Advances in Therapy for GI Cancers

The past year brought important advances, promisingfindings, and some potential disappointments tothe field of gastrointestinalcancer treatment. Herewith,we present select highlightsof the year in clinicalresearch.Targeted Therapyfor Advanced ColonCancerIn the setting of second-line therapy for advanceddisease, preliminary results of the NCI-sponsored,phase III E3200 trial has shown that the additionof bevacizumab (Avastin) to the FOLFOX4 regimenresults in a significant increase in median overallsurvival compared with FOLFOX4 alone (12.5 monthsvs 10.7 months, respectively). This trial in more than800 patients initially included a bevacizumab-alonearm, which was discontinued due to poor survival (seereport on page 5).Preliminary results of the TREE2 trial of bevacizumabwith oxaliplatin (Eloxatin)-based chemotherapy in thefirst-line treatment of advanced disease have shownthree regimens of oxaliplatin/5-FU with bevacizumabto yield acceptable tolerability and significantlyimproved overall response rates. A total of 213previously untreated patients received one of threeregimens (FOLFOX-B, bFOL-B, or CAPEOX-B). (Seereport on page 5 and glossary of regimens on page18). This trial suggests that oxaliplatin with bevacizumabmay be as effective as front-line management with IFLbevacizumab.A phase II trial of the epidermal growth factorreceptor (EGFR) inhibitor cetuximab (Erbitux) has shownthe ability of this agent to produce major objectiveresponses in patients with metastatic colorectal cancerwho had prior treatment (two courses of chemotherapyor adjuvant therapy plus one course of chemotherapy)including irinotecan (Camptosar), oxaliplatin, and afluoropyrimidine. Among 346 patients, partial responseoccurred in 12% and stable disease occurredin 32%. Although only nine patients without EGFRpositivityon immunohistochemistry were enrolled,EGFR status did not appear to influence likelihood ofresponse, a finding that also has been made withEGFR inhibitors in other disease settings. The presenceof mutations in EGFR, which has predicted response toinhibitors in other settings, did not predict response inthis trial (see report on page 7).Adjuvant Therapy for AdvancedColon CancerThe X-ACT trial showed that oral capecitabine(Xeloda) treatment was at least equivalent to bolus5-FU/LV as adjuvant therapy for resected stage IIIcolon cancer. Capecitabine treatment was associatedwith a significant improvement in 3-year recurrencefreesurvival (0.86 hazard ratio) in this phase III trial in nearly 2,000 patients, with trends towards improvementin overall survival. Capecitabine was associatedwith reduced frequency of many adverse events, includingneutropenia, diarrhea, stomatitis, nausea andvomiting, and alopecia, but an increased frequency ofhand-foot syndrome. Benefits in terms of reduced adverseevents were observed in both elderly and youngerpatients (see report on page 8). Further, a subanalysisof the trial showed that capecitabine treatment wasassociated with reduced overall medical expendituresand a dramatic reduction in patient time requirementsfor treatment and adverse effect management (seesidebar on page 9).A NSABP trial in more than 1,600 patients withstage II/III colorectal cancer has indicated that oral UFT(tegafur)/LV is very similar to the Mayo 5-FU/LV regimenin terms of 5-year overall, and disease-free survival.Grade 3 or 4 adverse events were also very similarin the treatment groups. Some quality of life outcomesfavored UFT/LV. UFT is not available in the US (seereport on page 16).In January 2004, the U.S. Food and Drug Administrationapproved Eloxatin for adjuvant treatment incombination with infusional 5-FU/LV in patients withstage III colon cancer. In the MOSAIC trial in more than2,000 patients, which formed the basis of approval,the combination significantly improved 4-year diseasefreesurvival in patients with stage III disease (69.7% vs61.0%) compared with 5-FU/LV alone. Grade 3 or 4toxicity was more common with oxaliplatin. Commontoxicities include granulocytopenia, paresthesias, diarrhea,nausea, and vomiting; paresthesias were observedin the majority of patients receiving the combination.Anaphylactic-like reactions are also increasinglyrecognized as occurring with oxaliplatin, requiringcaution during administration and occasional discontinuationof this agent (see report on page 11).First-Line and Subsequent Treatment ofAdvanced Colorectal CancerIn a Dutch phase III trial in 302 patients withmetastatic colorectal cancer, the first-line combinationof oxaliplatin plus 5-FU/folinic acid improved responserate and progression-free survival compared with 5-FU/folinic acid alone, although median overallsurvival did not differ by treatment. The oxaliplatinpatients had less diarrhea and stomatitis and moresensory neuropathy; 5% of patients receiving oxaliplatinhad grade 3 or 4 allergic adverse events (seereport on page 15).A retrospective pooled data analysis of randomizedtrials comparing the vascular endothelial growth factorinhibitor bevacizumab plus bolus 5-FU/LV with eitherIFL or 5-FU/LV alone in metastatic colorectal cancersuggests survival benefits with the addition of bevacizumab,including increases in overall and disease-freesurvival. This finding supports the initial observationsdemonstrating the survival advantage of adding bevacizumabto the IFL cytotoxic chemotherapy combinationas reported by Hurwitz in the New England Journalof Medicine (N Engl J Med 350(23):2335-2342,2004). It should be noted that the FDA and themanufacturer of Avastin (Genentech) issued a warningin August 2004 that the risk of serious arterial thromboticevents was increased approximately twofold inpatients with metastatic disease receiving bevacizumabplus 5-FU/LV compared with active comparatortreatments (see reports on page 14).The XELIRI combination of capecitabine and irinotecanhas shown promise for first-line treatment of metastaticcolorectal cancer in a number of recent earlyphasetrials. In a US phase II trial, the combination wasassociated with a 54% objective response rate andmedian survival of 16.8 months (see report on page13). In a Spanish phase II study, the combinationproduced an objective response rate of 37%, withmedian survival of 15.9 months. In both studies, thecombination was well tolerated, with the most commongrade 3 or 4 toxicities being neutropenia and diarrhea.Another phase II study has indicated that patients receivingfirst-line treatment with capecitabine/irinotecan(CAPIRI) or capecitabine/oxaliplatin (CAPOX) benefitto a similar degree with switching to the other regimenafter disease progression. Adverse events differ betweenthe two regimens (see report on page 18).Prevention: Statins and Colorectal CancerA case-control study in Northern Israel suggests thatstatin use for 5 years or more is associated with amarked reduction in risk for colorectal cancer. Statinsinhibit HMG-CoA reductase, which is overexpressed incolorectal cancer cell lines. Statin use was associatedwith a 46% reduction in risk after adjustment for anumber of factors, including aspirin/NSAID use, Ashkenaziethnicity (associated with increased risk), familyhistory of colorectal cancer in a first-degree relative,participation in a sports activity, vegetable consumption,and hypercholesterolemia. Risk reductions wereobserved for both colon cancer and rectal cancer. Anabsence of risk reduction in association with fiber usesuggests that the potential mechanism of protectionwith statin use is not cholesterol reduction per se.Prospective data on this issue would be of considerableinterest (see report on page 20).COX-2 InhibitorsThere is considerable uncertainty surrounding theoptimal use of COX-2 inhibitors at present. Rofecoxib(Vioxx) was voluntarily withdrawn from the marketafter increased cardiovascular event risk was observed(about twofold) in a study examining the use of theagent to prevent colon adenomas. Investigation ofcardiovascular risk in an NIH-sponsored study withcelecoxib (Celebrex) in prevention of colon adenomasalso showed increased cardiovascular risk, promptingdiscontinuation of celecoxib treatment in that study anda review of the many NIH-supported studies examiningCOX-2 inhibitors. Valdecoxib (Bextra) has also beenassociated with increased cardiovascular risk. Considerabledata will be necessary to determine the magnitudeof risk associated with these agents and in whatsettings unacceptable risk to benefit relationships becomeevident (see reports on pages 21 and 22).Advanced Pancreas and Other GI CancersIn a phase III trial of first-line treatment in 569patients with locally advanced or metastatic pancreaticcancer, the addition of the EGFR inhibitor erlotinib(Tarceva) to gemcitabine (Gemzar) was found toimprove survival at 1 year compared with gemcitabinealone (24% vs 17%, respectively), with no difference inobjective tumor response rates being observed (seereport on page 25). Adverse events with erlotinib wereprimarily the characteristic rash and diarrhea. In anotherphase III trial, first-line treatment with oxaliplatin plusgemcitabine (Gemzar) in 313 patients with unresectableor metastatic pancreatic cancer was associatedwith significantly improved objective response rate andprogression-free survival (5.8 vs 3.7 months) comparedwith gemcitabine alone. The combination was associatedwith more grade 3 or 4 thrombocytopenia, vomiting,and neurological symptoms, but these effectswere considered manageable (see report on page 26).SummaryOverall, the past 12 months in gastrointestinal cancertherapeutics was a period of continued exploration ofthe impact of targeted agents with cytotoxicchemotherapy and studies designed to optimize theuse and sequencing of multi-agent chemotherapy incombination with the first generation of targeted drugs.What is also clear is that the increasing therapeuticarmamentarium available to the medical oncologistdemands studies that examine subpopulations ofpatients that are more or less likely to benefit from aspecific regimen. Challenging ourselves to integratepharmacogenomics earlier into drug developmentefforts will do much to further improve the still narrowtherapeutic index associated with cytotoxicchemotherapy 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

Disclosures:

Dr. Abbruzzese has no significantfinancial interest or other relationship with the manufacturersof any products or providers of any service mentioned inthis article.