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.

Patients' perception of the usefulness of a question prompt sheet for advanced cancer patients when deciding the initial treatment: a randomized, controlled trial.

OBJECTIVE: The objective of this study was to evaluate the patients' perception of the usefulness of a question prompt sheet (QPS) in facilitating the involvement of advanced cancer patients during consultation. METHODS: Advanced cancer patients attending their first consultation after diagnosis were randomly assigned to the intervention group (received QPS and a hospital introduction sheet (HIS)) or the control group (received HIS only). Analysis was conducted on an intention-to-treat basis. The primary outcome measure was patient rating of the usefulness of the material(s) (numerical rating scale of 0-10). RESULTS: Sixty-three advanced cancer patients (72.4% response rate) were enrolled and analyzed. Nearly three-quarters of patients in both groups read the material(s) before consultation. The rated usefulness of the material(s) for asking questions of physicians was significantly higher in the intervention group than in controls (4.4 ± 3.6 and 2.7 ± 2.8, respectively; p = 0.033). The mean score of the usefulness of the material(s) for understanding the treatment plan tended to be higher in the intervention group than in the controls (4.9 ± 3.6 and 3.3 ± 2.8; p = 0.051). The mean score of willingness to use the material(s) in the future was significantly higher in the intervention group than in the controls (5.3 ± 3.8 and 2.8 ± 2.8; p = 0.006). There were no significant differences between the groups in the average total number of questions asked by patients (median, 1.0; interquartile range in both groups, 2.0). CONCLUSIONS: QPS provided before oncology consultation may be useful for advanced cancer patients, on the other hand, it did not directly promote patient confidence to ask questions.

Serum brain-derived neurotrophic factor and antidepressant-naive major depression after lung cancer diagnosis.

Previous studies have reported the existence of an association between brain-derived neurotrophic factor and major depression. However, the possible role of brain-derived neurotrophic factor in the pathophysiology of major depression after cancer diagnosis has not yet been investigated. Subjects were collected using the Lung Cancer Database project. Using the cut-off scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), 81 subjects with depression (HADS-D > 10) and 81 subjects without depression (HADS-D < 5) were selected. The two groups were matched for age, sex, clinical stage and performance status. The serum brain-derived neurotrophic factor levels were measured using an enzyme-linked immunosorbent assay method. The serum brain-derived neurotrophic factor levels were not statistically different between the subjects in the depression group [29.1 (13.6) ng/ml; mean (SD)] and the non-depression group [31.4 (10.6) ng/ml] (P = 0.22). In a stratified analysis by gender, however, the mean serum brain-derived neurotrophic factor level in the depression group tended to be lower than that in the non-depression group among women (n = 24 pairs, P = 0.06). Major depression after cancer diagnosis is not associated with serum brain-derived neurotrophic factor levels.

Development of Cushing's syndrome during effective chemotherapy for small cell lung cancer.

Paraneoplastic Cushing's syndrome caused by ectopic adrenocorticotropin (ACTH) production has been reported. However, most cases of this syndrome are diagnosed before first-line chemotherapy or at the time of disease recurrence. Here, we present a 53-year-old man who gradually developed the symptoms of Cushing's syndrome during effective chemotherapy for small cell lung cancer. His symptoms were controlled using mitotane, but his primary cancer progressed and he died 5 months after the start of chemotherapy. This very rare case of Cushing's syndrome associated with small cell lung cancer during effective chemotherapy is presented here.

Clinical outcome of small cell lung cancer with pericardial effusion but without distant metastasis.

BACKGROUND: Pericardial effusion is defined as M1a in the Union Internationale Contre le Cancer seventh tumor, node, metastasis edition for lung cancer. The clinical course of small cell lung cancer (SCLC) with pericardial effusion but without distant metastasis (M1a) has not been adequately investigated. METHODS: The medical records of patients with SCLC treated at the National Cancer Center Hospital East between July 1992 and December 2007 were reviewed. During this period, 766 patients were newly diagnosed as having SCLC. Thirty-three of the 416 patients with limited disease (LD) SCLC (8%) had pericardial effusion. Seventy-nine patients with LD-SCLC (19%) had ipsilateral pleural effusion or dissemination. Of these, 16 patients had both pericardial and ipsilateral pleural effusion. We divided the 96 M1a patients into two subgroups: group A (n = 33) included patients with pericardial effusion, and group B (n = 63) included patients with ipsilateral pleural effusion or disseminated pleural nodules but without pericardial effusion. RESULTS: The median survival time among the patients with LD-M1a was 13.4 months (95% confidence interval: 10.7-16.6 months), and the 1-, 2-, 3-, and 5-year survival rates were 56%, 18%, 9%, and 8%, respectively. The survival of the patients with LD-M1a was intermediate between those of the patients with LD-M0 and patients with extensive disease M1b (p < 0.0001). The overall survival period was not statistically different between groups A and B (p = 0.5182). Nineteen patients in group A received chemoradiotherapy, but only two patients survived for more than 2 years (2- and 5-year survival rate: 11% both). Twenty-six patients in group B received chemoradiotherapy, and four patients survived for more than 5 years (5-year survival rate: 18%). CONCLUSIONS: Long-term survival was achieved among patients with SCLC with pericardial effusion but without distant metastasis who successfully underwent chemoradiotherapy, although 5-year survival rate in these patients was relatively lower than in patients with SCLC with ipsilateral pleural effusion but without pericardial effusion or distant metastasis.

Phase I study of topotecan and cisplatin in patients with small cell lung cancer.

OBJECTIVE: A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. METHODS: Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m(2)/day), and cisplatin at a fixed dose of 60 mg/m(2), 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. RESULTS: A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m(2), respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m(2), respectively. The major toxicity in this combination was hematological events. CONCLUSIONS: For treatment-naive patients, the combined use of 0.65/60 mg/m(2) topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m(2) topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study.

Pharmacokinetic and pharmacodynamic profiles of subcutaneous administration of continuous erythropoietin receptor activator in lung cancer patients with anemia induced by chemotherapy.

Continuous erythropoietin receptor activator (C.E.R.A.) is an innovative erythropoiesis-stimulating agent with unique erythropoietin receptor activity and a prolonged half-life. C.E.R.A. is currently in development for the correction of anemia and stable hemoglobin (Hb) control at extended administration intervals in patients with cancer who are receiving chemotherapy. The purpose of this pharmacological study was to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of C.E.R.A. administered subcutaneously once every 3 weeks (Q3W) in lung cancer patients with anemia induced by chemotherapy. This open-label, multicenter study recruited 46 patients. Entry Hb levels were not more than 11.0 g/dl. Five dose levels of C.E.R.A. (2.1, 4.2, 6.3, 9 and 12 µg/kg) were tested in sequential cohorts of 8-11 patients for 12 weeks. The mean values for C.E.R.A half-life ranged from 143 to 247 h. The maximum serum concentration (C(max)) following the first administration of C.E.R.A. increased in proportion to the dose. The increase of Hb levels occurred in a dose-dependent manner. No serious adverse events reported as being related to C.E.R.A. were observed during the study period. Thrombovascular events were not observed in any patient. Anti-C.E.R.A antibodies were not detected in any patient. Thus, this pharmacological study confirmed the long half-life of C.E.R.A., thereby supporting subcutaneous administration of C.E.R.A. at the Q3W interval. PK and PD parameters demonstrated dose-proportionality over the range of doses tested in this study. Additionally, C.E.R.A. was generally well tolerated.

Severe interstitial lung disease associated with amrubicin treatment.

BACKGROUND: Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small cell lung cancer (SCLC), but the adverse pulmonary effects of amrubicin are less well known. We investigated the incidence of acute interstitial lung disease (ILD) in SCLC patients who had been treated with amrubicin. METHODS: Medical records were used to retrospectively investigate a total of 100 cases of SCLC patients treated with single-agent amrubicin therapy at the National Cancer Center Hospital East between June 2003 and March 2008. The patients' radiographic records and clinical data were reviewed to identify patients who had developed acute ILD after being treated with amrubicin. RESULTS: After receiving amrubicin, seven of the 100 SCLC patients subsequently developed pulmonary infiltrates, and they were identified as cases of acute ILD associated with amrubicin. Of the seven patients who developed ILD, six were treated with corticosteroids, and the ILD improved in three of them, but the other three patients died of respiratory failure. The incidence of ILD was 33% (4/12) among the patients with pre-existing pulmonary fibrosis (PF) and 3% (3/88) among the patients without PF, and the difference between the two groups was statistically significant (P = 0.0036). CONCLUSIONS: The results of this study indicated that amrubicin may cause severe ILD and that pre-existing PF was associated with a higher rate of ILD among SCLC patients treated with amrubicin. We recommend not administering amrubicin in the treatment of SCLC patients with pre-existing PF.

Vascular invasion is a strong prognostic factor after complete resection of node-negative non-small cell lung cancer.

BACKGROUND: The seventh edition of TNM classification for non-small cell lung cancer (NSCLC) has been approved. Vascular invasion has been reported as being a strong risk factor; therefore, we reviewed the impact of vascular invasion on new TNM classification. METHODS: We reviewed patients with completely resected NSCLC without lymph node metastasis treated at our institute between January 1993 and December 2003. Vascular invasion was examined using Victoria blue-van Gieson stains performed in maximum cut sections of tumor. Correlation between vascular invasion and other clinicopathologic factors, such as age, sex, histology, serum carcinoembryonic antigen (CEA) levels, smoking habitation, and T descriptors, were assessed. In addition, we evaluated the impact of vascular invasion on survival. RESULTS: A total of 826 patients were analyzed. Median age was 65 years (range, 32-86). Thirty-two percent of patients were > 70 years, 44% were women, 78% had adenocarcinoma, 41% were never smokers, 39% smoked > 30 pack-years, and 31% had elevated serum CEA levels. Vascular invasion was detected in 279 patients (33.8%) and more was observed in patients who were male, did not have adenocarcinoma, were smokers, and had elevated CEA levels. Positive vascular invasion was significantly correlated with worse prognosis compared with negative (5-year survival, 90.5% vs 71.0%, P < .001). This trend was observed in each subgroup of T1a (92.9% vs 72.5%, P < .001), T1b (89.7% vs 77.2%, P = .015), and T2a (86.3% vs 65.6%, P < .001). CONCLUSIONS: Vascular invasion was a strong prognostic factor in the revised TNM classification. Further investigation is warranted to generalize these findings.

Histopathologic features of the tumor budding in adenocarcinoma of the lung: tumor budding as an index to predict the potential aggressiveness.

INTRODUCTION: The term tumor budding has been applied to single cells or small clusters of up to four cells within the stromal tissue at the invasive margin of colorectal cancers. This morphologic feature is increasingly being recognized as an adverse prognostic factor. The purpose of this study was to evaluate the clinicopathologic significance of tumor budding in adenocarcinomas of the lung. METHODS: We investigated the relationship between tumor budding and clinicopathologic parameters of adenocarcinomas of the lung and the prognostic significance of tumor budding by reviewing the cases of 201 consecutive patients who had undergone complete resection of adenocarcinoma of the lung measuring 30 mm or less in diameter. We examined immunohistochemical profile of budding cells (BCs) by immunohistochemical staining with 14 antibodies. RESULTS: Tumor budding was observed in 78 (43.1%) of the 181 cases with invasive adenocarcinoma. The presence of tumor budding was significantly associated with lymph node metastasis (p = 0.005), pathologic stage (p < 0.001), vascular invasion (p = 0.003), lymphatic invasion (p = 0.009), and pleural invasion (p = 0.029). Examination of the relation between the presence of tumor budding and the predominant histologic subtype revealed that the predominant papillary subtype was significantly associated with the presence of tumor budding (p = 0.0023), whereas the predominant bronchioloalveolar carcinoma subtype was significantly associated with the absence of tumor budding (p < 0.001). The overall 5-year survival rates of the group with budding and the group without budding was 67.5% and 88.3%, respectively, and difference was significant (p = 0.0057). Compared with cancer cells forming nests, BCs displayed reduced expression of cellular adhesion molecule, E-cadherin, and beta-catenin (p < 0.05 and p < 0.05, respectively) and increased expression of laminin5-gamma2 (p < 0.05). However, BCs displayed reduced expression of differentiation marker, surfactant protein A (p < 0.05). Multivariate analysis revealed that tumor budding was significant independent prognostic factor of the small-sized adenocarcinoma of the lung. CONCLUSIONS: Our data showed that tumor budding in adenocarcinoma of the lung is a distinct morphologic feature that has biologic and prognostic significance.

The antitumor activity of NK012, an SN-38-incorporating micelle, in combination with bevacizumab against lung cancer xenografts.

BACKGROUND: It has been demonstrated that NK012, a novel 7-ethyl-10-hydroxycamptothecin (SN-38)-incorporating polymeric micelle, exerts significantly more potent antitumor activity against various human tumor xenografts than irinotecan (CPT-11) (a water-soluble prodrug of SN-38). Combination therapy of anticancer agents with bevacizumab (Bv), an anti-vascualr endothelial growth factor humanized monoclonal antibody, has more potently inhibited tumor growth than either agent alone. In the current study, the authors examined the antitumor effect of NK012 in combination with Bv against human lung cancer. METHODS: Nude mice bearing lung adenocarcinoma (PC-14 or A549 xenografts) were administered NK012 at SN-38-equivalent doses of 5 mg/kg or 30 mg/kg in combination with or without Bv at 5 mg/kg. CPT-11 at a dose of 66.7 mg/kg was administered with or without Bv at a dose of 5 mg/kg in the same experimental model. To evaluate interaction with Bv, the pharmacokinetics and microvessel density in tumors that were treated on each regimen were analyzed. RESULT: In vitro, the growth-inhibitory effect of NK012 was 50-fold more potent than that of CPT-11 and was almost equivalent to that of SN-38. In vivo studies revealed that the combination of NK012 plus Bv had significantly greater antitumor activity against human lung cancer xenografts compared with NK012 alone (PC-14, P=.0261; A549, P<.001). The pharmacokinetic profile of NK012 revealed that coadministration of Bv did not interfere with the accumulation of NK012. CONCLUSIONS: In this study, significant antitumor activity was noted with NK012 in combination with Bv against lung cancer cells. The current results warrant the clinical evaluation of NK012 in lung cancer.

Long-term outcome and late recurrence in patients with completely resected stage IA non-small cell lung cancer.

BACKGROUND: The purpose of this study was to quantify the risk of late recurrence in patients with stage IA non-small cell lung cancer (NSCLC) who remained recurrence-free for more than 5 years after resection. METHODS: Between August 1992 and December 2002, a total of 519 patients with stage IA NSCLC underwent complete resection at our institution. Recurrence-free probability was measured from the benchmark of 5 years after primary tumor resection to the date of first recurrence or last follow-up using the Kaplan-Meier method. RESULTS: Of a total of 519 patients, 434 remained recurrence-free for 5 years. Among these, 21 (4.8%) developed late recurrence more than 5 years after resection. Recurrence-free interval ranged from 1 to 53 months, and the median recurrence-free interval was 14 months from the benchmark of 5 years after primary tumor resection. The 5-year recurrence-free probability from the benchmark was 93%. Multivariate Cox analysis demonstrated that vascular invasion significantly influenced late recurrence (p = 0.038). The 5-year recurrence-free probability from the benchmark was 84% for patients with vascular invasion and 95% for patients without vascular invasion (p < 0.001). CONCLUSIONS: Patients with stage IA NSCLC with vascular invasion harbor a significant risk of late recurrence more than 5 years after complete resection. In patients with stage IA NSCLC with vascular invasion, 5 years without recurrence is not sufficient to conclude that NSCLC is cured. In contrast, patients without vascular invasion may be declared to be cured at 5 years after resection if they are recurrence-free.

Randomized phase 2 dose-finding study of weekly administration of darbepoetin alpha in anemic patients with lung or ovarian cancer receiving multicycle platinum-containing chemotherapy.

OBJECTIVE: This is the first clinical trial for Japanese to evaluate the dose-response and determine the clinically effective dose of darbepoetin alpha by weekly subcutaneously administration in anemic patients with lung cancer or ovarian cancer receiving chemotherapy. METHODS: Eligible patients were required to have anemia (hemoglobin level of 15.0 g/dl (for men) or 14.0 g/dl (for women), and reinstated at 50% of the previous weekly dose when the hemoglobin level decreased to

Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer.

INTRODUCTION: This study examined the frequency of hypertrophic pulmonary osteoarthropathy (HPO) and the clinical characteristics of lung cancer with HPO. METHODS: The results of 2625 lung cancer patients who underwent bone scintigraphy were reviewed to identify patients with HPO, which was diagnosed when the bone scintigram showed a diffuse, symmetric pattern of bilateral increased uptake in the long tubular bones. Clinical characteristics were investigated based on the clinical and pathologic records. RESULTS: Nineteen patients (0.72%) were found to have HPO: 17 were men, 17 were heavy smokers, and 13 had clinical stage IIIB or IV disease. Ten patients complained of pain or edema in the extremities, and seven of them had stage IIIB or IV disease. In four patients with clinical stage IIIB or IV disease, HPO was not detected at the first presentation, and the diagnosis was made after disease progression. The symptoms of HPO improved in two patients who underwent surgical resection but in only three of five patients who received chemotherapy. The HPO findings on the bone scintigram improved in 2 of 3 patients who underwent surgical resection and 5 of 11 patients who received chemotherapy. CONCLUSIONS: Less than 1% of the lung cancer patients developed HPO as a paraneoplastic manifestation. Males, heavy smokers, and advanced disease predominated in lung cancer patients with HPO. The symptoms and bone scintigram findings of HPO improved in half of the patients on treating the lung cancer.

Disease control as a predictor of survival with gefitinib and docetaxel in a phase III study (V-15-32) in advanced non-small cell lung cancer patients.

INTRODUCTION: This post hoc analysis investigated the relationship between tumor response and overall survival (OS) in pretreated advanced non-small cell lung cancer (NSCLC). METHODS: We conducted landmark survival analyses of V-15-32, a phase III study comparing gefitinib with docetaxel in pretreated advanced NSCLC. Best response at weeks 8, 12, 16, and 20, and visit response at week 4, were evaluated. RESULTS: Disease control (DC; complete response [CR], partial response [PR], or stable disease) was a better predictor of OS than CR/PR at all time points. The strongest predictor of OS for both gefitinib and docetaxel was DC at week 8 (hazard ratio [HR] DC versus non-DC: 0.30, 95% confidence interval [CI] 0.20-0.45, p < 0.001 for both treatments). DC at week 4 was also associated with longer survival compared with non-DC for both treatments (HR 0.33, 95% CI 0.23-0.49, p < 0.001 for gefitinib; HR 0.30, 95% CI 0.19-0.47, p < 0.001 for docetaxel). DISCUSSION: DC is a better predictor of OS with gefitinib and docetaxel than CR/PR in advanced pretreated NSCLC, with a best response of DC at week 8 the strongest predictor.

Long-term survival and risk factors for recurrence in stage I non-small cell lung cancer patients with tumors up to 3 cm in maximum dimension.

BACKGROUND: The purpose of this study was to evaluate patients with stage I non-small cell lung cancer (NSCLC) and tumors up to 3 cm in maximum dimension who underwent surgical resection on the revised TNM classification and to investigate the risk factors for recurrence. METHODS: Between 1994 and 2003, 713 consecutive stage I NSCLC patients with tumors up to 3 cm in maximum dimension underwent complete resection. Recurrence-free probability was estimated from the date of the primary tumor resection to the date of the first recurrence or the last follow-up using the Kaplan-Meier method. RESULTS: The recurrence-free probability of stage I NSCLC patients with tumors up to 3 cm in maximum dimension was 87% at 5 years. On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histologic differentiation (hazard ratio, 2.3), intratumoral vessel invasion (hazard ratio, 2.9), and visceral pleural invasion (VPI) (hazard ratio, 1.8). According to subgroup analyses combining these three risk factors, the 5-year recurrence-free probability was 94% for patients with zero or one factor (n = 492) and 71% for patients with two or three factors (n = 221), respectively (P < .001). CONCLUSION: In stage I NSCLC patients with tumors up to 3 cm in maximum dimension, we identified three risk factors for recurrence that independently increase their risk of recurrence. In addition to VPI, histologic differentiation and intratumoral vessel invasion should be examined and their data collected for the next revision of the TNM staging system.

Late recurrence of non-small cell lung cancer more than 5 years after complete resection: incidence and clinical implications in patient follow-up.

BACKGROUND: The purpose of this study was to evaluate the risk of late recurrence in patients who had undergone complete resection for non-small cell lung cancer (NSCLC) and remained recurrence-free for > or = 5 years. METHODS: Between 1993 and 2002, 1,358 patients with NSCLC underwent complete primary tumor resection and systematic lymph node dissection. Of these, 819 patients remained recurrence-free for 5 years. Recurrence-free probability was estimated from the benchmark of 5 years after primary tumor resection to the date of first recurrence or last follow-up, using the Kaplan-Meier method. Multivariate Cox regression was used to test the relationship of recurrence-free probability to various clinicopathologic factors. RESULTS: Of the 819 patients who were free of recurrence at 5 years, 87 (11%) developed a subsequent recurrence. The recurrence-free probabilities at 3 years and 5 years from the point of 5 years after primary tumor resection were 92% and 87%, respectively. The 5-year recurrence-free probabilities from the point of 5 years after primary tumor resection were 81% for patients with intratumoral vascular invasion (P < .001), and 89%, 84%, and 65% for patients with N0, N1, and N2 cancers, respectively (P < .001). Multivariate Cox analysis demonstrated that intratumoral vascular invasion and nodal involvement significantly influenced recurrence 5 years after complete resection (P = .030, P = .022, respectively). CONCLUSIONS: Patients with NSCLC with selected tumor characteristics have a significant risk of late recurrence. Therefore, 5 years might not be a sufficient amount of time to declare that NSCLC has been cured.

Synergistic antitumor activity of the SN-38-incorporating polymeric micelles NK012 with S-1 in a mouse model of non-small cell lung cancer.

The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.

Re-challenge chemotherapy for relapsed non-small-cell lung cancer.

There has been no report about re-challenge chemotherapy (RC) consisting of the same regimen as first-line chemotherapy in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy of RC as second-line chemotherapy in patients with relapsed NSCLC. We conducted a retrospective review of 28 consecutive NSCLC patients who were treated with RC and compared their clinical outcomes with those of 38 consecutive NSCLC patients who were treated with docetaxel (DOC) at our hospital between July 1992 and December 2003. The RC group consisted of 21 men and 7 women, with a median age of 62 years (range, 42-76 years). Most first-line regimens were platinum-based and the median administered course was 3 (range, 2-7). All patients had responded to the first-line chemotherapy and had performance status (PS) 1 at relapse. The median interval from the end of first-line chemotherapy to relapse was 5.0 months (range, 1.6-36.1 months). The overall response rate of RC was 29%. The median survival time from the beginning of RC was 17.0 months and the 1-year survival rate was 60%. RC led to a significantly better overall survival rate than DOC (p=0.0342). RC could be an active second-line regimen in patients with relapsed NSCLC who responded to first-line chemotherapy.

Individuals susceptible to lung adenocarcinoma defined by combined HLA-DQA1 and TERT genotypes.

Adenocarcinoma (ADC) is the commonest histological type of lung cancer, and its weak association with smoking indicates the necessity to identify high-risk individuals for targeted screening and/or prevention. By a genome-wide association study (GWAS), we identified an association of polymorphisms in the 6p21.31 locus containing four human leukocyte antigen (HLA) class II genes with lung ADC risk. DQA1*03 of the HLA-DQA1 gene was defined as a risk allele with odds ratio (OR) of 1.36 [95% confidence interval (CI) = 1.21-1.54, P = 5.3 x 10(-7)] by analysis of 1656 ADC cases and 1173 controls. DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)). Individuals homozygous both for the DQA1*03 and minor TERT alleles were defined as high-risk individuals with an OR of 4.76 (95% CI = 2.53-9.47, P = 4.2 x 10(-7)). The present results indicated that individuals susceptible to lung ADC can be defined by combined genotypes of HLA-DQA1 and TERT.