Hirohito Tada

Analysis of Epidermal Growth Factor Receptor Gene Mutation in Patients with Non–Small Cell Lung Cancer and Acquired Resistance to Gefitinib

Purpose: Non–small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this “acquired resistance” is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR. Experimental Design: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors. Results: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene. Conclusions: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.

Neuroendocrine Neoplasms of the Lung: A Prognostic Spectrum

PURPOSE Neuroendocrine (NE) tumors of the lung include typical carcinoid (TC), atypical carcinoid (AC), large-cell NE carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). Their clinicopathologic profiles and relative grade of malignancy have not been defined. PATIENTS AND METHODS From 10 Japanese institutes, 383 surgically resected pulmonary NE tumors were collected. The histologic diagnosis was determined by the consensus of a pathology panel consisting of six expert pathologists as TC, AC, LCNEC, or SCLC on the basis of the WHO classification, and its relationship to clinicopathologic profiles was analyzed. RESULTS Of the 383 tumors, 18 were excluded because of an improper specimen. The pathology panel reviewed the remaining 366 tumors, and a diagnosis of NE tumor was made in 318 patients (87.4%); 55 patients had TC, nine had AC, 141 had LCNEC, and 113 had SCLC. The 5-year survival rates of patients with all stages were as follows: 96.2% for TC, 77.8% for AC, 40.3% for LCNEC, and 35.7% for SCLC. There was significant prognostic difference between TC and AC as well as between AC and LCNEC+SCLC. However, there was no difference between LCNEC and SCLC, and their survival curves were superimposed. The multivariate analysis indicated that histologic type, completeness of resection, symptoms, nodal involvement, and age were significantly prognostic. CONCLUSION The grade of malignancy of NE tumors was upgraded in the following order: TC, AC, LCNEC, and SCLC. No prognostic difference was noted between LCNEC and SCLC. The high-grade NE histology uniformly indicated poor prognosis regardless of its histologic type.

A Prospective Radiological Study of Thin-Section Computed Tomography to Predict Pathological Noninvasiveness in Peripheral Clinical IA Lung Cancer (Japan Clinical Oncology Group 0201)

Purpose: Pathological noninvasiveness needs to be precisely predicted in preoperative radiological examinations of patients with early lung cancer for the application of limited surgery. Patients and Methods: Patients with clinical T1N0M0 peripheral lung cancer were recruited. Radiological findings of the main tumor were evaluated as to ground-glass opacity with thin-section computed tomography. The primary end point was specificity, i.e., the proportion of patients with radiologically diagnosed invasive lung cancer to patients with pathologically diagnosed invasive lung cancer. The precision-based planned sample size was 450. We expected that the lower limit of the 95% confidence interval (CI) for specificity should be satisfied in ≥97% of patients. Results: We enrolled 811 patients from 31 institutions between December 2002 and May 2004. The primary end point was evaluated in 545 patients. The specificity and sensitivity for the diagnosis of pathologically diagnosed invasive cancer were 96.4% (161/167, 95% CI: 92.3–98.7%) and 30.4% (115/378, 95% CI: 25.8–35.3%), respectively, i.e., a negative result. Nevertheless, the specificity for lung adenocarcinoma ≤2.0 cm with ≤0.25 consolidation to the maximum tumor diameter was 98.7% (95% CI: 93.2–100.0%), and this criterion could be used to radiologically define early adenocarcinoma of the lung. Conclusions: Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma ≤2.0 cm with ≤0.25 consolidation.

A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L)

A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter </=2 cm) peripheral non-small cell lung cancer, excluding radiologically determined non-invasive cancer. This study began in August 2009, and a total of 1100 patients will be accrued from 71 institutions within 3 years. The primary endpoint is overall survival. The secondary endpoints are post-operative respiratory function, relapse-free survival, proportion of local recurrence, adverse events, proportion of patients who complete segmentectomy, duration of hospitalization, duration of chest tube placement, operation time, blood loss and number of auto-sutures used. This study is one of the first intergroup studies in Japan between the Japan Clinical Oncology Group and the West Japan Oncology Group.

Phase II Trial of Preoperative Chemoradiotherapy Followed by Surgical Resection in Patients With Superior Sulcus Non–Small-Cell Lung Cancers: Report of Japan Clinical Oncology Group Trial 9806

PURPOSE To evaluate the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection for superior sulcus tumors (SSTs). PATIENTS AND METHODS Patients with pathologically documented non-small-cell lung cancer with invasion of the first rib or more superior chest wall were enrolled as eligible; those with distant metastasis, pleural dissemination, and/or mediastinal node involvement were excluded. Patients received two cycles of chemotherapy every 4 weeks as follows; mitomycin 8 mg/m(2) on day 1, vindesine 3 mg/m(2) on days 1 and 8, and cisplatin 80 mg/m(2) on day 1. Radiotherapy directed at the tumor and the ipsilateral supraclavicular nodes was started on day 2 of each course, at the total dose of 45 Gy in 25 fractions, with a 1-week split. Thoracotomy was undertaken 2 to 4 weeks after completion of the chemoradiotherapy. Those with unresectable disease received boost radiotherapy. RESULTS From May 1999 to November 2002, 76 patients were enrolled, of whom 20 had T4 disease; 75 patients were fully assessable. Chemoradiotherapy was generally well tolerated. Fifty-seven patients (76%) underwent surgical resection, and pathologic complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths, including two deaths owing to postsurgical complications and one death owing to sepsis during chemoradiotherapy. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. CONCLUSION This trimodality approach is safe and effective for the treatment of patients with SSTs.

Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. METHODS In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. FINDINGS Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). INTERPRETATION Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. FUNDING GlaxoSmithKline Biologicals SA.

Effects of preoperative chemotherapy and radiation therapy on human bronchial blood flow

OBJECTIVE We investigated the relationship between bronchial mucosal blood flow around the area of lung resection and the state of healing of the bronchial stump in patients after chemotherapy with or without radiation therapy. METHODS Ninety patients with primary lung cancer were divided into the following 3 groups: group A, 72 patients who had no preoperative therapy; group B, 10 patients who had chemotherapy; and group C, 8 patients who had chemoradiation (60 Gy) therapy. Bronchial mucosal blood flow was measured preoperatively, intraoperatively, and postoperatively (days 8-10) with a laser Doppler flowmeter. RESULTS In groups A and B bronchial mucosal blood flow was preserved sufficiently around the surgical site, and the healing of the bronchial stump was satisfactory. On the contrary, preoperative blood flow in group C was 70% of the preoperative value in group A and decreased further intraoperatively. Healing of the bronchial stump was poor, and a bronchopleural fistula occurred in one patient of group C. CONCLUSION Preoperative chemoradiation therapy may adversely affect bronchial mucosal blood flow and healing of the bronchial stump, although lymphadenectomy and preoperative chemotherapy had little effect. It is recommended that the bronchial stump should be covered with pedicled viable tissue after chemoradiation therapy for prophylaxis against bronchial complications.

Mutational analysis of the β-tubulin gene in lung cancer

Recently, several studies have suggested that a major mechanism of resistance to paclitaxel might involve mutations in the β-tubulin gene in tumor cells. To investigate the frequency of β-tubulin mutations in Japanese patients with small and non-small cell lung cancer, direct sequence analysis following reverse transcription-polymerase chain reaction (RT-PCR) of the β-tubulin gene was performed using total RNA from 20 lung cancer cell lines and 22 specimens from lung cancer patients. First-strand cDNA sequence analysis of the 42 samples showed silent mutations at codon 180 of the β-tubulin gene, which encodes the GTP-binding site of the protein, and codons 195 and 217. However, neither missense nor non-sense mutations affecting microtubule dynamics, within or near the GTP-binding site of the β-tubulin gene, were detected. These results indicate that β-tubulin gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients. Further investigations are needed to clarify the mechanism of drug resistance.

Combination Chemotherapy with Irinotecan and Cisplatin for Large-Cell Neuroendocrine Carcinoma of the Lung: A Multicenter Phase II Study

Introduction: We conducted a phase II study of combination chemotherapy with irinotecan (CPT) and cisplatin (CDDP) in patients with advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung. Methods: Patients received irinotecan (60 mg/m2, days 1, 8, and 15) and cisplatin (60 mg/m2, day 1) every 4 weeks for up to four cycles. The primary endpoint was the response rate. Expected and threshold values for the primary endpoint were 50% and 30%. Results: Forty-four patients were enrolled between January 2005 and November 2011. The response rate (RR) was 54.5% (95% confidence interval [CI], 38.8–69.6%). The median progression-free survival time was 5.9 months (95% CI, 5.5–6.3), and the median survival time was 15.1 months (95% CI, 11.2–19.0). A central pathological review of specimens from 41 patients demonstrated that 30 patients had LCNEC but that 10 patients had small-cell lung cancer (SCLC) and one had non–small-cell lung cancer with a neuroendocrine structure. The RR was 46.7% (95% CI, 28.3–65.7%) in the LCNEC group and 80% (95% CI, 44.4–97.5%) in the SCLC group (p = 0.0823). The median survival time was 12.6 months (95% CI, 9.3–16.0) in the LCNEC group and 17.3 months (95% CI, 11.2–23.3) in the SCLC group (p = 0.047). Conclusions: Combination chemotherapy with irinotecan and cisplatin was active in patients with LCNEC, but the RR and the overall survival period among the patients with LCNEC seemed to be inferior to those among the patients with SCLC. Small numbers of patients were a major limitation in this study.

A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903).

This study sought to ascertain whether induction‐concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC).