Colorectal Cancer

MADRID, SPAIN-Preliminaryresults of a phase III trial comparingcapecitabine (Xeloda) and oxaliplatin(Eloxatin)(CapeOx) with

NEW YORK-The combinationof UFT (an oral fluoropyrimidineconsisting of tegafur plus uracil) andleucovorin “is tolerable and efficacious”and “an excellent alternative to

ORLANDO-Neoadjuvantcapecitabine (Xeloda), oxaliplatin(Eloxatin), and preoperative pelvicradiotherapy (XELOX-RT) is a welltoleratedregimen in patients with locallyadvanced rectal cancer and pro

GUADALAJARA, SPAIN-Sequentialcycling of XELOX (capecitabine[Xeloda]/oxaliplatin [Eloxatin])and XELIRI (capecitabine/irinotecan

MADRID, SPAIN-Capecitabine(Xeloda) plus irinotecan (Camptosar),in a biweekly schedule as firstlinetreatment of locally advanced ormetastatic colorectal cancer, is an activeschedule with a manageable tox

BREMEN, GERMANY-CAPOXand FUFOX have comparabletoxicity profiles and efficacy in thefirst-line treatment of metastatic col

MUNICH, GERMANY-Irinotecan(Camptosar) plus fluorouracil(5-FU)/folinic acid (FOLFIRI) issignificantly better at controlling

ORLANDO-Preliminary datafrom a randomized, double-blind, placebo-controlled phase III trial showedthat the angiogenesis inhibitor PTK/

NEW YORK-“Bevacizumab(Avastin) appears to add to theefficacy of cetuximab (Erbitux) and

MANNHEIM, GERMANY-Complete or nearly complete responsesoccurred in 41% of patients in aphase II trial of capecitabine (Xeloda)

BIRMINGHAM, ALABAMA-“Capecitabine can replace continuousinfusion in regimens to treat colorectalcancer,” Scott Cole, MD, and colleaguesat the University of Alabama

ORLANDO-“Adding highdosebevacizumab (Avastin) to FOLFOX4improves overall survival, diseaseprogression-free survival (PFS),

ORLANDO-At a median follow-up of 51 months, data reported atASCO from the X-ACT phase III trial

ORLANDO-In first-line metastaticcolorectal cancer, capecitabine(Xeloda) is better tolerated than fluorouracil/leucovorin (5-FU/LV), and

ORLANDO-The additionof oxaliplatin (Eloxatin) to weekly bolusfluorouracil/leucovorin (5-FU/LV)

ORLANDO-Panitumumab,which binds to the epidermalgrowth factor receptor (EGFR), “demonstratedencouraging antitumor ac

In this issue, Dr. Saltz articulateshis opinion on a variety of questionsconcerning therapy for patientswith metastatic colorectal cancer.My commentary will reflect myopinions concerning these questions.

Advances in the treatment ofmetastatic colorectal cancer inthe past several years havebeen expeditious and exciting-evenchaotic-but with the median survivaldoubled since the use of single-agentfluoropyrimidines alone. However, newquestions continue to arise, directly affectingour daily practice in the care ofpatients with colorectal cancer. One ofthese issues, the optimal therapy formetastatic colorectal cancer, is wonderfullyexplored by Dr. Saltz in thisissue of ONCOLOGY. To understandthis issue better, we may have to approachthe question a little differently:That is, is it possible to standardizetreatment options for metastatic colorectalcancer?

Overweight and obesity increase the risk of developing several cancers.Once cancer develops, individuals may be at increased risk of recurrenceand poorer survival if they are overweight or obese. A statisticallysignificant association between overweight or obesity and breast cancerrecurrence or survival has been observed in the majority of populationbasedcase series; however, adiposity has been shown to have less of aneffect on prognosis in the clinical trial setting. Weight gain after breastcancer diagnosis may also be associated with decreased prognosis. Newevidence suggests that overweight/obesity vs normal weight may increasethe risk of poor prognosis among resected colon cancer patients and therisk of chemical recurrence in prostate cancer patients. Furthermore, obesecancer patients are at increased risk for developing problems followingsurgery, including wound complication, lymphedema, second cancers,and the chronic diseases affecting obese individuals without cancer suchas cardiovascular disease and diabetes. Mechanisms proposed to explainthe association between obesity and reduced prognosis include adiposetissue-induced increased concentrations of estrogens and testosterone,insulin, bioavailable insulin-like growth factors, leptin, and cytokines.Additional proposed mechanisms include reduced immune functioning,chemotherapy dosing, and differences in diet and physical activityin obese and nonobese patients. There have been no randomized clinicaltrials testing the effect of weight loss on recurrence or survival inoverweight or obese cancer patients, however. In the absence of clinicaltrial data, normal weight, overweight, and obese patients should beadvised to avoid weight gain through the cancer treatment process. Inaddition, weight loss is probably safe, and perhaps helpful, for overweightand obese cancer survivors who are otherwise healthy.

HOLLYWOOD, Florida-British researchers report that a three-step strategy of neoadjuvant chemotherapy, synchronous chemoradiation, then total mesorectal excision (TME) for patients with MRI-defined poor-risk rectal cancer produced

Many elderly individuals have substantial life expectancy, even inthe setting of significant illness. There is evidence to indicate that elderlyindividuals derive as much survival benefit as younger patientsfrom standard chemotherapy approaches in advanced colorectal cancer.Effective treatments should not be withheld from older patients onthe basis of age alone. Treatment decisions should be based on functionalstatus, presence of comorbidities, and consideration of drug-specifictoxicities that can be exacerbated in older individuals due to decreasedfunctional reserve. Infusional and weekly fluorouracil (5-FU)regimens are better tolerated than bolus and monthly regimens. Oralcapecitabine (Xeloda) reduces the frequency of a number of toxicitiescompared with bolus 5-FU, including stomatitis, a particularly debilitatingtoxicity in many elderly patients. The effectiveness and tolerabilityof oxaliplatin and irinotecan (Camptosar) appear to be similar inolder and younger patients. Older patients can also receive bevacizumab(Avastin), although caution is warranted in those with cardiovasculardisease. Overall survival in metastatic colorectal cancer improves withthe availability of multiple effective chemotherapeutic agents. The fullrange of effective therapies in advanced colorectal cancer should beextended to elderly patients.

Significant advances have been made in the treatment of advancedcolorectal cancer over the past 5 years, namely due to the introductionof three novel cytotoxic agents-capecitabine (Xeloda), irinotecan(Camptosar), and oxaliplatin (Eloxatin)-and the recent approval oftwo biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux).During this time period, the median survival of patients with advanced,metastatic disease has gone from 10 to 12 months to nearly 24 months.Intense efforts have focused on identifying novel targeted therapies thattarget specific growth factor receptors, critical signal transduction pathways,and/or key pathways that mediate the process of angiogenesis.Recent clinical trial results suggest that the anti-VEGF antibodybevacizumab can be safely and effectively used in combination witheach of the active anticancer agents used in colorectal cancer. Despitethe development of active combination regimens, significant improvementsin the actual cure rate have not yet been achieved. Combinationregimens with activity in advanced disease are being evaluated in theadjuvant and neoadjuvant settings. The goal is to integrate these targetedstrategies into standard chemotherapy regimens so as to advancethe therapeutic options for the treatment of advanced colorectal cancer.Finally, intense efforts are attempting to identify the critical molecularbiomarkers that can be used to predict for either clinicalresponse to chemotherapy and/or targeted therapies and/or the drugspecificside effects. The goal of such studies is to facilitate the evolutionof empiric chemotherapy to individually tailored treatments forpatients with colorectal cancer.

Although the idea of utilizing antiangiogenic agents to hinder tumor growthis not new,[1] and the discovery of angiogenesis in tumors is evenolder,[2] this field of research is still in its infancy. Much has been learnedabout angiogenesis in tumor growth and development, yet the process is exceedinglycomplex and tightly regulated by a sophisticated interplay between pro- andantiangiogenic factors. Decades will pass before these regulatory mechanisms arewell elucidated and understood.

There is substantial preclinical and clinical evidence that angiogenesisplays a role in the development of tumors and the progression ofmalignancies. Inhibiting angiogenesis has been shown to suppress tumorgrowth and metastasis in many preclinical models. These benefitshave translated to the clinic with both marketed and investigationalantiangiogenesis agents. The most prominent target of these compoundsis vascular endothelial growth factor (VEGF) and its receptors. However,several other factors are of interest as well. These include integrins,matrix metalloproteinases, and endogenous antiangiogenic factors. Datafrom late-stage clinical trials support the role of antiangiogenic agents incancer therapy and the significant role that VEGF plays in angiogenesis.Future research will focus on determining the tumor types and stages thatwill benefit most from antiangiogenic therapy and combining therapiesthat target different factors in the angiogenesis pathway.

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.