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CLINICAL CANCER ADVANCES 2012 ASCO’s Annual Report on Progress Against Cancer12 GASTROINTESTINAL CANCERS SPECIALTY EDITOR: FADI BRAITEH, MD, U.S. Oncology Research, Comprehensive Cancer Centers of Nevada GI cancers include those of the esophagus, stomach, liver, pancreas, biliary tract, small bowel, appendix, colon, rectum, and anus. This year, researchers reported important advances in the treatment of advanced colorectal cancer using new targeted drugs as single agents and new biologics in combination with cytotoxic therapies (drugs that kill cancer cells). In addition, one study determined a significant survival benefit using preoperative chemotherapy plus radiation in patients with esophageal and gastroesophageal junction cancers. Major Advances Preoperative chemotherapy and radiation therapy double overall survival for esophageal and gastroesophageal junction cancers Esophageal cancer is one of the most deadly cancers, causing more than 400,000 deaths per year worldwide. Although a cure is possible for patients whose tumors can be removed completely during surgery, this is not possible for approximately one quarter of patients and leads to poorer outcomes. On the basis of positive results from an early-phase clinical trial, researchers launched a phase III clinical trial to determine if treatment with chemotherapy and radiation therapy before surgery would improve the success of surgery and extend patient survival.1 In the trial, patients with adenocarcinoma, squamous cell carcinoma, and large-cell undifferentiated carcinoma of the esophagus or gastroesophageal junction were randomly assigned to chemotherapy (carboplatin and paclitaxel) plus radiation therapy followed by surgery (178 patients) or surgery alone (188 patients). This year, researchers reported that preoperative treatment yielded substantial benefits: 29% of patients experienced complete remissions; median overall survival was longer (49 v 24 months) and the death rate was 35% lower in patients who underwentpreoperative treatment compared with those who had surgery alone. Toxicities from this additional therapy were minor. These findings will likely change the standard of care for most patients with esophageal and gastroesophageal junction cancers, offering the possibility of cure for many Regorafenib prolongs overall survival in patients with metastatic colorectal cancer Regorafenib is a multitargeted experimental drug that blocksthe growth of tumor cells and blood vessels. The drug has shown promising antitumor effects in preclinical studies and is currently being tested in clinical trials for various cancer types (Sarcoma). This year, researchers reported results of a phase III clinical tial that sought to determine if regorafenib would extend overall survival in patients with metastatic colorectal cancer whose disease had progressed after all approved standard therapies.2 This international clinical trial (CORRECT) randomly assigned patients to receive regorafenib plus best supportive care (505 patients) or placebo plus best supportive care (255 patients). Results of an interim analysis of trial data show a notable improvement in median overall survival for regorafenib versus placebo (6.4 v 5.0 months). On the basis of these encouraging results, the study was unblinded to allow patients who had been receiving placebo to switch to regorafenib. In September this year, the FDA approved regorafenib to treat patients with metastatic colorectal cancer whose disease had progressed despite standard treatments. 3 Notable Advances Second-line treatment with bevacizumab extends overall survival in patients with metastatic colorectal cancer Bevacizumab added to chemotherapy is a standard first-line treatment for metastatic colorectal cancer. Bevacizumab isalso used as a second-line treatment for patients who had not been treated with the drug previously. But before this year, it was unclear if it was beneficial to administer bevacizumab as a second-line treatment to patients whose disease had progressed after first-line bevacizumab plus chemotherapy. To answer this question, researchers conducted a clinical trial in patients with inoperable metastatic colorectal cancer whose disease had worsened within 3 months of stopping initial treatment with bevacizumab and chemotherapy.4 In the study, patients were randomly assigned to receive bevacizumab plus chemotherapy (409 patients) or chemotherapy alone (411 patients). This year, investigators reported the first trial results, finding that the median overall survival was longer with combination treatment compared with chemotherapy alone (11.2 v 9.8 months). The combination treatment also delayed time to disease progression. The results of this randomized study support a rationale for continuing bevacizumab in patients whose disease worsens after first-line treatment with bevacizumab plus chemotherapy. It remains to be proven if this so-called recycling of bevacizumab after first-line therapy is a costeffective strategy that prolongs survival, with expected differences in application in Europe versus North America. Adding cetuximab to standard adjuvant chemotherapy does not improve outcomes in stage III colon cancer Approximately half of patients with stage III colon cancer (cancer that has spread to the lymph nodes surrounding the colon but not to other parts of the body) are cured by surgery and postoperative (adjuvant) chemotherapy, and efforts are ongoing to elevate such cure rates. Postoperative FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy has been shown to reduce recurrence rates and improve overall survival in those patients. This year, researchers reported results of a phase III studyevaluating whether adding the targeted drug cetuximab to FOLFOX improves outcomes for those patients. Cetuximab was previously approved to treat patients with metastatic colon cancer who do not carry alterations in the KRAS gene, as a single agent or in combination with irinotecan in previously treated patients with metastatic disease. In July 2012, the FDA granted its approval in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) as a first-line treatment for patients with metastatic disease without KRAS alterations as well. This trial—involving 2,686 patients with stage III colon cancer—found that survival rates for FOLFOX alone were 74.6% versus 71.5% for FOLFOX plus cetuximab in patients without KRAS alterations and 67% versus 65% in those with KRAS alterations.5 The results suggest that cetuximab should not be used in patients with stage III colon cancer after surgery and underscore the need for a better understanding of the distinct tumor biology in advanced colon cancers. Study identifies factors that predict which patients with metastatic colorectal cancer might benefit from chemotherapy Patients with advanced colorectal cancer typically undergo surgery to remove cancerous tissue that has spread to the liver. A recent clinical trial showed that patients who were treated with FOLFOX chemotherapy around the time of surgery (so-called perioperative chemotherapy) had a prolonged time to cancer progression compared with those who had undergone surgery alone. A retrospective analysis of clinical data from 342 patients who participated in that trial revealed that FOLFOX seems to benefit a particular subset of patients with liver metastases from colorectal cancer—those who have increased levels of a marker called carcinoembryonic antigen (CEA), have a body mass index lower than 30, and are fully active (performance status,0).6 Among patients with increased CEA levels, the rates of disease progression at 3 years were 35% for those who received perioperative chemotherapy versus 20% for those who underwent surgery alone. FDA approves cetuximab in combination with FOLFIRI chemotherapy for patients with metastatic colorectal cancer In July, the FDA approved cetuximab for use in combination with FOLFIRI chemotherapy for firstline treatment of patients with KRAS mutation–negative, epidermal growth factor receptor (EGFR)– expressing metastatic colorectal cancer. 7 Adding cetuximab to chemotherapy results in improved overall and progression-free survival for this group of patients. FDA approves ziv-aflibercept injection in combination with FOLFIRI chemotherapy for patients with metastatic colorectal cancer In August, the FDA approved the biologic ziv-aflibercept injection for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. This new targeted treatment offers the possibility of slowing disease progression in this subset of patients. 8 REFERENCES 1. van Hagen P, Hulshof MC, Lanschot JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-2084, 2012 2. Grothey A, Sobrero AF, Siena S, et al: Results of a phase III randomized, double-blind, placebocontrolled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. J Clin Oncol 30: 2012 (suppl; abstr LBA385) 3. US Food and Drug Administration: FDA approves new treatment for advanced colorectal cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm 4. Arnold D, Andre T, Bennouna J, et al: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol 30:203s, 2012 (suppl; abstr CRA3503) 5. Alberts SR, Sargent DJ, Nair S, et al: Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: A randomized trial. JAMA 307:1383-1393, 2012 6. Sorbye H, Mauer M, Gruenberger T, et al: Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983). Ann Surg 255:534-539, 2012 7. US Food and Drug Administration: Cetuximab in combination with Folfiri/Therascreen http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm310933.htm 8. US Food and Drug Administration: FDA Approves Zaltrap for metastatic colorectal cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncemen