Radiation Pneumonitis In Patients Research Articles

Predictive Factors for Radiation Pneumonitis in Patients Receiving Intensity-modulated Radiation Therapy for Thoracic Malignancy

Purpose: It is unknown whether established dose-volume parameters predictive of radiation pneumonitis (RP) are applicable to multiple disease sites. We investigated the factors associated with RP in a heterogeneous population of patients receiving thoracic radiation. Methods and materials: Ninety-nine patients who received thoracic radiation with helical tomotherapy were included in this retrospective chart review. Correlation studies were performed and significant clinical and dosimetric factors predictive for grade ≥ 3 RP were assessed using Cox multivariate analysis (MVA). Results: Fifty-two patients developed RP (grade 1-5), the majority having grade 1 toxicity. Five patients experienced grade ≥ 3 RP. Eleven patients developed ≥ 2 RP. The mean time to RP was 3 months. The sole predictor of RP on MVA was a lung volume receiving a maximum of 20 Gy (VS20) < 1600 cc’s (hazard ratio=14.7, p<0.01). The percentage of lung receiving ≥ 5 Gy or ≥ 20 Gy were not significant predictors for RP. The grade ≥ 3 RP-free survival at 1 year in patients with a VS20 <1600 cc’s versus ≥ 1600 cc’s was 50.0% and 97.1%, respectively (logrank, p<0.01). Results were similar when the RP threshold was lowered to include grade ≥ 2. Conclusions: A VS20 <1600 cc’s is a significant adverse factor associated with RP; this included cases that were RP grade ≥ 3 and ≥ 2. This is a new dosimetric parameter that can be utilized for treatment planning.

Predictors of grade ≥ 2 and grade ≥ 3 radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal radiotherapy

Grade ≥ 3 radiation pneumonitis (RP) is generally severe and life-threatening. Predictors of grade ≥ 2 are usually used for grade ≥ 3 RP prediction, but it is unclear whether these predictors are appropriate. In this study, predictors of grade ≥ 2 and grade ≥ 3 RP were investigated separately. The increased risk of severe RP in elderly patients compared with younger patients was also evaluated. Material and methods. A total of 176 consecutive patients with locally advanced non-small cell lung cancer were followed up prospectively after three-dimensional conformal radiotherapy. RP was graded according to Common Terminology Criteria for Adverse Events version 3.0. Results. Mean lung dose (MLD), mean heart dose, ratio of planning target volume to total lung volume (PTV/Lung), and dose-volume histogram comprehensive value of both heart and lung were associated with both grade ≥ 2 and grade ≥ 3 RP in univariate analysis. In multivariate logistic regression analysis, age and MLD were predictors of both grade ≥ 2 RP and grade ≥ 3 RP; receipt of chemotherapy predicted grade ≥ 3 RP only; and sex and PTV/Lung predicted grade ≥ 2 RP only. Among patients who developed high-grade RP, MLD and PTV/Lung were significantly lower in patients aged ≥ 70 years than in younger patients (p < 0.05 for both comparisons). Conclusions. The predictors were not completely consistent between grade ≥ 2 RP and grade ≥ 3 RP. Elderly patients had a higher risk of severe RP than younger patients did, possibly due to lower tolerance of radiation to the lung.

ATM Polymorphisms Predict Severe Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy

The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). We genotyped 3 potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [-111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive (chemo)radiation therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. Of 362 patients (72.4% of non-Hispanic whites), 56 (15.5%) experienced grade ≥3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29-0.83, P=.009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P=.036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P=.002). Such positive findings remained in non-Hispanic whites. ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.

Abstract A36: Predictors of radiation pneumonitis in patients with malignant lung tumors after chemoradiotherapy.

Abstract Background: Many patients diagnosed with lung cancer receive chemoradiotherapy (CRT) early in the course of their treatment. High-dose RT is usually delivered to the primary tumor and/or hilar lymph node metastases. This is anticipated to cause pulmonary complications. The reported incidence of radiation pneumonitis has varied widely in clinical studies ranging from 0 to 54%.(1). This wide range is probably the result of differences in the total radiation doses, number of fractions and fraction dose, and the differences in associated chemotherapy regimens. Aim of the work: To evaluate the association between the clinical, pulmonary function factors and radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemotherapy and radiotherapy (RT). Patients and methods: We prospectively reviewed the medical and radiation records of 76 lung cancer patients who were treated consecutively between January 2009 and February 2012 in the Department of Radiation Oncology at Cancer Institute, Assiut University. Patients were included if they had newly diagnosed and pathologically confirmed lung cancer, chemotherapy after thoracic radiotherapy, and availability of both radiographic images, pulmonary function tests and symptom assessment for determining the occurrence of pulmonary toxicity. The clinical and pulmonary function factors were analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between those factors and RP. Results: In patients who received chemotherapy as a part of the treatment, of the 76 patients, only 33 (42.5%) patients received induction chemotherapy, 43 (57.5%) received concurrent chemotherapy, The chemotherapy regimens that were used were Cisplatin, Gemcitabine or Navilbin. Median follow-up was 6.5 months (range 6.5-24). Twenty five patients, developed RP, 15 developed grade 2 RP, 8 patients developed grade 3 RP, 1 patient developed grade 4 toxicity, and 1 patient developed grade 5 toxicity. When PFT results were compared between the group of patients who developed pulmonary complication (25 patients) and the group who did not develop pulmonary complication (51 patients) related to CRT there was significant difference in means for FVC, FEV1, and FEV1%. Univariate analyses showed that chronic obstructive pulmonary disease (COPD) and Forced Expiratory Volume in the first second (FEV1) were associated with RP (p = 0.02). In multivariate analysis, FEV1 value (p = 0.001) and COPD (p = 0.014) were the most significant factors associated with RP. In addition, univariate analyses show that there is not significant difference statistically between the clinical parameters (sex, age, smoking and, induction chemotherapy, concurrent chemotherapy regimens of patients with and without RP. Conclusions: FEV1 value and COPD are useful indicators for risk of development and predicting RP in NSCLC patients treated with concurrent chemotherapy and RT. Citation Format: Wafaa Gadallah. Predictors of radiation pneumonitis in patients with malignant lung tumors after chemoradiotherapy. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A36.

Change in Diffusing Capacity After Radiation as an Objective Measure for Grading Radiation Pneumonitis in Patients Treated for Non-Small-Cell Lung Cancer

Scoring of radiation pneumonitis (RP), a dose-limiting toxicity after thoracic radiochemotherapy, is subjective and thus inconsistent among studies. Here we investigated whether the extent of change in diffusing capacity of the lung for carbon monoxide (DLCO) after radiation therapy (RT) for non-small-cell lung cancer (NSCLC) could be used as an objective means of quantifying RP. We analyzed potential correlations between DLCO and RP in 140 patients who received definitive RT (≥ 60 Gy) with or without chemotherapy for primary NSCLC. All underwent DLCO analysis before and after RT. Post-RT DLCO values within 1 week of the RP diagnosis (Grade 0, 1, 2, or 3) were selected and compared with that individual's preradiation values. Percent reductions in DLCO and RP grade were compared by point biserial correlation in the entire patient group and in subgroups stratified according to various clinical factors. Patients experiencing Grade 0, 1, 2, or 3 RP had median percentage changes in DLCO after RT of 10.7%, 13%, 22.1%, or 35.2%. Percent reduction in DLCO correlated with RP Grade ≤ 1 vs. ≥ 2 (p = 0.0004). This association held for the following subgroups: age ≥ 65 years, advanced stage, smokers, use of chemotherapy, volume of normal lung receiving at least 20 Gy ≥ 30%, and baseline DLCO or forced expiratory volume in 1 second ≥ 60%. By correlating percent change in DLCO from pretreatment values at the time of diagnosis of RP with RP grade, we were able to identify categories of RP based on the change in DLCO. These criteria provide a basis for an objective scoring system for RP based on change in DLCO.

Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] ≤37% and mean lung dose ≤20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis. ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer

Background and purposeTo quantify uncertainties in scoring radiation pneumonitis. Materials and methodsRecords of 434 patients irradiated for lung cancer from 2000 to 2010 were retrospectively reviewed; IRB-approved study. From these, 121 received ≥60Gy for non-small cell lung cancer (NSCLC) with ≥6 months follow-up. Patients where the physicians were uncertain of the diagnosis due to confounding factors were deemed “hard to score”. Subgroups were defined based on lung dosimetric parameters, and frequencies in different subgroups were compared via Fisher's exact test. Results21/121 of patients were considered to have pneumonitis; median follow 17 months. Of these, 10/21 were “hard to score”; reasons including acute COPD exacerbation, infection, and tumor progression. “Hard to score” pneumonitis was slightly more common in patients with a COPD history (15%) vs. without COPD (4%) (p=0.05); and with a pre-RT FEV1<1.7L (16%) vs. ≥1.7L (4%) (p=0.09). Rates of “unambiguous” pneumonitis trended to be non-significantly slightly higher in patients higher mean lung doses, V5, and V30. ConclusionRadiation pneumonitis occurred in 17% of patients undergoing RT for NSCLC; with diagnostic uncertainty in 48% of these. Poor pre-RT pulmonary function increases the rate of “hard to score” pneumonitis. Dosimetric parameters are slightly better related to “unambiguous” than “hard to score” pneumonitis, as expected.

Correlation of Conventional and Conformal Plan Parameters for Predicting Radiation Pneumonitis in Patients Treated with Breast Cancer

PurposeThe purpose of this study is to evaluate the correlation between the conventional plan parameters and dosimetric parameters obtained from conformal radiotherapy (RT) planning, and between these parameters and radiation pneumontitis (RP) incidence.MethodsClinical and dosimetric data of 122 patients that were treated with mastectomy and adjuvant 3D conformal RT (39% received 2-field RT [2-FRT], and in addition, 61% received 4-field RT [4-FRT]) were retrospectively analyzed. Central lung depth (CLD), maximum lung depth (MLD), and lung length were measured by the conventional plan. Lung dose-volume histograms (DVH) were created with conformal planning, and the lung volumes receiving 5 to 50 Gy (V5Gy to V50Gy) were calculated. Minimum (Dmin), maximum (Dmax), and mean doses (Dmean) for the ipsilateral lung and bilateral lungs were measured by DVH. Correlations between 3D dosimetric data and 2D radiographic parameters were analyzed.ResultsThe conventional plan parameters did not significantly differ between 2-FRT and 4-FRT. The conformal plan Dmin, Dmax, and Dmean values were higher in 4-FRT versus 2-FRT. CLD and MLD were correlated with DVH parameter V5Gy to V45Gy values for ipsilateral, as well as bilateral lungs for 2-FRT. MLD and ipsilateral Dmean via 2-FRT planning had the strongest positive correlation (r=0.76, p<0.01). Moderate correlations existed between CLD and ipsilateral and bilateral lung V5Gy-45Gy, and between MLD and bilateral lung V5Gy-45Gy values in 2-FRT. Only four patients developed symptomatic RP, 4 with 4-FRT and one with 2-FRT.ConclusionThe conformal plan parameters were strongly correlated with dose-volume parameters for breast 2-FRT. With only 4 cases of Grade 3 RP observed, our study is limited in its ability to provide definitive guidance, however assuming that CLD is an indicator for RP, V20Gy could be used as a predictor for RP and for 2-FRT. A well-defined parameters are still required to predict RP in 4-FRT.

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer

Analysis of dose–volume parameters predicting radiation pneumonitis in patients with esophageal cancer treated with 3D-conformal radiation therapy or IMRT

Multimodality therapy for esophageal cancer can cause various kinds of treatment-related sequelae, especially pulmonary toxicities. This prospective study aims to investigate the clinical and dosimetric parameters predicting lung injury in patients undergoing radiation therapy for esophageal cancer. Forty-five esophageal cancer patients were prospectively analyzed. The pulmonary toxicities (or sequelae) were evaluated by comparing chest X-ray films, pulmonary function tests and symptoms caused by pulmonary damage before and after treatment. All patients were treated with either three-dimensional radiotherapy (3DCRT) or with intensity-modulated radiotherapy (IMRT). The planning dose volume histogram was used to compute the lung volumes receiving more than 5, 10, 20 and 30 Gy (V5, V10, V20, V30) and mean lung dose. V20 was larger in the IMRT group than in the 3DCRT group (p = 0.002). V20 (>15%) and V30 (>20%) resulted in a statistically significant increase in the occurrence of chronic pneumonitis (p = 0.03) and acute pneumonitis (p = 0.007), respectively. The study signifies that a larger volume of lung receives lower doses because of multiple beam arrangement and a smaller volume of lung receives higher doses because of better dose conformity in IMRT plans. Acute pneumonitis correlates more with V30 values, whereas chronic pneumonitis was predominantly seen in patients with higher V20 values.

Radiation Pneumonitis Prediction Using Exhaled Nitric Oxide During Thoracic Irradiation

Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to accurately predict the individual risk. This is a prospective Phase II study to evaluate exhaled nitric oxide (eNO) as a predictive biomarker for radiation pneumonitis in patients receiving thoracic radiation.

Functional Promoter rs2868371 Variant of HSPB1 Associates with the Risk of Radiation Pneumonitis in Patients with Non-small Cell Lung Cancer Treated with Radiotherapy

Functional Promoter rs2868371 Variant of HSPB1 Associates with the Risk of Radiation Pneumonitis in Patients with Non-small Cell Lung Cancer Treated with Radiotherapy

Predictive factors for symptomatic radiation pneumonitis in 293 consecutively treated non-small cell lung cancer (NSCLC) patients receiving definitive radiation therapy.

7041 Background: Radiation pneumonitis is a potentially fatal complication in NSCLC patients treated with definitive radiotherapy. The ability to identify patients at risk for this complication would be of value to clinicians. The objective of this study was to identify significant predictors of grade 2 or higher radiation pneumonitis. Methods: Consecutive NSCLC patients receiving definitive non-stereotactic radiotherapy at the University of Pennsylvania between January 2003 to July 2010 were graded for post-treatment radiation pneumonitis using RTOG criteria. Demographic and treatment data were collected on all patients. Univariate and mutivariate analysis was used to determine predictors of grade 2 or higher pneumonitis. Results: Of 293 patients treated in this period, 47% were male, 52% received concurrent chemotherapy. Median prescription dose was 66.6Gy, median gross tumor volume was 91cc, and the median mean lung dose (MLD) was 16Gy. On univariate analysis, concurrent chemoradiation (p = 0.002; OR 2.7), MLD (p = 0.0001, OR = 1.14/Gy), KPS (p = 0.045, OR = 1.04/point), and N2/3 disease (p = 0.026, OR = 2.51) were significant predictors of pneumonitis. A multivariate analysis including all significant predictors on univariate analysis was performed and only MLD (p = 0.031, OR = 1.10/Gy) proved significant. The median MLD cutoff of 16Gy had a sensitivity/specificity of 72% and 55% respectively and positive and negative predictive value of 55% and 87% respectively. Of note, V20 (volume of lung receiving 20Gy or higher), smoking status, and pre-treatment pulmonary function tests including FEV1 and DLCO were not significant predictors of pneumonitis. Conclusions: MLD was a significant predictor of grade 2 or higher radiation pneumonitis in patients with NSCLC receiving definitive radiotherapy, while V20 was not. Additionally, the poor positive predictive value and specificity of MLD limits the clinical utility of this variable. This study underscores the need for more robust predictors of radiation pneumonitis.

Functional Polymorphisms of Base Excision Repair Genes XRCC1 and APEX1 Predict Risk of Radiation Pneumonitis in Patients With Non–Small Cell Lung Cancer Treated With Definitive Radiation Therapy

To explore whether functional single nucleotide polymorphisms (SNPs) of base-excision repair genes are predictors of radiation treatment-related pneumonitis (RP), we investigated associations between functional SNPs of ADPRT, APEX1, and XRCC1 and RP development. We genotyped SNPs of ADPRT (rs1136410 [V762A]), XRCC1 (rs1799782 [R194W], rs25489 [R280H], and rs25487 [Q399R]), and APEX1 (rs1130409 [D148E]) in 165 patients with non-small cell lung cancer (NSCLC) who received definitive chemoradiation therapy. Results were assessed by both Logistic and Cox regression models for RP risk. Kaplan-Meier curves were generated for the cumulative RP probability by the genotypes. We found that SNPs of XRCC1 Q399R and APEX1 D148E each had a significant effect on the development of Grade ≥2 RP (XRCC1: AA vs. GG, adjusted hazard ratio [HR] = 0.48, 95% confidence interval [CI], 0.24-0.97; APEX1: GG vs. TT, adjusted HR = 3.61, 95% CI, 1.64-7.93) in an allele-dose response manner (Trend tests: p = 0.040 and 0.001, respectively). The number of the combined protective XRCC1 A and APEX1 T alleles (from 0 to 4) also showed a significant trend of predicting RP risk (p = 0.001). SNPs of the base-excision repair genes may be biomarkers for susceptibility to RP. Larger prospective studies are needed to validate our findings.

Radiation pneumonitis in patients with lung and mediastinal tumours: a retrospective study of risk factors focused on pulmonary emphysema

To evaluate the impact of pulmonary emphysema (PE) on the incidence and severity of radiation pneumonitis (RP) in patients with lung and mediastinal tumours. 92 patients were enrolled. Involved-field radiation therapy (non-small cell carcinoma or mediastinal tumours in 69 patients; median 70 Gy) and accelerated hyperfractionation (limited disease small cell carcinoma in 23 patients; median 45 Gy) were performed. Common Terminology Criteria for Adverse Events v.3.0 was used to evaluate RP and the relationship with the percentage of pulmonary volume irradiated to >20 Gy (V20) and PE. PE was diagnosed by the presence of low-attenuation areas (LAAs) on CT scans and was classified into Grades 0-4 according to the extent of the LAAs. The median follow-up time was 16 months. The 6-month cumulative incidence of RP at Grade 3 or greater was 7.7% and 34.1% in patients with a V20 of <25% and ≥25%, respectively (p=0.017). In patients with PE Grades 0, 1, 2 and 3 or greater, the incidence of RP was 16.5%, 9.1%, 8.6% and 54.0%, respectively. As the PE Grade increased, the incidence of RP also increased significantly. The incidence and severity of RP are significantly higher in patients with a high V20 value as well as in those with severe PE.

Factors predicting radiation pneumonitis in locally advanced non-small cell lung cancer

PurposeThoracic radiotherapy is a major treatment modality of stage III non-small cell lung cancer. The normal lung tissue is sensitive to radiation and radiation pneumonitis is the most important dose-limiting complication of thoracic radiation therapy. This study was performed to identify the clinical and dosimetric parameters related to the risk of radiation pneumonitis after definitive radiotherapy in stage III non-small cell cancer patients.Materials and MethodsThe medical records were reviewed for 49 patients who completed definitive radiation therapy for locally advanced non-small cell lung cancer from August 2000 to February 2010. Radiation therapy was delivered with the daily dose of 1.8 Gy to 2.0 Gy and the total radiation dose ranged from 50.0 Gy to 70.2 Gy (median, 61.2 Gy). Elective nodal irradiation was delivered at a dose of 45.0 Gy to 50.0 Gy. Seven patients (14.3%) were treated with radiation therapy alone and forty two patients (85.7%) were treated with chemotherapy either sequentially or concurrently.ResultsTwenty-five cases (51.0%) out of 49 cases experienced radiation pneumonitis. According to the radiation pneumonitis grade, 10 (20.4%) were grade 1, 9 (18.4%) were grade 2, 4 (8.2%) were grade 3, and 2 (4.1%) were grade 4. In the univariate analyses, no clinical factors including age, sex, performance status, smoking history, underlying lung disease, tumor location, total radiation dose and chemotherapy were associated with grade ≥2 radiation pneumonitis. In the subgroup analysis of the chemotherapy group, concurrent rather than sequential chemotherapy was significantly related to grade ≥2 radiation pneumonitis comparing sequential chemotherapy. In the univariate analysis with dosimetric factors, mean lung dose (MLD), V20, V30, V40, MLDipsi, V20ipsi, V30ipsi, and V40ipsi were associated with grade ≥2 radiation pneumonitis. In addition, multivariate analysis showed that MLD and V30 were independent predicting factors for grade ≥2 radiation pneumonitis.ConclusionConcurrent chemotherapy, MLD and V30 were statistically significant predictors of grade ≥2 radiation pneumonitis in patients with stage III non-small cell lung cancer undergoing definitive radiotherapy. The cutoff values for MLD and V30 were 16 Gy and 18%, respectively.

Incidence of Radiation Pneumonitis after Thoracic Intensity Modulated Radiation Therapy

Combined radiotherapy and chemotherapy are the basis for treatment for many thoracic malignancies. Therapy is limited by acute, sub-acute, and long term side effects. Radiation pneumonitis is an acute to sub-acute side effect that can be life threatening. This study examines the Mayo Clinic experience with thoracic IMRT and uses dosimetric data to predict risk of pulmonary radiation toxicity. A retrospective review was conducted of the medical records of 96 consecutive patients who completed Intensity Modulated Radiation Therapy (IMRT) for thoracic malignancies at the Mayo Clinic from 2003-2008. NCI Common Toxicity Criteria Version 4 (CTC) pulmonary toxicity grades were used to identify patients with grade 2 or greater radiation pneumonitis during and up to 9 months after receiving radiation therapy. Extensive baseline demographic data was obtained on all patients. Lung dosage (V5, 8, 10, 13, 15, 20, 25, 30 Gy), mean lung dose, and total lung dose was obtained using dose volume histograms. Statistical analysis evaluated the predictive ability of each indicator in predicting development of radiation pneumonitis. Of the 96 patients 9 cases (9%) of CTC grade 2 or greater toxicity were identified. There was a single grade 3 event (1.5%). Median values for V5-V30 were 58.25% (V5), 45% (V8), 37.5% (V10), 30% (V13), 25.25% (V15), 17.25% (V20), 14% (V25), and 10.5% (V30). The median prescribed treatment dose was 60 Gy, and higher mean lung dose correlated with all grades of pneumonitis (p < 0.05) by univariate logistic regression analysis. All dosimetric parameters were predictive of subsequent development of pneumonitis, with V15 and V30 being most prognostic by receiver operating characteristic (ROC) analysis. Parameters V15 and V30 ROC area under the curves (AUC) were 0.762 and 0.767, indicating strong ability to predict the primary outcome: grade 2 or higher toxicity. ROC area under the curves for other parameters varied from 0.70 to 0.746. Lower baseline diffusion limiting capacity of carbon monoxide (DLCO) was also predictive of developing grade 2 or greater pneumonitis. Radiation pneumonitis is a clinically important side effect of thoracic radiation therapy. Rates of radiation pneumonitis in patients treated with IMRT appear to be equal or less than previously reported rates of pneumonitis in patients receiving 3DCRT. CTC toxicity levels of 2 or greater indicate clinically significant pneumonitis. Mean lung dose, the dosimetric variables V15 and V30, and baseline DLCO are all highly correlated with subsequent grade 2 or higher lung toxicity and should be carefully considered in treatment planning in order to minimize the incidence of severe pulmonary side effects.

Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy

BackgroundTo evaluate the association between the clinical, dosimetric factors and severe acute radiation pneumonitis (SARP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT).MethodsWe analyzed 94 LANSCLC patients treated with concurrent chemotherapy and IMRT between May 2005 and September 2006. SARP was defined as greater than or equal 3 side effects and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.The clinical and dosimetric factors were analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical, dosimetric factors and SARP.ResultsMedian follow-up was 10.5 months (range 6.5-24). Of 94 patients, 11 (11.7%) developed SARP. Univariate analyses showed that the normal tissue complication probability (NTCP), mean lung dose (MLD), relative volumes of lung receiving more than a threshold dose of 5-60 Gy at increments of 5 Gy (V5-V60), chronic obstructive pulmonary disease (COPD) and Forced Expiratory Volume in the first second (FEV1) were associated with SARP (p < 0.05). In multivariate analysis, NTCP value (p = 0.001) and V10 (p = 0.015) were the most significant factors associated with SARP. The incidences of SARP in the group with NTCP > 4.2% and NTCP ≤4.2% were 43.5% and 1.4%, respectively (p < 0.01). The incidences of SARP in the group with V10 ≤50% and V10 >50% were 5.7% and 29.2%, respectively (p < 0.01).ConclusionsNTCP value and V10 are the useful indicators for predicting SARP in NSCLC patients treated with concurrent chemotherapy and IMRT.

TGF-beta1 in serum and induced sputum for predicting radiation pneumonitis in patients with non-small cell lung cancer after radiotherapy

Research has confirmed that transforming growth factor-beta1 (TGF-beta1) is one of the cytokines related to radiation pneumonitis. But the level of TGF-beta1 in serum needed to predict radiation pneumonitis is still not clear. This study assessed the value of TGF-beta1 in both serum and induced sputum in predicting radiation pneumonitis, providing a reference for the radiotherapy of patients with non-small cell lung cancer (NSCLC). A total of 23 patients with NSCLC treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) in our department between November 2007 and January 2009 were analyzed and evaluated. TGF-beta1 levels in both serum and sputum were detected before and near the end of radiotherapy for all the patients. The TGF-beta1 level in serum was measured with enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry assays were used to detect TGF-beta1 expression in sputum sediment. Radiation pneumonitis was graded according to Radiation Therapy Oncology Group (RTOG) radiation scoring criteria every 3 weeks from the start to 3 months after the end of treatment. Radiation pneumonitis was noted in 9 patients in this cohort. The total incidence of radiation pneumonitis was 39.1% (9/23) and those with Grade II or worse was 30.4% (7/23). The absolute TGF-beta1 level in serum after radiotherapy was higher than before radiotherapy, but there was no statistical difference (P = 0.139). Patients with increased levels of TGF-beta1 had a higher incidence of radiation pneumonitis (45.5%) than those with decreased TGF-beta1 levels post-radiotherapy (40.0%). Though there was a tendency of higher incidence of radiation pneumonitis with increases in TGF-beta1 level, no statistical difference was found (P = 1.000). Patients with tumor response had higher incidence of radiation pneumonitis (50.0%) than patients without when TGF-beta1 levels in serum increased, but there was no statistical difference (P = 0.792). TGF-beta1 was positively expressed (brown yellow) in sputum on immunocytochemistry assays and located in the cytoplasm of either macrophages or epithelial cells. Macrophages were the main cells expressing TGF-beta1. A significantly higher positive expression rate (71.4%) was found in sputum post-radiotherapy than pre-radiotherapy (28.6%) (P = 0.015). The higher incidence of radiation pneumonitis (46.7%) was found in patients with positive TGF-beta1 expression in sputum post-radiotherapy than those with negative expression post-radiotherapy (14.3%) (P = 0.193). It may be more reasonable to predict radiation pneumonitis by combining the change of TGF-beta1 levels in serum with tumor response than just the change of TGF-beta1 levels in serum alone. TGF-beta1 can positively express in the sputum of patients with NSCLC, located in macrophages and epithelial cells, with macrophages as the main areas of expression. Patients with positively expressed TGF-beta1 in sputum after radiotherapy have a higher incidence of radiation pneumonitis than those with negative expressions. The positive expression of TGF-beta1 in sputum is expected to become a factor for predicting radiation pneumonitis.

Correlation of Patient-Related Factors and Dose-Volume Histogram Parameters with the Onset of Radiation Pneumonitis in Patients with Small Cell Lung Cancer

To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell lung cancer (SCLC). 242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor localization, benign lung disease) and treatment-related parameters (V(10)-V(40), mean lung dose [MLD]) were analyzed using χ(2)-tests for categorical parameters and logistic regression for continuous variables. 33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. All cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V(30) in regard to total lung and V(40) in regard to ipsilateral, contralateral and total lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V(30) of 13% to 30% given a V(30) of 35%. In contrast, no significant correlation was found for V(10) and V(20) and only a trend for MLD. In this series, high-dose radiation volume parameters, i.e., V(30) and especially V(40), were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk.