Stephen L. Graziano

Single-Agent Versus Combination Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The Cancer and Leukemia Group B (study 9730)

PURPOSE We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. RESULTS The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019). CONCLUSION Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.

ERCC1 Isoform Expression and DNA Repair in Non-Small-Cell Lung Cancer

BACKGROUND The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

Effect of Number of Lymph Nodes Sampled on Outcome in Patients With Stage I Non–Small-Cell Lung Cancer

PURPOSE We postulate that surgical sampling and pathologic evaluation of lymph nodes of surgical specimens from patients with stage I non-small-cell lung cancer (NSCLC) can have an effect on the time to recurrence and survival of these patients. PATIENTS AND METHODS We analyzed data on 442 patients with stage I NSCLC who were treated with surgical resection and some form of lymph node sampling. Associations between total lymph nodes sampled and disease-free survival (DFS) and overall survival (OS) were investigated. The effect of total lymph node stations sampled and the surgical techniques (random lymph node sampling, systematic sampling [SS], or complete mediastinal lymph node dissection [MLND]) on DFS and OS was also studied. Complete MLND and SS were defined as dissection or sampling of levels 4, 7, and 10 for right-sided lesions and levels 5 or 6 and 7 for left-sided lesions. RESULTS Patients were divided into quartiles on the basis of total number of lymph nodes sampled. Improved DFS and OS were associated with greater number of lymph nodes sampled. SS and MLND were associated with improved survival compared with random lymph node sampling. The total number of lymph nodes sampled maintained strong significance in the multivariate analysis. CONCLUSION These results indicate that examining a greater number of lymph nodes in patients with stage I NSCLC treated with resection increases the likelihood of proper staging and affects patient outcome. Such information is important not only for therapy and prognosis of individuals but also for identifying those who may benefit from adjuvant therapy.

The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer.

Small-cell lung cancer (SCLC), a chemotherapy-responsive disease, is characterized by neuroendocrine properties. In contrast, non-small-cell lung cancer (NSCLC) is at best moderately responsive to chemotherapy, and only 10% to 20% of cases demonstrate neuroendocrine properties. The present study is a retrospective analysis of the use of immunoperoxidase markers for neuron-specific enolase (NSE), Leu-7, and chromogranin A in NSCLC patients treated with chemotherapy. It was designed to determine if the presence of neuroendocrine markers predict for response to chemotherapy. The diagnostic slides and blocks were obtained on 52 NSCLC patients who were treated with chemotherapy (26 responders and 26 nonresponders). Immunoperoxidase studies were performed, and slides were scored without knowledge of the patients response. Markers were positive in responders and nonresponders, respectively, as follows: NSE, 14 of 26 (54%) versus seven of 26 (27%), P = .04; Leu-7, 11 of 25 (44%) versus five of 26 (19%), P = .08; and chromogranin A, three of 26 (12%) versus 0 of 26 (0%), P = .71. Two markers were positive in 10 of 26 responders (38%) and 0 of 26 nonresponders (0%), P less than .01. Responders with two or more positive markers showed superior survival (median, 79 weeks) compared with responders with fewer than two positive markers (median, 51 weeks) and nonresponders (median, 27 weeks). These data suggest that the presence of neuroendocrine markers in NSCLC is associated with an increased likelihood of response to chemotherapy and may add to the standard parameters (performance status, weight loss) used to select patients for chemotherapy.

Prognostic Significance of K-ras Codon 12 Mutations in Patients With Resected Stage I and II Non–Small-Cell Lung Cancer

PURPOSE The aim of this study was to investigate the prognostic importance of codon 12 K-ras mutations in patients with early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS We identified 260 patients with surgically resected stage I (n = 193) and stage II (n = 67) NSCLC with at least a 5-year follow-up. We performed polymerase chain reaction analysis of DNA obtained from paraffin-embedded NSCLC tissue, using mutation-specific probes for codon 12 K-ras. RESULTS K-ras mutations were detected in 35 of 213 assessable specimens (16.4%). K-ras mutations were detected in 27 of 93 adenocarcinomas (29.0%), one of 61 squamous cell carcinomas (1.6%), five of 39 large-cell carcinomas (12.8%), and two of 20 adenosquamous carcinomas (10%) (P = .001). G to T transversions accounted for 71% of the mutations. There was no statistically significant difference in overall survival for all patients with K-ras mutations (median survival, 39 months) compared with patients without K-ras mutations (median survival, 53 months; P = .33). There was no statistically significant difference in overall or disease-free survival for subgroups with stage I disease, adenocarcinoma, or non-squamous cell carcinoma or for specific amino acid substitutions. The median survival time for stage II patients with K-ras mutations was 13 months, compared with 38 months for patients without K-ras mutations (P = .03). CONCLUSION Codon 12 K-ras mutations were more common in adenocarcinomas than in squamous cell carcinomas. For the subgroup with stage II NSCLC, there was a statistically significant adverse effect on survival for the presence of K-ras mutations. However, when the entire group was considered, the presence of K-ras mutations was not of prognostic significance in this cohort of patients with resected early-stage NSCLC.

Survey of oncologists' perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials†

Prior research has documented the under‐representation in clinical trials of older patients with cancer. In part of a larger study to test the magnitude of these barriers to entering eligible older patients with carcinoma of the breast into clinical trials (Cancer and Leukemia Group B [CALGB] trial 9670), barriers to accruing eligible older patients to clinical trials were obtained from the physicians perspective.

Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

PURPOSE We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODS KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSION KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.

Chemoradiotherapy and Gefitinib in Stage III Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor and KRAS Mutation Analysis: Cancer and Leukemia Group B (CALEB) 30106, a CALGB-Stratified Phase II Trial

Introduction: This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer. Methods: Between May 2002 and April 2005, 63 patients were entered before the study closing early. All received two cycles paclitaxel 200 mg/m2 and carboplatin area under the curve 6 intravenous plus gefitinib 250 mg daily. Poor risk stratum 1 (≥5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk stratum 2 (performance status: 0–1weight loss and <5%) received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m2 plus carboplatin AUC 2. Consolidation gefitinib until progression was started after all toxicities were grade ≤2. Results: Acute high-grade infield toxicities were not clearly increased compared with historical CRT data. Poor-risk (N = 21) median progression-free survival was 13.4 months (95% confidence interval [CI]: 6.4–25.2) and median overall survival 19.0 months (95% CI: 9.9–28.4). Good-risk (N = 39) median progression-free survival was 9.2 months (95% CI: 6.7–12.2), and median overall survival was 13 months (95% CI: 8.5–17.2). Thirteen of 45 tumors analyzed had activating epidermal growth factor receptor (EGFR) mutations, and 2 of 13 also had T790M mutations. Seven tumors of 45 had KRAS mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type. Conclusions: Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising. Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.

Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection

PURPOSE The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern-lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). PATIENTS AND METHODS Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis. RESULTS A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01). CONCLUSION The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.

Carboplatin in malignant mesothelioma: A phase II study of the cancer and leukemia Group B

SummaryCarboplatin (400 mg/m2) was given at 28-day intervals to 41 patients with malignant mesothelioma. In all, 40 patients were eligible and evaluable for response. Partial responses were seen in 2 cases (5%); regression of evaluable disease, in 1 patient (2%); and stable disease, in 19 subjects (48%). A median of two doses of carboplatin per patient resulted in mild toxicity. Leukopenia (≤2,000 cells/μl) and thrombocytopenia (<100,000 cells/μl) were seen in only 6% and 20% of the patients, respectively. Median survival from study entry was estimated at 7.1 months, with a 1-year survival of 25%±7%. Carboplatin given at a dose of 400 mg/m2 at 28-day intervals shows minor activity against malignant mesothelioma.