Lung Cancer Management: Emerging Strategies

Advances in treatment ofnon-small-cell lung cancer(NSCLC) and otherlung cancers over thepast year include demonstrationof the benefitof adjuvant chemotherapyin early NSCLC; newindications for a numberof chemotherapeuticagents and moleculartargeted agents; and continued progress not onlyin efforts to identify early-stage disease through imaging,but also in determining optimal use of targetedtherapies.Adjuvant Chemotherapyfor Early-Stage NSCLCTwo phase III trials reported last year have demonstrateda significant benefit of adjuvant chemotherapyin early-stage NSCLC, suggesting a new standardof treatment. In the Cancer and Leukemia Group B9633 trial (CALGB 9633), 344 patients with stage IBNSCLC were randomized to paclitaxel (Taxol)/carboplatin (Paraplatin) or no further treatment aftercomplete surgical resection (see report on page 5).Adjuvant chemotherapy was associated with significant38% and 49% reductions in risk for 4-year allcausemortality and lung cancer mortality, respectively.Chemotherapy was well tolerated; grade 3 or 4neutropenia occurred in 36% of patients.In the Canadian JBR.10 trial, 482 patients withcompletely resected stage I or II disease were randomizedto adjuvant vinorelbine (Navelbine)/cisplatin(Platinol) or observation (see report on page 6).Adjuvant therapy was associated with a significant30% reduction in risk for death over 5 years and asignificant prolongation of median overall survival (94 vs 73 months). Adjuvant therapy was well toleratedin this trial, as well.Targeted TherapyThe U.S. Food and Drug Administration (FDA) approvedTarceva (erlotinib) as treatment for patientswith locally advanced or metastatic NSCLC whosedisease has continued to progress despite other therapies,including at least one prior chemotherapy regimen(see report on page 5). In a phase III doubleblinded,placebo-controlled trial in 731 patients from17 countries, erlotinib treatment significantly improvedoverall survival, progression-free survival, and tumorresponse rate compared with placebo. Epidermalgrowth factor receptor (EGFR) status was not part ofthe study protocol, but was looked at retrospectively.Among patients with known EGFR status, erlotinibsignificantly improved overall survival in EGFR-positivepatients but did not appear to improve survival inEGFR-negative patients. Adverse events were primarilyrash and diarrhea.Interestingly, a significant survival benefit witherlotinib treatment was seen in EGFR-positive patients who had never smoked. While survival benefit wasseen in all groups, it was especially high in neversmokers.The finding of survival benefit in never-smokerswas also made in a subset analysisof the TRIBUTE trial of erlotinib in NSCLC; neversmokerstended to be younger and female and tohave adenocarcinoma (see report on page 7).Molecular studies indicate that patients who are neversmokershave more mutations in the EGFR tyrosinekinase domain and that such mutations may confersensitivity to treatment with EGFR inhibitors. A moredefinitive analysis of this will await the final analysis ofthe BR21 trial.Other molecular studies have indicated that mutationsin the EGFR tyrosine kinase are significantlyassociated with response to the EGFR inhibitor gefitinib(Iressa), raising the possibility of screening for mutationsthat can identify patients likely to benefit fromtreatment (see report on page 8). Similar mutationsaffect the response to erlotinib. In the meantime, thepost-accelerated approval clinical trial of gefitinib inlung cancer patients failed to show survival benefit vsplacebo, despite an improved objective response rate;AstraZeneca has cautioned patients currently takinggefitinib to contact their physicians but to continuetaking the agent (see report on page 10).EGFR inhibitors clearly provide benefit in somepatients, and it has become a major initiative toidentify markers that predict such benefit.New Drug Findings and ApprovalsThe FDA approved Alimta (pemetrexed) for use incombination with cisplatin in patients with malignantpleural mesothelioma who are not candidates for curativesurgery, making this drug the first to be approvedin the treatment of this disease (see report on page19). In a randomized, single-blind trial in 448 chemotherapy-naive patients, pemetrexed plus cisplatin improvedmedian survival by 30% compared with cisplatinalone (12.1 vs 9.3 months); 1-year survival was 50.3% vs 38%. It is now recognized that pemetrexed must begiven with folic acid and vitamin B12 supplementation;among patients receiving supplementation throughoutthe study, median survival was 13.3 months in thepemetrexed group and 10.0 months in the cisplatinalonegroup. Hematologic toxicity was more commonin patients receiving pemetrexed.Pemetrexed has also been given accelerated approvalby the FDA for single-agent treatment of locallyadvanced or metastatic NSCLC in previously treatedpatients (see report on page 12). Approval was basedon a randomized, unblinded trial in 571 patients receivingsecond-line treatment with pemetrexed plus vitaminsupplementation or docetaxel. In an as-treated analysis,there were no significant differences between the Alimtaand docetaxel (Taxotere) groups with regard to responserate (9.1% vs 8.8%) or stable disease (45.8% vs46.4%) or rates of on-study death or drug-related death.Pemetrexed treatment was associated with significantreductions in a number of toxicities, including neutropenia,diarrhea, and alopecia.In other studies in NSCLC, an Italian phase II trial ofpemetrexed plus either carboplatin or oxaliplatin (Eloxatin)showed good response rates and favorable toxicity profilesfor the combinations in chemotherapy-naive patientswith unresectable locally advanced or metastatic NSCLC(see report on page 14). Response rates were 31.6% inthe pemetrexed/carboplatin arm and 26.8% in thepemetrexed/oxaliplatin arm, and median survival was10.5 months in both arms. Hematologic toxicities weremore common with pemetrexed/carboplatin.Nonhematologic toxicities were minimal.Investigation of inhalational therapy for lung cancercontinues (see reports on page 16). The Sustainedrelease Lipid Inhalation Targeting technology, or SLIT,developed to improve injectable or inhaled productsby producing a targeted, prolonged effect that canreduce systemic and local toxicity and permit dosereduction, has been examined in a phase I study usingcisplatin. No dose-limiting toxicity was observed in thestudy participants up to a maximum inhaled liposomaldose of 48 mg/m² every 2 weeks or 24 mg/m² everyweek. Preclinical studies using inhalational p53 indicatereduced tumor growth and longer survival intreated animals.Screening and Treatment Planning

• The National Lung Screening Trial has completedenrollment of 50,000 smokers or former smokers,who will be assessed to determine whether spiralcomputed tomography (CT) or chest x-ray to detectcancer prior to onset of symptoms can improve treatmentoutcome and reduce mortality (see page 20).
• The Early Lung Cancer Action Program (ELCAP)has tested CT screening over the last decade and hasreported substantially improved cure rates when cancersare detected early. CT is capable of identifyingtumors of much smaller size than are x-rays. Mostrecently, the technique of volume CT has beenexamined, which represents an improvement in resolutionover that achieved with spiral or helical CT. Ofcancers detected since 1993 in ELCAP, 80% werestage I disease, a marked improvement in diagnosisat this early stage compared with usual care, and the8-year case fatality rate for all patients undergoingresection was 4%.
• Researchers in Germany found that fused positronemission tomography (PET)/CT scanning was moreaccurate in defining TNM stage in NSCLC than PETalone, CT alone, or side-by-side PET and CT images.Fused PET/CT resulted in modification of surgicaltreatment plans in a substantial proportion of patientscompared with the other imaging approaches.
• Gated 4D PET/CT scanning has been shown toimprove detection of tumor motion during respiration,permitting determination of which patients may requirerespiration-gated radiation therapy and improvingthe accuracy of radiation treatment.

Tobacco-Related Issues

• A working group of the National Cancer Institute(NCI) released "Women, Tobacco, and Cancer:An Agenda for the 21st Century," a series of recommendations aimed at stimulating scientific researchinto tobacco-related cancers in women and developingevidence-based interventions to prevent the cancersworldwide (see page 23).
• The American Society of Clinical Oncology issetting up a commission comprising representativesfrom government, educational and scientific organizations,advocacy groups, and the private sector toassess tobacco-related social, medical, legal, and economicissues.
• The National Institutes of Health is funding sevennew centers participating in the NCI's TransdisciplinaryTobacco Use Research Center program, designed toimprove understanding of tobacco-related diseases andtheir control, as well as psychosocial factors that influencesmoking.In less hopeful news, a House-Senate conferencecommittee dropped a provision that would have giventhe FDA regulatory powers over tobacco products, aprovision the Senate had passed by a large margin aspart of the 2004 Foreign Sales Corporation tax cut bill.Taken together, however, the research developmentsof the past year have been quite promising on severalfronts, in terms of improvements in screening, diagnosis,staging, and treatment, and 2005 will likelycontinue to see further refinement in our understandingof how to optimize management of our patients withlung cancer through these state-of-the-art technologiesand therapies. In all, 2004 was a very good year forlung cancer research.

Roy S. Herbst, MD, PhD
Associate Professor of Medicine
Chief, Section of Thoracic Medical Oncology
Department of Thoracic/
Head and Neck Medical Oncology
University of Texas M. D. Anderson Cancer Center
Houston, Texas

Disclosures:

Dr. Herbst has received researchsupport from, served as a consultant or advisor for, andreceived honoraria from Genentech and AstraZeneca.