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.

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.

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.

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).

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 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 ).

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.

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.

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.

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.

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.

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.

Prognostic value of intraoperative pleural lavage cytology for non-small cell lung cancer: the influence of positive pleural lavage cytology results on T classification.

OBJECTIVE: Although positive pleural lavage cytology (PLC) has been demonstrated to be closely associated with a poor prognosis for patients with lung cancer, it has not been incorporated into the TNM staging system of the Union for International Cancer Control. The aim of our study was to retrospectively examine the clinical significance of PLC status and illustrate the recommendations of the International Pleural Lavage Cytology Collaborators (IPLCC) in a large national database. METHODS: The Japanese Joint Committee of Lung Cancer Registry database included 11,073 patients with non-small cell lung cancer who underwent resections in 2004. We extracted the clinicopathologic data for 4171 patients (37.3%) who underwent PLC. These patients were staged according to the seventh edition of the Union for International Cancer Control TNM classification and by recommendations of the IPLCC, in which T was singly upgraded up to a maximum of T4 for those who were PLC-positive. Prognoses based on these 2 systems were compared. RESULTS: A total of 217 patients (5.2%) were PLC-positive, which was significantly associated with a higher incidence of adenocarcinoma and advanced disease. The 5-year survival for patients with positive and negative PLC results were 44.5% and 72.8%, respectively, and this difference in survival was statistically significant (P < .001). Multivariate analysis showed that positive PLC status was an independent factor for a poor prognosis (hazard ratio, 1.57; P < .001). Significant differences in survival were also found between patients with positive and negative PLC results in the same T categories and stages, including T2a, T3, stage IB, and stage IIIA. The IPLCC recommendations adjusted the prognostic differences in all T categories and stages. The significant difference in survival disappeared between the 2 groups in all T categories and stages. CONCLUSIONS: Our results indicate that a T category upgrade is prognostically adequate for patients who are PLC-positive.

Surgery for small cell lung cancer: a retrospective analysis of 243 patients from Japanese Lung Cancer Registry in 2004.

INTRODUCTION: Indications for surgical resection for small cell lung cancer (SCLC) have been very limited. Because early-stage SCLC is a rare presentation of lung cancer, studies comparing surgical resection among a large number of patients are unlikely to be conducted. This study reports the most recent surgical outcomes of a large number of SCLC patients who underwent surgery in 2004. METHODS: In 2010, the Japanese Joint Committee of Lung Cancer Registry performed a nationwide retrospective registry study regarding the prognosis and clinicopathologic profiles of 11,663 patients who underwent resection for primary lung cancer in 2004. Of the 11,663 patients, 243 patients with SCLC (2.1%) were included in this study. The registry data of the patients with SCLC were analyzed, and the clinicopathologic profiles and surgical outcomes of the patients were evaluated. RESULTS: The 5-year survival rate for all cases (n = 243, 213 males, mean age 68.2 years) was 52.6%. The 5-year survival rates by c-stage and p-stage were as follows: IA, 64.3% (n = 132) and 72.3% (n = 93); IB, 45.7% (n = 36) and 61.1% (n = 51); IIA, 50.5% (n =25); and 44.8% (n = 27); IIB, 33.3% (n = 10) and 40.3% (n = 17); IIIA, 30.5% (n = 30) and 23.4% (n = 45); and IV, 0% (n = 7) and 0% (n = 9), respectively. A multivariate analysis showed that the significant prognostic factors were age, gender, c-stage, and surgical curability. A kappa value was moderate conformity between c-stage and p-stage in all cases. CONCLUSIONS: Surgical resection in selected patients with early-stage SCLC, especially stage I, had favorable results.

A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer).

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinomas (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients. PATIENTS AND METHODS: Patients with completely resected stage I-IIIA HGNEC received four cycles of irinotecan (60 mg/m(2), day 1, 8, 15) plus cisplatin (60 mg/m(2), day 1). This regimen was repeated every 4 weeks. The primary endpoint was the rate of completion of chemotherapy (defined as having undergone three or four cycles), and secondary endpoints were the rate of 3-year relapse-free survival (RFS), rate of 3-year survival and toxicities. RESULTS: Forty patients were enrolled between September 2007 and April 2010. Patients' characteristics were: median age (range) 65 [45-73] years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90%C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and that of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86 and 74% among 23 LCNEC patients, and 74 and 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutropenia, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and four patients (10%) had grade 3 nausea. No treatment-related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC by central pathological review. CONCLUSIONS: The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.

Resection of a second primary lung cancer in a lobe where small-cell lung cancer was previously treated with chemoradiotherapy: report of a case.

There are few reports of resected cases of second primary lung cancer in post-treatment survivors of small-cell lung cancer. Here, we report a surgical case of a 62-year-old female with second primary lung adenocarcinoma after chemoradiotherapy against small-cell lung cancer. She had been treated for small-cell lung cancer 2 years earlier, and achieved complete response after the treatment. A new nodular lesion was detected at a different segment in the right lower lobe. We performed a right lower lobectomy accompanied with systemic mediastinal nodal dissection. Histopathological findings revealed that the new nodular lesion was a second primary lung adenocarcinoma. No metastatic tumor was seen in the dissected lymph node; the initial tumor had disappeared completely. The postoperative course was uneventful, and she was discharged on day 10 after the operation. Ten months after the operation, she was free of recurrent tumor.

Clinicopathological characteristics and surgical results of lung cancer patients aged up to 50 years: the Japanese Lung Cancer Registry Study 2004.

OBJECTIVE: The clinicopathological characteristics and surgical results of young lung cancer patients were investigated. MATERIALS AND METHODS: Seven hundred and four (6.0%) patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10,959 patients older than 50 years. This epidemiological study is based on the single year registration of surgically treated patients in the major institutes in Japan. RESULTS: The 5-year overall survival rate (5Y-OS) and the 5-year lung cancer-related survival rate was 79.2%/69.0% (p<0.001) and 81.3%/76.6% (p=0.005) in the young/old groups, respectively. In the young/old groups, lobectomy and pneumonectomy was performed in 76.9%/78.0% and 5.7%/3.2%, respectively; adjuvant therapies were given preoperatively in 10.4%/4.7% (p<0.001) and postoperatively in 31.4%/24.5% (p<0.001). The proportions of patients with p-stage IIIA (18.2%) and adenocarcinoma histology (78.7%) were higher in the young group. The 5Y-OS was 94.8%/86.2% for p-stage IA (p<0.001), 87.0%/73.2% for p-stage IB (p=0.001), 61.0%/61.6% for p-stage IIA (p=0.595), 71.0%/48.4% for p-stage IIB (p=0.003), 49.6%/39.4% for p-stage IIIA (p=0.020), and 80.0%/24.8% for p-stage IIIB (p=0.012); it was 83.5%/80.7% for females (p=0.106) and 75.1%/62.3% for males (p<0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was 17.9%/13.4% in the young/old groups (p=0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p=0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p=0.013). Age up to 50 years was identified as an independent better prognostic factor on multivariate analysis. CONCLUSIONS: The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years.

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.

Radiographically determined noninvasive adenocarcinoma of the lung: survival outcomes of Japan Clinical Oncology Group 0201.

OBJECTIVE: The study objective was to evaluate the long-term survival of patients with radiographically determined noninvasive lung adenocarcinomas. METHODS: A prospective, multi-institutional study on image diagnosis to define early (noninvasive) adenocarcinomas of the lung (Japan Clinical Oncology Group 0201) has shown that a consolidation/tumor ratio on thin-section computed tomography 0.25 or less in cT1a (≤2.0 cm) could be used as a better radiologic criterion for a noninvasive pathology than a consolidation/tumor ratio 0.50 or less in cT1a-b (≤3.0 cm). From the prognostic viewpoints, these criteria were evaluated for 545 patients with adenocarcinoma who underwent lobectomy and lymph node dissection. RESULTS: The subjects consisted of 233 men and 312 women with a median age of 62 years. The median follow-up period among overall patients was 7.1 years (range, 0-8.5 years). The overall and relapse-free 5-year survivals of the overall patients were 90.6% and 84.7%, respectively. When a consolidation/tumor ratio 0.5 or less in cT1a-b was used as a cutoff, the 5-year overall survivals of radiologic noninvasive (121 patients, 22.2%) and invasive (424 patients, 77.8%) adenocarcinomas were 96.7% and 88.9%, respectively, and the difference was statistically significant (P < .001, log-rank test). With the use of a consolidation/tumor ratio 0.25 or less in cT1a, the 5-year overall survivals of radiologic noninvasive (35 patients, 12.1%) and invasive (254 patients, 87.9%) adenocarcinomas were 97.1% and 92.4%, respectively, and the difference was not statistically significant (P = .259). CONCLUSIONS: The radiologic criteria of a consolidation/tumor ratio 0.25 or less in cT1a (≤2.0 cm) and 0.50 in cT1a-b (≤3.0 cm) were both able to define a homogeneous group of patients with an excellent prognosis before surgery.