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Patients with initially unresectable colorectal liver metastases treated with bevacizumab (Avastin, Genentech) and FOLFOXIRI ( folinic acid-5-fluorouracil, oxaliplatin, irinotecan) had higher subsequent resection and response rates than a group of similar patients treated with bevacizumab and modified (m)FOLFOX6 (folinic acid-5-fluorouracil, oxaliplatin), according to a study published in Annals of Oncology. Joseph T. Ruggiero, M.D., associate professor of clinical medicine, was invited by Clinical Oncology News to provide perspective on the research. Read the full article here.

Joseph Ruggiero, M.D. Patients with liver-only metastatic colon cancer are a unique group. We have learned that an aggressive surgical approach that leads to a complete resection of the metastatic disease can lead to cure, even for patients with multiple and bilobar metastatic disease. An up-front multidisciplinary approach is, therefore, required to treat these patients. This includes a radiologist, a surgeon and a medical oncologist. The assessment of these patients requires meticulous imaging that should include a PET/CT scan to exclude extrahepatic disease. MRI with contrast usually also is required to define the anatomic distribution of disease to assess possible resection.

However, many questions regarding optimal management remain unanswered. Among the unanswered questions is the proper role for neoadjuvant or adjuvant chemotherapy in patients deemed resectable at the time of detection. Also unclear is the optimal regimen for down-staging patients deemed unresectable. In regard to the neoadjuvant approach to resectable patients, Nordlinger et al reported the results of the European Organisation for Research and Treatment of Cancer Intergroup trial 40983 in 2008 (Lancet 2008;371[9617]:1007-1016, PMID: 18358928). In this trial, patients who were deemed resectable with up to four lesions and no prior exposure to oxaliplatin were randomly assigned to surgery or neoadjuvant FOLFOX for three months followed by surgery and then another three months of chemotherapy. Mature analysis of this rather large study shows improvement in progression-free, but not overall, survival. The results of this study—and the fact that since this study was reported many patients have had prior oxaliplatin exposure during adjuvant therapy—have led many clinicians to proceed directly to surgery in resectable patients.

In regard to down-staging, Gruenberger et al reported the results of the Olivia trial in Annals of Oncology in 2015. This is a multi-institutional randomized trial to evaluate resection rates and safety of bevacizumab with either mFOLFOX6 or the three-drug regimen FOLFOXIRI in patients with liver-only metastatic colorectal cancer deemed unresectable by the local multidisciplinary team. The sample size was low, just 40 patients in each group. The authors noted that they believed this allowed assessment of relative resection rates, which was the primary end point. However, a study of this size is not powered to confirm the superiority of one therapy and must be considered exploratory only.

The use of FOLFOXIRI as initial therapy for metastatic colorectal cancer previously was reported in the Phase III TRIBE trial by Loupakis at al in October 2014 (N Engl J Med 371[17]:1609-1618, PMID: 25337750). In this trial, patients received bevacizumab with either FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) or FOLFOXIRI. The three-drug regimen had an increased response rate and improved progression-free survival compared with the FOLFIRI control arm. Overall survival was longer but not significantly so. As expected, FOLFOXIRI was associated with an increased incidence of grade 3/4 side effects, including neuropathy, stomatitis, diarrhea and neutropenia.

In the Olivia trial, as expected, FOLFOXIRI was associated with an improved response rate of 81% versus 62%. This is higher than the response rate in TRIBE, and the authors suggested that this may reflect the common belief that liver-only metastatic disease is more chemotherapy sensitive. The higher response rate in Olivia translated into a higher R0 resection rate (the primary end point of the trial) of 49% for bevacizumab-FOLFOXIRI versus 23% for bevacizumab-mFOLFOX6.

They also reported an improvement in progression-free survival. As expected, the improved response rate came at the cost of increased toxicity, particularly neutropenia and diarrhea. Of note, there was no evidence of increased surgical complications in the FOLFOXIRI cohort. The time to resection in both groups was similar (four months). It is now recognized that if surgery is contemplated for resection of hepatic metastases, then the neoadjuvant chemotherapy needs to be limited, to prevent hepatotoxicity before resection.

The challenge in interpreting such data is the absence of any standardized way to assess resectability. Even in a multidisciplinary setting, surgeons may not agree. Also, there will be many patients who despite even a major response to chemotherapy will never be resectable, based on the volume and extent of pretreatment involvement. Most of the patients in this trial had more than three metastatic lesions. It would have been helpful to know the range of the number of nodules in each cohort, whether nodules that resolved completely with chemotherapy were anatomically resected and whether any number of metastatic lesions was considered too many for inclusion on the trial. Finally, this study did not address the role of biologic agents, an area of research and controversy.

In summary, FOLFOXIRI is a highly active, albeit toxic regimen for advanced colorectal cancer. In a fit patient, it may be an excellent choice in the borderline resectable metastatic setting, in which a higher response rate may lead to a better opportunity for potentially curative surgery. This may not be the common scenario for our metastatic patients, but this paper suggests that this approach is feasible and safe when down-staging is appropriate.