John L. Marshall, MD

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