ONCOLOGY Vol 19 No 8

We applaud Dr. Cappuzzo andcolleagues for an excellentreview of an emerging fieldin lung cancer treatment. Since 2000,three drugs (docetaxel [Taxotere],pemetrexed [Alimta], and erlotinib[Tarceva]) have been approved by theUS Food and Drug Administration(FDA) for second-line therapy in non–small-cell lung cancer (NSCLC) basedon the results of phase III trials (seeTable 1).[1-4] It is also possible thatsimilar approval will be sought for otherdrugs (eg, topotecan [Hycamtin]),[5]and gefitinib (Iressa) remains an optionfor treatment in the third-line setting.

The two-part article, "ThromboembolicComplications ofMalignancy," by Drs. Linenbergerand Wittkowsky, provides a contemporaryand clear review of thepathogenesis, prevention, and treatmentof cancer-associated hypercoagulabilityand venous thrombosis. Questionsabout the cancer and coagulation connectioncontinue to abound and greatlyoutnumber evidence-based answers. Asthe relationship between cancer and coagulationgains attention from the medicaland surgical oncology communities(ie, not only from the coagulation community),the gap between questions andanswers will likely close.

Platinum-based chemotherapy offers a modest survival advantage overbest supportive care in chemotherapy-naive patients with a good performancestatus and advanced/metastatic non–small-cell lung cancer(NSCLC). Despite the survival benefit associated with first-line chemotherapy,the majority of patients will experience relapse or disease progression.In clinical practice, an increasing number of patients maintaina good performance status after first-line treatment and are eligible forfurther treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every3 weeks has been the standard of care for second-line chemotherapy sincethe year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolateagent with single-agent activity in first- and second-line treatment ofNSCLC. A large phase III study comparing docetaxel to pemetrexed insecond-line therapy demonstrated that pemetrexed is equally active andless toxic than docetaxel. Based on these results, pemetrexed is a reasonablesecond-line chemotherapy option for patients with recurrent, advancedNSCLC. Progress made in the field of molecular biology has led to theidentification of drugs active against specific cellular targets. Gefitinib(Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitorsof the epidermal growth factor receptor. Phase II and III trialshave demonstrated that these agents are active particularly in a subgroupof patients with specific biologic characteristics. Both drugs have beenapproved for the treatment of pretreated NSCLC. Other drugs, such ascetuximab (Erbitux) and bevacizumab (Avastin) have shown promisingactivity in NSCLC and are currently being tested in clinical trials.

Advanced cancer in the setting of liver dysfunction poses a dilemmafor physicians, as many cancer chemotherapeutic agents undergo hepaticmetabolism. Most cytotoxic drugs have a narrow therapeutic index,and the administration of chemotherapy to patients with liver impairmentresults in complicated safety issues. We present a concise reviewof cancer chemotherapy dosing in the setting of liver dysfunction.Although caution in treating all patients with hepatic failure is essential,the use of certain agents provokes greater concern than others.Continuous-infusion fluorouracil, capecitabine (Xeloda), mechlorethamine(Mustargen), cyclophosphamide, topotecan (Hycamtin), andoxaliplatin (Eloxatin) appear to be relatively well tolerated. On thecontrary, taxanes, vinca alkaloids, irinotecan (Camptosar), andanthracyclines may cause unacceptable toxicity if administered to patientswith poor hepatic function. For many anticancer agents, the paucityof data prohibits formal dosing recommendations, and most guidelinesremain empiric.

About 172,570 new cases ofnon–small-cell lung cancer(NSCLC) are expected to bediagnosed in 2005 in the United States,and almost as many will die of thedisease. Patients with effusions or metastaticdisease are candidates for combinationchemotherapy. The regimensof choice are platinum-based combinationchemotherapy schedules. Giventhat most patients will experience diseaseprogression despite their initialtreatment, they may be eligible for second-line chemotherapy, provided theyhave an acceptable performance status.

The article by Eklund, Trifilio,and Mulcahy begins to addressthe difficulties involved in dealingwith a special patient population-those with impaired hepatic function.The issues involved in dealing withabnormal liver function are distinctfrom those encountered with end-stagerenal disease (to be discussed in theAugust issue of ONCOLOGY); hepaticfunction due to tumor may improvewith successful therapy, while for dialysispatients, their renal disease isconsidered permanent.

The dosing of chemotherapy is,at best, an imperfect science.Long-standing convention hasus calculating body surface area totwo decimal places-a largely discreditedand unnecessary exercise-yet wehave so far failed to learn how to incorporatepotentially important variablesrelated to race, sex, and pharmacogenetics.This review, “ChemotherapyDosing in the Setting of Liver Dysfunction,”by Eklund et al highlightsanother limitation in our understandingof how to use chemotherapy: There islittle known about how to dose drugs inpatients with anything other than normalorgan function.

Advances in cancer treatmentover the past 50 years havecured or prolonged the life expectancyof many patients with cancer.These advances have accelerated overthe past 2 decades. Increasingly, physicianswho manage patients with cancerare turning their attention to the managementof the complications of malignancy,since these complications areoften avoidable, can shorten life spans,and can reduce quality of life.

Cappuzzo and colleagues havereviewed the present optionsof salvage therapy for advancednon–small-cell lung cancer(NSCLC). This issue is highly relevantnowadays, as many patients whofail palliative chemotherapy are stillin sufficiently good condition to receiveadditional therapy. It is ratherinstructive to note that 10 years agothe use of systemic chemotherapy foradvanced NSCLC was advocated butstill not standard, and today we haveseveral options for treating patients inthe second- and even third-line setting.Among these options are agents thatspecifically target molecular featuresof lung cancer, such as the epidermalgrowth factor receptor (EGFR)

Thromboembolism affects many patients with solid tumors and clonalhematologic malignancies. Thromboprophylaxis with low-molecularweightheparin (LMWH) is indicated for surgery and other high-risksituations, but not routinely for central venous catheters or nonsurgical,ambulatory management. Thrombotic events require full anticoagulationfor the duration of active disease and/or the prothromboticstimulus. LMWHs are safe and more effective than both unfractionatedheparin for initial therapy and warfarin for secondary prevention. Antiinflammatoryand antiangiogenic properties might account for thisadvantage and for a survival benefit of chronic LMWH in subgroupsof cancer patients. Ongoing studies are characterizing the cost-effectivenessand antitumor mechanisms of LMWHs, the potential utility ofnewer anticoagulants, and the ability of predictive models to identifyhigh-risk candidates for thromboprophylaxis.