Dataset Information

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

ABSTRACT: The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3? inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/carboplatin in 20-25% of the SCLC lines. Only 10-15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

SUBMITTER: Teicher BA

PROVIDER: S-EPMC5548882 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Teicher Beverly A BA Silvers Thomas T Selby Michael M Delosh Rene R Laudeman Julie J Ogle Chad C Reinhart Russell R Parchment Ralph R Krushkal Julia J Sonkin Dmitriy D Rubinstein Larry L Morris Joel J Evans David D

Cancer medicine 20170801 8

The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in ...[more]

PMID: 28766886

Similar Datasets

Project description:BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is an aggressive disease with poor survival, and platinum-etoposide chemotherapy is indicated as the mainstay of treatment. In this study, we compared the efficacy and safety between the cisplatin plus etoposide (EP) and carboplatin plus etoposide (EC) regimens.MethodsA total of 1305 patients with previously untreated ES-SCLC were included in this study. Data from five trials were collected from the public database Project Data Sphere. Survival analysis and adverse events (AEs) analysis were conducted.ResultsOf the 1305 patients, 800 received the EC regimen whereas 505 received the EP regimen as their front-line treatment. Overall, the median progression-free survival (PFS) and the median overall survival (OS) were 172 and 289 days, respectively. The EP and EC treatment groups did not have significantly different PFS or OS. After adjusting for age, sex, body mass index (BMI) and Eastern Cooperative Oncology Group (ECOG) performance status (PS), the EP regimen was independently associated with better PFS (hazard ratio [HR] = 0.76, 95% CI = 0.63-0.92, p = 0.0041) and OS (HR = 0.79, 95% CI = 0.64-0.97, p = 0.0220) among patients who were overweight and obese (BMI ≥ 25 kg/m2). In the safety analysis, patients who received the EC treatment experienced significantly more grade ≥ 3 AEs (n = 599, 74.9%) than those who received the EP treatment (n = 337, 66.7%; p = 0.002). Furthermore, the EC regimen was associated with a higher risk of grade 3-4 neutropaenia (p = 0.001), thrombocytopaenia (p < 0.001) and hyponatraemia (p = 0.036), whereas the EP regimen was associated with a higher risk of grade 3-4 vomiting (p = 0.021).ConclusionsIn summary, this study presented the efficacy and safety of the EC and EP regimens in patients with ES-SCLC in the first-line setting. Patients who are overweight and obese benefit more from the EP regimen than EC regimen. Approaches to define the optimal chemotherapy regimen in different BMI subgroups are needed.

Project description:BackgroundMany physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.ObjectiveThis was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).MethodsData from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.ResultsThe ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3-4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23-0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20-0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32-0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34-0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3-4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.ConclusionThe benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk-benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.

Project description:BackgroundPatients with extensive-stage small-cell lung cancer (ES-SCLC) have a particularly poor prognosis. And the treatment options for patients with relapsed or refractory ES-SCLC are limited. Thus, we conducted an open-label, multicenter, single-arm phase II clinical trial to assess the efficacy and safety of apatinib plus etoposide capsules as the third- or further-line treatment in ES-SCLC patients.MethodsPatients with ES-SCLC who experienced disease progression following 2 to 3 previous therapies from 11 medical centers in China were enrolled to receive apatinib (250 mg/d, continuously) and etoposide capsules (50 mg/d, on day 1-21, per 28 days). The treatment continued until disease progression, treatment intolerance, or death. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and safety.ResultsFifty-six patients with relapsed or refractory ES-SCLC were enrolled from January 2018 to February 2020 and 53 of them were eventually included in the evaluation population. The median follow-up was 9.8 months. At the data cut-off time (March 5, 2020), 39 patients (74%) had died and 44 (83%) had progressed. The median PFS was 3.0 months (95% CI, 2.1-3.9) and the median OS was 5.0 months (95% CI, 3.6-6.4). No complete responses were seen. Eleven patients (21%) showed a best response of partial response and 37 (70%) patients achieved stable disease. The ORR was 20.8% (11/53), and the disease control rate (DCR) was 90.6% (48/53). The 6-month OS rate was 40.1% (95% CI, 26.2-54). After 12 months, the OS rate was 18.4% (95% CI, 4.7-32.1). Possible treatment-related grade III/IV adverse events included leukopenia [8 (15.1%)], neutropenia [7 (13.2%)], anemia [4 (7.4%)], and hand-foot syndrome [2 (3.8%)]. During the study, no mortality occurred as a consequence of treatment.ConclusionsApatinib combined with etoposide capsules exhibits efficacy and has an acceptable safety profile. It could be used as a later-line treatment for ES-SCLC patients who have been heavily pretreated with standard therapies. Further exploration of apatinib combined with etoposide capsules in phase III trials is warranted.

Dataset Information

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Publications

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure