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.

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.

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.

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.

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.

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.

Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF. METHODS AND MATERIALS: C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for ß-galactosidase activity. RESULTS: Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days (P=.006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 ± 11.8 µg per lung; irradiation plus rapamycin, 21.4 ± 6.0 µg per lung; P=.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1ß and transforming growth factor ß induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P<.001). CONCLUSIONS: Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes.

Comparison of the Effectiveness of Radiofrequency Ablation With Stereotactic Body Radiation Therapy in Inoperable Stage I Non-Small Cell Lung Cancer: A Systemic Review and Pooled Analysis.

PURPOSE: To performed a systematic review and pooled analysis to compare clinical outcomes of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) for the treatment of medically inoperable stage I non-small cell lung cancer. METHODS AND MATERIALS: A comprehensive literature search for published trials from 2001 to 2012 was undertaken. Pooled analyses were performed to obtain overall survival (OS) and local tumor control rates (LCRs) and adverse events. Regression analysis was conducted considering each study's proportions of stage IA and age. RESULTS: Thirty-one studies on SBRT (2767 patients) and 13 studies on RFA (328 patients) were eligible. The LCR (95% confidence interval) at 1, 2, 3, and 5 years for RFA was 77% (70%-85%), 48% (37%-58%), 55% (47%-62%), and 42% (30%-54%) respectively, which was significantly lower than that for SBRT: 97% (96%-98%), 92% (91%-94%), 88% (86%-90%), and 86% (85%-88%) (P<.001). These differences remained significant after correcting for stage IA and age (P<.001 at 1 year, 2 years, and 3 years; P=.04 at 5 years). The effect of RFA was not different from that of SBRT on OS (P>.05). The most frequent complication of RFA was pneumothorax, occurring in 31% of patients, whereas that for SBRT (grade ≥3) was radiation pneumonitis, occurring in 2% of patients. CONCLUSIONS: Compared with RFA, SBRT seems to have a higher LCR but similar OS. More studies with larger sample sizes are warranted to validate such findings.

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.

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.

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.

Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy.

AIM: To elucidate the impact of different forms of radiation toxicities (esophagitis, radiation pneumonitis, mucositis and hoarseness), on the survival of patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Data were individually collected retrospectively for all patients diagnosed with NSCLC subjected to curatively intended radiotherapy (≥50 Gy) in Sweden during the time period 1990 to 2000. RESULTS: Esophagitis was the only radiation-induced toxicity with an impact on survival (hazard ratio=0.83, p=0.016). However, in a multivariate model, with clinical- and treatment-related factors taken into consideration, the impact of esophagitis on survival was no longer statistically significant (hazard ratio=0.88, p=0.17). CONCLUSION: The effect on survival seen in univariate analysis may be related to higher radiation dose and to the higher prevalence of chemotherapy in this group. The results do not suggest that the toxicities examined have any detrimental effect on overall survival.

Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-ß1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

Stereotactic body radiotherapy for Stage I lung cancer with chronic obstructive pulmonary disease: special reference to survival and radiation-induced pneumonitis.

This retrospective study aimed to evaluate radiation-induced pneumonitis (RIP) and a related condition that we define in this report--prolonged minimal RIP (pmRIP)--after stereotactic body radiotherapy (SBRT) for Stage I primary lung cancer in patients with chronic obstructive pulmonary disease (COPD). We assessed 136 Stage I lung cancer patients with COPD who underwent SBRT. Airflow limitation on spirometry was classified into four Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, with minor modifications: GOLD 1 (mild), GOLD 2 (moderate), GOLD 3 (severe) and GOLD 4 (very severe). On this basis, we defined two subgroups: COPD-free (COPD -) and COPD-positive (COPD +). There was no significant difference in overall survival or cause-specific-survival between these groups. Of the 136 patients, 44 (32%) had pmRIP. Multivariate analysis showed that COPD and the Brinkman index were statistically significant risk factors for the development of pmRIP. COPD and the Brinkman index were predictive factors for pmRIP, although our findings also indicate that SBRT can be tolerated in early lung cancer patients with COPD.

Clinical features, outcomes and treatment-related pneumonitis in elderly patients with esophageal carcinoma.

AIM: To investigate the clinical features and prognoses of elderly patients with esophageal carcinoma and to compare the effects of radiotherapy and rates of treatment-related pneumonitis (TRP) between elderly and non-elderly patients. METHODS: A total of 236 patients with esophageal carcinoma who received radiotherapy between 2002 and 2012 were enrolled. The patients were divided into two groups: an elderly group (age ≥ 65 years) and a non-elderly group (age < 65 years). The tumor position and stage, lymph node and distant metastases, and incidence and severity of TRP were compared. Multivariate analysis was applied to identify independent prognostic factors. RESULTS: The median overall survival times after radiotherapy in the elderly and non-elderly groups were 18.5 and 20.5 mo, respectively. Cox regression analysis showed that TRP grade and tumor-node-metastasis (TNM) stage were independent prognostic factors in the elderly group. High-dose radiotherapy (> 60 Gy) was associated with a high incidence of TRP. Tumor TNM staging was significantly different between the two groups in which TRP occurred. Multivariate analysis showed that TNM stage was an independent prognostic factor. Esophageal carcinoma in elderly patients was relatively less malignant compared with that in non-elderly patients. CONCLUSION: An appropriate dose should be used to decrease the incidence of TRP in radiotherapy, and intensity modulated radiation therapy should be selected if possible.

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.

Predictive factors for local control in primary and metastatic lung tumours after four to five fraction stereotactic ablative body radiotherapy: a single institution's comprehensive experience.

AIMS: We report the outcomes of a large lung stereotactic ablative body radiotherapy (SABR) programme for primary non-small cell lung cancer (NSCLC) and pulmonary metastases. The primary study aim was to identify factors predictive for local control. MATERIALS AND METHODS: In total, 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR using 48-60 Gy in four to five fractions. Local, regional and distant failure data were collected prospectively, whereas other end points were collected retrospectively. Potential clinical and dosimetric predictors of local control were evaluated using univariate and multivariate analyses. RESULTS: Of the 311 tumours, 240 were NSCLC and 71 were other histologies. The 2 year local control rate was 96% in stage I NSCLC, 76% in colorectal cancer (CRC) metastases and 91% in non-lung/non-CRC metastases. Predictors of better local control on multivariate analysis were non-CRC tumours and a larger proportion of the planning target volume (PTV) receiving ≥100% of the prescribed dose (higher PTV V100). Among the 45 CRC metastases, a higher PTV V100 and previous chemotherapy predicted for better local control. CONCLUSIONS: Lung SABR of 48-60 Gy/four to five fractions resulted in high local control rates for all tumours except CRC metastases. Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control.

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.