Analysis of early respiratory-related mortality after radiation therapy of non-small-cell lung cancer: feasibility of automatic data extraction for dose-response studies.

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC).Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables.Results: Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p<.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively.Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Re-irradiation in locally recurrent lung cancer patients.

PURPOSE: Lung cancer remains one of the tumour diagnoses with high lethality, although innovative treatment approaches have yielded improvements in local control and survival rates. There is still no consensus on how to treat local relapse in patients after first-line treatments. Radiotherapy may be considered in this situation; however, data supporting its effectiveness are rare. The purpose of this retrospective analysis was to evaluate outcomes of patients re-irradiated for thoracic tumours in terms of overall survival (OS), local progression-free survival (LPFS), toxicity and dose-volume parameters. PATIENTS AND METHODS: Sixty-two patients with locally recurrent previously irradiated lung cancer were analysed retrospectively (NSCLC n = 52, SCLC n = 10). Target volumes both in lung and mediastinum were re-irradiated with conventional three-dimensional or intensity-modulated radiotherapy techniques. Median overall dose of re-irradiation was 38.5 Gy (range 20-60 Gy) with a median single dose per fraction of 2 Gy (1.8-3.0 Gy). Clinical documents and treatment plans were evaluated. RESULTS: Median follow-up was 8.2 months (range 0-27 months). OS following re-irradiation was 9.3 months (range: 0-27 months) and LPFS was 6.5 months (range: 0-24 months). OS and LPFS were not affected by histology, total dose or patient age and gender. OS was improved in patients whose re-irradiation volumes included less than two mediastinal lymph node stations (p = 0.016). Twelve patients suffered from pneumonitis ≥grade II (19%) and two from pneumonitis grade III. One patient presumably died from pneumonitis grade V. A slight decline in forced expiratory volume (FEV1) was detected in post-re-irradiation lung function testing. CONCLUSIONS: Re-irradiation is an option for patients with tumour recurrence to control local progression and lower the symptom burden. Oncological outcome appears to be affected by size, location of mediastinal target volumes and lung function. Prospective clinical trials are warranted to substantiate the role of re-irradiation in recurrent lung cancer.

Analysis of risk factors for pulmonary complications in patients with limited-stage small cell lung cancer : A single-centre retrospective study.

INTRODUCTION: The most effective therapy in patients with limited-stage small cell lung cancer (LS SCLC) seems to be chemotherapy (using platinum-based regimens) and thoracic radiotherapy (TRT), which is followed by prophylactic cranial irradiation. MATERIALS AND METHODS: The analysed group comprised 217 patients who received combined treatment for LS SCLC, i.e. chemotherapy (according to cisplatin and etoposide schedule) and TRT (concurrent in 101 and sequential in 116 patients). The influence of chemoradiotherapy (ChT-RT) schedule on treatment results (frequency of complete response, survival rates, and incidence of treatment failure and complications) was evaluated, and the frequency and severity of pulmonary complications were analysed to identify risk factors. RESULTS: The 5­year survival rates in concurrent vs. sequential ChT-RT schedules were 27.3 vs. 11.7% (overall) and 28 vs. 14.3% (disease-free). The frequencies of adverse events in relation to concurrent vs. sequential therapy were 85.1 vs. 9.5% (haematological complications) and 58.4 vs. 38.8% (pulmonary fibrosis), respectively. It was found that concurrent ChT-RT (hazard ratio, HR 2.75), a total dose equal to or more than 54 Gy (HR 2.55), the presence of haematological complications (HR 1.89) and a lung volume receiving a dose equal to or greater than 20 Gy exceeding 31% (HR 1.06) were the risk factors for pulmonary complications. CONCLUSION: Pulmonary complications after ChT-RT developed in 82% of patients treated for LS SCLC. In comparison to the sequential approach, concurrent ChT-RT had a positive effect on treatment outcome. However, this is a factor that can impair treatment tolerance, which manifests in the appearance of side effects.

Potential clinical predictors of outcome after postoperative radiotherapy of non-small cell lung cancer.

AIM: The aim of this analysis was to investigate the impact of tumour-, treatment- and patient-related cofactors on local control and survival after postoperative adjuvant radiotherapy in patients with non-small cell lung cancer (NSCLC), with special focus on waiting and overall treatment times. PATIENTS AND METHODS: For 100 NSCLC patients who had received postoperative radiotherapy, overall, relapse-free and metastases-free survival was retrospectively analysed using Kaplan-Meier methods. The impact of tumour-, treatment- and patient-related cofactors on treatment outcome was evaluated in uni- and multivariate Cox regression analysis. RESULTS: No statistically significant difference between the survival curves of the groups with a short versus a long time interval between surgery and radiotherapy could be shown in uni- or multivariate analysis. Multivariate analysis revealed a significant decrease in overall survival times for patients with prolonged overall radiotherapy treatment times exceeding 42 days (16 vs. 36 months) and for patients with radiation-induced pneumonitis (8 vs. 29 months). CONCLUSION: Radiation-induced pneumonitis and prolonged radiation treatment times significantly reduced overall survival after adjuvant radiotherapy in NSCLC patients. The negative impact of a longer radiotherapy treatment time could be shown for the first time in an adjuvant setting. The hypothesis of a negative impact of longer waiting times prior to commencement of adjuvant radiotherapy could not be confirmed.

Clinical three-dimensional conformal radiotherapy research using repeated computed tomography scans for field reduction in older non-small-cell lung cancer patients.

This study investigated the curative and toxic effects of three-dimensional conformal radiotherapy (3D-CRT), using repeated CT scans for field reduction in older non-small-cell lung cancer (NSCLC) patients. 3D-CRT was administered to 36 older patients with NSCLC, and irradiation fields included the primary lesion and metastatic lymph nodes. After CT localization scanning, images were fed into a treatment planning system to delineate the gross tumor volume (GTV)1 and prepare Plan 1. After the DT50 (dose of the tumor is 50 Gy) increased from 50 Gy in 25 fractions to 54 Gy in 27 fractions, secondary CT localization scanning was performed to delineate GTV2 and prepare Plan 2; radiotherapy was administered continuously. When the DT increased to 60-65 Gy, tertiary CT scanning was performed to prepare another plan. The field was reduced to boost irradiation to the residual target volume until the total DT increased to 68-74 Gy. Compared with GTV1, the median absolute volume regression and median relative regression amounts for GTV2 were 68.85 cm(3) and 31.17%, respectively (Z = -2.673, P = 0.021). There were 8 cases of complete remission (22.2%), 20 of partial remission (55.6%), 7 of stable disease (19.4%), and 1 of progressive disease (2.8%). The total effectiveness rate was 77.8% and the 1- and 2-year survival rates were 63.9 and 27.8%, respectively. Radiation esophagitis and radiation pneumonia, the main toxic side effects, were tolerable. 3D-CRT, using repeated CT scans for field reduction in older NSCLC patients, could increase the local control and survival rates and relieve the toxic radiotherapy side effects.

Stereotactic body radiotherapy for pulmonary metastases. Prognostic factors and adverse respiratory events.

PURPOSE: The aim of this retrospective study was to evaluate the feasibility, safety, and effectiveness of stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS: Between April 2007 and March 2011, 87 patients underwent SBRT for pulmonary metastases using the in-house Air-Bag System(TM) to obtain the four-dimensional image for treatment planning and to reduce intrafractional intrathoracic organ motion with abdominal compression to reduce the risk of radiation pneumonitis. Survival and respiratory adverse events were analyzed. RESULTS: The 2- and 3-year overall survival (OS) rates were 47 and 32 %, and the corresponding cause-specific survivals were 52 and 36 %. The 2- and 3-year OS rates were 57 and 49 % for patients in group 1, respectively, while the corresponding OS rates were 48 and 21 %, and 40 and 32 % for patients in groups 2 and 3, respectively. The 2- and 3-year local control (LC) rates were 80 and 80 %, respectively. The corresponding intrathoracic progression-free survival rates were 40 and 32 %, respectively. Concerning adverse respiratory events after SBRT for pulmonary metastases, 14 % were grade 0 (G0), 66 % G1, 13 % G2, 6 % G3, and 1 % G4. Concerning the adverse respiratory events (NCI-CTC) by grade scale, 1- and 2-year cumulative probabilities of radiation pneumonitis were 12 and 20 % for G2 and 4 and 10 % for G3/4, respectively. The mean values for cumulative V20 were 11.6 ± 8.5 %, 29.8 ± 18.6 %, and 25.7 ± 12.8 % in G0/1, G2, and G3/4, respectively. The number of pulmonary metastases that could be safely treated with SBRT was 6 PTVs (or seven gross tumor volumes) within a cumulative V20 of 30 % under the restricted intrafractional respiratory tumor motion using the Air-Bag System(TM). CONCLUSION: We propose that the number of pulmonary metastases that can be safely treated with SBRT is 6 PTVs with a cumulative V20 of 30 % under the restricted respiratory tumor motion using the Air-Bag System(TM). SBRT for pulmonary metastases offers locally effective treatment for recurrent or residual lesions after first line chemotherapy.

Hyperpolarized (3)He pulmonary functional magnetic resonance imaging prior to radiation therapy.

PURPOSE: Radiation-induced lung injury (RILI) is the primary dose-limiting toxicity for radiation therapy of the lung, and although the effects of radiation dose on RILI development have been well characterized, the influence of chronic obstructive pulmonary disease (COPD) on the development of RILI and other outcomes is not well understood. The purpose of this small pilot study was to evaluate the relationship between hyperpolarized (3)He magnetic resonance imaging (MRI) measurements of COPD with RILI and 12-month survival in lung cancer patients undergoing radical radiotherapy and to evaluate the feasibility of pulmonary functional MRI as an image guidance∕planning tool for radiation therapy. METHODS: Fifteen non-small cell and small cell lung cancer patients underwent pulmonary function tests, x-ray computed tomography (CT), and hyperpolarized (3)He MRI prior to radical radiation therapy (≥60 Gy). Conventional thoracic (1)H and hyperpolarized (3)He MRI were acquired to generate ventilation defect percent and the apparent diffusion coefficient for the ipsilateral and contralateral lungs independently. CT was acquired postradiation therapy and qualitatively evaluated for radiological evidence of RILI and 12-month survival was reported. RESULTS: Hyperpolarized (3)He MRI measurements of COPD classified 10∕15 subjects with contralateral lung COPD (CLC), and five subjects without COPD [contralateral lung normal (CLN)]. Of the 10 subjects with CLC, only four had a previous clinical diagnosis of COPD. CT images were acquired postradiation therapy for 13 subjects, and for eight (62%) of these there was qualitative evidence of RILI, including 5∕9 CLC and 3∕4 CLN subjects. The one-year survival was 2∕10 for CLC and 3∕5 for CLN subjects. CONCLUSIONS: In this small pilot study, we report the use of (3)He MRI to stratify lung cancer patients based on MRI evidence of COPD and showed that comorbid COPD was present in the majority of lung cancer subjects stratified for radiation therapy. Lung cancer patients with imaging evidence of COPD did not have an increased incidence of RILI compared to patients without COPD. However, preliminary data presented here indicated that one-year survival in COPD subjects was lower than expected based on previously published survival rates, which may have implications for radiation therapy in lung cancer patients with comorbid COPD.

Analysis of cardiac and pulmonary complication probabilities after radiation therapy for patients with early-stage breast cancer.

OBJECTIVE: The purpose of this study was to evaluate the radiobiological implications of clinical use of respiratory-gated techniques for postoperative radiation therapy of early-stage left-sided breast cancer after breast-conserving surgery. MATERIAL AND METHODS: Radiation therapy treatment plans of 80 patients with early-stage breast cancer (stage I-II), receiving whole breast irradiation after breast-conserving therapy, were analyzed. The control group consisting of 47 patients received standard radiation therapy, and the respiratory-gated group consisting of 33 patients received deep inspiration-gated radiation therapy. Normal tissue complication probabilities (NTCP) for cardiac mortality and for clinical radiation-induced pneumonitis were calculated for all patients included in present study, using relative seriality model. NTCP data were analyzed for 113 radiation therapy plans, which included free breathing plans for the respiratory-gated groups. RESULTS: Pneumonitis probability was 0.6% (range 0.0-2.8%) and 0.3% (0.0-1.2%) for control and respiratory-gated group, respectively. Cardiac mortality was 1.3% (0.0-5.0%) and 0.2% (0.0-2.8%) for control and respiratory-gated group, respectively. Using respiratory-gated radiation therapy, NTCP was reduced in comparison with the control group by 83% (P<0.00001) and by 55% (P=0.01270) for cardiac mortality and for clinical radiation-induced pneumonitis, respectively. CONCLUSIONS: Use of respiratory-gated radiation therapy, for postoperative treatment of early-stage breast cancer, significantly reduces excessive cardiac mortality probability and pulmonary complication probability, as compared to standard radiation therapy techniques. This is especially important from heart complication probability point of view, as cardiac mortality remains one of the important issues of postoperative breast irradiation in patients with early stage breast cancer.

Analysis of radiation pneumonitis risk using a generalized Lyman model.

PURPOSE: To introduce a version of the Lyman normal-tissue complication probability (NTCP) model adapted to incorporate censored time-to-toxicity data and clinical risk factors and to apply the generalized model to analysis of radiation pneumonitis (RP) risk. METHODS AND MATERIALS: Medical records and radiation treatment plans were reviewed retrospectively for 576 patients with non-small cell lung cancer treated with radiotherapy. The time to severe (Grade >/=3) RP was computed, with event times censored at last follow-up for patients not experiencing this endpoint. The censored time-to-toxicity data were analyzed using the standard and generalized Lyman models with patient smoking status taken into account. RESULTS: The generalized Lyman model with patient smoking status taken into account produced NTCP estimates up to 27 percentage points different from the model based on dose-volume factors alone. The generalized model also predicted that 8% of the expected cases of severe RP were unobserved because of censoring. The estimated volume parameter for lung was not significantly different from n = 1, corresponding to mean lung dose. CONCLUSIONS: NTCP models historically have been based solely on dose-volume effects and binary (yes/no) toxicity data. Our results demonstrate that inclusion of nondosimetric risk factors and censored time-to-event data can markedly affect outcome predictions made using NTCP models.

Case Series of 23 Patients Who Developed Fatal Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer.

The purpose of this study was to examine the characteristics and treatment plans of patients who experienced fatal radiation pneumonitis after stereotactic body radiation therapy for primary or oligometastatic lung cancer. Records of 1789 patients treated with stereotactic body radiation therapy for primary or oligometastatic lung cancer were retrospectively reviewed to identify those who developed fatal radiation pneumonitis. Twenty-three (1.3%; 18 men and 5 women) patients developed fatal radiation pneumonitis after stereotactic body radiation therapy for lung cancer; their median age was 74 years. The mean Krebs von den Lungen-6 level and percent vital capacity were 1320 U/mL and 82%, respectively. Prestereotactic body radiation therapy computed tomography revealed pulmonary interstitial change in 14 (73.7%) of 19 patients in whom computed tomography data could be reviewed. Seven (30.4%) of 23 patients had regularly used steroids. The median time duration between stereotactic body radiation therapy commencement and pneumonia symptom appearance was 75 (range: 14-204) days. Median survival time following pneumonia symptom appearance was 53 (range: 4-802) days. The 6- and 12-month overall survival rates were 34.8% and 13.0%, respectively. The 6-month overall survival rates in patients with and without heart disease were 50.0%, 16.7%, and 46.7% for heart disease existence, respectively. There were 4 patients in whom fatal radiation pneumonitis occurred within 2 months after stereotactic body radiation therapy and who died within 1 month. Three of them had no pulmonary interstitial change before stereotactic body radiation therapy, but had heart disease. In summary, the survival time in this case series was generally short but varied widely. More than half of the patients had pulmonary interstitial change before stereotactic body radiation therapy, although immediately progressive fatal radiation pneumonitis was also observed in patients without pulmonary interstitial change. True risk factors for fatal radiation pneumonitis should be examined in a prospective study with a larger cohort.

Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival in Patients Treated With Lung Stereotactic Body Radiation Therapy (SBRT).

INTRODUCTION: The purpose of this study was to determine the impact of interstitial lung disease (ILD) on radiation pneumonitis (RP) and overall survival (OS) in lung stereotactic body radiation therapy (SBRT). METHODS: Patients treated with lung SBRT from 2004 to 2015 were included. Pretreatment computed tomography scans were reviewed and classified for interstitial changes by thoracic radiologists using American Thoracic Society guidelines and Washko and Kazerooni scores. RP was scored prospectively using Common Terminology Criteria for Adverse Events, version 3.0. Pretreatment imaging characteristics, clinical variables, and dosimetry were assessed by univariate (UVA) and multivariate analysis (MVA). OS was assessed by the log-rank test, and the impact of ILD on OS was assessed by Cox regression. RESULTS: Of the 537 patients assessed, 39 had interstitial changes (13 usual interstitial pneumonia [UIP], 24 possible UIP, and 2 inconsistent with UIP). RP was significantly higher in patients with ILD than in patients without ILD (grade ≥ 2, 20.5% vs. 5.8%; P < .01; grade ≥ 3, 10.3% vs. 1.0%; P < .01). Two of 3 grade 5 RP had imaging features of ILD. On UVA, ILD, Washko score, lung parameters performance status, and dose were significant predictors of grade ≥ 2 RP. On MVA, ILD (odds ratio, 5.81; 95% confidence interval, 2.28-14.83; P < .01) and mean lung dose (odds ratio, 1.40; 95% confidence interval, 1.14-1.71; P < .01) were predictors of RP. ILD did not significantly affect OS on UVA or MVA. Median survival was 27.4 months in the ILD cohort and 34.8 in the ILD-negative cohort (P = .17). DISCUSSION: ILD is a significant risk factor for RP in patients treated with lung SBRT. Computed tomography scans should be reviewed for evidence of ILD prior to SBRT.

Clinical and Dosimetric Factors Predicting Grade ≥2 Radiation Pneumonitis After Postoperative Radiotherapy for Patients With Non-Small Cell Lung Carcinoma.

PURPOSE: To identify clinical and dosimetric factors that would predict grade ≥2 radiation pneumonitis (RP) for patients undergoing postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC); and to use the factors identified to generate a predictive model to quantify risk of RP in such patients. METHODS AND MATERIALS: We retrospectively reviewed radiation therapy, radiographic, and clinical data from 199 patients who had received PORT, with or without chemotherapy, for NSCLC. Potential associations between dosimetric and clinical factors and RP were evaluated in univariate and multivariate Cox regression hazard models and competing risk analysis. Kaplan-Meier analysis was used to estimate overall survival and the cumulative incidence of RP, and receiver operating characteristic curve analysis to identify cutpoints for variables found to influence RP risk. The endpoint was grade ≥2 RP (symptomatic, requiring steroids or limiting instrumental activities of daily living). RESULTS: Thirty-seven patients (19%) developed grade ≥2 RP. Patient-related factors, type of surgery or chemotherapy, and radiation therapy-related factors were not associated with grade ≥2 RP; only lung V10 > 30% and lung V20 > 20% predicted grade ≥2 RP. Risk groupings were as follows: high risk, V10 > 30% and V20 > 20% (24 of 72 patients, 33%); intermediate risk, V10 > 30% and V20 ≤ 20% or V10 ≤ 30% and V20 > 20% (6 of 26 patients, 23%); and low risk, V10 ≤ 30% and V20 ≤ 20% (6 of 101 patients, 6%) (P < .0001). In a subgroup analysis of patients who had had lobectomy, corresponding incidences of RP were as follows: high risk, 20 of 59 (34%); intermediate risk, 5 of 22 (23%); and low risk, 6 of 70 (9%) (P = .001). CONCLUSIONS: The lung dose-volume variables V10 and V20 predicted risk of grade ≥2 RP among patients who underwent PORT for NSCLC.

Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma.

PURPOSE: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemithoracic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. METHODS AND MATERIALS: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at the University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non-cancer-related death within 6 months of IMRT. RESULTS: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p = 0.021), absolute volume of lung spared at 10 Gy (p = 0.025), percentage of lung volume receiving >or=20 Gy (V(20); p = 0.002), and mean lung dose (p = 0.013). On multivariate analysis, only V20 was predictive of PRD (p = 0.017; odds ratio, 1.50; 95% confidence interval, 1.08-2.08) or non-cancer-related death (p = 0.033; odds ratio, 1.21; 95% confidence interval, 1.02-1.45). CONCLUSION: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V20 was the only independent determinant for risk of PRD or non-cancer-related death. The mean V20 of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V20 should be kept as low as possible after extrapleural pneumonectomy.

Influence of Fractionation Scheme and Tumor Location on Toxicities After Stereotactic Body Radiation Therapy for Large (≥5 cm) Non-Small Cell Lung Cancer: A Multi-institutional Analysis.

PURPOSE: To describe the impact of fractionation scheme and tumor location on toxicities in stereotactic body radiation therapy (SBRT) for ≥5-cm non-small cell lung cancer (NSCLC), as part of a multi-institutional analysis. METHODS: Patients with primary ≥5-cm N0 M0 NSCLC who underwent ≤5-fraction SBRT were examined across multiple high-volume SBRT centers. Collected data included clinical/treatment parameters; toxicities were prospectively assessed at each institution according to the Common Terminology Criteria for Adverse Events. Patients treated daily were compared with those treated every other day (QOD)/other nondaily regimens. Stratification between central and peripheral tumors was also performed. RESULTS: Ninety-two patients from 12 institutions were evaluated (2004-2016), with median follow-up of 12 months. In total there were 23 (25%) and 6 (7%) grade ≥2 and grade ≥3 toxicities, respectively. Grades 2 and 3 pulmonary toxicities occurred in 9% and 4%, respectively; 1 patient treated daily experienced grade 5 radiation pneumonitis. Of the entire cohort, 46 patients underwent daily SBRT, and 46 received QOD (n=40)/other nondaily (n=6) regimens. Clinical/treatment parameters were similar between groups; the QOD/other group was more likely to receive 3-/4-fraction schemas. Patients treated QOD/other experienced significantly fewer grade ≥2 toxicities as compared with daily treatment (7% vs 43%, P<.001). Patients treated daily also had higher rates of grade ≥2 pulmonary toxicities (P=.014). Patients with peripheral tumors (n=66) were more likely to receive 3-/4-fraction regimens than those with central tumors (n=26). No significant differences in grade ≥2 toxicities were identified according to tumor location (P>.05). CONCLUSIONS: From this multi-institutional study, toxicity of SBRT for ≥5-cm lesions is acceptable, and daily treatment was associated with a higher rate of toxicities.

Reduction of cardiac and pulmonary complication probabilities after breathing adapted radiotherapy for breast cancer.

PURPOSE: Substantial reductions of cardio-pulmonary radiation doses can be achieved using voluntary deep inspiration breath-hold (DIBH) or free breathing inspiration gating (IG) in radiotherapy after conserving surgery for breast cancer. The purpose of this study is to evaluate the radiobiological implications of such dosimetric benefits. METHODS AND MATERIALS: Patients from previously reported studies were pooled for a total of 33 patients. All patients underwent DIBH and free breathing (FB) scans, and 17 patients underwent an additional IG scan. Tangential conformal treatment plans covering the remaining breast, internal mammary, and periclavicular nodes were optimized for each scan, prescription dose 48 Gy. Normal tissue complication probabilities were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. RESULTS: Previous computed tomography studies showed that both voluntary DIBH and IG provided reduction of the lung V50 (relative volume receiving more than 50% of prescription dose) on the order of 30-40%, and a 80-90% reduction of the heart V50 for left-sided cancers. Corresponding pneumonitis probability of 28.1% (range, 0.7-95.6%) for FB could be reduced to 2.6% (range, 0.1-40.1%) for IG, and 4.3% (range, 0.1-59%) for DIBH. The cardiac mortality probability could be reduced from 4.8% (range, 0.1-23.4%) in FB to 0.5% (range, 0.1-2.6%) for IG and 0.1% (range, 0-3.0%) for DIBH. CONCLUSIONS: Remarkable potential is shown for simple voluntary DIBH and free breathing IG to reduce the risk of both cardiac mortality and pneumonitis for the common technique of adjuvant tangential breast irradiation.

Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.

PURPOSE: To describe the initial experience at Dana-Farber Cancer Institute/Brigham and Women's Hospital with intensity-modulated radiation therapy (IMRT) as adjuvant therapy after extrapleural pneumonectomy (EPP) and adjuvant chemotherapy. METHODS AND MATERIALS: The medical records of patients treated with IMRT after EPP and adjuvant chemotherapy were retrospectively reviewed. IMRT was given to a dose of 54 Gy to the clinical target volume in 1.8 Gy daily fractions. Treatment was delivered with a dynamic multileaf collimator using a sliding window technique. Eleven of 13 patients received heated intraoperative cisplatin chemotherapy (225 mg/m(2)). Two patients received neoadjuvant intravenous cisplatin/pemetrexed, and 10 patients received adjuvant cisplatin/pemetrexed chemotherapy after EPP but before radiation therapy. All patients received at least 2 cycles of intravenous chemotherapy. The contralateral lung was limited to a V20 (volume of lung receiving 20 Gy or more) of 20% and a mean lung dose (MLD) of 15 Gy. All patients underwent fluorodeoxyglucose positron emission tomography (FDG-PET) for staging, and any FDG-avid areas in the hemithorax were given a simultaneous boost of radiotherapy to 60 Gy. Statistical comparisons were done using two-sided t test. RESULTS: Thirteen patients were treated with IMRT from December 2004 to September 2005. Six patients developed fatal pneumonitis after treatment. The median time from completion of IMRT to the onset of radiation pneumonitis was 30 days (range 5-57 days). Thirty percent of patients (4 of 13) developed acute Grade 3 nausea and vomiting. One patient developed acute Grade 3 thrombocytopenia. The median V20, MLD, and V5 (volume of lung receiving 5 Gy or more) for the patients who developed pneumonitis was 17.6% (range, 15.3-22.3%), 15.2 Gy (range, 13.3-17 Gy), and 98.6% (range, 81-100%), respectively, as compared with 10.9% (range, 5.5-24.7%) (p = 0.08), 12.9 Gy (range, 8.7-16.9 Gy) (p = 0.07), and 90% (range, 66-98.3%) (p = 0.20), respectively, for the patients who did not develop pneumonitis. CONCLUSIONS: Intensity-modulated RT treatment for mesothelioma after EPP and adjuvant chemotherapy resulted in a high rate of fatal pneumonitis when standard dose parameters were used. We therefore recommend caution in the utilization of this technique. Our data suggest that with IMRT, metrics such as V5 and MLD should be considered in addition to V20 to determine tolerance levels in future patients.

Single Nucleotide Polymorphisms in CBLB, a Regulator of T-Cell Response, Predict Radiation Pneumonitis and Outcomes After Definitive Radiotherapy for Non-Small-Cell Lung Cancer.

BACKGROUND: The immune system has important roles in tumor development and outcomes after cancer treatment. We evaluated whether single-nucleotide polymorphisms (SNPs) in the gene encoding casitas B-lineage lymphoma b protein (Cbl-b), an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function, were associated with outcomes after treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Samples from 393 patients with NSCLC treated with definitive radiotherapy at a single institution between March 1998 and February 2009 were used to genotype 3 potentially functional SNPs in CBLB (rs1042852 C>T, rs2305035 G>A, and rs7649466 C>G). We evaluated associations between these SNPs and local recurrence-free survival, distant metastasis-free survival, overall survival, and risk of radiation pneumonitis (RP). RESULTS: Having the rs2305035 A variant genotypes (AA or AG) was associated with better local recurrence-free survival (median 15.8 vs. 15.3 months; adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.60-0.98; P = .033), distant metastasis-free survival (median 15.4 vs. 14.0 months; adjusted HR, 0.74; 95% CI, 0.57-0.96; P = .024) and overall survival (median 23.5 vs. 22.8 months; adjusted HR, 0.72; 95% CI, 0.56-0.93; P = .013) after adjustment in a Cox proportional hazard model. Patients with these genotypes were also at greater risk of developing grade 3 or higher RP than were patients with GG genotypes in an adjusted Cox proportional hazard model. CONCLUSION: This is the first report that rs2305035 genotypes in CBLB were associated with clinical and RP risk among patients with NSCLC treated with definitive radiotherapy. These findings could assist in generating hypothesis for further mechanistic studies.

Factors Associated With Early Mortality in Patients Treated With Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Concurrent chemoradiation therapy (con-CRT) is recommended for fit patients with locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with toxicity, and observed survival continues to be limited. Identifying factors associated with early mortality could improve patient selection and identify strategies to improve prognosis. METHODS AND MATERIALS: Analysis of a multi-institutional LA-NSCLC database consisting of 1245 patients treated with con-CRT in 13 institutions was performed to identify factors predictive of 180-day survival. Recursive partitioning analysis (RPA) was performed to identify prognostic groups for 180-day survival. Multivariate logistic regression analysis was used to create a clinical nomogram predicting 180-day survival based on important predictors from RPA. RESULTS: Median follow-up was 43.5 months (95% confidence interval [CI]: 40.3-48.8) and 127 patients (10%) died within 180 days of treatment. Median, 180-day, and 1- to 5-year (by yearly increments) actuarial survival rates were 20.9 months, 90%, 71%, 45%, 32%, 27%, and 22% respectively. Multivariate analysis adjusted by region identified gross tumor volume (GTV) (odds ratio [OR] ≥100 cm(3): 2.61; 95% CI: 1.10-6.20; P=.029) and pulmonary function (forced expiratory volume in 1 second [FEV1], defined as the ratio of FEV1 to forced vital capacity [FVC]) (OR <80%: 2.53; 95% CI: 1.09-5.88; P=.030) as significant predictors of 180-day survival. RPA resulted in a 2-class risk stratification system: low-risk (GTV <100 cm(3) or GTV ≥100 cm(3) and FEV1 ≥80%) and high-risk (GTV ≥100 cm(3) and FEV1 <80%). The 180-day survival rates were 93% for low risk and 79% for high risk, with an OR of 4.43 (95% CI: 2.07-9.51; P<.001), adjusted by region. A clinical nomogram predictive of 180-day survival, incorporating FEV1, GTV, N stage, and maximum esophagus dose yielded favorable calibration (R(2) = 0.947). CONCLUSIONS: This analysis identified several risk factors associated with early mortality and suggests that future research in the optimization of pretreatment pulmonary function and/or functional lung avoidance treatment may alter the therapeutic ratio in this patient population.

Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

INTRODUCTION: We determined whether pretreatment immunologic parameters could predict the outcomes and toxicity in early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: The pretreatment leukocyte, lymphocyte, and neutrophil counts, serum albumin levels, neutrophil-to-lymphocyte ratio (NLR,) and platelet-to-lymphocyte ratio (PLR) were evaluated to determine the association with locoregional control, distant metastasis-free survival (DMFS), disease-specific survival (DSS), overall survival (OS), and treatment-related toxicity. The survival rates were estimated with Kaplan-Meier analysis and multivariate analysis using the Cox proportional hazards model. RESULTS: The data from 118 patients with a median follow-up period of 28.9 months were assessed. The 3-year local control, regional control, and DMFS rates were 97%, 87%, and 92%, respectively. The 3-year OS and DSS rates were 77% and 85%, respectively. On univariate analysis, none of the pretreatment immune parameters predicted for disease control. A higher NLR (P = .008), PLR (P = .002), neutrophil count (P = .059), and the presence of lymphocytopenia (P = .032) independently prognosticated for poor OS. Receiver operating characteristic curve analysis found NLRs > 2.18 and PLRs > 187.27 optimally predicted for poor 3-year OS (P = .0262 and P = .0089, respectively). A higher NLR predicted against the development of any symptomatic toxicity and against the development of symptomatic (grade ≥ 2) radiation pneumonitis on univariate analysis, and a higher serum albumin level independently predicted for the development of symptomatic radiation pneumonitis (P = .0491). CONCLUSION: In the setting of SBRT, an elevated pretreatment NLR, PLR, and neutrophil count and the presence of lymphocytopenia independently predicted for poor OS. Patients who presented with higher NLRs and lower serum albumin levels experienced less treatment-related symptomatic toxicity.

Genetic variants in PI3K/AKT pathway are associated with severe radiation pneumonitis in lung cancer patients treated with radiation therapy.

PI3K/AKT pathway plays important roles in inflammatory and fibrotic diseases while its connection to radiation pneumonitis (RP) is unclear. In this study, we explored the associations of genetic variants in PI3K/AKT pathway with RP in lung cancer patients with radiotherapy. Two hundred and sixty one lung cancer patients with radiotherapy were included in this prospective study (NCT02490319) and genotyped by MassArray and Sanger Sequence methods. By multivariate Cox hazard analysis and multiple testing, GA/GG genotype of AKT2: rs33933140 (HR = 0.272, 95% CI: 0.140-0.530, P = 1.3E-4, Pc = 9.1E-4), and the GT/GG genotype of PI3CA: rs9838117 (HR = 0.132, 95% CI: 0.042-0.416, P = 0.001, Pc = 0.006) were found to be strongly associated with a decreased occurrence of RP ≥ grade 3. And patients with the CT/TT genotype of AKT2: rs11880261 had a notably higher incidence of RP ≥ grade 3 (HR = 2.950, 95% CI: 1.380-6.305, P = 0.005, Pc = 0.025). We concluded that the genetic variants of PI3K/AKT pathway were significantly related to RP of grade ≥ 3 and may thus be predictors of severe RP before radiotherapy, if further validated in larger population.