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The purpose of this review was to establish what cancer education programs have been carried out aimed at adolescents and young adults (AYAs) and what outcomes they achieved. The databases used were MEDLINE, CINAHL, and Web of Science, and the search period was set as 2011-2020. The extracted literature was evaluated for quality using the Joanna Briggs Institute's critical appraisal tools. The subjects of the analysis were 29 studies: 10 randomized controlled trials and 19 quasi-experimental designs. Regarding the varieties of cancers found in the data, in descending order, 10 documents looked at cervical cancer, 9 looked at cancer in general, and 4 looked at breast cancer. Most studies focused on AYAs exclusively, with just three studies involving their parents simultaneously. Many studies used lecture-based intervention, with information technology-based interventions using websites and cell phones. Topics included in the program were cancer epidemiology, cancer risk factors, cancer warning signs and symptoms, prevention methods, and screening methods. After the intervention, all studies showed statistically significant improvements in at least one outcome measure, which included knowledge and awareness of cancer, health beliefs, and intent to take preventive action, demonstrating a basis for educational intervention. Educating AYAs about cancer at a time when their ways of life are becoming more concrete can be expected to have a positive impact on cancer preventing behaviors in adulthood, increase their parents' awareness of cancer, and have a positive impact on behavior around screening.

Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation.Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation.MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively.No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.

BACKGROUND For epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), administration of EGFR tyrosine kinase inhibitors (TKIs) is mandatory to prolong survival. To date, a comparison of second- and third-generation EGFR-TKIs has not been reported as far as we are aware. PATIENTS AND METHODS We retrospectively investigated the survival time of patients diagnosed with EGFR-mutated advanced or recurrent NSCLC who had received afatinib, a second-generation EGFR-TKI, or osimertinib, a third-generation EGFR-TKI, as the first-line treatment. RESULTS Among the 49 patients included in the study, 15 received afatinib and 34 received osimertinib. No significant differences in overall survival were observed between the two groups [afatinib vs. osimertinib=36 vs. 33 months (hazard ratio=2.917, 95% confidence interval=0.780-10.905; p=0.112)]. T790M mutation was detected in three of the patients in the afatinib group, and all three subsequently received osimertinib. The median overall survival of these three patients and of the 12 without the mutation were 63 and 36 months, respectively. CONCLUSION There was no apparent difference in the effect on survival between second- and third-generation EGFR-TKIs, whereas the sequential administration of second- followed by third-generation EGFR-TKIs appeared to confer a better long-term prognosis.

Background Although immune checkpoint inhibitors (ICIs) have made an immense breakthrough in cancer therapeutics, they can exert unique, immune-related adverse events. Among them, myocarditis is less frequent, but it is serious and often follows a lethal course. Methods To examine the changes in cardiac autoimmunity after ICI administration, we developed a mouse experimental autoimmune myocarditis (EAM) model via intraperitoneal administration of murine α-cardiac myosin heavy chain (MyHC-α) fragment. Thereafter, the mouse anti-PD-1 antibody (mPD1ab) was administered at two time points, subsequent to and concurrent with MyHC-α fragment administration. Results Severe EAM developed in 3 weeks; wide inflammatory lesions were observed in the cardiac sections. Furthermore, inflammatory/fibrotic genes, such as interleukin 1β, interleukin 6, and collagen 1, were upregulated, although the cardiac function was not significantly affected. The subsequent administration of mPD1ab at 2 weeks post administration of the first MyHC-α fragment exacerbated EAM, whereas the administration of mPD1ab concurrent with MyHC-α fragment administration did not exacerbate EAM. The subsequent administration of mPD1ab significantly increased the infiltration of cluster of differentiation (CD)4- and F4/80-positive cells, whereas the concurrent administration of mPD1ab significantly decreased the infiltration of CD4-positive cells, indicating that the concurrent and subsequent administration of mPD1ab had opposite effects on immune/inflammatory cell infiltration. Conclusions These data suggest that the appearance of ICI-induced autoimmune myocarditis might be related to autoimmune system activity before ICI administration. Although ICIs do not adversely affect patients with normal immune systems, we propose that ICI administration should be avoided in patients with autoimmune disorders.

Lung cancer is the most common form of cancer in humans and the leading cause of cancer-related death worldwide. Traditionally, lung cancer has been diagnosed as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). However, recent developments in molecular pathology have revolutionized the diagnosis and treatment of the disease, thus improving patient prognosis and increasing the number of survivors. In advanced NSCLC cases, molecularly targeted drugs for patients with positive driver gene mutation/rearrangement, and immune checkpoint inhibitors for those with a positive biomarker, have changed the standard of care. SCLC is a highly malignant entity. In addition to the chemotherapy and radiotherapy, immune checkpoint inhibitors have recently provided some hope for extended-stage SCLC. Smoking cessation is related to decreased morbidity. However, early metastasis remains a significant challenge. Recently, cancer therapy-related cardiovascular disease (CTRCD) has emerged as diverse pathophysiology, including fulminant myocarditis, fatal arrhythmia, pericarditis, hypertension, and thrombosis, that emerged with modern lung cancer therapies. Cardio-oncology is a new interdisciplinary collaboration to develop methodologies to manage cardiovascular risk factors and CTRCDs with the common goal of minimizing unnecessary interruption of cancer treatment and maximizing outcomes of lung cancer survivors.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Objectives Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. Materials and Methods DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test. Results We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. Conclusion Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.

Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma.This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777.Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events.The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma.Center for Clinical Trials, Japan Medical Association.

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMIN000026777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

Purpose Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. Methods Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. Results A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1–13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79–373). Conclusion Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. Clinical trial registration JAPIC Clinical Trials Information; JapicCTI-121751. Electronic supplementary material The online version of this article (10.1007/s00280-018-3618-4) contains supplementary material, which is available to authorized users.

Lessons Learned The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. Background We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. Methods In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. Results In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2, one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2, determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%–74.7%), respectively. Conclusion Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.

Background Thymic carcinoma is a rare malignant disease. Standard treatments have not been established for patients with advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy. Several trials reported the efficacy of multi-targeted inhibitors mainly targeting vascular endothelial growth factor receptor (VEGFR) for thymic carcinoma. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, fibroblast growth factor receptor (FGFR), RET, c-Kit etc.; it has shown anti-tumor activity with manageable toxicity profiles in several cancer types. We investigated the efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma (JMA-IIA00285). Methods An open-label, single-arm, multi-center phase II trial was conducted in patients with histologically confirmed thymic carcinoma. The eligibility criteria were disease progression after at least one prior platinum-based chemotherapy, ECOG-PS of 0 or 1, measurable lesions, and adequate organ functions. Patients received 24 mg of lenvatinib orally once daily until progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR) by independent radiological review. As per the SWOG two-stage design, the sample size of 40 had 80% power with one-sided alpha error of 5%; threshold ORR, 10%; and expected ORR, 25%. Results Between May 2017, and Feb 2018, 42 patients were enrolled from 8 institutions in Japan. The median follow-up period was 15.5 months (IQR 13.1-17.5). The 42 assessable patients had ORR of 38.1% (90%CI, 25.6-52.0), indicating statistically significant improvement in ORR. Of them, 16 had partial response, and 24 achieved stable disease. The most treatment-related adverse events of any grade were hypertension, diarrhea, and hand-foot syndrome, proteinuria, hypothyroidism, and decreased platelet count. Conclusions The efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These encouraging results suggest that lenvatinib could become one of the standard treatment options in patients with advanced or metastatic thymic carcinoma. Clinical trial identification JMA-IIA00285. Legal entity responsible for the study The authors. Funding Center for Clinical trials, Japan Medical Association and Eisai. Disclosure M. Satouchi: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Ignyta. J. Sato: Speaker Bureau / Expert testimony: AstraZeneca K.K.. Y. Okuma: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Pharmaceutical Company Ltd; Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Nippon Boehringer Ingelheim Co.; Speaker Bureau / Expert testimony: Bristol‐Myers Squibb Japan; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical.. S. Niho: Research grant / Funding (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. H. Mizugaki: Speaker Bureau / Expert testimony, Research grant / Funding (self): Boehringer Ingelheim; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Chugai Pharmaceutical. H. Murakami: Honoraria (self): AstraZeneca; Honoraria (self): Chugai pharma; Honoraria (self): Lilly Japan; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim. T. Kozuki: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical ; Honoraria (self), Research grant / Funding (self): Eli-Lilly; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical ; Honoraria (self): Ono Pharmaceutica; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): Beohringer-Ingelheim; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self): Pfizer; Research grant / Funding (self): Merck Biopharma. K. Nakamura: Speaker Bureau / Expert testimony: Eisai. A. Kuchiba: Speaker Bureau / Expert testimony: Chugai. N. Yamamoto: Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai; Advisory / Consultancy, Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa-Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Advisory / Consultancy: Otsuka; Advisory / Consultancy: Cimic. All other authors have declared no conflicts of interest.

This subgroup analysis of ASCEND-5 study demonstrated better efficacy of ceritinib compared with the standard second-line chemotherapy in chemotherapy- and crizotinib-pretreated Japanese patients with ALK-rearranged NSCLC., Background In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator’s choice], every 21 days). Results Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3–14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4–3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. Conclusions Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. ClinicalTrials.gov identifier NCT01828112

Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m2). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)

We report a rare case of large cell neuroendocrine carcinoma (LCNEC) of the lung with cancer-associated retinopathy (CAR). To our knowledge, only two cases of LCNEC with CAR have been reported, one in 1995 and another in 2013. CAR, typically associated with small cell lung cancer (SCLC), is one of the paraneoplastic syndromes with deterioration of visual acuity, visual field constriction, and photophobia. CAR is caused by an autoimmune system reaction against the same antigen in the tumor and retinal photoreceptor cells. To diagnose CAR, genetic retinal dystrophies or any other medical causes of retinopathy should be excluded, but there are no standard diagnostic criteria. Anti-retinal antibodies are known to be positive in CAR patients, and anti-recoverin antibodies are thought to be sensitive and specific to CAR. In our case, anti-recoverin antibodies were not detected by serum tests, but CAR could be diagnosed on the basis of ophthalmological findings including clinical symptoms, electroretinographic findings, and visual field tests. CAR with clinical features of rapid visual disorder should be considered in LCNEC patients as well as in SCLC patients.

Background: We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane. Method: Patients aged 20–74 years were recruited. In level 1, patients received S-1 (65 mg m−2) from day 1 to 14, and eribulin (1.1 mg m−2) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m−2. In level 3, S-1 was increased to 80 mg m−2. Results: Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m−2 and S-1 65 mg m−2). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure. Conclusion: Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.

SummaryAmatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m2. Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m2 and one at 200 mg/m2; the maximum tolerated dose of this study was determined to be 200 mg/m2. Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m2. The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

Background AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. Methods Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m2 (on days 1, 8 and 15 of a 28-day cycle). Results Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade ≥3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. Conclusion Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.

Purpose To determine ombrabulin’s maximum tolerated dose and dose recommended for Japanese patients with advanced solid tumors and to assess its antitumor activity and overall safety and pharmacokinetic profiles. Methods This was a multi-center, open-label, sequential-cohort, dose-escalation phase I study of ombrabulin, a vascular disrupting agent, administered once every 3 weeks. Patients were treated with 15.5, 25, 35, or 50 mg/m2 ombrabulin over a 30-min intravenous infusion. The recommended dose was the highest dose at which

Background: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. Methods: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. Results: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ⩾3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (⩾24 weeks) were reported. Conclusion: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.

Erythropoiesis‐stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data‐based meta‐analysis of three randomized, placebo‐controlled trials studying Japanese patients with chemotherapy‐induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29–0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75–1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA‐treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA‐treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy‐induced anemia.

Cushing's syndrome due to young small-cell lung cancer (SCLC) is recognized as being extremely rare. We herein present the case of a 35-year-old nonsmoking man who presented with thirst and polyuria. Laboratory examinations showed hyperglycemia, hypokalemia and liver enzyme elevation. Imaging examinations revealed the presence of multiple liver tumors and lymph node swelling. The levels of serum neuroendocrine tumor markers were elevated. The patient was diagnosed with SCLC based on the pathological examination of a biopsy specimen from the right supraclavicular lymph node. The physical findings, including proximal myopathy, truncal obesity and pigmentation suggested high levels of glucocorticoids. An immunohistochemical examination of the tumor showed that it was positive for adrenocorticotropin (ACTH). An endocrinological investigation allowed for the definitive diagnosis of SCLC with ectopic ACTH production.

Background Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies. Methods This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated. Results A total of 12 patients received saracatinib at doses of 50 (n = 3), 125 (n = 6), and 175 mg (n = 3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67 %), nausea (67 %), decreased appetite (58 %), lymphopenia (50 %) and pyrexia (50 %). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17 %). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased (n = 1); and grade 3 hypoxia (n = 1). Following a single dose, saracatinib median tmax across the doses was 2–4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8–2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n = 2; 125 mg, n = 1). Conclusions Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg.

Background: Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism. The ESA labelling was thus revised in Europe and the United States in 2008. This is the first randomised, phase III trial evaluating the efficacy and safety of epoetin-β (EPO), an ESA, dosed in accordance with the revised labelling, which specifies that ESAs should be administered to CIA patients with a haemoglobin level of ⩽10 g dl–1 and that a sustained haemoglobin level of >12 g dl–1 should be avoided. Methods: A total of 186 CIA patients (8.0 g dl–1⩽ haemoglobin ⩽10.0 g dl–1) with lung or gynaecological cancer were randomised to receive EPO 36 000 IU or placebo weekly for 12 weeks. Results: The proportion of patients receiving transfusions or with haemoglobin

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

The aim of this study was to investigate the safety and pharmacokinetics of motesanib (AMG 706), a small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and c-Kit in Japanese patients with advanced solid tumors. Patients were administered motesanib orally once daily (QD) at doses of 50, 100, and 125 mg QD. The total study duration for each patient consisted of three cycles of 28 days per cycle. The primary endpoints were the incidence of dose-limiting toxicities (DLTs), estimation of the maximum tolerated dose (MTD), and assessment of pharmacokinetic parameters of motesanib. Fifteen patients were enrolled and received motesanib. No DLTs were observed and, therefore, the MTD was not reached. Motesanib had acceptable toxicity at doses up to 125 mg QD. The pharmacokinetics of motesanib appears to be dose proportional. No objective responses per RECIST were observed. However, all 15 patients achieved stable disease, and five patients had durable (>24 weeks) stable disease. The results of this study demonstrate that motesanib is tolerable in Japanese patients at doses up to 125 mg QD.

We report a case of acute respiratory distress syndrome caused by uropathogenic Escherichia coli induced sepsis and treated successfully. A 56-year-old women admitted for high-fever, dyspnea, and disturbance of consciousness on September 11, 2006, was found in chest computed tomography (CT) on admission to have diffuse infiltration with bilateral pleural effusion. Abdominal CT on admission showed left hydronephrosis complicated with ureteral stones. Because of severe hypoxemia, mechanical ventilation was started from hospital day 1. She went into shock soon after admission. Under mechanical ventilation, she was administered several antibiotics and dopamine. Because sera endotoxins were elevated, she was treated by endotoxin adsorption therapy on hospital day 3. A urethral stent was indwelled in the ureter for drainage after endotoxin adsorption therapy. Because Escherichia coli was isolated from urine and blood cultures, she was diagnosed with acute respiratory distress syndrome (ARDS) caused by E. coli inducing septic shock. After therapy, her condition improved, and she was extubated on hospital day 9. Extracorporeal shock wave lithotripsy was conducted on hospital day 19 and she was discharged.

The objectives of this phase I dose-finding study of erlotinib were to investigate the toxicity profile, to confirm the acceptable toxicity of doses up to 150 mg/day, and to assess the pharmacokinetic (PK) profile and antitumor activity in Japanese patients with solid tumors.Patients with solid tumors not amenable to standard forms of treatment were included. Treatment cycle 1 consisted of single-dose administration on day 1, withdrawal on day 2, continuous daily administration from days 3-23, and withdrawal from days 24-30. Subsequent cycles (28 days) used continuous daily administration. The dose of erlotinib was escalated from 50 mg/day to 150 mg/day in 50-mg increments. PK evaluation was performed in all patients during cycle 1.Fifteen patients, aged 38-70 (median; 57) years with non-small-cell lung (n = 11), colorectal (n = 3) or head and neck (n = 1) cancer were enrolled. The major toxicities were rash, diarrhea and liver dysfunctions, which were generally mild and easily manageable. The good tolerability of erlotinib up to the dose of 150 mg/day was confirmed. One patient developed grade 5 treatment-related interstitial pneumonitis. Four of 11 evaluable patients achieved partial responses; all four had non-small-cell lung cancer (NSCLC). The peak plasma concentration of erlotinib, and the area under the concentration-time curve increased proportionally to the dose, suggesting linear PK.The recommended dose of erlotinib in Japanese patients is 150 mg/day. Further trials in Japanese NSCLC patients are warranted.

Pegylated liposomal doxorubicin (PLD, JNS002) is a formulation of doxorubicin encapsulated polyethylene-glycol coated liposomes with prolonged circulation time and unique toxicity profile. This phase 1 study was aimed at investigating the maximum tolerated dose (MTD), recommended dose, toxicity, pharmacokinetics, and antitumor activity in Japanese patients with solid tumors.Patients with solid tumors not amenable to standard forms of treatment were eligible. PLD was administered as an intravenous infusion every 4 weeks. Dose escalation of PLD was planned from 30 to 60 mg/m(2) in 10 mg/m(2) increments. The pharmacokinetics of total doxorubicin (encapsulated plus non-encapsulated) in plasma were examined for the first cycle of treatment.Fifteen patients, aged 49-69 (median; 56) years with advanced solid tumors were enrolled. The major non-hematological toxicities were hand-foot syndrome (HFS), rash and stomatitis. Myelosuppression, especially leukopenia and neutropenia were major hematological toxicities. Although HFS was not severe, a delay of doses for subsequent cycles was required with multiple dosing. The peak plasma concentration and the area under the concentration time curve of PLD increased proportionally to the dose. Objective response was observed in one patient and the normalization of tumor marker values in another. These two patients had been diagnosed with ovarian cancer.The recommended dose for phase 2 clinical studies of PLD in Japanese patients was 50 mg/m(2) every 4 weeks. The encouraging results prompted us to plan a subsequent clinical study of PLD against ovarian cancer.

Background To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. Methods Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. Results Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. Conclusions Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

肺がん個別検診は, 単なる肺癌早期発見のための手段としてだけでなく, 検診参加医に肺癌発見のためのノウハウを広げる絶好の機会であり, その結果として地域の肺癌患者の予後を改善できる可能性がある. この間接的な波及効果を検証するために1985年から1996年までの12年間を, 高槻市・島本町 (T/S地域) において肺がん個別検診が安定して運営されるようになった1991年以後 (後期) とそれ以前 (前期) にわけて, 同地域の肺癌死亡率を周辺3市 (I/S/H地域) を対照として比較検討した. その結果, 前期では10万人あたりの肺癌死亡率はT/S地域, I/S/H地域それぞれ37.0人と37.0人で全く同一であった (p=0.9787) が, 後期にはそれぞれ45.8人, 51.2人となり有意にT/S地域の方が低かった (p=0.0233). 近接した地域における肺癌罹患率が局地的に, わずか12年間の観察期間中に有意に低下するとは考えにくく, この死亡率の低下は高槻市・島本町における肺癌発見に関わる診療レベルが向上していることを示唆している. 同地域の肺がん個別検診事業が1991年にほぼ確立され, 運営されてきたことから, この診療レベルの向上が個別検診の波及効果によってもたらされた可能性が高い. 肺癌発見のためのノウハウを検診参加施設に広め, 診療レベルを向上させるという波及効果を目標の一つとして, 肺がん個別検診を企画し評価するべきである

We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC).Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose.Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%.This combination was well-tolerated and manifested a promising activity against HNSCC.

e20042Background: Concurrent platinum-based chemotherapy with thoracic radiation therapy (TRT) is well established with standard therapy in locally advanced NSCLC pts. Nanoparticle albumin-bound pa...

Neuropathic pain frequently occurs in cancer patients, but no drug therapy has been established for this type of disorder. The purpose of this study was to investigate the effect of duloxetine in cancer patients suffering from neuropathic pain.The subjects of the study were 15 cancer patients with neuropathic pain who visited the Kinki University Faculty of Medicine Hospital and met the International Association for the Study of Pain diagnostic criteria for neuropathic pain. Duloxetine was administered to patients in whom pregabalin could not be administered. The influence of duloxetine was investigated retrospectively with the use of a numerical rating scale.Pain was reduced in 7 out of the 15 patients. Sleepiness and the light-headed feeling were improved in four patients, in whom, however, the pain was not reduced. Thus, duloxetine was judged to be effective in 11 patients. The maintenance dose of duloxetine was 20-40 mg/day.Duloxetine administration may be effective for neuropathic pain in cancer patients who cannot tolerate pregabalin administration.