Clinical outcomes of three vs four fractions of MRI-guided brachytherapy in cervical cancer.

PURPOSE: MRI-guided brachytherapy (MRgBT) is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr. METHODS AND MATERIALS: This retrospective study included 241 consecutive patients with FIGO 2018 stage IB-IVA cervical cancer treated with definitive chemoradiation between April 2014 - March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF) and G2+ gastrointestinal (GI), urinary (GU) and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using the Gray's test. RESULTS: Of the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow up of 3.2 (range 0.2-9.2) years, there were 14 local, 41 regional nodal and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr vs 28 Gy/4 Fr group in 3-year DFS (77% vs 68%, P = 0.21), 3-year cumulative incidence of LF (5% vs 7%, P = 0.57), DF (22% vs 25%, P = 0.86), G2+ GI toxicity (11% vs 20%, P = 0.13), or G2+ vaginal toxicity (14% vs 17%, P = 0.48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = 0.03). CONCLUSION: Cervical cancer patients treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI and vaginal toxicity rates, and a trend towards lower G2+ urinary toxicity rate compared to those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer.

Generalizability of deep learning in organ-at-risk segmentation: A transfer learning study in cervical brachytherapy.

PURPOSE: Deep learning can automate delineation in radiation therapy, reducing time and variability. Yet, its efficacy varies across different institutions, scanners, or settings, emphasizing the need for adaptable and robust models in clinical environments. Our study demonstrates the effectiveness of the transfer learning (TL) approach in enhancing the generalizability of deep learning models for auto-segmentation of organs-at-risk (OARs) in cervical brachytherapy. METHODS: A pre-trained model was developed using 120 scans with ring and tandem applicator on a 3T magnetic resonance (MR) scanner (RT3). Four OARs were segmented and evaluated. Segmentation performance was evaluated by Volumetric Dice Similarity Coefficient (vDSC), 95 % Hausdorff Distance (HD95), surface DSC, and Added Path Length (APL). The model was fine-tuned on three out-of-distribution target groups. Pre- and post-TL outcomes, and influence of number of fine-tuning scans, were compared. A model trained with one group (Single) and a model trained with all four groups (Mixed) were evaluated on both seen and unseen data distributions. RESULTS: TL enhanced segmentation accuracy across target groups, matching the pre-trained model's performance. The first five fine-tuning scans led to the most noticeable improvements, with performance plateauing with more data. TL outperformed training-from-scratch given the same training data. The Mixed model performed similarly to the Single model on RT3 scans but demonstrated superior performance on unseen data. CONCLUSIONS: TL can improve a model's generalizability for OAR segmentation in MR-guided cervical brachytherapy, requiring less fine-tuning data and reduced training time. These results provide a foundation for developing adaptable models to accommodate clinical settings.

Utilization and Impact of a Radiation Nursing Clinic to Address Acute Care Needs for Patients with Gynecologic Cancers.

BACKGROUND: The risk factors for acute care utilization in gynecologic oncology patients are poorly understood. This study aimed to evaluate risk factors for the utilization of our centre's acute care radiation nursing clinic (RNC) by gynecologic oncology patients receiving radiotherapy (RT). METHODS: This was a retrospective cohort study of gynecological cancer patients treated with RT at an academic cancer centre between 1 August 2021 and 31 January 2022. Data on socio-demographics, clinical and treatment characteristics, and RNC visits were collected and summarized by descriptive statistics. The Wilcoxon rank sum test and chi-squared test/Fisher's exact test were used for comparisons of continuous and categorical variables, respectively. RESULTS: RT was delivered to 180 patients, of whom 42 (23%) received concurrent chemoradiation (CCR). Compared to those receiving RT alone, patients receiving CCR had higher rates of RNC utilization (55% vs. 19%, p < 0.001). Within the CCR cohort, patients who presented to the RNC were more likely to be unpartnered (43% vs. 11%, p = 0.04), receive a referral to Psychosocial Oncology (39% vs. 5.3%, p = 0.01), and experience treatment interruptions (52% vs. 16%, p = 0.02). There were no associations between RNC visits and age, disease site, or distance from the cancer centre. CONCLUSIONS: The receipt of CCR and specific psychosocial risk factors were associated with increased RNC utilization. Targeted strategies and early intervention to better meet the supportive care and psychosocial needs of this vulnerable population are needed.

Review of brachytherapy clinical trials: a cross-sectional analysis of ClinicalTrials.gov.

INTRODUCTION: Characterizing the landscape of clinical trials including brachytherapy can provide an overview of the current status and research trends which may guide further areas of investigation. METHOD: We queried 449,849 clinical trials from the ClinicalTrials.gov registry using brachytherapy-related keywords from 1980 to 2023, yielding 245 multi-arm and 201 single-arm, brachytherapy trials. Multi-arm and single-arm brachytherapy trials were compared using 12 trial protocol elements. RESULTS: The number of trials including brachytherapy has increased over time, with over 60% of trials registered in 2010 onwards. The majority of clinical trials were Phase 2 or 3, evaluated both safety and efficacy, and were funded by academic sponsors. The most common tumor sites evaluated in brachytherapy clinical trials include prostate, cervix, liver, endometrium, and breast. CONCLUSION: There remains continued interest in clinical trials including brachytherapy focused on evaluation of novel delivery systems, treatment planning, and new indications. More brachytherapy clinical trials are needed to define the optimal clinical utilization and advance prospective research in this field.

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

PURPOSE: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). EXPERIMENTAL DESIGN: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). RESULTS: The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). CONCLUSIONS: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation.

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.

Updated Trends in Cervical Cancer Brachytherapy Utilization and Disparities in the United States From 2004 to 2020.

PURPOSE: Lower brachytherapy utilization for cervical cancer patients is associated with decreased survival. This study examines more recent trends in brachytherapy utilization from 2004 to 2020 to assess any trend reversal after awareness increased regarding the importance of brachytherapy. METHODS AND MATERIALS: This study analyzed data from the National Cancer Database of patients with Federation of Gynecology and Obstetrics (FIGO) IB to IVA cervical cancer treated with radiation therapy between 2004 and 2020. To compare brachytherapy utilization over time, 2- to 3-year categories were created to account for potential variation seen in individual years. A multivariate log binomial regression with robust variance was used to estimate the incidence rate ratio (IRR) of brachytherapy utilization in each year category in reference to the 2004-2006 category. Additionally, risk factors for brachytherapy utilization were identified. RESULTS: Overall brachytherapy utilization for cervical cancer increased from 54.9% in 2004 to 75.7% in 2020. Compared with 2004 to 2006 when rates of utilization totaled 55.2%, brachytherapy utilization significantly increased to 63.4% in 2011 to 2014 (IRR, 1.15; 95% CI, 1.11-1.19), 66.0% in 2015 to 2017 (1.20 [1.16-1.23]), and 76.0% in 2018 to 2020 (1.38 [1.34-1.42]). Sociodemographic factors associated with lower brachytherapy utilization included Black race (0.94 [0.92-0.97]), Hispanic ethnicity (0.92 [0.90-0.95]), and age >59 years (age ≥60-69: 0.96 [0.94-0.98]; age ≥70-79: 0.89 [0.87-0.92]; age ≥80: 0.73 [0.69-0.77]). Positive predictors of brachytherapy utilization included having insurance (IRR, 1.11; 95% CI, 1.07-1.14). CONCLUSIONS: In patients with FIGO IB-IVA cervical cancer treated with radiation therapy from 2004 to 2020, brachytherapy utilization has increased during the past decade. These results are encouraging given the known benefit to cause-specific survival and overall survival provided by brachytherapy treatment and indicate a reversal in the trend of declining brachytherapy noted previously. Concerns related to disparities by race, ethnicity, and insurance status require further interventions.

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer.

PURPOSE: Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. METHODS: This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. RESULTS: With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. CONCLUSION: Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Updated Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States: A Surveillance, Epidemiology, and End-Results Study.

PURPOSE: Our previous Surveillance, Epidemiology, and End Results (SEER) study revealed a concerning decline in brachytherapy utilization in the United States between 1988 and 2009. This study evaluates recent trends in brachytherapy utilization in cervical cancer and identifies factors and survival benefit associated with the use of brachytherapy treatment. METHODS AND MATERIALS: Using SEER data, 8500 patients with International Federation of Gynecologists and Obstetricians 2009 stage IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 2000 and 2020 were identified. Logistic regression analysis was performed on potential factors associated with brachytherapy use: age, marital status, race, ethnicity, income, metropolitan status, year of diagnosis, SEER region, histology, grade, and stage. To adjust for differences between patients who received brachytherapy and those who did not, propensity-score matching was used. Multivariable Cox regression analysis assessed the association of brachytherapy use with cervical cancer-specific mortality (CSM) and all-cause mortality (ACM) in the matched cohort. RESULTS: Sixty-four percent of the 8500 women received brachytherapy in combination with EBRT; 36% received EBRT alone. The brachytherapy utilization rate declined sharply in 2003/2004 (lowest rate 44% in 2003) and then gradually improved especially in 2018 to 2020 (76%). Factors associated with higher odds of brachytherapy use included younger age, married (vs single), later years of diagnosis, certain SEER regions, and earlier stage. In the propensity-score matched cohort, brachytherapy treatment was associated with lower 4-year cumulative incidence of cancer death (32.1% vs 43.4%; P < .001) and better overall survival (64.0% vs 51.4%; P < .001). Brachytherapy treatment was independently associated with lower CSM (hazard ratio, 0.70; 95% CI, 0.64-0.76; P < .001) and ACM (hazard ratio, 0.72; 95% CI, 0.67-0.78; P < .001). CONCLUSIONS: Brachytherapy utilization among SEER regions has improved since 2004 in patients with stage IB2-IVA cervical cancer. Brachytherapy use remains independently associated with significantly lower CSM and ACM and is an essential component of treatment for patients with locally advanced cervical cancer.

Stages I-III Inoperable Endometrial Carcinoma: A Retrospective Analysis by the Gynaecological Cancer GEC-ESTRO Working Group of Patients Treated with External Beam Irradiation and 3D-Image Guided Brachytherapy.

BACKGROUND/PURPOSE: Analyse the outcomes of stages I-III inoperable endometrial cancer (IEC) patients treated with external-beam-irradiation (EBRT) and 3D-image-guided-brachytherapy (IGBT). MATERIAL AND METHODS: Medical records of IEC patients receiving EBRT + IGBT in eight European and one Canadian centres (2004-2019) were examined, including: pelvic ± para-aortic EBRT and lymph node boost; anaesthetic procedure, applicators, BT-planning imaging, clinical target volume (CTV), brachytherapy schedule, and EQD2 to the CTV(α/ß=4.5Gy) and D2 cm3(α/ß=3Gy) for organs at risk. Complications are evaluated using CTCAEv4 scores. The 2- and 5-year survival probability according to stages was estimated (cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS)). STATISTICS: descriptive analysis and the Kaplan-Meier method. RESULTS: 103 patients (stages: I-44, II-14, III-44) were included. Median follow-up: 28 months (7-170). All patients received pelvic ± para-aortic EBRT. Median D90-EQD2(α/ß=4.5) to the CTV:73.3 Gy (44.6-132.7), 69.9 Gy (44.7-87.9 and 75.2 Gy (55.1-97) in stages I, II, and III, respectively. Thirty patients presented relapse (stages: 10-I, 3-II, 17-III): 24 uterine (stages: 7-I, 3-II, 14-III), 15 nodal (stages: 4-I, 1-II, 10-III), and 23 distant (stages: 6-I, 2-II, 15-III). Five year CSS was 71.2% (stages: 82%-I-II and 56%-III) and DFS, LRFS, LRRFS, and DMFS were 55.5%, 59%, 72%, and 67.2%, respectively. Late G3-G4 complications (crude): 1.3% small bowel, 2.5% rectum, and 5% bladder. CONCLUSION: In stages I-III of the IEC, EBRT + IGBT offer good 2- and 5-year CSS of 88.7% and 71.2%, respectively, with the best outcomes in stages I-II. Prospective studies are needed to determine how better outcomes can be achieved.

A two-center experience: The impact of COVID-19 on two brachytherapy programs in Ontario - virtual care, service suspension and radiation therapy workflow.

INTRODUCTION: Most brachytherapy (BT) procedures require general anesthesia and are therefore considered aerosol generating medical procedures (AGMPs). The COVID-19 pandemic impacted BT as services were prioritized by balancing the harm associated with COVID-19 infection versus the effect of delay of potentially curative treatment. This article summarizes the impact of the pandemic on BT programs in two cancer centers in a Canadian province. METHODS: As part of a quality assurance project, a retrospective study was conducted for the first five months of the pandemic (March 1 to July 31, 2020). Chart review and COVID-19 related mitigation strategies were identified by BT Clinical Specialist Radiation Therapists (bCSRT) in each center using electronic medical records, departmental reports, policies and procedures. RESULTS: Impact included start of virtual care (VC), shortened fractionation, suspension of services and workflow changes.  Both centers implemented VC strategies to reduce clinic visits: "same-day size and treat" strategy for post-operative endometrial cancer patients and virtual patient education for all patients. BT services that were suspended were low-dose-rate and high-dose-rate (HDR) prostate treatments (Center 1), lung and esophagus HDR treatments (Center 2).  Workflow changes that affected staff and patients in both centers included COVID-19 screening and the use of personal protective equipment. The centers were marginally different in workflow adjustments for AGMP procedures.  Those considered high-risk AGMP and low-risk cancer were suspended temporarily with alternate treatment strategies sought for some patients. Others had temporizing treatment such as androgen deprivation therapy to facilitate oncological safe deferral of procedures. CONCLUSION: Both BT programs delivered treatment to most patients with minimal delays and cancellations, where feasible. Some of the pandemic workflow changes continued to the current state of the pandemic. Long-term follow-up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer.

BACKGROUND: This study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy. MATERIALS AND METHODS: Patients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years). They were treated with standardized target and organ-at-risk (OAR) contouring, planning, and IG-IMRT. Radiotherapy dose, based on clinicopathologic features, ranged from 45 Gy to 63 Gy to gross targets and 27 Gy to 36 Gy to elective targets. Chemotherapy was concurrent 5-fluorouracil and mitomycin C (weeks 1&5). Toxicity was prospectively graded using NCI CTCAE v.3 and RTOG scales. Logistic regression was used to assess the association between dose/volume parameters (e.g small bowel V5) and corresponding grade 2 + and 3+ (G2+/3 + ) toxicities (e.g. diarrhea). RESULTS: In total, 87 and 79 patients were included in the acute and late toxicity analyses, respectively. The most common acute G2 + toxicities were skin (dermatitis in 87 % [inguino-genital skin], 91 % [perianal skin]) and hematologic in 58 %. G2 + late anal toxicity (sphincter dysfunction), gastrointestinal toxicity, and skin toxicity were respectively experienced by 49 %, 38 %, and 44 % of patients. Statistically significant associations were observed between: G2 + acute diarrhea and small bowel V35; G2 + acute genitourinary toxicity and bladder D0.5cc; G2 + inguino-genital skin toxicity and anterior skin V35; G2 + perianal skin toxicity and posterior skin V15; G2 + anemia and lower pelvis bone V45. D0.5 cc was significantly predictive of late toxicity (G2 + anal dysfunction, intestinal toxicity, and inguino-genital/perianal dermatitis). Maximum skin toxicity grade was significantly correlated with the requirement for a treatment break. CONCLUSION: Statistically significant dose-volume parameters were identified and may be used to offer individualized risk prediction and to inform treatment planning. Additional validation of the results is required.

Radiation Therapy for Endometrial Cancer: An American Society for Radiation Oncology Clinical Practice Guideline.

PURPOSE: With the results of several recently published clinical trials, this guideline informs on the use of adjuvant radiation therapy (RT) and systemic therapy in the treatment of endometrial cancer. Updated evidence-based recommendations provide indications for adjuvant RT and the associated techniques, the utilization and sequencing of adjuvant systemic therapies, and the effect of surgical staging techniques and molecular tumor profiling. METHODS: The American Society for Radiation Oncology convened a multidisciplinary task force to address 6 key questions that focused on the adjuvant management of patients with endometrial cancer. The key questions emphasized the (1) indications for adjuvant RT, (2) RT techniques, target volumes, dose fractionation, and treatment planning aims, (3) indications for systemic therapy, (4) sequencing of systemic therapy with RT, (5) effect of lymph node assessment on utilization of adjuvant therapy, and (6) effect of molecular tumor profiling on utilization of adjuvant therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for quality of evidence grading and strength of recommendation. RESULTS: The task force recommends RT (either vaginal brachytherapy or external beam RT) be given based on the patient's clinical-pathologic risk factors to reduce risk of vaginal and/or pelvic recurrence. When external beam RT is delivered, intensity modulated RT with daily image guided RT is recommended to reduce acute and late toxicity. Chemotherapy is recommended for patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to II with high-risk histologies and those with FIGO stage III to IVA with any histology. When sequencing chemotherapy and RT, there is no prospective data to support an optimal sequence. Sentinel lymph node mapping is recommended over pelvic lymphadenectomy for surgical nodal staging. Data on sentinel lymph node pathologic ultrastaging status supports that patients with isolated tumor cells be treated as node negative and adjuvant therapy based on uterine risk factors and patients with micrometastases be treated as node positive. The available data on molecular characterization of endometrial cancer are compelling and should be increasingly considered when making recommendations for adjuvant therapy. CONCLUSIONS: These recommendations guide evidence-based best clinical practices on the use of adjuvant therapy for endometrial cancer.

GEC-ESTRO (ACROP)-ABS-CBG Consensus Brachytherapy Target Definition Guidelines for Recurrent Endometrial and Cervical Tumors in the Vagina.

PURPOSE: Representatives from the Gynecologic Groupe European de Curietherapie-European Society for Radiation Therapy and Oncology (GYN GEC-ESTRO), the American Brachytherapy Society (ABS), and the Canadian Brachytherapy Group (CBG) met to develop international consensus recommendations for target definitions for image-guided adaptive brachytherapy for vaginal recurrences of endometrial or cervical cancer. METHODS AND MATERIALS: Seventeen radiation oncologists and 2 medical physicists participated. Before an in-person meeting each participant anonymously contoured 3 recurrent endometrial/cervical cancer cases. Participants contoured the residual gross primary tumor volume (GTV-Tres), a high-risk clinical target volume (CTV-THR), and an intermediate-risk clinical target volume (CTV-TIR), on T2-weighted magnetic resonance images (MRIs). All contours were drawn using Falcon EduCase. Contours were reviewed at an in-person meeting during which a consensus document was created defining agreed-upon target definitions (Trial 1). After establishing these definitions, the group was sent one of the cases again (recurrent cervical cancer vaginal recurrence) and asked to contour the targets again (Trial 2). The Computerized Environment for Radiation Research (CERR) software (The Mathworks, Natwick, MA) was used to analyze the contours. Kappa statistics were generated to assess level of agreement between contours. A conformity index (CI), defined as the ratio between the intersection and union volume of a given pair of contours, was calculated. A simultaneous truth and performance level estimation (STAPLE) contour was created for the CTV-THR and CTV-TIR for the postmeeting case. RESULTS: Consensus definitions for GTV-Tres, CTV-THR, and CTV-TIR were established. Kappa statistics (Trial 1/Trial 2) for GTV-Tres, CTV-THR, and CTV-TIR were 0.536/0.583, 0.575/0.743 and 0.522/0.707. Kappa statistics for Trial 2 for the CTV-THR and CTV-TIR showed "substantial" agreement while the GTV-Tres remained at moderate agreement. CONCLUSIONS: This consensus provides recommendations to facilitate future collaborations for MRI-guided adaptive brachytherapy target definitions in endometrial/cervical vaginal recurrences.

A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer.

PURPOSE: Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT. PATIENTS AND METHODS: A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic. RESULTS: Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%-34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%-33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09). CONCLUSIONS: Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233.

Quality-of-Life Outcomes and Toxic Effects Among Patients With Cancers of the Uterus Treated With Stereotactic Pelvic Adjuvant Radiation Therapy: The SPARTACUS Phase 1/2 Nonrandomized Controlled Trial.

Importance: Adjuvant radiation plays an important role in reducing locoregional recurrence in patients with uterine cancer. Although hypofractionated radiotherapy may benefit health care systems and the global community while decreasing treatment burden for patients traveling for daily radiotherapy, it has not been studied prospectively nor in randomized trials for treatment of uterine cancers, and the associated toxic effects and patient quality of life are unknown. Objective: To evaluate acute genitourinary and bowel toxic effects and patient-reported outcomes following stereotactic hypofractionated adjuvant radiation to the pelvis for treatment of uterine cancer. Design, Setting, and Participants: The Stereotactic Pelvic Adjuvant Radiation Therapy in Cancers of the Uterus (SPARTACUS) phase 1/2 nonrandomized controlled trial of patients accrued between May 2019 and August 2021 was conducted as a multicenter trial at 2 cancer centers in Ontario, Canada. In total, 61 patients with uterine cancer stages I through III after surgery entered the study. Interventions: Stereotactic adjuvant pelvic radiation to a dose of 30 Gy in 5 fractions administered every other day or once weekly. Main Outcomes and Measures: Assessments of toxic effects and patient-reported quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and endometrial EN24) were collected at baseline, fractions 3 and 5, and at 6 weeks and 3 months of follow-up. Descriptive analysis was conducted, calculating means, SDs, medians, IQRs, and ranges for continuous variables and proportions for categorical variables. Univariate generalized linear mixed models were generated for repeated measurements on the quality-of-life scales. Results: A total of 61 patients were enrolled (median age, 66 years; range, 51-88 years). Tumor histologic results included 39 endometrioid adenocarcinoma, 15 serous or clear cell, 3 carcinosarcoma, and 4 dedifferentiated. Sixteen patients received sequential chemotherapy, and 9 received additional vault brachytherapy. Median follow-up was 9 months (IQR, 3-15 months). Of 61 patients, worst acute gastrointestinal tract toxic effects of grade 1 were observed in 33 patients (54%) and of grade 2 in 8 patients (13%). For genitourinary worst toxic effects, grade 1 was observed in 25 patients (41%) and grade 2 in 2 patients (3%). One patient (1.6%) had an acute grade 3 gastrointestinal tract toxic effect of diarrhea at fraction 5 that resolved at follow-up. Only patient-reported diarrhea scores were both clinically (scores ≥10) and statistically significantly worse at fraction 5 (mean [SD] score, 35.76 [26.34]) compared with baseline (mean [SD] score, 6.56 [13.36]; P < .001), but this symptom improved at follow-up. Conclusions and Relevance: Results of this phase 1/2 nonrandomized controlled trial suggest that stereotactic hypofractionated radiation was well tolerated at short-term follow-up for treatment of uterine cancer. Longer follow-up and future randomized studies are needed to further evaluate this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04866394.

Postoperative management of vulvar cancer.

The primary treatment for resectable vulvar cancer includes wide local excision of the primary tumor and surgical lymph node assessment. Following surgery, up to 40-50% of patients develop a local recurrence. Historically, the strongest predictor of local recurrence is a positive or close margin (defined as <8 mm), although recent studies question the importance of margin status. Post-operative radiotherapy to the vulva is recommended for all women with a positive margin where re-excision is not possible. Radiotherapy may also be considered in the setting of risk factors for local recurrence: close margin, lymphovascular invasion, large tumor size, and/or depth of invasion >5 mm. Nodal assessment is an important component of vulvar cancer management. A negative sentinel node is associated with a low false-negative predictive value (2% in patients with vulvar tumor <4 cm in GOG 173), 2-year groin recurrence rate of 2.3%, and 3-year disease-specific survival rate of 97% in patients with unifocal vulvar tumor <4 cm in the GROningen INternational Study on Sentinel nodes in Vulvar Cancer (GROINSS-V I) study. Thus, patients with tumor size <4 cm (without additional local risk factors) and negative sentinel node can be observed. Patients with sentinel node metastasis ≤2 mm can be treated with post-operative radiotherapy (2-year isolated groin recurrence rate of 1.6% in GROINSS-V II), as a safe alternative to lymphadenectomy. Patients with sentinel node metastasis >2 mm following sentinel node biopsy should undergo inguinofemoral lymphadenectomy followed by post-operative radiotherapy-based on the GROINSS-V II study, the 2-year isolated groin recurrence rate remains unacceptably high (22%) with radiotherapy alone. Retrospective studies suggest that the addition of concurrent chemotherapy to radiotherapy may improve survival. The ongoing GROINSS-V III study is investigating concurrent chemotherapy and radiotherapy dose escalation. The main goal of these post-operative treatments is to reduce the risk of local, and especially groin, recurrences, which are almost universally fatal.