Jie Lee

Whole-uterine versus individualized-uterine radiotherapy in locally advanced cervical cancer: clinical outcome and toxicity

Emerging evidence has suggested the safety and efficacy of individualized-uterine radiotherapy in locally advanced cervical cancer. This study aimed to compare the clinical outcomes and gastrointestinal toxicity of whole-uterine and individualized-uterine radiotherapy in women with locally advanced cervical cancer. A retrospective analysis was conducted on 220 patients with stage IB3 to IVA cervical cancer, treated with definitive chemoradiotherapy between 2014 and 2021 at 2 tertiary centers. The clinical target volume included the entire uterus (whole-uterine group) or an individualized-uterine volume based on the gross tumor with a 15 mm margin (individualized-uterine group). Local recurrence rate, overall survival, and progression-free survival were evaluated using the Kaplan-Meier method. 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 indicated severe toxicity. Overall, 128 (58.2%) and 92 (41.8%) patients received whole- and individualized-uterine radiotherapy with a median follow-up of 63.0 (interquartile range; 39.4-93.2) months and 64.8 (interquartile range; 47.3-85.6) months, respectively. Compared to the whole-uterine group, the individualized-uterine group had significantly lower volumes of small bowel, rectum, and sigmoid colon exposed to 45 Gy or 30 Gy (all p < .05). The 5-year local recurrence rate, overall survival, and progression-free survival in the whole- and individualized-uterine groups were 4.1% vs 0.0% (p = .054), 84.9% vs 87.6% (p = .48), and 74.7% vs 84.8% (p = .07), respectively. Fewer patients in the individualized group reported severe acute gastrointestinal toxicity (5.4% vs 23.4%, p < .001). The 5-year rates of severe late gastrointestinal toxicity were 7.4% and 0.0% in the whole- and individualized-uterine groups, respectively (p = .009). Individualized-uterine radiotherapy resulted in favorable clinical outcomes and reduced acute or late gastrointestinal toxicity compared to whole-uterine radiotherapy. This approach may offer an optimized balance between outcomes and toxicity in patients with locally advanced cervical cancer.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced‐stage ovarian cancer

AbstractBackgroundMalignant ascites is prevalent in advanced‐stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced‐stage ovarian cancer.MethodsWe evaluated 307 patients with advanced‐stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum‐based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre‐surgery and post‐chemotherapy portal‐venous phase contrast‐enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil‐lymphocyte ratio (NLR), and platelet‐lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator.ResultsThe median (range) age was 53 (23–83) years. The median duration (range) of follow‐up was 5.2 (1.1–11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: −3.9% vs. 2.2%, P &lt; 0.001; SMD: −4.0% vs. −0.4%, P &lt; 0.001; albumin: −4.4% vs. 2.1%, P &lt; 0.001; PNI: −8.4% vs. −0.1%, P &lt; 0.001; NLR: 20.6% vs. −29.4%, P &lt; 0.001; and PLR: 1.7% vs. −19.4%, P &lt; 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P &lt; 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: β = −3.19, P &lt; 0.001; NLR change: β = −0.02, P = 0.003; albumin change: β = 0.37, P &lt; 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: β = −1.28, P = 0.02; NLR change: β = −0.02, P &lt; 0.001; PNI change: β = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P &lt; 0.001) and an indirect effect mediated by NLR change (indirect effects = −1.61, 95% confidence interval [CI]: −2.22 to −1.08) and albumin change (indirect effects = −2.92, 95% CI: −4.01 to −1.94). Ascites had a direct effect on SMD change (P &lt; 0.001) and an indirect effect mediated by NLR change (indirect effects = −1.76, 95% CI: −2.34 to −1.22) and PNI change (indirect effects = −2.00, 95% CI: −2.79 to −1.36).ConclusionsMalignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced‐stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

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

AbstractBackgroundSkeletal 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.MethodsThis 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.ResultsThe 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.ConclusionsExplainable 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.

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer

AbstractBackgroundSarcopenia is commonly observed in patients with advanced‐stage epithelial ovarian cancer (EOC). However, the effect of body composition changes—during primary debulking surgery (PDS) and adjuvant platinum‐based chemotherapy—on outcomes of patients with advanced‐stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy.MethodsPre‐treatment and post‐treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast‐enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models.ResultsThe median follow‐up was 37.9 months. The median duration between pre‐treatment and post‐treatment CT was 182 days (interquartile range: 161–225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: −3.1 to −0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: −3.3 to −0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03–5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss &lt;5% or gain (5.4 vs. 11.2 months, P = 0.01). Pre‐treatment SMI (1 cm2/m2 decrease; hazard ratio: 1.08, 95% confidence interval: 1.03–1.11; P = 0.002) and SMI change (1%/180 days decrease; hazard ratio: 1.04, 95% confidence interval: 1.01–1.08; P = 0.002) were independently associated with poorer overall survival. SMD, body mass index, and total adipose tissue index at baseline and changes were not associated with overall survival.ConclusionsSkeletal muscle index decreased significantly during treatment and was independently associated with poor overall survival in patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy. The modified Glasgow prognostic score might be a predictor of SMI loss during treatment.

Prognostic value of muscle measurement using the standardized phase of computed tomography in patients with advanced ovarian cancer

The prognostic role of sarcopenia or myosteatosis is controversial in advanced-stage epithelial ovarian cancer (EOC). The phase of computed tomography (CT) could influence muscle measurement and confound its association with outcomes. This study evaluated the prognostic value of muscle measurement in patients with stage III EOC using a standardized phase of computed tomography. Pretreatment CT images of 147 patients with stage III EOC were analyzed. All CT images were contrast-enhanced and acquired according to the standardized protocol. Skeletal muscle index (SMI) and radiodensity (SMD) were measured using CT images at the level of the third lumbar vertebra. The skeletal muscle gauge (SMG) was calculated by multiplying SMI and SMD. Harrell's concordance index (C-index) and time-dependent receiver operating characteristic curves were used to measure the predictive value of the models. The median follow-up period was 37.5 mo. SMI, SMD, and SMG were independently associated with overall survival when adjusted for clinical variables. Adding SMG to the model including stage, residual tumor, and malignant ascites significantly improved C-indices (0.704 vs. 0.629; P < 0.001). Models including SMG had a superior C-index compared with models including SMI and SMD (0.704 vs. 0.668; P = 0.01). The SMG model achieved the highest area under the curve for 5-year overall survival prediction (0.619 for clinical model, 0.702 for SMI model, and 0.710 for SMG model). Muscle measurements obtained from a standardized phase of CT images were associated with survival in advanced-stage EOC. The integration of SMI and SMD into SMG may improve prognostication and unify findings in future studies.

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

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. 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. 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). 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.

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

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. 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. 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). 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.