Masataka Hirabayashi

Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial

BackgroundElderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status.MethodsWe screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746–750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate.ResultsThe response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred.ConclusionsTreatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities.Trial registrationThis trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436.

A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index.

OBJECTIVE Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. METHODS A retrospective cohort study was performed in two hospitals in Japan (2007-13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. RESULTS A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624-0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725-0.874). CONCLUSIONS This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis.

External validation of prognostic indices for overall survival of malignant pleural mesothelioma

OBJECTIVE There are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM. MATERIALS AND METHODS A retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrells c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism. RESULTS The participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444-0.620), 0.560 (0.472-0.648), 0.584 (0.452-0.716), and 0.525 (0.453-0.596) for surgery; 0.632 (0.539-0.724), 0.622 (0.548-0.696), 0.677 (0.587-0.766), and 0.545 (0.436-0.653) for chemotherapy; and 0.504 (0.365-0.644), 0.583 (0.456--0.710), 0.704 (0.508-0.899), and 0.583 (0.436-0.730) for BSC. CONCLUSIONS Each PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC.

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study

INTRODUCTION Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. RESULTS Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). CONCLUSIONS Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumabs efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Pleural effusion biomarkers and computed tomography findings in diagnosing malignant pleural mesothelioma: A retrospective study in a single center

In this study, we aimed to examine the clinical value of the pleural effusion (PE) biomarkers, soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (CYFRA 21–1) and carcinoembryonic antigen (CEA), and the utility of combining chest computed tomography (CT) findings with these biomarkers, in diagnosing malignant pleural mesothelioma (MPM). We conducted a retrospective cohort study in a single center. Consecutive patients with undiagnosed pleural effusions who underwent PE analysis between September 2014 and August 2016 were reviewed. This study included 240 patients (32 with MPM and 208 non-MPM). SMRP and the CYFRA 21-1/CEA ratio had a sensitivity and specificity for diagnosing MPM of 56.3% and 86.5%, and 87.5% and 74.0%, respectively. Using receiver operating characteristics (ROC) curve analysis of the ability of these markers to distinguish MPM from all other PE causes, the area under the ROC curve (AUC) for SMRP and the CYFRA 21-1/CEA ratio was 0.804 and 0.874, respectively. The sensitivity and specificity of SMRP combined with the CYFRA 21-1/CEA ratio were 93.8% and 64.9%, respectively. The sensitivity of the combination of SMRP, the CYFRA 21-1/CEA ratio, and the presence of Leung’s criteria (a chest CT finding that is suggestive of malignant pleural disease) was 93.8%. In conclusion, the combined PE biomarkers had a high sensitivity for diagnosing MPM, although the addition of chest CT findings did not improve the sensitivity of SMRP combined with the CYFRA 21-1/CEA ratio. Combination of these biomarkers helped to rule out MPM effectively among patients at high risk of suffering MPM and would be valuable especially for old frail patients who have difficulty in undergoing invasive procedures such as thoracoscopy.

Acute onset collagenous colitis associated with protein‐losing enteropathy

Collagenous colitis is a cause of chronic diarrhea. We report an atypical case of collagenous colitis, presenting with an acute onset, and associated with protein‐losing enteropathy. An 82‐year‐old woman was admitted with a 1 week history of nausea, appetite loss, and diarrhea. Serum albumin level was low. Protein leakage from the small intestine was found by a Technetium‐99m human serum albumin scintigraphy. We diagnosed the patient with collagenous colitis from pathology findings of multiple biopsies taken from the colon. This case implies that collagenous colitis should be considered in acute watery diarrhea, and that it can cause protein‐losing enteropathy.

1558PA NEW PROGNOSTIC INDEX FOR OVERALL SURVIVAL IN MALIGNANT PLEURAL MESOTHELIOMA

ABSTRACT Aim: Existing prognostic indices for malignant pleural mesothelioma (MPM) do not incorporate recent advances in oncology care and were not based on real-world clinical data. This study aimed to provide a prognostic index for overall survival (OS) in MPM patients receiving chemotherapy with pemetrexed (CTx) or best supportive care (BSC) in a present, real-world setting. Methods: A retrospective cohort study was performed using MPM patients treated in two tertiary hospitals in Japan between 2007 and 2013. The prognostic index was developed using CTx patients, then diagnostic performance of the index was evaluated in both CTx and BSC patients. The primary outcome was OS. The Cox proportional hazards model was used for multivariable analyses to detect prognostic factors. A final model was chosen based on both clinical and statistical significance. Harrells c index was calculated to examine the discrimination of the model. The bootstrapping technique was used for internal validation. Results: Participants comprised 283 patients (CTx, n=228; BSC, n=55). On multivariate Cox proportional regression analysis, risk factors for poor prognosis of OS for CTx patients included performance status >0, non-epithelial histological type, and stage IV disease. Since hazard ratios of individual risk factors ranged from 1.81 to 2.07, a prognostic index for OS was constructed using a simple count of the number of risk factors (PHS index). Median OS in CTx patients was shortened by each 1-point increase in PHS index: 948 days (95% confidence interval (CI), 884–1012 days) for score 0; 544 days (95%CI, 526–561 days) for 1; 362 days (95%CI, 347–375 days) for 2; and 214 days (95%CI, 186–242 days) for 3. Internal validation showed the model was robust (c index, 0.670; 95%CI, 0.619–0.721). Median OS for each PHS index with BSC was: 573 days (95%CI, not evaluable (NE) - NE) for 0; 402 days (95%CI, 370–434 days) for 1; 94 days (95%CI, 82–105 days) for 2; and 34 days (95%CI, 15–52 days) for 3. Discrimination was consistent in BSC patients (c-index, 0.799; 95%CI, 0.725–0.874). Conclusions: This index will provide clinicians and patients with a better framework for discussing prognosis at the time of diagnosis. Disclosure: All authors have declared no conflicts of interest.