Phase I/II study of nedaplatin and nab-paclitaxel for patients with previously untreated advanced squamous cell lung cancer: Kanto Respiratory Disease Study Group (KRSG) 1302.

BACKGROUND: Nedaplatin and nab-paclitaxel are each efficacious in the treatment of squamous cell lung cancer. PATIENTS AND METHODS: Eligibility criteria were: no prior chemotherapy, advanced squamous cell lung cancer; performance status 0-1, age > 20 years but < 75 years, and adequate hematologic, hepatic and renal function. Patients received escalating doses of nab-paclitaxel under a fixed dose of nedaplatin (100 mg/m2, day 1) every 3 weeks in phase I. The initial nab-paclitaxel dose was 100 mg/m2 on days 1 and 8 (level 1), and the next dose was 100 mg/m2 on days 1, 8, and 15 (level 2). In phase II, patients received the recommended doses. The primary endpoint was tumor response rate. RESULTS: In phase I, three patients at level 1 experienced no dose-limiting toxicities (DLTs) and two patients at level 2 experienced DLTs. Level 1 was thus determined as the recommended dose. Twenty-three patients were enrolled in phase II. The 3 patients in level 1 and 23 patients in phase II were included together for analyses. Three of these 26 patients were excluded from response analysis due to pneumonia and patient refusal. Response rate was 91.3% (95% confidence interval, 72.0-98.9%). Toxicities observed during all cycles were tolerable. CONCLUSIONS: The recommended dose for this combination was nedaplatin at 100 mg/m2 on day 1 and nab-paclitaxel at 100 mg/m2 on days 1 and 8 every 3 weeks. The combination of nedaplatin and nab-paclitaxel appears safe and efficacious in patients with untreated advanced squamous cell lung cancer.

Clinical Outcomes of Postoperative Adjuvant Chemotherapy for Surgically Resected High-Grade Pulmonary Neuroendocrine Carcinoma.

INTRODUCTION: Data on the clinical outcomes of patients receiving adjuvant chemotherapy for surgically resected high-grade pulmonary neuroendocrine carcinoma (HGNEC) (large-cell neuroendocrine carcinoma and small-cell lung cancer) are limited. This study aimed to evaluate the prognostic significance of adjuvant chemotherapy in patients with HGNEC. METHODS: We retrospectively analyzed patients with surgically resected HGNEC at five institutions in Japan between January 2006 and May 2016. RESULTS: A total of 143 patients were enrolled. Among them, 65 received adjuvant chemotherapy. Four patients who participated in clinical trials were excluded; the remaining 61 patients were included in the study. Fifty-six patients received adjuvant small-cell lung cancer-based chemotherapy. Twenty-five of 29 patients who relapsed after postoperative adjuvant chemotherapy received chemotherapy. The most commonly administered chemotherapy agent was amrubicin. The 3-year relapse-free and overall survival rates were 55.2% and 66.8%, respectively. The median relapse-free and overall survival times for the 25 patients who received chemotherapy after relapse were 12.9 and 27.5 months, respectively. Among them, 22 relapsed within 2 years. Patients who received platinum-doublet chemotherapy after relapse tended to have better time to progression disease and overall survival than those who received single-agent chemotherapy. CONCLUSIONS: Most patients with HGNEC received small-cell lung cancer-based regimens as postoperative adjuvant chemotherapy. Those who relapsed after adjuvant chemotherapy were mainly treated with amrubicin. Our findings suggest that platinum-doublet chemotherapy tends to improve the time to progression disease and overall survival in patients who relapse after postoperative adjuvant chemotherapy.

Clinical Significance of Tumor Markers for Advanced Thymic Carcinoma: A Retrospective Analysis from the NEJ023 Study.

The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan-Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05-2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31-3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Effectiveness and Safety of EGFR-TKI Rechallenge Treatment in Elderly Patients with Advanced Non-Small-Cell Lung Cancer Harboring Drug-Sensitive EGFR Mutations.

Background and Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-small-cell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75-87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients.

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (Ctrough) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the Ctrough of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.

Prognostic value of morphological characteristics assessed by CT scan in patients with non-small cell lung cancer treated with nivolumab.

BACKGROUND: Nivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non-small cell lung cancer (NSCLC) patients. Programmed death-ligand 1 (PD-L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown. METHODS: We performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground-glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes. RESULTS: A total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS). CONCLUSIONS: Interstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Interstitial septal thickening is an independent predictor of progression free survival in non-small lung cancer patients treated with nivolumab. WHAT THIS STUDY ADDS: The current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non-small cell lung cancer patients.

Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC. METHODS: Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated. RESULTS: Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR. CONCLUSIONS: Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.

Definitive Local Therapy for Oligo-recurrence in Patients With Completely Resected Non-small Cell Lung Cancer.

BACKGROUND: The aim of this study was to elucidate a curable subgroup among patients with non-small cell lung cancer (NSCLC) who developed postoperative recurrence. PATIENTS AND METHODS: Between 1986 and 2012, among the 1408 patients who underwent complete anatomic lung resection for NSCLC at our institution, 420 developed recurrence. After excluding 14 patients with insufficient information about recurrence, 406 were included in this retrospective study. We investigated the association between several clinicopathologic factors and postrecurrence overall survival (PR-OS) and postrecurrence progression-free survival (PR-PFS). RESULTS: The 5-year PR-OS and PR-PFS rates were 14.0% and 5.9%, respectively. By multivariate analysis, female sex, longer disease-free interval, specific targeted therapy, recent recurrence, oligo-recurrence, and definitive local therapy (DLT) were found to be independent favorable prognostic factors for both PR-OS and PR-PFS. Among these 6 prognostic factors, although female sex, longer disease-free interval, and specific targeted therapy were associated with a prolonged median PR-PFS time, they were not associated with an improved 5-year PR-PFS rate. In contrast, recent recurrence, oligo-recurrence, and DLT were associated with improvement in both the median PR-PFS time and 5-year PR-PFS rate. CONCLUSIONS: We found that recent recurrence, oligo-recurrence, and DLT were associated with an improved median PR-PFS time and long-term PR-PFS rate in patients with postoperative recurrence after complete resection of NSCLC. On the basis of these results, we believe that DLT should be considered first for patients with oligo-recurrence before applying noncurative treatment.

Efficacy and safety of first-line pembrolizumab monotherapy in elderly patients (aged ≥ 75 years) with non-small cell lung cancer.

PURPOSE: Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75 years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1. METHODS: A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded. RESULTS: Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88) years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0 months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS. CONCLUSIONS: Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.

Topotecan monotherapy for the treatment of relapsed small cell lung cancer in elderly patients: A retrospective analysis.

BACKGROUND: Topotecan is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). However, its efficacy in elderly patients with SCLC has not been validated. This study evaluated the feasibility and efficacy of topotecan monotherapy in elderly patients with relapsed SCLC. METHODS: Between January 2000 and March 2017, 43 patients aged ≥ 70 years received topotecan monotherapy for relapsed SCLC at four institutions. The clinical outcomes and adverse events of treatment were retrospectively analyzed. RESULTS: Twenty-nine patients (median age 75 years; range: 70-83 years) had sensitive-type relapse, while 14 (median age 78 years; range: 71-82 years) had refractory relapse. The median number of treatment cycles was two (range: 1-6). The response rate was 7.0% (10.3% and 0% in sensitive and refractory patients, respectively), while the disease control rate was 23.2% (20.6% and 42.8% in sensitive and refractory patients, respectively). Median progression-free survival was 1.9 months in sensitive patients and 1.4 months in refractory patients (P = 0.87). The median survival time from the start of topotecan therapy was 5.5 months in sensitive patients and 4.0 months in refractory patients (P = 0.64). Grade ≥ 3 hematological toxicities were as follows: leukopenia, 37.2%; neutropenia, 51.1%; anemia, 0%; thrombocytopenia, 32.5%; and febrile neutropenia, 9.3%. No treatment-related deaths occurred. CONCLUSION: Although hematological toxicities (particularly neutropenia) were severe, topotecan showed favorable disease control in both sensitive and refractory patients. Topotecan may thus be a preferred treatment for elderly patients with relapsed SCLC.

Clinical Impact of Post-Progression Survival on Overall Survival in Elderly Patients with Non-Small-Cell Lung Cancer Harboring Sensitive EGFR Mutations Treated with First-Line EGFR Tyrosine Kinase Inhibitors.

BACKGROUND/AIMS: More than 50% of patients with lung cancer are aged > 65 years, and non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer among both elderly and adult patients. Subsequent therapies confound the capability to discern the effect of first-line chemotherapy on overall survival (OS). Therefore, using individual-level data, our study aimed to determine the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients with NSCLC harboring sensitive EGFR mutations. METHODS: Between April 2008 and December 2015, we analyzed 68 elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. The relationships of PFS and PPS with OS were analyzed at an individual level. RESULTS: Linear regression analysis showed that PPS was more closely associated with OS (R2 = 0.54) than PFS was (R2 = 0.48). Best response at first-line treatment, performance status at the end of first-line treatment, and administration of EGFR-TKI rechallenge were significantly correlated with PPS. CONCLUSIONS: PPS has a stronger impact on OS than PFS does in elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. These results indicate that OS in this patient population may be influenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified in prospective studies.

Efficacy and safety of cytotoxic drug chemotherapy after first-line EGFR-TKI treatment in elderly patients with non-small-cell lung cancer harboring sensitive EGFR mutations.

PURPOSE: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is effective as first-line chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive EGFR mutations. However, whether the efficacy of second-line cytotoxic drug chemotherapy after first-line EGFR-TKI treatment is similar to that of first-line cytotoxic drug chemotherapy in elderly patients aged ≥ 75 years harboring sensitive EGFR mutations is unclear. Therefore, we aimed to investigate the efficacy and safety of cytotoxic drug chemotherapy after first-line EGFR-TKI treatment in elderly patients with NSCLC harboring sensitive EGFR mutations. METHODS: We retrospectively evaluated the clinical effects and safety profiles of second-line cytotoxic drug chemotherapy after first-line EGFR-TKI treatment in elderly patients with NSCLC harboring sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Between April 2008 and December 2015, 78 elderly patients with advanced NSCLC harboring sensitive EGFR mutations received first-line EGFR-TKI at four Japanese institutions. Baseline characteristics, regimens, responses to first- and second-line treatments, whether or not patients received subsequent treatment, and if not, the reasons for non-administration were recorded. RESULTS: Overall, 20 patients with a median age of 79.5 years (range 75-85 years) were included in our analysis. The overall response, disease control, median progression-free survival, and overall survival rates were 15.0, 60.0%, 2.4, and 13.2 months, respectively. Common adverse events included leukopenia, neutropenia, anemia, thrombocytopenia, malaise, and anorexia. Major grade 3 or 4 toxicities included leukopenia (25.0%) and neutropenia (45.0%). No treatment-related deaths were noted. CONCLUSION: Second-line cytotoxic drug chemotherapy after first-line EGFR-TKI treatment among elderly patients with NSCLC harboring sensitive EGFR mutations was effective and safe and showed equivalent outcomes to first-line cytotoxic drug chemotherapy.

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

A retrospective study of amrubicin monotherapy for the treatment of relapsed small cell lung cancer in elderly patients.

PURPOSE: Amrubicin is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). Previous studies reported its effectiveness and severe hematological toxicity. However, the efficacy of amrubicin monotherapy in elderly patients with SCLC has not been described. The objective of this study was to investigate the feasibility of amrubicin monotherapy in elderly patients and its efficacy for relapsed SCLC. METHODS: A retrospective cohort study design was used. We retrospectively evaluated the clinical effects and adverse events of amrubicin treatment in elderly (≥70 years) SCLC patients with relapsed SCLC. RESULTS: Between November 2003 and September 2015, 86 patients (aged ≥70 years) received amrubicin monotherapy for relapsed SCLC at four institutions. There were 42 cases of sensitive relapse (S) and 44 of refractory relapse (R). S cases with median age of 75 years (range 70-85 years) and R cases with median age of 74 years (range 70-84 years) were included in our analysis. The median number of treatment cycles was three (range 1-9), and the response rate was 33.7% (40.5% in the S and 27.2% in the R cases). Median progression-free survival time was 4.0 months in the S and 2.7 months in the R patients (p = 0.013). Median survival time from the start of amrubicin therapy was 7.6 months in the S and 5.5 months in the R cases (p = 0.26). The frequencies of grade ≥3 hematological toxicities were as follows: leukopenia, 60.4%; neutropenia, 74.4%; anemia, 11.6%; thrombocytopenia, 16.2%; and febrile neutropenia, 17.4%. Treatment-related death was observed in one patient. CONCLUSION: Although hematological toxicities, particularly neutropenia, were severe, amrubicin showed favorable efficacy, not only in the S but also in the R cases, as shown in previous studies. Amrubicin could be a preferable standard treatment in elderly patients with relapsed SCLC. These results warrant further evaluation of amrubicin in elderly patients with relapsed SCLC by a prospective trial.

[A Case of Synchronous Double Cancer of the Lung and Stomach That Responded to Cisplatin and S-1 Combination Chemotherapy].

A 55-year-old man experienced weight loss, as noted by a physician who was examining him for hypertension. Upper gastrointestinal endoscopy revealed a tumor lesion with an ulcer on the posterior wall of the greater curvature. A biopsy confirmed the presence of an adenocarcinoma(HER2 negative), and demonstrated enlarged para-aortic lymph nodes. Thus, stage IV type 3 ulcer infiltration-type gastric cancer was diagnosed. Computed tomography was included in the examination, and demonstrated nodular shadows in the right lower lobe and enlarged mediastinal nodes, as well as bilateral multiple granular shadows. Hence, bronchoscopy was performed, and another adenocarcinoma(EGFR mutation negative/EML4-ALK gene fusion negative)was diagnosed. Immunostaining showed that the pulmonary and gastric adenocarcinoma tissues were different, and synchronous double cancer was diagnosed. Four courses of CDDP/S-1were administered, and both the lesions showed a partial response.

Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer.

OBJECTIVES: Gefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC. PATIENTS AND METHODS: Pharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250 mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing. RESULTS: The subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168-781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698-13991) ng/mL h. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%-93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD. CONCLUSION: Elevated gefitinib exposure might be associated with drug-induced ILD.

Phase II study of concurrent chemoradiotherapy with carboplatin and vinorelbine for locally advanced non-small-cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) have locally advanced disease with poor prognosis. Although concurrent chemoradiotherapy is the standard treatment, more effective regimens are required. The aim of this study was to assess the safety and efficacy of concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine in patients with locally advanced NSCLC. Patients with unresectable, stage IIIA or IIIB NSCLC were eligible for enrollment if they exhibited a performance status of 0-2 and were ≤75 years of age. Patients were treated with carboplatin at an area under the plasma concentration vs. time curve of 2.5 mg/ml/min and vinorelbine at 20 mg/m2 on days 1 and 8 every 3 weeks. Thoracic radiotherapy at a total dose of 60 Gy was concurrently administered (2 Gy per fraction). Twenty-eight patients (23 men and 5 women; median age, 67 years; range 47-75 years) were enrolled in the present study. The overall response rate was 85.7% [95% confidence interval (CI), 67.3-96.0%] and the disease control rate was 96.4% (95% CI, 81.7-99.9%). The median survival time (MST) was 23 months and the median progression-free survival (PFS) time was 8 months. Grade 3-4 toxicities included neutropenia, thrombocytopenia, anemia and infection in 100, 14, 46 and 36% of patients, respectively. One patient (4%) developed grade 3 radiation esophagitis that resolved completely without residual dilation. Grade 3 radiation pneumonitis occurred in 2 patients (7%); however, the symptoms and radiographic abnormalities subsided with corticosteroid therapy. In conclusion, concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine is well-tolerated and effective in patients with locally advanced NSCLC.

Evaluation of the safety and efficacy of combination chemotherapy with vinorelbine and platinum agents for patients with non-small cell lung cancer with interstitial lung disease.

BACKGROUND: Acute chemotherapy-associated exacerbation of interstitial lung disease (ILD) can occur in patients with non-small cell lung cancer (NSCLC). The safety and efficacy of cytotoxic chemotherapy has not yet been established for NSCLC with ILD. Thus, patients with advanced NSCLC with ILD usually receive only best supportive care. The aim of this study was to assess the safety and efficacy profiles of the combination chemotherapy of vinorelbine and a platinum agent in patients with advanced NSCLC with ILD. PATIENTS AND METHODS: Nineteen patients with advanced NSCLC with ILD treated with vinorelbine and a platinum agent, either cisplatin or carboplatin, were retrospectively reviewed to examine acute exacerbation of ILD, toxicity, response rate, and survival time. Additionally, possible predictive factors for acute chemotherapy-associated exacerbation of ILD were analyzed. RESULTS: The response rate was 42.1%, the progression-free survival time was 4.4 months, the median survival time was 7.4 months, and the one-year survival rate was 36.8%. Neutropenia was the most frequent grade 3 to 4 toxicity and it occurred in 63.2% of patients. Acute chemotherapy-associated exacerbation of ILD occurred in three patients (15.8%) and caused the death of one of these patients (5.3%). No variables were identified as being predictive factors for acute chemotherapy-associated exacerbation of ILD. CONCLUSION: The combination chemotherapy with vinorelbine and a platinum agent can be considered as a treatment option for patients with advanced NSCLC with ILD, with careful management after sufficient evaluation of the risks and the benefits.

Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer.

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46-74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.