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Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

ABSTRACT: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles.Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.

SUBMITTER: Shen X

PROVIDER: S-EPMC3050732 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

Shen Xinglei X Denittis Albert A Werner-Wasik Maria M Axelrod Rita R Gilman Paul P Meyer Thomas T Treat Joseph J Curran Walter J WJ Machtay Mitchell M

Radiation oncology (London, England) 20110216

<h4>Background</h4>This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).<h4>Methods</h4>Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of ...[more]

PMID: 21324160

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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:ImportanceFew clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.ObjectiveTo determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.Design, setting, and participantsThis open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.InterventionsPatients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.Main outcomes and measuresThe primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.ResultsOf the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n?=?217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n?=?216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority?=?.003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.Conclusion and relevanceCarboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.

Project description:BackgroundEndostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).MethodsNineteen patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-l, and adequate organ function were treated with 60-66 Gy thoracic radiation therapy over 30-33 fractions concurrent with weekly 7.5 mg/m(2) endostatin for 14 days, 50 mg/m(2) paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m(2) endostatin for 14 days, 150 mg/m(2) paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment. The objective response rate was recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria.ResultsSix patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 12 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% (95% confidence interval [CI], 51%-97%). The median progression-free survival was 10 months (95% CI, 7.6-12.3 months), and the median overall survival was 14 months (95% CI, 10.7-17.2 months). Early 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity a few months after chemoradiotherapy, leading to the early closure of the trial according to the study design.ConclusionsThe result of concurrent endostatin treatment with chemoradiotherapy in locally advanced unresectable NSCLC did not meet the goal per study design with unacceptable toxicity. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined. (NCT 01158144).

Dataset Information

Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

Publications

Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

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