A multiagent chemotherapy regimen should become the new standard front-line treatment of metastatic pancreatic adenocarcinoma, according to authors of a phase III trial presented at this year's ASCO Annual Meeting.¹

Compared with single-agent gemcitabine (Gemzar), the new treatment, FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin), produced significantly better outcomes in chemotherapy-naive patients, including an 11.1-month median overall survival (OS), said lead researcher Thierry Conroy, MD, of Centre Alexis Vautrin in Vandoeuvre-les-Nancy, France.

Longest Survival

"This is the first time that a phase III trial has shown an 11-month median survival for patients with metastatic pancreatic cancer," Dr. Conroy said.

Patients who received only gemcitabine-the current standard of care-had a median OS of just 6.8 months, which Dr. Conroy said is similar to that reported in prior studies. OS was the primary endpoint for this multicenter study, known as the Prodige 4/ACCORD 11 trial. He presented the final results in 342 adult patients during the Gastrointestinal (Noncolorectal) Cancer Oral Abstract Session of the Annual Meeting.

"We recommend FOLFIRINOX as the new international standard of care for patients with metastatic pancreatic cancer," Dr. Conroy said.

He added that the regimen should be standard only for patients with a normal or near-normal bilirubin level and a high performance status (0-1) based on criteria from the Eastern Cooperative Oncology Group (ECOG), as was the case for their patients.

Good News

The study results were good news for physicians, who, according to Dr. Conroy, have few good options to treat patients with this incurable disease.

The discussant, Margaret A. Tempero, MD, Professor of Medicine at the University of California, San Francisco, commented, "We have had very little good news in a long, long time."

She added, "This is groundbreaking work. It provides more evidence that gemcitabine does not need to be the anchor drug."

However, Dr. Tempero said she is unsure whether FOLFIRINOX should become the new international standard of care for high-performance-status patients with this cancer, for reasons that included "very concerning" toxicity.

"Our enthusiasm over the benefit of this regimen must by tempered by its attendant side effects," she said.

Dr. Conroy, however, said the regimen's toxicity was manageable.

FOLFIRINOX caused significantly higher rates of grade 3/4 neutropenia (45.7% vs 18.7% for gemcitabine), grade 3/4 febrile neutropenia (5.4 % vs 0.6%, respectively), and grade 3/4 thrombocytopenia (9.1% vs 2.4%), he reported. The experimental arm also had significantly higher rates of the following grade 3/4 adverse events: peripheral neuropathy, vomiting, fatigue, and diarrhea.

Groups Well Balanced

The investigators reported no major differences in patient characteristics between treatment arms (n = 171 in each), but the gemcitabine arm had slightly more lung metastases, according to Dr. Conroy.

In this intent-to-treat analysis, the investigators randomly assigned participants to receive either single-agent gemcitabine weekly (1,000 mg/m² IV over 30 minutes, weekly with 1 week off after week 7, then weekly for 3 weeks every 28 days) or FOLFIRINOX every 2 weeks. The experimental regimen consisted of 85 mg/m² of oxaliplatin and 400 mg/m² of leucovorin over the first 2 hours, 180 mg/m² of irinotecan in a 90-minute infusion, followed by a bolus of 5-FU (400 mg/m²) on day 1, and a continuous, 46-hour infusion of 5-FU at a dosage of 2,400 mg/m². Chemotherapy was recommended for 6 months.

Only about 9% of gemcitabine-treated patients had a confirmed partial response rate, but more than 31% of patients receiving FOLFIRINOX did, Dr. Conroy said.

Median progression-free survival was reportedly 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group. The difference was highly significant, as was the more than 4-month difference in median OS, the authors' statistical analysis showed (both P < .0001).

At 1 year, 48.4% of patients in the FOLFIRINOX arm were still alive compared with 20.6% in the other arm, according to Dr. Conroy. Over a median follow-up of 26.6 months, 273 patients died.

Adjuvant Setting

The investigators plan to study the FOLFIRINOX combination in an adjuvant setting, a move that Dr. Tempero welcomed.

"This needs to be advanced to the adjuvant setting, where we can accept a regimen with more toxicity," she said.
Dr. Tempero called the study well stratified with a highly selected patient population. However, she pointed out that the patient population had an unusually low rate of primary tumors in the head of the pancreas-approximately one-third of patients, rather than the usual 50% to 60%. Because primary tumors in the body and tail of the pancreas rarely cause biliary obstruction, fewer patients than average may have had biliary stents in place, she noted.

"Most of my patients have biliary stents, and I would be very reluctant to put them on a regimen with this degree of neutropenia," Dr. Tempero commented. She added that patients who receive FOLFIRINOX must have access to a capable biliary team and should receive good supportive care. ■

Reference

1. Conroy T, Desseigne F, Ychou M, et al: Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. 2010 ASCO Annual Meeting. Abstract 4010. Presented June 7, 2010.