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Journal ArticleDOI

Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.

TL;DR: Several treatment-related risk factors predict the development of symptomatic pneumonitis, and elderly patients who undergo CCRT with carboplatin-paclitaxel chemotherapy are at highest risk.
Abstract: Background Radiation pneumonitis is a dose-limiting toxicity for patients undergoing concurrent chemoradiation therapy (CCRT) for non-small cell lung cancer (NSCLC). We performed an individual patient data meta-analysis to determine factors predictive of clinically significant pneumonitis. Methods and Materials After a systematic review of the literature, data were obtained on 836 patients who underwent CCRT in Europe, North America, and Asia. Patients were randomly divided into training and validation sets (two-thirds vs one-third of patients). Factors predictive of symptomatic pneumonitis (grade ≥2 by 1 of several scoring systems) or fatal pneumonitis were evaluated using logistic regression. Recursive partitioning analysis (RPA) was used to define risk groups. Results The median radiation therapy dose was 60 Gy, and the median follow-up time was 2.3 years. Most patients received concurrent cisplatin/etoposide (38%) or carboplatin/paclitaxel (26%). The overall rate of symptomatic pneumonitis was 29.8% (n=249), with fatal pneumonitis in 1.9% (n=16). In the training set, factors predictive of symptomatic pneumonitis were lung volume receiving ≥20 Gy (V 20 ) (odds ratio [OR] 1.03 per 1% increase, P =.008), and carboplatin/paclitaxel chemotherapy (OR 3.33, P P =.09); the model remained predictive in the validation set with good discrimination in both datasets (c-statistic >0.65). On RPA, the highest risk of pneumonitis (>50%) was in patients >65 years of age receiving carboplatin/paclitaxel. Predictors of fatal pneumonitis were daily dose >2 Gy, V 20 , and lower-lobe tumor location. Conclusions Several treatment-related risk factors predict the development of symptomatic pneumonitis, and elderly patients who undergo CCRT with carboplatin-paclitaxel chemotherapy are at highest risk. Fatal pneumonitis, although uncommon, is related to dosimetric factors and tumor location.

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Journal ArticleDOI
TL;DR: The Clatterbridge Cancer Centre and Liverpool Heart and Chest Hospital, Liverpool; University of Aberdeen, Aberdeen, UK; Center for Medical Imaging, University of Groningen, Groningen; Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands; and Department of Thoracic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK.

1,498 citations


Cites background from "Predicting radiation pneumonitis af..."

  • ...Moreover, in a recent metaanalysis on risk factors for symptomatic radiation pneumonitis, elderly patients who received carboplatin–paclitaxel chemotherapy were at highest risk [42]....

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Journal ArticleDOI
01 Jul 2019-Chest
TL;DR: Current research advances include high-precision radiation techniques, an improved understanding of the molecular basis of RILI, the development of small and large animal models, and the identification of candidate drugs for prevention and treatment.

257 citations

Journal ArticleDOI
TL;DR: Current understanding of the pathological and molecular consequences of lung exposure to ionizing radiation, and pharmaceutical interventions that may be beneficial in the prevention or curtailment of RILI, and therefore enable a more durable therapeutic tumor response are summarized.
Abstract: Radiation pneumonitis (RP) and radiation fibrosis (RF) are two dose-limiting toxicities of radiotherapy (RT), especially for lung, and esophageal cancer. It occurs in 5-20% of patients and limits the maximum dose that can be delivered, reducing tumor control probability (TCP) and may lead to dyspnea, lung fibrosis, and impaired quality of life. Both physical and biological factors determine the normal tissue complication probability (NTCP) by Radiotherapy. A better understanding of the pathophysiological sequence of radiation-induced lung injury (RILI) and the intrinsic, environmental and treatment-related factors may aid in the prevention, and better management of radiation-induced lung damage. In this review, we summarize our current understanding of the pathological and molecular consequences of lung exposure to ionizing radiation, and pharmaceutical interventions that may be beneficial in the prevention or curtailment of RILI, and therefore enable a more durable therapeutic tumor response.

189 citations

Journal ArticleDOI
TL;DR: EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC.

141 citations


Cites background from "Predicting radiation pneumonitis af..."

  • ...[22] found that the PC regimen was an independent predictive factor of RP (OR of PC relative to EP1⁄4 3....

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Journal ArticleDOI
TL;DR: Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability, and efforts to reduce the V 60 should be prioritized, with further research needed to identify and validate new predictive factors.
Abstract: 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 .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 Conclusions Clinically significant RE is common, but life-threatening complications occur in

141 citations


Cites background or methods from "Predicting radiation pneumonitis af..."

  • ...Recursive partitioning analysis (RPA) was performed incorporating significant predictors of esophagitis identified from multivariable logistic regression as described previously (6) and was used to create risk groups....

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  • ...Given that all patients in this meta-analysis received concurrent chemotherapy, this could not be assessed directly, although the different chemotherapy agents did not seem to affect RE risk, as they appear to do with pneumonitis risk (6)....

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  • ...The full search strategy, including electronic searches and hand searches for data published in abstract form or unpublished, has been reported previously (6)....

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  • ...The first substudy examining predictors of radiation pneumonitis was recently reported (6)....

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References
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Journal ArticleDOI
TL;DR: The three-dimensional dose, volume, and outcome data for lung are reviewed in detail and it is confirmed that there is no evident threshold "tolerance dose-volume" levels and there are strong volume and fractionation effects.
Abstract: The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold "tolerance dose-volume" levels. There are strong volume and fractionation effects.

892 citations

Journal ArticleDOI
TL;DR: Cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.
Abstract: BACKGROUND Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed. METHODS Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided. RESULTS Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy. CONCLUSIONS Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.

584 citations


"Predicting radiation pneumonitis af..." refers background in this paper

  • ...Lung volume receiving 20 Gy (%) 819 30 (7-78)...

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  • ...In the context of palliative chemotherapy, a meta-analysis has demonstrated that cisplatin is a more active first-line treatment against NSCLC than carboplatin: cisplatin achieves superior response rates, and in some subgroups it improved survival (18)....

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  • ...15) Lung volume receiving 5 Gy (%) 404 38 (14-100)...

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Journal ArticleDOI
TL;DR: An association between DVH parameters and RP risk has been demonstrated in the literature, but the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified.

393 citations


"Predicting radiation pneumonitis af..." refers background or result in this paper

  • ...Many earlier studies included heterogeneous groups of patients not necessarily applicable to modern NSCLC treatment (ie, patients treated without chemotherapy, with older radiation therapy techniques, or for nonlung malignancies); correlations between baseline variables and pneumonitis outcomes are generally weak; and results are rarely validated in separate datasets (2, 3)....

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  • ...Recursive partitioning analysis of radiation pneumonitis risk in p non-small-cell lung cancer (NSCLC)....

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  • ...Several studies have identified relationships between baseline patient-related or dose-related factors and rates of radiation pneumonitis (2), but predictive models have not been widely implemented for several reasons....

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  • ...The onset of radiation pneumonitis after radical CCRT for NSCLC is associated with significant morbidity and occasionally mortality....

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  • ...The goal of this first component of the STRIPE project was to develop and validate a predictive model for radiation pneumonitis in patients receiving modern CCRT for the treatment of locally advanced NSCLC....

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Journal ArticleDOI
TL;DR: The incidence and grade of RP are significantly related to the V20 value, and V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.
Abstract: Purpose: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy ( V20 ) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. Methods and Materials: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8–2.0 Gy fractions once daily to a total of 48–66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. Results: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of ≤20%, 21–25%, 26–30%, and ≥31%, respectively ( p V20 was the only factor associated with RP of Grade 2 or greater. Conclusion: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

314 citations


"Predicting radiation pneumonitis af..." refers background in this paper

  • ...Lung volume receiving 20 Gy (%) 819 30 (7-78)...

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  • ...Data were available on 836 patients from 12 different sources (Table 1), all previously reported in whole or in part, including 10 articles (3, 5-13) and 2 abstracts (14, 15), some of which provided updated datasets....

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Journal ArticleDOI
TL;DR: Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms and should be considered a standard regimen in the management of locally advanced unresectable NSCLC.
Abstract: Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non–small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m2 on day 1)/vindesine (3 mg/m2 on days 1, 8)/cisplatin (80 mg/m2 on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m2)/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. A...

241 citations


"Predicting radiation pneumonitis af..." refers methods in this paper

  • ...Lung volume receiving 20 Gy (%) 819 30 (7-78)...

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  • ...The carboplatin/ paclitaxel CCRT combination has been compared in a 3-arm randomized noninferiority study against irinotecan/carboplatin and mitomycin/vindesine/cisplatin, with the latter considered the “standard” arm (19)....

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  • ...15) Lung volume receiving 5 Gy (%) 404 38 (14-100)...

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