[Treatment outcome of latent tuberculosis infection in persons with fibrotic pulmonary lesions].

Objective　This study aimed to evaluate the treatment outcome of latent tuberculosis infection (LTBI) in persons with fibrotic pulmonary lesions, treated with isoniazid (INH) or rifampicin (RFP) in Nishinari Ward, Osaka City.Methods　As part of a tuberculosis screening program by chest X-ray (CXR), we selected persons who met the following four criteria for initiation of LTBI treatment:①Anti-tuberculosis treatment has not been performed for more than one month in the past. ②CXR shows fibrotic pulmonary lesions.③Fibrotic pulmonary lesions with CXR have not changed for more than one year.④QuantiFERON TB Gold-in-tube (QFT) shows positive values (≥0.35 IU/mL).　Before treatment, the blood samples were within the standard values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and serum creatinine. Treatment with INH was stopped when AST or ALT levels were elevated to more than 150 IU/L, or symptoms of liver dysfunction appeared even when AST or ALT levels were less than 150 IU/L. After liver dysfunction improved, treatment with RFP was started.　Treatment completion was defined as being dispensed with INH for ≥180 days or RFP for ≥120 days.Results　The 27 participants were all male and their age was 68.4±6.6 years. Of the 27 participants, 14 (51.9%) completed treatment with INH. Of the remaining 13 persons, nine (69.2%) stopped treatment with INH because of liver dysfunction. Nine restarted RFP treatment and all participants completed the treatment without interruption by liver dysfunction. In total, 23 (85.2%) completed the treatment.Conclusion　LTBI treatment with INH in persons with fibrotic pulmonary lesions in the area where people in financial need live was stopped because of liver dysfunction; however, changes from INH to RFP could improve treatment outcomes.

Molecular Epidemiological Study on Passive Smoking and Estrogen Receptor Expression in Never-smokers with Non-small Cell Lung Cancer.

Background: Although sex hormones are thought to play an important role in the carcinogenesis of non-small cell lung cancer (NSCLC) in never-smokers, the causative mechanism remains unknown. Passive smoking (PS) is common among East Asian women and has been suggested to be a potential cause of the disease. Methods: We systematically evaluated the expression of estrogen receptor (ER), the prevalence of PS, and genetic mutations using tumor samples from a prospectively registered cohort of never-smokers with lung cancer. The study enrolled 92 never-smokers with NSCLC. Expression of ERa, ERP, and progesterone receptor (PR) was examined via immunohistochemical staining (IHC). Detailed PS information was obtained through a standardized questionnaire. The cumulative dose of PS (CPS) was evaluated as a sum of the number of exposure years at home and/or in the work place. Results: Nuclear expression of ERa, ERP, and PR was detected in 0, 14, and 3 cases, respectively. ERP was more frequently overexpressed in earlier stage cancer (p=0.043). Ninety patients (97.9%) had a PS history, and the median CPS was 47.5 years (range, 0-103 years). There was no significant correlation between the amount of PS -and ERP expression (p=0.101). Twelve patients (85.7%) had Epidermal growth factor receptor ,EGFR) mutations in 14 .tumors expressing ERP, and a trend towards an association between ERP expression and EGFR mutations (p =0.067) was -observed. Conclusions: Nuclear expression of ERP was more frequently observed in early stage NSCLC in never-smokers.

The Macroscopic Appearance of Computed Tomography-guided Needle Biopsy Specimens Correlates with Tumor Metastasis in Non-small Cell Lung Cancer.

BACKGROUND: Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC). METHODS: A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis. RESULTS: In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026). CONCLUSIONS: These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.

Pulmonary Tuberculosis Incidence among Interferon-Gamma Release Assay-Positive Individuals with Latent Tuberculosis Infection and Fibrotic Lesions in a Vulnerable Urban Population in Osaka City, Japan, 2015-2021.

Latent tuberculosis infection (LTBI) with fibrotic lesions (FL) can progress to active tuberculosis (TB). Most previous studies have used tuberculin skin tests, which have lower specificity than interferon-gamma release assays (IGRAs), for LTBI diagnosis. This study evaluated the incidence of active TB among individuals with LTBI (diagnosed using IGRAs) and FL in Nishinari District, Osaka City. In total, 54 men (mean age: 68.7 years) were enrolled, of whom 10 (18.5%) were homeless, and 36 (66.7%) were welfare recipients. The median observation period was 1,084 days (range: 64-2,907 days). The incidence rate of active TB among individuals with LTBI and FL was 1.18 (95% confidence interval: 0.32-4.29) cases per 100 person-years. Among the 19 participants who had not been treated with anti-TB therapy, one (5.3%) progressed to active TB, and among the 30 participants who had completed anti-TB treatment, one (3.3%) progressed to active TB. The other 5 participants did not have TB. This study revealed the incidence of active TB among individuals with LTBI, diagnosed using IGRAs, and FL in a vulnerable urban population. The higher incidence than that reported in previous studies reinforces the importance of improved LTBI management strategies, including chest radiography screening, and LTBI treatment.

Reaction of plasma adiponectin level in non-small cell lung cancer patients treated with EGFR-TKIs.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used to treat advanced non-small cell lung cancer (NSCLC) patients with activated EGFR mutations, and are associated with excellent response and improvement of performance status. Adipose tissue produces and releases substances called adipokines, which include adiponectin, leptin, resistin, and hepatocyte growth factor (HGF), etc. Previously, we reported that high levels of plasma HGF at diagnosis indicated intrinsic resistance to EGFR-TKIs. EGFR-TKIs have been hypothesized to affect these adipokines. METHODS: This prospective study, to evaluate the correlation between plasma adiponectin and insulin levels and non-hematological adverse effects in advanced NSCLC following EGFR-TKIs administration, was conducted at the Osaka City University Hospital. Plasma adiponectin and insulin levels were determined at diagnosis and on treatment day 30. RESULTS: Overall 33 patients were enrolled. We obtained plasma samples for analyses from all patients at diagnosis and from 26 patients on day 30. Increased adiponectin (13.69 to 14.42 microg/mL, p = 0.0092), and decreased insulin (404.0 to 351.2 pg/mL, p = 0.022) were observed after EGFR-TKI treatments. High levels of adiponectin at diagnosis were associated with severities of skin rash (p = 0.035). CONCLUSIONS: The adiponectin was affected by EGFR-TKI treatments for NSCLC. Besides, the adverse events by EGFR-TKIs were influenced by the plasma adipokines at diagnosis. Our study may provide useful information regarding patient outcomes to EGFR-TKI treatments. A prospective large clinical trial is warranted to clarify these results.

Skeletal-related events in advanced lung adenocarcinoma patients evaluated EGFR mutations.

BACKGROUND: The rate of lung cancer metastasis to the bone is high and skeletal-related events (SREs) decrease the quality of life in many patients. Recently, it was found that a subgroup of patients with non-small cell lung cancer (NSCLC) have specific mutations in the EGFR (epidermal growth factor receptor) gene. We assessed the SREs in advanced lung adenocarcinoma patients that evaluated EGFR mutations in whom bone metastasis was present. METHODS: We retrospectively investigated the clinical records of 377 patients with advanced NSCLC. Patients were evaluated for the presence of EGFR mutations, bone metastases, the incidence of SREs, and treatment history before the first SRE. RESULTS: A total of 78 patients who were evaluated for EGFR mutations had bone metastasis from lung adenocarcinoma. The most frequent site of bone metastasis was the spine (36.2%). SREs occurred in 37 patients (47.4%), the most common of which was bone radiotherapy (41.0%). Significant differences were not observed in the sites of bone metastases or the patterns of SREs between patients with and without EGFR mutations. The median time from bone metastasis to the first SRE was 5.8 months in all of the subjects, history of EGFR-tyrosine kinase inhibitor (TKI) treatment was significantly associated with longer median time to first SRE (14.2 months vs 1.3 months, p < 0.0001), and the median time to first SRE of patients with PS 0-1 was longer (8.5 months vs 0.9 months, p = 0.0023). CONCLUSIONS: We found that SRE patterns have no difference between EGFR mutation positive and negative, and that the time from bone metastasis to the first SRE was longer in advanced lung adenocarcinoma patients with good PS and history of EGFR-TKI treatment.

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903).

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

Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer.

BACKGROUND: Rash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies. METHODS: The frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types. RESULTS: A total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21-0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17-1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52-2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54-6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21-7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20-5.07; *p = 0.93). CONCLUSIONS: The frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.

Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population.

BACKGROUND: Rash, liver dysfunction, and diarrhea are known as adverse events of erlotinib and gefitinib. However, clinical trials with gefitinib have reported different adverse events compared to those with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib and not of erlotinib. It has been hypothesized that gefitinib therapy results in different adverse events compared to erlotinib therapy. METHODS: The frequency of each adverse event was evaluated in a case-control study on Japanese patients who were treated with gefitinib or erlotinib. The CYP2D6 phenotype was categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of adverse events with each factor, including CYP2D6 activities as well as treatment types. RESULTS: A total of 112 patients received gefitinib therapy, 74 patients received erlotinib therapy, and 17 patients received erlotinib and gefitinib sequentially. The OR of developing rash with gefitinib versus erlotinib treatment was 0.38 (95% confidence interval [CI], 0.15-0.86). The OR of developing diarrhea with gefitinib versus erlotinib treatment was 0.46 (95% CI, 0.22-0.94). The OR of developing liver dysfunction with gefitinib versus erlotinib treatment was 3.30 (95% CI, 1.59-7.22). Reduced function of CYP2D6 was not associated with an increased risk of any adverse events in both gefitinib and erlotinib cohorts. CONCLUSIONS: Erlotinib had higher rate of rash and diarrhea than gefitinib. Liver dysfunction occurred significantly more often in the gefitinib group than in the erlotinib group.

[Carcinomatous meningitis in a post-operative patient with lung adenocarcinoma for which erlotinib was effective - a case report].

A 53-year-old female was admitted to our hospital complaining of disturbance of consciousness and hallucinations. About one year and 5 months ago she had adenocarcinoma of the lung, which was treated with surgery and chemotherapy. Computed tomography and magnetic resonance imaging revealed that her lung cancer had relapsed as caricinomatous meningitis and multiple lung metastases. She was treated with erlotinib, which rapidly resulted in disappearance of her symptoms. She still continues to receive erlotinib therapy without suffering from evident relapse 7 months after the initiation of the treatment.

Reaction of plasma hepatocyte growth factor levels in non-small cell lung cancer patients treated with EGFR-TKIs.

Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non-small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post-treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty-one patients were enrolled. Plasma hepatocyte growth factor levels on post-treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post-treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut-off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.

A phase II study of cisplatin and irinotecan as induction chemotherapy followed by concomitant thoracic radiotherapy with weekly low-dose irinotecan in unresectable, stage III, non-small cell lung cancer: JCOG 9706.

OBJECTIVE: It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. METHODS: Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m(2) on days 1 and 29, with irinotecan 60 mg/m(2) on days 1, 8, 15, 29, 36, and 43 and 30 mg/m(2) on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). RESULTS: From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2-75.9%). The median survival time was 16.5 (95% confidence interval, 12.6-19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4-77.1%) and 32.9% (95% confidence interval, 21.6-44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. CONCLUSIONS: Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.

Clinical outcome of amrubicin therapy according to the prior chemotherapy sensitivities of extensive small cell lung cancer.

BACKGROUND: Amrubicin (AMR) is an active agent for relapsed small cell lung cancer (SCLC). However, the activity of AMR in refractory relapsed patients is controversial. The objective of this retrospective analysis was to evaluate the efficacy and safety of AMR as second-line chemotherapy in SCLC, especially refractory relapsed SCLC. METHODS: Between July 2003 and February 2009, a total of 27 patients were treated with AMR at a dosage of 40 mg x m(-2) x day(-1) on days 1-3 every 3 weeks. Safety was assessable for all patients. Efficacy was evaluated in 26 patients (one patient was not assessable for response), in 12 patients with chemotherapy-sensitive relapse and 14 patients with chemotherapy-refractory relapse. Sensitive relapse means that a first-line response lasted more than 90 days. Refractory relapse means that either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days. RESULTS: Thirteen patients (50%, 95% CI, 31% to 69%) had partial response, including 6 (50%) of the 12 patients with chemotherapy-sensitive relapse and 7 (50%) of 14 patients with chemotherapy-refractory relapse. Median survival times of patients with chemotherapy-sensitive and -refractory relapse were 9.7 months and 8.4 months, respectively, showing significant difference (p = 0.0337). Adverse events were observed in all 27 patients. Grade 3 and 4 neutropenia was seen in 8 patients (29.6%) and 15 patients (55.5%), respectively. Grade 3 and 4 thrombocytopenia occurred in 10 patients (37.0%) and 2 patients (7.4%). Non-hematologic toxicities were generally mild, except for febrile neutropenia. Febrile neutropenia was seen in 6 patients (22.2%). No treatment-related deaths occurred. CONCLUSIONS: AMR is an active agent for the treatment of relapsed SCLC, especially chemotherapy-refractory relapse SCLC, with predictable and manageable toxicities.

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

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

An Exploratory Phase II Study of Eribulin Re-challenge After Short Term Therapy of 5-Fluorouracil for HER2 Negative, Advanced or Recurrent Breast Cancer.

BACKGROUND/AIM: In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration. RESULTS: Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports. CONCLUSION: In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report.

Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities.

Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m(2) on days 1-3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E(max) model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.

Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial.

AIM: This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. PATIENTS AND METHODS: Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. RESULTS: Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. CONCLUSION: Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage III Non-small Cell Lung Cancer: The Final Report.

OBJECTIVES: A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small cell lung cancer was conducted. MATERIALS AND METHODS: We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non-small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week. RESULTS: Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively. CONCLUSIONS: Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.