Lung Cancer

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]

Given that there is no validated test for early lung cancer detection,the current standard approach to lung cancer detection is to wait forsigns or symptoms to develop. In that setting, newly detected lung canceris generally rapidly fatal resulting in over 157,000 deaths annually.Sole dependence on tobacco control is an insufficient public healthresponse to lung cancer, since most newly diagnosed individuals areeither former smokers or never smokers. Finding a more effective wayto diagnose premetastatic lung cancer would be a crucial step towardan improved lung cancer-related mortality rate. Based on studies ofbreast cancer screening, we know that achieving optimal benefit fromearly cancer detection also involves defining the most effective, efficient,and safest approach to the clinical management of screen-identifiedlung cancer. In this review, we consider how to build on the successesof other cancer screening efforts to detect and manage earlylung cancer. This involves outlining the specific elements for lung cancerthat could make a screening program safe, affordable, and effective.We also explore the current standards of early lung cancer managementand target areas where potential pitfalls and opportunities forimprovement exist.

ROCKVILLE, Maryland-The Food and Drug Administration (FDA) has approved Eli Lilly’s Alimta (peme-trexed disodium for injection) in combination with cisplatin (Platinol) for the treatment of malignant pleural mesotheli-oma in patients who are not candidates for curative surgery. Alimta, an orphan drug, received priority review and is the first agent approved for the treatment of the asbestos-related disease. The FDA’s action follows more than 3 decades of efforts to develop an effective chemotherapy for malignant pleural mesothelioma.

This special "annual highlights" supplement to Oncology News International is a compilation of some of the major advances in the management of gastrointestinal cancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

Both advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer pose significanttherapeutic challenges to clinicians due to their high mortalityrates. The past 2 decades witnessed an evolution in the approach to thetreatment of these diseases. In metastatic nonSMQ-8211-SMQsmall-cell lung cancer, trials ofrecently developed chemotherapy regimens have shown increased response ratesand improved quality of life. Several large, randomized phase III trials in unresectablenonSMQ-8211-SMQsmall-cell lung cancer have demonstrated that treatment with chemotherapyand radiation in combination leads to superior outcomes compared with radiationalone. This supplement highlights current treatment options with chemoradiationfor patients with advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer.

Patients with locally advanced or metastatic nonSMQ-8211-SMQsmall-cell lungcancer (stage III and IV) who are not candidates for surgery and exhibitgood performance status are typically treated with concurrent radiationand platinum-based chemotherapy for disease palliation. Platinum-based chemotherapies, used alone or with radiation therapy, offera small but significant survival benefit compared with supportivecare. The incorporation of first-line agents such as gemcitabine(Gemzar), vinorelbine (Navelbine), and paclitaxel, as well as secondlineagents such as docetaxel (Taxotere), in doublet and triplet combinationshas had a further significant therapeutic impact. Randomizedtrials have shown that cisplatin-based therapy in combination with newagents results in improved 1- and 2-year survival rates in patients withadequate performance status. The 1-year survival benefit has significantlyimproved, with greater symptom relief and improved quality oflife in these patients. Thus, delaying disease progression with combinationchemotherapy appears both beneficial and cost-effective in patientswith advanced nonSMQ-8211-SMQsmall-cell lung cancer. Newer approachesSMQ-8212-SMQincluding targeting critical signaling pathways, such as tyrosine kinasereceptors, angiogenesis, and downstream signal transductionmechanismsSMQ-8212-SMQmay provide novel agents with an improved toxicity profileand the potential for better disease management.

Survival for patients with stage III nonSMQ-8211-SMQsmall-cell lung cancer hasgradually improved in recent years, with median survival times increasingfrom less than 10 months to more than 18 months. These increasesare thought to result primarily from advances in chemoradiation. Thisarticle reviews major advances in the development of chemoradiationfor patients with locally advanced nonSMQ-8211-SMQsmall-cell lung cancer. Resultsfrom cooperative group trials suggest that concurrent chemoradiationis superior to sequential therapy and may replace sequential therapy asthe new standard of care in patients with good performance status.Technological advances such as 18F-fluorodeoxyglucose positron emissiontomography (PET) staging can be used to improve patient selectionand predict survival. Locoregional control may be improved byaltering radiation fractionation or delivery (eg, hyperfractionation, highdoseinvolved-volume radiotherapy, 3D conformal radiotherapy). Novelagents and regimens in combination with radiation are being investigatedto further improve therapeutic outcomes.

Rash is a class effect of HER1/epidermal growth factor receptor(EGFR)-targeted agents, and has occurred with high frequency and ina dose-dependent manner in clinical trials of these agents in cancerpatients. Analysis of phase II trials of erlotinib (Tarceva) in non–smallcelllung cancer, head and neck cancer, and ovarian cancer shows asignificant association between rash severity and objective tumor response.Rash severity was highly significantly associated with survivalin patients with non–small-cell lung cancer receiving erlotinib; mediansurvival in patients with no rash was 46.5 days, compared with257 days in those with grade 1 rash (P < .0001) and 597 days in thosewith grade 2/3 rash (P < .0001). Similarly, for the combined non–smallcelllung cancer, head and neck cancer, and ovarian cancer studies,median survival in patients with no rash was 103 days, compared with191 days in those with grade 1 rash (P = .0001) and 266 days in thosewith grade 2/3/4 rash (P = .0001). Similar findings have been madewith cetuximab (Erbitux) and in some settings with gefitinib (Iressa).The strong association of rash severity with response/survival suggeststhat rash may serve as a marker of response to erlotinib treatment andmay be used to guide treatment to obtain optimal response. Dosingerlotinib at the maximum tolerated dose, which is associated with morefrequent and more severe rash, may improve response rates and survivaldurations. Further study of the potentially important associationbetween rash and outcome of treatment with EGFR-targeted agents isneeded.

Erlotinib (Tarceva) is an orally available selective small-moleculeinhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentrationof 2 nM for purified tyrosine kinase. This agent has beenshown to produce stasis or regression of tumor growth in human cancerxenograft models, including non-small-cell lung cancer models.Ongoing preclinical investigations indicate that inhibition of the MAPKand Atk signaling pathways downstream of HER1/EGFR may be requiredfor optimal antitumor effects. Erlotinib exhibits inhibition ofMAPK and Atk kinases at concentrations higher than those requiredfor HER1/EGFR tyrosine kinase inhibition; such findings suggest thatmaximal inhibition of HER1/EGFR, requiring high erlotinib doses, isnecessary for optimum antitumor activity. These considerations aresupported by tumor models, including non-small-cell lung cancermodels, showing dose-related antitumor effects up to high doses oferlotinib. Erlotinib exhibits additive antitumor effects when combinedwith chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel,gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy,and other targeted agents (eg, bevacizumab [Avastin]). Recent studiesindicate that erlotinib inhibits the EGFRvIII mutant at concentrationshigher than those required for inhibition of wild-type receptor. Ongoinginvestigation will help to determine optimal dosing and dose frequencyof erlotinib in various cancers in the clinical setting.

Non–small-cell lung cancer represents a growing global burden andremains a therapeutic challenge. Only small improvements in survivalhave been made with standard chemotherapeutic approaches to advanceddisease in recent history. Novel biologic targeted therapies offerthe potential of improving patient management and treatment outcomesin non–small-cell lung cancer. Prominent among these novelagents are the HER1/epithelial growth factor receptor (EGFR) inhibitors.One of these agents, gefitinib (Iressa), is already approved for usein advanced, refractory non–small-cell lung cancer. Erlotinib (Tarceva)is a promising HER1/EGFR inhibitor in phase III evaluation as firstlinetherapy combined with chemotherapy and as second-/third-linemonotherapy in advanced non–small-cell lung cancer. In addition,erlotinib is being evaluated in combination with the angiogenesis inhibitorbevacizumab (Avastin), a strategy combining two new modalitiesin cancer treatment. Results of these trials will provide importantinformation on optimal use of these new targeted therapies and mayoffer the promise of improving the treatment of non–small-cell lungcancer.

In phase I trials in healthy volunteers and patients with refractorycancers, erlotinib (Tarceva) was well tolerated and showed activityagainst non–small-cell lung cancer and other tumors. The dose identifiedfor further clinical development was 150 mg/d; at this dose, erlotinibachieves high exposure, with maximum concentrations greater than2,000 ng/mL and 24-hour area under the concentration-time curvegreater than 35,000 ng • h/L. In a phase II trial in 57 patients withpreviously treated advanced non–small-cell lung cancer, erlotinib treatmentproduced an objective response rate of 12.3% and a stable diseaserate of 38.6%, with median duration of response of 19.6 weeks;median overall survival was 8.4 months and 1-year survival was 40%,with 9 patients remaining alive over follow-up of greater than 18 months.No grade 4 toxicity was observed, and grade 3 toxicity was minimal. Inan ongoing phase II trial in bronchioloalveolar carcinoma, erlotinibtreatment has produced objective response in 26% of 50 evaluable patients,with median duration of response not yet having been reached.An ongoing phase II trial is examining the combination of erlotinibwith the angiogenesis inhibitor bevacizumab (Avastin) in previouslytreated non–small-cell lung cancer; phase I evaluation revealed no doselimitingtoxicities at tested doses and provided evidence of antitumoractivity. Two phase III trials are examining erlotinib in combinationwith carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) orcisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatmentin advanced non–small-cell lung cancer. The phase III BR.21trial is assessing erlotinib monotherapy in advanced refractory non–small-cell lung cancer. Results of these phase II trials will soon beavailable.

The identification of predictive or surrogate markers of response toHER1/epidermal growth factor receptor (EGFR) inhibitor treatmentwould permit selection of patients most likely to respond to such treatment.Markers could consist of tumor characteristics (eg, characteristicsof the receptor or downstream signaling molecules and determinantsof resistance) or host characteristics (eg, pharmacokinetic parametersand toxicities). The occurrence of rash may constitute a surrogatemarker of response to erlotinib (Tarceva) treatment in patientswith non–small-cell lung cancer and other cancers. The erlotinib markeridentification program has been designed to identify and investigateother candidate markers by analysis of a large number of clinicalsamples from patients enrolled in erlotinib trials in non–small-cell lungcancer, including the phase III TALENT and TRIBUTE trials oferlotinib combined with chemotherapy and the phase III BR.21 trial oferlotinib monotherapy in advanced non–small-cell lung cancer. Thisprogram should both contribute to understanding of the molecular biologyof HER1/EGFR inhibition and result in identification of potentialmarkers that can be evaluated in the clinical setting.

Moderate consumption of red wine may decrease the risk of lung cancer in men, according to a study published in the October Cancer Epidemiology, Biomarkers and Prevention journal (17: 2692–2699, 2008).

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.