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The treatment of advanced non-small cell lung cancer has been with systemic chemotherapy and usually consists of a platinum doublet chemotherapy. The identification of somatic driver mutations has resulted in new drugs that target these mutations. This report discusses the two most important new targeted therapy drugs for the treatment of advanced non-small cell lung cancer that have these driver mutations.

Introduction: We evaluated the role of glutathione-related genotypes on overall survival, time to progression, adverse events, and quality of life (QOL) in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from initial treatment with platinum-based chemotherapy and subsequently randomized to receive daily oral carboxyaminoimidazole or a placebo., Methods: Of the 186 total patients, 113 had initial treatment with platinum therapy and DNA samples of whom 46 also had QOL data. These samples were analyzed using six polymorphic DNA markers that encode five important enzymes in the glutathione metabolic pathway. Patient QOL was assessed using the Functional Assessment of Cancer Therapy-Lung and the UNISCALE QOL questionnaires. A clinically significant decline in QOL was defined as a 10% decrease from baseline to week-8. Multivariate analyses were used to evaluate the association of the genotypes on the four endpoints., Results: Patients carrying a GCLC 77 genotype had a worse overall survival (hazard ratio (HR) = 1.5, p = 0.05). Patients carrying the GPX1-CC genotype had a clinically significant decline in the UNISCALE (odds ratio (OR): 7.5; p = 0.04), total Functional Assessment of Cancer Therapy-Lung score (OR: 11.0; p = 0.04), physical (OR: 7.1; p = 0.03), functional (OR: 5.2; p = 0.04), and emotional well-being constructs (OR: 23.8; p = 0.01)., Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients' survival after platinum-based chemotherapy. GPX1 may be an inherited factor in predicting patients' QOL. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens, drug toxicities, disease progression, and QOL are critical.

Purpose: This study assessed whether maintenance therapy with carboxyaminoimidazole (CAI), compared to placebo, prolonged overall survival in stage IIIB/IV NSCLC patients who had tumour regression or stable disease after treatment with one chemotherapy regimen., Methods: After completion of chemotherapy, patients were randomized to receive daily oral CAI at 250mg or placebo. Treatment continued until patient refusal, disease progression or unacceptable adverse event (AE). Quality of life (QOL) was assessed by UNISCALE and Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L)., Results: Registration was halted early for slow accrual (targeted 360, randomized 186: 94 CAI, 92 placebo). All patients were off active treatment at time of analyses. Non-haematologic AEs (primarily grade 1, 2) observed significantly more often in the CAI group included fatigue (54.5% versus 29.3%), anorexia (31.1% versus 13.0%), nausea (62.2% versus 30.4%), vomiting (32.2% versus 14.1%), neurosensory (60.0% versus 44.6%) and ataxia (33.3% versus 16.3%). Patients discontinued treatment for AEs, death on study or refusal more often in the CAI group (36.0% versus 8.7%, p<0.0001). No significant differences in survival or time to progression were observed (median: CAI versus placebo: 11.4 months versus 10.5 months, log rank p=0.54; 2.8 months versus 2.4 months, log rank p=0.50). More patients receiving CAI reported a clinically significant (10-point) decline in QOL particularly on the functional (58% versus 37%, p=0.05) construct of FACT-L and UNISCALE (72% versus 51%, p=0.04)., Conclusion: The addition of CAI following chemotherapy does not provide clinical benefit or improvement in QOL over placebo in advanced NSCLC.

Background: In this pooled analysis, the authors examined correlations between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between clinically significant changes in QOL and patient-reported adverse events (AE)., Methods: Data from 6 lung cancer clinical trials that involved 358 patients were pooled. All trials incorporated the Uniscale and 1 of 3 multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. Spearman rank correlations and a Bland-Altman approach were used to assess agreement. Time-to-event analysis was performed using the Kaplan-Meier method., Results: Correlations between the Uniscale and multiple-item assessments were substantial (correlation coefficient = 0.49-0.66). At least 1 10-point decline was reported in the Uniscale and multiple-item assessments by 58% of patients and 39% of patients, respectively. At least 1 severe AE (grade >or=3) was reported in 35% of patients postbaseline. The percent agreement between experiencing a severe AE and a decline in QOL was 48% and 59% for the Uniscale and multiple-item assessments, respectively. The median time to the first 10-point decline in QOL for the Uniscale and multiple-item assessments was 67 days and 142 days, respectively, and the median time to the first occurrence of a severe AE was 304 days., Conclusions: Information gleaned from the single-item Uniscale assessment was comparable to that gleaned from multiple-item global measures. There was moderate agreement between QOL and AE. A 10-point decline in QOL occurred earlier than Common Toxicity Criteria AE reporting. This suggests the need for inclusion of a QOL instrument in lung cancer clinical trials.

In the United States, lung cancer kills more men and woman than the next three most common cancers combined. Unfortunately, the long-term outcome of lung cancer is still dismal with a 5-year survival rate of 15%. However, significant improvements in median survival times and 1-year and 2-year survival rates have been achieved in the last decade. This progress has been accomplished not only because of better surgical techniques but also because of the use of platinum-based regimens with newer chemotherapy agents and, more recently, targeted therapy. The role of chemotherapy as an integral part of the treatment of lung cancer has expanded significantly, particularly in the last few years with the proven benefit of adjuvant chemotherapy. For advanced stage non-small cell lung cancer (NSCLC), chemotherapy prolongs survival and improves quality of life in patients with good performance status, and appears to provide symptomatic improvement in patients with decreased performance status. Platinum-based doublet chemotherapy regimens are now the standard of care in patients with advanced stage NSCLC, and non-platinum-based combination therapies are reasonable alternatives in certain populations. The combination of the vascular endothelial growth factor inhibitor bevacizumab and chemotherapy has proven to prolong survival. As agents such as monoclonal antibodies, small molecules inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and tested, we are optimistic that these agents will result in improvement in the survival and quality of life of lung cancer patients.

Background: Performance scores predict benefits and toxicities from chemotherapy. Among older cancer patients, however, many investigators have empirically called for a detailed assessment of activities of daily living, claiming that the utility of performance scores is limited in this older population. This study's goals were therefore twofold: (1). to explore the predictive capability of an activities questionnaire and of performance score with respect to chemotherapy's toxicity and efficacy; (2). to describe the daily activities of older patients as they undergo chemotherapy for incurable metastatic lung cancer., Methods: As part of a multi-institutional therapeutic trial, this study included 48 patients >or=65 years of age with metastatic non-small-cell lung cancer. All were assigned an Eastern Cooperative Oncology Group (ECOG) performance score and completed an activity questionnaire (Voorrips) prior to the initiation of carboplatin and paclitaxel. Patients were monitored for toxicity (CTC, version 2) and cancer status., Results: Within this cohort, ECOG performance scores were poor at predicting grade 3 or worse toxic events ( P=0.71, Mantel-Haenszel chi-squared). In contrast, the activity questionnaire categories did predict grade 3 or worse toxicity ( P=0.03) with a positive association observed between greater levels of activity and lower toxicity rates. Neither instrument predicted 90-day disease progression, although there was a trend that suggested a positive association between favorable scores and lower progression rates ( P=0.051). Patients described a broad range of daily activities., Conclusion: Activity questionnaires capture a broad range of data that may prove useful in predicting toxicity among older cancer patients.

Objective: To compare the survival of patients with medically inoperable or unresectable stage III non-small cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy.Design: Randomized, prospective phase III trial.Setting: Multi-institutional cooperative oncology group.Patients: A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution.Interventions: Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy.Main Results: Major clinical responses were observed in 31 of 56 (55%; 95% Cl, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; Cl, 51% to 76%) treated with radiation only (P greater than 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P greater than 0.2). The median survival time was 313 days compared with 317 days, respectively (P greater than 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (Cl, 32% to 58%), 16% (Cl, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (Cl, 33% to 60%), 21% (Cl, 11% to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002).Conclusion: Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P greater than 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC).Methods and Materials: Treatment began with two cycles of topotecan (1 mg/m(2)) Days 1 to 5 and paclitaxel (175 mg/m(2)) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard "cohorts of 3" design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m(2)) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade > or =4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade > or =3 dyspnea, or Grade > or =2 pneumonitis.Results: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade > or =3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months.Conclusion: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine. [ABSTRACT FROM AUTHOR]

Purpose: This Phase III study was performed to determine whether chemotherapy plus b.i.d. or q.d. radiotherapy (RT) resulted in superior survival for patients with Stage III non-small-cell lung cancer (NSCLC).Methods and Materials: Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of ≤1 were randomized to receive either standard q.d. RT (60 Gy in 30 daily fractions) or split-course b.i.d. RT (30 Gy in 20 fractions b.i.d.) followed by a 2-week break and then 30 Gy in 20 fractions b.i.d. Both arms included etoposide and cisplatin (EP) during RT.Results: Between December 1994 and February 1999, 246 patients were accrued and 234 were deemed eligible and included in the analyses. Of the 234 patients, 123 had Stage IIIa disease and 111 had Stage IIIb disease. The incidence of severe (Grade 3 or greater) acute nonhematologic toxicity (q.d. RT, 53% vs. b.i.d. RT, 65%) and severe (Grade 3 or greater) hematologic toxicities (thrombocytopenia, 41% q.d. RT vs. 39% b.i.d. RT; neutropenia, 80% q.d. RT vs. 81% b.i.d. RT) was not significantly different between the treatment arms. Five patients (3 in q.d. RT group and 2 in b.i.d. RT group) died as a result of acute toxicity. The follow-up ranged from 2 to 73 months (median 43). No significant differences were found between the q.d. and b.i.d. RT arms in terms of time to progression (p = 0.9; median 9.4 and 9.6 months, respectively), overall survival (p = 0.4; median 14 and 15 months and 2-year survival rate 37% and 40%, respectively), and cumulative incidence of local failure (p = 0.6; 2-year rate 45% and 41%, respectively).Conclusion: This program of split-course b.i.d. RT plus EP was not superior to standard q.d. RT plus EP. The toxicity, tumor control, and survival rates were similar with either b.i.d. or q.d. RT. Our future efforts will concentrate on new combinations of systemic therapy and innovative methods of administering increasing doses of RT. [Copyright &y& Elsevier]