The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BACKGROUND: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. METHODS: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. DISCUSSION: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. TRIAL REGISTRATION: NCT05230251 (ClinicalTrials.gov).

Quality-adjusted survival in women with gynecologic malignancies receiving IMRT after surgery: A Ppatient Rreported Ooutcome study of NRG oncology's RTOG 1203.

INTRODUCTION: NRG/RTOG 1203 compared 3-D conformal radiotherapy (3D CRT) to intensity-modulated radiotherapy (IMRT) in patients with endometrial or cervical cancer requiring post-operative radiotherapy after hysterectomy. The purpose of this study was to report the first quality-adjusted survival analysis comparing the two treatments. METHODS: NRG/RTOG 1203 randomized patients having undergone hysterectomy to either 3DCRT or IMRT. Stratification factors included RT dose, chemotherapy, and disease site. The EQ-5D, both index and visual analog scale (VAS), were obtained at baseline, 5 weeks after the start of RT, 4-6 weeks post RT and 1 and 3-years post RT. EQ-5D index and VAS scores along with quality-adjusted survival (QAS) were compared between treatment arms using the t-test at a two-sided significance level of 0.05. RESULTS: NRG/RTOG 1203 enrolled 289 patients of which 236 consented to participate in the patient reported outcome (PRO) assessments. QAS was higher in women treated with IMRT, 1374 vs 1333 days (p = 0.5) compared to patients treated with 3DCRT, but this difference was not statistically different. Patients treated with IMRT had less of a decline in VAS score 5 weeks post RT, -5.04, compared to patients treated with 3DCRT, -7.48, although not statistically significant (p = 0.38). CONCLUSION: This is the first report of the use of the EQ-5D comparing two radiotherapy techniques in the treatment of gynecologic malignancies after surgery. While there were no significant differences in QAS and VAS scores between patients who received IMRT vs. 3DCRT, RTOG 1203 was not powered to show statistical differences in these secondary endpoints.

3D image-guided interstitial brachytherapy for primary vaginal cancer: A multi-institutional experience.

PURPOSE/OBJECTIVES: High dose rate (HDR) interstitial brachytherapy (ISBT) boost is integral for definitive radiation treatment of primary vaginal cancer. Technological advances with CT or MRI guidance provide improved precision and ability to treat more extensively invasive tumors over historical techniques, but reported experience is limited. We sought to provide updated outcome and toxicity data for women with primary vaginal cancer undergoing treatment with a modern ISBT technique. MATERIAL/METHODS: Databases of primary vaginal carcinoma patients treated at two Canadian academic cancer institutions were combined including patient, tumor and treatment characteristics, and survival outcomes and toxicity data. Descriptive statistics, survival estimates based on the Kaplan-Meier method, and univariable/multivariable Cox proportional hazards regression analyses are reported. RESULTS: Between 2002 and 2017, 67 women with primary vaginal cancer were treated with 3D HDR ISBT. FIGO stage distribution was I (22.4%), II (50.8%), III (17.9%), IVa (9.0%). All patients received external beam radiotherapy and HDR ISBT of 500-750 cGy per fraction over 2-4 fractions. Median follow-up was 2.68 years (95% confidence interval: 2.04-6.04). Cumulative rate of grade 3-4 genitourinary/gastrointestinal toxicity was 10.4%. Four patients developed vaginal fistula. Progression-free survival at 2 and 3 years was 73.5% and 66.4% for all patients, 78.3% and 75.0% for stage I-II and 61.6% and 46.2% for stage III-IVa, respectively (log-rank p = 0.252). CONCLUSIONS: Use of 3D image-guided HDR ISBT boost was safe and resulted in improved survival outcomes compared to historical rates in this series of primary vaginal cancer patients. Prospective study is warranted to better define clinical and dosimetric predictors of local control.

Patient and family financial burden associated with cancer treatment in Canada: a national study.

GOAL: To determine patient-reported financial and family burden associated with treatment of cancer in the previous 28 days across Canada. METHODS: A self-administered questionnaire (P-SAFE v7.2.4) was completed by 901 patients with cancer from twenty cancer centres nationally (344 breast, 183 colorectal, 158 lung, 216 prostate) measuring direct and indirect costs related to cancer treatment and foregone care. Monthly self-reported out-of-pocket-costs (OOPCs) included drugs, homecare, homemaking, complementary/ alternative medicines, vitamins/supplements, family care, accommodations, devices, and "other" costs. Travel and parking costs were captured separately. Patients indicated if OOPC, travel, parking, and lost income were a financial burden. RESULTS: Mean 28-day OOPCs were CA$518 (US Purchase Price Parity [PPP] $416), plus CA$179 (US PPP $144) for travel and CA$84 (US PPP $67) for parking. Patients self-reporting high financial burden had total OOPCs (33%), of CA$961 (US PPP $772), while low-burden participants (66%) had OOPCs of CA$300 (US PPP $241). "Worst burden" respondents spent a mean of 50.7% of their monthly income on OOPCs (median 20.8%). Among the 29.4% who took time off work, patients averaged 18.0 days off. Among the 26.0% of patients whose caregivers took time off work, caregivers averaged 11.5 days off. Lastly, 41% of all patients had to reduce spending. Fifty-two per cent of those who reduced spending were families earning < CA$50,000/year. CONCLUSIONS: In our Canadian sample, high levels of financial burden exist for 33% of patients, and the severity of burden is higher for those with lower household incomes.

Brucella Exposure Risk Events in 10 Clinical Laboratories, New York City, USA, 2015 to 2017.

From 2015 to 2017, 11 confirmed brucellosis cases were reported in New York City, leading to 10 Brucella exposure risk events (Brucella events) in 7 clinical laboratories (CLs). Most patients had traveled to countries where brucellosis is endemic and presented with histories and findings consistent with brucellosis. CLs were not notified that specimens might yield a hazardous organism, as the clinicians did not consider brucellosis until they were notified that bacteremia with Brucella was suspected. In 3 Brucella events, the CLs did not suspect that slow-growing, small Gram-negative bacteria might be harmful. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), which has a limited capacity to identify biological threat agents (BTAs), was used during 4 Brucella events, which accounted for 84% of exposures. In 3 of these incidents, initial staining of liquid media showed Gram-positive rods or cocci, including some cocci in chains, suggesting streptococci. Over 200 occupational exposures occurred when the unknown isolates were manipulated and/or tested on open benches, including by procedures that could generate infectious aerosols. During 3 Brucella events, the CLs examined and/or manipulated isolates in a biological safety cabinet (BSC); in each CL, the CL had previously isolated Brucella Centers for Disease Control and Prevention recommendations to prevent laboratory-acquired brucellosis (LAB) were followed; no seroconversions or LAB cases occurred. Laboratory assessments were conducted after the Brucella events to identify facility-specific risks and mitigations. With increasing MALDI-TOF MS use, CLs are well-advised to adhere strictly to safe work practices, such as handling and manipulating all slow-growing organisms in BSCs and not using MALDI-TOF MS for identification until BTAs have been ruled out.

Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial.

BACKGROUND: Patients with high-risk prostate cancer are at increased risk of lymph node metastasis and are thought to benefit from whole pelvis radiotherapy (WPRT). There has been recent interest in the use of hypofractionated radiotherapy in treating prostate cancer. However, toxicity and cancer outcomes associated with hypofractionated WPRT are unclear at this time. This phase II study aims to investigate the impact in quality of life associated with hypofractionated WPRT compared to conventionally fractionated WPRT. METHODS: Fifty-eight patients with unfavourable intermediate-, high- or very high-risk prostate cancer will be randomized in a 1:1 ratio between high-dose-rate brachytherapy (HDR-BT) + conventionally fractionated (45 Gy in 25 fractions) WPRT vs. HDR-BT + hypofractionated (25 Gy in 5 fractions) WPRT. Randomization will be performed with a permuted block design without stratification. The primary endpoint is late bowel toxicity and the secondary endpoints include acute and late urinary and sexual toxicity, acute bowel toxicity, biochemical failure-, androgen deprivation therapy-, metastasis- and prostate cancer-free survival of the hypofractionated arm compared to the conventionally fractionated arm. DISCUSSION: To our knowledge, this is the first study to compare hypofractionated WPRT to conventionally fractionated WPRT with HDR-BT boost. Hypofractionated WPRT is a more attractive and convenient treatment approach, and may become the new standard of care if demonstrated to be well-tolerated and effective. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04197141 on December 12, 2019.

Stereotactic Ablative Radiotherapy for Recurrent or Metastatic Gynecological Cancer: Extending Lives?

OPINION STATEMENT: Recent phase II clinical trials suggest that stereotactic ablative radiation therapy (SABR) can potentially improve survival for patients with oligometastatic cancer. However, these studies have mostly enrolled primaries other than gynecologic malignancies. While level I evidence is limited, recent publications exploring the use of SABR for oligometastatic gynecologic cancers have indicated a potential role for this treatment in para-aortic lymph node recurrences, and in visceral and brain metastases. The use of SABR for recurrences in the pelvis presents a number of challenges as these patients have often received previous radiation treatment. In these settings, care must be taken to avoid trespassing normal tissue tolerance with SABR leading to toxicity, especially as the potential benefit of SABR in this setting is not based on high-level evidence. Although SABR is feasible and in general safe for oligometastatic gynecologic malignancies, insufficient data are available to indicate whether it is associated with improved survival. Clinical judgment that incorporates patient and tumor factors is needed to determine if SABR is appropriate for selecting patients. Future directions include combining SABR with novel systemic therapies, determining optimal sequencing of treatments, and generating more robust randomized data pertaining to the use of SABR for oligometastatic gynecologic cancers.

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis.

OBJECTIVE: As the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation. METHODS: Retrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models. RESULTS: Post-operative management included observation (50%), chemotherapy and radiotherapy (RT) (27%), RT only (16%) and chemotherapy only (7%). The 178 RT patients received external beam (EBRT, 16%), vaginal vault brachytherapy (VVB, 56%) or both (28%). Among patients without any adjuvant treatment, 5-year local control (LC), disease free survival (DFS) and cancer-specific survival (CSS) were 82% (95% confidence interval: 74-88), 70% (62-78) and 90% (82-94), respectively. CSS in patients without adjuvant treatment was improved with adequate surgical staging (100% vs. 87% (77-92), log-rank p=0.022). Adjuvant VVB was associated with improved LC (5-year 96% (91-99) vs. 84% (76-89), log-rank p=0.007) and DFS (5-year 79% (66-88) vs. 71% (63-77), log-rank p=0.033). Adjuvant chemotherapy was associated with better LC (5-year 96% (90-98) vs. 84% (77-89), log-rank p=0.014) and DFS (5-year 84% (74-91) vs. 69% (61-76), log-rank p=0.009). On multivariable analysis, adjuvant chemotherapy and VVB were associated with improved LC while adjuvant chemotherapy and age were significant for DFS. CONCLUSIONS: In stage IA serous or clear cell uterine cancer, adjuvant RT and chemotherapy were associated with better LC and DFS. Observation may be appropriate in patients who have had adequate surgical staging.

Image-guided radiation therapy for post-operative gynaecologic cancer: patient set up verification with and without implanted fiducial markers.

BACKGROUND: Intensity modulated radiotherapy (IMRT) is increasingly being used to treat gynaecological malignancies in the postoperative setting. The purpose of this study was to evaluate the use of image-guided radiotherapy (IGRT) using cone-beam computed tomography (CBCT) with fiducial markers for daily localization. MATERIAL AND METHODS: A single institution study was performed of consecutive cervical or endometrial cancer patients receiving adjuvant external beam radiotherapy (n = 15). Patients were set up at treatment using daily CBCT and alignment of implanted fiducial markers. Image registration was retrospectively completed based on soft tissue matching and the resulting couch shifts from each IGRT method were compared (n = 122). RESULTS: The median shift between IGRT methods was 2 mm, 1 mm and 1 mm in the anterior-posterior (A-P), superior-inferior (S-I), and lateral directions, respectively. The largest deviations were observed in the A-P direction; however, more than 90% were within 5 mm and 63.9% were within 2.5 mm. CONCLUSIONS: IGRT based on soft tissue match provides a noninvasive convenient method for daily localization and is accurate within treatment uncertainty for the majority of cases.

A Population-Based Assessment of Urologic Procedures and Operations After Surgery or Pelvic Radiation for Cervical Cancer.

OBJECTIVE: The treatment of cervical cancer can result in genitourinary morbidity. We measured selected urologic procedures after the treatment of cervical cancer with either surgery or radiation. METHODS: We used administrative data from the province of Ontario Canada to identify adult women who had nonmetastatic cervical cancer and were treated with surgery or radiation between 1994 and 2014. Study outcomes were surgical or procedure codes representing ureteric repair or fistula repair. Stress incontinence surgery, minimally invasive urologic procedures, open bowel/bladder surgeries, and secondary malignancy were measured to compare between treatment modalities. Multivariable Cox proportional hazards models were used. RESULTS: Our final cohort consisted of 7311 women (median follow-up, 7.0 years [interquartile range, 2.9-13.3 years]), of which 3354 (44.9%) underwent radiation, and 3957 (54.1%) underwent surgery. After treatment of cervical cancer, ureteral repair was less common after surgery (3.4%) compared with radiation (10.3%) (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19-0.32). Fistula repair was uncommon (0.9%) and occurred significantly more often in the surgery and radiation group compared with the radiation-alone group (HR, 4.02; 95% CI, 1.80-9.00). Overall, stress incontinence surgery was uncommon (2.2%) but was significantly more likely after surgery versus radiation (HR, 3.73; 95% CI, 2.13-6.53). Minimally invasive urologic procedures were less common after surgery compared with radiation (HR, 0.49; 95% CI, 0.44-0.54). Open bowel/bladder surgeries were similar among treatment modalities, and secondary malignancy was less common after treatment with surgery versus radiation (HR, 0.60; 95% CI, 0.39-0.92; P = 0.02). CONCLUSIONS: Women treated for cervical cancer undergo ureteral stricture interventions at 0.8% per year over the 20 years after their treatment; this risk is higher among women who receive radiation treatment. Fistula repair is rare after cervical cancer.

Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1-3 metastases.

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32-59 % for FACT-Br and 0-16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.

Role of Adjuvant Therapy for Stage IA Serous and Clear Cell Uterine Cancer: Is Observation a Valid Strategy?

OBJECTIVES: The adjuvant treatment of early stage IA serous and clear cell carcinomas of the uterus is controversial. The aims of the study were to report on a single institution experience treating these high-risk early uterine cancers and to identify women who may be suitable for observation alone. METHODS AND MATERIALS: A retrospective review of patients presenting from 2003 to 2013 with pathologic stage IA (International Federation of Gynecology and Obstetrics 2009) serous or clear cell uterine carcinoma was performed. Patient and disease characteristics, surgical staging, treatment details, and recurrence data were collected. Recurrence rates and 5-year actuarial estimates of recurrence free survival (RFS) were the primary outcomes of interest. RESULTS: A total of 77 patients with stage IA were identified. Median (range) follow-up was 34 (1-108) months. Staging lymphadenectomy was performed in 83%. Adjuvant treatment was given to 27 patients, whereas 50 underwent observation. There were 12 recurrences total, with the 5-year RFS 79% for the cohort, with no statistically significant difference between observation and adjuvant treatment. Only 4 patients received adjuvant chemotherapy and none recurred. In the observation cohort, the presence versus absence of myometrial invasion showed a trend to poorer 5-year RFS (75% vs 93%, P = 0.06). CONCLUSIONS: Observation seems to be a valid strategy in those patients with stage IA serous and clear cell carcinoma without myometrial invasion. The presence of any myometrial invasion may confer a higher risk of recurrence, although further studies are needed to determine the optimal adjuvant treatment regimen.

An organizational guideline for gynecologic oncology services.

OBJECTIVES: Documented variations in practice compelled the need to establish a network that would facilitate the flow of patients through the care continuum of a provincial health care system in accordance with best practices. Therefore, a guideline was developed to provide recommendations for the optimal organization of gynecologic oncology services in this higher resource location to improve access to multidisciplinary care and appropriate treatment. METHODS: A systematic review was conducted of Web sites of international guideline developers, relevant cancer agencies, and Medline and EMBASE from 1996 to 2011 using search terms related to gynecologic malignancies, combined with organization of services, patterns of care, and various facility and physician characteristics. The results of the review were combined with expert consensus and stakeholder consultation to develop a gynecologic oncology services organizational guideline. RESULTS: The evidence review yielded a lower quality evidence base; therefore, recommendations were determined through consensus, including guidance for physician and hospital specialization, and other domains including human and physical resources. Definitive surgical treatment of most invasive cancers by subspecialist gynecologic oncologists is recommended. In addition, it is recommended that these subspecialists provide care within designated gynecologic oncology centers. The recommendations also outline which services, such as radiation therapy, may be provided in other affiliated centers. Multidisciplinary team management is also endorsed. CONCLUSIONS: These recommendations are intended to allow a collaborative community of practice, supported by formal interorganizational processes, to evolve to facilitate adherence to guidelines and best practices at a system-wide level.

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.

Adjuvant carboplatin and paclitaxel with "sandwich" method radiotherapy for stage III or IV endometrial cancer: long-term follow-up at a single-institution.

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.

Hypofractionated Radiotherapy in Gynecologic Malignancies-A Peek into the Upcoming Evidence.

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.

Deep learning-based ultrasound auto-segmentation of the prostate with brachytherapy implanted needles.

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.

Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-term Update of NRG/RTOG 9202.

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.