Lung Cancer

Although no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.

NEW ORLEANS-Subgroup analysis of data from the TRIBUTE trial indicates that erlotinib (Tarceva), when given in combination with carboplatin (Paraplatin) and paclitaxel, provides a survival benefit to never-smoking patients with previously untreated advanced non-small-cell lung cancer (NSCLC). Vincent A. Miller, MD, of Memorial Sloan-Kettering Cancer Center, presented the results at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 7061). In contrast, the combination of erlotinib and chemotherapy did not provide any survival benefit to the entire population of NSCLC patients enrolled in the trial (abstract 7011).

Recent advances in molecularclassification and the adventof noncytotoxic molecularlytargeted therapies have offered increasedhope of improving the diagnosis,treatment, and prognosis forpatients with non–small-cell lung cancer(NSCLC).[1] Yet the use of chemotherapyin NSCLC has continuedto evolve over recent years with theappearance of newer cytotoxic agentsthat have improved the outcome forpatients. Doublet combination chemotherapyhas become the standardof care for patients with advanceddisease and good performance status.Prolongation of survival has also beenshown with second-line chemotherapyfor patients whose tumors are refractoryto first-line agents.[1]

Drs. Patel, Blum, and Argirishave provided a detailed, thoroughreview of induction chemotherapyfor non–small-cell lungcancer (NSCLC). They also discussstaging and the relative merits of avariety of invasive and noninvasivetechniques for staging lung cancer.

Lung cancer remains the leading cause of cancer death in Americanmen and women. Non–small-cell lung cancer (NSCLC) accountsfor 85% of these cases. Although surgery is the best curative approachfor resectable NSCLC, long-term survival for patients with operabledisease remains poor. More than half of patients who initially presentwith stage I to IIIA disease experience relapse of metastatic disease.Postoperative adjuvant therapy has been evaluated in several randomizedtrials, and provides a survival benefit. It appears reasonable tolook to induction chemotherapy, or preoperative chemotherapy, to providea similar improvement in survival with early treatment ofmicrometastatic disease. Multiple trials of induction therapy have beencarried out with encouraging results. The use of various induction regimenswith chemotherapy alone or chemotherapy combined with radiotherapyfor stage IIIA NSCLC is under investigation. Randomized trialsare under way to better define the role of induction therapy in themultimodality treatment of NSCLC.

Stereotatic body radiation therapy (SBRT) is a rapidly evolving cancertreatment method in which concepts and techniques previously developedfor brain tumor radiosurgery are adapted to eradicate tumorselsewhere in the body. The spatial accuracy, conformality, and steepradiation dose gradients of radiosurgery, which have been critical to itssuccess in the treatment of intracranial tumors, are applied in SBRT totreat a variety of extracranial tumors. Early results demonstrate excellentresponse rates and low toxicity with a variety of hypofractionateddose regimens and localization/immobilization techniques. This articleprovides an overview of the rationale and results of SBRT for specificindications, descriptions of some methods of treatment delivery, anddiscussion of potential areas of future investigation.

Only a minority of elderly patientswith advanced non–small-cell lung cancer(NSCLC) have been offered palliativechemotherapy, as indicated by clinicalsurveys beginning in the 1980s.Lilenbaum’s thorough review of thetreatment of locally advanced and metastaticNSCLC studies in two specialpopulations (elderly and Eastern CooperativeOncology Group [ECOG]performance status [PS] 2 patients)highlights a new trend seen with theadvent of better-tolerated chemotherapyregimens.

Lilenbaum’s paper highlightingrecent controversies in the managementof advanced non–small-cell lung cancer (NSCLC) inthe elderly and in vulnerable performancestatus (PS) populations is bothtimely and relevant. A recent Surveillance,Epidemiology and End Results(SEER) analysis suggests that nearly50% of all patients diagnosed withNSCLC are 70 years of age or older.Non–small-cell lung cancer generallypeaks in incidence in the elderly, andthe population of the United States iscontinually aging, with nearly 20%expected to be over age 65 by theyear 2030.[1]

The benefits of chemotherapy in non–small-cell lung cancer(NSCLC) patients remains, to some extent, restricted to younger patientswith a good performance status (PS). It has long been assumedthat chemotherapy is too toxic and of marginal benefit for elderlyNSCLC patients and those with a PS of 2. Nevertheless, retrospectiveanalyses and more recent prospective trials have suggested that suchpatients enjoy longer survival and a better quality of life when treatedwith chemotherapy. This article will review the data and discuss theirclinical implications.

It is well known that the prognosisfor patients with brain metastasesfrom small cell lung cancer(SCLC) is very poor, with mediansurvivals in the range of 3 to 14months.[1-3] As pointed out by Quanet al, brain metastasis is an importantissue, given that approximately 60%of SCLC patients will develop brainmetastases sometime in the course oftheir disease. Quan et al set out towrite an article on the treatment ofbrain metastases from SCLC, but theyoften have to refer to the results ofstudies of brain metastases from othersites. Unfortunately, many studiesspecifically exclude SCLC-relatedbrain metastases, and therefore,advances in their treatment havebeen few.

The use of chemotherapy in the treatment of early and advancednon–small-cell lung cancer (NSCLC) has increased during the pastdecade. One of the main reasons for the increased acceptance of chemotherapyis the development of several new cytotoxic agents with aunique mechanism(s) of action and high single-agent activity, combinedwith a favorable toxicity profile. Pemetrexed (Alimta) is a novelantifolate that inhibits several enzymes involved in DNA synthesis(thymidylate synthase [TS], dihydrofolate reductase [DHFR], andglycinamide ribonucleotide formyltransferase [GARFT]). Pemetrexed’stoxicity is markedly reduced by folic acid and vitamin B12 supplementation.The compound has been studied extensively in various tumor types,including NSCLC. In NSCLC, pemetrexed at 500 mg/m2, every 3 weeks,given IV over 10 minutes, has shown promising activity, and can safelybe administrated with vitamin supplementation. After registration,single-agent pemetrexed will certainly add to the chemotherapeuticoptions available for pretreated patients and will most likely changesignificantly chemotherapy prescriptions in second-line chemotherapy.In first-line chemotherapy, the role of platinum-based and -free combinationdoublet chemotherapy with pemetrexed still needs to be defined.Phase II data indicate high efficacy combined with favorabletoxicity for pemetrexed in combination with cisplatin, carboplatin(Paraplatin), oxaliplatin (Eloxatin), gemcitabine (Gemzar), andvinorelbine (Navelbine). This review summarizes the clinical experienceobtained thus far during the early clinical development ofpemetrexed in NSCLC.

Standard first-line chemotherapy for the majority of patients withadvanced non–small-cell lung cancer (NSCLC) consists of platinumbasedcombination regimens including one of the newer-generationagents, such as gemcitabine (Gemzar), a taxane, vinorelbine(Navelbine), or irinotecan (Camptosar). Several effective regimens areavailable, the choice of which will depend on treatment goals, individualpatient or disease factors, as well as physician preferences. Thispaper surveys randomized trials of many of the newer-generation chemotherapycombinations in patients with advanced NSCLC to examineseveral issues, such as which new-generation regimen to use, whethera platinum agent is needed, the optimal number of drugs in the combination,and treatment duration.

The novel multitargeted antimetabolite pemetrexed (Alimta), recentlyapproved by the US Food and Drug Administration for the treatment ofmesothelioma when combined with cisplatin, is also active in first- andsecond-line non–small-cell lung cancer (NSCLC). In a phase III trialcomparing single-agent pemetrexed vs docetaxel (Taxotere) as secondlinetherapy in advanced NSCLC, survival was shown to be comparablebetween these agents, but side effects were significantly less frequentand severe for patients who received pemetrexed. In the frontlinesetting, phase II studies have shown significant activity and a veryfavorable toxicity profile of the combination of pemetrexed with a platinumagent. Pemetrexed has been well tolerated at systemic doses as aradiosensitizer when given as concurrent chest radiation, and a phaseI study is under way to assess its tolerability in combination withcarboplatin (Paraplatin) in this setting. Pemetrexed is an importantaddition to the armamentarium of medicines used to treat thoracicmalignancies, and merits study in combination with other drugs havingnovel mechanisms of action.

The purpose of this paper is to provide an overview of the clinical presentation, diagnosis, and treatment of brain metastases in patients with SCLC, with a focus on current trends and developments in the treatment of this disease.

Quan and colleagues have providedan important and timelyreview on the treatment ofbrain metastases in patients with smallcell lung cancer (SCLC). We certainlyagree with the comments and viewsof the authors, but wish to emphasizeseveral aspects of central nervoussystem (CNS) metastases in SCLCpatients.

Malignant mesothelioma is a devastating disease with an onset 20to 60 years after exposure to asbestos. Although most cytotoxic agentshave been evaluated for the treatment of mesothelioma, few single agentshave consistently yielded response rates above 20%. Antimetabolitesare the most active drugs against mesothelioma, and of these, theantifolate group is the most widely studied and effective. Pemetrexed(Alimta), a new antifolate, may be more active because of its differentmechanism of action. Several clinical trials have evaluated pemetrexedalone and in combination with a platinum agent for patients with malignantmesothelioma. A pivotal phase III trial has demonstrated thatcombination chemotherapy with pemetrexed and cisplatin improvessurvival, response rate, pulmonary function, and quality of life comparedwith single-agent cisplatin. Additional trials are evaluatingpemetrexed in the neoadjuvant setting and in combination with othercytotoxic and targeted agents.

Data from adjuvant trials clearly indicate that one of the most importantproblems in patients with resected non-small-cell lung cancer(NSCLC) is compliance to chemotherapy. In the postoperative setting,significant comorbidities and incomplete recovery after surgery oftenmake it difficult for patients to tolerate or comply with systemic therapy.Therefore, it may be preferable to deliver chemotherapy before surgeryas "neoadjuvant" or "induction" chemotherapy. The rationale for usinginduction chemotherapy is based on evidence that chemotherapymight reduce tumor burden and possess activity againstmicrometastases, resulting in improved results by surgery, radiotherapy,or a combination. Moreover, induction therapy facilitates in vivo assessmentof tumor response or resistance. Potential drawbacks includethe risk of perioperative complications, and the possibility that the tumormass may become unresectable due to disease progression. Duringthe past decade, four phase III randomized trials evaluated the roleof induction chemotherapy in stage IIIA NSCLC. The first three studiesconsistently showed that induction chemotherapy improves survivalcompared with surgery alone. More recently, a large phase III trialperformed by French investigators suggested a survival benefit in stageI/II patients, but not stage IIIA. The high activity of new platinumbasedchemotherapy-based on response rate and 1-year survival inadvanced disease-reinforces the rationale for the use of these newcombinations in early-stage NSCLC, especially for a subset of patientstraditionally treated with surgery alone. Several phase III trials arecurrently evaluating the role of new doublets as induction chemotherapy;these are discussed in the article. The results of these ongoingphase III trials should help clarify the role of induction chemotherapyin early-stage disease.

Several decades of chemotherapy trials in non–small-cell lung cancer(NSCLC) have clearly shown a survival benefit for chemotherapyover best supportive care. However, only short-lived responses are attained,with an average of four cycles of chemotherapy, before tumorprogression is observed. Second-line chemotherapy has been demonstratedto improve outcome, with docetaxel (Taxotere) as the predominantcytotoxic drug. A recent randomized trial in second-line NSCLCindicated that the novel drug pemetrexed (Alimta) attained the sameresponse, time to progression, and survival as docetaxel. This findingushers in a new age in second-line treatment that can be further invigoratedby the addition of targeted agents. Accumulated evidence indicatesthat overexpression of epidermal growth factor receptor andHER2/neu, which occurs frequently in NSCLC, leads to the deregulationof PI3K and MAPK, activating Akt and enhancing chemoresistance.Future clinical trials in NSCLC will include tailored andmultitargeted therapy and pemetrexed represents a significant step forSward in this direction.

Standard first-line chemotherapy regimens in advanced non-smallcelllung cancer (NSCLC) include carboplatin (Paraplatin)/paclitaxel,cisplatin/docetaxel (Taxotere), cisplatin/gemcitabine (Gemzar), andcisplatin/vinorelbine (Navelbine). An informal meta-analysis of 13 randomizedtrials of these regimens in NSCLC indicates no marked differencesin terms of response rates or survival, but toxicity advantageswith cisplatin/gemcitabine and cisplatin/vinorelbine regimens. An informalmeta-analysis to assess the feasibility of substituting carboplatinfor cisplatin in combination with gemcitabine or docetaxel shows nomarked differences in efficacy between cisplatin- and carboplatincontainingregimens, although a slight trend favoring carboplatin/gemcitabine treatment may be observed; comparison of toxicity profilesamong carboplatin-based regimens suggests advantages forcarboplatin/gemcitabine treatment. A formal meta-analysis of 13 trialscomparing gemcitabine/platinum combinations with other platinumbasedregimens in NSCLC indicates significant improvements inprogression-free survival and overall survival with gemcitabine/platinum treatment. On balance, available data suggest that carboplatin/gemcitabine may be the first-line option with the best therapeutic index.

The treatment of advanced non–small-cell lung cancer (NSCLC)has evolved rapidly over the past few years. Systemic chemotherapy isassociated with both quality of life and modest survival benefit for patientswith advanced NSCLC. Platinum-based doublet combinationsare the “standard of care.” The US Food and Drug Administration(FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to beused in combination with cisplatin for the treatment of advanced NSCLCin the first-line setting. Randomized clinical trials have established comparableefficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine andother platinum doublets. Nonhematologic toxicities occur at a lowerfrequency with carboplatin/gemcitabine combinations compared withother “standard” platinum-based doublets, whereas dose-limitingthrombocytopenia, the most common toxicity, rarely requires therapeuticintervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the3-week regimen is preferred. The combination of carboplatin andgemcitabine is an effective regimen with an acceptable toxicity profilefor the treatment of advanced NSCLC. This regimen can also be usedas a foundation for the development of innovative combinations withmolecularly targeted agents.

Research to identify the optimal drugs for use in chemoradiotherapyhas led to the development of the potent radiosensitizing agentgemcitabine (Gemzar), which has exhibited excellent activity in non-small-cell cancer. When used in sequential chemoradiotherapy regimens,gemcitabine has been associated with response rates of 57% to68%. A full dose of gemcitabine (1,000 mg/m2) can be safely used asinduction therapy, and there is no definitive indication of enhancementof radiotoxicity. In addition, results from phase I/II trials supportthe efficacy of concurrent gemcitabine/radiation therapy in improvingoverall response rates and overall survival. Rates of 68%, 37%, and28%, respectively, for 1-, 2-, and 3-year survival have been reported forgemcitabine/cisplatin chemotherapy administered concurrently withradiotherapy. Although the optimal dose has yet to be determined, aweekly dose of 300 mg/m2 appears to be effective with an acceptabletoxicity level. Additional clinical trials are warranted to assess the longtermefficacy and safety of gemcitabine in combination with other chemotherapeuticagents and radiation therapy for treatment of non-smallcelllung cancer.

Several new antimetabolites, administered alone or in combination,are changing the therapeutic landscape for thoracic cancer. Two-drugcombinations involving these newer drugs are becoming the standardof care for non–small-cell lung cancer (NSCLC), largely due to improvementsin survival rates, time to disease progression, and responserates as well as an improved safety profile. Gemcitabine (Gemzar) haselicited considerable interest in this disease, as a combination partnerin chemotherapeutic regimens. Another promising agent is pemetrexed(Alimta), a folate-based inhibitor of thymidylate synthase. In preclinicaldevelopment, pemetrexed both alone and in combination with othercytotoxic agents has exhibited activity across a broad range of tumormodels, including NSCLC and mesothelioma. In clinical trials of patientswith NSCLC, pemetrexed has been an effective, well-toleratedagent that can be used as monotherapy or in combination with otheragents at full dose. In clinical trials of patients with mesothelioma, thecombination of pemetrexed and cisplatin demonstrated a significantimprovement in survival, response, and patient quality-of-life parameters.The principle toxicities of pemetrexed can be minimized by folateand vitamin B12 supplements.

WASHINGTON-The Early Lung Cancer Action Program (ELCAP) has tested CT screening over the last decade and shown significant improvements in screening technology and substantially improved cure rates for cancers caught early.

BETHESDA, Maryland-Convincing evidence indicates that physical activity can significantly reduce the risk of colon and breast cancer, according to a newly released National Cancer Institute (NCI) fact sheet. Moreover, studies also suggest a link between exercise and a reduced risk of cancers of the prostate, lung, and endometrium. However, despite the documented cancer and other health benefits of exercise, "recent studies have shown that more than 60% of Americans do not engage in enough regular physical activity," NCI said. The new publication summarizes the evidence supporting the role of exercise in cancer risk reduction and the possible underlying biological mechanisms

Locally advanced non–small-cell lung cancer represents 30% to 40%of all pulmonary malignancies. Most patients will die of the diseaseafter aggressive contemporary treatments. Therefore, significant improvementin therapeutic methods must be implemented to improveoverall survival rates. The arrival of a new generation of chemotherapeuticagents-including the taxanes, gemcitabine (Gemzar), andtopoisomerase inhibitors such as irinotecan (Camptosar) and topotecan(Hycamtin)-offers the hope of significant advances in the treatmentof lung cancer. Irinotecan and topotecan are camptothecin derivativesthat inhibit topoisomerase I enzyme. It is believed that topoisomerase Iinhibitors stabilize a DNA/topoisomerase I complex and interact withreplication machinery to cause cell death. A significant amount of datademonstrates that these topoisomerase I inhibitors also act asradiosensitizers. With the increasing data that support concurrentchemoradiation treatment for malignancies, including lung cancer andhead and neck cancers, there is an impetus to pursue the additionaldrugs that may potentially improve local control and survival. Irinotecanis undergoing early clinical trials in the combined-modality setting inseveral different disease sites. This paper will review the data on therole of camptothecin derivatives as a radiosensitizer and as a componentof combined-modality therapy for lung cancer. It is hoped thatnewer treatment strategies, like the combination of radiation andtopoisomerase I inhibitors, will have a significant impact on cure ratesin the future.

Among patients with lung cancer, approximately 15% have smallcelllung cancer (SCLC). The clinical characteristics of SCLC tend tobe more aggressive, but also more sensitive to chemotherapy and radiationtherapy than those of non-SCLC. Irinotecan (Camptosar) is aderivative of camptothecin, an inhibitor of the nuclear enzymetopoisomerase I. Irinotecan has been shown to exhibit excellent antitumoractivity against SCLC in monotherapy regimens and in combinationwith cisplatin. A phase III trial comparing irinotecan and cisplatin(IP) with etoposide and cisplatin (EP) in patients with previously untreatedextensive-stage SCLC (ED-SCLC) was conducted. Patients inthe IP arm responded significantly better than patients in the EP arm.In the IP arm, the response rate was 84%, and median overall survivalwas 12.8 months. A phase II trial of irinotecan, cisplatin, and etoposide(IPE) administered weekly (arm A) or every 4 weeks (arm B) for EDSCLC(JCOG 9902-DI) was also performed. In arm B, the responserate was 77% and the median overall survival was 12.9 months. A randomizedtrial comparing IP with IPE administered every 3 weeks inpatients with previously untreated ED-SCLC is presently being performedin Japan.

New agents with improved systemic activity are needed for the treatmentof lung cancer. Irinotecan (Camptosar) is a promising agent inadvanced non–small-cell (NSCLC) and small-cell lung cancer (SCLC).In a Japanese phase III trial of advanced NSCLC, irinotecan oririnotecan/cisplatin demonstrated a significant survival advantage comparedto the standard of vindesine/cisplatin. Similar North Americanphase III trials focusing on irinotecan’s role in NSCLC are under way.Ongoing trials have also been launched to corroborate the significantsurvival advantage reported by a Japanese phase III trial for irinotecan/cisplatin vs standard etoposide/cisplatin in extensive SCLC. Currentand planned trials in NSCLC with irinotecan in combination withgemcitabine (Gemzar), the taxanes, and other new agents, and thoracicradiotherapy should also provide useful clinical data. Moreover,trials in SCLC are investigating the rationale of combining irinotecanwith a platinum agent as a component of chemoradiotherapy regimens.Promising data from these and other studies will further elucidate arole for irinotecan in the management of lung cancer.

Lung cancer is a major health problem worldwide. Non–small-celllung cancer (NSCLC) accounts for 80% to 85% of all lung cancers,while small-cell lung cancer (SCLC) accounts for 15% to 20% of cases.For early-stage and locally advanced NSCLC (stages I through III), amultimodality treatment approach is appropriate because it improvessurvival. Combination chemotherapy is currently the standard treatmentfor good performance patients with metastatic disease. Elderlypatients (≥ 70 years) with metastatic NSCLC also benefit from treatment.In SCLC, concurrent radiation therapy and chemotherapy is thestandard for limited disease, while chemotherapy is the treatment forextensive disease. Novel innovative therapies, which could includemolecular targeting agents, are needed to treat both NSCLC and SCLC.

The authors begin their articleby presenting the current stateof affairs regarding lung cancerand the rationale as to why itwould seem to be an obvious candidateto benefit from a program ofearly diagnosis followed by earlytreatment. Briefly summarized, thedisease is the number one cancer killer,it is nearly uniformly fatal whendiagnosis is symptom-prompted, andit is highly curable when found in itsearly stage.

At this time, two positions aboutlung cancer screening are defensiblebased on current evidence.First, it is quite reasonable todefend the position that there is insufficientevidence to recommend population-based screening for lung cancerwith spiral computed tomography(CT) for individuals at increased riskfor lung cancer.[1] Despite very favorableresults from observationalstudies,[2-4] broad consensus aboutpolicy depends, at a minimum, on resultsfrom a prospective randomizedtrial comparing lung cancer mortalityin an experimental group with a controlgroup. Ideally, this comparison isbetween a group invited to screeningand a group receiving usual care, andsuch trials have begun in France, theNetherlands, and Italy, but decisionsalso may be made for alternative comparisonsif circumstances warrant adifferent randomization scheme. TheNational Lung Screening Trial has justcompleted recruiting 50,000 individualsat elevated risk to a prospectiverandomized trial comparing chest radiographyto spiral CT.[5]