Clinical Investigation
Predicting Esophagitis After Chemoradiation Therapy for Non-Small Cell Lung Cancer: An Individual Patient Data Meta-Analysis

Accepted for oral presentations at the Canadian Association of Radiation Oncologists’ Annual Meeting 2013 and the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO), Atlanta, GA, September 22-25, 2013.
https://doi.org/10.1016/j.ijrobp.2013.07.029Get rights and content

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.

Introduction

For patients with locally advanced non-small cell lung cancer (NSCLC), the addition of concurrent chemotherapy to radiation therapy provides the best chance of cure, achieving an absolute improvement in survival of 10% at 2 years in comparison with sequential chemotherapy and radiation (1). However, this improvement in survival comes at a cost: patients receiving concurrent chemoradiation therapy (CCRT) have an approximately 5-fold increase in the risk of acute radiation esophagitis (RE) compared with patients receiving sequential treatment, and in 1 randomized trial, 21% of patients on the CCRT arm had treatment discontinued because of severe RE (1). Symptoms of acute RE include odynophagia, dysphagia, and retrosternal pain, in some cases resulting in weight loss and requiring analgesics, intravenous fluids, hyperalimentation, the insertion of a percutaneous gastrostostomy tube, or some combination of these 2, 3.

The ability to accurately predict RE might facilitate strategies to mitigate risk and thus improve the therapeutic ratio. To that end, numerous studies have attempted to assess predictors of RE, examining patient and tumor characteristics, dosimetric factors, and the use of chemotherapy (2). However, such studies have not yet resulted in the widespread adoption of any prediction model, partly because of the heterogeneity of reported results across studies, the lack of external validation, and the inclusion of patients treated with older approaches (eg, sequential chemotherapy and radiation therapy) that may not be applicable to modern practice. One of the largest previous studies developed a practical prediction model (www.predictcancer.org) that was validated on 3 separate cohorts but included patients with small cell lung cancer and NSCLC, many of whom did not receive concurrent chemotherapy (4).

Recent guidelines for assessing normal tissue toxicity risk recommended the pooling of individual patient data to undertake meta-analyses in an effort to overcome some of the limitations of previous research (5). As a result, the collaborative project named Systematic analysis of toxicity after radical irradiation: pneumonitis and esophagitis (STRIPE) was launched to determine predictors of radiation pneumonitis and esophagitis in patients receiving CCRT. The first substudy examining predictors of radiation pneumonitis was recently reported (6). The goal of this component of the STRIPE project was to create and validate a predictive model for RE in a population of patients with locally advanced NSCLC receiving curative-intent, modern CCRT.

Section snippets

Methods and Materials

A systematic review was conducted using MEDLINE to identify articles published between 1993 and January 2011 reporting on dosimetric predictors of pneumonitis and RE. The full search strategy, including electronic searches and hand searches for data published in abstract form or unpublished, has been reported previously (6). Authors were contacted and invited to submit datasets (prospective or retrospective) with individual patient data. Institutional Research Ethics Board approval was obtained.

Results

Data were available on 1082 patients from 15 different sources, 12 previously reported in whole or in part—11 articles 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 1 abstract (18)— representing patients from North America, Europe, Asia, and Australia (Table 1). Baseline clinical characteristics are shown in Table 2. The median follow-up time was 26 months, and the median overall survival was 19 months. The median total dose delivered was 65 Gy (range, 14-81.6 Gy), and most patients received ≤2

Discussion

Radiation esophagitis is a common adverse event in patients receiving CCRT and can have a deleterious impact on quality of life and treatment compliance 2, 3. This study, which to our knowledge is the largest such study reported to date on patients receiving CCRT, suggests that high-dose metrics are the most important predictors of RE. The V60 emerged as the best predictor for both moderate and severe RE. Patients with a very low V60 <1% have a low risk of RE (<5% risk of grade ≥3 toxicity),

Acknowledgments

The authors thank Gabriel Bolt for assistance with literature review, and Drs Achilles Fakiris, Joke Bakker, Daniel Mullen, Ellen van Reij, Michael Lawrence, Eric Xanthopoulos, Shiva Das, Mary Duffy, Philippe Lambin, and David Ball for assistance with provision of data.

References (20)

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Supported by a clinician-scientist grant from the Ontario Institute for Cancer Research (to D.A.P.), and by National Institutes of Health Grant CA69579 (to L.B.M.).

Conflict of interest: Dr Senan has received research funding from Sanofi-Aventis and is a member of the trial management group (not reimbursed) for the phase 3 PROCLAIM study evaluating concurrent chemoradiation therapy schemes for stage III lung cancer, which is sponsored by Eli Lilly. Dr Barriger holds a leadership position with D3 Oncology Solutions, is a member of the Via Oncology Pathways Physician Advisory Committee, and is the Radiation Oncology Esophageal and Lung (Small Cell and Non-Small Cell) Committee Co-Chair. The authors report no other conflict of interest.

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