ONCOLOGY Vol 18 No 6

ORLANDO-Ginger has been used for years to treat gastrointestinal upset, but for the first time, a large double-blind multicenter randomized study has shown ginger supplements can successfully stem chemotherapy-related nausea, University of Rochester in New York investigators reported at ASCO 2009 (abstract 9511). Some 70% of patients experience nausea and vomiting related to chemotherapy. While vomiting can largely be prevented with anti-emetics, nausea is typically more difficult to prevent and treat.

Dr. O’Connell has done a remarkablejob of discussingmodalities available for patientswith intermediate- to high-riskfully resected large bowel malignancies.Indeed, the title “Current Statusof Adjuvant Therapy for ColorectalCancer” is an underestimate of thearticle’s contents, as he nicely detailsthe past development of standard-ofcareadjuvant (and neoadjuvant, whenappropriate) treatments as well. As isclearly pointed out in the article, adjuvanttherapy works. Adding fluorouracil(5-FU) with or without radiationto surgery already saves thousandsof lives each year, and the enticing possibilityof throwing newer chemotherapeuticagents (eg, oxaliplatin)and/or targeted therapies (bevacizumab[Avastin]) into the mix makespotential future successes even greater.

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.

The use of hepatic arterial infusion (HAI) chemotherapy in patientswith liver-only colorectal metastases is based on the pharmacologicprinciple that the regional administration of some drugs can lead tohigher drug concentrations at the site of the metastases and avoid systemictoxicity. Early randomized trials resulted in high response ratesbut did not lead to a survival advantage with HAI. More recent trialshave utilized improved surgical techniques and strict guidelines regardingdose reduction or cessation of HAI chemotherapy, resulting in asignificant reduction in toxicity. In patients with unresectable liver metastases,two recent European trials using HAI fluorouracil (5-FU)again failed to demonstrate an improvement in survival, but both wereplagued by a high complication rate with an associated high proportionof patients failing to receive the assigned treatment. In contrast,the preliminary results of a recent Cancer and Leukemia Group B trialdid demonstrate a survival advantage with HAI floxuridine when comparedto systemically administered 5-FU. Trials investigating the useof HAI chemotherapy in the adjuvant setting have yielded mixed results.Moreover, in light of improved response rates and overall survivalwith newer more active chemotherapeutic and novel agents, theabsolute role of HAI chemotherapy remains undefined.

Adjuvant therapy with chemotherapy and/or radiation therapy inaddition to surgery improves outcome for patients with high-risk carcinomasof the colon or rectum. For colon cancer, fluorouracil (5-FU)combined with leucovorin is a current standard of care that improveslong-term survival. A recent European trial (MOSAIC) has documentedsignificant improvement in 3-year disease-free survival when oxaliplatin(Eloxatin) was added to infusional 5-FU and leucovorin in the FOLFOXregimen. Two US cooperative group trials will evaluate the addition ofantiangiogenesis therapy with bevacizumab (Avastin) to chemotherapy.A third trial will evaluate FOLFOX, irinotecan (Camptosar) combinedwith infusional 5-FU and leucovorin (FOLFIRI), and the sequentialuse of FOLFOX followed by FOLFIRI. In rectal cancer, postoperative5-FU–based chemotherapy combined with irradiation can improve bothlocal tumor control and survival. The German Rectal Cancer Grouphas recently reported that preoperative combined-modality therapy isless toxic and more effective in preventing local tumor relapse comparedto similar treatment given postoperatively. A coordinated pair ofcooperative group clinical trials will evaluate oral capecitabine (Xeloda)as a radiation enhancer in the preoperative setting, and the FOLFOXand FOLFIRI regimens compared to 5-FU and leucovorin followingsurgery. Predictive and prognostic molecular markers will be studiedin these new adjuvant therapy clinical trials for both colon and rectalcancer with the goal of developing future regimens tailored to individualpatients. There has been a recent and dramatic increase in thepace of drug development for colorectal cancer which holds promise tofurther improve curative therapy as part of a multidisciplinary approachin the surgical adjuvant setting.

The treatment of colorectal cancer has undergone enormous changesin the past decade. From a disease with a single treatment option (ie,fluorouracil, a modestly effective drug), the treatment options haveevolved to include at least five new classes of antineoplastic agents.Among the considerable number of recently approved drugs, two aremonoclonal antibodies and are the testing ground for our rapidly emergingknowledge about cancer cell biology. Cetuximab (Erbitux) targetsthe epidermal growth factor receptor, an important molecule involvedwith cell cycling, survival, invasion, and metastasis. Bevacizumab(Avastin) neutralizes the vascular endothelial growth factor, blockingits ability to activate its receptor on the endothelial cells. The developmentof both antibodies resulted from decades of research in molecularand cell biology, as well as preclinical and clinical studies, and signalsa new paradigm where the tumor cells’ own unique features areexploited in a rational way.

In the “Current Status of AdjuvantTherapy for Colorectal Cancer,”Dr. O’Connell provides importanthighlights of historical and recent developmentsin adjuvant treatment forcolon and rectal cancer. In addition,he provides insight into the future directionsof research for adjuvant therapyof cancer of the colon and rectum.As the review is thorough, wewould like to expand upon a coupleof areas including lymph node evaluation,changes to the staging system,and the use of molecular prognosticand predictive markers in futurestudies.

Drs. Whisenant and Venookhave provided us with a summaryof the role of hepaticarterial infusion (HAI) chemotherapyfor patients with metastatic colorectalcancer. In their abstract they state thatthere is confusion about whether HAIfor unresectable liver metastases isuseful, because European studies havebeen negative; they go on to say thatthe work in adjuvant therapy hasmixed results. I would like to offersome different interpretations.

Drs. Hoff, Ellis, and Abbruzzesehave provided a thoroughand useful overview of thecurrent status of the two new monoclonalantibodies, cetuximab (Erbitux)and bevacizumab (Avastin), that haverecently become available for the treatmentof colorectal cancer.

In the past 5 years, the treatment ofmetastatic colorectal cancer hasseen unparalleled advances. Medianoverall survivals reported inphase III trials have almost doubledand are poised to break the 2-yearbarrier very soon, perhaps as early asthis year. This has been made possiblethrough the introduction of a varietyof active agents into the treatmentof this disease.

In their article, Drs. Whisenant andVenook review data regarding thevalue of hepatic arterial infusion(HAI) chemotherapy for hepatic colorectalmetastases. In fact, their analysisreveals the absence of anymaterial progress in HAI therapy sincethe first reports of continuous infusionof chemotherapy through the hepaticartery.[1] During the sameperiod, there has been dramatic improvementin hepatic imaging, outcomefrom hepatic resection, systemicchemotherapy, and survival followingtreatment of hepatic colorectalmetastases. Failure of HAI therapy toadvance in parallel with other treatmentsfor liver metastases-whetherused prior to or after resection, or asdefinitive treatment for unresectabledisease apparently confined to the liver-suggests a limited role for HAItherapy in this disease. Several pointswarrant discussion.

Colorectal cancer is the second most common cause of cancerrelateddeath in the United States. Approximately 30% to 40% of patientswith colorectal cancer have locoregionally advanced or metastaticdisease on presentation and cannot be cured with surgical therapy.After many years without significant change, systemic therapy forcolorectal cancer is rapidly evolving. The past decade has seen the introductionof new chemotherapeutic agents such as irinotecan(Camptosar), oxaliplatin (Eloxatin) and the oral 5-FU prodrugcapecitabine (Xeloda). Combination studies of these new agents withthe standard 5-FU/leucovorin have extended median survival in patientswith advanced colorectal cancer for up to 21 months. In addition,targeted agents with activity in colorectal cancer have emergedand are promising. This article reviews the current treatment recommendationsfor patients who present with advanced colorectal cancer.Survival in patients with advanced colorectal cancer is on a positivetrajectory. The hope that some patients with advanced disease will belong-term survivors (even without surgery) appears to be within therange of possibility.