Perioperative Chemotherapy Reduces Risk of Liver Metastases in Colorectal Cancer (2007)

CHICAGO—For the first time, researchers have shown that giving perioperative chemotherapy reduces the risk of resectable liver metastases in colorectal cancer patients, compared with the use of surgery alone. In the study of 364 patients, the recurrence-free survival rate in those who received neoadjuvant and adjuvant chemotherapy was 42%, compared with 33% for patients treated with surgery alone, reported Bernard Nordlinger, MD, Professor of Surgery and Chairman of Surgery and Oncology at Ambroise Pare Hospital of the Assistance Publique-Hopitaux de Paris. Speaking here at the ASCO Annual Meeting, Dr. Nordlinger said that perioperative chemotherapy reduced the risk of relapse in patients with liver metastases considered resectable on imaging—and even more in patients whose metastases were actually resected. And it was safe. “This treatment should be proposed as the new standard for these patients,” he said. Dr. Nordlinger noted that 40% to 50% of the one million people diagnosed with colorectal cancer worldwide each year develop liver metastases. After resection alone—the current standard of care—recurrence is common and the five-year survival rate is only 30%, he said. Study Details The European Organization for Research and Treatment of Cancer (EORTC) Intergroup Phase III Study 40983 included 182 patients randomized to perioperative chemotherapy plus surgery and 182 patients randomized to surgery alone. Of those, 151 in the surgery-plus-chemotherapy arm and 152 in the surgery arm completed the study on protocol. The patients had up to four liver metastases. Patients in the chemotherapy arm were given six cycles of FOLFOX4 (oxaliplatin, leucovorin, and fluorouracil [5-FU]) over three months, both before and after surgery. At a median follow-up period of 3.9 years, the absolute difference in profession-free survival rates was 9.2%, which was highly significant, Dr. Nordlinger said. This corresponded to a 27% relative reduction in risk in the risk of recurrence in patients who received perioperative chemotherapy.Figure: Bernard Nordlinger, MD: “Perioperative chemotherapy reduced the risk of relapse in patients with liver metastases considered resectable on imaging and even more in patients whose metastases were actually resected.”Multidisciplinary Approach Stressed One of the keys to the approach is utilizing a multidisciplinary medical team to evaluate the patients and decide if their metastases are resectable, he said. “These findings support a multidisciplinary approach to care, with all members of the health care team collaborating to determine the optimal combination of chemotherapy and surgery.” Side effects were “as expected,” Dr. Nordlinger said. After preoperative chemotherapy, about 2% of patients developed Grade 3 sensory neuropathy, 8% had Grade 3 diarrhea, and 18% had Grade 3–4 neutropenia. During postoperative chemotherapy, about 10% of patients developed Grade 3 sensory neuropathy, 5% developed Grade 3 diarrhea, and 35% developed Grade 3–4 neutropenia. There were no chemotherapy-related deaths. During surgery, 25% of patients in the perioperative chemotherapy arm and 16% of those in the surgery-alone arm developed reversible complications such as liver insufficiency or bleeding. Less than one percent of patients died during surgery. Commentary Commenting on the findings, A. William Blackstock, MD, Professor of Radiation Oncology at Wake Forest University School of Medicine, said that one of the most striking factors about the regimen is its safety. “The chemotherapy didn't compromise getting these patients to surgery,” he said. Dr. Blackstock urged caution, however, in using regimens other than FOLFOX4 before they are thoroughly tested in clinical trials. Stephen I. Shibata, MD, a medical oncologist at City of Hope Cancer Center, agreed with the researchers that perioperative chemotherapy should become the standard of care for some patients with resectable liver metastases and that a multidisciplinary team that includes a medical oncologist and a surgeon must be employed. “This study clearly demonstrates that chemotherapy can improve outcomes in terms of relapse-free survival in patients with curative liver resection,” he said. Dr. Shibata added that he is sure oncologists will have questions about the timing of the chemotherapy and whether other drugs can be used. But, he added “there is room for ongoing clinical trials to answer these questions. Study Discussant The study's Discussant, Nicholas J. Petrelli, MD, Medical Director of the Helen Graham Cancer Center in Newark, DE, and Professor of Surgery at Thomas Jefferson University in Philadelphia, said, “Disease-free survival is an important endpoint when we talk about colorectal cancer patients with resectable liver metastases.” However, he said it is too soon to declare perioperative treatment with FOLFOX4 as a standard of care.Figure: Eric Van Cutsem, MD, PhD: “The combination of FOLFIRI and cetuximab is a new first-line option for the treatment of patients with metastatic colorectal cancer.”“Hepatic resection is the only potential curable treatment for colorectal cancer-associated liver metastases” and is still a good option for such patients, Dr. Petrelli said. He cautioned that the researchers did not show that the chemotherapy regimen extends overall survival and that morbidity increases with prolonged courses of the drugs. The results are “encouraging,” he said, “but questions remain.” Cetuximab for Colorectal Cancer In a separate study presented at the meeting, researchers reported that colorectal cancer patients who received the monoclonal antibody cetuximab in addition to a standard chemotherapy regimen were 15% less likely to have disease progression than those who received chemotherapy alone. In the study, known as Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL), 599 patients were randomized to receive FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus cetuximab and 599 patients to receive FOLFIRI alone. The primary endpoint of improvement in the one-year progression-free survival rate “was clearly met,” said chief investigator Eric Van Cutsem, MD, PhD, Professor in the Digestive Oncology Unit at the University Hospital Gasthuisberg in Leuven, Belgium. Specifically, the progression-free survival rate was 34% in patients given cetuximab and 23% in those given chemotherapy alone. The time to progression was almost nine months versus eight months in the two groups, respectively. A New Option “The combination of FOLFIRI and cetuximab is a new [first-line] option for the treatment of patients with metastatic colorectal cancer,” Dr. Van Cutsem said. Currently, cetuximab is approved for the second- and third-line treatment of metastatic colorectal cancer. At a news briefing at the meeting, Dr. Blackstock agreed that the cetuximab combination offer some patients another option. At the same time, he said, the benefit associated with the regimen was modest and will not change clinical practice. More ASCO Articles Coming in Future Issues! ▪NSCLC: (1) Induction Chemo Shown to Extend Survival; (2) Bevacizumab Works with Cisplatin-Gemcitabine Combo; (3) Estrogen Levels Found to Affect Survival; (4) CP-751871 IGF-1R Antibody as First-Line Therapy Produces High Response Rates; (5) Pemetrexed Found Cost-Effective in Second-Line Advanced NSCLC Compared with Docetaxel & Best Supportive Care; (6) Only Moderate Responses with Continuous Daily Dosing of Sunitinib ▪Neuroendocrine Tumors: RAD00l Inhibitor of mTOR Used with Octreotide Shows Activity