Factors Associated With Early Mortality in Patients Treated With Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Concurrent chemoradiation therapy (con-CRT) is recommended for fit patients with locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with toxicity, and observed survival continues to be limited. Identifying factors associated with early mortality could improve patient selection and identify strategies to improve prognosis. METHODS AND MATERIALS: Analysis of a multi-institutional LA-NSCLC database consisting of 1245 patients treated with con-CRT in 13 institutions was performed to identify factors predictive of 180-day survival. Recursive partitioning analysis (RPA) was performed to identify prognostic groups for 180-day survival. Multivariate logistic regression analysis was used to create a clinical nomogram predicting 180-day survival based on important predictors from RPA. RESULTS: Median follow-up was 43.5 months (95% confidence interval [CI]: 40.3-48.8) and 127 patients (10%) died within 180 days of treatment. Median, 180-day, and 1- to 5-year (by yearly increments) actuarial survival rates were 20.9 months, 90%, 71%, 45%, 32%, 27%, and 22% respectively. Multivariate analysis adjusted by region identified gross tumor volume (GTV) (odds ratio [OR] ≥100 cm(3): 2.61; 95% CI: 1.10-6.20; P=.029) and pulmonary function (forced expiratory volume in 1 second [FEV1], defined as the ratio of FEV1 to forced vital capacity [FVC]) (OR <80%: 2.53; 95% CI: 1.09-5.88; P=.030) as significant predictors of 180-day survival. RPA resulted in a 2-class risk stratification system: low-risk (GTV <100 cm(3) or GTV ≥100 cm(3) and FEV1 ≥80%) and high-risk (GTV ≥100 cm(3) and FEV1 <80%). The 180-day survival rates were 93% for low risk and 79% for high risk, with an OR of 4.43 (95% CI: 2.07-9.51; P<.001), adjusted by region. A clinical nomogram predictive of 180-day survival, incorporating FEV1, GTV, N stage, and maximum esophagus dose yielded favorable calibration (R(2) = 0.947). CONCLUSIONS: This analysis identified several risk factors associated with early mortality and suggests that future research in the optimization of pretreatment pulmonary function and/or functional lung avoidance treatment may alter the therapeutic ratio in this patient population.

Is intermediate radiation dose escalation with concurrent chemotherapy for stage III non-small-cell lung cancer beneficial? A multi-institutional propensity score matched analysis.

PURPOSE: The clinical benefits and risks of dose escalation (DE) for stage III non-small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. METHODS AND MATERIALS: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. RESULTS: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0 months). There was an increase in grades III to V lung toxicity associated with ID (13.0% vs 4.9%, respectively). CONCLUSIONS: No significant overall survival benefits were found with intermediate DE; however, more grade III or greater lung toxicity was observed. The separation of survival curves after 15 months of follow-up suggests that a small overall survival improvement associated with intermediate DE cannot be excluded.

Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis.

PURPOSE: Concurrent chemoradiation therapy (CCRT) improves survival compared with sequential treatment for locally advanced non-small cell lung cancer, but it increases toxicity, particularly radiation esophagitis (RE). Validated predictors of RE for clinical use are lacking. We performed an individual-patient-data meta-analysis to determine factors predictive of clinically significant RE. METHODS AND MATERIALS: After a systematic review of the literature, data were obtained on 1082 patients who underwent CCRT, including patients from Europe, North America, Asia, and Australia. Patients were randomly divided into training and validation sets (2/3 vs 1/3 of patients). Factors predictive of RE (grade≥2 and grade≥3) were assessed using logistic modeling, with the concordance statistic (c statistic) used to evaluate the performance of each model. RESULTS: The median radiation therapy dose delivered was 65 Gy, and the median follow-up time was 2.1 years. Most patients (91%) received platinum-containing CCRT regimens. The development of RE was common, scored as grade 2 in 348 patients (32.2%), grade 3 in 185 (17.1%), and grade 4 in 10 (0.9%). There were no RE-related deaths. On univariable analysis using the training set, several baseline factors were statistically predictive of RE (P<.05), but only dosimetric factors had good discrimination scores (c>.60). On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade≥2 and grade≥3 RE, with good calibration and discrimination. Recursive partitioning identified 3 risk groups: low (V60<0.07%), intermediate (V60 0.07% to 16.99%), and high (V60≥17%). With use of the validation set, the predictive model performed inferiorly for the grade≥2 endpoint (c=.58) but performed well for the grade≥3 endpoint (c=.66). CONCLUSIONS: Clinically significant RE is common, but life-threatening complications occur in <1% of patients. Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability. Efforts to reduce the V60 should be prioritized, with further research needed to identify and validate new predictive factors.

Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction.

BACKGROUND AND PURPOSE: The aim was to demonstrate similar pain relief with two schedules of radiotherapy for painful bone metastases. MATERIALS AND METHODS: A total of 160 patients were assigned to receive a single 8-Gy fraction or 30 Gy in 10 fractions. Pain intensity was measured on an ordinal pain scale of 0-10. Partial response was defined as a pain reduction of two points or more and complete response as a pain score of zero at the treated area. Response follow-up was at 3, 12, 24 and 48 weeks. RESULTS: The overall response was 75% in the 8-Gy arm and 86% in the 30-Gy arm. Complete response and partial response rates were 15% and 60% in the 8-Gy arm, 13% and 73% in the 30-Gy arm. Acute toxicity was of 18% in the 30-Gy arm and of 12% in the 8-Gy arm. These differences were not statistically significant. The re-treatment rate was 28% vs 2% in the 8-Gy and 30-Gy arms, respectively, these were statistically significant. CONCLUSIONS: A single-fraction regimen of 8 Gy was as safe and effective as a multifraction regimen of 30 Gy for painful bone metastases in terms of pain relief.