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Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

ABSTRACT: Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease, and appropriate patients are candidates for chemoradiotherapy with curative intent. The optimal treatment paradigm is currently undefined. Concurrent chemoradiotherapy, compared with sequential chemotherapy and thoracic radiation therapy (TRT), results in superior overall survival outcomes as a result of better locoregional control. Recent trials have revealed efficacy for newer chemotherapy combinations similar to that of older chemotherapy combinations with concurrent TRT and a lower rate of some toxicities. Ongoing phase III trials will determine the roles of cisplatin and pemetrexed concurrent with TRT in patients with nonsquamous histology, cetuximab, and the L-BLP25 vaccine. It is unlikely that bevacizumab will have a role in stage III disease because of its toxicity. Erlotinib, gefitinib, and crizotinib have not been evaluated in stage III patients selected based on molecular characteristics. The preliminary results of a phase III trial that compared conventionally fractionated standard-dose TRT (60 Gy) with high-dose TRT (74 Gy) revealed an inferior survival outcome among patients assigned to the high-dose arm. Hyperfractionation was investigated previously with promising results, but adoption has been limited because of logistical considerations. More recent trials have investigated hypofractionated TRT in chemoradiotherapy. Advances in tumor targeting and radiation treatment planning have made this approach more feasible and reduced the risk for normal tissue toxicity. Adaptive radiotherapy uses changes in tumor volume to adjust the TRT treatment plan during therapy, and trials using this strategy are ongoing. Ongoing trials with proton therapy will provide initial efficacy and safety data.

SUBMITTER: Stinchcombe TE

PROVIDER: S-EPMC3360908 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

Stinchcombe Thomas E TE Bogart Jeffrey A JA

The oncologist 20120424 5

Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease, and appropriate patients are candidates for chemoradiotherapy with curative intent. The optimal treatment paradigm is currently undefined. Concurrent chemoradiotherapy, compared with sequential chemotherapy and thoracic radiation therapy (TRT), results in superior overall survival outcomes as a result of better locoregional control. Recent trials have revealed efficacy for newe ...[more]

PMID: 22531360

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Project description:ImportanceLocal failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor.ObjectiveTo evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival.Design, setting, and participantsThis prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors.InterventionsOral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT.Main outcomes and measuresGraded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). The cumulative incidence of local failure was 39% (95% CI, 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI, 6.2-17.1 months). Median overall survival for all patients was 41.1 months (95% CI, 19.0-63.1 months); the 5-year mean (SE) overall survival rate was 37.1% (8.2%).Conclusions and relevanceThis study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT.Trial registrationClinicalTrials.gov identifier: NCT00589056.

Project description:Purpose:To investigate the prognostic utility of the prognostic nutritional index (PNI) in stage IIIB non-small-cell lung carcinoma (NSCLC) patients undergoing concurrent chemoradiotherapy (CRT). Methods:A total of 358 stage IIIB NSCLC patients who received a total dose of 60-66 Gy (2 Gy/fraction) radiotherapy and ?1 cycle(s) of platinum-based chemotherapy were analyzed. The receiver operating curve analysis was utilized to identify the optimal PNI cut-off value demonstrating a significant connection with the overall survival (OS), locoregional progression-free survival (LRPFS), and progression-free survival (PFS). Results:At a median follow-up time of 22.5 months (range: 2.4-123.5), 30.2% and 14% of the patients were still alive and free of disease progression, respectively.The median OS, LRPFS, and PFS were 25.2 [95% confidence interval (CI): 36.3-46.6 months], 15.4 (95% CI: 26.6-35.3 months), and 10.7 (95% CI: 36.8-69.9 months), individually, for the whole study accomplice. The ROC analysis revealed an optimum rounded cut-off that associated meaningfully with each of the OS [area under the curve (AUC): 84.1%; sensitivity: 75.9%;72.4% specificity], LRPFS (AUC: 92.4%; sensitivity: 87.9%; 85.1% specificity), and PFS (AUC: 80.1%; sensitivity: 73.7%; 71.6% specificity) at a value of 40.5. Comparative analyses revealed that the patients presenting with PNI?40.5 had significantly inferior OS (16.8 vs 36.7; P<0.001), LRPFS (11.5 vs 19.5; P<0.001), and PFS (8.6 vs 13.6; P<0.001) outcomes compared to patients with PNI>40.5. In univariate analyses, lower T-stage (1-2 vs 3-4; P< 0.001), lower N-stage (N2 vs N3; P< 0.001), anemia status (absent vs present; P< 0.001), weight loss status (<5% vs ?5%; P< 0.001), and PNI group (?40.5 vs >40.5; P<0.001) were the factors found to be associated with OS, LRPFS and PFS results. The results of multivariate analysis exhibited that the PNI was independently associated with each of the OS (P<0.001), LRPFS (P<0.001), and PFS (P<0.001) outcomes. Conclusion:The pretreatment PNI appears to be a robust novel prognostic factor that stratifies patients with stage IIIB NSCLC into two significantly distinct survival groups after CRT.

Project description:BackgroundTo observe the dynamic changes of blood perfusion with whole-tumor computed tomography (CT) perfusion imaging using texture analysis in patients with unresectable stage IIIA/B non-small cell lung cancer (NSCLC) treated with recombinant human endostatin (Endostar).MethodsThis phase II clinical trial recruited 11 patients diagnosed with stage IIIA/B NSCLC. Histological examination prior to treatment revealed squamous cell carcinoma in 4 cases and adenocarcinoma in 7 cases. All patients underwent contrast-enhanced perfusion CT at baseline and a second CT scan 1 week after treatment initiation with Endostar. CT perfusion images including blood flow (BF), blood volume (BV), and permeability (PMB) were imported into OmniKinetics software to quantitatively assess the texture features. Skewness, kurtosis, and entropy were calculated at baseline and after anti-angiogenic therapy. Changes in tumor were analyzed using Wilcoxon signed-rank test. The association of parameters with survival was evaluated using Cox proportional hazards regression model.ResultsThere were no statistical differences in the mean values of BF, BV, and PMB before and after treatment (P=0.594, 0.477 and 0.328, respectively). The skewness on BF images demonstrated significant differences at baseline and after treatment (0.6±2.7 vs. 1.0±2.6, P=0.010), while skewness of BV and PMB showed no significant variation (P=0.477 and 0.213, respectively). The kurtosis and entropy for BF, BV and PMB showed no significant differences (all P>0.05). In adenocarcinoma, the mean BF showed no significant differences at baseline and after treatment (76.5±25.7 vs. 101.2±46.4, P=0.398), while skewness for BF was significantly higher after treatment than at baseline (-0.19±3.3 vs. 0.59±3.2, P=0.028). No significant associations were found between perfusion CT imaging parameters and progression-free survival.ConclusionsThese results suggested that blood perfusion showed improvement with whole-tumor perfusion CT using texture analysis in patients with stage IIIA/B NSCLC treated by Endostar.

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Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

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Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

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