ABSTRACT
We conducted a multicenter phase II trial to evaluate the efficacy and safety of S-1 and irinotecan combination therapy in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Epidermal growth factor receptor-mutated non-small-cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy received 80 mg/m2 S-1 on days 1-14 and 70 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. The primary endpoint was disease control rate 8 weeks after enrollment. The secondary endpoints were progression-free survival, overall response rate, and safety. We enrolled 25 patients from five hospitals. The patients underwent a median of four cycles. The disease control rate, 8 weeks after enrollment, was 84% (95% confidence interval 63.9-95.5%). Progression-free survival and overall survival were 5.0 and 17.1 months, respectively. The overall response rate was 52.0%. Grade ≥ 3 adverse events were reported in 56.0% of patients: hematological toxicities of leukopenia (44%), neutropenia (52%), anemia (20%), thrombocytopenia (20%), and febrile neutropenia (16%). Non-hematological toxicities of grade ≥ 3 included elevated alanine aminotransferase (4%), anorexia (8%), nausea (4%), diarrhea (16%), and pulmonary embolism (4%). None developed grade 5 toxicities. Combination therapy with S-1 and irinotecan in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy demonstrated high effectiveness with tolerable toxicities. Future phase III studies are needed to evaluate the role of this treatment in such patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Disease-Free Survival , ErbB Receptors , Humans , Irinotecan/therapeutic use , Japan , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mutation , Protein Kinase Inhibitors/therapeutic useABSTRACT
OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , CD8-Positive T-Lymphocytes , Humans , Lung Neoplasms/surgery , Neoplasm Recurrence, Local , Prognosis , Small Cell Lung Carcinoma/surgeryABSTRACT
OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (Pâ¯<â¯0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Calcium-Binding Proteins , Carcinoma, Non-Small-Cell Lung/radiotherapy , Humans , Iodine Radioisotopes , Lung Neoplasms/radiotherapy , Membrane Proteins/metabolism , Neoplasm Recurrence, Local , Pilot Projects , Radioimmunotherapy , Retrospective StudiesABSTRACT
OBJECTIVES: Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. PATIENTS AND METHODS: We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). RESULTS: We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86-30.79] in a mutation-positive group vs 10.39 months (6.96-13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29-0.89, p = 0.019) but not overall survival (OS). CONCLUSION: These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC.
ABSTRACT
PURPOSE: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer. METHODS: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. RESULTS: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045). CONCLUSION: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation. CLINICAL TRIAL REGISTRATION: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/surgery , Cisplatin/administration & dosage , DNA-Binding Proteins/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Endonucleases/metabolism , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , Postoperative Period , Ribonucleoside Diphosphate Reductase/metabolism , Treatment Outcome , GemcitabineABSTRACT
OBJECTIVES: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. PATIENTS AND METHODS: The enrolled patients had treatment-naïve, advanced NSCLC with ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4-6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7-84.8) vs. 47.6% (95% CI: 28.3-67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0-10.2) vs. 4.1 months (95% CI: 3.3-5.4) (HR, 0.60 [95% CI, 0.30-1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8-not reached) vs. 11.9 months (95% CI: 7.3-17.4) (HR, 0.56 [95% CI, 0.24-1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. CONCLUSION: Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Diseases, Interstitial/pathology , Lung Neoplasms/drug therapy , Aged , Albumins/administration & dosage , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Diseases, Interstitial/complications , Lung Diseases, Interstitial/drug therapy , Lung Neoplasms/complications , Lung Neoplasms/pathology , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Prospective Studies , Survival RateABSTRACT
BACKGROUND: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. MATERIALS AND METHODS: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. RESULTS: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. CONCLUSION: DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. IMPLICATIONS FOR PRACTICE: This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/pathology , Membrane Proteins/metabolism , Small Cell Lung Carcinoma/pathology , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Lung Neoplasms/surgery , Male , Middle Aged , Small Cell Lung Carcinoma/metabolism , Small Cell Lung Carcinoma/surgeryABSTRACT
A prospective study has previously reported on the incidence of bone metastasis (BM) and skeletal-related events (SREs) in patients with advanced lung cancer. The aim of the present study was to prospectively investigate how the quality of life (QOL) of patients with advanced lung cancer was affected by SREs. Patients with stage IIIB or IV non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) at any stage were followed up every four weeks to determine if they had developed SREs. QOL questionnaires were conducted at enrollment, at 3- and 12-months later and at 1 month after the onset of SREs, using QOL scores including the EuroQOL-5 Dimension (EQ-5D), Functional Assessment of Cancer Therapy-General (FACT-G) and activities of daily living (ADL) scores obtained by the Barthel Index. A total of 274 patients were enrolled in the study. At enrollment the EQ-5D and Barthel Index scores were lower in patients with SREs compared with patients without SREs. A chronological analysis revealed no statistically significant changes in either QOL or ADL in any of the patients. For 14 patients in whom QOL data was collected following the onset of SREs, the evaluation undertaken on the four subscales of the FACT-G revealed a significant decline in emotional functioning following the onset of SREs.
ABSTRACT
BACKGROUND: This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR. METHODS: Enrolled patients had treatment-naïve, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4-6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL). RESULTS: Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1-6) and 4 (range 1-20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0-72.6%]. The ORR was 48.0% (95% CI 34.8-61.5%), and disease control rate was 86.0% (95% CI 73.8-93.0%). The median PFS and OS were 6.5 months (95% CI 5.8-7.2 months) and 21.4 months (95% CI 15.9-26.9 months), respectively. Although grades ≥ 3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment. CONCLUSIONS: Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR. TRIAL REGISTRATION: UMIN000005872.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mutation , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Aged , Bevacizumab/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Pemetrexed/administration & dosage , Prognosis , Prospective Studies , Quality of Life , Survival Rate , Young AdultABSTRACT
INTRODUCTION: In the phase III JCOG0301 trial, chemoradiotherapy (CRT) with daily low-dose carboplatin showed significant benefits in elderly patients with locally advanced non-small-cell lung cancer (NSCLC) compared with radiotherapy (RT) alone. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT in elderly patients are not well elucidated. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. PATIENTS AND METHODS: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT or CRT. Prognosis and adverse events data were collected beyond those in the initial report. Late toxicities were defined as occurring more than 90 days after RT initiation. RESULTS: From September 2003 to May 2010, 200 patients (RT arm, n = 100; CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better overall survival than the RT arm (hazard ratio, 0.743; 95% confidence interval, 0.552-0.998; 1-sided P = .0239). The proportion of Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) and treatment-related death have been seen since the initial report that was published. CONCLUSION: Long-term follow-up confirmed the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT compared with RT alone.
Subject(s)
Adenocarcinoma/therapy , Carcinoma, Large Cell/therapy , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy/mortality , Lung Neoplasms/therapy , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Prognosis , Survival RateABSTRACT
The uncommon mutations in the EGFR (the epithelial growth factor receptor) gene include a heterogeneous group of genomic alterations within exons 18-21. The clinical response of patients with such mutations to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment, however, remains unclear. We herein report a case of advanced lung adenocarcinoma harboring complex exon 18 G719X (Gly719Xaa) and exon 20 S768I (Ser768Ile) mutations. The patient started to receive afatinib and has exhibited good response without progression for 12 months. Second-generation EGFR-TKIs might be an optimal treatment option for non-small cell lung cancers harboring these types of rare EGFR mutation.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Quinazolines/therapeutic use , Adenocarcinoma/diagnostic imaging , Adenocarcinoma of Lung , Afatinib , Aged , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/pathology , Exons/drug effects , Female , Humans , Lung Neoplasms/diagnostic imaging , Mutation , Treatment OutcomeABSTRACT
OBJECTIVE: Carboplatin-based regimens are the standard regimens for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, the efficacies of these regimens are unsatisfactory. We previously identified carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) as promising new carboplatin-based regimens. Accordingly, we conducted a randomized phase II study to identify the appropriate regimen for future phase III trials. MATERIALS AND METHODS: Chemotherapy-naïve patients with ES-SCLC were randomly assigned to receive 4-6 cycles of carboplatin [area under the curve (AUC) 5.0, day 1] plus irinotecan (70mg/m2, days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35mg/m2, days 1-3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). The secondary endpoints were the progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment due to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51-84 years); proportion of males, 84%. The ORRs were 79% and 89% in the CI and CA arms, respectively. The median PFS values were 5.1 and 6.2 months in the CI and CA arms, respectively [CA; hazard ratio (HR)=0.59, 95% confidence interval (CI): 0.35-0.98, P=0.042]. The grade 3 or higher toxicity severities were neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%). No treatment-related deaths were observed. CONCLUSION: CA was numerically more effective than CI, with acceptable toxicity, in chemo-naïve ES-SCLC patients. CA could be selected for future phase III trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology , Aged , Aged, 80 and over , Anthracyclines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carboplatin/administration & dosage , Female , Humans , Irinotecan , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Small Cell Lung Carcinoma/mortality , Treatment OutcomeABSTRACT
Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperidines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Adult , Aged , Anaplastic Lymphoma Kinase , Antineoplastic Agents/adverse effects , Carbazoles/adverse effects , Carcinoma, Non-Small-Cell Lung/chemistry , Carcinoma, Non-Small-Cell Lung/secondary , Disease Progression , Disease-Free Survival , Female , Follow-Up Studies , Humans , Hyperbilirubinemia/chemically induced , Lung Neoplasms/chemistry , Lung Neoplasms/pathology , Male , Middle Aged , Piperidines/adverse effects , Receptor Protein-Tyrosine Kinases/analysis , Retreatment , Survival Rate , Symptom Assessment , Time FactorsABSTRACT
Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.
Subject(s)
Biomarkers, Tumor/analysis , Lung Neoplasms/chemistry , Membrane Proteins/analysis , Nerve Tissue Proteins/analysis , Receptor, Notch1/analysis , Small Cell Lung Carcinoma/chemistry , Aged , Chi-Square Distribution , Disease-Free Survival , Female , Humans , Immunohistochemistry , Japan , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , Multivariate Analysis , Pneumonectomy , Proportional Hazards Models , Risk Factors , Small Cell Lung Carcinoma/mortality , Small Cell Lung Carcinoma/surgery , Time Factors , Treatment Outcome , Up-RegulationABSTRACT
The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-ßRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-ßRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-ßRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310-0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-ßRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.
Subject(s)
Biomarkers, Tumor/metabolism , Lung Neoplasms/pathology , Mediator Complex/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Small Cell Lung Carcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Aged , Carcinoma, Large Cell/metabolism , Carcinoma, Large Cell/pathology , Carcinoma, Large Cell/surgery , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Female , Follow-Up Studies , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Lung Neoplasms/surgery , Male , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Prognosis , Receptor, Transforming Growth Factor-beta Type II , Small Cell Lung Carcinoma/metabolism , Small Cell Lung Carcinoma/surgery , Survival RateABSTRACT
BACKGROUND: Volume-based parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), on F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) are useful for predicting treatment response in nonsmall cell lung cancer (NSCLC). We aimed to examine intra- and inter-operator reproducibility to measure the MTV and TLG, and to estimate their dependency on the uptake time. METHODS: Fifty NSCLC patients underwent preoperative FDG-PET. After an injection of FDG, the whole body was scanned twice: at the early phase (61.4 ± 2.8 min) and delayed phase (117.7 ± 1.6 min). Two operators independently defined the tumor boundary using three different delineation methods: (1) the absolute SUV threshold method (MTVp and TLGp; p = 2.0, 2.5, 3.0, 3.5), (2) the fixed% SUVmax threshold method (MTVq% and TLGq%; q = 35, 40, 45), and (3) the adaptive region-growing method (MTVARG and TLGARG). Parameters were compared between operators and between phases. RESULTS: Both the intra- and inter-operator reproducibility were high for all parameters using any method (intra-class correlation > 0.99 each). MTV3.0 and MTV3.5 resulted in a significant increase from the early to delayed phase (P < 0.05 for both), whereas MTV2.0 and MTV2.5 neither increased nor decreased (P = n.s.). All of the MTVq% values significantly decreased over time (P < 0.01), whereas MTVARG and TLG with any delineation method increased significantly (P < 0.05). CONCLUSIONS: High reproducibility of MTV and TLG was obtained by all of the methods used. MTV2.0 and MTV2.5 were the least sensitive to uptake time, and may be good alternatives when we compare images acquired with different uptake times, although applying constant uptake time is important for volume measurement.
Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Fluorodeoxyglucose F18/metabolism , Lung Neoplasms/diagnostic imaging , Positron-Emission Tomography/methods , Radiopharmaceuticals/metabolism , Aged , Aged, 80 and over , Female , Glycolysis , Humans , Male , Middle Aged , Observer Variation , Prognosis , Reproducibility of Results , Retrospective Studies , Tumor BurdenABSTRACT
OBJECTIVES: Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC. PATIENTS AND METHODS: We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013. RESULTS: Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of <20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI). CONCLUSION: These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.(1).
Subject(s)
Lung Neoplasms/mortality , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/mortality , Small Cell Lung Carcinoma/pathology , Aged , Aged, 80 and over , Biomarkers , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Small Cell Lung Carcinoma/surgery , Treatment OutcomeABSTRACT
PURPOSE: Amrubicin and re-challenge of platinum doublet are both effective treatments for sensitive-relapsed small-cell lung cancer (SCLC). However, no comparative study of these treatments has been reported. This randomized study was conducted to select the most suitable regimen for future evaluation. PATIENTS AND METHODS: SCLC patients who had relapsed more than 90 days after their first-line platinum-doublet regimen were randomized to receive amrubicin (40mg/m(2), days 1-3) or re-challenge with platinum doublet. Primary endpoint was objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival and toxicity profiles. We assumed that an ORR of 50% indicates potential usefulness, while that of 30% would constitute the lower limit of interest (alpha 0.1; beta 0.1). Initial estimated accrual was 28 patients to each arm. RESULTS: From February 2008 to June 2013, 60 patients were enrolled and 57 patients (27 amrubicin and 30 re-challenge) were found to be evaluable for efficacy and safety. The ORR and PFS were 67% (90% confidence interval, 52-82) and 5.4 months in the amrubicin group, and 43% (90% confidence interval, 28-58) and 5.1 months in the re-challenge group, respectively. Although grade 3 febrile neutropenia was observed in 19% of patients in the amrubicin group, these episodes were transient and manageable. Non-hematological toxicities were generally moderate and no treatment-related death was observed in either group. CONCLUSION: Only amrubicin met the primary endpoint. Moreover, amrubicin demonstrated superior efficacy over re-challenge of platinum with acceptable levels of toxicity. Further evaluation of amrubicin for sensitive-relapsed SCLC is warranted.
Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Small Cell Lung Carcinoma/drug therapy , Adult , Aged , Aged, 80 and over , Anthracyclines/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carboplatin/administration & dosage , Chemotherapy-Induced Febrile Neutropenia/etiology , Cisplatin/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Humans , Irinotecan , Japan , Male , Middle Aged , Retreatment , Survival RateABSTRACT
INTRODUCTION: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non-responders. METHODS: Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin-paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders. RESULTS: Five (4.9%) and 9 (8.2%) cases in the carboplatin-paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin-paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) (P=0.044 and P=0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (OS). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation. CONCLUSIONS: NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Smoking/adverse effects , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/genetics , Clinical Trials, Phase III as Topic , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , Exons/drug effects , Exons/genetics , Female , Gefitinib , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation/drug effects , Mutation/genetics , Paclitaxel/administration & dosage , Retrospective Studies , Sequence Deletion/drug effects , Sequence Deletion/genetics , Treatment OutcomeABSTRACT
OBJECTIVE: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL). METHODS: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 - 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL. RESULTS: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups. CONCLUSION: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.