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This retrospective observational study evaluated cost effectiveness of first-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) with pemetrexed/platinum (Pem/Plat) relative to paclitaxel/carboplatin (Pac/Carbo) and paclitaxel/carboplatin/bevacizumab (Pac/Carbo/Bev). Patients initiating first-line treatment from 2006 to 2009 were identified in electronic medical records of 20 US oncology practices. Pem/Plat patients were matched 1:1 on important characteristics with Pac/Carbo and Pac/Carbo/Bev patients and followed for 1 year to assess progression, survival, and costs. Bootstrapping was used to calculate the probability of falling within quadrants of the incremental cost-effectiveness plane. Kaplan-Meier analysis and Cox proportional hazards regression modeling were also performed. Three hundred Pem/Plat patients (mean age, 67.6 years; male, 56.0%; PS 0/1, 71.0%) were matched with 300 patients in the other cohorts. Median PFS was 134 days (Pem/Plat) versus 106 days (Pac/Carbo) (hazard ratio [HR]: 0.67, P < 0.001) and 126 days (Pac/Carbo/Bev) (HR: 0.68, P < 0.001). Median OS was 298 days (Pem/Plat) versus 218 days (Pac/Carbo) (HR: 0.88, P = 0.08) and 271 days (Pac/Carbo/Bev) (HR: 0.93, P = 0.31). Pem/Plat therapy costs were higher versus Pac/Carbo ($21,841 higher PFS; $19,137 higher OS; P ≤ 0.05) and lower versus Pac/Carbo/Bev ($15,160 lower PFS; $19,946 lower OS; P ≤ 0.05). Pem/Plat had a greater probability of higher costs/higher effectiveness versus Pac/Carbo (PFS, 90.1%; OS, 96.3%) and lower costs/higher effectiveness versus Pac/Carbo/Bev (PFS, 69.5%; OS, 85.0%). Pem/Plat had higher cost and effectiveness than Pac/Carbo; depending on a payer's or society's willingness to pay, Pem/Plat may be considered cost effective compared with Pac/Carbo. Pem/Plat yielded greater effectiveness with lower costs than Pac/Carbo/Bev., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study., Material and Methods: This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration)., Results: TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration., Conclusion: Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.

Purpose: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the activity of irinotecan in malignant mesothelioma (CALGB protocol 9733)., Patients and Methods: Twenty-eight patients accrued between January 1998 and January 1999 received irinotecan 125 mg/m2 by intravenous infusion over 90 min weekly for 4 weeks, every 6 weeks. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Twenty-five patients had pleural mesothelioma; two patients had peritoneal mesothelioma, and one patient had pericardial mesothelioma. Sixty-one percent of patients had epithelial histology., Results: There were no complete or partial responders. Thirty-three percent of patients had stable disease and 52% were shown to have progressive disease at the first reassessment. One patient was not evaluable for response. Median survival from study entry was 9.3 months (95% CI 4.5-13.2 months); 1-year survival was estimated at 46% (95% CI 28-65%). Toxicity was moderately severe. Grade 3 or 4 toxicities included neutropenia in 28% of patients, lymphopenia in 43%, and diarrhea in 18%. Three patients died of treatment-related toxicities. All three experienced grade 4 diarrhea, two also had neutropenic sepsis., Conclusion: Single-agent irinotecan in this dose and schedule has considerable toxicity in patients with malignant mesothelioma and has no anti-tumor activity. The relatively long median survival seen in this study principally reflects the prognostic features of the accrued patients.

Purpose: This Phase II trial was designed to determine the response rate, survival, failure-free survival, and toxicity of second-line therapy with karenitecin in patients with relapsed or refractory non-small cell lung cancer (NSCLC)., Methods: Eligibility criteria included: only one prior chemotherapy program, measurable disease, performance status 0-1, adequate hematologic, renal, and hepatic function. Cases were stratified as relapsed or refractory., Results: Fifty-five patients were accrued and 52 were eligible of whom 28 had relapsed and 24 had refractory disease. Overall patient characteristics were: median age 63 years (range, 45-79 years), 52% males, 63% performance status 1, 50% adenocarcinoma, 21% squamous, 15% large cell, and 12% undifferentiated NSCLC. In both strata, one patient each (4%) had a partial response and 12 patients each (43% for relapsed, 50% for refractory) had stable disease. Median survival was 10.4 months (95% CI, 8.5-17.0) for relapsed NSCLC and 6.0 months (95% CI, 3.7-9.7) for refractory NSCLC. One-year survival was 36% (95% CI, 14-58%) and 21% (95% CI, 5-37%) for relapsed and refractory NSCLC, respectively. Frequent toxicities were neutropenia (grade 3/4 in 15/15%) and thrombocytopenia (grade 3/4 in 17/8%). No patient had lethal toxicity., Conclusion: Second-line treatment with karenitecin was tolerable with reversible bone marrow suppression as the major toxicity. The partial response rates, median survival times, and 1-year survival rates in the relapsed and refractory subgroups are comparable to overall second-line outcomes for other agents considered active in this clinical setting.

Purpose: A major problem with the staging system for non-small cell lung cancer (NSCLC) is clinical underestimation of the extent of disease. Many patients with clinical stage 1 disease do not retain that designation following surgical resection. Herein, we present data from Cancer and Leukemia Group B (CALGB) protocol 9761 evaluating the correspondence between clinical and pathologic analysis in early stage NSCLC., Methods: Five hundred and two patients with suspected or biopsy-proven NSCLC classified as clinical stage 1 (T1-2, N0) by computed tomography (CT) scan or cervical mediastinoscopy were prospectively enrolled in CALGB 9761. The purpose of CALGB 9761 was to prospectively evaluate molecular markers of micrometastatic disease in stage 1 NSCLC. Enrollment occurred at 11 selected institutions within the CALGB. Patients with clinically suspected resectable early stage lung cancer were eligible for enrollment if they had no evidence of mediastinal or hilar adenopathy on CT scan or if they had CT evidence of potential N2 or N3 disease (lymph node > or =1.0 cm) but with negative mediastinoscopy. No prior chemotherapy or radiotherapy was permitted., Results: Of the 502 patients felt to have clinical stage 1 NSCLC enrolled in CALGB 9761, 489 underwent resection with complete surgical staging and routine histopathologic analysis. From these 489 patients, only 422 (86.3%) turned out to have pathologically documented NSCLC. Of these 422 patients, 302 (71.6%) had pathologic stage 1 disease (173 stage 1A and 129 stage 1B). Despite clinical assessment of stage 1 disease, 59 (14%) patients had pathologic stage 2 disease, 57 (13.5%) had stage 3 disease, and four (0.9%) patients had stage 4 disease. Of the patients undergoing resection for clinical stage 1 NSCLC, 65 patients did not have NSCLC (44 had benign disease and 21 had malignancies other than NSCLC) and two additional patients had dual synchronous primary NSCLC tumors and were not eligible for the study. Overall, only 61.7% (302 of 489) of patients with suspected stage 1 NSCLC disease retained that stage and diagnosis after complete surgical staging, while 38.3% had an inaccurate pre-operative clinical stage or diagnosis., Conclusions: The results from this prospective trial demonstrate the poor predictive value of current clinical staging techniques in early stage NSCLC. These findings will serve as a benchmark for comparison of future clinical imaging modalities and other tests evaluating early stage NSCLC.

Purpose: To assess the efficacy and toxicity of 6-hydroxymethylacylfulvene (HMAF; MGI-114, irofulven) as therapy for relapsed or refractory non-small cell lung cancer., Methods: A two-stage phase II design was employed separately for refractory and relapsed patients to differentiate between ineffective treatment (response rate < or =10%) and active treatment (response rate > or =30%). Eligible patients received HMAF 11 mg/m2 per day intravenously over 5 min on days 1-5, with cycles repeated every 28 days., Results: Thirty-six patients (15 relapsed; 21 refractory) were treated, and no responses were seen., Toxicity: Grade 3 neutropenia and grade 3 thrombocytopenia each occurred in 11% of the patients. Grade 3 nausea occurred in 47%; grade 3-4 vomiting in 42%. Twenty-two percent developed grade 3 fatigue. Eleven percent developed grade 3 hallucinations., Conclusions: HMAF, administered at this dose and schedule, is not active as salvage therapy for relapsed or refractory non-small cell lung cancer.

Purpose: The CALGB performed a phase II multicenter study to evaluate the activity of oral capecitabine in patients with malignant mesothelioma (CALGB 39807)., Patients and Methods: Between November 15, 2000 and August 31, 2001, 27 patients with mesothelioma were enrolled in this study. Capecitabine was administered at 2500 mg/m(2) per day divided in two doses for 14 days followed by a seven-day break. Cycles were repeated every 21 days with restaging performed every two cycles and therapy continuing for up to six cycles. One patient withdrew from the study prior to receiving therapy and is removed from further analysis. Eligibility criteria included no prior treatment, PS 0-1 by CALGB criteria and histologically documented mesothelioma., Patient Characteristics: gender; male 19 (73%), female seven; median age 70 (range 40-81); histology: epithelial 15 (58%), mixed eight (31%), unclassified three; site of origin pleura, 25 (96%); weight loss in previous six months of more than 10% in seven (27%), symptoms longer than six months in five (19%)., Results: One patient (4%) had a confirmed PR while 10 (38%) achieved SD for 2-6 cycles. Ten patients (38%) had PD as their best response. There were three patients unevaluable for response and two early deaths. Median survival and failure free survival were 4.9 (95% CI 4-10.8) and 2.4 (95% CI 1.5-4.2) months respectively with a one-year survival of 23% (95% CI 11-49%). Grade three or greater toxicities encountered by at least 10% of patients included lymphopenia (12%), fatigue (12%), dehydration (12%) and diarrhea (15%). Three patients (12%) had grade three skin toxicity or hand-foot syndrome. One patient died of treatment related toxicity during cycle one., Conclusion: The antitumor activity of capecitabine is insufficient to warrant further exploration in patients with malignant mesothelioma.

Pemetrexed disodium is an antimetabolite with multiple sites of action. It inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyl transferase (GARFT). As a single agent it is active against a variety of solid tumors. One phase II trial demonstrated a 14.5% response rate for single-agent pemetrexed disodium in patients with previously untreated mesothelioma. The combination of pemetrexed disodium and cisplatin was associated with very encouraging regression rates in mesothelioma patients treated as part of a phase I trial. A subsequent trial showed similarly encouraging activity (10 partial responses out of 25 evaluable patients [40%]) in mesothelioma patients treated with pemetrexed and carboplatin. A large, prospectively randomized, phase III trial of cisplatin alone versus cisplatin and pemetrexed with vitamin support has been completed. The findings will be presented at the 38th Annual Meeting of the American Society of Clinical Oncology in May 2002., (Copyright 2002 Published by Elsevier Science Ireland Ltd.)

Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.

Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.

Purpose: The CALGB conducted a phase II multicenter trial to evaluate the activity of gemcitabine in malignant mesothelioma (CALGB protocol 9530)., Patients and Methods: Seventeen patients were accrued between February 1996 and May 1996 and received gemcitabine 1500 mg/m(2) by intravenous infusion over 30 min weekly for 3 weeks, followed by a 1 week break. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Nine patients had epithelial cell type and eight had mixed or sarcomatoid cell types. There were 11 cases with measurable disease and six with evaluable disease., Results: There were no complete or partial responders. Eight patients had stable disease, seven developed progressive disease, and two were not evaluable for tumor response. Two patients had minor responses. Median survival from study entry was 4.7 months (95% CI 3.1-12.9 months); one year survival was 24% (95% CI 10-55%). One patient remains alive at 37 months. There were two early deaths, one from disease progression and one from pneumonia. Toxicity was mild and included anemia, lymphopenia and infection; no patient experienced grades three or four thrombocytopenia., Conclusion: No antitumor activity was observed for single-agent gemcitabine in patients with malignant mesothelioma in this multicenter phase II study.

In order to explore non-cisplatin containing regimens for advanced non-small cell lung cancer, Cancer and Leukemia Group B conducted a randomized Phase-II study of two novel combinations, paclitaxel/ifosfamide and vinorelbine/ifosfamide. Both regimens were active with a 38% response rate (95% CI: 24%, 53%) and 31% (95% CI: 18%, 47%), respectively. Median survivals were 8.5 and 7.4 months. Toxicity, mostly neutropenia, was acceptable. These two combinations establish a 'proof of principle' that non-cisplatin containing regimens also have activity in this setting.

Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.

Induction chemotherapy prior to definitive local treatment improves the survival of patients with Stage III non-small cell lung cancer. Several strategies to improve on the impact of 2 or 3 cycles of conventional induction chemotherapy are under study. Immediate concurrent chemoradiation followed by surgery has been evaluated extensively in the Phase II setting. This approach is now the subject of a Phase III trial in North America. Increasing the number of induction chemotherapy cycles or using high dose chemotherapy with autologous stem cell support are other strategies currently under evaluation. Understanding whether either of these approaches will improve survival for patients with Stage III NSCLC must await future Phase III trials.

Patients with untreated extensive small cell lung cancer (SCLC) with CALGB performance scores 0-2 were treated with etoposide 200 mg/m2/day on days 1-3 and cisplatin doses of 20, 30, or 35 mg/m2/day days 1-3 in a Phase I/II format. Of the nine patients treated at the 35 mg/m2/day cisplatin dose in the Phase I portion of the study, Grade 4 leukopenia occurred in five patients and Grade 4 thrombocytopenia in four. There were two deaths due to myelosuppression and sepsis. This dose was thus considered the maximum tolerated dose (MTD), and a Phase II trial was then conducted using this treatment program. In the Phase II trial of 39 patients, the objective response rate was 67% (95% confidence interval, 50-81%) with 21% complete responses (CI 9-36%). Median survival was 10.5 months. Grade 4-5 leukopenia was seen in 57% and Grade 4-5 thrombocytopenia in 56%. The MTD defined by this Phase I trial represents a 67-100% increase in etoposide and a 32-42% increase in cisplatin dosage compared to prior studies. The observed objective response rates with this regimen are comparable to studies using conventional doses, but hematological toxicity was higher.

This Phase II study was designed to determine the efficacy of two chemotherapy regimens with G-CSF support for patients with advanced non-small cell lung cancer (NSCLC). One-hundred and one patients with Stage IIIB or IV NSCLC and performance status 0-1 were randomized to receive ifosfamide 2.0 g/m2 days 1-3, mesna 400 mg/m2 at 0, 4, 6 h days 1-3, cisplatin 33 mg/m2 days 1-3 or etoposide 200 mg/m2 days 1-3, cisplatin 35 mg/m2 days 1-3. Both groups received G-CSF 5 micrograms/kg SQ day 4 to the post day 11 absolute neutrophil count > 10 000. For the 47 eligible patients receiving ifosfamide/mesna/cisplatin, the response rate was 26% (95% confidence interval: 14-40%) and the median survival 7.5 months (95% confidence interval: 5.8-11.0 months). Grade 3 or worse toxicities were: neutropenia 75%, thrombocytopenia 70%, infection 21%. There were two treatment-related deaths due to infection. For course 1, the median absolute neutrophil count nadir was 1.3, platelet nadir 96 000 and incidence of febrile neutropenia 16%. For the 48 eligible patients receiving etoposide/cisplatin, the response rate was 21% (95% confidence interval: 11-35%) and median survival 5.8 months (95% confidence interval: 4.5-9.7 months). Grade 3 or worse toxicities were: neutropenia 90%, thrombocytopenia 58%, infection 29%. There were three treatment-related deaths due to infection. For course 1, the median absolute neutrophil count was 0.2, platelet nadir 80 000 and incidence of febrile neutropenia 33%. For both ifosfamide/mesna/cisplatin and etoposide/cisplatin, median duration of Grade IV neutropenia was short (< or = 4 days), time to subsequent courses 21 days and dose delivered > 95% of planned dose. Although G-CSF allowed full doses of drugs to be delivered on schedule, both ifosfamide/mesna/cisplatin and etoposide/cisplatin produced response rates and survival similar to other cisplatin-based regimens. In view of the significant cost of G-CSF and no obvious improvement in response rate, survival or toxicity profile, G-CSF cannot be recommended with these chemotherapy regimens for patients with advanced NSCLC.

A multi-institutional cooperative group trial was undertaken by the Cancer and Leukemia Group B (CALGB) to evaluate the efficacy of the combination of cisplatin and intravenous etoposide for the treatment of metastatic or recurrent non-small cell lung cancer (NSCLC). The doses used were those previously determined to be the maximally tolerated dose of this drug combination. Forty patients were entered into the trial, 37 of whom were eligible for evaluation. Cisplatin (35 mg/M2/day for 3 days) and etoposide (200 mg/M2/day for 3 days) were administered every 28 days for a planned 6 cycles of therapy. Sixteen of 37 evaluable patients (43%) responded to therapy. Myelosuppression was the dominant toxicity, with 89% of the patients experiencing grade 4 neutropenia, and nearly half grade 3 or 4 thrombocytopenia. Median survival was 8.5 months, with 30% of the patients alive at 1 year and 10% alive at 2 years. Malaise, fatigue, and peripheral neuropathy were the other major toxicities. The combination of etoposide at the dose of 200 mg/M2/day for 3 days and cisplatin at 35 mg/M2/day for 3 days is a highly potent combination against metastatic non-small cell carcinoma.

Since the mid-1980s, the American Cooperative Cancer Treatment Groups (Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, North Central Cancer Treatment Group. Radiation Therapy Oncology Group, Southwest Oncology Group) have performed several multimodality trials exploring combinations of chemotherapy and radiation in patients with Stage III non-small cell lung cancer. The initial trials had a sequential design with induction chemotherapy followed by radiation. Later trials have emphasized concurrent chemoradiation with or without induction chemotherapy. These trials have begun to have an impact on what is considered 'standard' therapy for patients with Stage III non-small cell lung cancer (NSCLC).

Radiation therapy alone has been 'standard' management of patients with Stage III non-small cell lung cancer for several decades. Palliative benefits are routinely achieved but significant survival benefits have not been documented. Patterns of failure in Stage III patients emphasize the need to pursue better treatment for both local macroscopic disease and distant micrometastatic sites. Improved control in both areas will be necessary to meaningfully enhance outcome for the universe of Stage III NSCLC patients. Several randomized trials show a significant survival benefit when cisplatin-containing induction chemotherapy is administered prior to locoregional treatment. In the favorable subset of Stage III patients selected for study by CALGB, the surviving fraction at 2-5 years post-therapy was > or = 2-fold larger in the chemoradiation group than in the cohort treated with radiation alone. The French trial documented a significant decrease in distant metastases rate among the chemotherapy treated patients. In all the trials where patterns of failure are discussed, local disease persistence is the overwhelming rule. Future trials must evaluate improved induction chemotherapy approaches. Stage III patients are an ethical population in which to test induction therapy with new drug combinations randomized against already 'active' regimens for comparative efficacy. End points would be initial response rates, patterns of failure, and overall survival. The feasibility of high-dose chemotherapy regimens with growth factor and hematopoietic support followed by aggressive radiation must be tested. If feasible, trials randomizing high dose versus conventional dose induction programs within the context of sequential multimodality therapy should follow. Intensified radiation approaches such as hyperfractionation or CHART should be paired with active concurrent chemotherapy following induction chemotherapy alone. Pursuit of these approaches over the next several years will hopefully produce major improvements in treatment efficacy and lead to enhanced survival expectations for the large group of patients worldwide with Stage III NSCLC.

Disseminated micrometastatic disease limits the effectiveness of even the most aggressive locoregional treatment strategies in patients with early stage non-small cell lung cancer. One trial of the Lung Cancer Study Group (LCSG) demonstrated a significant decrease in the hazard rate for distant recurrence produced by adjuvant CAP chemotherapy after surgical resection and radiation therapy. French investigators found a significant decrease in distant metastases formation following sequential chemotherapy, radiation, and then additional chemotherapy compared to radiation alone in patients with stage III disease. However, other completed trials are either inconclusive, incompletely analyzed thus far or show no evidence of an effect of adjuvant chemotherapy on distant metastases. Additional data from recently completed or current trials will hopefully clarify the impact of adjuvant chemotherapy on distant micrometastases in patients with potentially curable non-small cell lung cancer (NSCLC).