'Blown Away' By Adjuvant FOLFIRINOX in Pancreatic Cancer

Alexander M. Castellino, PhD

December 19, 2018

"Remarkable" results with a new adjuvant chemotherapy regimen in patients with earlier stage pancreatic cancer have already changed clinical practice, experts report.

After surgery, patients who received adjuvant chemotherapy with a regimen of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) had significantly better outcomes than patients who were given gemcitabine (Gemzar, Eli Lilly) in the PRODIGE 24–ACCORD trial.

Details of the results were published online today in the New England Journal of Medicine.

"On average, the patients lived 20 months longer and were cancer free for 9 months longer compared with the standard of care, gemcitabine," lead investigator Thierry Conroy, MD, director of the Institut de Cancérologie de Lorraine in France, told Medscape Medical News.

"This should impact how we treat patients with pancreatic cancer [who undergo surgery] around the world," he added.

In fact, it already has.

These results were first presented in June at the American Society of Clinical Oncology (ASCO) 2018 annual meeting, as reported by Medscape Medical News.

Hedy L. Kindler, MD, professor of medicine at the University of Chicago, tells Medscape Medical News that when she heard these data at the meeting she was "blown away…the next day I had the chemotherapy order sets changed," she said.

"The results are truly practice changing, which in pancreatic cancer is so uncommon," Kindler said. "Most trials [in pancreatic cancer] move the bar incrementally; this is a real change, a genuine advance," she added.

Most trials move the bar incrementally; this is a real change, a genuine advance. Dr Hedy L. Kindler

"We have seen trials with incremental improvement in overall survival (OS), but not with a median OS of 54 months," she added.

Kindler authored the accompanying editorial, in which she described the results as "impressive" and the survival as "truly unprecedented."

She pointed out that this trial was a culmination of more than 10 years of work that initially established FOLFIRINOX as standard treatment of advanced pancreatic cancer.

The investigators deserve to be congratulated on a beautifully designed study with a high level of quality control, she said.  

"The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors," she writes.

Manish Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine and New York-Presbyterian, New York, who was not associated with the study, echoed similar sentiments. "I already have been using this regimen in this setting. This was a well-designed and well performed study. The data are compelling and practice changing," he told Medscape Medical News..

"This is a landmark study that examines the best adjuvant therapy for pancreatic cancer. It is an important study because it affects thousands of patients worldwide. It is broadly applicable and will change practice for many," Shah said.

Study Details

In the open-label, phase 3 study, 493 patients enrolled across 58 centers in France and 19 centers in Canada were randomized to receive modified FOLFIRINOX (n = 247) or gemcitabine (n = 246) and formed the intent-to-treat population.

Participants were between 18 and 79 years of age, with histologically confirmed pancreatic ductal adenocarcinoma who had undergone R0 or R1 resection within 3 to 12 weeks prior to randomization.

The trial was designed to detect a 3-year disease-fee survival (DFS) of 10% between the modified FOLFIRINOX and gemcitabine groups. Patients in the gemcitabine group received the standard dose on day 1, 8, and 15, every 28 days for 24 weeks (6 cycles). Patients in the modified FOLFIRINOX group received oxaliplatin, leucovorin, irinotecan, and fluorouracil every 14 days for 24 weeks (12 cycles).

In the modified version of the FOLFIRINOX regimen, the 5-fluorouracil bolus was dropped and, based on a protocol-specified safety analysis, irinotecan dose was reduced from 180 mg/m2 to 150 mg/m2 after the enrollment of 162 patients. Conroy explained that the regular FOLFIRINOX regimen that is used in the advanced pancreatic cancer setting was more toxic, and that this modified regimen circumvented some of the toxicities seen.

Conroy explained that using gemcitabine alone in the control group was appropriate; although the combination of gemcitabine and capecitabine (Xeloda, Genentech) is also currently used as standard of care in the adjuvant setting, this combination was established only after the trial began, he explained.  

Added Kindler, the editorialist: "Moreover, it is challenging to give both drugs, especially in the US population due to folate supplementation in the US diet. In addition, the combination [of gemcitabine and capecitabine] improved OS, but not PFS."

Patients selected in this trial had to be able to receive modified FOLFIRINOX. In addition, all patients were required to have postsurgical CT or MRI and to have postoperative serum CA 19-9 levels <180 U/mL to minimize the risk of including patients with metastatic disease. A central review of surgical reports, postsurgical CT and MRI scans, and pathology reports was undertaken to determine prognostic factors. "It is admirable that central review…[was] performed in a trial of this size, thus ensuring the enrollment of eligible patients and the proper characterization of prognostic factors," Kindler observes.

For ethical reasons, an independent data and safety monitoring committee recommended an early analysis of the findings, and the final results reported were from the database lock of April 13, 2018. Conroy told Medscape Medical News that patients continue to have follow-up for future updates.

Study Results

Patients in the modified FOLFIRINOX and gemcitabine groups received a median of 12 and 6 cycles, respectively. Correspondingly, median duration of treatment was 24.6 and 24.0 weeks. Significantly more patients in the gemcitabine group received all planned cycles of treatment (79% vs 66.4%; P = .002).

With a median follow-up of 33.6 months, the median DFS was significantly longer for patients receiving modified FOLFIRINOX (21.6 vs 12.8 months for gemcitabine) and hazard ratio (HR) for cancer-related event, second cancer, or death was 0.58 (95% confidence interval [CI], 0.46 – 0.73; P < .001). Three-year DFS was 39.7% for patients in the FOLFIRINOX group and 21.4% for those in the gemcitabine group.

"The hazard ratio of 0.58 is impressive," Shah said. "It means that patients who received FOLFIRINOX had a 42% chance of better DFS. For patients who are able to receive the three-drug combination, this will be the new standard," he said.

"The disease-free survival in the gemcitabine group, at 12.8 months, is similar to that observed in the CONKO-001, ESPAC-4, and other trials, which argues against selection bias," Kindler noted in her editorial. CONKO-001 established 6 months of adjuvant gemcitabine as a standard of care and ESPAC-4 provided evidence for superior median OS with the combination of gemcitabine and capecitabine vs gemcitabine alone in a similar patient population.

The benefits of modified FOLFIRINOX (vs gemcitabine) extended to other secondary endpoints of OS (median: 54.4 vs 35.0 months; HR for death, 0.64; P = .003); metatatsis-free survival (MFS; median: 30.4 vs 17.7 months; HR for distant disease or death, 0.59; P < .001); and cancer-specific survival (median: not reached vs 36.4 months; HR for death due to treatment or treatment-related complication, 0.63; P = .003).

Three-year OS (63.4% vs 48.6%), MFS (48.2% vs 30.9%), and cancer-specific survival (66.2% vs 51.2%) was also significantly higher for patients in the modified FOLFIRINOX group.    

Modified FOLFIRINOX Associated With Significant Adverse Events

Grade 3/4 adverse events were reported in a significantly higher proportion of patients on modified FOLFIRINOX (75.9% vs 52.9% on gemcitabine); grade 4 events were similar across the two groups (12.2% for modified FOLFIRINOX vs 12% for gemcitabine). All toxicities, except oxaliplatin-induced peripheral neuropathy (persistent at 3 years in two patients), were reversible.

Grade 3/4 adverse events significantly higher with modified FOLFIRINOX (vs gemcitabine) included diarrhea (18.6% vs 3.7%), increase in γ-glutamyltransferase level (18.3% vs 8.4%), paresthesia (12.7% vs 5.4%), fatigue (11.0% vs 4.6%), sensory peripheral neuropathy (9.3% vs 8.7%), nausea 5.5% vs 0.8%), vomiting (5.1% vs 1.3%), abdominal pain (3.4% vs 0.4%), and mucositis (2.5% vs 0%). Thrombocytopenia was significantly higher with gemcitabine (4.5% vs 1.3% for modified FOLFIRINOX). Although neutropenia was similar between the two groups, significantly more patients who received FOLFIRINOX also received granulocyte colony-stimulating factor (G-CSF 62.2% vs 3.7% for gemcitabine and G-CSF).

Who Should Be Treated With Modified FOLFIRINOX?

Is the modified FOLFIRINOX regimen that was used in this trial appropriate for all patients who undergo surgery for pancreatic cancer?

The French team led by Conroy is an experienced group of investigators who are able to deal with the toxicities of the regimen, Kindler comments.

"When one sees outcomes this terrific, we should want to try it in the appropriate patient," she added.

When one sees outcomes this terrific, we should want to try it in the appropriate patient. Dr Hedy L. Kindler

Conroy explained that most of the toxicities can be appropriately managed. "The modified FOLFIRINOX regimen is safe, there is no toxic death. With dose adjustments and delays, and skipping bolus 5-FU and reducing the dose of irinotecan are all accompanied with no reduction in the efficacy," he said.

He also indicated that, with the published study, a supplementary appendix will provide dose modifications for the management of adverse events.

"The patients in the study have made it through a Whipple [the surgical procedure of pancreaticoduodenectomy]," Kindler said. Moreover, the study ensured that CA 19-9 levels were below 180 U/mL within 3 to 12 weeks of surgery to be able to withstand chemotherapy. "We do not want to give this regimen to an average person," she added.

Patients who undergo a pancreatic resection may not be in the best shape to receive aggressive chemotherapy, Shah explained. "We need to be able to select our patients for this regimen better. We don't want to give them such aggressive therapy that they can't tolerate it. But we also want to give them the most effective therapy possible. We need to know better how to strike this balance," he said.

Challenges Remaining in Pancreatic Cancer

Kindler noted that advances in precision medicine have yet to make an impact in pancreatic cancer and only 8% of patients are cured. Surgery is the only potential cure, she notes, but only 15% to 20% of patients are candidates for resection and only 4% of patients will live for longer than 10 years.

Pancreatic cancer is due to become the second leading cause of cancer death in the US in the coming decade, Kindler said. Against these numbers, results of the current study will impact a minority of patients with pancreatic cancer, she pointed out.

Conroy and Kindler explained that the strides seen with targeted therapies and immunotherapies have not made their way into pancreatic cancer for a reason. "There are no drugs that can block the main mutation in pancreatic cancer—KRAS," Conroy said. "Pancreatic cancers are immunologically cold," Kindler added. Conroy explained that trials of immune checkpoint inhibitors have been disappointing because microsatellite instability is rather rare. Moreover, the stroma occupies about 90% of the tumor and secretes suppressive factors in the tumor microenvironment.

Shah pointed out that as good as the data are, the majority of patients on this study still developed recurrence and ultimately died of pancreatic cancer. "We need to continue to work to improve patient outcomes in this aggressive and deadly disease," he said.

"Although pancreatic cancer remains recalcitrant for the majority of patients who present with more advanced disease, for some patients at least adjuvant FOLFIRINOX provides a glimmer of hope," Kindler told Medscape Medical News.

PRODIGE (Partenariat de Recherche en Oncologie Digestive) 24 was supported by R&D Unicancer (which received a grant from Chugai Pharmaceutical), as well as by a grant from the French Ministry of Health and the Institut National du Cancer , and by the French National League against Cancer . The Canadian part of the trial was supported by a grant from the Canadian Cancer Society and by grants from 7 Days in May.

Dr Conroy reports receiving travel support from Roche; several coauthors list relationships with various pharmaceutical companies, and two coauthors are employees of R&D Unicancer, which sponsored the trial. Dr Kindler reports personal fees from many pharmaceutical companies outside the submitted work. Dr Shah has disclosed no relevant financial relationships.

N Engl J Med. Published December 19, 2018. Full text, Editorial

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