Zosia Chustecka

June 28, 2012

June 28, 2012 — Gemcitabine has been the standard of care for the treatment of pancreatic cancer for more than 15 years, and despite many clinical trials, very few have shown superior results. But there has been a "turning point" in clinical research on pancreatic cancer, says Margaret A. Tempero, MD, professor of medicine at the University of California, San Francisco.

Speaking at the 14th World Congress on Gastrointestinal Cancer, which was organized in partnership with the European Society for Medical Oncology and held in Barcelona, Spain, she said that the improvement over gemcitabine in both progression-free survival (PFS) and overall survival (OS) seen with the FOLFIRINOX chemotherapy regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is the "type of stride forward that we hope to see."

These results, from the PRODIGE4-ACCORD 11 trial, were published last year in the New England Journal of Medicine (2011;364:1817-1825). Conducted in 342 patients with metastatic pancreatic cancer, the trial showed a significant improvement in median OS — from 6.8 months with gemcitabine to 11.1 months with FOLFIRINOX. PFS also improved, from 3.4 to 6.4 months. The authors said these survival times were the best ever seen in metastatic pancreatic cancer.

New Standard of Care?

So should FOLFIRINOX be the new standard of care? This was the question being debated at the Barcelona meeting.

Marc Ychou, MD, PhD, Centre Regional de Lutte Contre le Cancer Val D' Aurelle - Paul Lamarque, Montpellier, France, emphasized that this was one of the first times that a study has shown efficacy better than that with gemcitabine alone. "There have been lots of negative trials," he said, and while the combination of erlotinib (Tarceva, Genentech) with gemcitabine showed a statistically significant improvement (and is approved for first-line treatment), this difference was not "clinically significant."

However, the FOLFIRINOX regimen was more toxic than gemcitabine alone.

"The toxicity is very concerning," Dr. Tempero commented, noting in particular the myelosuppression and fatigue.

However, Dr. Ychou pointed out that the toxicity "is manageable, especially if we use prophylactic G-CSF" (granulocyte colony-stimulating factors). There was no degradation in quality of life, he noted, pointing out that the Global Health Status was similar in both treatment groups, and the time to definition of quality-of-life degradation was actually worse in the gemcitabine group, probably because of progression of disease.

The results are generalizable to quite a large proportion of patients with metastatic cancer, he said, and concluded that "this is the best treatment" for such patients if they are younger than 75 years of age, have a good performance status, and have low bilirubin levels (<1.5 times the upper limit of normal).

Dr. Tempero was more circumspect, and she questioned how generalizable the results were. Among the participants in this trial, fewer patients had the head-of-pancreas lesions that would be typically seen in a metastatic pancreatic cancer population. This may have resulted in fewer patients having indwelling pancreatic stents, which can be an infection risk, especially with myelosuppressive regimens.

This may have resulted in an "unintentional bias," she suggested.

She also quoted verbatim the conclusions of the NEJM authors, who were headed by Thierry Conroy, MD, from the Centre Alexis Vautrin, Vandoeurve lès Nancy, France. They concluded 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."

"Clearly they did not feel it is a standard of care," she said, emphasizing that the authors had proposed it as an option.

Dr. Tempero asked her epidemiology colleagues to estimate how many patients with metastatic pancreatic cancer fit the criterion proposed by the authors as being suitable for FOLFIRINOX. They estimated that from the patient populations seen at their respective centers, about 40% are older than age 76 years, about 50% have biliary stents, 20% have coexisting heart disease, and, although the percentage who have a good performance status is unknown, she would hazard a guess that it was about 50%.

"So clearly it is not a standard of care for all patients," Dr. Tempero said, but she emphasized that it offers a new option for some patients, and having options is "very, very good."

Data from the United States show that the FOLFIRINOX regimen was taken up soon after the results were presented for the first time at the American Society of Clinical Oncology annual meeting in June 2010 but indicate that it is being used in a small percentage of all patients. In a poster presented here, Victor Gastanaga, PhD, and colleagues from the Center for Observational Research at Amgen Inc reported that they used proprietary electronic health records data from approximately 650,000 cancer patients from institutions comprising 330 oncology clinics in the United States. Those data provide "a unique resource to evaluate actual clinic practice," they comment.

They looked specifically at the period between July 2010 and February 2012 and found that the use of FOLFIRINOX was "steadily increasing." They identified 3519 patients with active pancreatic cancer. Of those who had staging information, 1004 were metastatic at the time of diagnosis; of these, 623 were treated with chemotherapy or a biological agent. FOLFIRINOX was used in 81 patients (13%) at any time after the diagnosis, and 50 patients (8%) received it as first-line therapy.

Dr. Tempero commented that in the United States, the FOLFIRINOX regimen has been taken up but has also been modified by various centers, with some opting to delete the bolus 5-fluorouracil and others reducing the doses to decrease toxicity. However, from a show of hands among the audience, it appeared that European clinicians are sticking to the FOLFIRINOX regimen as described in the NEJM paper, and Dr. Ychou argued that there is no evidence to support modifications.

Eileen O'Reilly, MD, assistant professor at the Memorial Sloan-Kettering Cancer Center, New York, New York, said FOLFORINOCX had "convincingly demonstrated superiority" over gemcitabine alone in the metastatic pancreatic cancer setting, and is now being tested in locally advanced disease, and in the neoadjuvant and adjuvant settings.

Another Chemotherapy Option Soon?

Several speakers at the meeting mentioned the anticipation surrounding an ongoing phase 3 trial of nab-paclitaxel in pancreatic cancer, from which results are expected to be announced in about 6 months. Earlier results from a phase 2 trial had shown a median OS greater than 11 months with nab-paclitaxel.

Another phase 3 that is in its final stages, which also follows promising results from a phase 2 trial, is investigating a monoclonal antibody directed against prostate stem cell antigen (PSCA); the drug is designated AGS-PSCA.

Other new therapeutic approached being explored in pancreatic cancer and highlighted at the meeting by Dr. O'Reilly include drugs targeting the insulin growth factor-1 receptor, such as MK-0646, AMG-479, and OSI-906, and compound targeting the hedgehog pathway, including GDC-0449/ vismodegib, IPI-926/saridegib, and LDE225.

14th World Conference on Gastrointestinal Cancer (WCGC)

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