Advances in Therapy for GI Cancers

The past year brought important advances, promising findings, and some potential disappointments to the field of gastrointestinal cancer treatment. Herewith, we present select highlights of the year in clinical research. Targeted Therapy for Advanced Colon Cancer In the setting of second- line therapy for advanced disease, preliminary results of the NCI-sponsored, phase III E3200 trial has shown that the addition of bevacizumab(Drug information on bevacizumab) (Avastin) to the FOLFOX4 regimen results in a significant increase in median overall survival compared with FOLFOX4 alone (12.5 months vs 10.7 months, respectively). This trial in more than 800 patients initially included a bevacizumab-alone arm, which was discontinued due to poor survival (see report on page 5). Preliminary results of the TREE2 trial of bevacizumab with oxaliplatin(Drug information on oxaliplatin) (Eloxatin)-based chemotherapy in the first-line treatment of advanced disease have shown three regimens of oxaliplatin/5-FU with bevacizumab to yield acceptable tolerability and significantly improved overall response rates. A total of 213 previously untreated patients received one of three regimens (FOLFOX-B, bFOL-B, or CAPEOX-B). (See report on page 5 and glossary of regimens on page 18). This trial suggests that oxaliplatin with bevacizumab may be as effective as front-line management with IFLbevacizumab. A phase II trial of the epidermal growth factor receptor (EGFR) inhibitor cetuximab(Drug information on cetuximab) (Erbitux) has shown the ability of this agent to produce major objective responses in patients with metastatic colorectal cancer who had prior treatment (two courses of chemotherapy or adjuvant therapy plus one course of chemotherapy) including irinotecan(Drug information on irinotecan) (Camptosar), oxaliplatin, and a fluoropyrimidine. Among 346 patients, partial response occurred in 12% and stable disease occurred in 32%. Although only nine patients without EGFRpositivity on immunohistochemistry were enrolled, EGFR status did not appear to influence likelihood of response, a finding that also has been made with EGFR inhibitors in other disease settings. The presence of mutations in EGFR, which has predicted response to inhibitors in other settings, did not predict response in this trial (see report on page 7). Adjuvant Therapy for Advanced Colon Cancer The X-ACT trial showed that oral capecitabine(Drug information on capecitabine) (Xeloda) treatment was at least equivalent to bolus 5-FU/LV as adjuvant therapy for resected stage III colon cancer. Capecitabine treatment was associated with a significant improvement in 3-year recurrencefree survival (0.86 hazard ratio) in this phase III trial in nearly 2,000 patients, with trends towards improvement in overall survival. Capecitabine was associated with reduced frequency of many adverse events, including neutropenia, diarrhea, stomatitis, nausea and vomiting, and alopecia, but an increased frequency of hand-foot syndrome. Benefits in terms of reduced adverse events were observed in both elderly and younger patients (see report on page 8). Further, a subanalysis of the trial showed that capecitabine treatment was associated with reduced overall medical expenditures and a dramatic reduction in patient time requirements for treatment and adverse effect management (see sidebar on page 9). A NSABP trial in more than 1,600 patients with stage II/III colorectal cancer has indicated that oral UFT (tegafur)/LV is very similar to the Mayo 5-FU/LV regimen in terms of 5-year overall, and disease-free survival. Grade 3 or 4 adverse events were also very similar in the treatment groups. Some quality of life outcomes favored UFT/LV. UFT is not available in the US (see report on page 16). In January 2004, the U.S. Food and Drug Administration approved Eloxatin for adjuvant treatment in combination with infusional 5-FU/LV in patients with stage III colon cancer. In the MOSAIC trial in more than 2,000 patients, which formed the basis of approval, the combination significantly improved 4-year diseasefree survival in patients with stage III disease (69.7% vs 61.0%) compared with 5-FU/LV alone. Grade 3 or 4 toxicity was more common with oxaliplatin. Common toxicities include granulocytopenia, paresthesias, diarrhea, nausea, and vomiting; paresthesias were observed in the majority of patients receiving the combination. Anaphylactic-like reactions are also increasingly recognized as occurring with oxaliplatin, requiring caution during administration and occasional discontinuation of this agent (see report on page 11). First-Line and Subsequent Treatment of Advanced Colorectal Cancer In a Dutch phase III trial in 302 patients with metastatic colorectal cancer, the first-line combination of oxaliplatin plus 5-FU/folinic acid improved response rate and progression-free survival compared with 5-FU/folinic acid alone, although median overall survival did not differ by treatment. The oxaliplatin patients had less diarrhea and stomatitis and more sensory neuropathy; 5% of patients receiving oxaliplatin had grade 3 or 4 allergic adverse events (see report on page 15). A retrospective pooled data analysis of randomized trials comparing the vascular endothelial growth factor inhibitor bevacizumab plus bolus 5-FU/LV with either IFL or 5-FU/LV alone in metastatic colorectal cancer suggests survival benefits with the addition of bevacizumab, including increases in overall and disease-free survival. This finding supports the initial observations demonstrating the survival advantage of adding bevacizumab to the IFL cytotoxic chemotherapy combination as reported by Hurwitz in the New England Journal of Medicine (N Engl J Med 350(23):2335-2342, 2004). It should be noted that the FDA and the manufacturer of Avastin (Genentech) issued a warning in August 2004 that the risk of serious arterial thrombotic events was increased approximately twofold in patients with metastatic disease receiving bevacizumab plus 5-FU/LV compared with active comparator treatments (see reports on page 14). The XELIRI combination of capecitabine and irinotecan has shown promise for first-line treatment of metastatic colorectal cancer in a number of recent earlyphase trials. In a US phase II trial, the combination was associated with a 54% objective response rate and median survival of 16.8 months (see report on page 13). In a Spanish phase II study, the combination produced an objective response rate of 37%, with median survival of 15.9 months. In both studies, the combination was well tolerated, with the most common grade 3 or 4 toxicities being neutropenia and diarrhea. Another phase II study has indicated that patients receiving first-line treatment with capecitabine/irinotecan (CAPIRI) or capecitabine/oxaliplatin (CAPOX) benefit to a similar degree with switching to the other regimen after disease progression. Adverse events differ between the two regimens (see report on page 18). Prevention: Statins and Colorectal Cancer A case-control study in Northern Israel suggests that statin use for 5 years or more is associated with a marked reduction in risk for colorectal cancer. Statins inhibit HMG-CoA reductase, which is overexpressed in colorectal cancer cell lines. Statin use was associated with a 46% reduction in risk after adjustment for a number of factors, including aspirin(Drug information on aspirin)/NSAID use, Ashkenazi ethnicity (associated with increased risk), family history of colorectal cancer in a first-degree relative, participation in a sports activity, vegetable consumption, and hypercholesterolemia. Risk reductions were observed for both colon cancer and rectal cancer. An absence of risk reduction in association with fiber use suggests that the potential mechanism of protection with statin use is not cholesterol reduction per se. Prospective data on this issue would be of considerable interest (see report on page 20). COX-2 Inhibitors There is considerable uncertainty surrounding the optimal use of COX-2 inhibitors at present. Rofecoxib(Drug information on rofecoxib) (Vioxx) was voluntarily withdrawn from the market after increased cardiovascular event risk was observed (about twofold) in a study examining the use of the agent to prevent colon adenomas. Investigation of cardiovascular risk in an NIH-sponsored study with celecoxib(Drug information on celecoxib) (Celebrex) in prevention of colon adenomas also showed increased cardiovascular risk, prompting discontinuation of celecoxib treatment in that study and a review of the many NIH-supported studies examining COX-2 inhibitors. Valdecoxib(Drug information on valdecoxib) (Bextra) has also been associated with increased cardiovascular risk. Considerable data will be necessary to determine the magnitude of risk associated with these agents and in what settings unacceptable risk to benefit relationships become evident (see reports on pages 21 and 22). Advanced Pancreas and Other GI Cancers In a phase III trial of first-line treatment in 569 patients with locally advanced or metastatic pancreatic cancer, the addition of the EGFR inhibitor erlotinib (Tarceva) to gemcitabine(Drug information on gemcitabine) (Gemzar) was found to improve survival at 1 year compared with gemcitabine alone (24% vs 17%, respectively), with no difference in objective tumor response rates being observed (see report on page 25). Adverse events with erlotinib were primarily the characteristic rash and diarrhea. In another phase III trial, first-line treatment with oxaliplatin plus gemcitabine (Gemzar) in 313 patients with unresectable or metastatic pancreatic cancer was associated with significantly improved objective response rate and progression-free survival (5.8 vs 3.7 months) compared with gemcitabine alone. The combination was associated with more grade 3 or 4 thrombocytopenia, vomiting, and neurological symptoms, but these effects were considered manageable (see report on page 26). Summary Overall, the past 12 months in gastrointestinal cancer therapeutics was a period of continued exploration of the impact of targeted agents with cytotoxic chemotherapy and studies designed to optimize the use and sequencing of multi-agent chemotherapy in combination with the first generation of targeted drugs. What is also clear is that the increasing therapeutic armamentarium available to the medical oncologist demands studies that examine subpopulations of patients that are more or less likely to benefit from a specific regimen. Challenging ourselves to integrate pharmacogenomics earlier into drug development efforts will do much to further improve the still narrow therapeutic index associated with cytotoxic chemotherapy with or without targeted agents. James L. Abbruzzese, MD
M. G. and Lillie A. Johnson Chair
for Cancer Treatment and Research
Professor of Medicine
Chairman, Department of Gastrointestinal
Medical Oncology
The University of Texas M. D. Anderson Cancer Center
Houston, Texas