Best-Ever Survival Data in Advanced Pancreatic Cancer in NEJM

Nick Mulcahy

May 11, 2011

May 11, 2011 — A chemotherapy combination has been shown to provide the best survival time ever reported in metastatic pancreatic cancer, according to a study from French researchers.

However, the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) was considerably more toxic than gemcitabine in the phase 3 trial.

Data from the study, which were first presented at the 2010 meeting of the American Society of Clinical Oncology (ASCO) and reported by Medscape Medical News at that time, are now available in the May 12 issue of the New England Journal of Medicine.

The key data are largely the same, but there is new information on quality-of-life measures in the published paper, said lead author Thierry Conroy, MD, from the Centre Alexis Vautrin, Vandoeurve les Nancy, France.

Gemcitabine, used alone or in combination with other agents, has been the "reference regimen" for advanced pancreatic cancer treatment for an extended period of time, write Dr. Conroy and colleagues from 48 centers in France.

However, the study authors propose that FOLFIRINOX is now a first-line option for patients with metastatic pancreatic cancer "who are younger than 76 years, and who have a good performance status ([Eastern Cooperative Oncology Group score (ECOG)] 0 or 1), no cardiac ischemia and normal or nearly normal bilirubin levels."

Dr. Conroy told Medscape Medical News that the French national guidelines will "probably" include FOLFIRINOX as the new standard of care in this setting when they are published in the future.

In the 342-patient trial, known as PRODIGE 4/ACCORD 11, the chemotherapy combination resulted in an overall survival of 11.1 months compared with 6.8 months with gemcitabine alone (hazard ratio [HR], 0.57; P < .0001). After 1 year, 48.4% of patients who received the combination were still alive compared with 20.6% of those who received gemcitabine alone. Progression-free survival significantly improved to 6.4 months with the combination compared with 3.4 months with gemcitabine alone (HR, 0.47; P < .0001). In addition, the objective response rate was 31.6% in the FOLFIRINOX group vs 9.4% in the gemcitabine group (P < .001).

At ASCO, Dr. Conroy pointed out that the overall survival seen with the combination is the longest that has ever been reported in a phase 3 trial in this setting.

Toxicity Is "Very Concerning"

In the newly published paper, the authors emphasize that FOLFIRINOX was an effective treatment for metastatic pancreatic adenocarcinoma, but only for those patients with a good ECOG performance status; the study was limited to patients with ECOG scores of 0 to 1.

Patients randomly assigned to the FOLFIRINOX regimen received oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2, given as a bolus, followed by 2400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks. Patients receiving gemcitabine received a dose of 1000 mg/m2 weekly for 7 of 8 weeks, and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response.

"The safety profile was less favourable than that of gemcitabine," the authors state.

FOLFIRINOX, compared with gemcitabine, was associated with a statistically significant higher incidence of grade 3 or 4 neutropenia (45.7% vs 21%), febrile neutropenia (5.4% vs 1.2%), thrombocytopenia (9.1% vs 3.6%), diarrhea (12.7% vs 1.8%), and sensory neuropathy (9% vs 0), as well as grade 2 alopecia (11.4% vs 1.2%), the authors report.

At ASCO, discussant Margaret Tempero, MD, from the University of California–San Francisco, described the toxicity of the 4-drug therapy as "very concerning."

Dr. Tempero was "not sure" that FOLFIRINOX should become the new international standard of care for metastatic pancreatic cancer. She also cautioned that "enthusiasm must be tempered by its attendant side effects." Patients receiving this regimen will need access to good supportive care and a capable biliary team, she added.

Dr. Tempero also said this was "groundbreaking work," and added that this approach should be advanced to "the adjuvant setting, where we can accept a regimen with more toxicity."

Quality of Life Surprise

Even though the FOLFIRINOX regimen had a considerably worse adverse events profile, patients receiving the therapy fared better on a number of quality-of-life measures compared with patients receiving gemcitabine, the investigators say.

Patients' quality of life was assessed with the European Organization for Research and Treatment of Cancer quality-of-life core questionnaire. The questionnaires were to be completed every 2 weeks.

At baseline, the 2 treatment groups had "no significant differences" in quality of life, and as the study carried on, patient compliance in completing the questionnaires was high (about 78%) and was very similar between the 2 groups.

Notably, at 6 months, only 31% of the patients in the FOLFIRINOX group had a significant decrease in the scores on the questionnaire's Global Health Status and Quality of Life scale vs 66% in the gemcitabine group (hazard ratio, 0.47; P < .001), the authors report.

"Significant increases in the time until definitive deterioration in the quality of life were also noted in the FOLFIRINOX group for all functional and symptom scales and with respect to appetite loss, dyspnea, and constipation," they also note.

Time to a definitive decrease in the scores that were associated with diarrhea, insomnia, or financial difficulties caused by a physical condition or medical treatment did not differ significantly between regimens, they also report.

The trial was supported by Amgen and grants from the French government and the French National League Against Cancer. Dr. Conroy disclosed no relevant financial relationships, but 5 of his colleagues reported multiple conflicts, including relationships with Amgen.

N Engl J Med. 2011;364:1817-1825. Summary

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