were given gemcitabine plus nab-paclitaxel (arm 2).

The median age in arm 1 was 66 years, versus 64 years in arm 2. Among patients who received mFOLFIRINOX, 65% (n = 36) were male, versus 51% (n = 24) of those who received gemcitabine/nab-paclitaxel. Additionally, 62% (n = 34) of patients on arm 1 and 66% of those in arm 2 had a Zubrod performance score of 0. The majority of patients on both arms 1 and 2 were reported to have head tumors, at 80% and 83%, respectively.

Moreover, in arm 1, 84% of patients completed preoperative chemotherapy, 73% underwent surgical resection, and 49% completed their treatment. In arm 2, 85% of patients finished their preoperative chemotherapy, 70% received surgical resection, and 40% completed treatment.

Among 102 patients determined to be eligible for evaluation, no significant difference between arms 1 and 2 with regard to overall response rate, at 9% versus 21%, respectively (P = .15). R0 resection was experienced by 85% of 40 patients in arm 1 and 85% of 33 patients in arm 2 who had undergone surgical resection. Moreover, node-negative resection was achieved in 40% and 45% of patients on arms 1 and 2, respectively.

Pathologic complete or major response was experienced by 25% of patients in arm 1 versus 42% patients in arm 2. Additionally, the median disease-free survival from resection was 10.9 months in arm 1 versus 14.2 months in arm 2.

No unexpected safety signals were reported with the regimen. The most commonly reported grade 3 or 4 effects included hematologic toxicities, fatigue, diarrhea, nausea, and neuropathy. In the neoadjuvant setting, more patients on arm 2 reported neutropenia compared with those on arm 1, at 27% versus 19%, respectively. Slightly more patients on arm 1 reported diarrhea compared with those on arm 1, at 11% versus 4%, respectively.

The most frequently reported effects associated with surgery included anemia (14% in arm 1 vs 3% in arm 2) and anorexia (5% vs 0%, respectively). Notably, lower rates of grade 3 or 4 toxicities were reported in the adjuvant setting versus the neoadjuvant setting. Although the trial was not demonstrate improved survival with perioperative chemotherapy, patients who received treatment did not experience significant post-operative complications.

The study findings may lead to new opportunities for other research focused on molecular testing and chemotherapy in patients with early-stage pancreatic cancer, according to the study authors.

“In summary, the present study did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trail in resectable pancreatic cancer,” the study authors concluded. “We demonstrate the feasibility of multidisciplinary treatment using perioperative chemotherapy for [these patients]…These findings serve as a platform for studying novel therapies for patients with neoadjuvant/perioperative resectable pancreatic cancer in future trials.”

References

1. Sohal DPS, Duong M, Ahmad SA, et al. Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma a phase 2 randomized clinical trial. JAMA Oncol. Published online January 21, 2021. doi:10.1001/jamaoncol.2020.7328
2. Pre-surgery chemotherapy is possible for early stage pancreatic cancer patients. News release. EurekAlert. January 21, 2021. Accessed January 21, 2021. http://bit.ly/3cdBiJt.