BARCELONA, Spain—Choosing between the two effective front-line regimens for patients with advanced pancreas adenocarcinoma who have good performance status is a challenge. Both FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel have been proven active in this disease, but have not been compared head-to-head in first line treatment.
The relative merits of each as initial therapy were discussed at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer by Eileen M. O'Reilly, MD, Associate Director, Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College.
Of the many factors to consider in treatment selection—medical comorbidities, sequencing, liver function, patient preference, toxicity, side effects, practical considerations, neuropathy, performance scores, and age—O'Reilly said performance status is the most important.
“The key issue is what the patients look like when they walk through the door,” she said, citing a meta-analysis that confirms its importance in identifying who will benefit from combination therapy (BMC Cancer 2008;8:82).
And in the CALGB 80303 trial, overall survival by performance status (pooled) showed patients with PS-0 status had a distinct advantage, 8 months overall survival compared with 4.8 months for PS-1 patients and 2.8 months for PS-2 (J Clin Oncol 2010;28:3617-3622).
Optimal Front-Line Regimen?
For first-line treatment in metastatic disease, the preferred National Comprehensive Cancer Network regimens in 2015 for patients with good performance status are either enrollment in a clinical trial, or FOLFIRINOX, or gemcitabine/nab-paclitaxel. Other possibilities are gemcitabine plus erlotinib, a gemcitabine-based combination, or single-agent gemcitabine.
O'Reilly said there are no clear data to guide which of the two active front-line regimens is optimal, “but it is fair to say that gemcitabine/nab-paclitaxel may be relevant to a broader group of patients as well as to older patients with a less robust performance status.”
Gemcitabine/nab-paclitaxel may also be easier to add on with other agents, she said, but this has not been proven.
A comparison of single-agent gemcitabine with FOLFIRINOX in the ACCORD trial suggests single-agent gemcitabine is generally the less less toxic, she said. More grade 3-4 adverse events were seen among the 167 patients receiving FOLFIRINOX compared with the 169 patients taking gemcitabine. Of note were neutropenia (45.7% for FOLFIRINOX versus 21.0% for gemcitabine), febrile neutropenia (5.4% versus 1.2%, respectively), and thrombocytopenia (9.1% versus 3.6%) (N Engl J Med 2011;364:1817-25).
O'Reilly also cited the overall survival rate in the MPACT trial, which showed gemcitabine/nab-paclitaxel superior to gemcitabine alone, 8.5 months versus 6.7 months, respectively. There was also a statistically significant relative response rate and progression-free survival (N Eng J Med 2013;369:1691-1703, J Natl Cancer Inst 2015;107:dju413).
The cost of front-line therapy for pancreatic cancer may help guide selection, according to O'Reilly. A recent analysis (ASCO GI 2015 Abstract 368) estimated the costs based on Medicare drug sales and physician fee schedules; the cost for grade 3-4 adverse events with 5 days of hospitalization for febrile neutropenia; and the cost of outpatient support for nausea, vomiting, and diarrhea.
The approximate monthly costs in 2014 were $12,000 for gemcitabine/nab-paclitaxel, $8,000 for dose modified gemcitabine/nab-paclitaxel, $7,500 for FOLFIRINOX, $2,500 for carboplatin-paclitaxel, and $2,000 for gemcitabine alone.
Interestingly, most of the monthly cost for the two gemcitabine/nab-paclitaxel regimens was for the drugs. In contrast, the major cost for FOLFIRINOX, gemcitabine alone, and carboplatin-paclitaxel was from treatment of toxicities.
“That tells us something as we utilize these regimens,” O'Reilly said.
Another study (ASCO GI 2015 Abstract 429) compared cost effectiveness and supportive care for FOLFIRINOX and for gemcitabine/nab-paclitaxel. That study found that, while the rate of all grade adverse events was higher for FOLFIRINOX (95% versus 84%), the time to therapy discontinuation was approximately the same, 3.8 months versus 3.4 months.
There are no biomarkers to guide selection between these two regimens, but retrospective data from several U.S. oncology trials with more than 2,000 patients receiving first-line FOLFIRINOX or a gemcitabine-based regimen show the two front runners with very similar overall survivals (ASCO 2014 Abstract 4132).
Median survival in the FOLFIRINOX trials was 11.2 months, compared with 10.2 months in trials with gemcitabine/nab-paclitaxel, and 7.0 months in trials with other gemcitabine-based combinations.
“This can provide some comfort for this equipoise with regard to front-line treatments,” O'Reilly noted.
Head-to-Head Comparison Trial Ongoing
An ongoing randomized phase II trial will hopefully answer questions about the relative merits of FOLFIRINOX and gemcitabine/nab-paclitaxel, in this case as therapy for resectable pancreatic cancer.
The Southwest Oncology Group S1505 trial is still accruing, O'Reilly said, but added the outcomes will likely provide more information about toxicity rather than overall signal (NCI02562716).
About 50 percent of patients with pancreas adenocarcinoma receive second-line therapy. The impact on survival is unclear, particularly because few patients receive therapy on trial in second line, O'Reilly explained.
But it does contribute to overall survival, as shown in the NAPOLI-1 trial that compared MM-398 plus 5-FU/LV against 5-FU/LV alone, with overall survival of 6.1 months versus 4.2 months, respectively (Lancet 2016;387:545-557).
O'Reilly ended with a note on poorer performance-status patients, saying either gemcitabine/nab-paclitaxel or gemcitabine with or without erlotinib/capecitabine could be appropriate.
Other Options in Pancreatic Cancer
O'Reilly's admonition to consider performance status was echoed by another speaker, Margaret A. Tempero, MD, Director of the UCSF Pancreas Center and Professor of Medicine, Division of Hematology and Oncology, University of California San Francisco.
In her presentation, Tempero said the future in this cancer and all others is in biomarkers that can predict which patients will respond to treatment. At the moment, there is no biomarker for pancreatic cancer, but biomarker-driven trials are in progress. Meanwhile, there are other options for clinicians besides FOLFIRINOX and gemcitabine/nab-paclitaxel.
“Let's build on both FOLFIRINOX and gemcitabine/nab-paclitaxel,” Tempero said, listing gemcitabine-capecitabine, gemcitabine-cisplatin, GTX (gemcitabine, docetaxel, and capecitabine), and gemcitabine-erlotinib as potential choices.
Robert H. Carlson is a contributing writer.