Background: We proposed adjunctive statistical standardization of quantitated ER and PgR to improve inter-laboratory comparability of biomarker results and therapeutic management of breast cancer. Adjunctive statistical standardization of quantitated HER2 is used here; we also examined the effects on outcome of ultra-low HER2 and very low statistically standardized HER2. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumors. IHC HER2 HSCORE and % positivity (%+) were centrally assessed by machine image quantitation, and statistically standardized to mean of 0, standard deviationn (SD) of 1 followig Box-Cox variance stabilization transformations of 1.) natural logarithm (ln with addition of 0.1 to 0 HSCOREs and 0 %+), 2. square root. Additionally, centrally assessed FISH HER2 and CEP17 values were used to define ASCO/CAP categorizatiion. Post hoc, the effects of ultra-low HER2 , IHC 0 with (0,10%] 1+ stain, were examined. The primary endpoint was distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years. Survival was described with Kaplan-Meier plots and tested with the univariate Wilcoxon (Peto-Prentice) test statistic. We examined cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1). Cox multivariant regressions were adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, baseline patient demographics, ER and PgR; 2-sided Wald tests had nominal significance if p<0.05. Results: Of 7576 women accrued to MA.27, 2900 women had ER, 2726 had PgR, and 2680 had HER2 results; 2325 had all three biomarkers for multivariant investigations. Twenty-five women received received herceptin with only one experiencng a DDFS event. ASCO/CAP categorization significantly differentiated univariate DDFS (p=0.01). Image analysis identified 57% of IHC 0 to have ultra-low HER2. Five-year DDFS for IHC 0 without stain was 92% [95% CI (90,95); N=864] which was similar to that for ultra-low HER2 of 96% [95% CI (94,97); N=1143]. Statistical standardization did not significantly differentiate univariate DDFS (p=0.08-0.27). DDFS for ln standardized values <-1.0 (HSCORE, or %+ <0.1) was similar to that with standardized values >1.0 (HSCORE >19, or %+ >14): for HSCORE <1.0, 5-year DDFS was 92% [95% CI (85.98); N=88] vs for >1.0, 92% [95% CI (89,95); N=577]; for %+, 5-year DDFS was 91% [95% CI (85,98); N=102] vs >1.0, 92% [95% CI (89,95); N=613].In multivariant assessments with ASCO/CAP guideline and statistically standardized data, both ER (p=0.65-0.94) and HER2 (p=0.20-0.97) were not significantly associated with the DDFS primary endpoint in models with PgR; while higher PgR had significantly better DDFS (p<.003) in models with ER and HER2. Conclusions: ASCO/CAP HER2 guidelines significantly differentiated univariate DDFS although not values of IHC 0 and ultra-low HER2, with <10% weak stain. Statistical standardization did not differentiate univariate DDFS. Image quantitation identified very small numbers of 1+/2+/3+ intensity stained nuclei. DDFS was similar for any intensity of low ln(HER2) stain (<1 SD below the mean) compared to any intensity of higher HER2 stain (>1 SD above the mean), although we offer caution in assessment of ultra-low, or very low, HER2 stain due to the dynamic range of the HER2 assay. Neither ASCO/CAP nor standardized HER2 had multivariant significance in these hormone receptor rich patient tumors. The adjunctive statistical standardization of ER, PgR, and HER2 performed here is similar to that mandated for clinical practice by the World Health Organization for BMD. Citation Format: Judith-Anne Chapman, Jane Bayani, Sandip SenGupta, John M.S. Bartlett, Tammy Piper, Mary Anne Quintayo, Shakeel Virk, Paul E. Goss, James N. Ingle, Matthew J. Ellis, George W. Sledge, G. Thomas Budd, Manuela Rabaglio, Rafat H. Ansari, Richard Tozer, David P. D'Souza, Haji Chalchal, Silvana Spadafora, Vered Stearns, Edith A. Perez, Karen A. Gelmon, Timothy J. Whelan, Catherine Elliott, Lois E. Shepherd, Bingshu E. Chen, Karen J. Taylor. Adjunctive statistical standardization of quantitated adjuvant HER2 and very low statistically standardized HER2 in CCTG MA.27 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-06.

PURPOSE:Erectile dysfunction (ED) is a common side effect of any prostate cancer treatment and the role of vessel-sparing low dose rate brachytherapy (LDR-BT) technique has not been previously described. MATERIALS AND METHODS:PRIAPUS (NCT04718987) is a prospective, single-arm clinical trial evaluating feasibility of a novel LDR BT technique designed to spare the prostatic neurovascular bundles (NVB) contralateral to the index lesion. Intermediate-risk prostate cancer patients with clinically significant disease contained to one lobe of the prostate were enrolled. Primary objective was for 70% of patients to achieve acceptable dose to CTV while sufficiently sparing ED-related structures. Dosimetry was evaluated on a 1-month postimplant CT-scan. RESULTS:Fifteen patients have been consented with 14 patients treated on trial. In the 1-month postprocedure scan, the mean CTV D90% was 152 Gy (SD ± 10.7 Gy). All patients but two had a CTV D90% >140 Gy. The mean urethra D30% was 129% (SD ± 9%). The mean contralateral NVB D50% was 60.8 Gy (SD ± 12.1 Gy), with 11 of 14 implants failing to meet the prespecified goal. The ipsilateral NVB which was not spared received a mean D50% of 128 Gy (SD ± 32 Gy). The mean penile bulb D10% was 31 Gy (SD ± 13 Gy). Only 2 patients had a postimplant dosimetry that met all prespecified criteria. CONCLUSIONS:A novel LDR BT technique is capable of drastically reduce dose to the cNVB, although this reduction did not meet the stringent dose constraints specified in this trial.

PURPOSE:To evaluate a commercial deep-learning based auto-contouring software specifically trained for high-dose-rate gynecological brachytherapy. METHODS AND MATERIALS:We collected CT images from 30 patients treated with gynecological brachytherapy (19.5-28 Gy in 3-4 fractions) at our institution from January 2018 to December 2022. Clinical and artificial intelligence (AI) generated contours for bladder, bowel, rectum, and sigmoid were obtained. Five patients were randomly selected from the test set and manually re-contoured by 4 radiation oncologists. Contouring was repeated 2 weeks later using AI contours as the starting point ("AI-assisted" approach). Comparisons amongst clinical, AI, AI-assisted, and manual retrospective contours were made using various metrics, including Dice similarity coefficient (DSC) and unsigned D2cc difference. RESULTS:Between clinical and AI contours, DSC was 0.92, 0.79, 0.62, 0.66, for bladder, rectum, sigmoid, and bowel, respectively. Rectum and sigmoid had the lowest median unsigned D2cc difference of 0.20 and 0.21 Gy/fraction respectively between clinical and AI contours, while bowel had the largest median difference of 0.38 Gy/fraction. Agreement between fully automated AI and clinical contours was generally not different compared to agreement between AI-assisted and clinical contours. AI-assisted interobserver agreement was better than manual interobserver agreement for all organs and metrics. The median time to contour all organs for manual and AI-assisted approaches was 14.8 and 6.9 minutes/patient (p < 0.001), respectively. CONCLUSIONS:The agreement between AI or AI-assisted contours against the clinical contours was similar to manual interobserver agreement. Implementation of the AI-assisted contouring approach could enhance clinical workflow by decreasing both contouring time and interobserver variability.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI ( P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773 ).

Purpose Radiotherapy is a well-established curative treatment for localized prostate cancer. Radiotherapy dose escalation is associated with lower rates of biochemical and local failure. Moreover, dose escalation with a high-dose-rate brachytherapy (HDR-BT) boost has been correlated with low toxicity rates. This study aimed to review toxicities, biochemical, and local control rates of patients treated with a single fraction 15 Gy HDR-BT boost followed by external beam radiation therapy (EBRT). Materials and Methods Data was retrospectively collected from 179 consecutive prostate cancer patients who underwent treatment with HDR-BT boost and EBRT from February 2014 until February 2020 at a single tertiary cancer. All patients underwent HDR-BT at the study institution and 112 (62,5%) EBRT at the institution. All procedures were performed with the patient under general anesthesia, guided by transrectal ultrasound, using 10 to 18 needles. Axial images of the prostate were captured into the treatment planning system, and subsequent contours and intraoperative planning were performed. Standard dosimetry constraints of the institution were adhered to. External beam radiation therapy was administered in 15 to 25 fractions, with total doses ranging from 3750 to 4600 cGy. Pelvic nodal inclusion was at the discretion of the Radiation Oncologist. Data collection involved a review of electronic medical records for each patient, with staging based on NCCN Version 1.2024 Prostate Guidelines and clinical notes assessed for toxicity analyses graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Following treatment, patients were either discharged to a regional cancer center or regularly monitored for 4-5 years before discharge to a primary care practitioner. PSA levels were monitored every six months for the first two years, then annually until the completion of 5 years. Biochemical failure was defined as a nadir PSA level plus 2.0 ng/ml according to the Phoenix criterion, with local failures confirmed through prostate biopsy and disease progression in any event of local failure, nodal, or distant metastasis. Results 179 patients meeting the inclusion criteria were analyzed. The median follow-up time was 3 years. The distribution of risk groups was as follows: favorable intermediate risk (FIR) (13.2%), unfavorable intermediate risk (UIR) (57.1%), high risk (HR) (25.4%), and very high risk (VHR) (2.6%). 95 patients (52.2%) had cT1, 67 (36.8%) had cT2, 15 (8.2%) had cT3 disease. The median baseline PSA was 9 ng/mL (IQR: 6.19 - 15.45), with a median prostate volume of 37 cc (IQR: 29.75 - 46.25) and six cores (IQR: 4 - 9) involved with prostate cancer. Sixty-six percent of patients received hormonal therapy, with a median duration of 6 months. Urinary toxicity occurred in 23% of the patients, with 19.8% experiencing grade 1 or 2 toxicity and 3.2% experiencing grade 3. There were no urinary or gastrointestinal toxicities graded as 4 or 5. Only one patient developed urinary retention after the HDR-BT procedure, requiring the insertion of a urinary catheter. Out of 179 patients, 26 (14,5%) experienced biochemical recurrence. The crude rate of biochemical relapse per risk category was 12%, 14%, 28%, and 20% for FIR, UIR, HR, and VHR prostate cancer patients, respectively. Disease progression was observed in 18 of the 26 biochemical failures for an overall rate of 10% in the cohort (18/179), with the following locations of disease progression: 5.0% (9 patients) developed local failure, 3.3% (6 patients) had distant metastasis, and 1.6% (3 patients) had nodal metastasis. Conclusions In this large single institutional study, 15 Gy HDR-BT boost plus EBRT resulted in favorable biochemical recurrence rates and local failure across various risk categories. The incidence of urinary retention post brachytherapy and urinary and gastrointestinal G3+ toxicity was very low.

PURPOSE ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS MA.27 (ClinicalTrials.gov identifier: NCT00066573 ) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤–1; (–1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS ( P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated ( P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS ( P = .001) in models with ER. CONCLUSION Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤–1.

Abstract Background: Adjuvant breast cancer therapy is informed by whether a tumour is positive or negative for the biomarkers ER, PgR, and HER2, often without regard to level of positivity. Quantitation has been proposed to improve therapeutic management. Adjunctive statistical standardization has been proposed to improve inter-laboratory comparability of biomarkers results. Methods: This primary report utilized adjunctive statistical standardization of machine-quantitated image analysis biomarker assessments. CCTG MA.27 (NCT00066573) is an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 were centrally assessed, with FISH (HER2;HER2/CEP17) determinations for equivocal IHC HER2. HSCOREs were statistically standardized to a mean of 0, standard deviation of 1 following Box-Cox variance stabilization transformations of square for ER and natural logarithm for PgR (0.1 was added to 0 HSCOREs). The primary endpoint was STEEP distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years. Survival was described with Kaplan-Meier plots. The univariate Wilcoxon (Peto-Prentice) test statistic was used with usual designation of negative/positive (0; >0), and standardized cut-points at standard deviations about mean of 0(<-1; (-1,0]; (0,1]; >1). Cox multivariate regressions adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics, utilized likelihood ratio tests. Nominal significance was p=0.05. Results: Of the 7576 women accrued, 3048 had machine-quantitated image analysis results: 2900 (95%) for ER; 2726 (89%) for PgR. Only 8 women were ASCO/CAP ER- (HSCORE 0); PgR HSCORE was 0 for 533. Statistically standardized units differentiated DDFS ER levels (p< 0.001) and PgR levels (p< 0.001). In adjusted multivariate analyses, higher ER HSCORE was associated with better DDFS (p=0.05) with weak evidence of an association (p=0.11) for standardized HSCORE, and no significant association (respectively, p=0.28, p=0.54) in models with PgR. Higher PgR was associated with better DDFS (p=0.001) in all multivariate assessments, including those with ER. Conclusions: DDFS was superior for patients with higher ER and PgR standardized units compared with those with HSCOREs <-1. Adjunctive statistical standardization, similar to that mandated for clinical practice by the World Health Organization for BMD, should improve inter-laboratory comparability of biomarker results for similar patient populations. Biomarker N DDFS DDFS 5-year (%) 95% CI ER total 2900 ER <-1 506 86 (82, 91) ER (-1, 0] 934 94 (92, 96) ER ( 0, 1] 919 94 (92, 96) ER >1 541 96 (93, 98) PgR total 2726 PgR <-1 734 89 (86, 92) PgR (-1, 0] 439 92 (89, 95) PgR ( 0, 1] 967 95 (93, 96) PgR >1.0 586 98 (97,100) Citation Format: Judy-Anne Chapman, Jane Bayani, Sandip SenGupta, John MS Bartlett, Tammy Piper, Mary Anne Quintayo, Shakeel Virk, Paul Goss, James Ingle, Matthew Ellis, George Sledge Jr, George Budd, Manuela Rabaglio, Rafat Ansari, Richard Tozer, David D'Souza, Haji Chalchal, Silvana Spadafora, Vered Stearns, Edith A. Perez, Karen Gelmon, Timothy Whelan, Catherine Elliott, Lois Shepherd, Bingshu Chen, Karen Taylor. Adjunctive statistical standardization of quantitated machine image analysis of Estrogen and Progesterone Receptors: CCTG MA.27 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-10.

Purpose Standard low dose rate (LDR) permanent-seed prostate brachytherapy (BT) aims to deliver the prescribed dose to the entire prostate while minimizing dose to the urethra, bladder and rectum. However, LDR brachytherapy has been linked with long-term erectile dysfunction, possibly from excessive dose to the prostatic neurovascular bundles and/or the penile bulb. Therefore, the PRIAPUS trial (NCT04718987) proposed a novel approach with subtotal prostate treatment while sparing the region around the contralateral neurovascular bundle (NVB) for patients with unilateral clinically significant disease. In this study, we report a detailed dosimetric analysis comparing standard LDR brachytherapy versus treatment with this modified LDR BT technique. Materials and Methods The first 13 patients from the PRIAPUS trial (15 enrolled, 14 treated, 13 analyzed) were analyzed alongside a retrospectively collected comparator group of 15 patients not enrolled in PRIAPUS and treated with standard LDR prostate BT within the same year. LDR BT incorporated an intraoperative procedure using I-125 seeds implanted with a Mick applicator and guided by live transrectal ultrasound imaging. Both techniques aimed for a prescription dose of 145 Gy to the target, which for the standard procedure was defined as the prostate while for the PRIAPUS study was the prostate excluding a 5-mm expansion around the contralateral NVB. Dose constraints used for planning were: target V100% > 90%, V150% < 50%, V200% < 10%, D90% > 145 Gy; urethra D30% < 130%, D10% < 150%; and rectum V100% < 1cc. In addition, the PRIAPUS protocol required the median dose to the contralateral NVB < 50 Gy and the penile bulb D10 < 50 Gy. Since the contralateral NVB could not be reliably seen on ultrasound, it was contoured on a pre-implant MRI, and a surface-based deformable image registration algorithm matching prostate contours was used to map the NVB to the live ultrasound. A CT was acquired approximately 30 days after the procedure and rigidly registered to an MRI for post-implant dosimetric assessment of the target, urethra and NVB. Statistical testing was performed using an independent samples t-test with a significance level of 5%. Results Dosimetric comparison between 13 PRIAPUS and 15 standard implants revealed several significant differences between groups. Regarding target V100, PRIAPUS patients exhibited a mean (standard deviation) of 92% (±3%), whereas standard implants had a mean of 95% (±2%), resulting in a 3% mean difference (p=0.01). Additionally, the mean median NVB dose for standard implants was 127.6 Gy (±26.2 Gy) whereas PRIAPUS patients’ contralateral NVB had a mean median dose of 60.7 Gy (±12.6 Gy) indicating a mean 67 Gy difference (p < 0.001). No statistically significant dosimetric differences were noticed for the urethra. Average dose metrics across both patient groups are summarized in Table 1. Conclusions Within the PRIAPUS cohort, significant sparing of the contralateral neurovascular bundle was achieved relative to standard LDR brachytherapy but came at the cost of a small reduction in target volume coverage contralateral to the involved lobe.

BACKGROUND:Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM). OBJECTIVE:We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202). DESIGN, SETTING, AND PARTICIPANTS:From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated. RESULTS AND LIMITATIONS:With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02). CONCLUSIONS:With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT. PATIENT SUMMARY:In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use.

BACKGROUND AND PURPOSE Anemia is common in locally advanced cervical cancer. Clinical practice varies greatly for management of anemia during brachytherapy, with some centres providing red cell transfusion to increase hemoglobin levels above 100 g/L. MATERIALS AND METHODS This is a retrospective observational cohort study of adult patients with cervical cancer treated with brachytherapy at two academic hospitals. One hospital (H1) uses a liberal transfusion strategy with hemoglobin threshold of 100 g/L during brachytherapy and the other uses a restrictive target of 70 g/L (H2). RESULTS Overall, 336 patients met inclusion criteria (H1: 150 patients, H2: 186 patients). 11 patients were excluded (2 at H1, 9 at H2). Demographics at both sites were comparable, except for cancer stage and smoking history. External beam radiation and chemotherapy provided was similar. Hemoglobin values were compared at baseline (within 4 weeks of oncology consult), and prior to the first and second brachytherapy treatments. In total, 101red blood cell (RBC) units were transfused to patients at H1 and 19 units to patients at H2. Patients were followed for a median of 37.0 months (0.6-80.5) at H1, and 33.3 months (1.6-82.0) at H2. There was no significant difference in progression-free or overall survival. Multivariable logistic regression analysis showed that FIGO stage was a predictor for both overall survival and cancer progression. Age, tumor size, chemotherapy, and hemoglobin levels were not predictors of disease progression or mortality. CONCLUSIONS The practice of liberal transfusion should be re-evaluated in the absence of robust data to support its use.

Radiotherapy (RT) has a fundamental role in the treatment of gynecologic malignancies, including cervical and uterine cancers. Hypofractionated RT has gained popularity in many cancer sites, boosted by technological advances in treatment delivery and image verification. Hypofractionated RT uptake was intensified during the COVID-19 pandemic and has the potential to improve universal access to radiotherapy worldwide, especially in low-resource settings. This review summarizes the rationale, the current challenges and investigation efforts, together with the recent developments associated with hypofractionated RT in gynecologic malignancies. A comprehensive search was undertaken using multiple databases and ongoing trial registries. In the definitive radiotherapy setting for cervical cancers, there are several ongoing clinical trials from Canada, Mexico, Iran, the Philippines and Thailand investigating the role of a moderate hypofractionated external beam RT regimen in the low-risk locally advanced population. Likewise, there are ongoing ultra and moderate hypofractionated RT trials in the uterine cancer setting. One Canadian prospective trial of stereotactic hypofractionated adjuvant RT for uterine cancer patients suggested a good tolerance to this treatment strategy in the acute setting, with a follow-up trial currently randomizing patients between conventional fractionation and the hypofractionated dose regimen delivered in the former trial. Although not yet ready for prime-time use, hypofractionated RT could be a potential solution to several challenges that limit access to and the utilization of radiotherapy for gynecologic cancer patients worldwide.

OBJECTIVE:To evaluate disease-free survival (DFS) and overall survival (OS) associated with adjuvant carboplatin and paclitaxel chemotherapy interposed with radiation for advanced endometrial cancer. METHODS:This is a cohort study of adult women with stage III or IV endometrial cancer treated at a single institution, between April 2002 and October 2017. Tumor and treatment characteristics were recorded. Treatment consisted of 4 cycles of intravenous paclitaxel and carboplatin every 3 weeks, followed by external beam radiotherapy to the pelvis (45-50 Gy), and another 2 cycles of chemotherapy. One cohort of patients were prospectively enrolled from 2002 through 2006 and an additional cohort from 2007 to 2017, which was retrospectively analyzed. Primary endpoints for this study were DFS and OS rates which were calculated using Cox regression models. RESULTS:Eighty-two patients with a median age of 66.5 years (range, 35-83 years) were included. Median follow-up was 46 months (range, 9-196 months). Most patients had stage IIIC disease (62.2%) and serous carcinoma histology (46.3%). Median OS was 146 months and median DFS was 71 months. A 5-year OS and DFS were 64.9% and 55.7%, respectively. Age >60 years subgroup was at a significantly higher risk of DFS event or death. Histological subtype, location of positive nodes, and cancer stage (IIIa vs. higher stage) did not correlate to a higher risk of recurrence or death. CONCLUSION:Long term follow-up and a larger population confirm that the chemoradiotherapy sandwich method yields favorable outcomes in patients with high-risk endometrial cancer.

Purpose Erectile disfunction (ED) is a common long-term side effect of any prostate cancer treatment. Radiation-related ED is thought to be a vascular process, related to venous occlusion caused by radiation. Low dose-rate (LDR) brachytherapy (BT) is a well-established treatment modality that has an undisputable dose conformality and a theoretical advantage in reducing dose to erectile-related structures when compared to EBRT options. Nevertheless, the role of vessel-sparing LDR-BT technique has not been previously described. Materials and Methods PRIAPUS (NCT 04718987) is a prospective, single-arm clinical trial evaluating feasibility and dosimetry associated with a novel LDR BT technique that aims to spare ED-related structures, including the prostatic neurovascular bundles (NVB) contralateral to the index lesion and the penile bulb (Figure 1). The trial planned to accrue 15 patients with intermediate-risk prostate cancer staged with MRI, with clinically significant disease (CSD) contained to one lobe of the prostate. Primary objective was for 70% of patients to achieve acceptable dose to the target structure while sufficiently sparing ED-related structures. Dosimetry was evaluated on a one-month post-implant CT-scan. In order of priority, the trial's dosimetric goals are: target D90% ≥ 140 Gy, urethra D30% < 130%, contralateral NVB median dose ≤ 50 Gy, and penile bulb D10% ≤ 50 Gy. The LDR BT workflow involved a pre-procedural prostate mpMRI for NVB definition, intra-operative use of a deformable image registration algorithm to translate NVB contours from pre-implant MRI to the live ultrasound images, and intraoperative planning using loose 125-Iodine radioactive seeds with a prescription dose of 145 Gy. Results Fifteen patients have been consented: one withdrew consent before receiving treatment, one awaits treatment, and 13 have been successfully treated with post-implant dosimetry available for analysis. In the one-month post-procedure scan, the mean target D90% was 153 Gy (SD ± 10 Gy). All patients but one had a target D90% > 140 Gy. The mean urethra D30% was 129% (SD ±10%). The mean contralateral NVB D50% was 60 Gy (SD ± 13 Gy), with 10 of 13 implants failing to meet the pre-specified goal. For comparison, the ipsilateral NVB which was not spared received a mean D50% of 131 Gy (SD ± 33 Gy). The mean penile bulb D10% was 32 Gy (SD ± 13 Gy). Only two patients had a post-implant dosimetry that met all pre-specified criteria, and so this trial's primary dosimetric endpoint will not be met after the last patient receives treatment. Conclusions The pre-specified dosimetric goals were found stringent and seldom achievable and future trials with this technique will require relaxation of the contralateral NVB constraint. While the primary dosimetric endpoint was not met, a substantial dose sparing to the contralateral NVB was achieved while maintaining an ablative dose to the subtotal prostate. Figure 1- Mid-gland T2 axial sequence at 1-month post LDR BT implant in a patient with CSD located in the right lobe. Note dose avoidance to the contralateral neurovascular bundle (contoured in yellow). Prescription dose (in pink colour) is delivered to the subtotal prostate (in blue). Yellow and green lines represent 120% and 150% isodoses.

BACKGROUND:Accurate segmentation of the clinical target volume (CTV) corresponding to the prostate with or without proximal seminal vesicles is required on transrectal ultrasound (TRUS) images during prostate brachytherapy procedures. Implanted needles cause artifacts that may make this task difficult and time-consuming. Thus, previous studies have focused on the simpler problem of segmentation in the absence of needles at the cost of reduced clinical utility.PURPOSE:To use a convolutional neural network (CNN) algorithm for segmentation of the prostatic CTV in TRUS images post-needle insertion obtained from prostate brachytherapy procedures to better meet the demands of the clinical procedure.METHODS:A dataset consisting of 144 3-dimensional (3D) TRUS images with implanted metal brachytherapy needles and associated manual CTV segmentations was used for training a 2-dimensional (2D) U-Net CNN using a Dice Similarity Coefficient (DSC) loss function. These were split by patient, with 119 used for training and 25 reserved for testing. The 3D TRUS training images were resliced at radial (around the axis normal to the coronal plane) and oblique angles through the center of the 3D image, as well as axial, coronal, and sagittal planes to obtain 3689 2D TRUS images and masks for training. The network generated boundary predictions on 300 2D TRUS images obtained from reslicing each of the 25 3D TRUS images used for testing into 12 radial slices (15° apart), which were then reconstructed into 3D surfaces. Performance metrics included DSC, recall, precision, unsigned and signed volume percentage differences (VPD/sVPD), mean surface distance (MSD), and Hausdorff distance (HD). In addition, we studied whether providing algorithm-predicted boundaries to the physicians and allowing modifications increased the agreement between physicians. This was performed by providing a subset of 3D TRUS images of five patients to five physicians who segmented the CTV using clinical software and repeated this at least 1 week apart. The five physicians were given the algorithm boundary predictions and allowed to modify them, and the resulting inter- and intra-physician variability was evaluated.RESULTS:Median DSC, recall, precision, VPD, sVPD, MSD, and HD of the 3D-reconstructed algorithm segmentations were 87.2 [84.1, 88.8]%, 89.0 [86.3, 92.4]%, 86.6 [78.5, 90.8]%, 10.3 [4.5, 18.4]%, 2.0 [-4.5, 18.4]%, 1.6 [1.2, 2.0] mm, and 6.0 [5.3, 8.0] mm, respectively. Segmentation time for a set of 12 2D radial images was 2.46 [2.44, 2.48] s. With and without U-Net starting points, the intra-physician median DSCs were 97.0 [96.3, 97.8]%, and 94.4 [92.5, 95.4]% (p < 0.0001), respectively, while the inter-physician median DSCs were 94.8 [93.3, 96.8]% and 90.2 [88.7, 92.1]%, respectively (p < 0.0001). The median segmentation time for physicians, with and without U-Net-generated CTV boundaries, were 257.5 [211.8, 300.0] s and 288.0 [232.0, 333.5] s, respectively (p = 0.1034).CONCLUSIONS:Our algorithm performed at a level similar to physicians in a fraction of the time. The use of algorithm-generated boundaries as a starting point and allowing modifications reduced physician variability, although it did not significantly reduce the time compared to manual segmentations.

Purpose High-dose-rate (HDR) brachytherapy (BT) plays an important role in the management of many gynecological cancers. As part of BT planning, normal tissue structures must be segmented, which is time-consuming and subject to inter-observer variability. Recently, deep-learning-based auto-contouring tools have been introduced into the clinic, primarily in the setting of external beam radiotherapy, and have resulted in promising efficiency gains. However, auto-contouring of normal tissues within BT presents additional challenges due to the presence of applicators. In this study, we evaluate the performance of the pre-clinical release of a commercial deep-learning-based auto-contouring software for use in gynecological BT. Materials and Methods Limbus Contour recently developed artificial intelligence models specifically for use in gynecological HDR-BT. Models were trained from a multi-institutional dataset of >250 patient images with a variety of applicators. For this study, CT images were collected from 135 patients treated at a single institution from January 2018 to December 2022 using plastic and titanium applicators, including: tandem and ring, tandem and ovoid, and template-based interstitial. From this cohort, 107 patients were included in the Limbus training dataset. To evaluate model performance, a held-back dataset of 23 patients from this cohort was selected for model testing. Clinically used contours for bladder, rectum, and sigmoid were compared with those generated by Limbus using standard geometric accuracy metrics, including Dice similarity coefficient (DSC) and mean distance to agreement (MDA). Geometric comparisons excluded regions 1.5 cm superior and 1.5 cm inferior to the intermediate-risk clinical target volume. Unsigned D2cc dose metrics for these same structures were compared between clinical and Limbus contours. To benchmark these results, the analogous comparisons were performed on the remaining five patients in the dataset, which were each retrospectively contoured by four radiation oncologists. Results The DSC mean ± standard deviation (SD) when comparing Limbus versus clinical contours and retrospective RO contours to one another were respectively 0.87 ± 0.07 and 0.88 ± 0.03 for bladder (p=0.32), 0.77 ± 0.09 and 0.64 ± 0.20 for rectum (p=0.004), 0.57 ± 0.21 and 0.48 ± 0.27 for sigmoid (p=0.27). Similarly, the corresponding comparisons for MDA were respectively 1.4 ± 0.6 mm and 1.4 ± 0.4 mm for bladder (p=0.83), 2.3 ± 1.0 mm and 5.0 ± 4.2 mm for rectum (p=0.002), and 16.1 ± 25.7 mm and 16.1 ± 14.6 mm for sigmoid (p=0.99). Unsigned D2cc dose differences for Limbus vs clinical contours and retrospective RO vs RO contours were respectively: 0.94 ± 0.90 Gy and 0.60 ± 0.43 Gy for bladder (p=0.11), 0.57 ± 0.49 Gy and 0.57 ± 0.46 Gy for rectum (p=0.98), and 1.1 ± 1.7 Gy and 1.5 ± 1.1 Gy for sigmoid (p=0.46). Corresponding box-and-whisker plots are shown in Figure 1. Conclusions When comparing auto-contoured bladder, rectum, and sigmoid structures with the clinically used contours, dose metrics were similar to metrics seen when RO contours were compared with one another. Geometry metrics were also similar, except for rectum, where Limbus agreed better with the clinical contours than ROs with one another, potentially due to variation in the rectal-sigmoid interface.