Molecular Factors Associated with Pemetrexed Sensitivity According to Histological Type in Non-small Cell Lung Cancer.

BACKGROUND: This study was designed to investigate potential molecules that predict chemosensitivity to pemetrexed (Alimta®) in surgically resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Chemosensitivity to ALM and other drugs was assessed by succinate dehydrogenase inhibition (SDI) test in 69 NSCLC samples (55 adenocarcinomas, and 14 squamous cell carcinomas). The mRNA expression levels of Alimta®-target enzymes [thymidylate synthase (TYMS); dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT)], Alimta®-metabolizing enzymes [γ-glutamyl hydrase (GGH) and folylpolyglutamate synthase] and an Alimta® transporter [reduce folate carrier (RFC)] were measured and examined for potential correlations to chemosensitivity. RESULTS: The squamous cell carcinoma samples showed higher TYMS expression and lower RFC expression than did the adenocarcinoma samples. In the adenocarcinoma sample analyses, GGH expression was inversely correlated to sensitivity. CONCLUSION: The histology-dependent differences in chemosensitivity to Alimta® may be attributed to the histology-dependent differences in TYMS and RFC expression. In adenocarcinomas, GGH potentially represents a marker for chemosensitivity to Alimta®.

Influence of the distance between home and the hospital on patients with surgically resected non-small-cell lung cancer.

OBJECTIVES: There have been no previous reports examining how the travel distance affects the outcomes of non-small-cell lung cancer (NSCLC) patients. In this study, we examined the influence of the distance from home to the hospital on patients with NSCLC who underwent surgical resection. METHODS: From 2006 to 2011, 607 consecutive patients with NSCLC who had undergone pulmonary resection were enrolled. The patients were divided into three groups according to the distance from their home to the hospital: 0 < 10, 10-30 and >30 km. We analysed the short-term and long-term outcomes according to the group. RESULTS: Two hundred and ninety-six patients lived less than 10 km from the hospital, 111 patients lived 10-30 km and 200 patients lived more than 30 km. There were no differences in the demographics, including age, European Cooperative Oncology Group performance status, histological type, surgical procedure and pathological stage, between the three groups. The mean postoperative hospital stay was as follows: 13.9 days in the <10 km group, 13.3 days in the 10-30 km group and 14.3 days in the >30 km group (P = 0.04). There were no significant differences in the median length of follow-up (50, 47, 43 months, P = 0.24), disease-free survival (DFS) (5-year DFS, 68.1, 68.2 and 70.1%, P = 0.89) or overall survival (OS) (5-year OS, 80.6, 78.8 and 79.4%, P = 0.99) between the three groups. CONCLUSIONS: The distance between home and the hospital was not found to influence the long-term outcomes of the patients with surgically resected NSCLC. Therefore, the travel distance should not represent a contraindication to surgical resection and postoperative therapy for NSCLC.

Post-recurrence survival of elderly patients 75 years of age or older with surgically resected non-small cell lung cancer.

PURPOSE: The purpose of this study was to evaluate the outcomes of elderly patients 75 years of age or older with recurrent non-small cell lung cancer (NSCLC). METHODS: A total of 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence. The rate of the post-recurrence survival and predictors were analyzed independently in a group of younger patients (<75 years) and a group of elderly patients (≥75 years). RESULTS: There were 215 younger patients (<75 years) and 65 elderly (≥75 years) patients at the time of diagnosis of recurrence. The median post-recurrence survival time and the five-year survival rate of all cases were 25 months and 20.8%, respectively. There were no significant survival differences between the younger and elderly groups (p = 0.20). A univariate analysis determined that gender, Eastern Cooperative Oncology Group performance status, smoking status, histological type and epithelial growth factor receptor (EGFR) mutation status were factors influencing the post-recurrence survival among the elderly patients. In addition, a multivariate analysis determined the EGFR mutation status to be an independent prognostic factor for the post-recurrence survival. CONCLUSIONS: Elderly patients 75 years of age or older in this study achieved satisfactory long-term outcomes.

Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer.

The aim of the present study was to retrospectively evaluate the feasibility of cisplatin/pemetrexed/bevacizumab (CPB) therapy at a bevacizumab (BEV) dose of 15 mg/kg as a first-line chemotherapeutic strategy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). A total of 31 consecutive patients with non-squamous NSCLC were treated with first-line chemotherapy of CPB at a BEV dose of 15 mg/kg at the National Kyushu Cancer Center (Fukuoka, Japan) between November 2009 and December 2011. Clinical characteristics, response rate (RR), progression-free survival (PFS) time, overall survival (OS) time and adverse events were retrospectively analyzed. The 31 patients exhibited a male:female ratio of 21:10 and a median age of 60 years (range, 38-76 years). In total, 5 patients were of clinical stage III and 26 patients were of stage IV, 15 had a performance status of 0 and 16 had a performance status of 1, and 29 patients were diagnosed with adenocarcinoma and 2 were diagnosed with adenosquamous carcinoma. The EGFR mutation status was positive (exon 19 deletion), wild-type and unknown in 3, 21 and 7 patients, respectively. A total of 28 patients (90.3%) received a minimum of four courses of CPB therapy. Hematological toxicities classified as grade III or higher included neutropenia (29.0%), anemia (3.2%) and thrombocytopenia (3.2%), however, no severe non-hematological toxicities were observed. Additionally, 22 patients (71.0%) exhibited a partial response and 9 (29.0%) exhibited stable disease, resulting in a RR of 71.0% [95% confidence interval (CI), 41-74]. The median PFS and OS times were 8.4 months (95% CI, 7.9-9.0) and 28.5 months (95% CI, 26.4-30.6), respectively. Therefore, CPB therapy at a BEV dose of 15 mg/kg appears to be a feasible treatment strategy for patients with advanced non-squamous NSCLC.

Associations between driver gene mutations and cytotoxic chemosensitivity in patients with non-small cell lung cancer.

BACKGROUND/AIM: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement often have a better prognosis when they are treated with specific inhibitors than when treated with cytotoxic agents. However, the associations between gene mutations and cytotoxic chemosensitivity are still unclear. The objective of the present study was to identify which clinicopathological factors, including genetic mutations, influence chemosensitivity, determined using the succinate dehydrogenase inhibition (SDI) test in patients with NSCLC. MATERIALS AND METHODS: The chemosensitivity of tumor tissues from 96 patients with NSCLC who underwent surgical resection was evaluated using the SDI test. RESULTS: In patients with adenocarcinoma, tumors with EGFR gene mutations were significantly more sensitive to 5-fluorouracil (5-FU) than tumors without EGFR gene mutations (p<0.0149). CONCLUSION: Our data suggest that patients with adenocarcinoma harboring EGFR gene mutations may be susceptible to 5-FU.

Preoperative concurrent chemoradiotherapy followed by extrapleural pneumonectomy for patients with non-small cell lung cancer with malignant pleural effusion and/or pleural nodules: Ten-year results of a prematurely terminated single institute phase II trial.

BACKGROUND: Malignant pleural effusion and/or pleural nodules are a final stage of disease extension of non-small cell lung cancer (NSCLC), which is currently classified as M1a-Stage IV disease. The role of surgery, especially extrapleural pneumonectomy (EPP) for local disease control and its impact on the survival of patients remains uncertain. PATIENTS AND METHODS: This single institute phase II trial was performed from March 1997 to March July 2004 to assess the effects of induction concurrent chemoradiotherapy (CRT) using a pro-drug of 5-FU, uracil-tegafur (UFT(®), Taiho Pharmaceutical Co., Ltd, Tokyo, Japan), plus cisplatin concurrently with 40 Gy hemithorax radiation followed by EPP. Intraoperative hypotonic cisplatin treatment in the pleural cavity before resection of the pericardium and diaphragm was performed. The primary endpoint of this study was the overall survival (OS), and the secondary endpoint was the disease-free survival (DFS), safety, response to the induction CRT, local disease control period in the affected thorax and the type of disease recurrence. RESULTS: This trial was prematurely terminated because of the slow registration pace. During the study period, 11 patients were enrolled. There were five males and six females, with a median age of 55 (36-64) years. All patients had adenocarcinoma. All patients received the planned induction CRT. Five patients achieved a partial response and five achieved stable disease, and one patient could not be evaluated. One patient underwent exploratory thoracotomy due to unresectable chest wall invasion, and nine patients (81.8%) underwent EPP. No perioperative deaths were encountered. The median follow-up time was matured at 32.1 (range 15.0-100) months. The one-, three- and five-year DFS rates were 77.8% (95%CI: 50.6-100%), 11.1% and 11.1% (95%CI: 95%CI: 0-31.7%), respectively. The one-, three- and five-year OS rates were 100.0%, 33.3% (95%CI: 2.5-64.1%) and 22.2% (95%CI: 0.0-49.4%), respectively. Recurrence developed in eight of nine patients who underwent EPP (88.9%). All first recurrent sites were distant regions, and no ipsilateral local recurrence was identified. CONCLUSION: The trimodality treatment used in this trial appears to be a choice of treatment for highly selected patients. However, the impact on the survival of NSCLC patients with malignant pleural effusion and/or pleural nodules still remains uncertain given the small number of patients enrolled in the study.

Role of surgical resection for patients with limited disease-small cell lung cancer.

OBJECTIVES: Although chemotherapy and radiotherapy are recommended for patients with limited disease small cell lung cancer (LD-SCLC), several series have reported favorable survival outcomes even in patients with stages II and III disease who underwent surgical resection. The purpose of this study is to compare the outcomes of the use of surgical resection to the other conventional non-surgical treatments in patients with LD-SCLC with respect to each clinical stage. MATERIALS AND METHODS: We retrospectively reviewed 277 patients who received treatment for LD-SCLC and compared the outcomes of the use of surgical resection to the other conventional non-surgical treatments. RESULTS: The clinical stage was stage I in 50 cases (18%), stage II in 53 cases (19%) and stage III in 174 cases (63%). Eighty-eight patients received surgical resection and 189 patients were treated with non-surgical treatment. Surgery was performed in 44 patients (88%) with stage I, 27 patients (52%) with stage II and 17 patients (10%) with stage III disease. The five-year survival rates of the patients according to clinical stage were 58% in stage I, 29% in stage II and 18% in stage III. The five-year survival rates of the patients with and without surgical resection according to clinical stage were as follows: 62% and 25% in stage I (p<0.01), 33% and 24% in stage II (p=0.95), 18% and 18% in stage III (p=0.35), respectively. In 44 propensity score-matched pairs with stages II and III disease, including matching for variables such as age, gender and the PS, the five-year survival rates was better in patients with surgical resection than in those without surgery (p=0.04). CONCLUSION: Surgical resection is effective for the patients with stage I LD-SCLC and some cases of stage II or III disease.

Concurrent chemoradiotherapy for patients with postoperative recurrence of surgically resected non-small-cell lung cancer.

BACKGROUND: A few reports have evaluated the outcomes of concurrent chemoradiotherapy (CRT) for patients with postoperative recurrence of non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of those, 280 patients had experienced postoperative recurrence by the end of 2012. Thirty-five patients received concurrent CRT as initial treatment of the recurrent disease. We retrospectively reviewed these cases, analyzed the outcomes of concurrent CRT after surgical resection, and examined the factors that predict long-term postrecurrence survival. RESULTS: The most common sites of recurrence in this cohort were the lymph nodes in 24 patients, followed by the lung in 5 patients and bone in 6 patients. The median radiation dose given as the initial treatment of recurrence was 60 Gy (range, 30-60 Gy). Chemotherapy included a platinum agent in all cases; cisplatin-based chemotherapy was administered in 23 cases, and a carboplatin-based chemotherapy regimen was administered in 12. The median progression-free and postrecurrence survival after CRT was 13 months (range, 4-127 months) and 31 months (range, 5-127 months), respectively. Seven patients were still alive without evidence of disease for > 3 years after the recurrence diagnosis. The ECOG performance status (PS), surgical procedure, and types of platinum agents used were independent prognostic factors for postrecurrence survival. CONCLUSION: Concurrent CRT for recurrent NSCLC is a promising therapy for selected patients. A poor PS and postpneumonectomy state were poor prognostic factors for patients who received concurrent CRT.

Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer.

OBJECTIVES: The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. METHODS: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. RESULTS: The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). CONCLUSIONS: It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy.

Results of S-1-based chemotherapy for platinum (and antrathycline)-refractory advanced thymic carcinoma.

AIM: The aim of the present study was to retrospectively evaluate the role of S-1-based chemotherapy for patients with relapsed advanced thymic carcinoma (TC). PATIENTS AND METHODS: This study was a retrospective review of TC patients who had received S-1-based chemotherapy for patients with platinum- and antrathycline-failure TC. Patients received S-1 monotherapy or S-1/gemcitabine combination therapy, that were repeated until disease progression. RESULTS: The patients consisted of 4 males and 4 females with a median age of 59 years (range=41-71); 2 with squamous cell carcinoma, 3 with undifferentiated carcinoma, 1 with poorly-differentiated neuroendocrine carcinoma and 2 not otherwise specified. Grade 3 or higher toxicity was only neutropenia (25.0%). No treatment-related death was observed. The response rate was 50.0% (95% confidence interval (CI)=21.5-78.5%). The median progression free-survival (PFS) and overall survival (OS) of S-1-based chemotherapy were 6.0 and 13.5 months, respectively. CONCLUSION: S-1-based chemotherapy was found to be potentially useful for patients with relapsed TC.

Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations.

PURPOSE: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis. EXPERIMENTAL DESIGN: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib. RESULTS: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib. CONCLUSIONS: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients.

Split-dose cisplatin and vinorelbine as adjuvant chemotherapy for completely resected non-small cell lung cancer.

AIM: The aim of the present study was to evaluate the feasibility of, and compliance with a regimen using split-dose cisplatin and vinorelbine (split-CV) as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The treatment schedule included cisplatin at 40 mg/m(2) and vinorelbine at 25 mg/m(2) administered intravenously on days 1 and 8, every three weeks for four cycles. RESULTS: This study included 22 patients (male/female; 12/10) with a median age of 67 (range 50-76) years; 10 had clinical stage II and 12 stage III; 21 had ECOG 0 and 1 patient ECOG 1; 15 patients had adenocarcinoma, 5 squamous cell and 2 adenosquamous carcinoma; 18 patients had undergone lobectomy, 3 pneumonectomy and 1 segmentectomy. Seventeen out of 22 patients (77%) received the planned 4 cycles. The main adverse events were grade 3/4 neutropenia (76%) and anemia (12%). The average total doses of cisplatin and vinorelbine were 285 mg/m(2) and 177 mg/m(2), respectively. CONCLUSION: The split-CV regimen is well-tolerated as adjuvant chemotherapy for completely resected NSCLC.

Local treatment of oligometastatic recurrence in patients with resected non-small cell lung cancer.

OBJECTIVES: We previously reported a retrospective study indicating the prognostic impact of the local treatment of oligometastatic recurrence after a complete resection for non-small cell lung cancer (NSCLC). In the present study, we prospectively observed postoperative oligometastatic patients and investigated the effects of local treatment on progression-free survival (PFS). METHODS: Using a prospectively maintained database of patients with completely resected NSCLC treated between October 2007 and December 2011, we identified 52 consecutive patients with postoperative recurrence, excluding second primary lung cancer. Of these patients, 31 suffering from distant metastases alone without primary site recurrence were included in this study. According to the definition of 'oligometastases' as a limited number of distant metastases ranging from one to three, 17 patients had oligometastatic disease. Of those 17 patients, four patients with only brain metastasis were excluded from the analysis. RESULTS: The oligometastatic sites included the lungs in five patients, bone in four patients, the lungs and brain in two patients, the adrenal glands in one patient and soft tissue in one patient. Eleven of the 13 patients first received local treatment. Three patients (lung, adrenal gland, soft tissue) underwent surgical resection, and the remaining eight patients received radiotherapy. The median PFS was 20 months in the oligometastatic patients who received local treatment. There were five patients with a PFS of longer than two years. The metastatic sites in these patients varied, and one patient had three lesions. On the other hand, the two remaining patients first received a systemic chemotherapy of their own selection. The PFS of these two patients was five and 15 months, respectively. CONCLUSION: Local therapy is a choice for first-line treatment in patients with postoperative oligometastatic recurrence.

Expression of Brachyury gene is a significant prognostic factor for primary lung carcinoma.

BACKGROUND: The clinical significance of Brachyury expression and its relationship to epithelial-mesenchymal transition in primary lung carcinoma is unclear. METHODS: Expression of Brachyury mRNA was investigated in 104 surgically resected primary lung carcinoma tissues. Immunohistochemical analysis of Brachyury transcription factor, Slug, E-cadherin, IL-8, N-cadherin, and Ki67 was performed in 67 of 104 cases, and their expression was correlated to prognoses and clinicopathological factors. RESULTS: Brachyury mRNA expression in primary lung carcinoma tissues was a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage (P < 0.05). Brachyury mRNA expression was significantly inversely correlated to E-cadherin expression (P = 0.0252) and positively correlated to IL-8 protein (P = 0.0241) and to Slug protein (P = 0.0243) in adenocarcinoma tissues. CONCLUSIONS: A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma.

Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: A single institution experience.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a relatively rare, aggressive neoplasm associated with asbestos exposure. Extrapleural pneumonectomy (EPP) is often performed for resectable MPM as part of a multidisciplinary treatment; however, available data on treatments for recurrence after EPP are limited. METHODS: The clinical records of consecutive MPM patients who underwent EPP at our institution from 2001 to 2010 were retrospectively reviewed. There were 10 patients who underwent EPP with or without perioperative chemotherapy; of these, recurrence was observed in eight patients. RESULTS: The overall median survival time and time to recurrence were 49.6 months and 15.4 months, respectively, after EPP. The first recurrence occurred within the ipsilateral thorax in four patients. These patients all underwent local treatments for their recurrence, including surgery or radiotherapy and with or without systemic chemotherapy. Other first recurrences were seen in the peritoneal space of two patients and in the contralateral lung of two patients. These patients received platinum-based systemic chemotherapy for their recurrence. The median survival time after the first recurrence was 17.8 months, and the 2-year survival rate was 23.4%. CONCLUSIONS: Most patients who underwent EPP developed tumor recurrences. Direct tumor extension may be a major mechanism of recurrence. Aggressive treatment for recurrent MPM after EPP, including locoregional control and/or systemic chemotherapy, was important for achieving long-term survival.