Phase III study of adjuvant gemcitabine compared with adjuvant uracil-tegafur in patients with completely resected pathological stage IB-IIIA non-small cell lung cancer (WJTOG0101).

BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.

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.

A phase II trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (PEOPLE Study).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. METHODS: Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non-AE-IPF rate during postoperative days 0-30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. RESULTS: From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7-99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5-99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3-5 adverse events were observed. CONCLUSIONS: Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients. TRIAL REGISTRATION: This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (REGISTRATION NUMBER: UMIN000007774 ).

Stereotactic body radiotherapy for second pulmonary nodules after operation for an initial lung cancer.

OBJECTIVE: A second lung cancer is occasionally observed in patients who underwent surgical resection of the index lung cancer. The purpose of this study is to evaluate stereotactic body radiation therapy for second lung cancer. METHODS: Fifty-one medically inoperable patients who underwent stereotactic body radiation therapy for second lung cancer were the subjects: 31 cases of multiple primary lung cancer and 20 of pulmonary metastasis from the index cancer. Clinical stage was T1a in 27 patients, T1b in 13 patients and T2a in 11 patients, and 70% of subjects had impaired respiratory function. Histology of second lung cancer was adenocarcinoma in 16 patients, squamous cell carcinoma in 9 patients and not assessed in 25 patients. The interval between index cancer operation and stereotactic body radiation therapy was 31 months (range: 4-171). The total stereotactic body radiation therapy doses were 48 Gy in 4 fractions or 60 Gy in 10 fractions. RESULTS: With the median follow-up of 36 months, 3-year overall survival rates were 62% with the median survival time of 46 months. Cause-specific survival was 73% at 3 years. Overall survival for multiple primary lung cancer and pulmonary metastasis was quite similar: 62 and 61% at 3 years, respectively. Three-year overall survival was 77% for T1a and 43% for T1b or T2a. Grade 2 pulmonary toxicities occurred in five patients and one patient died of Grade 5 pneumonitis. CONCLUSIONS: Even though the subjects were medically inoperable, the survival outcomes of stereotactic body radiation therapy were favorable. Furthermore, having acceptable toxicity, stereotactic body radiation therapy is feasible and could be an option for multiple primary lung cancer and pulmonary metastasis after surgical resection for the index cancer.

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Perihippocampal Meningeal Carcinomatosis Following Hippocampal Avoidance Prophylactic Cranial Irradiation in Small Cell Lung Cancer: A Case Report.

Prophylactic cranial irradiation (PCI) for limited disease small cell lung cancer is the standard of care for curative treatment of this disease. However, neurocognitive dysfunction is one of the late adverse events of PCI and is often problematic. Recently, hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is sometimes performed to prevent neurocognitive dysfunction after PCI. In HA-PCI, the question is whether or not metastases appear around the hippocampus that were not irradiated. We have experienced a case of perihippocampal meningeal carcinomatosis after HA-PCI. We also draw attention to the potential risks of performing HA-PCI based on this experience.

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).

BACKGROUND: 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). METHODS: Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m(2) and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible. RESULTS: Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021). CONCLUSIONS: The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC.

Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT).

PURPOSE: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation. PATIENTS AND METHODS: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS). RESULTS: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively. CONCLUSION: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.

Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.

BACKGROUND: Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. METHODS: We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. FINDINGS: Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p<0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died. INTERPRETATION: Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel. FUNDING: West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies.

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

Results of treatment for thymic neuroendocrine tumours: multicentre clinicopathological study.

OBJECTIVES: A thymic neuroendocrine tumour (TNET) is rare, and few comprehensive reports of treatment results have been presented. To clarify the clinicopathological characteristics of TNET in affected patients, outcomes were retrospectively examined using cases accumulated in a multicentre survey. METHODS: Thirty patients (25 men and 5 women) who underwent surgical resection or biopsy procedures at 10 institutions of the Thoracic Surgery Study Group of Osaka University (TSSGO) between January 1986 and June 2015 and pathologically diagnosed with TNET were enrolled. RESULTS: The examined tumours were classified as typical carcinoid in 7 patients, atypical carcinoid in 11 patients, large-cell neuroendocrine carcinoma in 3 patients and small-cell carcinoma in 9 patients, of which 2 underwent surgical biopsy procedures and 28 surgical resection, with a macroscopic complete resection procedure performed in 27 patients. Induction therapy was performed in 2 patients and adjuvant therapy in 10 patients. Thirteen patients had recurrence, with distant metastasis, especially in bone and lung tissues, more frequent than local recurrence. Overall survival was 77% after 5 years and 35% after 10 years, whereas relapse-free survival was 48% and 29%, and cancer-specific survival was 90% and 48%, respectively. Overall survival was significantly better in patients who underwent macroscopic complete resection (P = 0.010). As for relapse-free survival patients, TNM Stage I or II (P = 0.011) and received adjuvant therapy patients (P = 0.042) showed good survival rates. CONCLUSIONS: The prognosis of patients with TNET was favourable in those treated with macroscopic complete resection. Survival is promising even in patients with postoperative recurrence, following treatment utilized for pulmonary neuroendocrine tumour or gastroenteropancreatic neuroendocrine tumour.

A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer.

INTRODUCTION: We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC. METHODS: In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (arm A) or a group receiving orally administered UFT (250 mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively. RESULTS: Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63-76] in arm A versus 73% (95% CI: 66-78) in arm B (hazard ratio = 0.92, 95% CI: 0.55-1.41, p = 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio = 0.92, 95% CI: 0.63-1.34, p = 0.50]). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]). CONCLUSIONS: As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810).

A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung.

BACKGROUND: In a previous phase 3 trial of adjuvant chemotherapy after resection of non-small-cell lung cancer, a combination of uracil and tegafur (often referred to as UFT) taken orally was shown to prolong survival. A subgroup analysis disclosed that most patients who benefited had pathological stage I adenocarcinoma. METHODS: We randomly assigned patients with completely resected pathological stage I adenocarcinoma of the lung to receive either oral uracil-tegafur (250 mg of tegafur per square meter of body-surface area per day) for two years or no treatment. Randomization was performed with stratification according to the pathological tumor category (T1 vs. T2), sex, and age. The primary end point was overall survival. RESULTS: From January 1994 through March 1997, 999 patients were enrolled. Twenty patients were found to be ineligible and were excluded from the analysis after randomization; 491 patients were assigned to receive uracil-tegafur and 488 were assigned to observation. The median duration of follow-up for surviving patients was 73 months. The difference in overall survival between the two groups was statistically significant in favor of the uracil-tegafur group (P=0.04 by a stratified log-rank test). Grade 3 toxic effects occurred in 10 of the 482 patients (2 percent) who actually received uracil-tegafur. CONCLUSIONS: Adjuvant chemotherapy with uracil-tegafur improves survival among patients with completely resected pathological stage I adenocarcinoma of the lung.

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.

Lobe-Specific Nodal Dissection for Clinical Stage I and II NSCLC: Japanese Multi-Institutional Retrospective Study Using a Propensity Score Analysis.

OBJECTIVES: The purpose of this study was to assess the surgical outcomes according to the extent of mediastinal lymph node dissection for patients with NSCLC by using a nationwide registry database. METHODS: From among 11,663 patients in a Japanese lung cancer registry study for 2004, 5392 patients with clinical stage (c-stage) I or II NSCLC that was completely resected by lobectomy and either systematic (SND) or lobe-specific nodal dissection (LSD) were enrolled. Patients who received preoperative therapy or had middle lobe tumor were excluded. In the LSD group, inferior mediastinal (subcarinal) nodes were not dissected for upper lobe tumors, and superior mediastinal nodes were not dissected for lower lobe tumors. To reduce the selection bias, an inverse probability of treatment weighting method using a propensity score was implemented. RESULTS: LSD and SND were performed in 1268 patients (23.5%) and 4124 patients (76.5%), respectively. The LSD group included more upper lobe and c-stage I tumors and less pathological N2 disease than the SND group. Extended pathological N2 disease outside LSD area was found in 3.2% of the SND group. The 5-year overall survival was 81.5% in the LSD group and 75.9% in the SND group. An inverse probability of treatment weighting-adjusted Cox model showed that LSD did not have a negative prognostic impact and instead was associated with favorable survival (hazard ratio = 0.68, 95% confidence interval: 0.60-0.77). CONCLUSIONS: This retrospective registry study suggested that LSD is an alternative to SND for selected patients with c-stage I or II NSCLC. Future prospective studies are warranted to determine whether LSD is applicable and provides clinical benefit for the general population of patients with c-stage I or II NSCLC.

Predictors of non-neoplastic lesions in lung tumours showing ground-glass opacity on thin-section computed tomography based on a multi-institutional prospective study†.

OBJECTIVES: Peripheral small lung tumours (LTs) showing ground-glass opacity (GGO) tend to be treated without preoperative histological diagnosis due to difficulty in obtaining tissue samples. Exclusion of non-neoplastic lesions (NNLs) is essential when considering non-surgical treatment such as stereotactic radiotherapy. Here, we sought to determine preoperative factors associated with NNLs in peripheral LTs using data from a prospective study that investigated the efficacy of lesser pulmonary resection (JCOG0804/WJOG4507L). METHODS: The key eligibility criteria of the study were as follows: (i) peripherally located definitive or suspected LC with maximum diameter ≤2 cm and (ii) radiological non-invasive tumour with consolidation/tumour ratio (CTR) of ≤0.25 based on thin-section computed tomography (CT). Among all the resected LTs, incidences of NNL and precancerous lesions were examined. Also, logistic regression analysis was conducted to investigate the predictors of NNL using maximum tumour dimension (≤1 cm/>1 cm) and CTR (0/>0) as an explanatory variable. RESULTS: Between May 2009 and April 2011, 333 patients were prospectively enrolled from 51 institutions into the study. Among 333 patients, 345 LTs were included in the analysis. There were 314 (91.0%) LCs, 17 (4.9%) precancerous lesions and 14 (4.1%) non-cancerous lesions. Maximum tumour dimension ≤1 cm was identified as a significant predictor of NNLs with logistic regression analysis. There were 10 (8.6%) NNLs in 116 LT ≤1 cm, but 4 (1.7%) NNLs in 229 LTs >1 cm. CONCLUSIONS: NNLs were found in only 4.1% of peripheral LTs with GGO. However, when the tumour diameter was ≤1 cm, ∼10% were NNLs, necessitating a histological diagnosis when non-surgical treatment was considered.

Surgical Intervention for Non-Small-Cell Lung Cancer Patients with Pleural Carcinomatosis: Results From the Japanese Lung Cancer Registry in 2004.

INTRODUCTION: A subset of non-small-cell lung cancer (NSCLC) patients with malignant pleural effusion and/or malignant pleural nodules is now classified as stage IV and is generally considered a contraindication to surgery. However, several reports have demonstrated that the prognosis of patients with pleural carcinomatosis first detected at thoracotomy is relatively favorable. The aim of this study was to describe the results of surgical intervention in NSCLC patients with pleural carcinomatosis in Japan. METHODS: In 2010, the Japanese Joint Committee of Lung Cancer Registry conducted a nationwide registration of lung cancer patients who underwent surgery in 2004. Using this database, we performed a retrospective study focused on pleural carcinomatosis. We examined the clinicopathological features, the current status of therapy, and surgical outcomes in patients with pleural carcinomatosis. RESULTS: Among the 11,420 registered NSCLC patients, 329 (2.9%) patients had pleural carcinomatosis. The median survival time and 5-year survival rate of 313 patients without other metastatic disease were 34.0 months and 29.3%, respectively. Primary tumor resection was performed in 256 (81.8%) patients, and macroscopic complete resection was achieved in 152 (48.6%) patients, with 5-year survival rates of 33.1% and 37.1%, respectively. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (p < 0.001), best stage nodal status (p = 0.002), and the presence or absence of gross residual tumor (p = 0.013) were independent predictors of survival. CONCLUSION: In our surgical registry for NSCLC, patients with pleural carcinomatosis accounted for 2.9%, and macroscopic complete resection for them was associated with better survival.

A prematurely terminated phase III trial of intraoperative intrapleural hypotonic cisplatin treatment in patients with resected non-small cell lung cancer with positive pleural lavage cytology: the incidence of carcinomatous pleuritis after surgical intervention.

BACKGROUND: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. METHODS: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes. RESULTS: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008). CONCLUSIONS: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.

A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304).

The purpose of this study was to evaluate the efficacy of adjuvant chemotherapy with three courses of cisplatin and vindesine, in comparison to observation only, for N2 non-small cell lung cancer that had been completely resected. Patients with pathologically demonstrated mediastinal lymph node metastasis (N2), who had undergone complete resection, were randomized to observation or adjuvant chemotherapy (cisplatin 80 mg/m2 on day 1; vindesine 3 mg/m2 on days 1 and 8: x3 courses). Cycles started within 6 weeks after complete resection and were repeated every 4 weeks. This trial was terminated before accumulation of the planned numbers for registration because of a slow accrual rate. A total of 119 patients were randomized (59 patients in the adjuvant arm and 60 with surgery alone). The median survival was 36 months for both groups. Postoperative cisplatin with vindesine chemotherapy was not shown to be efficacious in cases of completely resected N2 non-small cell lung cancer in this setting of timing, dose and agents studied.