Factors predicting radiation pneumonitis in lung cancer patients: a retrospective study

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Abstract

Purpose: To evaluate clinical and lung dose–volume histogram based factors as predictors of radiation pneumonitis (RP) in lung cancer patients (PTs) treated with thoracic irradiation.

Methods and materials: Records of all lung cancer PTs irradiated at our Institution between 1994 and 2000 were retrospectively reviewed. Eighty-four PTs with small or non-small-cell lung cancer, irradiated at >40 Gy, with full 3D dosimetry data and a follow-up time of >6 months from start of treatment, were analysed for RP. Pneumonitis was scored on the basis of SWOG toxicity criteria and was considered a complication when grade≥II. The following clinical parameters were considered: gender, age, surgery, chemotherapy agents, presence of chronic obstructive pulmonary disease (COPD), performance status. Dosimetric factors including prescribed dose (Diso), presence of final conformal boost, mean lung dose (Dmean), % of lung receiving ≥20, 25, 30, 35, 40, and 45 Gy (respectively V20→V45), and normal tissue complication probability (NTCP) values were analysed. DVHs data and NTCP values were collected for both lungs considered as a paired organ. Median and quartile values were taken as cut-off for statistical analysis. Factors that influenced RP were assessed by univariate (log-rank) and multivariate analyses (Cox hazard model).

Results: There were 14 PTs (16.6%) who had ≥grade II pulmonary toxicity. In the entire population, the univariate analysis revealed that many dosimetric parameters (Diso, V20, V30, V40, V45) were significantly associated with RP. No significant correlation was found between the incidence of RP and Dmean or NTCP values. Multivariate analysis revealed that the use of mitomycin (MMC) (P=0.005) and the presence of COPD (P=0.026) were the most important risk factor for RP. In the group without COPD (55 PTs, seven RP) a few dosimetric factors (Dmean, V20, V45) and NTCP values (all models) were associated with RP in the univariate analysis (P≤0.06). According to the multivariate analysis, the use of MMC was independently associated with RP (P=0.007), while Dmean approached statistical significance (P=0.082).

Conclusions: In this study the use of mitomycin or the presence of COPD is associated with a higher risk of RP. In the entire population NTCP values were not significantly correlated with the incidence of RP. Mean lung dose shows a clear trend toward statistical significance in the patient group without COPD.

Introduction

Lung cancer is the leading cause of cancer-related death for both men and women worldwide. Among the various treatment methods in use, thoracic radiation therapy (RT) remains arguably the most effective and most widely used treatment for locally advanced or medically inoperable non-small cell lung cancer (NSCLC), and limited disease small cell lung cancer (SCLC). A number of randomised studies and large meta-analyses have also demonstrated a survival advantage for patients (PTs) treated with combined chemoradiation [1]. Moreover, post-operative RT is still widely used even though it has been criticised by recent studies suggesting more strict patient selection criteria [2].

Radiation pneumonitis (RP), which manifests within a period of 1–8 months after radiotherapy (RT), is one of the most significant complications. RT-induced pulmonary symptoms occur in about 20% of all PTs irradiated for lung cancer or other thoracic neoplasms, while subclinical functional and radiological changes are seen in an even larger fraction of PTs [3], [5], [26].

Several studies have investigated the relationship between a number of clinical factors including age, gender, performance status, pulmonary comorbidity, tumour site, changes in plasma, cytokine transforming growth factor-β levels, histology and the development of severe RP [27], [29], [33], [37], [38]. Some authors have focused their analyses on PTs treated with combined modality treatment (chemoradiotherapy), for which an increased risk of RP has been postulated [8], [17], [18], [19], [31], [34], [36], [38]. However, most of these studies did not take into account 3D dosimetry data.

Previous reports have identified ‘simple’ dosimetric risk factors for RP [31]. More recently, however, based on the detailed dosimetric information provided by three-dimensional (3D) treatment planning tools, other researchers have related the risk and severity of RP to specific DVH parameters [4], [14], [15], [24], [28], and a few studies have characterised the dose–response curve for RP following RT by means of biological models [7], [12], [21].

While there are a number of differences in the published reports, there is some consensus about the association between a few of the dosimetric factors (mainly the mean lung dose Dmean) and the incidence of RP [15]. Most lung cancer PTs showed poor pre-treatment pulmonary function and among those patients, chronic obstructive pulmonary disease (COPD) was not an uncommon clinical finding. However, the role of pre-treatment lung function and the influence of covariates such as chemotherapy agents are still under debate [13], [35].

We herein report our experience of radiation induced pulmonary toxicity in a group of 84 patients with lung cancer, all with lung dose–volume histogram (DVHs) data, prescribed dose >40 Gy and >6 months of follow-up from the start of RT. As this is a retrospective study, no quantitative pulmonary function tests were available in all PTs; however, each patient was classified as having or not having pre-treatment COPD. We attempted to retrospectively identify clinical and dosimetric factors that could aid in the prediction of RP.

Section snippets

Patient eligibility

The records of all PTs with localised lung cancer and treated with radiotherapy (RT) in the Radiotherapy Department of Istituto Scientifico San Raffaele between November 1994 and August 2000, were reviewed with the intent of studying the lung response to radiation. A total of 84 PTs were identified who met the following inclusion criteria: limited disease SCLC (12 PTs) or NSCLC (72 PTs) treated with RT dose greater than 40 Gy, no pneumonectomy before or after RT, availability of CT-based 3D

Results

Fourteen PTs (16.7%) developed radiation pneumonitis: 12 grade II, one grade III and one grade V. The actuarial incidence at 6 and 12 months was 15.7±4.2% and 17.2±4.4%, respectively. The median time to development of RP was 4.5 months (range: 1–10 months). Radiographic films proved that all RPs were localised in the ipsilateral lung.

Univariate analysis was performed for several clinical and dosimetric factors to analyse their impact on the development of RP and the results are summarised in

Discussion

Recently Seppenwoolde and Lebesque [35] have reviewed the role of patient specific aspects, dosimetric factors and model calculations in quantifying the effects of partial lung irradiation. Both simple dosimetric parameters (such as Dmean or V20) and NTCP models are associated with the incidence of RP, but accurate predictability should include pre-existent pulmonary function and other potential covariates, such as anticancer drugs. This paper reports the results of a retrospective single

Conclusions

In summary, the results of this retrospective study showed a significant correlation between pre-treatment COPD and the risk of RP. There was a higher risk of RP in patients treated with induction chemotherapy with MMC-containing regimens.

In the entire population group, NTCP values estimated from the Lyman model with any of the published sets of parameters were not significantly correlated with the incidence of RP.

In the subgroup of 55 PTs without COPD, mean lung dose was a nearly significant

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