New Combinations, Increased Use of Markers Predicted in GI Cancers

PHILADELPHIA-"We tend tothink of colorectal cancer (CRC), gastriccancer, and pancreatic cancer ashomogenous diseases with monolithicapproaches to therapy, but in realitywe have a very large, heterogeneouspopulation of patients whose individualrisks we have just begun to understand.Few patients get on study, andwe base all of our standard treatmentson those small numbers of patients.That leaves many questions unanswered,"stated Daniel G. Haller, MD,of the University of Pennsylvania inPhiladelphia.Patients have not yet begun to beselected prospectively for trials basedon simple measures such as performancestatus, polymorphisms that predicttoxicity, or predictive markers forresponse. The question Dr. Haller asksis should studies be continued simplybecause there is a response withoutconsidering the fact that agents mayhave become more toxic and moreexpensive?Colorectal CancerThe major issues in chemotherapyfor metastatic CRC are whether thereare optimal first- and second-line regimens,advantages of single-agent vscombination chemotherapy, patientselection, selection of drugs based onpredictive markers, duration of therapy(continuous vs fixed), sequencingof chemotherapy, and optimal endpointsfor clinical trials (overall survival,time to disease progression, orclinical benefit).Avenues of investigation for treatmentof metastatic CRC include thedesire to substitute oral fluoropyrimidinesfor infusional agents because oftheir suitability for combination regimenswith oxaliplatin (Eloxatin) andirinotecan (Camptosar) and use withirradiation. According to Dr. Haller,the key new agents for investigationare probably epidermal growth factorreceptor inhibitors such as cetuximab(Erbitux) and antiangiogenesis agentssuch as bevacizumab (Avastin).

"Unless we've been living in a crypt,we all know about the N9741 datashowing that FOLFOX (fluorouracil[5-FU], leucovorin, oxaliplatin) is agood candidate for first-line use," Dr.Haller stated (see Table 1). FOLFOXwas similarly effective for second-lineuse (see Table 2).Researchers trying to determine theoptimal sequence for deploying thevarious 5-FU/irinotecan and 5-FU/oxaliplatin regimens have thus far notidentified any significant difference inthe sequences tested. "There really isno difference between FOLFOX-6 andFOLFIRI (5-FU/leucovorin/irinotecan)in the meaningful endpoint ofresponse," Dr. Haller added. "Themain differences are in toxicity."Molecular profiling studies areseeking prognostic markers to identifypatients with good survival who donot need adjuvant chemotherapy andpredictive markers to identify patientswho will benefit from therapy. Thebiologic markers of prognosis inCRC most likely to enter trials arethymidylate synthase levels, microsatelliteinstability, and allelic loss in chromosome18."Looking at our progress in firstlinetreatment of metastatic CRC, wefind that response rate and survivalhave both increased," Dr. Hallerrevealed.In adjuvant treatment, the MOSAICtrial comparing infusional 5-FU/leucovorin with or without oxaliplatin(FOLFOX-4) showed thatFOLFOX produced improvements in3-year disease-free survival (77.8% vs72.9%, P < . 01). This difference isboth statistically significant and clinicallyrelevant, according to Dr. Haller.Other trials have shown that an improvementin 3-year survival translatesinto a 5-year-survival advantage.The question of how to identifysubgroups of patients with differentpotentials for benefit or toxicity remainsan important one. A recentpooled analysis of data from adjuvantrectal cancer trials showed that T andN stages have independent prognosticsignificance. Single risk factors of N+disease confined to the wall or N- diseaseextending beyond the wall withoutadherence or invasion are bothassociated with survival and diseasecontrol. This analysis concluded thatthe new T and N stages best reflectprognosis and should be used topresent information to patients.Gastric CancerThe direction for treatment of patientswith gastric cancer is less clear.The V 325 phase III trial attempted tolearn whether adding docetaxel (Taxotere)to the standard regimen of cisplatinand 5-FU was beneficial. Interimanalysis suggests significantimprovements in response rate, progression-free survival, and overall survivalfrom the three-drug regimen."This is a very active combinationbut it is not the easiest to give. We havehad a lot of discussion about the factthat a quarter of the patients, many ofwhom were responding, stopped therapybecause they saw no point in continuing,"Dr. Haller said.With regard to adjuvant chemotherapy,interpreting results from previousindividual trials is complicatedby the fact that many used suboptimalchemotherapy regimens. Meta-analysesare consistent with possible survivalbenefits. "The de facto standard, aswith rectal cancer, has become chemoradiation,"Dr. Haller stated. "Thequestion remains: Does every one ofthese patients need radiation therapy,or are some going to benefit simplyfrom better surgery and adjuvantchemotherapy?"The MAGIC trial of neoadjuvantepirubicin (Ellence), cisplatin, 5-FU(ECF), surgery, and postoperative ECFvs surgery alone showed a small survivaladvantage for the combinationregimen. In a slightly larger trial, withbetter patient selection, Dr. Haller believesthat this would have been a definitivelypositive result.Pancreatic CancerGemcitabine (Gemzar) combinationshave attracted much attention inthe treatment of patients with pancreaticcancer. "All of these have hadpromising phase II data and not-so-promising phase III data," Dr. Hallersaid. "One of the issues is that we maynot know how to give gemcitabinemost effectively. It is a pro-drug andmay not reach its full potential whengiven over 30 minutes rather than prolongedinfusion."Data on the irinotecan/gemcitabinecombination presented at theAmerican Society of Clinical Oncology(ASCO) 2003 meeting suggestedthat although there was a better responserate with the combination thanwith gemcitabine alone, it did nottranslate into a survival advantage. Aphase III trial of gemcitabine/cisplatinwas similarly disappointing, Dr. Hallerconcluded.