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Background: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC., Patients and Methods: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR., Results: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity., Conclusions: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Nedaplatin and nab-paclitaxel are each efficacious in the treatment of squamous cell lung cancer., Patients and Methods: Eligibility criteria were: no prior chemotherapy, advanced squamous cell lung cancer; performance status 0-1, age > 20 years but < 75 years, and adequate hematologic, hepatic and renal function. Patients received escalating doses of nab-paclitaxel under a fixed dose of nedaplatin (100 mg/m 2 , day 1) every 3 weeks in phase I. The initial nab-paclitaxel dose was 100 mg/m 2 on days 1 and 8 (level 1), and the next dose was 100 mg/m 2 on days 1, 8, and 15 (level 2). In phase II, patients received the recommended doses. The primary endpoint was tumor response rate., Results: In phase I, three patients at level 1 experienced no dose-limiting toxicities (DLTs) and two patients at level 2 experienced DLTs. Level 1 was thus determined as the recommended dose. Twenty-three patients were enrolled in phase II. The 3 patients in level 1 and 23 patients in phase II were included together for analyses. Three of these 26 patients were excluded from response analysis due to pneumonia and patient refusal. Response rate was 91.3% (95% confidence interval, 72.0-98.9%). Toxicities observed during all cycles were tolerable., Conclusions: The recommended dose for this combination was nedaplatin at 100 mg/m 2 on day 1 and nab-paclitaxel at 100 mg/m 2 on days 1 and 8 every 3 weeks. The combination of nedaplatin and nab-paclitaxel appears safe and efficacious in patients with untreated advanced squamous cell lung cancer., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Dacomitinib is the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC). EGFR-TKIs are often re-administered in Japan after the disease progression prior EGFR-TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting., Methods: Patients who received dacomitinib for advanced EGFR-mutant NSCLC who had progressed after EGFR-TKI in nine institutions in Japan were included in the analyses., Results: In total, 43 patients were analyzed. The median progression-free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5-5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4-not reached). The overall response rate was 25.5% (95% CI, 13.1-33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis., Conclusion: In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR-TKI. The benefit was especially pronounced in patients with the exon 21 mutation., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

A 70-year-old woman with bilateral pleural effusion and respiratory failure was admitted to our hospital. Nephrotic syndrome due to minimal change disease had been diagnosed four months before admission. Because blood tests and a pleural fluid analysis did not reveal the etiology of her condition, we performed a video-assisted thoracoscopic pleural biopsy. No specific thoracoscopic findings were noted. The pathological findings revealed an increase in immunoglobulin G4 (IgG4)-positive cells; IgG4-related pleuritis was diagnosed. Her pleuritis improved with oral corticosteroid therapy. A further investigation was performed on previous kidney samples; however, the etiology of the nephrotic syndrome was not IgG4-related disease but minimal change disease.

Background: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC)., Methods: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m 2 was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety., Results: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed., Conclusion: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.

Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative-intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum-based chemotherapy were enrolled. The patients received S-1 orally twice daily at a dose of 40-60 mg/m 2 for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one-sided). Twenty-six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3-46.9) and an 80.8% disease control rate (90% CI, 65.4-90.3). The median PFS was 4.3 months (95% CI, 2.3-10.3 months) and median OS was 27.4 months (95% CI, 16.6-34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment-related death was observed. S-1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736)., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Cabozantinib inhibits tyrosine kinases including MET, AXL, VEGFR2, RET, KIT, and ROS1 and has demonstrated antitumor activity in multiple tumor types. The primary objective of this phase 1 study (NCT01553656) was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of cabozantinib in Japanese patients., Patients and Methods: Patients with advanced solid tumors were enrolled at 2 sites in Japan. After determining the MTD and RP2D, an expansion in non-small-cell lung cancer (NSCLC) consisting of 3 molecularly defined cohorts (EGFR mutation; KRAS mutation; ALK, RET, or ROS1 fusion) was initiated. The study was registered with ClinicalTrials.gov (NCT01553656)., Results: Forty-three Japanese patients were enrolled (dose escalation, n = 23; NSCLC expansion, n = 20). The MTD of cabozantinib capsules was 60 mg daily, and the RP2D of cabozantinib tablets was 60 mg daily. Dose-limiting toxicities were hypertension, proteinuria, and venous embolism. Safety and pharmacokinetics in Japanese patients were consistent with those in non-Japanese patients. Common adverse events included palmar-plantar erythrodysesthesia, hypertension, and diarrhea. Reduction in tumor lesion size was observed in multiple tumor types in the dose-escalation cohorts, with partial responses observed in 4 of 9 patients with NSCLC (EGFR mutation, n = 1; ALK fusion, n = 2; and RET fusion, n = 1). In the NSCLC expansion, 4 patients with EGFR-mutant NSCLC had partial responses; the remaining 16 (EGFR mutation, n = 11; KRAS mutation, n = 2; ALK fusion, n = 1; and RET fusion, n = 2) had stable disease as best response., Conclusion: Cabozantinib had a manageable safety profile in Japanese patients with solid tumors. Responses were observed in diverse molecular subtypes of NSCLC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice., Materials and Methods: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation., Results: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E., Conclusion: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Our case patient was a 38-year-old pregnant Japanese woman who underwent emergency Caesarean section because of massive vaginal bleeding due to a low-lying placenta. Immediately after delivery, she presented with rapidly progressive dyspnea. Contrast-enhanced computed tomography revealed bilateral pleural effusion, lung nodules, multiple liver tumors, and multiple osteolytic lesions. Accordingly, epidermal growth factor receptor-mutant advanced lung adenocarcinoma was diagnosed. This report highlights the occurrence of rapid progression of lung cancer following delivery that led to postpartum acute respiratory failure, rather than due to pulmonary thromboembolism associated with the existing deep venous thrombosis of the inferior vena cava.

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3+3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m 2 /day for QD, and 210.7 mg/m 2 /day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor.This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST., (©2019 American Association for Cancer Research.)

Objective: Netupitant is a novel, selective neurokinin-1 receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting, a distressing side effect of chemotherapy. This double-blind, randomized, Phase II study investigated the dose-response of oral netupitant in Japanese patients receiving highly emetogenic chemotherapy., Methods: Chemotherapy-naïve patients were randomized (1:1:1) to a single oral netupitant 30-, 100- or 300-mg dose before chemotherapy initiation. Patients received concomitant palonosetron (0.75 mg intravenously [i.v.] Day 1) and dexamethasone (9.9 mg i.v. Day 1, 8 mg orally Days 2-4)., Results: Overall, 402 patients (30 mg: 134; 100 mg: 135; 300 mg: 133) were treated and evaluable for efficacy and safety. The primary endpoint of overall (0-120 h after chemotherapy administration) complete response (CR) rate (no emesis, no rescue medication) was 64.2%, 60.0% and 54.9% in the 30-, 100- and 300-mg arms, respectively, without statistical significance for dose-response. The safety profile of netupitant was comparable in the three arms. The plasma concentrations of netupitant and its metabolites increased with the dose increase from 30 mg to 300 mg., Conclusions: No dose-response relationship of netupitant in terms of overall CR rate was observed in this study. Netupitant was well tolerated at all doses without clinically harmful safety signals observed., Clinical Trial Registration: JapicCTI-142 483.

Lynch syndrome is caused by mutations in mismatch repair genes that lead to microsatellite instability (MSI). An increased number of mutation-associated neoantigens have been observed in patients with high-frequency MSI (MSI-H) cancer; in addition, membranous programmed death ligand-1 (PD-L1) tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. MSI-H cancer patients are therefore considered to be susceptible to immune checkpoint blockade. We herein report for the first time a case of lung adenocarcinoma with Lynch syndrome and the response to nivolumab.

Background: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented., Patients and Methods: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics., Results: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%)., Conclusion: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC)., Methods: A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m 2 ). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1-4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24-120 h after the start of cisplatin treatment)., Results: 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3-83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2-90.7, P < 0.001) in the 5 mg group (P value for H 0 : complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively., Conclusions: Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates., Clinical Trial Information: UMIN000014214.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Because most lung cancers are diagnosed at advanced stages, we are forced to conduct molecular testing using small biopsy samples. Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is emerging as a minimally invasive biopsy technique. Here, we examined the usefulness of EBUS-TBNA to evaluate programmed death-ligand 1 (PD-L1) expression in lung cancer., Methods: Using 97 consecutive cases of lung cancer diagnosed by EBUS-TBNA, from which 20 transbronchial biopsy (TBB) samples were available, we evaluated the number and morphological intactness of tumor cells in EBUS-TBNA and TBB samples. Additionally, given the intratumoral heterogeneity in primary lesions and the small sample size of biopsies, we also compared the tumor PD-L1 expression between the biopsy samples and the corresponding surgical materials., Results: EBUS-TBNA collected a significantly larger number of tumor cells than TBB (P < .001); the median number (interquartile range) of cells was 1149 (379-3334) in EBUS-TBNA and 435 (218-1085) in TBB. The crush rate in EBUS-TBNA was significantly lower than in TBB (P < .001). These showed the excellence of EBUS-TBNA. Additionally, PD-L1 positivity of EBUS-TBNA showed a good concordance with the corresponding primary tumor (r = 0.75; P = .086; n = 6) as well as with lymph node metastasis (r = 0.93; P = .02; n = 5). Moreover, PD-L1 positivity between EBUS-TBNA and TBB (n = 16), TBB and the corresponding primary tumor (n = 41), and lymph node metastasis and the corresponding primary tumor (n = 47) showed a moderate correlation (all r > 0.48; all P < .001), strengthening the potential concordance between EBUS-TBNA and primary tumor in PD-L1 positivity., Conclusion: Our study suggests EBUS-TBNA as a promising method to evaluate PD-L1 expression in lung cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In patients with non-small-cell lung cancer harboring an epithelial growth factor receptor (EGFR) active mutation, central nervous system progression after a response to EGFR tyrosine kinase inhibitors is frequent. Central nervous system metastasis, especially leptomeningeal carcinomatosis (LMC), is a serious complication and no standard treatment has been established for LMC. Here, we report two cases in which the addition of bevacizumab to erlotinib enhanced the efficacy against LMC; as a result, radiographic abnormalities decreased markedly and symptoms were well controlled. This combination treatment may be useful to treat LMC in patients with EGFR-positive non-small-cell lung cancer.

Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib., Patients and Methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS., Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR., Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC)., Patients and Methods: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea)., Results: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369)., Conclusion: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point., Clinical Trial Registry Identifier: UMIN000004863., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome-wide methylation profile of SCLC. We investigated the genome-wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non-negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non-CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for treatment of the aggressive tumor., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC., Materials and Methods: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity., Results: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea., Conclusion: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Small-cell lung carcinoma (SCLC) is a type of lung cancer with neuroendocrine differentiation and a poor prognosis that is widely believed to arise in the central lung. Thyroid transcription factor-1 (TTF-1) is a peripheral marker of lung adenocarcinoma that is also highly expressed in SCLC. In this study, we examined whether SCLC is really a central-type tumor and the relationship between tumor location, TTF-1 expression and prognosis of SCLC.Ninety six SCLCs, diagnosed from biopsies or surgical materials, for which detailed computed tomography (CT) images were available, were collected consecutively from Japanese patients between 2004 and 2011. We examined the location of the primary tumor (central or peripheral) using thin-sliced CT, a TTF-1 immunohistochemical expression, and clinicopathology including prognosis.Of the 96 SCLCs, 74% (71/96) were of the peripheral type and found to have a significantly worse prognosis than central-type tumors. TTF-1 immunoreactivity was identified in 79 tumors (82%), 78% of which (62/79) were of the peripheral type and 22% of which were central. TTF-1 expression was significantly correlated with peripheral location (P = 0.030). Multivariate analysis revealed that high TNM stages and the peripheral location were independent markers for poor survival.The majority of SCLCs were of the peripheral type. The peripheral-type SCLC expressed TTF-1 more frequently and had a poorer prognosis than central-type tumors did. Further analysis on original sites of SCLC, using molecular methodology, or based on another ethnicity, should be warranted.

This study evaluated the prognostic value of positron emission tomography/computed tomography (PET/CT) using (18) F-fluoroazomycin arabinoside (FAZA) in patients with advanced non-small-cell lung cancer (NSCLC) compared with (18) F-fluorodeoxyglucose (FDG). Thirty-eight patients with advanced NSCLC (stage III, 23 patients; stage IV, 15 patients) underwent FAZA and FDG PET/CT before treatment. The PET parameters (tumor-to-muscle ratio [T/M] at 1 and 2 h for FAZA, maximum standardized uptake value for FDG) in the primary lesion and lymph node (LN) metastasis and clinical parameters were compared concerning their effects on progression-free survival (PFS) and overall survival (OS). In our univariate analysis of all patients, clinical stage and FAZA T/M in LNs at 1 and 2 h were predictive of PFS (P = 0.021, 0.028, and 0.002, respectively). Multivariate analysis also indicated that clinical stage and FAZA T/M in LNs at 1 and 2 h were independent predictors of PFS. Subgroup analysis of chemoradiotherapy-treated stage III patients revealed that only FAZA T/M in LNs at 2 h was predictive of PFS (P = 0.025). The FDG PET/CT parameters were not predictive of PFS. No parameter was a significant predictor of OS. In patients with advanced NSCLC, FAZA uptake in LNs, but not in primary lesions, was predictive of treatment outcome. These results suggest the importance of characterization of LN metastases in advanced NSCLC patients., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30 mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15 mg/kg) plus erlotinib (150 mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30 mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15 mg/kg every 21 days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.

Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 μmol/ml (3.5-34.6 μmol/ml). The pretreatment plasma homocysteine levels were above 11.5 μmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation.

A randomized Phase II dose-finding trial comparing olanzapine 10 mg with olanzapine 5 mg for patients receiving highly emetogenic chemotherapy with cisplatin was started in June 2014. The purpose of the trial is to evaluate the efficacy and safety of the two olanzapine doses and to determine which is more promising as a test arm for comparison with the current standard antiemetic care (a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone) in a subsequent Phase III trial. Patients receiving cisplatin-containing regimens will be randomized to the olanzapine 10 or 5 mg arm. A total of 150 patients will be accumulated from nine institutions over 2 years. The primary endpoint is complete response defined as no emetic episodes and no use of rescue medications in the delayed (24-120 h) phase. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000014214., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: This phase II study was conducted to evaluate the efficacy and safety of docetaxel and bevacizumab combination therapy in patients with previously-treated non-squamous non-small cell lung cancer (Nsq NSCLC)., Patients and Methods: Patients with histologically- or cytologically-confirmed Nsq NSCLC, 20-74 years of age, who had performance status 0-2, and had undergone at least one prior chemotherapy course were eligible for the study. Patients were treated with docetaxel (60 mg/m(2)) and bevacizumab (15 mg/kg) on day 1, which was repeated every three weeks until progressive disease or unacceptable toxicity occurred. The primary end-point was the response rate (RR) and the planned sample size was 28 patients., Results: Between May 2010 and July 2011, 28 patients were enrolled (16 males, 12 females; median age=65 years; performance status 0/1: 19/9; adenocarcinoma/other: 22/6; number of prior chemotherapy courses 1/2/3 or more: 16/5/7). Twenty-eight patients were included in the toxicity analysis, out of whom 27 were evaluable for response. Objective response was observed in 18 patients (partial response in 18, stable disease in 8, progressive disease in 1); the RR and disease control rates were 66.7% and 96.0%, respectively. The median follow-up was 23.9 months, median progression-free survival was 7.2 months, and median overall survival was 21.6 months. The main toxicity associated with this regimen was myelosuppression (grade 3/4 neutropenia: 82.1%; febrile neutropenia: 21%). Mild non-hematological toxicity was observed but there was no severe bleeding., Conclusion: The combination regimen of docetaxel-plus-bevacizumab is very active in patients with previously-treated Nsq NSCLC and warrants further research., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC., Methods: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients., Results: Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 μg/mL and AUC₂₄ was 4.29 μg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients., Conclusions: Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.

Background: Gefitinib and erlotinib are used to treat advanced non-small cell lung cancer (NSCLC). Gefitinib is a common first-line treatment, but most patients develop resistance. This phase II study evaluated the efficacy of erlotinib after acquired resistance to gefitinib., Patients and Methods: Between January 2008 and September 2009, we enrolled 50 patients with advanced NSCLC who had received one or more chemotherapy regimens, including gefitinib monotherapy to which they had partial responses (PR) or stable disease (SD). Erlotinib (150 mg) was administered until disease progression or unacceptable toxicity. Patients were 11 males, 39 females; median age 65 years (range=36-81 years); 46 with adenocarcinoma; performance status 0/1/2: 24/19/7; and smoking status, never/former/current: 33/15/2. Prior gefitinib response, PR/SD: 36/14. Median duration of prior gefitinib therapy was 419 days (range=63-1,540 days). Median interval after gefitinib therapy was 29 days (range=13-1,198 days)., Results: Of 47 patients on erlotinib, four showed PR and 29 showed SD [response rate, 8.5%; disease control rate (DCR), 70.2%]. DCR for patients who continued gefitinib treatment for more than one year was significantly higher (81.5%) than for patients who could not continue (57.1%; p=0.018); but was not affected by prior gefitinib response or treatment interval. Median tiMETo treatment failure: 100 days (95% confidence interval=90-110 days); median overall survival: 342 days (95% confidence interval=242-442 days). Rash (78%) and diarrhea (68%) were the most common adverse reactions; grade 5 pneumonitis occurred in one patient (2%)., Conclusion: Erlotinib treatment after gefitinib failure may prolong the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors treatment.

Objective: The role of platinum agents plus irinotecan has been unclear for elderly patients with extensive disease small-cell lung cancer. We conducted a feasibility study to evaluate the safety and efficacy of carboplatin plus irinotecan in preparation for a planned Phase III study., Methods: Based on another Phase I study, carboplatin area under the curve of four Day 1 plus irinotecan 50 mg/m(2) Days 1 and 8 every 3 weeks for four courses was administered. Patients aged ≥70 years with a performance status of 0-2 were eligible. The primary endpoint was feasibility, defined as the percentage of patients who have received three or more courses of chemotherapy. If the feasibility was ≥60% in the first 10 patients, this endpoint would be considered to be met., Results: Eleven patients were registered. The median age was 77 years, and nine patients had a performance status of 1. Ten patients completed four courses of treatment, and neither dose omission nor modification was required. The feasibility was 91% (10/11) and the relative dose intensity was 76.9%. Because neutropenia was frequently prolonged, the next course was delayed in 53% of all courses. Other toxicities were generally mild, and the only Grade 4 toxicity was hyponatremia. The overall response rate was 90% (9/10), and the progression-free survival and the overall survival were 5.1 and 10.9 months, respectively., Conclusions: This regimen appears to be feasible and effective. Based on these results, a Phase II/III trial comparing carboplatin plus etoposide with carboplatin plus irinotecan for elderly patients with extensive disease small-cell lung cancer is being planned by the Japan Clinical Oncology Group.

A secondary epidermal growth factor receptor (EGFR) mutation, the substitution of threonine 790 with methionine (T790M), leads to acquired resistance to reversible EGFR-tyrosine kinase inhibitors (EGFR-TKIs). A non-invasive method for detecting T790M mutation would be desirable to direct patient treatment strategy. Plasma DNA samples were obtained after discontinuation of gefitinib or erlotinib in 75 patients with non-small cell lung cancer (NSCLC). T790M mutation was amplified using the SABER (single allele base extension reaction) technique and analyzed using the Sequenom MassARRAY platform. We examined the T790M mutation status in plasma samples obtained after treatment with an EGFR-TKI. The SABER assay sensitivity using mixed oligonucleotides was determined to be 0.3%. The T790M mutation was detected in 21 of the 75 plasma samples (28%). The presence of the T790M mutation was confirmed by subcloning into sequencing vectors and sequencing in 14 of the 21 samples (66.6%). In this cohort of 75 patients, the median progression-free survival (PFS) of the patients with the T790M mutation (n = 21) was not statistically different from that of the patients without the mutation (n = 54, P = 0.94). When patients under 65 years of age who had a partial response were grouped according to their plasma T790M mutation status, the PFS of the T790M-positive patients (n = 11) was significantly shorter than that of the T790M-negative patients (n = 29, P = 0.03). The SABER method is a feasible means of determining the plasma T790M mutation status and could potentially be used to monitor EGFR-TKI therapy., (© 2013 Japanese Cancer Association.)

Background: Although pemetrexed/cisplatin (P-C) is a standard treatment for advanced non-squamous non-small cell lung cancer (Nsq-NSCLC), neither its efficacy nor the effects of potential differences between driver mutations, such as the anaplastic lymphoma kinase (ALK) translocation and epidermal growth factor receptor (EGFR) mutations, have been thoroughly examined., Patients and Methods: A single-arm phase II study of P-C was conducted in Japanese patients with chemo-naïve advanced Nsq-NSCLC. Patients received four cycles of pemetrexed (500 mg/m(2)) combined with cisplatin (75 mg/m(2)) on day 1 every three weeks. The primary end-point was the response rate (RR) and the secondary end-points were toxicity, progression-free survival (PFS), and overall survival (OS)., Results: A total of 50 patients were analyzed (males, 68%; adenocarcinoma, 80%). The RR was 44.0%. The median PFS and OS were 4.3 months and 22.2 months, respectively. Toxicities were mild, and no new toxicity profiles were identified. Among the 39 out of 50 samples, six (15.4%) presented ALK translocation and nine (23.1%) presented EGFR mutations; of the remaining patients, 24 (61.5%) were wild-type for both ALK and EGFR. Objective response was observed in two out of six patients with ALK translocations, six out of nine with EGFR mutations, and in 11 (45.8%) wild-type patients., Conclusion: The combination of pemetrexed and cisplatin was effective and safe in Japanese patients with Nsq-NSCLC. We did not observe obvious differences in the efficacy of P-C between patients with ALK translocation or EGFR mutation and those with wild-type genotype.

Purpose: To determine the recommended dose (RD) in concurrent conformal radiotherapy with S-1 and cisplatin chemotherapy for inoperable stage III non-small-cell lung cancer., Patients and Methods: Eligible patients with inoperable stage III non-small-cell lung cancer, age ≥ 20 years, performance status 0-1 received 4 cycles of intravenous cisplatin (60 mg/m(2), day 1) and oral S-1 (80, 100, or 120 mg based on body surface area, days 1-14) repeated every 4 weeks. Radiation doses were 66, 70, and 74 Gy for arms 1, 2, and 3, respectively., Results: A total of 24 patients were enrolled in our study, including 6 in arm 1, 6 in arm 2, and 12 in arm 3. The patients consisted of 14 men and 10 women, with a median age of 63 years (range, 44-73 years). The median follow-up was 27.3 months (range, 8.5-42.6 months) for all patients and 33.9 months (range, 15.2-42.6 months) for those still alive. Grade 3 febrile neutropenia, lung toxicities, and heart toxicities occurred in 2, 2, and 2 patients, respectively. Dose-limiting toxicity occurred in 2, none, and 1 patient in arms 1, 2, and 3, respectively. The median survival was not reached, and the 2-year survival rate was 70% (95% CI, 51%-89%). Two-year local relapse-free survival and distant metastasis-free survival were 74% (95% CI, 56%-92%) and 45% (95% CI, 25%-65%), respectively., Conclusions: High-dose radiotherapy with S-1 and cisplatin is feasible, and 74 Gy was determined as the recommended dose., (Copyright © 2013. Published by Elsevier Inc.)

S-1 is a new oral fluoropyrimidine derivative designed to enhance anticancer activity and reduce gastrointestinal toxicity. This phase II trial aimed to evaluate S-1 in patients with relapsed small cell lung cancer (SCLC). SCLC patients who had experienced treatment failure with ≥1 prior chemotherapies were eligible. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and adequate organ function. Treatment consisted of oral S-1 at 40 mg/m 2 twice/day for 28 days every 6 weeks. Twenty-six patients were enrolled, 85% of whom were males. The median age was 68 years (range, 33-79) and 81% of the patients had a performance status of 0-1, and 46% of the patients had relapse-sensitive SCLC. An objective response was obtained in only 1 patient (3.8%), and the median progression-free survival (PFS) was 1.1 months. The median overall survival was 5.3 months, and the 1-year survival rate was 23%. The most common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rash (7.7%), infection (7.7%) and diarrhoea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. In conclusion, S-1 has minimal single-agent activity in relapsed SCLC.

Although progastrin-releasing peptide (proGRP) is used as a serum tumor marker for small cell lung cancer (SCLC), high serum pro-GRP concentrations are observed in some non-small-cell lung cancers (NSCLCs). The characteristics of these NSCLCs are not well known. To determine the clinicopathological features of NSCLC in patients with elevated serum proGRP concentrations, serum proGRP values were assessed in 654 advanced lung cancer patients, and positive (>46pg/mL) NSCLC specimens were subjected to cytological and histopathological reevaluation. Serum proGRP concentrations were positive in 34 of 421 NSCLC patients (8.1%) and 186 of 233 SCLC patients (80%). Histological subtypes of the 34 NSCLC patients at diagnosis were 20 adenocarcinomas, 5 squamous cell carcinomas, 4 large cell carcinomas, and 5 large cell neuroendocrine carcinomas. Six of 27 cytology specimens contained characteristic neuroendocrine morphology. Immunohistochemical analysis showed that 11 of 17 tumors were positive for neuroendocrine markers (64.7%). Twenty of 34 serum proGRP-positive NSCLC patients received platinum-based chemotherapy, and the response rate was 55.0%. These results suggest that serum proGRP-positive NSCLCs may have neuroendocrine differentiation. In addition, serum proGRP-positive NSCLCs may have clinical characteristics that are different from other NSCLCs., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment., Methods: Eligibility criteria included histologically confirmed NSCLC, age range of 20-74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m(-2) and was escalated in patients by 25 mg m(-2) increments up to a maximum dose of 150 mg m(-2)., Results: Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45-75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0-1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32-82 days); median overall survival, 244 days (95% CI, 185-303 days); and 1-year survival rate, 32.6%., Conclusion: The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy.

Preliminary safety findings are presented from the open-label Phase I part of a combined Phase I/II study of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable Stage III non-small-cell lung cancer after primary chemoradiotherapy. Six patients received four or more once-weekly vaccinations with L-BLP25 1000 μg subcutaneously prior to a preliminary safety evaluation. Treatment continued with once-weekly vaccinations with L-BLP25 1000 μg subcutaneously until week 8, then maintenance vaccinations every 6 weeks until progressive disease. Cyclophosphamide (300 mg/m(2) i.v. single dose) was given 3 days before first vaccination. Median age was 63.5 years and performance status was 0-1. No serious adverse events occurred; none necessitated discontinuation. L-BLP25-related adverse events (Grade 1) were myalgia, arthralgia and nausea; cyclophosphamide-related adverse events comprised dysgeusia, anorexia and nausea. The first evaluation of L-BLP25 in Japanese patients shows that it is well tolerated, and the safety profile is consistent with that seen in previous studies of Caucasian patients.

A 56-year-old man was admitted, and was given a diagnosis of adenocarcinoma of the lung (T2N0M0, clinical stage IB), but pleural dissemination was found during surgery. A computed tomography (CT) scan 10 months after surgery revealed enlargement of the mediastinal lymph nodes and a thrombus in the pulmonary artery. Although the patient was immediately given warfarin and heparin, the warfarin was discontinued due to liver dysfunction, and the thromboembolism in his pulmonary artery recurred. The epidermal growth factor receptor (EGFR) mutation investigation of the surgical specimen revealed an EGFR point mutation at exon 21 (L858R). Gefitinib treatment was started and his levels of plasma D-dimer immediately decreased. The mediastinal lymph nodes shrank, and the thrombus in the pulmonary artery had disappeared on a CT scan 2 months after gefitinib treatment. Tumor regression was observed, and no recurrence of the pulmonary embolism was found 10 months after gefitinib treatment. Gefitinib was therefore a very effective treatment not only for lung cancer, but also for pulmonary embolism due to lung cancer.

Background: To assess the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation for unresectable stage III non-small-cell lung cancer (NSCLC)., Methods: Eligible patients were 20-74 years old and had histologically or cytologically confirmed NSCLC, a performance status of 0-1, and no prior chemotherapy. Patients were treated with cisplatin (60 mg m(-2) on day 1) and S-1 (orally at 40 mg m(-2) per dose, b.i.d., on days 1-14), with the treatment repeated every 4 weeks for four cycles. Beginning on day 2, a 60-Gy thoracic radiation dose was delivered in 30 fractions., Results: Of 50 patients, 48 were eligible. Partial response was observed in 42 patients (87.5%; 95% CI: 79.1-96.9%). This regimen was well tolerated. Common toxicities included grade 3/4 neutropenia (32%), grade 3/4 leukopenia (32%), grade 3/4 thrombocytopenia (4%), grade 3 febrile neutropenia (6%), grade 3 oesophagitis (10%), and grade 3 pneumonitis (5%). Median progression-free survival was 12.0 months and median overall survival was 33.1 months. The 1- and 2-year survival rates were 89.5 and 56%, respectively., Conclusion: This chemotherapy regimen with concomitant radiotherapy is a promising treatment for locally advanced NSCLC because of its high response rates, good survival rates, and mild toxicities.

Purpose: To investigate the activity of gemcitabine combined with irinotecan in patients with relapsed small cell lung cancer (SCLC)., Patients and Methods: SCLC patients who had experienced treatment failure with one prior chemotherapy were eligible. Patients were required to have a performance status of 0-2 and adequate organ function. Treatment consisted of gemcitabine (1,000 mg/m(2)) and irinotecan (150 mg/m(2)) on days 1 and 15 of a 28 day cycle., Results: Thirty-one patients were enrolled and 30 patients received protocol treatment (10 had refractory disease and 20 had sensitive disease). The median age was 64 years, and the median performance status was one. An objective response was obtained in 36.7% (95% CI: 17.3.1-56.0%) of the patients. The median overall survival time was 14.4 months, and the 1 year survival rate was 51%. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%)., Conclusion: Gemcitabine plus irinotecan is an active regimen that seems to be well-tolerated by patients with previously treated SCLC.