Thoracic Toxicity Research Articles

Clinical Outcome-Related Cancer Pathways and Mutational Signatures in Patients With Unresectable Esophageal Squamous Cell Carcinoma Treated With Chemoradiotherapy

Definitive chemoradiotherapy (dCRT) is a standard-of-care for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). However, even in individuals treated with the same dCRT regimen, differences in the local control rate and radiation-induced thoracic toxicity exist (radiation-induced esophagitis [RIE]). Here, we describe a comprehensive genomic evaluation of pretreatment tumor tissue samples from 183 patients with ESCC using targeted sequencing of 474 cancer-related genes. The association between endpoints (progression-free survival [PFS], overall survival, locoregional relapse-free survival, distant metastasis-free survival), toxicity (RIE) and genomic features, including altered pathways and the mutational signature, was analyzed. An independent cohort of 84 stage II-III patients with ESCC was used for validation. Gene alterations in the cell cycle pathway were identified in 87% of cases. Other frequently altered pathways included PI3K-AKT (45.9%), NOTCH (38.3%), NRF2 (36.6%), RKT-RAS (28.4%), and homologous recombination repair (HRR; 20.2%). HRR pathway alterations correlated with shortened PFS (mutation vs wild-type: 9.00 vs 14.40 months, hazard ratio, 2.10; 95% confidence interval, 1.29-3.44), while altered RTK-RAS pathways were correlated with worse overall survival in patients with ESCC treated with chemoradiotherapy (mutation vs wild-type: 23.70 vs 33.50 months; hazard ratio, 1.65; 95% confidence interval, 1.01-2.69). Furthermore, enrichment of apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures (signatures 2 and 13) was identified in ESCC tumors with altered HRR pathways. High APOBEC signatures and an altered HRR pathway were correlated with poor prognoses in dCRT-treated ESCC. Moreover, the APOBEC signature and/or the presence of HRR pathway alterations were associated with poor PFS and overall survival, which was validated in an independent whole exome sequence cohort. Notably, the altered HRR pathway was also associated with high-grade RIE toxicity in patients with ESCC. Collectively, our results support the use of comprehensive genomic profiling to guide treatment and minimize RIE in patients with ESCC.

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer.

Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and radiotherapy-associated toxicity. There is an urgent need to identify genetic determinants that can explain patients’ likelihood to develop recurrence and radiotherapy-associated toxicity following CRT. In this study, we performed comprehensive genomic profiling, using a 474-cancer- and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients’ baseline clinical characteristics and genomic features, including tumor genetic, genomic and molecular pathway alterations, as well as single nucleotide polymorphisms (SNPs), were correlated with progression-free survival (PFS), overall survival (OS), and radiotherapy-associated pneumonitis and/or esophagitis development after CRT. A total of 122 patients were enrolled between 2014 and 2019, with 84 (69%) squamous cell carcinomas and 38 (31%) adenocarcinomas. Genetic analysis confirmed the association between the KEAP1-NRF2 pathway gene alterations and unfavorable survival outcome, and revealed alterations in FGFR family genes, MET, PTEN, and NOTCH2 as potential novel and independent risk factors of poor post-CRT survival. Combined analysis of such alterations led to improved stratification of the risk populations. In addition, patients with EGFR activating mutations or any oncogenic driver mutations exhibited improved OS. On the other hand, we also identified genetic markers in relation to radiotherapy-associated thoracic toxicity. SNPs in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis respectively. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles related to higher susceptibility to pneumonitis and esophagitis overall. Moreover, through their roles in genome integrity and replicative fidelity, somatic alterations in ZNF217 and POLD1 might also serve as risk predictors of high-grade pneumonitis and esophagitis. Taken together, leveraging targeted next-generating sequencing, we identified a set of novel clinically applicable biomarkers that might enable prediction of survival outcomes and risk of radiotherapy-associated thoracic toxicities. Our findings highlight the value of pre-treatment genetic testing to better inform CRT outcomes and clinical actions in stage III unresectable NSCLCs.

Comprehensive Next-Generation Sequencing Reveals Novel Predictive Biomarkers of Recurrence and Thoracic Toxicity Risks After Chemoradiation Therapy in Limited Stage Small Cell Lung Cancer

Although definitive chemoradiation therapy (dCRT) remains the most effective treatment modality in limited stage small cell lung cancer (SCLC), some patients progress quickly or develop serious radiation-induced thoracic toxicity (RITT). Molecular correlates of response to dCRT remain to be explored.Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation therapy response-related genes. Exploratory associations of progression-free survival, overall survival, and RITT with clinical features, tumor genetics, genomic and molecular pathway alterations, and single nucleotide polymorphisms were conducted.In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS, and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that single nucleotide polymorphisms in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated with increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment.Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DNA damage repair pathways, in the regulation of dCRT response.

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Toxicity and Efficacy in Non-Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and risk of radiation-induced thoracic toxicity (RITT). There is an urgent need to identify genetic determinants that can explain patients' likelihood to develop recurrence and RITT following CRT. <h3>Materials/Methods</h3> We performed comprehensive genomic profiling, using a 474-cancer and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients' clinical and genomic features were correlated with progression-free survival (PFS), overall survival (OS), and high-grade RITT development, after CRT. <h3>Results</h3> A total of 122 patients were enrolled (median age, 62 years; 87% males). Of these, the majority (n = 84, 69%) had squamous cell carcinoma (SCC) and the remaining 38 (31%) were adenocarcinoma (ADC). Median PFS and OS of the cohort were 11.4 and 34.6 months, respectively. No clear survival difference was seen between the histological subtypes or other clinical features, other than an association between smoking history and an unfavorable outcome (PFS HR = 1.89 [95% CI, 1.11-3.21], <i>P</i> = 0.02; OS HR = 1.59 [0.80-3.16], <i>P</i> = 0.19). Genetic association analysis identified alterations in NOTCH2, KEAP1, FGFR1/3 alterations as potential risk factors of CRT resistance, with reduced PFS and OS compared with patients carrying the respective wild-type genes. The rates of grade 2 or higher (high-grade) radiation-induced pneumonitis and esophagitis were 32% and 13%, respectively. Polymorphisms in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis, respectively. Moreover, XRCC5 (rs3835) was also associated with an earlier occurrence of high-grade esophagitis. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles associated with an increased susceptibility to RITT overall. <h3>Conclusion</h3> Our results provide a set of clinically usable predictive biomarkers for chemo-radiotherapy toxicity and efficacy. These findings suggest that pre-treatment testing for a combination of genetic variants, which likely act together to confer resistance or toxicity after CRT, might be clinically useful.

Early High-Grade Thoracic Toxicity After Palliative Radiotherapy for Non-Small Cell Lung Cancer.

Introduction: Palliative radiotherapy or chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) may cause thoracic toxicities due to the radiation dose delivered to the lungs, heart, and esophagus. We studied severe thoracic toxicities resulting in hospitalization or death during the acute and sub-acute phase, i.e., three months from commencing radiotherapy. In addition, risk factors were identified. Methods: A retrospective review of 165 patients treated with three-dimensional conformal palliative radiotherapy or CRT was performed. The prescribed total dose was equivalent to at least 30 Gy in 10 fractions. Uni- and multivariate analyses were employed.Results: Twelve patients (7%) were hospitalized within three months from the start of radiotherapy or CRT. Six patients were hospitalized for esophagitis, three for dyspnea most likely caused by pneumonitis, and three for cardiac arrhythmia. Fatal toxicity was not observed. However, 19% of the 165 patients died from tumor-related causes during the time period of interest. In multivariate analysis, the only esophageal dose was significantly associated with the risk of hospitalization. Conclusion: The safety profile of palliative radiotherapy or CRT in the acute and subacute phases was satisfactory. The hospitalization rate can be reduced by lowering the esophageal dose, as long as safe lung and heart doses can be maintained.

CT-based ventilation imaging in radiation oncology.

A form of lung function imaging is emerging that uses phase-resolved four-dimensional CT (4DCT or breath-hold CT) images along with image processing techniques to generate lung function maps that provide a surrogate of lung ventilation. CT-based ventilation (referred to as CT-ventilation) research has gained momentum in Radiation Oncology because many lung cancer patients undergo four-dimensional CT simulation as part of the standard treatment planning process. Therefore, generating CT-ventilation images provides functional information without burdening the patient with an extra imaging procedure.CT-ventilation has progressed from an image processing calculation methodology, to validation efforts, to retrospective demonstration of clinical utility in Radiation Oncology. In particular, CT-ventilation has been proposed for two main clinical applications: functional avoidance radiation therapy and thoracic dose–response assessment. The idea of functional avoidance radiation therapy is to preferentially spare functional portions of the lung (as measured by CT-ventilation) during radiation therapy with the hypothesis that reducing dose to functional portions of the lung will lead to reduced rates of radiation-related thoracic toxicity. The idea of imaging-based dose–response assessment is to evaluate pre- to post-treatment CT-ventilation-based imaging changes. The hypothesis is that early, imaging-change-based response can be an early predictor of subsequent thoracic toxicity. Based on the retrospective evidence, the clinical applications of CT-ventilation have progressed from the retrospective setting to on-going prospective clinical trials. This review will cover basic CT-ventilation calculation methodologies, validation efforts, presentation of clinical applications, summarize on-going clinical trials, review potential uncertainties and shortcomings of CT-ventilation, and discuss future directions of CT-ventilation research.

Characterizing Spatial Lung Function for Esophageal Cancer Patients Undergoing Radiation Therapy

Patients with esophageal cancer treated with chemoradiation and surgery can develop pulmonary complications. Four-dimensional computed tomography-ventilation (4DCT-ventilation) is a developing imaging modality that uses 4DCT data to calculate lung ventilation. 4DCT-ventilation has been studied in the lung-cancer population but has yet to be extended to patients with esophageal cancer. The purpose of this study was to characterize 4DCT-ventilation-based spatial lung function for patients with esophageal cancer. Thirty-five patients with esophageal cancer who underwent 4DCT scans participated in the study. A 4DCT-ventilation map was calculated using the patient's 4DCT imaging and a density change-based algorithm. To assess each patient's ventilation profile, radiologist interpretations and quantitative metrics were used. A radiologist interpreted the 4DCT-ventilation images for lobar-based defects and gravity-dependent atelectasis. The 4DCT-ventilation maps were reduced to single metrics intended to reflect the degree of ventilation heterogeneity. The quantitative metrics included the coefficient of variation and metrics based on the ventilation in each lung and each lung third (superior-inferior ventilation [Vent-SI] and anteroposterior ventilation). The functional profile of patients with esophageal cancer was characterized and compared (using the Mann-Whitney test) for cohorts based on thoracic comorbidities and radiologist-identified defects. Radiologist observations revealed that 26% of patients with esophageal cancer had lobar-based defects and 46% had gravity-dependent atelectasis. The baseline values were 0.52±0.20 (mean±SD), 11.2±12.5, and 72.5±14.6 for the coefficient of variation, the ventilation ratio of right to left lung, and Vent-SI metrics, respectively. The Vent-SI values were significantly different between patients with and without thoracic comorbidities (P=.05), and the anteroposterior ventilation metric was able to delineate patients with and without gravity-dependent atelectasis (P<.01). Our data demonstrate that approximately 30% of patients with esophageal cancer have significant ventilation heterogeneities. The current work uses radiologist observations and quantitative metrics to characterize 4DCT ventilation-based lung function for patients with esophageal cancer and presents data that can be used for future applications of 4DCT-ventilation to reduce thoracic toxicity for patients with esophageal cancer.

Interim Analysis of a Two-Institution, Prospective Clinical Trial of 4DCT-Ventilation-based Functional Avoidance Radiation Therapy

Functional imaging has been proposed that uses 4DCT images to calculate 4DCT-based lung ventilation (4DCT-ventilation). We have started a 2-institution, phase 2 prospective trial evaluating the feasibility, safety, and preliminary efficacy of 4DCT-ventilation functional avoidance. The trial hypothesis is that the rate of grade ≥2 radiation pneumonitis could be reduced to 12% with functional avoidance, compared with a 25% rate of pneumonitis with a historical control. The trial employed a Simon 2-stage design with a planned futility analysis after 17 evaluable patients. The purpose of this work is to present the trial design and implementation, dosimetric data, and clinical results for the planned futility analysis. Eligible patients were patients with lung cancer who were prescribed doses of 45 to 75Gy. For each patient, the 4DCT data were used to generate a 4DCT-ventilation image using the Hounsfield unit technique along with a compressible flow-based image registration algorithm. Two intensity modulated radiation therapy treatment plans were generated: (1) a standard lung plan and (2) a functional avoidance treatment plan that aimed to reduce dose to functional lung while meeting target and normal tissue constraints. Patients were treated with the functional avoidance plan and evaluated for thoracic toxicity (presented as rate and 95% confidence intervals [CI]) with a 1-year follow-up. The V20 to functional lung was 21.6%±9.5% (mean±standard deviation) with functional avoidance, representing a decrease of 3.2% (P<.01) relative to standard, nonfunctional treatment plans. The rates of grade ≥2 and grade ≥3 radiation pneumonitis were 17.6% (95% CI, 3.8%-43.4%) and 5.9% (95% CI, 0.1%-28.7%), respectively. Dosimetrically, functional avoidance achieved reduction in doses to functional lung while meeting target and organ at risk constraints. On the basis of Simon's 2-stage design and the 17.6% grade ≥2 pneumonitis rate, the trial met its futility criteria and has continued accrual.

SP-0012: The use of ACE inhibitors to attenuate thoracic irradiation-inducedcardiopulmonary toxicity.

SP-0012: The use of ACE inhibitors to attenuate thoracic irradiation-inducedcardiopulmonary toxicity.

A Prospective Study of the Effect of Different Palliative Radiotherapy Fractionation Schedules on Tumor Response and Toxicity in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Background: The optimal dose of palliative radiotherapy (RT) in symptomatic advanced lung cancer is unclear. Patients and methods: Patients with advanced NSCLC who were indicated for thoracic palliative RT with age up to 65 y and Performance Status (PS) 0 - 2 and no significant cardiac or lung co-morbidities were randomized into two fractionation arms: arm A: 30 Gy/10 over 2 weeks and arm B: 27 Gy/6 over 3 weeks (2 fractions per week) using 2 anterior posterior (AP-PA) fields in both arms. Primary end points were symptomatic and radiological tumor response, respiratory functions assessment. Secondary end point was toxicity. Results: From December 2014 to October 2015, 40 patients were randomized, 20 patients in each arm. There was statistically insignificant higher symptomatic improvement in arm B. Four weeks after treatment, 12 out of 40 patients (30%), 6 patients in each arm, had radiological Partial Response (PR) of the primary thoracic lesion without significant difference between the two arms. There was a tendency for improvement in the post treatment mean Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1) in each arm without statistical significance. There were no reported skin reactions or esophagitis in both arms up to 4 weeks after treatment. Eleven out of the 40 patients (27.5%), 6 in arm B and 5 in arm A, had radiological signs of radiation pneumonitis without significant difference between both arms. Conclusion: The two RT fractionation schedules showed equal efficacy in terms of symptoms relief, radiological response of the primary thoracic tumor, respiratory functions and toxicity. Thus the 27 Gy/6 fractionation arm appears preferable compared to 30 Gy/10 arm to minimize the patients’ visits and load on the machines.

Use of 4-Dimensional Computed Tomography-Based Ventilation Imaging to Correlate Lung Dose and Function With Clinical Outcomes

Four-dimensional computed tomography (4DCT)-based ventilation is an emerging imaging modality that can be used in the thoracic treatment planning process. The clinical benefit of using ventilation images in radiation treatment plans remains to be tested. The purpose of the current work was to test the potential benefit of using ventilation in treatment planning by evaluating whether dose to highly ventilated regions of the lung resulted in increased incidence of clinical toxicity. Pretreatment 4DCT data were used to compute pretreatment ventilation images for 96 lung cancer patients. Ventilation images were calculated using 4DCT data, deformable image registration, and a density-change based algorithm. Dose-volume and ventilation-based dose function metrics were computed for each patient. The ability of the dose-volume and ventilation-based dose-function metrics to predict for severe (grade 3+) radiation pneumonitis was assessed using logistic regression analysis, area under the curve (AUC) metrics, and bootstrap methods. A specific patient example is presented that demonstrates how incorporating ventilation-based functional information can help separate patients with and without toxicity. The logistic regression significance values were all lower for the dose-function metrics (range P=.093-.250) than for their dose-volume equivalents (range, P=.331-.580). The AUC values were all greater for the dose-function metrics (range, 0.569-0.620) than for their dose-volume equivalents (range, 0.500-0.544). Bootstrap results revealed an improvement in model fit using dose-function metrics compared to dose-volume metrics that approached significance (range, P=.118-.155). To our knowledge, this is the first study that attempts to correlate lung dose and 4DCT ventilation-based function to thoracic toxicity after radiation therapy. Although the results were not significant at the .05 level, our data suggests that incorporating ventilation-based functional imaging can improve prediction for radiation pneumonitis. We present an important first step toward validating the use of 4DCT-based ventilation imaging in thoracic treatment planning.

Genetic Variations in TGFβ1, tPA, and ACE and Radiation-Induced Thoracic Toxicities in Patients with Non–Small-Cell Lung Cancer

We hypothesized that radiation-induced thoracic toxicity (RITT) of the lung, esophagus and pericardium share a similar mechanism, and aimed to examine whether genetic variation of transforming growth factor-beta1 (TGFβ1), tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE), are associated with RITT in patients with non-small-cell lung cancer (NSCLC). Patients with stage I-III NSCLC were enrolled and received radiotherapy (RT). Blood samples were obtained pre-RT and at 4 to 5 weeks during RT, and plasma TGF-β1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood pre-RT were analyzed for the following frequent genetic variations: TGFβ1 509C/T, tPA -7351 C/T, and ACE I/D. RITT score was defined as the sum of radiation-induced toxicity grades in esophagus, lung, and pericardium. Seventy-six NSCLC patients receiving definitive RT were enrolled. Patients with TGFβ1 509CC had higher mean grade of esophagitis (1.4 ± 0.2 versus 0.8 ± 0.2, p = 0.019) and RITT score (2.6 ± 0.3 versus 1.6 ± 0.3, p = 0.009) than T allele carriers. Although no significant relationship was observed between RITT and the tPA or ACE variants individually, patients with any high-risk alleles (tPA CC or ACE D or TGFβ1 509CC) had significantly higher grade of developing combined RITT (p < 0.001). Patients with TGFβ1 509CC had greater increase of plasma TGF β1 levels at 4 to 5 weeks during RT than T allele carriers did (CC 1.2 ± 0.2 versus T 0.7 ± 0.1, p = 0.047). This exploratory study demonstrated that sensitivity of radiation toxicity may be determined by genomic factors associated with TGFβ1 and genes involved in TGFβ1 pathway.

WE‐C‐BRA‐08: Using 4DCT‐Based Ventilation Imaging to Correlate Lung Dose and Function with Clinical Outcomes

Purpose: An exciting form of ventilation imaging is being developed based on 4‐dimensional computed tomography (4DCT) data. Because 4DCTs are routine for thoracic radiation therapy, calculating ventilation maps from 4DCT data does not add extra dosimetric or monetary cost. Studies have discussed designing treatment plans to avoid highly‐ventilated areas of the lung. However, the hypothesis that using ventilation in treatment planning can reduce thoracic toxicity remains to be tested. The purpose of our work was to determine whether incorporating ventilation‐based functional information could improve prediction for clinical thoracic toxicity. Methods: The study used 96 lung cancer patients, 17 of whom developed radiation pneumonitis (CTCAE 3.0 Grade&gt;=3). Pre‐treatment 4DCT data, spatial registration, and a density‐change based model were used to compute pre‐treatment ventilation maps for each patient. Using dose and ventilation, we calculated dose‐volume and dose‐function histograms, mean lung doses (MLD), and ventilation‐weighted MLD (fMLD). The ventilation‐weighted dosimetric values were compared between the pneumonitis group and the non‐pneumonitis group using a two‐sample t‐test. The ventilation‐based functional data were incorporated into a predictive dose‐response model and maximum likelihood was used to determine whether incorporating functional data could significantly improve the model fit to clinical toxicity data. Results: Specific patient examples illustrate that using functional dose metrics can lead to better estimates of toxicity. The fMLD was higher for patients that developed pneumonitis (20.8 Gy) than for those that did not (18.9 Gy), however, the results were not significant (p=0.251). Although fMLD improved model fit over using MLD, the difference in fits was not found to be significant (p=0.312). Conclusions: This is the first study that has attempted to link irradiating ventilated portions of the lung to clinical outcomes. Although promising data were presented, the results were not statistically significant. Future work will include more patients and further functional information with perfusion imaging.

Genetic Variation in TGFβ1, tPA and ACE May Predict Radiation-induced Thoracic Toxicity in Patients with Non-small Cell Lung Cancer

Transforming growth factor belta1 (TGFβ1), tissue plasminogen activator (tPA) and angiotensin-converting enzyme (ACE) are known to be associated with normal tissue irradiation damage. Genetic variation within these genes has been identified as risk factor for this damage. We hypothesized that the following single nucleotide polymorphisms (SNPs) of TGFβ1 509C/T, tPA -7351 C/T and ACE I/D are associated with radiation induced thoracic toxicity (RITT) in patients with non-small cell lung cancer (NSCLC).

Dose de tolérance à l’irradiation des tissus sains : l’œsophage

The esophagus is a musculo-membranous tube through which food passes from the pharynx to the stomach. Due to its anatomical location, it can be exposed to ionizing radiation in many external radiotherapy indications. Radiation-induced esophageal mucositis is clinically revealed by dysphagia and odynophagia, and usually begins 3 to 4 weeks after the start of radiation treatment. With the rise of multimodality treatments (e.g., concurrent chemoradiotherapy, dose escalation and accelerated fractionation schemes), esophageal toxicity has become a significant dose-limiting issue. Understanding the predictive factors of esophageal injury may improve the optimal delivery of treatment plans. It may help to minimize the risks, hence increasing the therapeutic ratio. Based on a large literature review, our study describes both early and late radiation-induced esophageal injuries and highlights some of the predictive factors for cervical and thoracic esophagus toxicity. These clinical and dosimetric parameters are numerous but none is consensual. The large number of dosimetric parameters strengthens the need of an overall analysis of the dose/volume histograms. The data provided is insufficient to recommend their routine use to prevent radiation-induced esophagitis. Defining guidelines for the tolerance of the esophagus to ionizing radiation remains essential for a safe and efficient treatment.

Low rate of thoracic toxicity in palliative paraspinal single fraction stereotactic body radiation therapy

Background There has been an increase in the utilization of single-fraction stereotactic body radiation therapy (SBRT) to treat thoracic structures, but there have been few reports describing toxicity outcomes with this treatment.

Low rate of thoracic toxicity in palliative paraspinal single-fraction stereotactic body radiation therapy

Background There has been an increase in the utilization of single-fraction stereotactic body radiation therapy (SBRT) to treat thoracic structures, but there have been few reports describing toxicity outcomes with this treatment. Methods We evaluated 119 sites (114 patients) with no prior history of thoracic radiation were treated from 10/1/2003 to 10/27/2008 with single-fraction SBRT to thoracic structures. The median dose to the gross tumor volume was 2400 cGy (range 1800–2400 cGy), as was the median dose to the planning target volume (range 1600–2400 cGy). A detailed review of thoracic toxicities was performed to include pneumonitis or Grade 2 or higher esophageal and bronchial toxicity. In addition, we retrospectively contoured the esophagus and bronchus of 48 patients treated in 2004–2005, prior to the establishment of dose constraints to determine the range of doses that these structures received. Results Of the contoured patients, the median dose to the hottest 1 cc (D1cc) of the esophagus was 1250 cGy (range 158–2572 cGy). The median bronchial D1cc was 1101 cGy (range 260–2211 cGy). At a median follow-up of 11.6 months, there were seven Grade 2 or higher esophageal toxicities, including one Grade 3 and one Grade 4 toxicities. There were two bronchial toxicities, one Grade 2 and one Grade 3. There were no cases of pneumonitis. Conclusions High-dose single-fraction SBRT is well tolerated to the thoracic region, with most patients tolerating high doses to central structures without significant toxicity.

Pharmacokinetic Evaluation of Intrapleural Carboplatin in Patients with Malignant Pleural Effusion

Carboplatin 360 mg/m2 was administered intrapleurally to 4 patients with malignant pleural effusion. Simultaneous pleural fluid and plasma samples were collected at various times after treatment to measure the total and filterable levels of platinum. The pleural area under the concentration versus time curve (AUC) for filterable platinum was 26- to 98-fold greater than the corresponding plasma AUC, plasma levels remaining in the range of 3 to 18 μmol/L. The concentrations of platinum in plasma were compared with those observed in 7 additional patients receiving the same dose of carboplatin intravenously. The comparative intrapleural and intravenous therapy led to peak concentrations of platinum 6 to 7 times lower after intrapleural than after intravenous treatment, in significantly lower partial AUCs, and in prolonged levels of filterable platinum following intrapleural treatment. No significant difference, either for total or for filterable platinum, was noted comparing the overall plasma exposure. Systemic clearance and mean residence time values for filterable platinum in plasma were about 1.8 times lower and 2 times higher, respectively, after intrapleural treatment than after intravenous administration. Both the cumulative urinary excretion and renal clearance, as well as the apparent volume of distribution at steady-state for filterable platinum, were comparable with the values obtained after intravenous carboplatin. The observed differences in plasma pharmacokinetics between the 2 routes of administration mainly reflect the delayed absorption of carboplatin into the systemic circulation after intrapleural treatment. The locoregional treatment was well tolerated by all patients, and no symptoms of thoracic discomfort or acute toxicity were noted.