Radiation therapy margin reduction for patients with localized prostate cancer: A prospective study of the dosimetric impact and quality of life.

OBJECTIVES: To investigate the impact of reducing Clinical Target Volume (CTV) to Planning Target Volume (PTV) margins on delivered radiation therapy (RT) dose and patient reported quality-of-life (QOL) for patients with localized prostate cancer. METHODS: Twenty patients were included in a single institution IRB-approved prospective study. Nine were planned with reduced margins (4 mm at prostate/rectum interface, 5 mm elsewhere), and 11 with standard margins (6/10 mm). Cumulative delivered dose was calculated using deformable dose accumulation. Each daily CBCT dataset was deformed to the planning CT (pCT), dose was computed, and accumulated on the resampled pCT using a parameter-optimized, B-spline algorithm (Elastix, ITK/VTK). EPIC-26 patient reported QOL was prospectively collected pre-treatment, post-treatment, and at 2-, 6-, 12-, 18-, 24-, 36-, 48-, and 60-month follow-ups. Post -RT QOL scores were baseline corrected and standardized to a [0-100] scale using EPIC-26 methodology. Correlations between QOL scores and dosimetric parameters were investigated, and the overall QOL differences between the two groups (QOLMargin-reduced -QOLcontrol ) were calculated. RESULTS: The median QOL follow-up length for the 20 patients was 48 months. Difference between delivered dose and planned dose did not reach statistical significance (p > 0.1) for both targets and organs at risk between the two groups. At 4 years post-RT, standardized mean QOLMargin-reduced -QOLcontrol were improved for Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, and Sexual EPIC domains by 3.5, 14.8, 10.2, and 16.1, respectively (higher values better). The control group showed larger PTV/rectum and PTV/bladder intersection volumes (7.2 ± 5.8, 18.2 ± 8.1 cc) than the margin-reduced group (2.6 ± 1.8, 12.5 ± 8.3 cc), though the dose to these intersection volumes did not reach statistical significance (p > 0.1) between the groups. PTV/rectum intersection volume showed a moderate correlation (r = -0.56, p < 0.05) to Bowel EPIC domain. CONCLUSIONS: Results of this prospective study showed that margin-reduced group exhibited clinically meaningful improvement of QOL without compromising the target dose coverage.

Recurrence Risk Stratification for Women With FIGO Stage I Uterine Endometrioid Carcinoma Who Underwent Surgical Lymph Node Evaluation.

OBJECTIVE: The aim of this study was to estimate the recurrence risk based on the number of prognostic factors for patients with stage I uterine endometrioid carcinoma (EC) who underwent surgical lymph node evaluation (SLNE) and were managed with observation. METHODS: We queried our database for women with FIGO-2009 stage I EC who underwent surgical staging including SLNE. Multivariate analysis with stepwise model selection was used to determine independent risk factors for 5-year recurrence-free survival (RFS). Study groups based on risk factors were compared for RFS, disease-specific survival, and overall survival. RESULTS: A total of 706 patients were identified: median age was 60 years (range, 30 to 93 y) and median follow-up was 120 months. Median number of examined lymph nodes was 8 (range, 1 to 66). 91% were stage IA, 75% had grade 1 and lymphovascular space invasion was detected in 6%. Independent predictors of 5-year RFS included age 60 years and above ( P =0.038), grade 2 ( P =0.003), and grade 3 ( P <0.001) versus grade 1. Five-year RFS for group 0 (age less than 60 y and grade 1) was 98% versus 92% for group 1 (either: age 60 y and older or grade 2/3) versus 84% for group 2 (both: age 60 y and above and grade 2/3), respectively ( P <0.001). Five-year disease-specific survival was 100% versus 98% versus 95%, ( P =0.012) and 5-year overall survival was 98% versus 90% versus 81%, for groups 0, 1, and 2, respectively ( P <0.001). CONCLUSIONS: In patients with stage I EC who received SLNE and no adjuvant therapy, only age 60 years and above and high tumor grade were independent predictors of recurrence and can be used to quantify individualized recurrence risk, whereas lymphovascular space invasion was not an independent prognostic factor in this cohort.

The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women With FIGO Stage II Uterine Endometrioid Carcinoma.

OBJECTIVE: The objective of this study was to investigate the prognostic significance of the depth of cervical stromal invasion (CSI) in women with FIGO stage II uterine endometrioid adenocarcinoma (EC). METHODS: Our database of women with EC was quired for patients with stage II EC. Pathologic slides were retrieved and reviewed by gynecologic pathologists to determine cervical stromal thickness and depth of CSI as a percentage of stromal thickness (%CSI). Kaplan-Meier, univariate, and multivariate analyses were used to compare recurrence-free, disease-specific (DSS), and overall survival (OS) between women who had<50% versus ≥50% CSI. Univariate and multivariate analyses were used to assess other prognostic variables associated with survival endpoints. RESULTS: A total of 117 patients were included in our study who had hysterectomy between 1/1990 and 8/2021. Seventy-nine patients (68%) with <50% and 38 (32w%) with ≥50% CSI. After a median follow-up of 131 months, 5-year DSS was significantly worse for women with ≥50% CSI (78% vs. 91%; P =0.04). However, %CSI was not an independent predictor for any of the studied survival endpoints. Independent predictors of worse 5-year recurrence-free survival and DSS included FIGO grade 3 tumors ( P =0.02) and the presence of lymphovascular space invasion ( P =0.03). Grade 3 tumors were the only independent predictor of worse 5-year OS ( P =0.02). CONCLUSIONS: Our results suggest that deep CSI is not an independent prognostic factor for survival endpoints in women with stage II uterine endometroid adenocarcinoma. The lack of independent prognostic significance of the depth CSI needs to be validated in a multi-institutional analysis.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Quantification of recurrence risk based on number of adverse prognostic factors in women with stage I uterine endometrioid carcinoma

Objective: The goal was to develop an updated model to predict the risk of recurrence, based on the number of adverse pathologic features in women with International Federation of Gynecology and Obstetrics stage I uterine endometrioid carcinoma, who did not undergo any adjuvant treatment. Material and Methods: Women at a single center who underwent surgical staging without adjuvant therapy between January 1990 and December 2019 were included. Cox proportional hazards model was used to identify independent predictors of relapse free survival (RFS). Prognostic groups were then created based on the number of independent predictors of recurrence that were identified (0, 1, or 2-3 risk factors). Overall survival (OS) and disease specific survival (DSS) were also calculated for each group. Results: In total 1133 women were eligible for inclusion. Median follow-up was 84 months. Independent prognostic factors of recurrence included: age ≥60; grade 2 or 3 differentiation; and presence of lymphovascular space invasion (LVSI). Due to the small number of patients with either 2 or 3 risk factors, these groups were combined into one (group 2/3). Isolated vaginal cuff recurrence was the most common site of recurrence in all study groups (2%, 7%, and 17% for groups 0, 1, and 2/3, respectively). Five-year RFS rates were 96%, 85%, and 57% for groups 0, 1, and 2/3 (p<0.01), respectively. Five-year DSS rates were 99%, 96%, and 85% and 5-year OS rates were 94%, 85%, and 62% (p<0.01), respectively. Conclusion: We identified older age, high grade, and presence of LVSI as independent predictors of recurrence for women with stage I uterine endometrioid carcinoma. Using these prognostic factors, recurrence risk can be quantified for individual patients, and these factors can be used in deciding the appropriate adjuvant management course.

Matched-pair Analysis for Survival Endpoints Between Women With Early-stage Uterine Carcinosarcoma and Uterine Serous Carcinoma.

OBJECTIVE: The objective of this study was to compare survival endpoints between women with uterine carcinosarcoma and those with uterine serous carcinoma utilizing matching analysis. METHODS: Patients with stages I to II who underwent hysterectomy at our institution were included in this analysis. Patients with carcinosarcoma were then matched to patients with serous carcinoma based on stage, and adjuvant management received (observation, radiation treatment alone, chemotherapy alone, or combined modality with radiotherapy and chemotherapy. Recurrence-free survival, disease-specific survival, and overall survival were calculated for the 2 groups. RESULTS: A total of 134 women were included (67 women with carcinosarcoma and 67 with serous carcinoma, matched 1:1). There was no statistically significant difference between the 2 groups regarding 5-year recurrence-free survival (59% vs. 62%), disease-specific survival (66% vs. 67%), or overall survival (53% vs. 57%), respectively. The only independent predictor of shorter recurrence-free survival for the entire cohort was the lack of adjuvant combined modality therapy, while lower uterine segment involvement was the only independent predictor for shorter disease-specific survival. Lack of lymph node dissection and lack of adjuvant combined modality therapy were independent predictors of shorter overall survival. DISCUSSION: When matched based on stage and adjuvant treatment, our study suggests that there is no statistically significant difference in survival endpoints between women with early-stage carcinosarcoma and serous carcinoma. Adjuvant combined modality treatment is an independent predictor of longer recurrence-free survival and overall survival.

The impact of race, comorbid conditions and obesity on survival endpoints in women with high grade endometrial carcinoma.

OBJECTIVE: To estimate overall survival, disease-specific survival, and progression-free survival among high grade endometrial carcinoma cases and to determine factors impacting survival for non-Hispanic white and non-Hispanic black women. METHODS: We identified high grade endometrial carcinoma cases among non-Hispanic white and non-Hispanic black women from ongoing institutional studies, and determined eligibility through medical record and pathologic review. We estimated effects of demographic and clinical variables on survival outcomes using Kaplan Meier methods and Cox proportional hazards modelling. RESULTS: Non-Hispanic Black women with BMI <25.0 had poorest overall survival compared to non-Hispanic white women with BMI <25.0 (HR 3.03; 95% CI [1.35, 6.81]), followed by non-Hispanic black women with BMI 25.0+ (HR 2.43; 95% CI [1.28, 4.60]). A similar pattern emerged for disease-specific survival. Non-Hispanic black women also had poorer progression-free survival than non-Hispanic white women (HR 1.40; 95% CI [1.01, 1.93]). Other significant factors impacting survival outcomes included receipt of National Cancer Center Network (NCCN) guideline-concordant treatment (GCT), earlier stage at diagnosis, and fewer comorbid conditions. CONCLUSIONS: BMI and race interact and modify the association with high grade endometrial carcinoma survival. Other potentially modifiable factors, such as reducing comorbidities and increasing access to GCT will potentially improve survival after diagnosis of high grade endometrial carcinomas. A better understanding of the molecular drivers of these high grade carcinomas may lead to targeted therapies that reduce morbidity and mortality associated with these aggressive tumors.

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer.

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P < .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P < .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens.

The Impact of Adjuvant Management Strategies on Outcomes in Women With Early Stage Uterine Serous Carcinoma.

Objective To determine the impact of different adjuvant strategies on outcomes in women with early-stage uterine serous carcinoma (USC). Methods Our retrospective database for women with endometrial carcinoma was queried for women with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I-II USC who underwent surgical staging between January 1991 and April 2019 followed by adjuvant management (observation, radiation therapy (RT), chemotherapy (CT), or combined modality treatment (CRT)). Chi-square tests were performed to compare differences in outcome by type of adjuvant management. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were assessed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses (MVA) were performed to identify statistically significant predictors of survival endpoints. Results We identified 171 women who met our inclusion criteria. The median follow-up time was 70.5 months. Seventy-five percent of the study cohort was FIGO stage IA, 13% were stage IB, and 12% were stage II. All women underwent pelvic lymph node dissection with a median number of dissected lymph nodes of 14. Omentectomy was performed in 64% of patients. Adjuvant RT was utilized in 56% of women (65 patients received vaginal brachytherapy alone, 10 patients received pelvic RT, and 21 patients received a combination of both). The most commonly used chemotherapy regimen was carboplatin and paclitaxel with a median number of cycles of six. A total of 44% of the cohort received CRT, 12% received RT alone, 19% received chemo alone, and 25% were observed. Five-year RFS was 73% for those who received CRT, 84% for those who received RT alone, 68% for those who received CT alone, and 55% for those who were observed (p=0.13). Five-year DSS was 81%, 94%, 71%, and 60%, respectively (p=0.02). Five-year OS was 76%, 70%, 60%, and 56%, respectively (p=0.11). On MVA of OS and DSS, a higher percentage of myometrial invasion, the presence of lower uterine segment involvement, positive peritoneal cytology, and receipt of chemotherapy alone/observation were independent predictors of worse outcomes. The sole independent predictor of worse RFS on MVA was the presence of positive peritoneal cytology. Conclusion In this cohort of women with early-stage USC who underwent surgical staging, adjuvant radiation treatment with or without chemotherapy was associated with improved survival endpoints and trended toward improved recurrence rates.

Volumetric-Modulated Arc Radiotherapy with Daily Image-Guidance Carries Better Toxicity Profile for Higher Risk Prostate Cancer.

PURPOSE: To compare radiotherapy-induced toxicity for localized prostate-cancer (PCa) treated with versus without daily image-guidance. PATIENTS AND METHODS: We identified consecutive intermediate and high-risk localized PCa patients treated with definitive radiotherapy using intensity-modulated radiotherapy (IMRT) with variable duration of androgen-deprivation therapy (ADT) within 2015-2016 (Arm-A) and 2005-2007 (Arm-B). Arm-A cases received daily online imaging guidance (IGRT) using cone-beam computed tomography (CBCT) unlike Arm-B candidates with no daily IGRT. After reporting demographic, clinico-pathological features and treatment details, we compared acute (within 3 months post-therapy) and late RT-induced toxicities between study groups graded by RTOG/CTCAE criteria. Uni/multivariate analyses (UVA/MVA) were performed to identify independent predictors for RT-related side-effects. RESULTS: We were able to identify 257 cases who met our inclusion criteria. Overall, median age was 73 years (48-85), 67% had intermediate-risk and 47% received ADT. Arm-A included 72 patients who received IMRT delivered using volumetric-modulated arc therapy (VMAT), whereas, Arm-B was formed of 185 cases who utilized step-and-shoot static IMRT. Clinico-pathological features and treatment details were non-different across study arms except that Arm-A had more Grade Group 3, higher median total dose (79.2 vs. 74 Gy) and more pelvic lymph-nodes RT (p <0.05). Although acute toxicity was similar across groups, Arm-B encountered higher late toxicity score, more intense late genitourinary side-effects (P=0.008), with non-different late lower-gastrointestinal toxicities. On MVA, lack of daily CBCT, African-American race and higher comorbidities were independently predictive for late toxicities.  Conclusion: IMRT with daily CBCT permitted safe delivery of dose-escalated IMRT with improved toxicity profile for higher-risk prostate cancer.

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

Does the Interval Between Hysterectomy and Start of Adjuvant Radiation Treatment Influence Survival in Women With Endometrial Carcinoma?: A National Cancer Database analysis.

OBJECTIVE: The objective of this study was to analyze the impact of the time interval (TI) between hysterectomy and initiation of adjuvant radiation treatment (ART) on overall survival (OS) among women with early stage endometrial carcinoma (EC) using the National Cancer Database (NCDB). MATERIALS AND METHODS: The NCDB was queried for women with the International Federation of Gynecology and Obstetrics (FIGO) stage I to II EC who underwent hysterectomy followed by ART. We examined the prognostic impact of TI on OS using the cutoff ≤8 or >8 weeks to initiate radiation treatment (RT). Two groups of patients were created. Kaplan-Meier curves were created for OS analysis. Predictors of OS were identified. RESULTS: A total 16,520 women were identified. The median follow-up time for the entire cohort was 59.1 months. Median age was 63 years, and 82% were FIGO stage I. Pelvic external beam RT alone was used in 9569 (58%) and vaginal brachytherapy alone in 4265 women (26%). In total, 10,040 women (61%) received RT ≤8 weeks. Delay in initiating RT >8 weeks was associated with shorter 5-year OS (P=0.048). Independent predictors of shorter OS includes older age, African American race, higher comorbidity burden, higher tumor grade, the presence of lymphovascular invasion and stage II tumors. Although TI in initiating RT was a significant predictor for OS in univariate analysis, its independent significance of OS was lost on multivariate analysis (P=0.28). CONCLUSION: Our study suggests that TI between hysterectomy and initiation of ART was not an independent predictor of OS in women with early stage EC.

A deep dive into understanding tumor foci classification using multiparametric MRI based on convolutional neural network.

PURPOSE: Deep learning models have had a great success in disease classifications using large data pools of skin cancer images or lung X-rays. However, data scarcity has been the roadblock of applying deep learning models directly on prostate multiparametric MRI (mpMRI). Although model interpretation has been heavily studied for natural images for the past few years, there has been a lack of interpretation of deep learning models trained on medical images. In this paper, an efficient convolutional neural network (CNN) was developed and the model interpretation at various convolutional layers was systematically analyzed to improve the understanding of how CNN interprets multimodality medical images and the predictive powers of features at each layer. The problem of small sample size was addressed by feeding the intermediate features into a traditional classification algorithm known as weighted extreme learning machine (wELM), with imbalanced distribution among output categories taken into consideration. METHODS: The training data collection used a retrospective set of prostate MR studies, from SPIE-AAPM-NCI PROSTATEx Challenges held in 2017. Three hundred twenty biopsy samples of lesions from 201 prostate cancer patients were diagnosed and identified as clinically significant (malignant) or not significant (benign). All studies included T2-weighted (T2W), proton density-weighted (PD-W), dynamic contrast enhanced (DCE) and diffusion-weighted (DW) imaging. After registration and lesion-based normalization, a CNN with four convolutional layers were developed and trained on tenfold cross validation. The features from intermediate layers were then extracted as input to wELM to test the discriminative power of each individual layer. The best performing model from the tenfolds was chosen to be tested on the holdout cohort from two sources. Feature maps after each convolutional layer were then visualized to monitor the trend, as the layer propagated. Scatter plotting was used to visualize the transformation of data distribution. Finally, a class activation map was generated to highlight the region of interest based on the model perspective. RESULTS: Experimental trials indicated that the best input for CNN was a modality combination of T2W, apparent diffusion coefficient (ADC) and DWIb50 . The convolutional features from CNN paired with a weighted extreme learning classifier showed substantial performance compared to a CNN end-to-end training model. The feature map visualization reveals similar findings on natural images where lower layers tend to learn lower level features such as edges, intensity changes, etc, while higher layers learn more abstract and task-related concept such as the lesion region. The generated saliency map revealed that the model was able to focus on the region of interest where the lesion resided and filter out background information, including prostate boundary, rectum, etc. CONCLUSIONS: This work designs a customized workflow for the small and imbalanced dataset of prostate mpMRI where features were extracted from a deep learning model and then analyzed by a traditional machine learning classifier. In addition, this work contributes to revealing how deep learning models interpret mpMRI for prostate cancer patient stratification.

Charlson Comorbidity score influence on prostate cancer survival and radiation-related toxicity.

INTRODUCTION: In addition to survival endpoints, we explored the impact of Charlson Comorbidity-Index (CCI) on the acute and late toxicities in men with localized prostate cancer who received dose-escalated definitive radiotherapy (RT). MATERIALS AND METHODS: CCI scores at diagnosis and survival outcomes were identified for men with intermediate/high-risk prostate cancer treated with RT (1/2007-12/2012). Study-cohort was accordingly grouped into no, mild and severe comorbidity (CCI-0, 1 or 2+). CCI-groups were compared for demographics, prognostic-factors; and RT-related toxicities based on RTOG/CTCAE criteria. Kaplan-Meier curves and Uni/multivariate (MVA) analyses were used to examine the influence of CCI-group on overall (OS), disease-specific (DSS) and biochemical-relapse free (BRFS) survival. RESULTS: We included 257 patients with median age 73 years (48-85), 53% African-American and 67% had intermediate-risk. Median prostate RT-dose was 76 Gy; and 47% received androgen-deprivation therapy. CCI-0,1,2+ groups encompassed 76 (30%), 54 (21%) and 127 (49%) patients, respectively and were well-balanced. Ten and 15-years OS were significantly different (76% versus 46% versus 55% for 10-years OS and 53% versus 31% versus 14% for 15-years OS for CCI-0 versus CCI-1[HR:2.25; CI[1.31-3.87]] versus CCI-2+[HR:2.73; CI[1.73-4.31]]; p < 0.001. CCI-0 had better DSS than CCI-2+ (HR:2.23; CI[1.06-4.68]; p = 0.03) and BRFS was similar (p = 0.99). Late G2/3 RT-toxicities were more common in CCI-2+ (47%) than CCI-1 (44%) and CCI-0 (29%), p = 0.032; with non-different acute-toxicities (p = 0.62). On MVA, increased CCI was deterministic for OS (HR:3.65; CI [1.71:7.79]; p < 0.001) and was only marginal for DSS (HR:2.55; CI [0.98-6.6]; p = 0.05) with no impact on BRFS (p > 0.05). CONCLUSIONS: Higher CCI is a significant predictor for late RT-related side-effects and shorter OS in men with localized prostate cancer. Baseline comorbidities should be considered during initial counseling and follow up visits.

Disparities in the Use of Single-fraction Stereotactic Radiosurgery for the Treatment of Brain Metastases From Non-small Cell Lung Cancer.

PURPOSE: Radiation treatment patterns in patients with brain metastases from non-small cell lung cancer (NSCLC) have not been well elucidated. The National Cancer Database (NCDB) was used to evaluate trends in the use of whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) for brain metastasis from NSCLC. METHODS: This NCDB study included patients > 18 years old with metastatic NSCLC treated with single-fraction SRS or WBRT between 2004 and 2014. Chi-square, t-test, and multivariable logistic regression analyses were used to identify predictors of SRS versus WBRT. RESULTS: Of 40,803 patients, 34,183 (83.8%) received WBRT and 6,620 (16.2%) received SRS. SRS utilization increased from 7% (157 cases) in 2004 to 37% (1,346 cases) in 2014 (p < .001). SRS was utilized more by academic than community facilities (22% versus 13%, p < .001). The strongest independent predictors of SRS included year of diagnosis in 2010-2014 versus 2004-2009 (odds ratio [OR] 2.62, 95% CI 2.46-2.79, p < .0001), metropolitan versus rural (OR 2.26, CI 1.79-2.85, p < .0001), distance from cancer-reporting facility of ≥ 30 versus < 30 miles (OR 2.36, CI 2.18-2.56, p < .0001), private insurance versus non-insured patients (OR 1.96, CI 1.68-2.29, p < .0001), and academic versus community facility (OR 1.76, CI 1.66-1.87, p < .0001). CONCLUSION: SRS for NSCLC brain metastases has steadily increased in the United States; however, WBRT remains the most commonly used. Wide geographic and socioeconomic variations exist in the utilization of SRS and WBRT for this patient population.

Automatic Segmentation of the Prostate on CT Images Using Deep Neural Networks (DNN).

PURPOSE: Recent advances in deep neural networks (DNNs) have unlocked opportunities for their application for automatic image segmentation. We have evaluated a DNN-based algorithm for automatic segmentation of the prostate gland on a large cohort of patient images. METHODS AND MATERIALS: Planning-CT data sets for 1114 patients with prostate cancer were retrospectively selected and divided into 2 groups. Group A contained 1104 data sets, with 1 physician-generated prostate gland contour for each data set. Among these image sets, 771 were used for training, 193 for validation, and 140 for testing. Group B contained 10 data sets, each including prostate contours delineated by 5 independent physicians and a consensus contour generated using the STAPLE method in the CERR software package. All images were resampled to a spatial resolution of 1 × 1 × 1.5 mm. A region (128 × 128 × 64 voxels) containing the prostate was selected to train a DNN. The best-performing model on the validation data sets was used to segment the prostate on all testing images. Results were compared between DNN and physician-generated contours using the Dice similarity coefficient, Hausdorff distances, regional contour distances, and center-of-mass distances. RESULTS: The mean Dice similarity coefficients between DNN-based prostate segmentation and physician-generated contours for test data in Group A, Group B, and Group B-consensus were 0.85 ± 0.06 (range, 0.65-0.93), 0.85 ± 0.04 (range, 0.80-0.91), and 0.88 ± 0.03 (range, 0.82-0.92), respectively. The Hausdorff distance was 7.0 ± 3.5 mm, 7.3 ± 2.0 mm, and 6.3 ± 2.0 mm for Group A, Group B, and Group B-consensus, respectively. The mean center-of-mass distances for all 3 data set groups were within 5 mm. CONCLUSIONS: A DNN-based algorithm was used to automatically segment the prostate for a large cohort of patients with prostate cancer. DNN-based prostate segmentations were compared to the consensus contour for a smaller group of patients; the agreement between DNN segmentations and consensus contour was similar to the agreement reported in a previous study. Clinical use of DNNs is promising, but further investigation is warranted.

Geometric and dosimetric impact of anatomical changes for MR-only radiation therapy for the prostate.

PURPOSE: With the move towards magnetic resonance imaging (MRI) as a primary treatment planning modality option for men with prostate cancer, it becomes critical to quantify the potential uncertainties introduced for MR-only planning. This work characterized geometric and dosimetric intra-fractional changes between the prostate, seminal vesicles (SVs), and organs at risk (OARs) in response to bladder filling conditions. MATERIALS AND METHODS: T2-weighted and mDixon sequences (3-4 time points/subject, at 1, 1.5 and 3.0 T with totally 34 evaluable time points) were acquired in nine subjects using a fixed bladder filling protocol (bladder void, 20 oz water consumed pre-imaging, 10 oz mid-session). Using mDixon images, Magnetic Resonance for Calculating Attenuation (MR-CAT) synthetic computed tomography (CT) images were generated by classifying voxels as muscle, adipose, spongy, and compact bone and by assignment of bulk Hounsfield Unit values. Organs including the prostate, SVs, bladder, and rectum were delineated on the T2 images at each time point by one physician. The displacement of the prostate and SVs was assessed based on the shift of the center of mass of the delineated organs from the reference state (fullest bladder). Changes in dose plans at different bladder states were assessed based on volumetric modulated arc radiotherapy (VMAT) plans generated for the reference state. RESULTS: Bladder volume reduction of 70 ± 14% from the final to initial time point (relative to the final volume) was observed in the subject population. In the empty bladder condition, the dose delivered to 95% of the planning target volume (PTV) (D95%) reduced significantly for all cases (11.53 ± 6.00%) likely due to anterior shifts of prostate/SVs relative to full bladder conditions. D15% to the bladder increased consistently in all subjects (42.27 ± 40.52%). Changes in D15% to the rectum were patient-specific, ranging from -23.93% to 22.28% (-0.76 ± 15.30%). CONCLUSIONS: Variations in the bladder and rectal volume can significantly dislocate the prostate and OARs, which can negatively impact the dose delivered to these organs. This warrants proper preparation of patients during treatment and imaging sessions, especially when imaging required longer scan times such as MR protocols.