International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationImpact of Toxicity Grade and Scoring System on the Relationship Between Mean Lung Dose and Risk of Radiation Pneumonitis in a Large Cohort of Patients With Non–Small Cell Lung Cancer
Introduction
Patients receiving radiotherapy (RT) to the thorax are at risk of developing radiation pneumonitis (RP), an interstitial pulmonary inflammation that typically occurs within 6 months of radiotherapy. The mildest cases are detected radiographically, without any accompanying symptoms, whereas clinically evident RP may involve cough, fever, and shortness of breath. When symptoms are more severe, patients may require treatment with steroids or oxygen, and life-threatening RP necessitates assisted ventilation. Limiting the incidence and severity of RP is an important goal in designing radiation treatment plans to the thorax.
Many normal tissue complication probability (NTCP) studies have sought to improve our understanding of the relationship between the dose distribution to normal lung and the resulting risk of RP. A fairly consistent picture has emerged, in that most NTCP studies find a significant association between the mean lung dose (MLD) and RP risk 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. However, quantitative comparisons among studies are impeded by several factors. Chief among these is that different studies have used different scoring systems to grade pulmonary complications. Also, different authors have selected different threshold levels of toxicity to define the binary (yes/no) RP endpoint for analysis, e.g., symptomatic RP (yes) vs. no RP symptoms (no), or Grade ≥3 RP (yes) vs. Grade 0–2 RP (no). Reported incidence rates have also been affected by differences in follow-up; some studies have included all patients, regardless of follow-up, whereas others have included only patients with a specified minimum follow-up, usually 6 months after the end of RT.
The toxicity scoring system currently recommended by the National Cancer Institute (NCI) is the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE3.0) (23), which replaced the previous NCI scoring system, the Common Toxicity Criteria, version 2.0 (CTC2.0) (23). The CTC2.0 scoring system coincides with that of the Southwest Oncology Group (SWOG) (24). Other scoring systems in widespread use include those of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer (RTOG/EORTC) (25), the Eastern Cooperative Oncology Group (ECOG) (26), the World Health Organization (WHO) (27), and the Late Effects Normal Tissue Task Force (LENT/SOMA) (28). Of these, the grading systems that have been used most often in NTCP studies of RP are the RTOG/EORTC (denoted here, for brevity, as the RTOG system), CTC2.0 ( = SWOG), and CTCAE3.0 scales.
The goal of this study was to compute the risk of RP assessed using three scoring systems (RTOG, CTC2.0, and CTCAE3.0), analyzed at each nonlethal threshold level of RP (Grades 1 through 4), in a large cohort of patients with inoperable non–small cell lung cancer (NSCLC) receiving definitive radiotherapy. This analysis provides quantitative information suitable for comparing the RP risk estimates from our large cohort to those reported by others. Because RP risk depends strongly on MLD, risk estimates are presented here as functions of MLD. The functions selected for this purpose (probit, logistic, and log-logistic) are the dose–response models used in the radiation oncology literature. We illustrate, by means of several examples, how the RP risk estimates from our study compare with those reported by others.
Section snippets
Patient population
The patient population for this study consisted of the subset of patients from our recent studies of RP risk 29, 30 who had ≥6 months of follow-up after the end of RT. As described previously 29, 30, all patients had newly diagnosed NSCLC and received definitive three-dimensional conformal radiotherapy or intensity-modulated radiotherapy, with or without chemotherapy, at the University of Texas M. D. Anderson Cancer Center (UTMDACC) from 1999 to 2005.
Treatments and treatment plans
Radiotherapy treatments are described in
Results
Of the 575 patients included in our previous studies of RP risk after definitive radiotherapy for NSCLC 29, 30, 442 had ≥6 months of follow-up after the end of RT and comprise the study cohort for these analyses. In the Appendix, we illustrate the impact on RP risk estimates of deviating from the requirement of a 6-month follow-up time.
Table 2 lists the numbers of patients having each combination of RP grades according to the RTOG, CTC2.0, and CTCAE3.0 scoring systems. For example, there were
Discussion
The estimates of RP risk derived in this study for various toxicity scoring systems and threshold levels of RP are intended to help facilitate comparisons between RP incidence in our large cohort and the risk estimates reported by others, while taking the dose–volume effects of radiation into account. Several examples of such comparisons are described in this section.
Figure 2 shows the data of Yorke et al. (15) from a study of 78 patients in which the endpoint for analysis was Grade ≥3 RP
References (37)
- et al.
Dose–volume histogram and 3-D treatment planning evaluation of patients with pneumonitis
Int J Radiat Oncol Biol Phys
(1994) - et al.
Estimation of pneumonitis risk in three-dimensional treatment planning using dose–volume histogram analysis
Int J Radiat Oncol Biol Phys
(1995) - et al.
Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients
Int J Radiat Oncol Biol Phys
(1998) - et al.
Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non–small cell lung cancer (NSCLC)
Int J Radiat Oncol Biol Phys
(1999) - et al.
Radiation-induced pulmonary toxicity: a dose–volume histogram analysis in 201 patients with lung cancer
Int J Radiat Oncol Biol Phys
(2001) - et al.
Receiver operating characteristic curves to assess predictors of radiation-induced symptomatic lung injury
Int J Radiat Oncol Biol Phys
(2002) - et al.
Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy
Int J Radiat Oncol Biol Phys
(2002) - et al.
Radiation pneumonitis following treatment of non-small-cell lung cancer with continuous hyperfractionated accelerated radiotherapy (CHART)
Int J Radiat Oncol Biol Phys
(2003) - et al.
Dose-volume analysis of lung complications in the radiation treatment of malignant thymoma: A retrospective review
Radiother Oncol
(2003) - et al.
Factors predicting radiation pneumonitis in lung cancer patients: A retrospective study
Radiother Oncol
(2003)
Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability
Int J Radiat Oncol Biol Phys
Toxicity and outcome results of RTOG 9311: A Phase I–II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma
Int J Radiat Oncol Biol Phys
Dose–volume histogram analysis as predictor of radiation pneumonitis in primary lung cancer patients treated with radiotherapy
Int J Radiat Oncol Biol Phys
Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study
Int J Radiat Oncol Biol Phys
Modeling radiation pneumonitis risk with clinical, dosimetric, and spatial parameters
Int J Radiat Oncol Biol Phys
Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis
Int J Radiat Oncol Biol Phys
Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT)
Int J Radiat Oncol Biol Phys
A nomogram to predict radiation pneumonitis, derived from a combined analysis of RTOG 9311 and institutional data
Int J Radiat Oncol Biol Phys
Cited by (38)
Characterizing Pulmonary Function Test Changes for Patients With Lung Cancer Treated on a 2-Institution, 4-Dimensional Computed Tomography-Ventilation Functional Avoidance Prospective Clinical Trial
2023, Advances in Radiation OncologyCitation Excerpt :Lung toxic effects caused by radiation are commonly scored via the Common Terminology Criteria for Adverse Events16 or the Radiation Therapy Oncology Group (RTOG) scoring system.1 Radiation pneumonitis can present several clinical challenges: symptoms and radiographic changes may not necessarily progress in parallel, differentiation between pneumonitis and tumor progression is often challenging, more frequent prescription of steroids may result in higher-grade pneumonitis more frequently, and pneumonitis is often not thought of as a quantitative measure.1,17,18 Pulmonary function tests (PFTs) include parameters such as diffusing capacity for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC).
Parameters of the Lyman Model for Calculation of Normal-Tissue Complication Probability: A Systematic Literature Review
2023, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :The largest NTCP range occurred at an EUD of approximately 36.1 Gy, with a range of 35.2% to 93.4% (Fig. 1 as well as Supplementary Fig. EA2 and Table EA15). We found 6 publications providing 11 parameter sets for the grouped endpoint “symptomatic pneumonitis” for the MDL model (Table 2).8,19-23 The parameters were obtained from clinical data for irradiation, mainly for lung cancer but also for a variety of other cancers in some publications (including esophageal cancer, breast cancer, lymphoma, sarcoma, thymoma, and pulmonary metastases).
Results of a Multi-Institutional Phase 2 Clinical Trial for 4DCT-Ventilation Functional Avoidance Thoracic Radiation Therapy
2022, International Journal of Radiation Oncology Biology PhysicsRadiographic patterns of symptomatic radiation pneumonitis in lung cancer patients: Imaging predictors for clinical severity and outcome
2020, Lung CancerCitation Excerpt :Understandably, the organs immediately adjacent to the tumor receive higher radiation dose, and therefore radiation pneumonitis (RP) is the most common dose-limiting toxic effect in patients receiving chest radiotherapy for lung cancer [12,13]. Of the toxicity criteria used to evaluate RP, the Radiation Therapy Oncology Group (RTOG) criteria and the Common Terminology Criteria for Adverse Events (CTCAE) are most commonly used [14–16]. The CTCAE can be applied to evaluate adverse effects to any type of cancer therapy beyond radiotherapy, and thus provide more comparable grading across different treatments.
Validation of Effective Dose as a Better Predictor of Radiation Pneumonitis Risk Than Mean Lung Dose: Secondary Analysis of a Randomized Trial
2019, International Journal of Radiation Oncology Biology PhysicsExternal validation of an NTCP model for acute esophageal toxicity in locally advanced NSCLC patients treated with intensity-modulated (chemo-)radiotherapy
2018, Radiotherapy and OncologyCitation Excerpt :However, toxicity for the patients in cohorts D and E was scored using the CTCAE grading scales for AET. Differences between scoring systems were reported to be of importance in modeling of toxicity, for instance for modeling the risk of radiation-induced pneumonitis [46]. It is likely that such differences in grading scales affect AET modeling as well.
Conflicts of interest: none