Colorectal Cancer

In the past several years, the impact of the new biologic therapies oncolorectal cancer has been dramatic. The focus of this article is to summarizesome of the key advances of incorporating biologically targetedtherapies into the routine management of patients with colorectal cancer.We will review important data presented at the 2005 American Society ofClinical Oncology annual meeting and discuss the incorporation of thesedata into the most optimal management of our patients, including howbest to manage side effects and keep quality of life as high as possible.

Several developments in the past few years have incrementally progressedthe field and provided additional insights into the managementof advanced colorectal cancer. This review discusses the componentsof current cytotoxic chemotherapy regimens for advanced colorectalcancer: fluorouracil (5-FU), capecitabine (Xeloda), irinotecan(Camptosar), and oxaliplatin (Eloxatin). The equivalence of severalfront-line regimens has provided opportunities for increased tailoringof therapies for individual patients. Preliminary data onpharmacogenomics provides hope that we will be able to better matchpatients with regimens and doses on the basis of individualized predictionsof toxicity and response. The importance of second-line therapyin overall survival has again been highlighted; the best outcomes haveoccurred in patients treated with 5-FU, oxaliplatin, and irinotecan incombination with targeted therapies during the course of their disease.Elderly patients are no exception to this finding. Combination regimensand second-line therapy should be offered to elderly patients whohave adequate performance status and no contraindicated comorbidconditions, without regard for their chronological age.

Colorectal cancer is a worldwide public health problem, with nearly 800,000new cases diagnosed each year resulting in approximately 500,000deaths. In the United States, it is the second leading cause of cancer mortality,and nearly 60,000 deaths will be attributed to this disease in 2005. Whendiagnosed as advanced, metastatic disease, colorectal cancer is traditionally associatedwith a poor prognosis, with 5-year survival rates in the range of 5% to 8%. Thissurvival rate has remained unchanged over the past 35 to 40 years. However, duringthe past 5 years, significant advances have been made in treatment options so thatimprovements in 2-year survival are now being reported, with median survival ratesin the 21- to 24-month range in patients with metastatic disease.

Continuing advances in immunology and molecular biology duringthe past several decades have provided optimism that immunomodulatorystrategies may be clinically useful in patients with cancer.Key advances have included: (1) recognition of the critical role of theantigen-presenting cell and greatly improved understanding of antigenprocessing and presentation, including the molecular interactionsbetween HLA molecules and antigenic epitopes on the antigen-processingcell and the receptors on T cells, and (2) the roles ofcostimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the inductionand maintenance of an immune response. In addition, newtechniques have allowed us to identify immunogenic antigenic determinants,alter their binding affinities, and evaluate the overall successof the intervention through both in vivo and in vitro assays.Carcinoembryonic antigen (CEA) is overexpressed in a large numberof gastrointestinal, lung, and breast cancers. Clinical trials have establishedtreatment protocols using viral vectors to immunize patients toCEA without producing deleterious autoimmune phenomena. By combiningvarious vectors to include MUC-1 and/or CEA plus costimulatorymolecules in a prime-and-boost regimen, we are beginning to see signsthat this intervention can not only produce changes in immune functionbut also potentially improve clinical outcomes. Phase III studies totest these hypotheses are under way.

ORLANDO-Sentinel lymph node mapping (SLNM) upstaged nodal metastases in 15% of colon cancer patients in a single-institution retrospective study of more than 300 colon cancer patients at stages T1 to T4. Routine pathological examination after conventional surgery understages 15% to 20% of colorectal cancer patients, the researchers said. Thus, SLNM has a potential survival benefit: "Higher numbers of patients with nodal metastases in the group that underwent SLNM went on to receive chemotherapy," they reported. "This may explain the reduced recurrence rates seen in these patients, which may lead to prolonged survival."

ORLANDO-Adding high-dose bevacizumab (Avastin) to FOLFOX4 improves overall survival, progression-free survival (PFS), and response in previously treated patients who have advanced colorectal cancer, Bruce J. Giantonio, MD, reported at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 2). Dr. Giantonio, of the University of Pennsylvania, presented results of the Eastern Cooperative Oncology Group (ECOG) E3200 study.

Despite enormous advances in the treatment of colorectal cancer,there is no single standard treatment approach for all patients. However,there are general principles of management that can be used toguide therapy. The clinician who fails to individualize therapy forcolorectal cancer is likely not taking full advantage of all therapeuticoptions available. Reviewing key clinical evidence that can help informdecision-making, this article addresses important questions in colorectalcancer management, including: Should bevacizumab (Avastin) be acomponent of most patients’ first-line treatment? Is there a role forcontinuing bevacizumab in subsequent regimens? Is there a role forcetuximab (Erbitux) in standard first-line chemotherapy? Are therepractices in colorectal cancer that have become widely accepted withoutdirect supportive data?

OTTAWA, CANADA-Forolder and less fit cancer patients, whoare more likely to experience greatertoxicity but less benefit from combinationchemotherapy, a more reason

PARIS, FRANCE-Analysisof disease-free survival data at 4 yearsinto the MOSAIC trial “amplifies thebenefit of FOLFOX4 obtained at 3

NAPLES, ITALY-As firstlinetherapy in elderly patients withmetastatic colorectal cancer, XELOX(capecitabine [Xeloda] and oxaliplatin(Eloxatin]) achieved an objectivetumor response rate of 41% (abstract

ORLANDO-XELOX (capecitabine[Xeloda] and oxaliplatin [Eloxatin])is effective and well tolerated asfirst-line treatment for elderly patients

BOLOGNA, ITALY-Preliminaryresults of a small phase II advancedcolorectal cancer trial comparinga protracted fluorouracil

HOUSTON-Concomitantboost radiotherapy plus capecitabine(Xeloda) produces pathologic responserates comparable to those of

VILLEJUIF, FRANCE-In thefirst randomized comparison of aschedule of FOLFOX6 (fluorouracil[5-FU], leucovorin, oxaliplatin [Eloxatin])vs standard XELOX (capecitab

NEW YORK-Adding bevacizumab(Avastin) to oxaliplatin [Eloxatin]/fluorouracil or to oxaliplatin/capecitabine (Xeloda) improves re

DURHAM, North Carolina-The addition of bevacizumab(Avastin) to XELOX (capecitabine[Xeloda] and oxaliplatin [Eloxatin])results in a new, highly active regimen

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