New combination of cancer drugs can improve outcomes in patients whose pancreatic cancer is too close to a blood vessel to be removed safely


If the American Cancer Society’s projections prove accurate, more people will die from pancreatic cancer than from breast, brain, ovarian or prostate cancer this year.

One reason pancreatic cancer is so lethal is its resistance to traditional chemotherapy.

But West Virginia University surgical oncologist Brian Boone is exploring whether FOLFIRINOX – a new combination of cancer drugs – can improve outcomes in patients whose pancreatic cancer is “borderline resectable,” meaning that a tumor may be too close to a blood vessel to be removed safely.

“The way pancreatic tumors sit, they’re very close to several important blood vessels that you really can’t live without.

That’s where chemotherapy comes into play,” said Boone, an assistant professor in the School of Medicine’s Department of Surgery.

“We try to shrink the tumor off of the vein and change it from borderline resectable to resectable, or removable by surgery.”

In a recent meta-analysis of 24 studies, Boone and a team of researchers considered 313 cases of borderline resectable pancreatic cancer that physicians treated with FOLFIRINOX.

They analyzed the patients’ overall survival rates.

They also evaluated how frequently tumors shrank enough to be surgically removed.

The team found that FOLFIRINOX prolonged patients’ lives, on average, and made surgery possible in more instances.

For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.

At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.

The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.

“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.

The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.

previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.

In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.

The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.

The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.

Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.

The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).

The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.

Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.

Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.

Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.

The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”

The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.

SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.

Their findings appear in the Journal of the National Cancer Institute.

“There’s no control group, but when you compare it to what we’ve historically seen in patients that are borderline resectable and that we take straight to surgery, FOLFIRINOX resulted in better survival and better rates of resection,” Boone said.

More than two-thirds – or 67.8 percent – of the cancers included in the study responded well enough to FOLFIRINOX that they could be completely removed surgically.

“Historically, complete removal of the tumor is accomplished in a far lower number of patients without treatment before surgery and often requires removal of a portion of the vein,” he said.

“Historically, complete removal of the tumor is accomplished in a far lower number of patients without treatment before surgery and often requires removal of a portion of the vein,” he said.

On average, patients who took FOLFIRINOX survived for 22.2 months overall.

Without the drug, patients with borderline resectable cancer tend to survive for about 12 months, based on Boone’s clinical experience.

“There’s really been a paradigm shift for pancreatic cancer, now that we have better drugs,” he said.

Despite these improvements in treatment, pancreatic cancer is currently the fourth deadliest, and “it’s climbing the ladder in terms of the number of people it kills,” said Carl Schmidt, chief of the Surgical Oncology Division.

“In my 10 years of being in practice, there’s been more interest in pancreatic cancer, but moving the needle is really hard.”

To that end, Boone, Schmidt and their colleagues are pursuing studies that span the laboratories where scientists conduct basic-science experiments, the infusion rooms where patients receive treatment and the operating rooms where oncologists perform surgery.

“We’re developing a full spectrum of pancreatic cancer research.

That’s why we do the basic science: we’re identifying patients at the bedside and trying to find solutions in the lab,” Boone said.

“And it’s all driven by trying to make outcomes better for patients that we take care of every day.”

More information: Quisette P Janssen et al, Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis, JNCI: Journal of the National Cancer Institute (2019). DOI: 10.1093/jnci/djz073

Journal information: Journal of the National Cancer Institute
Provided by West Virginia University


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