Lung Cancer

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

ASCO—Adjuvant cisplatin (Platinol)-based chemotherapy significantly improved survival in patients with completely resected non-small-cell lung cancer (NSCLC), Thierry Le Chevalier, MD, reported at the plenary session of the 39th Annual Meeting of the American Society of Clinical Oncology (abstract 6). Dr. Le Chevalier, professor of medicine, Gustav-Roussy Institute, Villejuif, France, concluded that adjuvant chemotherapy could be recommended and might prevent 7,000 deaths worldwide from NSCLC every year. The International Adjuvant Lung Cancer Trial (IALT), which included 1,867 patients treated in 148 centers in 33 countries across five continents, showed that chemotherapy conferred a 4.1% absolute benefit in overall survival and a 5.1% absolute benefit in disease-free survival after 5 years.

Dr. Kelly has written an excellentarticle demonstrating theclinical significance of achievingstable disease in advanced non–small-cell lung cancer (NSCLC)patients. This hypothesis is supportedby clinical data from two phase IItrials (Iressa Dose Evaluation in AdvancedLung Cancer [IDEAL-1 andIDEAL-2]) of the epidermal growthfactorreceptor (EGFR) inhibitor gefitinib(ZD1839, Iressa) in previouslytreated patients. She appropriatelypoints out that although tumor shrinkageis a conventionally used end pointfor cytotoxic drugs, it may not be appropriatefor the “novel” cytostaticagents. For these agents, stabilizationof disease without obvious tumorshrinkage may result in a clinicalbenefit.

Dr. Karen Kelly has written atimely discussion on the clinicalbenefit of achieving stabledisease in advanced non–smallcelllung cancer (NSCLC). The goalsof current therapy are to palliate symptoms,optimize quality of life (QOL),and prolong survival. It is argued thattumor shrinkage may not be mandatoryto achieve these goals, particularlyin the evaluation of moleculartargeted therapies that may be cytostaticrather than cytotoxic in theirmechanism of action. However, stabledisease is not regarded as evidenceof therapeutic efficacy byregulatory authorities. Furthermore, ifbased on radiologic measurements Continued on page 968.alone, this designation encompasses aheterogeneous population that includespatients who demonstrate unequivocaltumor shrinkage as well asmany with tumor growth. Therefore,the case is presented to define stabledisease in terms of clinical benefit byincorporating alternative trial endpoints such as symptom control, QOL,or biologic end points.

The cytostatic, molecular-targeted therapies becoming available forlung cancer and other human solid tumors are more likely to result instable disease than to produce tumor regression. In the setting ofadvanced lung cancer, stable disease provides significant benefit to thepatient. However, in the context of clinical trials, stable disease isvaguely defined, difficult to measure, and may represent a heterogeneouspatient population. The inclusion of alternative trial end pointssuch as symptom improvement and biologic activity may help to identifypatients who have achieved clinically relevant stable disease. Theepidermal growth factor receptor–tyrosine kinase inhibitor gefitinib(Iressa) has been shown to produce partial responses and stable diseasein patients with advanced lung cancer who have previously receivedtreatment with standard chemotherapies. In the monotherapy trials ofgefitinib, stable disease was correlated with improvements in diseaserelatedsymptoms and quality of life-the most meaningful end pointsfor the patient with advanced lung cancer. Thus, with the introductionof new molecular-targeted agents, stable disease with clinical benefitshould become an important goal of anticancer therapy.

In a campaign mounted against theuse of prophylactic cranial irradiation(PCI) in small-cell lung cancer(SCLC), the battle cry of the anti-PCI crowd 10 to 15 years ago was“Fry now, pay later.” The problemwas that some patients survived andseemed to suffer from the treatment.In those days, the high frequency ofbrain metastasis was underestimated.It was commonly thought that withoutPCI, 20% of patients failed at sitesin the brain, and with PCI, only 5%failed.

Prophylactic cranial irradiation(PCI) in patients with locallyadvanced non–small-cell lungcancer (NSCLC) remains an area ofcontroversy. Dr. Gore has provided areview of the literature, including randomizedand nonrandomized studiesand, in particular, the ongoing RadiationTherapy Oncology Group trial(RTOG 0214), which is randomizingNSCLC patients to PCI or observation.

ROCKVILLE, Maryland—The Food and Drug Administration (FDA) has granted accelerated approval to Iressa tablets (gefitinib, AstraZeneca) as monotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) in patients whose disease has progressed despite treatment with platinum-based and docetaxel (Taxotere) chemotherapy. The Oncologic Drugs Advisory Committee (ODAC) had recommended approval of Iressa on September 24, 2002. However, the FDA delayed action on the recommendation for 3 months to analyze new Japanese data that indicated Iressa was associated with an unexpected and often-fatal rate of interstitial lung disease (ILD).

This review by Dr. Gore emphasizesthe significance of theproblem of brain metastases inpatients with locally advanced non–small-cell lung cancer (NSCLC). Thearticle should prompt medical and radiationoncologists to consider enrollingpatients in the ambitious study ofprophylactic cranial irradiation (PCI)led by the Radiation Therapy OncologyGroup (RTOG L-0214). Statisticsfrom the ongoing RTOG study arecomplicated, but essentially, the researchersare looking for a 20% increasein median survival for patientsreceiving PCI. This would make theimpact of PCI in NSCLC comparableto that observed in limited small-celllung cancer (SCLC).

Over the past decade, studies have shown improved survival inpatients with locally advanced non–small-cell lung cancer. This can beattributed to better systemic therapy, growing experience with combined-modality therapy, technologic advances allowing for increasedradiation doses, better supportive care, and better patient selection.With longer survival, we are seeing an increase in the incidence ofcentral nervous system (CNS) metastases. Prophylactic cranial irradiation(PCI) decreases the incidence of CNS metastases in these patientsand may have a favorable impact on quality of life and overall survival.This paper reviews the incidence of CNS metastases in non–small-celllung cancer patients, past experience with PCI, and a current studyevaluating the impact of PCI on survival, neuropsychological function,and quality of life.

Areport focused on women [andsmoking] is greatly neededNo longer are the first signsof an epidemic of tobacco-related diseasesamong women being seen, aswas the case when the [first such reportfrom the US Surgeon General in1980] was written. Since 1980, hundredsof additional studies have expandedwhat is known about the healtheffects of smoking among women, andthis report summarizes that knowledge.Today the nation is in the midst of afull-blown epidemic. Lung cancer,once rare among women, is now theleading cause of female cancer deathin this country, accounting for 25% ofall cancer deaths among women.

Drs. Novello and Le Chevalierhave reviewed the subject ofchemotherapy for non–smallcelllung cancer (NSCLC) in greatdetail, organized under numerous subheadings.I will systematically commenton each section of this excellentoverview, which deals with most ofthe published or recently presenteddata on the subjects discussed. Insome cases, trials of multimodalitytherapies, and not just chemotherapy,are included in the review.

The prognosis of patients with advanced non–small-cell lung cancer(NSCLC) remains poor. Systemic chemotherapy prolongs survivalin this group of patients and palliates symptoms compared to bestsupportive care alone but more effective therapeutic strategies areneeded. Novel agents that selectively target biological pathways oftumor growth offer hope of improving response and survival ratesbeyond what has been achieved with standard cytotoxic chemotherapy.Part 2 of this two-part article addresses the role of chemotherapy inlocally advanced and advanced NSCLC, including the use of novelagents, considerations in elderly patients, and studies of second-linetreatment.

Drs. Novello and Le Chevalierhave written a comprehensivereview on the role of chemotherapyin the treatment of non–smallcelllung cancer (NSCLC). Theirreview spans chemotherapy’s controversialuse in early-stage disease toits mainstream use in late-stage disease.The authors highlight the controversiesin the treatment andresearch of all stages of NSCLC anddiscuss ongoing research in combiningchemotherapy with the new molecularlytargeted agents.

Drs. Novello and Le Chevalierhave produced a comprehensivesummary of a large numberof trials of chemotherapy for allstages of non–small-cell lung cancer(NSCLC). This is a broad subjectarea, constantly changing and rifewith controversy; selecting the keytrials with international relevance isno small feat. Nonetheless, the reviewhighlights many salient issuesin the treatment of lung cancer.

Non–small-cell lung cancer (NSCLC) accounts for approximately80% of all lung tumors. Patients diagnosed with early-stage diseasegenerally undergo surgery, but up to 50% develop local or distantrecurrences. The benefit of chemotherapy in this disease is modest, butnew drugs and combined strategies offer hope of improved survivalrates. Because the disease recurs outside the chest in 70% of cases, oneof the foremost goals of therapy is to prevent distant dissemination. Tothis end, chemotherapy may be administered preoperatively or afterresection of the tumor. The first part of this article, which concludesnext month, will address adjuvant and neoadjuvant chemotherapy inearly-stage non–small-cell lung cancer.

HOUSTON-Introgen Therapeutics, Inc. has published data from its phase II study combining Advexin, an adenoviral vector containing the p53 tumor-suppressor gene, with radiation therapy in patients with nonmetastatic non-small-cell lung cancer (NSCLC) (Clinical Cancer Research, January 2003). The patients were ineligible to receive surgery or combination therapy with radiation and chemotherapy.

Small-cell lung cancer is an aggressive tumor associated with highrates of regional or distant metastases at diagnosis. Although highlychemosensitive to agents given in the first-line setting (eg, etoposideand cisplatin), most patients relapse and have a poor prognosis.Treatment options for relapsed patients include radiotherapy forlimited-stage disease and chemotherapy or combined modalities foradvanced-stage disease. In clinical practice, however, some oncologistsmaintain that chemotherapy provides an insufficient survivalbenefit to justify the sometimes debilitating toxicity associated with themore active regimens in particular. Other potential barriers to furthertreatment include patient comorbidities, performance status, site(s) ofprogression, progression-free interval, and previous treatments. However,numerous clinical trials demonstrate that some patients benefitfrom treatment, achieving prolonged survival, symptom palliation,improved quality of life, and the opportunity, albeit rare, for durableremission. Additionally, several novel chemotherapeutics are availablethat alone or in combination help patients lead an improvedquality of life. Finally, alternative routes and schedules-oral formulations,weekly administration, and prolonged treatment vacations-have been developed to deliver chemotherapy to patients with poorperformance status or multiple comorbidities. This article reviews theadvantages and disadvantages of treating recurrent small-cell lungcancer and summarizes the utility of several active agents.

In this issue of ONCOLOGY, Dr.John Eckhardt provides an excellentreview of the challenge oftherapy for patients with small-celllung cancer (SCLC) who relapse afterfirst-line therapy. Dr. Eckhardt outlinesthe prognostic factors influencingresponse to second-line treatment,survival, and treatment-related toxicity.These prognostic factors includethe response to first-line therapy, theprogression-free interval, and performancestatus. The influence of the chemotherapyregimen and the durationof treatment on symptom palliationand quality of life are also discussed.Dr. Eckhardt provides an excellentsummary of the activity of multipleagents in the second-line setting.

NEW YORK-The investigational epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (Tarceva, also known as OSI-774) produced objective remissions and mild toxicity in stage IV non-small-cell lung cancer (NSCLC) patients who had undergone a number of prior chemotherapy regimens, according to results of a phase II study.

Small-cell lung cancer (SCLC)poses one of the greatest managementchallenges in clinicaloncology, as the mortality rate approaches95% within 2 years afterpresentation for patients with extensivedisease, despite widespread useof combination chemotherapy.[1]Given a disease that is largely managedby the community physician andfor which recent definitive clinicaltrials are relatively scarce,[2] it isincumbent upon the clinician to becognizant of the critical factors innostudies suggesting that three-drugcombinations are indicated.

BRIDGEWATER, New Jersey-The US Food and Drug Administration (FDA) has approved Taxotere (docetaxel, Aventis) as first-line therapy, in combination with cisplatin (Platinol), in patients with unresectable, locally advanced or metastatic non-small-cell lung cancer (NSCLC).

ROCHESTER, Minnesota-In a Mayo Clinic study of low-dose helical CT screening for lung cancer, nearly 70% of the study participants had one or more suspicious lung nodules, but only 1.4% of all nodules proved to be malignant. The other 98.6% were benign "and therefore were false-positive findings," said lead investigator Stephen J. Swensen, MD, professor of radiology. The results, he said, offer reasons for optimism as well as reasons for doubt that CT screening for lung cancer will ultimately save lives by reducing disease-specific mortality.

NEW YORK- A combination of vinorelbine (Navelbine) and gemcitabine (Gemzar) showed similar efficacy to the standard platinum-based regimen for advanced non-small-cell lung cancer (NSCLC) and a different toxicity profile in a phase II study presented at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

Drs. Basche and Kelly presentan excellent comprehensivereview of the treatment ofnon–small-cell lung cancer in olderpersons. Articles such as this, whichfocus on the older patient, are of paramountimportance for several reasons.First, cancer is a disease ofaging, with an 11-fold increased incidenceand a 16-fold increase in cancer-related mortality among patientsover age 65 compared to those under65.[1] Second, the population is aging,and in the year 2030, approximately22% will be over 65.[1] Third,data on older cancer patients are limitedsecondary to an underrepresentationof this population in clinicaltrials.[2,3] Based on these facts, acomprehensive review of the availabledata is important, especially toguide future research.

The importance of cancer as aproblem in the elderly is gainingincreasing appreciationdue, in part, to the demographicchanges taking place in this countryand around the world and their associationto the incidence of cancer.Ongoing epidemiologic research overthe past several decades has consistentlyconfirmed the continuing trendtoward an aging population. In theUnited States, an anticipated 20.1%of the population will be 65 years ofage or older by 2030, the number ofpeople 75 years of age or older willhave tripled, and the 85-or-older agegroup will have doubled.[1]

WASHINGTON-The failure of most states to put the money they receive from the Master Settlement Agreement with the tobacco industry into tobacco-control programs will increase their future health care costs for lung cancer and other tobacco-related illnesses, according to two nonprofit health groups. An independent analysis of data published in October 2002 found that states with the highest incidence of lung cancer generally spent the least amount of money for tobacco control.