Oral vinorelbine plus cisplatin with concomitant radiotherapy as induction therapy for stage III non-small cell lung cancer: Results of a single-arm prospective cohort study.
ABSTRACT: BACKGROUND:Concurrent chemoradiotherapy (CCRT) is an optimal recommended treatment for stage III non-small cell lung cancer (NSCLC). Herein, we aimed to investigate the efficacy and safety of oral vinorelbine plus cisplatin with concomitant radiotherapy for stage III NSCLC. METHODS:This prospective, open-label, single-arm, observational cohort study was performed between January 2010 and September 2016. Patients were treated with two cycles of chemotherapy with 60 mg/m2 intravenous cisplatin on day 1 and 50 mg/m2 oral vinorelbine on days 1, 8, and 15; radiotherapy was administered concurrently from day 1 when chemotherapy was initiated. A total dose of 66-70 Gy radiotherapy was delivered in daily fractions of 2 Gy for 6.5-7 consecutive weeks. The tumor response was assessed after completing concomitant treatment. RESULTS:A total of 58 patients were enrolled and analyzed; 31 patients had stage IIIA NSCLC and 27 had stage IIIB NSCLC. After induction CCRT, 31 patients achieved an objective response (complete response in one and partial response in 30; the response rate was 53.4%). The median progression-free survival was 6.73 months (95% confidence interval [CI], 5.42-7.91), duration of response was 12.30 months (95% CI, 5.59-19.01), and overall survival was 24.83 months (95% CI, 19.26-30.21). No treatment-related mortality was observed, and neutropenia was the most common grade 3 and 4 treatment-related toxicity (11 patients; 18.9%). CONCLUSIONS:CCRT with the weekly regimen of oral vinorelbine plus triweekly cisplatin was effective and safe for stage III NSCLC.
Project description:Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT.Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy.Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis.In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens.ClinicalTrials.gov, NCT01839032.
Project description:BACKGROUND:Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy. METHODS:Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60?Gy, comprising 2?Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UMIN000002420). RESULTS:From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm. CONCLUSIONS:The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.
Project description:Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.
Project description:Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.Due to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)).The benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.
Project description:In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated.Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m d1, 8; 40 mg/m d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m d1, 8 and 8 mg/m d22, 29; (2) 20 mg/m d1, 8 and 8 mg/m d22, 29; (3) 20 mg/m d1, 8; 15 mg/m d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography.Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients.C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m d7 and 250 mg/m weekly, cisplatin 50 mg/m d1, 8; 40 mg/m d22 and vinorelbine 20 mg/m d1, 8; 15 mg/m d22, 29 for 5 weeks together with RT.
Project description:PURPOSE:The outcomes of locoregionally advanced nasopharyngeal carcinoma patients treated with concurrent chemoradiation (CCRT) using intensity-modulated radiotherapy (IMRT) with/without neoadjuvant chemotherapy (NCT) were evaluated. MATERIALS AND METHODS:Eighty-three patients who underwent NCT followed by CCRT (49%) or CCRT with/without adjuvant chemotherapy (51%) were reviewed. To the gross tumor, 67.5 Gy was prescribed. Weekly cisplatin was used as concurrent chemotherapy. RESULTS:With a median follow-up of 49.4 months, the 5-year local control, regional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival rates were 94.7%, 89.3%, 77.8%, 68.0%, and 81.8%, respectively. In multivariate analysis, the American Joint Committee on Cancer stage (p = 0.016) and N stage (p = 0.001) were negative factors for DMFS and DFS, respectively. Overall, NCT demonstrated no benefit and an increased risk of severe hematologic toxicity. However, compared to patients treated with CCRT alone, NCT showed potential of improving DMFS in stage IV patients. CONCLUSION:CCRT using IMRT resulted in excellent local control and survival outcome. Without evidence of survival benefit from phase III randomized trials, NCT should be carefully administered in locoregionally advanced nasopharyngeal carcinoma patients who are at high-risk of developing distant metastasis and radiotherapy-related mucositis. The results of ongoing trials are awaited.
Project description:<h4>Objective</h4>The aim of this study was to compare the efficacy and toxicity of different concurrent chemoradiotherapy (CCRT) regimens in the treatment of advanced cervical cancer (CC) by adopting a network meta-analysis.<h4>Methods</h4>We searched PubMed and Cochrane Library from the inception of these databases to September 2016, and all cohort studies (CSs) related to different CCRT regimens in the treatment of CC were included. A network analysis was adopted to compare the combination of direct and indirect evidence, to analyze the odds ratio (OR), and to draw a surface under the cumulative ranking curve of the efficacy and toxicity of different CCRT regimens for CC. Cluster analyses were used to group each category based on similar treatment regimens.<h4>Results</h4>Nineteen CSs were enrolled in this network meta-analysis, including 12 CCRT regimens (radiotherapy [RT], CCRT [cisplatin], CCRT [vinorelbine], CCRT [paclitaxel], CCRT [hydroxyurea], CCRT [cisplatin?+?FU], CCRT [cisplatin?+?gemcitabine], CCRT [cisplatin?+?docetaxel], CCRT [cisplatin?+?paclitaxel], CCRT [cisplatin?+?amifostine], CCRT [cisplatin?+?FU?+?hydroxyurea], and CCRT [cisplatin?+?vincristine?+?bleomycin]). The results of the network meta-analysis showed that regarding efficacy, the overall response rate of CCRT (cisplatin?+?docetaxel) was higher than RT, and the 5-year overall survival (OS) rate of CCRT (cisplatin?+?FU?+?hydroxyurea) was relatively higher than CCRT (hydroxyurea). As for toxicity, CCRT (cisplatin) had a lower incidence of leukopenia than CCRT (hydroxyurea), CCRT (cisplatin?+?FU) and CCRT (cisplatin?+?paclitaxel), and the incidences of diarrhea and vomiting in CCRT (cisplatin) were lower than those in CCRT (cisplatin?+?gemcitabine). Additionally, the cluster analysis showed that CCRT (cisplatin) had relatively lower incidences of both hematotoxicity and gastrointestinal toxicity, and CCRT (paclitaxel) had lower gastrointestinal toxicity than other regimens.<h4>Conclusion</h4>Our study demonstrated that CCRT (cisplatin?+?docetaxel) might be the best choice of CCRT regimens in the treatment of CC, and the 5-year OS rate of CCRT (cisplatin?+?FU?+?hydroxyurea) might be the highest among these different regimens. CCRT (cisplatin) might have the lowest toxicity among all the CCRT regimens.
Project description:Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age <or=75 years, and adequate organ function were eligible. Both docetaxel and cisplatin were given on days 1, 8, 29, and 36. Doses of docetaxel/cisplatin (mg m(-2)) in the phase I study portion were escalated as follows: 20/30, 25/30, 30/30, 30/35, 30/40, 35/40, 40/40, and 45/40. Beginning on day 1 of chemotherapy, thoracic radiotherapy was given at a total dose of 60 Gy with 2 Gy per fraction over 6 weeks. In the phase I portion, the maximum tolerated doses (MTD) among 33 patients were docetaxel 45 mg m(-2) and cisplatin 40 mg m(-2). The major dose-limiting toxicity (DLT) was radiation oesophagitis. The recommended doses (RDs) for the phase II study were docetaxel 40 mg m(-2) and cisplatin 40 mg m(-2). A total of 42 patients were entered in the phase II portion. Common toxicities were leukopenia, granulocytopenia, anaemia, and radiation oesophagitis, with frequencies of grade >or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.
Project description:<h4>Importance</h4>Treatment of locally advanced non-small cell lung cancer (NSCLC) remains challenging. The rationale of combining a cyclooxygenase 2 (COX-2) inhibitor with concurrent chemoradiation (CCRT) was based on results of preclinical research and prospective clinical studies; however, no randomized clinical trial has provided evidence of a direct comparison with CCRT alone.<h4>Objective</h4>To determine the effect of combined selective COX-2 inhibition with standard CCRT on survival among patients with unresectable stage III NSCLC.<h4>Design, setting, and participants</h4>A single-center, open-label, randomized phase 2 clinical trial was performed among 96 patients who had histologically and cytologically confirmed unresectable stage III NSCLC. Participants were enrolled from November 2011 to August 2015. Data were analyzed from February to October 2018.<h4>Intervention</h4>Patients were randomized to receive thoracic radiation, 60 Gy, for 6 weeks concurrent with etoposide and cisplatin or the same regimen of CCRT combined with 200 mg of celecoxib, taken twice daily.<h4>Main outcomes and measures</h4>The primary end point was overall survival. The secondary end points were the proportion of patients with treatment-related toxic effects, progression-free survival, and overall survival in subgroups with and without the COX-2 genotype.<h4>Results</h4>A total of 100 patients were randomized. Following the exclusion of 4 outliers, 96 participants (96.0%) were analyzed (51 randomized to CCRT alone and 45 randomized to CCRT with celecoxib; mean [SD] age, 60.0 [8.3] years; 73.0 [76.0%] male). The median overall survival time was 32.8 (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 (95% CI, 25.8-45.2) months in the group that received CCRT alone (P = .88). Celecoxib with CCRT was well tolerated; the incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49). Among patients with the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio, 0.36; 95% CI, 0.13-1.04; P = .05) or overall survival (hazard ratio, 0.50; 95% CI, 0.15-1.72; P = .26) compared with CCRT alone.<h4>Conclusions and relevance</h4>In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic radiation pneumonitis. Among patients with the high-risk genotype, adding celecoxib to CCRT did not improve overall or progression-free survival.<h4>Trial registration</h4>ClinicalTrials.gov identifier: NCT01503385.
Project description:Background and purpose:We investigated the incidence and dose-volume relationships of radiation pneumonitis (RP) after concurrent chemoradiotherapy (CCRT) followed by durvalumab for locally advanced non-small-cell lung cancer (LA-NSCLC). Materials and methods:We retrospectively analyzed records of 36 patients with LA-NSCLC who underwent CCRT followed by durvalumab. Incidence of RP was analyzed for correlations with clinical factors and dose-volume parameters of lung in radiotherapy. Results:All patients received 60 Gy in 30 fractions of radiotherapy with concurrent chemotherapy. Over a median follow-up period of 7 months, incidence of grade ?2 RP was 36% (including grade 3 RP: 5% and grade 5 RP: 3%). Age, sex, Brinkman index, and blood test results did not significantly differ between patients with grade ?2 RP and grade ?1 RP. Dose-volume parameters (lung volumes that received 5 Gy, 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and mean lung dose) were significantly higher among patients with grade ?2 RP compared with patients with grade ?1 RP. Conclusion:Incidence of grade ?2 RP was 36% after CCRT followed by durvalumab for LA-NSCLC, but did not significantly differ from those of patients treated with CCRT alone. Lung dose-volume parameters were significantly correlated with RP.