Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial.

Background: To investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Methods: CORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020-October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 µg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models. Results: Overall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70-1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0-16.0) and 14.0 (12.0-16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively. Conclusion: In patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test. Clinical Trial Registration: ClinicalTrials.gov, NCT04703205.

Multicenter, single-arm phase II study of modified carboplatin/nab-paclitaxel in untreated performance status 2 patients with advanced non-small cell lung cancer: TORG1426.

Background: Currently, only a few treatment options exist for performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC), whereas the carboplatin/nab-paclitaxel (CBDCA/nab-PTX) regimen is attracting attention as a standard of care for PS 0-1 patients because of its wide suitability and modest risk of peripheral neuropathy. However, the treatment dose and schedule should be optimized for PS 2 patients. Therefore, we planned a single-arm phase II study to characterize the efficacy and tolerability of our modified CBDCA/nab-PTX regimen for untreated PS 2 patients with advanced NSCLC. Methods: Enrolled patients were treated with CBDCA (area under the curve 5 on day 1) plus nab-PTX (70 mg/m2 on days 1, 8, and 15) every 4 weeks for up to six cycles. The primary endpoint was the progression-free survival (PFS) rate at 6 months. As exploratory analyses, the reasons for PS 2 (disease burden versus comorbidities/indeterminant) and the Charlson Comorbidity Index (CCI) were evaluated as efficacy indicators. Results: This study was terminated early because of slow accrual. Seventeen patients [median age, 68 years (range, 50-73 years)] received a median of three cycles. The 6-month PFS rate, median PFS, and median overall survival were 20.8% [95% confidence interval (CI): 0-41.6], 3.0 months (95% CI: 1.7-4.3), and 9.5 months (95% CI: 5.0-14.0), respectively. Exploratory analyses suggested better overall survival in patients whose PS was not attributable to the disease burden (median, 9.5 vs. 7.2 months) or whose CCI was ≤3 (median, 15.5 vs. 7.2 months). Grade 3-4 adverse events occurred in 12 (71%) patients, and grade 5 pleural infection occurred in one (6%) patient. Meanwhile, only one (6%) patient each experienced grade 1 peripheral neuropathy and grade 2 interstitial pneumonitis. Conclusions: No conclusion could be drawn from this study because of its early termination. However, our modified CBDCA/nab-PTX regimen might be useful for PS 2 patients who hesitate to use regimens other than nab-PTX, and particularly patients concerned about peripheral neuropathy or interstitial pneumonitis. The potential role of PS 2 and CCI as efficacy predictors for this regimen should be further examined.

Promising Response to Dabrafenib Plus Trametinib in a Patient with Peritoneal Carcinomatosis from Non Small Lung Cancer Harboring BRAF V600E Mutation.

Background: The prognosis of peritoneal carcinomatosis in patients with lung cancer is poor. However, some cases of peritoneal carcinomatosis from lung cancer harboring specific gene alterations have responded to molecular targeted drugs. B-Raf proto-oncogene (BRAF) mutations occur in about 2-4% of NSCLCs, with about half of these cases having the BRAF V600E mutation. Concomitant inhibition of BRAF with dabrafenib and inhibition of the downstream mitogen-activated protein kinase with trametinib showed efficacy in NSCLC patients with the BRAF V600E mutation. Herein, we report a patient with peritoneal carcinomatosis from lung cancer with the BRAF V600E mutation who responded to dabrafenib plus trametinib. Case Presentation: A 67-year-old Japanese male never-smoker was diagnosed with stage IA3 lung adenocarcinoma. He underwent thoracoscopic left lower lobectomy but developed recurrence of the cancer with peritoneal carcinomatosis 33 months after the operation. An Oncomine Dx target test of the resected specimen was positive for the BRAF V600E mutation. He was started on dabrafenib 150 mg twice per day and trametinib 2 mg once per day. He had a good clinical response to dabrafenib/trametinib therapy with resolution of abdominal distention. He continued dabrafenib/trametinib treatment without disease progression for 7 months, with no severe adverse effects. Conclusion: This case highlights the importance of assessing genetic alterations in lung cancer patients with peritoneal carcinomatosis and treating them with appropriate molecular targeted drugs.

Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.

IMPORTANCE: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. OBJECTIVE: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. INTERVENTIONS: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. RESULTS: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier: UMIN000023761.

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.

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

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

MET amplification results in heterogeneous responses to osimertinib in EGFR-mutant lung cancer treated with erlotinib.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is approved for untreated, or previously EGFR-TKI-treated T790M-positive EGFR-mutated non-small cell lung carcinoma (NSCLC). We investigated the heterogeneity of responses to osimertinib and its underlying mechanisms. A patient with EGFR-L858R-mutated NSCLC was treated with erlotinib. Following treatment, he developed brain and multiple bone metastases and was eventually diagnosed with NSCLC with EGFR-T790M mutation. The responses of various tumor specimens to osimertinib were heterogeneous. We investigated EGFR-T790M and MET amplification using PCR and FISH in autopsy specimens of the cervical spine, lumbar spine, and brain. We established the KNZ osimertinib-resistant (KNZ_OR) tumor cell line with MET amplification using a cervical spine lesion that was intrinsically resistant to osimertinib. We evaluated the effects of MET knockdown and MET inhibitor on KNZ_OR cell sensitivity to osimertinib in vitro and in vivo. Osimertinib-resistant lesions (cervical spine and brain) showed EGFR-L858R and MET amplification, but not EGFR-T790M, whereas osimertinib-sensitive lesions (lumbar spine) showed EGFR-L858R and -T790, but not MET amplification. Osimertinib decreased the association of amplified MET with L858R-mutated EGFR but increased that with human epidermal growth factor receptor 3 in KNZ_OR cells. MET knockdown or MET inhibitor sensitized KNZ_OR cells to osimertinib in vitro, indicating that MET amplification induced osimertinib resistance. Combination with osimertinib plus crizotinib induced tumor shrinkage in the KNZ_OR xenograft model. Hence, MET amplification might induce heterogeneous responses to osimertinib in EGFR-mutated NSCLC. Further investigations on mutated EGFR and amplified MET might lead to the development of effective therapies.

Real-world assessment of afatinib for patients with EGFR-positive non-small cell lung cancer.

Introduction Afatinib is used to treat patients with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations; however, the clinicopathological factors that predict this drug's effectiveness in real-world settings remain unclear. We therefore evaluated the effectiveness of afatinib in such patients and assessed potential prognostic factors. Methods We retrospectively investigated patients with NSCLC who received first-line afatinib between July 2014 and August 2018. Variables (including sex, age, performance status, neutrophil-to-lymphocyte ratio, EGFR genotype, smoking status, clinical stage prior to treatment [stage IV vs.. postoperative recurrence], presence or absence of brain metastases, body surface area, any afatinib dose reductions, and afatinib starting dose [40 vs.. 20 or 30 mg]) were subjected to a Cox proportional hazards regression model to estimate progression-free survival (PFS). Results Forty-eight patients with a median age of 67 years were included; the objective response rate was 62.5% (30 patients). The median PFS was 14.1 months; the PFS periods were 11.8 and 15.9 months for patients receiving 40 mg versus 20-30 mg of afatinib (P = 0.41), respectively, and were 14.5 and 13.8 months for patients who required afatinib dose reduction and those who did not, respectively (P = 0.80). The PFS tended to be longer in patients without brain metastases (albeit not significantly). Ultimately, no significant predictive values for PFS were identified. Conclusions Afatinib is effective for patients with NSCLC harboring common EGFR mutations irrespective of their clinicopathological backgrounds. A direct comparison of afatinib and osimertinib in treatment-naïve patients is warranted to determine the optimal standard of care.

Bronchoesophageal fistula formation after three courses of nivolumab for carcinoma of unknown primary with a subgroup of lung squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) are widely used in both monotherapy and combination chemotherapy for various types of cancers. Nivolumab is the most popular among ICIs, and the number of adapted malignant diseases for nivolumab is increasing. Bronchoesophageal fistula formation is a serious complication of the treatment for esophageal or lung cancer. However, the development of bronchoesophageal fistula as a complication of ICIs is obscure. A 59-year-old man who was diagnosed with carcinoma of unknown primary with a subgroup of lung squamous cell carcinoma had bronchoesophageal fistula formation after three cycles of nivolumab as the fourth line treatment. Before the initiation of nivolumab, he had received two esophageal stents and an angiogenesis inhibitor. These are known risk factors for fistula formation. This is a rare case showing that nivolumab monotherapy might induce bronchoesophageal fistulae. Therefore, clinicians should be aware of the factors related to fistula formation when using ICIs.

Aberrant Methylation of Tumor Suppressive miRNAs in Bile from Patients With Pancreaticobiliary Diseases.

BACKGROUND/AIM: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases. MATERIALS AND METHODS: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined. RESULTS: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases. CONCLUSION: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases.

Patient-derived xenograft models of non-small cell lung cancer for evaluating targeted drug sensitivity and resistance.

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.

Questionnaire survey on patient awareness of invasive rebiopsy in advanced non-small cell lung cancer.

BACKGROUND: Treatment strategies for patients with non-small cell lung cancer (NSCLC) depend on various factors including physical condition, complications, tumor histology, and molecular profiling. Even if initial chemotherapy is efficacious, almost all patients develop treatment resistance. Invasive rebiopsy from sites of recurrence might provide insight into resistance mechanisms and aid in the selection of suitable sequential antitumor drugs. However, invasive rebiopsy might be challenging because of limited tissue availability and patient burden. Therefore, this study aimed to assess awareness of invasive rebiopsy among non-small cell lung cancer patients. METHODS: This prospective questionnaire survey was performed between June 2015 and March 2016 in patients with advanced non-small cell lung cancer. The survey was carried out at two time points: before starting first-line chemotherapy (cohort 1), and at the time of disease progression after initial chemotherapy, but before second-line chemotherapy (cohort 2). RESULTS: In this study, 50 and 30 patients were enrolled in cohorts 1 and 2, respectively. In cohort 1, 37 (74%) patients agreed to rebiopsy, if disease progression occurred, whereas 18 (60%) patients in cohort 2 agreed to invasive rebiopsy at disease progression. The primary reasons for rebiopsy rejection were poor physical condition and patient burden related to the initial biopsy. Seven patients answered the survey questions during the treatment course, and the acceptance rate was lower among patients who agreed to rebiopsy at disease progression than before treatment. CONCLUSIONS: Invasive rebiopsy can lead to distress in some patients. To improve the consent rate for tissue rebiopsy, treatment strategies including rebiopsy should be discussed with patients during the early treatment phase.

Activity of Nivolumab and Utility of Neutrophil-to-Lymphocyte Ratio as a Predictive Biomarker for Advanced Non-Small-Cell Lung Cancer: A Prospective Observational Study.

BACKGROUND: The immune checkpoint inhibitor nivolumab is entering routine oncologic practice. We investigated the safety and efficacy of nivolumab in the real world and alternative predictive factors for survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a prospective observational study to evaluate the activity of nivolumab treatment for chemotherapy-refractory NSCLC. Patients were treated with nivolumab once every 2 weeks, and the efficacy was assessed every 8 ± 2 weeks. RESULTS: Fifty-two patients were enrolled after nivolumab approval in Japan. These patients received a median of 4 (range, 1-43) cycles of nivolumab. Overall objective response was observed in 12 patients (23.1%). Median progression-free survival was 2.1 (95% confidence interval, 1.0-3.2) months, and 1-year overall survival rate was 59.9%. A total of 23 immune-related adverse events occurred in 20 patients, as follows: 7 cases of pneumonitis, 6 of oral mucositis, 5 of hypothyroidism, 2 of colitis, 2 of liver dysfunction, and 1 of arthritis. All patients recovered after appropriate management. A pretreatment neutrophil-to-lymphocyte ratio (NLR) of ≥ 5 was significantly associated with poor prognosis compared to NLR < 5 (hazard ratio, 4.52; 95% confidence interval, 1.84-11.14; P = .013), independently. CONCLUSION: Nivolumab showed promising activity with a manageable safety profile in clinical practice, consistent with effects of previous clinical trials. This drug could affect a specific population of patients with advanced NSCLC, and pretreatment NLR was a candidate for surrogate markers for survival benefit of patients with NSCLC treated with nivolumab.

Prognostic significance of the 8th edition of the TNM classification for patients with extensive disease small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is typically categorized according to disease extent as limited or extensive, and utility of the 8th TNM classification, recommended for lung cancer staging, which demonstrates a strong association with non-small-cell lung cancer (NSCLC) management, remains unclear. METHODS: This retrospective study included 277 consecutive SCLC patients treated at a single institution between 2008 and 2016. RESULTS: According to the currently used two-stage system, 186 (65.7%) of the patients were classified as having extensive disease (ED)-SCLC. Among the ED-SCLC patients, ten (5.3%), 38 (20.4%), 32 (17.2%), and 106 (57.0%) were categorized into stages M0, M1a, M1b, and M1c, respectively, according to the 8th TNM classification. There was a significant difference in overall survival based on the M descriptors: 15.8 (95% CI 9.4-22.2) months in the M1b group vs 7.3 (95% CI 5.7-8.9) months in the M1c group (P<0.001). Multivariate analysis showed that in addition to the known prognostic factors such as performance status, serum albumin, and lactate dehydrogenase, M descriptor was a prognostic factor (HR 1.95, 95% CI 1.38-2.77; P<0.001). CONCLUSION: The 8th TNM classification has a prognostic value in SCLC. Similarly to NSCLC, treatment approaches should be considered on the basis of the 8th TNM classification, especially stage IVA separate from stage IVB in ED-SCLC patients.

Nab-paclitaxel plus carboplatin as an effective and safe chemotherapy regimen for pulmonary carcinosarcoma with interstitial lung disease: A case report.

Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.

Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016.

BACKGROUND: Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. RESULTS: A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1-36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074). CONCLUSIONS: A combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004368 . Registered date; October 11, 2010 (Retrospectively registered).

Phase I study of Nedaplatin, a platinum based antineoplastic drug, combined with nab-paclitaxel in patients with advanced squamous non-small cell lung cancer.

Background This study was designed to determine the recommended dose of a combination of nedaplatin (NED) and nab-paclitaxel (nab-PTX) in chemotherapy-naive patients with advanced squamous non-small-cell lung cancer (NSCLC). Methods Patients received escalating doses of NED on day 1 and nab-PTX on days 1, 8, and 15 every 4 weeks by an intravenous infusion for up to six cycles. Results A dose of 100 mg/m2 NED and 100 mg/m2 nab-PTX was determined to be the recommended dose for patients with advanced squamous NSCLC. The study had an overall response rate of 66.7% (95% confidence interval [CI]: 38.4-88.2) and disease control rate of 93.3% (95% CI: 68.1-99.8). The median progression-free survival time and survival time was 7.0 months (95% CI: 5.9-8.1) and 13.1 months (95% CI: 6.2-20.1), respectively. The most common adverse events were neutropenia (grade 3/4, 33%) and leukopenia (grade 3/4, 27%). Although peripheral neuropathy was observed in 5 patients (grade 1/2), non-hematological toxic effects were relatively mild. Febrile neutropenia, pneumonitis, and treatment-related death were not observed. Conclusions The combination of NED and nab-PTX was a tolerable and effective regimen and its recommended dose was 100 mg/m2 and 100 mg/m2, respectively, in chemotherapy-naive patients with advanced squamous NSCLC (UMIN000010963).

The role of prophylactic cranial irradiation for patients with small-cell lung cancer.

Small-cell lung cancer (SCLC) has a particular propensity to metastasize to the brain, affecting ~10% of SCLC patients at diagnosis, but may occur in more than 50% of 2-year survivors. Most cytotoxic drugs have limited ability to cross the blood-brain barrier, and the effectiveness of chemotherapy for brain metastasis is limited. Therefore, prophylactic cranial irradiation (PCI) has been proposed to treat SCLC. A meta-analysis revealed that PCI significantly decreased the risk of brain metastasis and increased the 3-year survival rate; it has been established as a standard therapy for limited-disease SCLC. However, certain aspects of PCI remain unclarified, including the roles in resected SCLC and extensive-disease SCLC, and its neurotoxicities. In addition, information on PCI has been obtained from old clinical trials without the use of new imaging devices, such as magnetic resonance imaging. Evidence from advanced imaging techniques is needed in this era.

Evaluation of concurrent chemoradiotherapy for locally advanced NSCLC according to EGFR mutation status.

Concurrent chemoradiotherapy (cCRT) is the standard treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, the efficacy and safety of this treatment has not been compared between patients who possess epidermal growth factor receptor (EGFR) mutations and patients with wild-type EGFR. The objective of the present study was to evaluate the effect of the presence of EGFR gene mutations in patients with LA-NSCLC receiving cCRT. Between January 2007 and December 2013, the records of 64 patients were reviewed retrospectively. The data were statistically analyzed to evaluate the efficacy of cCRT according to EGFR mutation status. In total, 15/64 were revealed to possess EGFR mutations, 23%, and comprised the mutant EGFR group. The progression-free survival time was significantly shorter in the mutant EGFR group compared with the patient group with tumors exhibiting wild-type EGFR, 6.3 and 9.5 months, respectively (P<0.001). The overall survival rate was longer in the mutant EGFR group compared with the wild-type EGFR group, although the difference was not statistically significant, 37.1 and 21.1 months, respectively (P=0.26). The disease recurred in all of the patients of the mutant EGFR group, whilst the recurrence rate in the wild-type EGFR group was 89%. The frequency of distant metastasis was significantly higher in the mutant EGFR group compared with the wild-type EGFR group. In conclusion, these data suggest that additional studies are required to identify strategies for reinforcing the efficacy of cCRT, with a focus on the potential use of EGFR tyrosine kinase inhibitors for patients exhibiting an EGFR mutation.