ONCOLOGY Vol 18 No 9

Trastuzumab (Herceptin) is a therapeutic monoclonal antibody specificfor the human epidermal growth factor receptor type 2 (HER2), acell-surface tyrosine kinase receptor overexpressed by 25% to 30% ofbreast cancers. The drug is now regarded as one option for standardtherapy in HER2-overexpressing metastatic breast cancers. It is associatedwith a moderate response rate as a single agent, and in combinationwith standard chemotherapy, can produce greater response ratesand prolong the survival of women with advanced breast cancer. Itsactivity in metastatic breast cancer has led to active clinical trials examiningits potential role in the neoadjuvant and adjuvant settings.The successful clinical development of trastuzumab provides furtherproof of principle that biologically targeted therapies can have a profoundimpact on the management of breast cancer. Here we review theclinical development of this novel agent, emphasizing the potential fortherapeutic synergy when trastuzumab is combined with both standardchemotherapy and innovative molecularly targeted and biologic agents.

The relationship between age andmelanoma prognosis is growingmore apparent and presentsinteresting scientific and social questions.My colleagues and I publishedtwo papers analyzing melanoma patientsfrom our institution. Our firstpaper examined a population of 620patients during a 26-year period, andour most recent paper analyzed 1,018melanoma patients over 30 years.[1,2]In both of these studies, age remainedan important prognostic predictor ofdisease-free and disease-specific survivalbased on multivariate analysis(Cox proportional hazard). We alsoapplied a novel classification and regressiontree (CART) evaluation ofthe data that showed age maintaininga significant influence on disease-freesurvival. Age maintained importancein disease-specific survival when genderwas used as the first parameter tosegregate the entire patient populationbefore applying tree-structuredstatistics.

In this issue of ONCOLOGY,Scheithauer and Blum write aninformative review on the chemotherapeuticside effect of hand-footsyndrome, a not uncommon toxicityof several chemotherapeutic agents.They focus their discussion on capecitabine(Xeloda) and review the literatureregarding the best way to managehand-foot syndrome. Capecitabine isan oral fluoropyrimidine that is convertedto fluorouracil (5-FU) intratumorallyand delivers sustained 5-FU,thus simulating continuous-infusionregimens. It is now widely acceptedthat continuous-infusion regimens of5-FU are more effective and less toxicthan bolus regimens. However,historically, continuous-infusion regimensof 5-FU have not been in favorin the United States for logisticreasons.

Scheithauer and Blum have madean important contribution to thediscussion of hand-foot syndrome,an increasingly common disorder.They emphasize the occurrenceof hand-foot syndrome in the contextof therapy with capecitabine (Xeloda),a prodrug for fluorouracil (5-FU)that in many ways mimics the continuousinfusion of that compound. Theauthors point out that the only provenmethod for managing hand-foot syndromeis interruption and/or reductionin the dose of the administeredtreatment, and they cite retrospectivedata from completed trials in colorectalcancer to support the hypothesisthat such a policy does not impair treatmentefficacy. We feel that severalpoints deserve further amplification.

Hand-foot syndrome is a localized cutaneous side effect associatedwith the administration of several chemotherapeutic agents, includingthe oral fluoropyrimidine capecitabine (Xeloda). It is never life-threateningbut can develop into a painful and debilitating condition thatinterferes with patients' normal daily activities and quality of life. Severalsymptomatic/prophylactic treatments have been used to alleviatehand-foot syndrome, but as yet there is insufficient prospective clinicalevidence to support their use. The only proven method of managinghand-foot syndrome is treatment modification (interruption and/or dosereduction), and this strategy is recommended for patients receivingcapecitabine. Retrospective analysis of safety data from two largephase III trials investigating capecitabine as first-line therapy in patientswith colorectal cancer confirms that this strategy is effective inthe management of hand-foot syndrome and does not impair the efficacyof capecitabine. This finding is supported by studies evaluatingcapecitabine in metastatic breast cancer. Notably, the incidence andmanagement of hand-foot syndrome are similar when capecitabine isadministered in the metastatic and adjuvant settings, as monotherapy,or in combination with docetaxel (Taxotere). It is important that patientslearn to recognize the symptoms of hand-foot syndrome, so thatprompt symptomatic treatment and treatment modification strategiescan be implemented.

Worldwide, oral fluoropyrimidineshave become attractiveoptions in the treatmentof patients with colorectal cancer.Capecitabine (Xeloda), the only commerciallyavailable oral fluorouracil(5-FU) analog in the United States,was rationally designed to provideprolonged exposure to 5-FU and togenerate 5-FU preferentially withintumor tissue.Capecitabine is absorbedunchanged through the gastrointestinalwall and is converted to 5-FU viaa three-step enzymatic cascade. It isfirst hydrolyzed in the liver by carboxylesteraseto 5'-deoxy-5-fluorocytidine(5'-DFCR). The next stepoccurs in the liver and tumor tissue,where cytidine deaminase converts5'-DFCR to 5'-deoxy-5-fluorouridine(5'-DFUR). Finally, 5'-DFUR isconverted to 5-FU by thymidinephosphorylase, which is preferentiallyexpressed in tumors

The clinical development of trastuzumab(Herceptin) for thetreatment of HER2-overexpressingbreast cancer has been perhapsthe most important recentadvance in the management of metastaticbreast cancer. In their rigorousand comprehensive review, Emensand Davidson highlight the importanttrials that resulted in the US Food andDrug Administration (FDA) approvalof trastuzumab, discuss combinationchemotherapy options with trastuzumab,and preview promising futurestrategies for combining trastuzumabwith other targeted biologic agents.

There is little that can be done toimprove on this excellentreview by Emensand Davidson.In particular, the section on the preclinicalpharmacology of trastuzumab(Herceptin) provides a concise summaryof the multiplicity of mechanismsattributable to this fascinatingcompound. One of those mechanisms-its immunomodulatory effectthrough antibody-dependent cell-mediatedcytotoxicity-has led not onlyto clinical trials of interleukin-2 (Pro-leukin), as cited by the authors, but toother investigative approaches as well.

Melanoma incidence and mortality continue to rise unabated in older individuals. Early clinical detection should take into account the different subtypes.