Clinical outcomes in borderline and locally advanced pancreatic cancer with the addition of low-dose-rate brachytherapy to standard of care therapy.

PURPOSE: Surgical resection remains the only curative therapy for pancreatic cancer. Unfortunately, many patients have borderline or unresectable disease at diagnosis due to proximity of major abdominal vessels. Neoadjuvant chemotherapy and radiation are used to down-stage, however, there is a risk that there will be a positive/close surgical margin. The CivaSheet is a low-dose-rate (LDR) brachytherapy device placed at the time of surgery to target the area of highest risk of margin positivity. The purpose of this study is to assess the clinical value of brachytherapy in addition to standard-of-care therapy in pancreatic therapy. METHODS AND MATERIALS: Between 2017 and 2022 patients with borderline and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and radiation followed by surgical resection were included. There were 2 cohorts of patients: (1) Those who had the LDR brachytherapy device placed at the time of surgery and (2) those who did not. Sixteen of 19 (84%) patients who had brachytherapy were enrolled in a prospective clinical trial (NCT02843945). Patients were matched for comorbidities, cancer staging, and treatment details. The primary outcome was progression-free survival (PFS). RESULTS: Thirty-five patients were included in this analysis, 19 in the LDR brachytherapy group and 16 in the comparison cohort. The 2-year PFS was 21% vs. 0% (p = 0.11), 2-year OS was 26% vs. 13% (p = 0.43), and the pancreatic cancer cause-specific survival was 84% vs. 56% (p = 0.13) in favor of the brachytherapy patients. CONCLUSIONS: Use of LDR brachytherapy at the time of resection shows a trend towards improved progression free and overall survival for patients with borderline or locally advanced pancreatic cancer treated with neoadjuvant chemoradiation.

Prognostic Effect of Mismatch Repair Status in Early-Stage Endometrial Cancer Treated With Adjuvant Radiation: A Multi-institutional Analysis.

PURPOSE: The aim of this work was to report the effect of mismatch repair (MMR) status on outcomes of patients with stage I-II endometrioid endometrial adenocarcinoma (EEC) who receive adjuvant radiation therapy. METHODS AND MATERIALS: This is a multi-institutional retrospective cohort study across 11 institutions in North America. Patients with known MMR status and stage I-II EEC status postsurgical staging were included. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated via the Kaplan-Meier method. Univariable and multivariable analyses were performed via Cox proportional hazard models for RFS and OS. Statistical analyses were conducted using SPSS version 27. RESULTS: In total, 744 patients with a median age at diagnosis of 65 years (IQR, 58-71) were included. Most patients were White (69.4%) and had Federation of Obstetrics and Gynecology 2009 stage I (84%) and Federation of Obstetrics and Gynecology grade 1 to 2 (73%). MMR deficiency was reported in 234 patients (31.5%), whereas 510 patients (68.5%) had preserved MMR. External beam radiation therapy with or without vaginal brachytherapy was delivered to 186 patients (25%), whereas 558 patients (75%) received vaginal brachytherapy alone. At a median follow-up of 43.5 months, the estimated crude OS and RFS rates for the entire cohort were 92.5% and 84%, respectively. MMR status was significantly correlated with RFS. RFS was inferior for MMR deficiency compared with preserved MMR (74.3% vs 88.6%, P < .001). However, no difference in OS was seen (90.8% vs 93.2%, P = .5). On multivariable analysis, MMR deficiency status was associated with worse RFS (hazard ratio, 1.86; P = .001) but not OS. CONCLUSIONS: MMR status was independently associated with RFS but not OS in patients with early-stage EEC who were treated with adjuvant radiation therapy. These findings suggest that differential approaches to surveillance and/or treatment based on MMR status could be warranted.

Utilizing a novel hybrid brachytherapy technique FINITO (Freehand Interstitial Needles in addition to Tandem and Ovoid) for locally advanced cervical cancer.

PURPOSE: We aimed to assess the clinical feasibility and advantages of using a novel hybrid brachytherapy technique by placing Freehand Interstitial Needles in addition to the Tandem and Ovoid applicator (FINITO) for the treatment of locally advanced cervical cancer (LAC). METHODS AND MATERIALS: A retrospective analysis was performed on two cohorts of patients with LACC treated at our institution: 29 patients in the FINITO group and 17 patients in the control group using T&O only approach. Clinical outcomes of interest included local control (LC), progression-free survival (PFS), overall survival (OS), and rates of acute and late toxicities. Kaplan-Meier methodology was used to estimate OS, PFS, and LC. Wilcoxon signed-rank test was used to compare the median values for dosimetry parameters. A p-value of ≤ 0.05 was considered statistically significant. All statistical analyses were performed using RStudio. RESULTS: At a median of 2 years there was no difference in rates of OS, PFS or LC between the FINITO and the control group of patients. The 2-year OS, PFS, and LC for the FINITO group were 59% (95% CI 34%-100%), 58% (95% CI 38%-89%), and 84% (95% CI 69%-100%), respectively. Late toxicities were significantly lower in the FINITO group for both gastrointestinal and genitourinary symptoms (p = 0.001 and 0.01, respectively) as compared to the T&O group. CONCLUSION: Based on the equivalent LC rate and lower toxicity profile, our FINITO technique appears to be an excellent alternative to the standard intracavitary brachytherapy in patients with advanced disease, especially in resource-limited settings.

PARP inhibitors in the treatment of ARID1A mutant ovarian clear cell cancer: PI3K/Akt1-dependent mechanism of synthetic lethality.

Introduction: Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme involved in the repair of DNA single-strand breaks (SSB). The recent development of poly(ADP-ribose) polymerase inhibitors (PARPi) results from over 45 years of studies. When the activity of PARP1 or PARP2 is compromised, DNA SSB lesions are unresolved and can be converted to DNA double-strand breaks (DSBs) by the cellular transcription mechanisms. ARID1A (also called BAF250a) is an important component of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex. ARID1A gene demonstrates >50% of mutation rate in ovarian clear-cell carcinomas (OCCC). Mutated or downregulated ARID1A significantly compromises the Homologous Recombination Repair (HRR) of DNA DSB. Results: The present study demonstrated that downregulated or mutated ARID1A attenuates DNA HRR through stimulation of the PI3K/Akt1 pathway and makes tumor cells highly sensitive to PARPi and PARPi/ionizing radiation (IR) combination. We showed that PI3K/Akt1 pathway plays an important role in the sensitization of cancer cell lines with compromised function of ARID1A to PARPi treatment. Discussion: We believe that using of PARPi monotherapy or in combination with radiation therapy is an appealing strategy for treating ARID1A-mutated cancers, as well as many other types of PI3K/Akt1-driven cancers.

Change in vaginal length and sexual function in women who undergo surgery ± radiation therapy for endometrial cancer.

PURPOSE: Endometrial Cancer (EC) is the most common gynecologic malignancy in the United States. Standard treatment is TAH/BSO with radiation therapy (RT) and chemotherapy given based on risk. Treatment can cause significant vaginal changes, including shortening, narrowing, loss of elasticity, atrophy, and dryness. These are not life threatening, but affect a woman's physical, psychological, and social functioning. Adjuvant vaginal dilator use is often advised, but there are inconsistent recommendations on use. This prospective study compared vaginal length changes and sexual function in women compliant with dilation versus not after surgery and RT. METHODS AND MATERIALS: Enrolled patients underwent surgery for Stage I-IIIC EC ±RT. Vaginal dilator use was recommended for women receiving RT (external beam or brachytherapy). Vaginal length was measured with a vaginal sound and the Female Sexual Function Index (FSFI) was used to assess sexual function. RESULTS: Forty-one enrolled patients had sufficient data for analysis. Dilation significantly increased FSFI scores (p = 0.02) while RT without dilation showed a significant decrease (p = 0.04). Dilation helped maintain vaginal length for all patients (0 cm vs. 1.8 cm loss (p = 0.03)). Individual arms did not show statistically significant changes in length with dilation, though the trend showed RT without dilation had an average loss of 2.3 cm as compared to only 0.2 cm for regular dilation. Notably, there was no difference in length change with dilation for surgery alone versus surgery and RT (p = 0.14). CONCLUSION: This data provides novel, prospective evidence of the benefit of vaginal dilation for maintaining vaginal length and improving sexual health after any pelvic treatment for EC. This evidence also supports that the addition of RT after surgery does not appear to significantly worsen vaginal shortening. This study has important implications for providing a strong foundation for future studies and helping to establish solid clinical management criteria for the prevention of vaginal stenosis and promotion of female sexual health.

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.

Sociodemographic and Clinical Factors Associated With Radiation Treatment Nonadherence and Survival Among Rural and Nonrural Patients With Cancer.

PURPOSE: Cancer treatment nonadherence is associated with higher rates of cancer recurrence and decreased survival. Rural patients with cancer experience a 10% higher mortality rate compared with their nonrural counterparts; geographic differences in nonadherence may contribute to this increased mortality. The goal of this study was to assess for geographic disparities and determine sociodemographic and clinical factors associated with radiation therapy (RT) nonadherence and survival among rural and nonrural patients with cancer. METHODS AND MATERIALS: We examined cancer registry, medical records, and billing claims data at a safety net academic medical center. Geographic residence was defined as rural versus nonrural by US Department of Agriculture 2013 Rural-Urban Continuum Codes. Other factors assessed were age, sex, race, marital status, insurance type, employment, area median household income, residential distance to cancer treatment center, clinical stage, cancer type, treatment modality, total radiation dose received, and radiation dose per fraction. We used Cox proportional hazards modeling to examine 7 ways of operationalizing nonadherence and selected the definition that resulted in the best model fit statistics and prediction of mortality. Overall survival rates were estimated with the Kaplan-Meier method. We then examined nonadherence as the main exposure along with additional covariates in least absolute shrinkage and selection operator penalized survival analyses and as the outcome in our multivariable generalized linear regression analyses predicting nonadherence. We considered 2-way interaction terms with the main exposure, geographic residence. RESULTS: We identified 3,077 patients with cancer who averaged 62 years old, were 59% female, 34% Black, and 14% rural. Twenty-two percent of patients missed at least 2 fractions and missed an average of 10% of their treatment plan. Rural patients experienced a higher mortality rate than nonrural patients (53% vs 42%, P < .0001). Survival was assessed through December 31, 2021, with a mean follow-up of 4.5 years. Proportion of missed fractions as the indicator of nonadherence provided the best model fit statistics and prediction of survival. Marital status, employment status, tumor, nodes, metastases stage, cancer type, and age at diagnosis significantly affected survival, in addition to a treatment delay by geographic residence interaction effect. Specifically, patients residing in rural areas who experienced a treatment delay were more than twice as likely to die as nonrural residents who also experienced a treatment delay, and nearly twice as likely to die as rural residents who did not experience a treatment delay. The 2-year survival rate was 76% for nonrural residents who did not experience a treatment delay versus 27% for rural residents who experienced a treatment delay. Patients who were widowed, had stage 4 cancer, or lung cancer were more likely to be nonadherent. Finally, patients residing in rural areas who experienced a treatment delay were more likely to subsequently be nonadherent. CONCLUSIONS: In a geographically and racially diverse population, RT nonadherence is a significant concern that affects survival, yet it is a modifiable risk factor. We demonstrated that rural residence was associated with both RT nonadherence and poorer overall survival. Rural patients with a treatment delay had the lowest overall survival, compared with both nonrural survivors and rural survivors without delay. Rural residents who are delayed in starting treatment are at heightened risk for poor outcomes and should receive targeted support to mitigate the observed disparities. Additional patient populations that may benefit from targeted treatment adherence support include widowed patients and those with stage 4 cancer or lung cancer.

Radiation Oncology Virtual Education Rotation (ROVER) 2.0 for Residents: Implementation and Outcomes.

The COVID-19 pandemic catalyzed the integration of a virtual education curriculum to support radiation oncologists in training. We report outcomes from Radiation Oncology Virtual Education Rotation (ROVER) 2.0, a supplementary virtual educational curriculum created for radiation oncology residents globally. A prospective cohort of residents completed surveys before and after the live virtual webinar sessions (pre- and post-surveys, respectively). Live sessions were structured as complex gray-zone cases across various core disease sites. Resident demographics and responses were summarized using means, standard deviations, and proportions. Nine ROVER sessions were held from October 2020 to June 2021. A total of 1487 registered residents completed the pre-survey, of which 786 attended the live case discussion and 223 completed post-surveys. A total of 479 unique radiation oncology residents (of which 95, n = 19.8%, were international attendees) from 147 institutions (national, n = 81, 55.1%; international, n = 66, 44.9%) participated in the sessions. There was similar participation across post-graduate year (PGY) 2 through 5 (range n = 86 to n = 105). Of the 122 unique resident post-surveys, nearly all reported learning through the virtual structure as "very easy" or "easy" (97.5%, n = 119). A majority rated the ROVER 2.0 educational sessions to be "valuable or "very valuable" (99.2%, n = 121), and the panelists-attendee interaction as "appropriate" (97.5%, n = 119). Virtual live didactics aimed at radiation oncology residents are feasible. These results suggest that the adoption of the ROVER 2.0 curricula may help improve radiation oncology resident education.

Investigation of Isotoxic Dose Escalation and Plan Quality with TDABC Analysis on a 0.35 T MR-Linac (MRL) System in Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy (MRgRT) for Primary Pancreatic Cancer.

This study investigates plan quality generated by an MR-Linac (MRL) treatment planning system (TPS) for 5-fraction stereotactic body radiation therapy (SBRT) of primary pancreatic cancer (PCa). In addition, an isotoxic dose escalation was investigated with the MRL TPS based on stereotactic MR-guided adaptive radiation therapy (SMART) trial constraints. A clinical workflow was developed for adaptive and non-adaptive treatments with the MRL, on which a time-driven activity-based costing (TDABC) analysis was performed to quantify clinical efficacy. Fifteen PCa patients previously treated with a conventional Linac were retrospectively re-planned for this study. Three plans were generated for each patient using the original prescription dose (PD) and organ at risk (OAR) constraints (Plan 1), following SMART trial's OAR constraints but with the original PD (Plan 2), starting with Plan 2, following an isotoxic dose escalation strategy where the dose was escalated until any one of the SMART trial's OAR constraints reached its limit (Plan 3). Conformity index (CI) and the ratio of the 50% isodose volume to PTV (R50%) conformity metrics were calculated for all 45 MRL plans, in addition to standard dose-volume indices. Forty-five MRL plans were created which met their respective dosimetric criteria described above. For Plan 1, the MRL TPS successfully achieved equivalent or lower OAR doses while maintaining the prescribed PTV coverage for the 15 plans. A maximum dose to the small bowel was reduced on average by 4.97 Gy (range: 1.11-10.58 Gy). For Plan 2, the MRL TPS successfully met all SMART trial OAR constraints while maintaining equivalent PTV coverage. For Plan 3, the MRL TPS was able to escalate the prescription dose from the original 25-33 Gy by, on average, 36 Gy (range: 15-70 Gy), and dose to the PTV was successfully escalated to at least 50 Gy for all 15 plans. These achievements were made possible, in part, due to the omission of the ITV afforded by the MRL's real-time target tracking technology and sharper dose penumbra due to its unique dual-focus MLC design. The 0.35T MRL TPS can generate plans that are equivalent to conventional Linac-based plans for SBRT of PCa. Through analyzing Plan 2 and 3 strategies, and due to the real-time target localization capabilities of the MRL system, increased OAR sparing and/or target dose escalation are possible.

Education in gynecological brachytherapy.

Brachytherapy is an essential component in the curative treatment of many gynecological malignancies. In the past decade, advances in magnetic resonance imaging and the ability to adapt and customize treatment with hybrid interstitial applicators have led to improved clinical outcomes with decreased toxicity. Unfortunately, there has been a shift in clinical practice away from the use of brachytherapy in the United States. The decline in brachytherapy is multifactorial, but includes both a lack of exposure to clinical cases and an absence of standardized brachytherapy training for residents. In other medical specialties, a clear relationship has been established between clinical case volumes and patient outcomes, especially for procedural-based medicine. In surgical residencies, simulation-based medical education (SBME) is a required component of the program to allow for some autonomy before operating on a patient. Within radiation oncology, there is limited but growing experience with SBME for training residents and faculty in gynecological brachytherapy. This review includes single institutional, multi-institutional and national initiatives using creative strategies to teach the components of gynecological brachytherapy. These efforts have measured success in various forms; the majority serve to improve the confidence of the learners, and many have also demonstrated improved competence from the training as well. The American Brachytherapy Society launched the 300 in 10 initiative in 2020 with a plan of training 30 competent brachytherapists per year over a 10 year period and has made great strides with a formal mentorship program as well as externships available to senior residents interested in starting brachytherapy programs. Moving forward, these curricula could be expanded to provide standardized brachytherapy training for all residents. SBME could also play a role in initial certification and maintenance of certification. Given the burden of disease, it would be valuable to develop similar training for providers in low and middle income countries.

CivaSheet intraoperative radiation therapy for pancreatic cancer.

The treatment of borderline resectable (BR) pancreatic cancer is challenging and requires a multidisciplinary approach with chemotherapy, radiation and surgical resection. Despite using chemotherapy and radiotherapy in the neoadjuvant setting, achievement of negative surgical margins remains technically challenging. Positive margins are associated with increased local recurrences and worse overall survival and there are no standard options for treatment. The CivaSheet is an FDA-cleared implantable sheet with a matrix of unidirectional planar low-dose-rate (LDR) Palladium-103 (Pd-103) sources. The sources are shielded on one side with gold to spare radio-sensitive structures such as the bowel. The sheet can easily be customized and implanted at the time of surgery when there is concern for close or positive margins. The CivaSheet provides an interesting solution to target the region of close/positive margins after pancreatectomy. Here we discuss the physical properties, the dosimetry, clinical workflow and early patient outcomes with the CivaSheet in pancreatic cancer.

Transarterial Chemoembolization with LC Bead LUMI followed by Stereotactic Body Radiation Therapy in Treatment of Hepatocellular Carcinoma.

PURPOSE: Transarterial chemoembolization (TACE) in combination with stereotactic body radiation therapy (SBRT) is a promising therapy for patients with hepatocellular carcinoma (HCC). A radiopaque drug-eluting embolic bead used during TACE, called LC Bead LUMI (Boston Scientific), was developed to allow improved visualization during TACE. The purpose of this case series is to assess the visibility of LUMI after TACE and discuss its potential use as an alignment tool for SBRT. METHODS: Fourteen patients with HCC (median age 69) received TACE using LUMI immediately followed by SBRT to 50 Gy in 5 fractions (13 patients) or 40 Gy in 5 fractions (1). Computed tomography (CT) simulation and cone beam CT (CBCT) images taken before each fraction were compared with immediate post-TACE imaging. Success of the LUMI bead opacification was graded from excellent to poor visualization. Patients were followed to assess target lesion response, disease control, survival, and the long-term visibility of LUMI beads. RESULTS: CBCT immediately after TACE with LUMI displayed excellent tumor visibility for 6 of 13 patients (46.2%), moderate tumor visibility for 4 patients (30.8%), and poor tumor visibility for 3 patients (23.1%). When comparing CBCTs used for SBRT image verification to post-TACE CBCT, 53.8% remained unchanged and 46.2% deteriorated from excellent to moderate or moderate to poor, but none deteriorated from excellent to poor visualization. Median follow-up was 13 months (range 2-35). On average, LUMI beads were visible on noncontrast CT up to 20 months after SBRT. CONCLUSIONS: LC Bead LUMI has the ability to provide liver tumor demarcation on noncontrast and cone beam CT weeks to months following TACE. It can serve as an alignment tool and could improve the therapeutic ratio in liver SBRT by allowing for tumor margin reduction with a potential decrease in the risk of toxicity when treating HCC in facilities without magnetic resonance imaging-linear accelerator.

Transitioning Roles from Residency to Attending Physician in Radiation Oncology.

Moving from the role of resident into that of a young attending is one of the most anticipated transitions in a medical trainee's career path. Radiation oncology residency training is typically apprentice-style focused in the outpatient setting, which carries additional unique challenges. Twenty-seven junior attendings at academic institutions within their first 5 years of practice were sent an online open-ended questionnaire in 2018 regarding aspects of their practice using a snowball sampling method. Responses were collected, and a thematic analysis was conducted in which two independent reviewers coded the responses. Nineteen junior attendings (70%) from 18 institutions completed the questionnaire. General themes included the importance of cultivating relationships for peer support and to be professional and polite as confidence was gained to enable them to be seen as an attending. All respondents felt that bringing an open mind, balance, and adaptability was crucial in their transition. Respondents stayed up to date on literature and practices by subscribing to journals, courses, and participation in resident education. Forty-two percent of young attendings were matched with a mentor at their new institution through a formal mentor-mentee relationship. Respondents wished that they had more autonomy during residency to prepare for independent practice. Transitioning from residency to a junior attending provides unique stressors and challenges. Allowing for residents to have more autonomy during their training, such as a senior resident clinic, may help improve this transition by providing an opportunity for independent decision-making with guidance as appropriate.

Radiation Oncology Education Collaborative Study Group Annual Spring Symposium: Initial Impact and Feedback.

The Radiation Oncology Education Collaborative Study Group (ROECSG) is an international collaborative network of radiation oncology (RO) professionals with the goal of improving RO education. This report summarizes the first two ROECSG annual symposia including an overview of presentations and analysis of participant feedback. One-day symposia were held in June 2018 and May 2019. Programs included oral and poster presentations, RO education leadership perspectives, and keynote addresses. Post-symposia surveys were collected. Research presentations were recorded and made available online. The 2018 symposium was had 36 attendees from 25 institutions in three countries. The 2019 symposium had 76 individuals from 41 institutions in five countries. Attendees represented diverse backgrounds including attending physicians (46%), residents (13%), medical students (14%), physicists (2%), nurses (1%), and program coordinators (1%). Fifty-five oral presentations were given with 53 released online. Ninety percent of attendees rated the symposium as improving their knowledge of RO educational scholarship, 98% felt the symposium provided the opportunity to receive feedback on RO education scholarship, and 99% felt that the symposium fostered the development of collaborative RO education projects. ROECSG was rated higher than professional organizations in fostering educational scholarship (p<0.001). All attendees felt that the symposium produced new RO education scholarship ideas and provided unique networking opportunities. The first two ROECSG symposia drew a diverse population of attendees and provided unique opportunities for presentation of RO education scholarship. Future ROECSG symposia will be designed to enhance opportunities to present RO education scholarship and to facilitate networking.