John L. Marshall, MD

The three papers contained in this supplement to ONCOLOGY were designed to serve as practical "keep on the shelf" references for the current management of metastatic colon cancer and screening and management of patients at high risk of colon cancer.

In medicine today, we all promise to offer the best medical care available to each of our patients, and I would argue that most of us believe we are delivering on this promise. But how do we know that we are living up to that promise? Outside of board exams and CME requirements, there is virtually no internal scoring of our performance. The legal community has been happy to judge us, and they created a legal term—standard of care—against which we are all to be compared. The original intent of this term was to define a minimum level of care, a lowest common denominator. If we at least offered the standard of care, we were delivering acceptable care. We would not be committing malpractice. This is nothing to brag about, but at least we were not dangerous.

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.

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.

Recent advances in understandingthe cellular mechanismsthat determine tumor developmentand progression havespawned a plethora of the so-called“smart therapies”-targeting variousaspects of aberrant cell signaling.Some of the most promising of theseinclude agents targeting tumor angiogenesis,among them the vascularendothelial growth factor (VEGF)-specific humanized monoclonal antibodybevacizumab (Avastin), whichis the most advanced antiangiogenicagent in clinical development. Theinitial promise of this agent is nowsupported by proof-of-concept clinicaldata and is discussed in the comprehensivereview by Olszewski andcolleagues. But the question remains:How does bevacizumab achieve thisclinical benefit?

The manuscript written by Drs.Hoff, Ellis, and Abbruzzese isan outstanding overview of thedevelopment, mechanism of action,and key clinical data for bevacizumab(Avastin) and cetuximab (Erbitux).Over the past several years,the landscape for treating patients withcolorectal cancer has changed dramaticallywith the inclusion of irinotecan(Camptosar), oxaliplatin (Eloxatin),and capecitabine (Xeloda). Then, beforewe can even catch our breath,along come cetuximab and bevacizumab.The next several years will befocused on testing these agents in avariety of clinical trial settings to optimizetheir use for patients with colorectalcancers. Three issues come tomind after reviewing the Hoff et almanuscript: (1) semantics, (2) awkwardUS Food and Drug Administration(FDA) indications, and (3) money.

Irinotecan (CPT-11, Camptosar) is one of the new generation ofchemotherapeutic agents that has activity in advanced colorectal cancer.It has antitumor efficacy as a single agent, and also has beencombined with fluorouracil (5-FU) and leucovorin (IFL) to treat thesepatients. Randomized studies have confirmed the superiority of IFL to5-FU and leucovorin alone with regard to patient survival, time toprogression, and tumor response rate. The optimal schedule for combiningthese agents remains uncertain, but in the United States, theschedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks,according to the schedule reported by Saltz et al, has been widely used,although with some toxicity (especially myelosuppression and diarrhea).In an attempt to improve the tolerability of IFL, some haveadvocated modifying the schedule of IFL to weekly for 2 weeks, withrepeated cycles every 21 days. Twenty-three patients with advancedcolorectal cancer have been treated on this schedule at a single institution.Therapy was well tolerated, with 35% of patients experiencinggrade 3/4 neutropenia, two of whom had episodes of febrile neutropenia,and 9% with grade 3/4 diarrhea. The median relative dose intensityof irinotecan administered in the first 18 patients treated with thisregimen was 94%. These data support the hypothesis that modifying theschedule of administration of IFL improves the tolerability and abilityto deliver the regimen, but must be confirmed by randomized prospectivestudies, which may also attempt to evaluate the role of bolus 5-FUin the treatment of advanced colorectal cancer.

Both irinotecan (CPT-11, Camptosar) and epirubicin (Ellence) are significant chemotherapeutic agents that are used in the management of many different cancers. Each agent works through the inhibition of topoisomerases, and inhibition of topoisomerases I and II may possibly result in significant clinical synergy. This phase I clinical study represents an investigation of the first combination of irinotecan and epirubicin in patients with advanced cancer.

Capecitabine (Xeloda) is the first orally available fluoropyrimidine approved for use in patients with cancer. It was initially approved for use in metastatic breast cancer, but significant data also support its use in the management