Lung Cancer

The 6th University of Texas M. D. Anderson Cancer Center Investigators’Workshop was held on July 16–20, 2003, in Amelia Island, Florida.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular emphasis on the broadly used agent irinotecan(Camptosar), and also novel regimens or agents.

Malignant pleural mesothelioma (MPM) is a disease with a poorprognosis, related in part to the aggressiveness of this disease, and inpart due to the lack of drugs that have demonstrated tumor activity.Historically, antifolates such as methotrexate have been the most activedrugs in the treatment of mesothelioma. Newer antifolates haverecently demonstrated higher efficacy than older regimens in the treatmentof this rare disease. One of these agents, pemetrexed (Alimta),has been evaluated both as a single agent and as part of a combinationregimen. Pemetrexed has been studied in three trials in patients withMPM, and two phase I trials included patients with MPM. In a phaseII trial, pemetrexed was studied as a single agent in patients with MPM.Seven of 64 patients achieved partial responses, with a median overallsurvival of 10.7 months. A large, randomized, phase III trial was conductedto compare pemetrexed/cisplatin with cisplatin. The responserate was 41.3% compared with 16.7%, median survival was 12.1 monthscompared with 9.3 months, and 1-year survival was 50.3% vs 38% inthe pemetrexed/cisplatin and cisplatin arms, respectively. The combinationof pemetrexed/cisplatin also demonstrated superiority in qualityof life and pulmonary functioning analysis when compared withcisplatin.

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folatedependentenzymes thymidylate synthase, dihydrofolate reductase, andglycinamide ribonucleotide formyltransferase. Pemetrexed has demonstratedactivity in clinical trials in a variety of tumor types, includinglung, breast, colon, mesothelioma, pancreatic, gastric, bladder, headand neck, and cervix. Pemetrexed is rapidly metabolized into activepolyglutamate forms that are potent inhibitors of several tetrahydrofolatecofactor-requiring enzymes critical to the synthesis of purines and thymidine.Functionally, pemetrexed acts as a prodrug for its polyglutamateforms. Two different transporters are known to take extracellular folates,and some antifolates, into the cell. These are the reduced folate carrierand the folate receptor. One of the many attributes that make pemetrexedunique is that methodology has been developed to eliminate and controlmany of its associated clinical toxicities. Multivariate analyses demonstratedthat pretreatment total plasma homocysteine levels significantlypredicted severe thrombocytopenia and neutropenia, with orwithout associated grade 3/4 diarrhea, mucositis, or infection. Routinevitamin B12 and folic acid supplementation have resulted in decreasedfrequency/severity of toxicities associated with pemetrexed without affectingefficacy, making this novel antifolate a safe and efficaciousanticancer agent.

Pemetrexed (Alimta) possesses broad antitumor activity. It has beenevaluated in non–small-cell lung cancer (NSCLC) as front-line chemotherapyin a comprehensive phase II evaluation. While variousantifolates have been previously evaluated in clinical trials, drug developmentwas stopped or delayed in light of their lack of efficacy oroccurrence of life-threatening toxicities. While similar trends were observedwith pemetrexed early in development, investigators institutedfolic acid and vitamin B12 supplementation to minimize these toxicitieswithout hampering drug efficacy. This article briefly summarizes thecurrent evidence that supports the role of pemetrexed-based combinationsin clinical trials for chemonaive patients with advanced NSCLC.

According to the updated 2004 guidelines of the American Societyof Clinical Oncology (ASCO) on the treatment of advanced non–smallcelllung cancer (NSCLC), docetaxel (Taxotere) can be considered thestandard second-line chemotherapy in patients relapsing after frontlinetherapy. This was based on two phase III trials (TAX 317 and TAX320) that demonstrated the superiority of docetaxel at 75 mg/m2 in theparameters of survival, quality of life, and disease/symptom controlwhen compared to best supportive care or alternative single-agent chemotherapy.The response rate was approximately 6%, with a mediansurvival time of 7 months and a 1-year survival rate of 30%. Despitethe activity demonstrated, this schedule showed an important toxicityprofile, with grade 3/4 neutropenia and febrile neutropenia occurringin 70% and 11% of patients, respectively. However, the results obtainedby these studies stimulated research interest in new drugs for this diseasesetting. Pemetrexed (Alimta), a new multitargeted antifolate, hasachieved promising results in NSCLC treatment, as a single agent or incombination with other drugs. In the second-line setting, a large phaseII study demonstrated good activity of pemetrexed, with an acceptabletoxicity profile. This led to a phase III registration trial that comparedpemetrexed at 500 mg/m2 to the standard docetaxel dose of 75 mg/m2.While results from this trial demonstrated a similar efficacy of the tworegimens in response rate and survival, pemetrexed achieved a bettersafety profile. These results support the use of pemetrexed as a newoption in the second-line treatment of NSCLC.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

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