Design approach and benefits of the 3D-printed vaginal individualized applicator (VIA).

PURPOSE: Interstitial gynecologic brachytherapy necessitates precise needle placement, requiring time and expertise. We aimed to simplify interstitial procedures and facilitate optimal needle distribution with individualized vaginal templates to guide interstitial needles. MATERIALS/METHODS: We developed the 3D-printed vaginal individualized applicator (VIA), a cylindrical template containing individualized internal channels that guide interstitial needles to cover the tumor extent. Eight patients underwent VIA only interstitial implants (VIA only), and five intact cervical cases were treated using tandem and customized VIA (VIA + T). Procedure length, number of needles utilized and dosimetric measures were evaluated. RESULTS: VIA was successfully designed and used clinically for 24 procedures (8 VIA only, 16 VIA + T). Average procedure needle insertion time reduced from 80.9 min for traditional interstitial to 42.9 min for VIA only, approximately 47% shorter with a similar mean high risk CTV volume (28.3 cc VIA only vs. 32.4 cc) and excellent dosimetry with average CTV V100% (94.3% and 94.4%). VIA + T was particularly useful in patients with small vaginal canals and large tumor size. For the five VIA + T patients average tumor size was 68.0cc (range 26.6-143.5 cc). VIA + T procedures were approximately 20% shorter than hybrid procedures with other applicators with mean length of 20.1 min and an average of 6.8 needles (range 3-12). CONCLUSION: Our novel 3D-printed VIA facilitates gynecologic interstitial brachytherapy by simplifying needle placement, reducing procedure time, and maintaining excellent dosimetry. VIA can be customized for various clinical scenarios, particularly beneficial for large tumors or small vaginal canals.

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.

Development and clinical implementation of simple needle attachment post placement interstitial template (SNAPP-IT) enabling a shorter, more direct needle path while preserving tumor visualization.

PURPOSE: Historical gynecologic interstitial brachytherapy templates block direct tumor visualization during needle placement, presenting an opportunity for clinical innovation to develop a novel interstitial template allowing direct tumor visualization during needle insertion. METHODS AND MATERIALS: We designed and implemented a novel interstitial template, simple needle attachment post placement interstitial template (SNAPP-IT), that allowed direct visualization of the target vaginal tumor during interstitial needle placement while maintaining the ability to individually secure needles to the template, allow a vaginal cylinder, suture holes for securing to the perineum, MRI compatibility and sterilizable for repeat use. Procedure outcomes including procedure time, needle path lengths, and plan dosimetry were prospectively captured in a patient database. RESULTS: Forty gynecologic interstitial brachytherapy cases were recorded (20 SNAPP-IT, 20 traditional templates). Needle insertion depth was reduced using the SNAPP-IT in comparison with traditional interstitial templates (11.8 cm vs. 3.6 cm, p < 0.0001). The average CTV volume was 25.6 cc for SNAPP-IT and 20.7 cc for traditional; both methods averaged a similar number of needles (15.8, 15.6). Dosimetric constraints were similarly met in both treatment groups. Procedures performed using the SNAPP-IT were shorter compared with those performed with traditional interstitial devices (83.4 minutes vs. 100.7 minutes) and there were no post-operative infections in the SNAPP-IT group. CONCLUSIONS: Implementation of a novel gynecologic interstitial brachytherapy template (SNAPP-IT) reduced procedure times, allowed direct tumor visualization, and decreased needle insertion depth. SNAPP-IT provides a useful alternative approach for vaginal interstitial brachytherapy, may increase brachytherapist efficiency with complex procedures and potentially expands access to interstitial brachytherapy.

Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control.

OBJECTIVES: Emerging data suggests that abnormal (nuclear) ß-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal ß-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control. METHODS: We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with ß-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier. RESULTS: Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal ß-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal ß-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal ß-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal ß-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal ß-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03). CONCLUSION: Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal ß-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Developing Next-Generation 3-Dimensional Printing for Cervical Cancer Hybrid Brachytherapy: A Guided Interstitial Technique Enabling Improved Flexibility, Dosimetry, and Efficiency.

PURPOSE: We developed a 3-dimensionally (3D) printed tandem anchored radially guiding interstitial template (TARGIT) to increase the simplicity of intracavitary/interstitial technique for tandem-and-ovoid (T&O) procedures in cervical cancer brachytherapy. This study compared dosimetry and procedure logistics between T&O implants using the original TARGIT versus the next-generation TARGIT-Flexible-eXtended (TARGIT-FX) 3D-printed template designed for practice-changing ease-of-use with further simplified needle insertion and increased flexibility in needle placement. METHODS AND MATERIALS: This single-institution retrospective cohort study included patients undergoing T&O brachytherapy as part of definitive cervical cancer treatment. Procedures used the original TARGIT from November 2019 through February 2022 and the TARGIT-FX from March 2022 through November 2022. The FX design features full extension to the vaginal introitus with 9 needle channels and allows for needle additions or depth adjustments intraprocedure and after computed tomography/magnetic resonance imaging. RESULTS: A total of 148 implants were performed, 68 (46%) with TARGIT and 80 (54%) with TARGIT-FX, across 41 patients. Across implants, the TARGIT-FX achieved higher mean V100% (+2.8%, P = .0019), and across patients, the TARGIT-FX achieved higher D90 (+2.0 Gy, P = .037) and higher D98 (+2.7 Gy, P = .016) compared with the original TARGIT. Doses to organs at risk were overall similar between templates. Procedure times for TARGIT-FX implants were 30% shorter on average than for those using the original TARGIT (P < .0001), and 28% shorter on average for the subset of implants with high-risk clinical target volume ≥30 cc (P = .013). All residents (100%, N = 6) surveyed regarding the TARGIT-FX indicated ease-of-use for needle insertion and interest in applying the technique in future practice. CONCLUSIONS: The TARGIT-FX achieved shorter procedure times with increased tumor coverage and similar normal tissue sparing compared with the previously applied TARGIT and illustrates the potential of 3D printing to enhance efficiency and shorten the learning curve for intracavitary/interstitial procedure technique in cervical cancer brachytherapy.

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.

Executive summary of the American Radium Society appropriate use criteria for management of uterine clear cell and serous carcinomas.

BACKGROUND: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies. OBJECTIVE: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of current published literature from peer-reviewed journals. A well-established methodology (modified Delphi) was used to rate the appropriate use of diagnostic and therapeutic procedures for the management of uterine clear cell and serous carcinomas. RESULTS: The primary treatment for non-metastatic uterine clear cell and serous carcinomas is complete surgical staging, with total hysterectomy, salpingo-oophorectomy, omentectomy, and lymph node staging. Even in early-stage disease, patients with uterine clear cell and serous carcinomas have a worse prognosis than those with type I endometrial cancers, warranting consideration for adjuvant therapy regardless of the stage. Given the aggressive nature of these malignancies, and until further research determines the most appropriate adjuvant therapy, it may be reasonable to counsel patients about combined-modality treatment with systemic chemotherapy and radiotherapy. CONCLUSION: Patients diagnosed with uterine clear cell and serous carcinomas should undergo complete surgical staging. Multimodal adjuvant therapies should be considered in the treatment of both early-stage and advanced-stage disease. Further prospective studies or multi-institutional retrospective studies are warranted to determine optimal sequencing of therapy and appropriate management of patients based on their unique risk factors. Long-term surveillance is indicated due to the high risk of locoregional and distant recurrence.

Applying 3D-Printed Templates in High-Dose-Rate Brachytherapy for Cervix Cancer: Simplified Needle Insertion for Optimized Dosimetry.

PURPOSE: In cervical cancer brachytherapy, adding interstitial needles to intracavitary applicators can enhance dosimetry by improving target coverage while limiting normal tissue dose. However, its use is limited to a subset of practitioners with appropriate technical skill. We designed tandem anchored radially guiding interstitial templates (TARGITs) with a 3-dimensional (3D) printing workflow to optimize needle placement and facilitate greater ease-of-use of intracavitary/interstitial (IC/IS) technique. This study compared dosimetry and procedure characteristics between tandem and ovoid (T&O) implants using TARGIT technique versus non-TARGIT technique. METHODS AND MATERIALS: This single-institution retrospective cohort study included patients undergoing T&O brachytherapy as part of definitive radiation treatment for cervical cancer between February 2017 and January 2021. TARGIT technique was implemented from November 2019 onwards; all prior procedures involved non-TARGIT technique using a no needle or freehand needle approach. Target coverage, dose to organs at risk, and procedure times were evaluated and compared between TARGIT technique and non-TARGIT technique. RESULTS: The cohort included 70 patients with cervical cancer who underwent 302 T&O procedures: 68 (23%) with TARGIT technique and 234 (77%) with non-TARGIT technique, which included 133 no needle and 101 freehand needle implants. TARGIT implants involved longer average procedure times (+6.3 minutes, P < .0001). TARGIT implants achieved a higher mean high-risk clinical target volume V100% than non-TARGIT implants (+4.4%, P = .001), including for large tumors 30 cm3 or greater (+8.1%, P = .002). Average D90 was 4.6 Gy higher and average D98 was 3.2 Gy higher for TARGIT technique compared with non-TARGIT technique (P = .006 and P = .02). Total treatment doses to rectum, bowel, and bladder were not significantly different for TARGIT versus non-TARGIT technique. CONCLUSIONS: The 3D-printed TARGIT approach to T&O brachytherapy achieved greater tumor coverage while sparing normal tissues, particularly for large tumor volumes, with only a slight increase in average procedure time. TARGIT represents a creative technological solution for increasing accessibility of advanced IC/IS brachytherapy technique for cervical cancer definitive radiation treatment.

Imaging to optimize gynecological radiation oncology.

Gynecological cancers have particularly benefited from the increasing use of imaging to guide radiation treatment planning for both external beam radiation and brachytherapy. While the different gynecological cancers have varying use of imaging, certain trends predominate. CT represents an economical choice for evaluating initial disease extent or potential metastasis at follow-up, particularly for endometrial and ovarian cancers. F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is particularly useful for assessing the initial disease extent and longer term treatment response of squamous predominant cancers, including cervical, vaginal, and vulvar cancers. With its excellent pelvic soft tissue discrimination, MRI provides the greatest assistance in evaluating the local extent of gynecological tumors, including initial evaluation for non-operative endometrial and vulvar cancer, and assessment before, after and during brachytherapy for cervix, locally recurrent endometrial, and primary vaginal cancers. With more limited availability of MRI, ultrasound can also help guide brachytherapy, particularly during procedures. The benefits of using imaging to better spare bone marrow or earlier assessment of treatment response are topics still being explored, in particular for cervical cancer. As imaging along with radiation oncology technologies continue to evolve and develop, such as with MRI-linacs and ultra high dose rate (FLASH) radiation, we may continue to see increasing use of imaging for advancing gynecological radiation oncology.

Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience.

The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.

Comparison of survival, acute toxicities, and dose-volume parameters between intensity-modulated radiotherapy with or without internal target volume delineation method and three-dimensional conformal radiotherapy in cervical cancer patients: A retrospective and propensity score-matched analysis.

BACKGROUND: To evaluate whether the use of the internal target volume (ITV) delineation method improves the performance of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in terms of survival, acute toxicities, and dose-volume parameters. METHODS: A total number of 477 cervical cancer patients who received concurrent chemoradiotherapy (CCRT) from January 2012 to December 2016 were retrospectively analyzed. They were divided into four groups: the non-ITV (N-ITV) + IMRT, ITV + IMRT, N-ITV + 3DCRT, and ITV + 3DCRT groups, with 76, 41, 327, and 33 patients, respectively. Survival analysis was performed with the Kaplan-Meier and the log-rank tests, and acute toxicity analysis was performed with the chi-squared test and the binary logistic regression test. Using the propensity score matching (PSM) method, 92 patients were matched among the four groups, and their dose-volume parameters were assessed with the Kruskal-Wallis method. RESULTS: The median follow-up time was 49 months (1-119) for overall survival (OS). The 5-year OS rate was 66.4%. The ITV delineation method was an independent prognostic factor for OS (HR [95% CI]: 0.52 [0.27, 0.98], p = 0.044) and progression-free survival (PFS) (HR [95% CI]: 0.59 [0.36, 0.99], p = 0.045). The ITV + IMRT group had the lowest incidence rate (22%) and the N-ITV + IMRT group had the highest incidence rate of grade ≥3 hematological toxicity (HT) (46.1%) among the four groups. The pelvic bone marrow relative V10, V20, and V30 in the N-ITV + IMRT group was higher than those in the ITV + IMRT and N-ITV + 3DCRT groups (p < 0.05). CONCLUSIONS: The use of ITV for IMRT treatment planning was associated with improved overall survival and progression-free survival, with lower HT rate.

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

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

Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer.

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

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

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

Role of brachytherapy in stage III endometrial cancer treated with adjuvant chemotherapy: Identifying factors predictive of a survival benefit.

OBJECTIVES: To determine which patients with stage III endometrial cancer receiving adjuvant chemotherapy derive benefit from the addition of vaginal brachytherapy, as stage III is a highly heterogeneous population with substantial variations in practice. METHODS: Patients with FIGO stage III endometrial carcinoma diagnosed 2004-2016 who underwent at least total hysterectomy and adjuvant multiagent chemotherapy were identified in the National Cancer Database. The primary outcome was overall survival according to receipt of brachytherapy, stratified by histologic type, pathological features, and status of pelvic external beam radiotherapy (EBRT), and analyzed using the Kaplan-Meier method and Cox multivariable regression. RESULTS: In total, 9369 patients were identified (24% stage IIIA, 5% stage IIIB, 71% stage IIIC; 61% endometrioid, 39% nonendometrioid histology), and 28% received brachytherapy. In the endometrioid cohort, brachytherapy was associated with a 5% absolute increase in 3-year overall survival (87% vs. 82%, p < 0.0001), which persisted in multivariable analysis (adjusted hazard ratio 0.74, 95% confidence interval 0.64-0.84, p < 0.0001). The benefit of brachytherapy was greater in patients not also receiving EBRT, and in patients with vaginal/parametrial extension, grade 3 disease, lymphovascular invasion, and/or deep myometrial invasion. In the nonendometrioid cohort, brachytherapy was associated with a significant survival benefit in univariable but not multivariable analysis, regardless of EBRT status or pathological features. CONCLUSIONS: Factors predictive of brachytherapy benefit were endometrioid histology and pathological risk factors for local recurrence. Additionally, brachytherapy appeared more beneficial in patients not already receiving pelvic EBRT. Further research is warranted to determine which stage III patients may be best served by brachytherapy, EBRT, or both.

Intensity modulated Ir-192 brachytherapy using high-Z 3D printed applicators.

Gynecologic cancers are often asymmetric, yet current Ir-192 brachytherapy techniques provide only limited radial modulation of the dose. The shielded solutions investigated here solve this by providing the ability to modulate between highly asymmetric and radially symmetric dose distributions at a given location. To find applicator designs that can modulate between full dose and less than 50% dose, at the dimensions of the urethra, a 2D calculation algorithm was developed to narrow down the search space. Two shielding design types were then further investigated using Monte Carlo and Boltzmann-solver dose calculation algorithms. 3D printing techniques using ISO 10993 certified biocompatible plastics and 3D printable tungsten-loaded plastics were tested. It was also found that shadowing effects set by the shape of the shielding cannot be easily modulated out, hence careful design is required. The shielded applicator designs investigated here, allow for reduction of the dose by over 50% at 5 mm from the applicator surface in desired regions, while also allowing radially symmetric dose with isodose line deviations less than 0.5 mm from circular. The shielding designs were also chosen with treatment delivery time in mind. Treatment times for these shielded designs were found to be less than 1.4 times longer than a 6-channel unshielded cylinder for the equivalent fully symmetric dose distribution. The 2D calculation methods developed here provide a simple way to rapidly evaluate shielding designs, while the 3D printing techniques also allow for devices with novel shapes to be rapidly prototyped. Both TOPAS Monte Carlo and Acuros BV calculations show that significant dose shaping and organ at risk sparing can be achieved without significantly compromising the plan in regions that require the full dose.

Validated limited gene predictor for cervical cancer lymph node metastases.

PURPOSE: Recognizing the prognostic significance of lymph node (LN) involvement for cervical cancer, we aimed to identify genes that are differentially expressed in LN+ versus LN- cervical cancer and to potentially create a validated predictive gene signature for LN involvement. MATERIALS AND METHODS: Primary tumor biopsies were collected from 74 cervical cancer patients. RNA was extracted and RNA sequencing was performed. The samples were divided by institution into a training set (n = 57) and a testing set (n = 17). Differentially expressed genes were identified among the training cohort and used to train a Random Forest classifier. RESULTS: 22 genes showed > 1.5 fold difference in expression between the LN+ and LN- groups. Using forward selection 5 genes were identified and, based on the clinical knowledge of these genes and testing of the different combinations, a 2-gene Random Forest model of BIRC3 and CD300LG was developed. The classification accuracy of lymph node (LN) status on the test set was 88.2%, with an Area under the Receiver Operating Characteristic curve (ROC-AUC) of 98.6%. CONCLUSIONS: We identified a 2 gene Random Forest model of BIRC3 and CD300LG that predicted lymph node involvement in a validation cohort. This validated model, following testing in additional cohorts, could be used to create a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) tool that would be useful for helping to identify patients with LN involvement in resource-limited settings.

Parametric Response Mapping of Coregistered Positron Emission Tomography and Dynamic Contrast Enhanced Computed Tomography to Identify Radioresistant Subvolumes in Locally Advanced Cervical Cancer.

PURPOSE: To identify subvolumes that may predict treatment response to definitive concurrent chemoradiation therapy using parametric response mapping (PRM) of coregistered positron emission tomography (PET) and dynamic contrast-enhanced (DCE) computed tomography (CT) in locally advanced cervical carcinoma. METHODS AND MATERIALS: Pre- and midtreatment (after 23 ± 4 days of concurrent chemoradiation therapy) DCE CT and PET imaging were performed on 21 patients with cervical cancer who were enrolled in a pilot study to evaluate the prognostic value of CT perfusion for primary cervical cancer (NCT01805141). Three-dimensional coregistered maps of PET/CT standardized uptake value (SUV) and DCE CT blood flow (BF) were generated. PRM was performed using voxel-wise joint histogram analysis to classify voxels within the tumor as highly metabolic and perfused (SUVhiBFhi), highly metabolic and hypoxic (SUVhiBFlo), low metabolic activity and hypoxic (SUVloBFlo), or low metabolic activity and perfused (SUVloBFhi) tissue based on thresholds determined from population means of pretreatment PET SUV and DCE CT BF. Relationships between baseline pretreatment imaging metrics and relative changes in metabolic tumor volume (ΔMTV), calculated from before treatment and during treatment imaging, were determined using univariable and multivariable linear regression models. RESULTS: The relative volume of three PRM subvolumes significantly changed during treatment (SUVhiBFhi: P = .04; SUVhiBFlo: P = .0008; SUVloBFhi: P = .02), whereas SUVloBFlo did not (P = .9). Pretreatment PET SUVmax (r = -.58, P = .006), PET SUVmean (ρ = -.59, P = .005), DCE CT BFmean (r = -.50, P = .02), tumor volume (ρ = -.65, P = .001) and PRM SUVhiBFhi (ρ = -.59, P = .004) were negatively correlated with ΔMTV, whereas PRM SUVloBFlo was positively related to ΔMTV (r = .77, P < .0001). In a multivariable model that predicted ΔMTV, PRM SUVloBFlo, which combines both PET/CT and DCE CT, was the only significant variable (ß = 1.825, P = .03), dominating both imaging modalities independently. CONCLUSIONS: PRM was applied in locally advanced cervical carcinoma treated definitively with chemoradiation, and radioresistant subvolumes were identified that correlated with changes in MTV and predicted treatment response. Identification of these subvolumes may assist in clinical decision making to tailor therapies, such as brachytherapy, in an effort to improve patient outcomes.