Cardiac Dose Predicts the Response to Concurrent Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

Definitive concurrent chemoradiation (CCRT) is the standard treatment for cervical esophageal cancer and non-surgical candidates. Initial treatment response affects survival; however, few validated markers are available for prediction. This study evaluated the clinical variables and chemoradiation parameters associated with treatment response. Between May 2010 and April 2016, 86 completed CCRT patients' clinical, dosimetric, and laboratory data at baseline and during treatment were collected. Cox regression analysis assessed the risk factors for overall survival (OS). A receiver operating characteristic curve with Youden's index was chosen to obtain the optimal cut-off value of each parameter. Treatment response was defined per Response Evaluation Criteria in Solid Tumors v.1.1 at the first post-CCRT computed tomography scan. Responders had complete and partial responses; non-responders had stable and progressive diseases. Logistic regression (LR) was used to evaluate the variables associated with responders. The Cox regression model confirmed the presence of responders (n = 50) vs. non-responders (n = 36) with a significant difference in OS. In multivariate LR, cardiac dose-volume received ≥10 Gy; the baseline hemoglobin level, highest neutrophil to lymphocyte ratio during CCRT, and cumulative cisplatin dose were significantly associated with the responders. The initial clinical treatment response significantly determines disease outcome. Cardiac irradiation may affect the treatment response.

Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer.

Purpose: To investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methods: This retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). Results: Overall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7-9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. Conclusion: Reduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer.

BACKGROUND: Skeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour-intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method. METHODS: This study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum-based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre- and post-treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease-specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models. RESULTS: The median (inter-quartile range) age of the cohort was 52 (46-59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854-0.859) and F1 score (0.726, 95% confidence interval: 0.722-0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss. CONCLUSIONS: Explainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.

Optimal prophylactic para-aortic radiotherapy in locally advanced cervical cancer: anatomy-based versus margin-based delineation.

OBJECTIVE: Precise delineation of the para-aortic nodal region is critical for the optimal therapeutic ratio of prophylactic para-aortic radiotherapy. We aimed to evaluate the para-aortic control and patient-reported gastrointestinal toxicity in patients with locally advanced cervical cancer who received anatomy-based or margin-based prophylactic para-aortic radiotherapy. METHODS: We analyzed 160 patients with locally advanced cervical cancer who received prophylactic extended-field radiotherapy between January 2014 and November 2019 at two tertiary centers. Para-aortic nodal regions were delineated based on the anatomic principle-based atlas or marginal expansion from the aorta and inferior vena cava. The Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events was used to assess acute gastrointestinal toxicity, and a score of ≥3 was defined as severe gastrointestinal toxicity. RESULTS: Seventy-six (47.5%) and 84 (52.5%) patients received anatomy-based and margin-based prophylactic para-aortic radiotherapy, respectively. The median follow-up was 40.1 months (IQR 25.5-58.9). Para-aortic nodal failures occurred in one (1.3%) patient in the anatomy-based para-aortic radiotherapy group and in one (1.2%) patient in the margin-based para-aortic radiotherapy group (p=1.00). There was no in-field or marginal para-aortic nodal failure. The 3-year para-aortic recurrence-free survival for anatomy-based and margin-based para-aortic radiotherapy was 98.6% and 98.8%, respectively (p=0.94). Patients who received anatomy-based para-aortic radiotherapy reported less severe acute gastrointestinal toxicity than those who received margin-based para-aortic radiotherapy (13.2% vs 29.8%, p=0.01). A comparison of gastrointestinal toxicities showed that patients who received anatomy-based para-aortic radiotherapy reported significantly less severe gastrointestinal toxicity than those who received margin-based para-aortic radiotherapy in terms of frequency of diarrhea (7.9% vs 20.2%, p=0.03), severity of abdominal pain (3.9% vs 14.3%, p=0.03), and interference of abdominal pain (2.6% vs 11.9%, p=0.03). CONCLUSION: Anatomy-based prophylactic para-aortic radiotherapy achieved excellent para-aortic control and a lower incidence of severe patient-reported gastrointestinal toxicity. These findings suggest that anatomy-based delineation optimizes clinical outcomes of prophylactic para-aortic radiotherapy in locally advanced cervical cancer.

Muscle Loss During Androgen Deprivation Therapy Is Associated With Higher Risk of Non-Cancer Mortality in High-Risk Prostate Cancer.

The changes in body composition are early adverse effects of androgen deprivation therapy (ADT); however, their prognostic impact remains unclear in prostate cancer. This study aimed to evaluate the association between body composition changes and survival in patients with high-risk prostate cancer. We measured the skeletal muscle index (SMI) and total adipose tissue index (TATI) at the L3 vertebral level using computed tomography at baseline and within one year after initiating ADT in 125 patients with high-risk prostate cancer treated with radiotherapy and ADT between 2008 and 2018. Non-cancer mortality predictors were identified using Cox regression models. The median follow-up was 49 months. Patients experienced an average SMI loss of 5.5% over 180 days (95% confidence interval: -7.0 to -4.0; p<0.001) and TATI gain of 12.6% over 180 days (95% confidence interval: 9.0 to 16.2; p<0.001). Body mass index changes were highly and weakly correlated with changes in TATI and SMI, respectively (Spearman ρ for TATI, 0.78, p<0.001; ρ for SMI, 0.27, p=0.003). As a continuous variable, each 1% decrease in SMI was independently associated with a 9% increase in the risk of non-cancer mortality (hazard ratio: 1.09; p=0.007). Moreover, the risk of non-cancer mortality increased 5.6-fold in patients with SMI loss ≥5% compared to those with unchanged SMI (hazard ratio: 5.60; p=0.03). Body mass index and TATI were not associated with non-cancer mortality. Muscle loss during ADT is occult, independent of weight change, and independently associated with increased non-cancer mortality in patients with high-risk prostate cancer.

Low cardiac dose and neutrophil-to-lymphocyte ratio predict overall survival in inoperable esophageal squamous cell cancer patients after chemoradiotherapy.

We aimed to determine the prognostic significance of cardiac dose and hematological immunity parameters in esophageal cancer patients after concurrent chemoradiotherapy (CCRT). During 2010-2015, we identified 101 newly diagnosed esophageal squamous cell cancer patients who had completed definitive CCRT. Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR), at baseline, during, and post-CCRT were analyzed. Cox proportional hazards were calculated to identify potential risk factors for overall survival (OS). Median OS was 13 months (95% confidence interval [CI]: 10.38-15.63). Univariate analysis revealed that male sex, poor performance status, advanced nodal stage, higher percentage of heart receiving 10 Gy (heart V10), and higher NLR (baseline and follow-up) were significantly associated with worse OS. In multivariate analysis, performance status (ECOG 0 & 1 vs. 2; hazard ratio [HR] 3.12, 95% CI 1.30-7.48), heart V10 (> 84% vs. ≤ 84%; HR 2.24, 95% CI 1.26-3.95), baseline NLR (> 3.56 vs. ≤ 3.56; HR 2.36, 95% CI 1.39-4.00), and follow-up NLR (> 7.4 vs. ≤ 7.4; HR 1.95, 95% CI 1.12-3.41) correlated with worse OS. Volume of low cardiac dose and NLR (baseline and follow-up) were associated with worse patient survival.

Association of bowel radiation dose-volume with skeletal muscle loss during pelvic intensity-modulated radiotherapy in cervical cancer.

BACKGROUND: Radiation-induced bowel damage may compromise nutrient absorption and digestion and affect body composition during pelvic radiotherapy in patients with locally advanced cervical cancer (LACC). This study aimed to evaluate the relationship between bowel radiation dose-volume and body composition changes during pelvic radiotherapy. METHODS: Data of 301 LACC patients treated with chemoradiotherapy were analyzed. Changes in skeletal muscle index (SMI) and density (SMD), and total adipose tissue index (TATI) were measured from computed tomography images at the L3 vertebral level. A reduction in SMI, SMD, or TATI of ≥10% was classified as "loss." Bowel V45 indicates the bowel volume (mL) receiving a radiation dose of ≥45 Gy. The relationship between body composition and bowel V45 was analyzed using logistic regression models. RESULTS: After treatment, 61 (20.3%), 81 (26.9%), and 97 (32.2%) patients experienced SMI, SMD, and TATI loss, respectively. Increased bowel V45 was independently associated with increased odds of SMI loss (odds ratio [OR]: 1.012; 95% confidence interval [CI]: 1.007-1.018; p<0.001) and TATI loss (OR: 1.006; 95% CI: 1.001-1.010; p=0.01), but not with SMD loss (OR: 1.005; 95% CI: 1.000-1.009; p=0.054). The cut-off value with the highest accuracy for predicting SMI loss was V45 ≥222 mL; a higher rate of SMI loss was noted in 40.0% of patients with V45 ≥222 mL than in 13.7% of patients with V45 <222 mL (p<0.001). CONCLUSIONS: Higher bowel dose-volume was significantly associated with muscle loss during pelvic radiotherapy. Bowel dose-volume consideration is required in individualized nutritional counseling and supportive care in clinical practice.

Progressive Skeletal Muscle Loss After Surgery and Adjuvant Radiotherapy Impact Survival Outcomes in Patients With Early Stage Cervical Cancer.

The effect of skeletal muscle loss associated with surgery and adjuvant radiotherapy on survival outcomes in patients with early-stage cervical cancer remains unclear. We analyzed the data of 133 patients with early-stage cervical cancer who underwent surgery and adjuvant radiotherapy between 2013 and 2018 at two tertiary centers. Skeletal muscle changes were measured using computed tomography scans at baseline, at simulation for radiotherapy, and at 3 months post-treatment. A decrease of ≥5% in the skeletal muscle was defined as "muscle loss." The Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was used to assess gastrointestinal toxicity. The Patient-Generated Subjective Global Assessment (PG-SGA) was used for nutritional assessment. Predictors of overall survival were identified using the Cox regression models. The median follow-up period was 3.7 years. After treatment, 32 patients (24.1%) experienced muscle loss. The rate of muscle loss was higher in patients with PRO-CTCAE score ≥3 or PG-SGA score ≥4 at the end of radiotherapy than in patients with PRO-CTCAE score ≤2 or PG-SGA score 0-3 (75.0 vs. 10.5%, p < 0.001; 71.4 vs. 2.2%, p < 0.001). The 3-year overall survival was significantly lower in patients with muscle loss than in those with muscle preserved (65.6 vs. 93.9%, p < 0.001). Multivariate analysis showed that muscle loss was independently associated with poor overall survival (hazard ratio, 4.55; 95% confidence interval: 1.63-12.72; p < 0.001). Muscle loss after surgery and adjuvant radiotherapy was associated with poor overall survival in patients with early-stage cervical cancer. Muscle loss is associated with patient-reported gastrointestinal toxicity and deterioration in nutritional status.

Muscle Loss after Chemoradiotherapy as a Biomarker of Distant Failures in Locally Advanced Cervical Cancer.

This study aimed to evaluate whether computed tomography (CT)-based muscle measurement predicts distant failure in patients with locally advanced cervical cancer (LACC). Data from 278 patients with LACC who underwent chemoradiation therapy (CCRT) between 2004 and 2017 were analysed. Changes in the skeletal muscle index (SMI), skeletal muscle density, and total adipose tissue index during CCRT were calculated from CT images taken at the baseline and after CCRT. The predictive capability of CT-based muscle measurement for distant failure was evaluated using Cox proportional hazards regression, Harrell's concordance index (C-index), and time-dependent receiver operating characteristic curves. SMI loss ≥ 5% was independently associated with worse distant recurrence-free survival (DRFS) (HR: 6.31, 95% CI: 3.18-12.53; p < 0.001). The addition of muscle change to clinical models, including International Federation of Gynaecology and Obstetrics (FIGO) stage, lymph nodes, pathology, and squamous cell carcinoma-antigen, achieved higher C-indices (0.824 vs. 0.756; p < 0.001). Models including muscle change had superior C-indices than those including weight change (0.824 vs. 0.758; p < 0.001). The area under the curve for predicting 3-year DRFS was the highest for the muscle-loss model (0.802, muscle-loss model; 0.635, clinical model; and 0.646, weight-loss model). Our study demonstrated that muscle loss after CCRT was independently associated with worse DRFS and that integrating muscle loss into models including classical prognostic factors improved the prediction of distant failure.

Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer.

BACKGROUND: Treatment-related toxicities and decreased levels of patient performance during cancer therapy might contribute to body composition changes and thereby impact outcomes. However, the effect of longitudinal body composition changes on outcomes in patients with advanced endometrial cancer is unknown. This study investigated the association between body composition changes during staging surgery and adjuvant chemoradiotherapy and outcomes in patients with stage III endometrial cancer. METHODS: Pretreatment and post-treatment computed tomography (CT) images of 131 patients with stage III endometrial cancer who were treated between 2008 and 2016 were analysed. All CT images were contrast enhanced and acquired according to the standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured from two sets of CT images obtained at the level of the third lumbar vertebra. The skeletal muscle gauge was calculated by multiplying SMI by SMD (SMI × SMD). Predictors of overall survival and progression-free survival were identified using Cox regression models. RESULTS: The median follow-up was 50.6 (range 12.1-117.0) months. Overall, body mass index (BMI) changes during treatment were 0.4% per 210 days (95% confidence interval: -0.6 to 1.4; P = 0.41), and patients experienced an average SMD loss of 2.1% per 210 days (95% confidence interval: -4.0 to -0.2; P = 0.03). Weight loss and SMD loss ≥5% were observed in 23 (17.6%) and 54 (41.2%) patients, respectively. The changes in SMD did not correlate with those in BMI (Spearman's ρ for SMD, -0.13; P = 0.13). SMD change (per 1 Hounsfield unit/210 days decrease) was independently associated with poorer overall survival (hazard ratio: 1.32, 95% confidence interval: 1.14-1.52; P < 0.001) and progression-free survival (hazard ratio: 1.28, 95% confidence interval: 1.12-1.43; P < 0.001). Our results did not show association between survival and pretreatment myosteatosis and sarcopenia or changes in SMI and total adipose tissue index during treatment. The pretreatment skeletal muscle gauge was associated with treatment modifications such as delays, dose reductions, and discontinuation of chemotherapy. CONCLUSIONS: Skeletal muscle radiodensity decreased significantly during treatment and was independently associated with poorer survival in patients with stage III endometrial cancer who underwent staging surgery and adjuvant chemoradiotherapy. SMD loss was occult and occurred independently of BMI change.

Prognostic significance of lung radiation dose in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: The prognostic significance of radiation dose to the lung or heart is unknown in esophageal cancer patients receiving neoadjuvant chemoradiotherapy followed by surgery (trimodal therapy). This study aimed to determine the association between lung and heart radiation dose volumes and prognosis of esophageal cancer after trimodal therapy. METHODS: This study reviewed 123 esophageal cancer patients treated with trimodal therapy in two tertiary institutions between 2010 and 2015. The dose-volume histogram parameter of Vx was defined as the percentage of total organ volume receiving a radiation dose of x (Gy) or more. Predictors of overall survival (OS) were identified using Cox regression models. Receiver-operating characteristic curves were used to select cut-off values for dose-volume. RESULTS: Median follow-up was 28.3 months (range: 4.7-92.8 months). Median OS and progression-free survival were 34.0 months (95% confidence interval [CI]: 27.4-40.6 months) and 24.8 months (95% CI, 18.9-30.7 months), respectively. Multivariate analyses showed that lung V20 (hazard ratio, 1.09; 95% CI: 1.04-1.14; p < 0.001) and lung V5 (hazard ratio, 1.02; 95% CI: 1.00-1.05; p = 0.03) were associated with OS when adjusting for surgical margin and pathological treatment response. The 5-year OS for patients with lung V20 ≤ 23% vs. patients with lung V20 > 23% was 54.4% vs. 5% (p < 0.001) whereas that for patients with lung V5 ≤ 56% vs. patients with lung V5 > 56% was 81.5% vs. 23.4% (p < 0.001). Mean heart dose showed no association with survival outcomes. CONCLUSIONS: Lung radiation dose was independently associated with survival outcomes in esophageal cancer patients treated with neoadjuvant chemoradiotherapy and surgery.

Image-guided study of inter-fraction and intra-fraction set-up variability and margins in reverse semi-decubitus breast radiotherapy.

BACKGROUND: This study aimed to evaluate the inter-fraction set-up error and intra-fraction motion during reverse semi-decubitus (RSD) breast radiotherapy, and to determine a planning target volume (PTV) margin. MATERIAL AND METHODS: Pre- and post-treatment cone-beam computed tomography (CBCT) scans were prospectively acquired at fractions 1, 4, 7, 8, 11, and 14 for 30 patients who underwent RSD breast radiotherapy. Online correction for initial set-up error greater than 5 mm or 2° was performed and post-correction CBCT was acquired. An off-line analysis was performed to quantify initial and residual inter-fraction set-up errors and intra-fraction motion in three-dimensions. Patient inter-fraction errors were analysed for time trends during the course of radiotherapy. PTV margins were calculated from the systematic and random errors. RESULTS: The initial inter-fraction population systematic errors were 1.8-3.3 mm (translation) and 0.5° (rotation); random errors were 1.8-2.1 mm (translation) and 0.3-0.5° (rotation). After online correction, the residual inter-fraction population systematic errors were 1.2-1.8 mm (translation) and 0.3-0.4° (rotation); random errors were 1.4-1.6 mm (translation) and 0.3-0.4° (rotation). Intra-fraction population systematic and random errors were ≤ 1.3 mm (translation) and ≤ 0.2° (rotation). The magnitude of inter-fraction set-up errors in the anterior-posterior direction, roll, and yaw were significantly correlated with higher body weight and body mass index (BMI). The inter-fraction set-up error did not change significantly as a function of time during the course of radiotherapy. The magnitude of intra-fraction motion was not correlated with patient characteristics and treatment time. The total PTV margins accounting for pre-correction and intra-fraction errors were 6.5-10.2 mm; those accounting for post-correction and intra-fraction errors were 4.7-6.3 mm. CONCLUSIONS: CBCT is an effective modality to evaluate and improve the inter-fraction set-up reproducibility in RSD breast radiotherapy, particularly for patients with higher BMI. Intra-fraction motion was minimal during RSD breast radiotherapy.

Skeletal Muscle Loss Is an Imaging Biomarker of Outcome after Definitive Chemoradiotherapy for Locally Advanced Cervical Cancer.

Purpose: This study investigates the association between body composition change during concurrent chemoradiotherapy (CCRT) and outcome in patients with locally advanced cervical cancer (LACC).Experimental Design: Pre- and posttreatment CT images of 245 patients with LACC who were treated between 2004 and 2015 were analyzed. Skeletal muscle index (SMI) and density (SMD), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) were measured from two sets of CT images at the level of the L3 vertebra. Sarcopenia and a low SMD were defined using published cut-off points. Predictors of overall survival (OS) and cancer-specific survival (CSS) were analyzed using Cox regression models.Results: The median follow-up was 62.7 (range, 7.3-152.3) months. Among the 245 patients, 127 (51.8%) had pretreatment sarcopenia, and 154 (62.9%) had a low SMD. SMI did not decrease significantly during CCRT, 0.6%/150 days [95% confidence interval (CI), -1.8-0.6; P = 0.35]. However, SMI loss during CCRT of >10.0%/150 days was independently associated with poorer OS (HR, 6.02; 95% CI, 3.04-11.93; P < 0.001) and CSS (HR, 3.49; 95% CI, 1.44-8.42; P = 0.006) when adjusted for FIGO stage, pathology, and treatment. Pretreatment sarcopenia and change of SMD, SATI, and VATI during CCRT were not associated with survival.Conclusions: Skeletal muscle measurements could be imaging biomarkers to predict outcomes for patients with LACC in clinical practice. Further studies are needed to determine whether multimodal interventions can preserve skeletal muscle mass and thereby improve survival. Clin Cancer Res; 24(20); 5028-36. ©2018 AACR.

The Effect of Body Mass Index and Weight Change on Late Gastrointestinal Toxicity in Locally Advanced Cervical Cancer Treated With Intensity-modulated Radiotherapy.

OBJECTIVE: To evaluate the effects of body mass index (BMI) and weight change during radiotherapy on the development of toxicity in patients with locally advanced cervical cancer (LACC) treated with intensity-modulated radiotherapy (IMRT). METHODS: A total of 245 patients were analyzed after undergoing definitive IMRT treatment between 2004 and 2015 for stage IB2 to stage IVA LACC. The patients were divided into 3 groups: underweight (BMI <18.5 kg/m), normal weight (BMI 18.5-24.9 kg/m), and overweight (BMI ≥25.0 kg/m). The relationships between toxicity, clinical factors, and the bowel dose-volume histogram were analyzed. V45 indicated the bowel volume that received a radiation dose of 45 Gy. RESULTS: The median follow-up period was 63 months. The V45 was similar among the 3 groups. The 5-year rates of grade 3 or higher late gastrointestinal toxicities were 18.6%, 4.0%, and 4.2% for the underweight, normal weight, and overweight groups, respectively (P = 0.002). In the multivariable analysis, underweight (hazard ratio, 13.99; 95% confidence interval, 3.22-60.82; P < 0.001) and weight loss (> -5%) (hazard ratio, 5.91; 95% confidence interval, 1.75-19.98; P = 0.004) were significant predictors of grade 3 or higher-grade late gastrointestinal toxicities. CONCLUSION: A BMI of less than 18.5 kg/m and weight loss (> -5%) were associated with a higher risk of grade ≥3 or higher late gastrointestinal toxicity in patients with LACC treated with definitive IMRT. Future research on the development of a standardized and structured approach to improve the therapeutic ratio for the supportive care of patients with LACC is needed.

Impact of para-aortic recurrence risk-guided intensity-modulated radiotherapy in locally advanced cervical cancer with positive pelvic lymph nodes.

OBJECTIVES: A previous study has suggested the benefit of sub-renal vein radiotherapy (SRVRT) for pelvic lymph node (PLN)-positive cervical cancer. In order to better select patients for SRVRT, this study aimed to evaluate the value of a risk-based radiation field based on PLN location and number in PLN-positive cervical cancer. METHODS: We reviewed 198 patients with FIGO stage IB2-IVA cervical cancer, positive PLNs, and negative para-aortic lymph nodes (PALNs) from 2004 to 2015 at two tertiary centers. All patients underwent pelvic radiotherapy (PRT) or SRVRT with IMRT. The SRVRT extended the PRT field cranially to the level of the left renal vein. The prescribed doses were 45-50.4Gy in 1.8Gy per fraction. RESULTS: Overall, 118 and 80 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage, common iliac PLNs, and number of PLNs. The median follow-up was 63months (range: 7-151months). PALN failure was experienced by 28 patients (23.7%) in the PRT group and 1 patient (1.3%) in the SRVRT group (p<0.001). Compared with PRT, SRVRT significantly improved 5-year PALN recurrence-free survival (56.8% vs. 100%, p<0.001) and cancer-specific survival (56.5% vs. 93.9%, p<0.001) among patients with common iliac PLNs or ≥3 PLNs. No significant differences were observed in these outcomes among patients with PLNs below the common iliac bifurcation and 1-2 PLNs. The SRVRT did not increase severe toxicities. CONCLUSIONS: Risk-based radiation field based on PLN location and number could optimize outcomes for PLN-positive cervical cancer.

Prophylactic lower para-aortic irradiation using intensity-modulated radiotherapy mitigates the risk of para-aortic recurrence in locally advanced cervical cancer: A 10-year institutional experience.

OBJECTIVE: To evaluate the effects of prophylactic sub-renal vein radiotherapy (SRVRT) using intensity-modulated radiotherapy (IMRT) for cervical cancer. METHODS: A total of 206 patients with FIGO stage IB2-IVA cervical cancer and negative para-aortic lymph nodes (PALNs) who underwent pelvic IMRT (PRT) or SRVRT between 2004 and 2013 at our institution were reviewed. SRVRT cranially extended the PRT field for PALNs up to the left renal vein level. The prescribed dose was consistent 50.4Gy in 28 fractions. RESULTS: Overall, 110 and 96 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage and positive pelvic lymph nodes (PLNs). The median follow-up time was 60months (range, 7-143). For the total study population, the 5-year PALN recurrence-free survival (PARFS) and overall survival (OS) for PRT vs. SRVRT were 87.6% vs. 97.9% (p=0.03) and 74.5% vs. 87.8% (p=0.04), respectively. In patients with FIGO III-IVA or positive PLNs, the 5-year PARFS and OS for PRT vs. SRVRT were 80.1% vs. 96.4% (p=0.02) and 58.1% vs. 83.5% (p=0.012), respectively. However, there were no significant differences in these outcomes for patients with FIGO IB-IIB and negative PLNs. In a multivariate analysis, only SRVRT was associated with better PARFS (HR, 0.21; 95% CI, 0.06-0.78; p=0.02). The SRVRT did not significantly increase severe late toxicities. CONCLUSION: Prophylactic SRVRT using IMRT reduced PALN recurrence with tolerable toxicities, supporting the application of risk-based radiation fields for cervical cancer.

Safety and efficacy of semiextended field intensity-modulated radiation therapy and concurrent cisplatin in locally advanced cervical cancer patients: An observational study of 10-year experience.

Patients with locally advanced cervical cancer (LACC) are at risk of para-aortic lymph node (PALN) metastasis. Pelvic concurrent chemoradiotherapy, the current standard treatment for LACC, has a PALN failure rate of 9% according to the Radiation Therapy Oncology Group Trial 90-01, suggesting that it may not completely eliminate all microscopic tumors in the PALNs. To minimize the toxicities associated with conventional prophylactic extended-field radiotherapy, our institute use prophylactic semiextended field radiotherapy that includes only the PALNs below the level of the renal vessels. Use of intensity-modulated radiotherapy (IMRT) is another means of reducing the incidence of toxicity. This study evaluated the safety and efficacy of prophylactic semiextended field IMRT (SEF-IMRT) and concurrent cisplatin chemotherapy in patients with LACC.We retrospectively assessed survival and toxicity in 76 patients with stage IB2-IVA cervical cancer and negative PALNs who received prophylactic SEF-IMRT and concurrent weekly cisplatin (40 mg/m) between 2004 and 2013. The region targeted by SEF-IMRT included the PALNs below the level of the renal vessels, and the prescribed dose was 50.4 Gy in 28 fractions. Brachytherapy was administered at a dose of 30 Gy in 6 fractions. Survival outcomes were calculated by using the Kaplan-Meier method, and acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0.All patients completed the planned SEF-IMRT, as well as brachytherapy. Acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities were observed in 2, 0, and 41 patients, respectively. The median follow-up time after SEF-IMRT was 55 (range, 11-124) months. Eight patients developed out-field distant recurrences without PALN failure, and 1 patient experienced out-field PALN failure with simultaneous distant metastasis. No patients had late genitourinary toxicities, and 3 patients had late grade 3 gastrointestinal toxicities. The 5-year overall survival, disease-free survival, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively.For patients with LACC, prophylactic PALN irradiation up to the level of the renal vessels reduced PALN recurrence and resulted in favorable outcomes with few severe toxicities.

Development of delineation for the left anterior descending coronary artery region in left breast cancer radiotherapy: An optimized organ at risk.

BACKGROUND AND PURPOSE: The left anterior descending coronary artery (LAD) and diagonal branches (DBs) are blurred on computed tomography (CT). We aimed to define the LAD region (LADR) with adequate inclusion of the LAD and DBs and contouring consistency. METHODS AND MATERIALS: The LADR was defined using coronary CT angiograms. The inclusion ratio was used to assess the LAD and DBs inclusion by the LADR. Four radiation oncologists delineated the LAD and LADR, using contrast-enhanced CT of 15 patients undergoing left breast radiotherapy. The Sørensen-Dice similarity index (DSI), Jaccard similarity index (JSI), and Hausdorff distance (HD) were calculated to assess similarity. The mean dose (Dmean) and maximum dose (Dmax) to the LAD and LADR were calculated to compare consistency. Correlations were evaluated using Pearson's correlation coefficient. RESULTS: The inclusion ratio of the LAD by the LADR was 96%. The mean DSI, JSI, and HD values were respectively 27.9%, 16.7%, and 0.42mm for the LAD, and 83.1%, 73.0%, and 0.18mm for the LADR. The Dmean between the LAD and LADR were strongly correlated (r=0.93). CONCLUSION: Delineation of the LADR significantly improved contouring similarity and consistency for dose reporting. This could optimize dose estimation for breast radiotherapy.

Dosimetric predictors of acute haematological toxicity in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy.

OBJECTIVE: Haematological toxicity (HT) is common in patients with oesophageal cancer (EC) treated with chemoradiotherapy (CRT). The Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines provide no dose constraints for the bone marrow (BM) to avoid HT. We aimed to determine dosimetric factors associated with HT during CRT for EC. METHODS: 41 patients with EC treated with neoadjuvant cisplatin and 5-fluorouracil-based CRT were retrospectively reviewed. Associations between the dose-volume histogram parameters of thoracic bones and blood cell count changes during CRT were assessed using logistic regression analyses. Receiver-operating characteristic curves were used to derive optimal dosimetric planning constraints. Vx indicates the total organ volume percentage exceeding a radiation dose of x (Gy). RESULTS: Greater thoracic vertebrae and rib irradiation doses, including mean vertebral dose (MVD), thoracic vertebrae V5-30 (TVV5-30), mean rib dose and rib V5-20, were associated with increased leukopenia (grade ≥ 3) risk. Additional BM sites (sternum, scapulae and clavicles) did not influence HT. White blood cell and absolute neutrophil count nadirs were associated with increased irradiation doses to the thoracic vertebrae, ribs and sternum. Chemotherapy cycle number was not significantly associated with severe neutropenia or leukopenia. Cut-off values with the highest likelihood of avoiding leukopenia were MVD < 25.9 Gy, TVV20 < 70% and TVV10 < 77%. CONCLUSION: Thoracic bone irradiation dose was significantly associated with HT after adjusting for chemotherapy effects. Efforts to maintain MVD < 25.9 Gy, TVV10 < 77% and TVV20 < 70% could reduce HT. ADVANCES IN KNOWLEDGE: This is the first study addressing issues concerning HT in patients with neoadjuvant CRT-treated EC.