Advancing Treatment of GI Cancers

The past year has witnessed important advances in chemotherapy for colorectal cancer and continued maturation of molecular approaches to management of other GI malignancies. This special supplement to ONI highlights research in adjuvant and neoadjuvant therapy, with new strategies and drug combinations for improving outcomes; targeted therapy; reports on potential new biomarkers and vaccines; and interesting epidemiologic findings in pancreatic vs colorectal cancer. Chemotherapy in Colorectal Cancer In the following text and elsewhere in this supplement, a number of combination chemotherapy regimens are discussed. For your convenience, these regimens are defined in the glossary on page 3. FOLFOX: The N9741 trial demonstrated the superiority of the FOLFOX regimen over the IFL regimen in first-line treatment of metastatic colorectal cancer (CRC), forming the basis of FDA approval of oxaliplatin(Drug information on oxaliplatin) (Eloxatin) in this regimen and setting.Subsequently, the large-scale phase III MOSAIC trial showed the benefits of FOLFOX4 extend to the adjuvant setting (see report on page 6). Over 3 years of follow-up, FOLFOX4 was associated with improved disease-free survival and reduced risk of recurrence vs LV/5-FU2 in advanced CRC, with benefits observed in patients with stage II and stage III disease and in all other patient subsets. Overall, 3- year disease-free survival was 77.8% in the FOLFOX4 arm and 72.9% in the LV/5-FU2 arm. No increases in mortality or vascular events during adjuvant therapy were observed with FOLFOX4 vs LV/5-FU2. However, FOLFOX4 was associated with relatively high frequencies of grade 3/4 neutropenia (41%), grade 3 sensory neuropathy during treatment (12%), and any-grade neuropathy at 1 year (29%). In adjuvant chemotherapy regimens, oral capecitabine(Drug information on capecitabine) (Xeloda) may represent a substitute for 5-FU/LV offering significant advantages in regard to the toxicity observed with FOLFOX, without loss of effectiveness. In a planned safety analysis of the X-ACT trial comparing oral capecitabine vs 5-FU/LV as adjuvant therapy in metastatic colon cancer, capecitabine produced significantly less grade 3/4 neutropenia (2% and 3% in patients < 65 and ≥ 65 years vs 26% and 27%, respectively) and significantly less stomatitis, but more frequent hand-foot syndrome (see page 5). XELOX: The combination of capecitabine plus oxaliplatin has indeed been shown to be active in advanced CRC. In an international phase II trial in patients with metastatic CRC, first-line treatment with XELOX produced a response rate of 55%, progression- free survival of 7.7 months, overall survival of 19.5 months, and 1-year survival of 71% (see page 12). Neutropenia was observed in only 7% of patients, and grade 3/4 hand-foot syndrome was observed in 3%. An ongoing phase II trial in patients aged > 70 years has also shown good activity of XELOX as first-line treatment, with observed neuropathy (grade 3 neuropathy in 11%) tending to resolve within 2 weeks (see page 9). An additional phase II trial by Austrian researchers suggests benefits in progression- free survival (10.5 months vs 6 months) with a dose-intense XELOX regimen vs one using standarddose capecitabine as first-line treatment of metastatic disease. The dose-intense regimen was not associated with any significant increase in hematologic or nonhematologic toxicity (see page 10). Capecitabine/irinotecan: Capecitabine has also shown promise in replacing infusional 5-FU/LV in the IFL and FOLFIRI regimen as a partner with irinotecan(Drug information on irinotecan) (see page 7). In an ongoing phase II multicenter study, continuous, flat-dose capecitabine plus weekly irinotecan as first-line treatment for metastatic or locally advanced disease resulted in objective response in 31% and stable disease in 31% of 49 evaluable patients; currently, median time to disease progression is 5.4 months and median overall survival is 16.7 months. No grade 3/4 neutropenia was seen. In another recently reported phase II study, first-line treatment for metastatic disease with a XELIRI regimen produced an objective response rate of 46%; grade 3 hand-foot syndrome was observed in only 6% of patients, and grade 3/4 neutropenia in 25%. Neoadjuvant Therapy Gastric cancer: In an NYU study in patients with locally advanced gastric cancer, cisplatin(Drug information on cisplatin) (Platinol)/ irinotecan was given prior to surgery and intraperitoneal floxuridine (FUDR)/cisplatin given after surgery (see page 18). Neoadjuvant therapy resulted in tumor downstaging in more than 50% of patients, but complete response was observed in only 1 of 32 evaluable patients. Nearly all patients had some form of grade 3/4 toxicity, 16 with grade 3/4 neutropenia. Rectal cancer: The large-scale German Rectal Cancer Study in patients with locally advanced rectal cancer found preoperative chemoradiation therapy (5-FU chemotherapy) is associated with improved outcomes vs postoperative chemoradiation therapy (see page 11). Preoperative therapy was associated with a reduced 5-year rate of local recurrence and improved sphincter preservation. No significant differences were seen in the 5-year rates of distant recurrence, disease-free survival, or overall survival. The frequencies of grade 3/4 toxicities were similar, but the preoperative group had lower rates of severe diarrhea and a reduced frequency of chronic anastomotic site stenosis. Molecular Approaches Targeted therapy: In a phase III trial in previously untreated patients with metastatic CRC, the addition of the vascular endothelial growth factor inhibitor bevacizumab(Drug information on bevacizumab) (Avastin) to IFL treatment resulted in increased response rate (45% vs 35%), overall survival (20.3 vs 15.6 months), time to disease progression (10.6 vs 6.2 months), and response duration (10.4 vs 7.1 months) compared with IFL alone (see page 13). Bevacizumab was well tolerated. Grade 3 hypertension occurred in more bevacizumab-treated patients (10.9% vs 2.3%). GI perforation was a rare adverse event seen only in the bevacizumab group; while many of these episodes were apparently not life-threatening, bowel perforations have been seen in other studies and further studies to understand the pathogenesis of these episodes are warranted. On February 26, 2004, Genentech, Inc. announced FDA approval of Avastin in combination with IV 5-FUbased chemotherapy for first-line or previously untreated metastatic colorectal cancer (see page 10). In a large randomized phase II trial in patients with endothelial growth factor receptor (EGFR)-positive metastatic CRC who had progressed on irinotecan treatment, the addition of the EGFR monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux) to irinotecan resulted in improved response rate (22.9% vs 10.8%), stable disease rate (55.5% vs 32.4%), and time to disease progression (4.1 vs 1.5 months) vs cetuximab alone; survival duration did not differ significantly (8.6 vs 6.9 months), perhaps partly reflecting elective cross-over to combination therapy from the monotherapy group at time of disease progression (see report on page 13). The most frequent grade 3/4 toxicities in the combination arm were diarrhea and neutropenia; the most frequent serious side effects in the monotherapy arm were asthenia and acneiform rash, with rash observed to correlate with both objective response and survival. The results of this study and other studies of cetuximab in this patient population supported recent FDA approval for cetuximab monotherapy or cetuximab/ irinotecan for second-line management of advanced colorectal cancer (see page 10). Vaccines: At ECCO, investigators reported interesting phase I findings in patients with resected pancreatic cancer who received a vaccine derived from heat shock proteins taken from each patient's own tumor (see page 20). In 10 evaluable patients, autologous vaccination with HSPPC-96 had no significant toxicities and apparent survival benefits: average survival after surgery for pancreatic cancer is 14 to 15 months; median survival in this small group has been 2.5 years, with 1 patient disease-free after 5 years. The vaccine, in phase III trials in renal cell carcinoma and metastatic melanoma, is also being evaluated in colorectal and gastric cancer. Biomarkers: There is a wide array of candidate molecular markers for poor outcome and poor response to 5-FU in colon cancer. Data from ECOG/ intergroup trials in stage III disease indicated improved outcome with 5-FU treatment in patients with retained chromosome 18q alleles (eg, DCC, Smad 4, Smad 2) (5-year survival 74% vs 50% in those without the allele) and in those with microsatellite instability (MSI) with a transforming growth factor (TGF)-β1-RII mutation (74% vs 46% in those with MSI but no TGF-β1-RII mutation) (see page 15). In other research, telomerase may be an early marker for pancreatobiliary malignancies, with a telomerase immunostaining technique of potential use as a screening tool (see page 23). Aspirin in Pancreatic vs Colorectal Ca Surprising findings were reported in late 2003 regarding aspirin(Drug information on aspirin), which the large-scale Nurses' Health Study found may increase risk of pancreatic cancer when taken over long periods of time (see page 24). In colorectal cancer, however, other studies, including the Nurses' Health Study, concluded that regular use of aspirin (and NSAIDs) is protective (see page 17). While randomized controlled clinical trials are needed before conclusions can be drawn, investigators indicated the results may partly reflect biologic differences between these two types of GI cancer. Emerging Opportunities It is increasingly clear that GI cancers-some of the most challenging of all human malignancies-are responding to novel cytotoxic combinations and the first generation of targeted therapeutics. It is logical to assume that as our basic knowledge of GI malignancies expands, new opportunities will continue to emerge. Further, the improving therapeutic index of the targeted agents may allow development of practical strategies for introduction of these interventions earlier in the carcinogenic process, potentially at a point in the natural history of a malignancy when the beneficial therapeutic effects may be even more pronounced. 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