Lara Hathout

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

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. 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. 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. 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.

The Prognostic Impact of MLH1 Promoter Hypermethylation in Stage I-II Endometrial Cancer Treated With Adjuvant Radiation Therapy: A Multi-Institutional Retrospective Study

To assess the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and define the patterns of recurrence in stage I or II endometroid endometrial cancer (EEC) treated with adjuvant radiation therapy. In a retrospective, institutional review board-approved, multi-institutional cohort study, 814 patients with stage I or II EEC with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1, or PMS2 mutations were classified as somatic deficient MMR (sdMMR), whereas tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazards. Statistical analyses were conducted using SPSS version 27. The median age at diagnosis was 65 years (IQR, 58-71), and most patients had grade 2 or 3 disease (59.2%), ≥50% myometrial invasion (56.0%), and absence of lymphovascular space invasion (58%). Vaginal brachytherapy was delivered to 643 (78.1%) patients, and 180 (21.9%) patients received external beam radiation (EBRT) ± vaginal brachytherapy (VBT). MMR was proficient in 550 (67.6%) patients and deficient in 264 (32.4%) patients. Of the patients with dMMR, most patients harbored MLH1ph (n = 171, 66%), and 93 patients (35.2%) had somatic dMMR. Tumor size ≥ 3.8 cm [hazard ratio (HR), 2.2; P = .003], MMR deficient versus proficient (HR, 2.7; P < .001), and EBRT ± VBT versus VBT alone (HR, 1.9; P = .032) were associated with decreased RFS on MVA. On subgroup analysis including patients with dMMR only, patients with MLH1ph had worse RFS compared with patients with sdMMR (HR, 1.9; 95% CI, 1.1-3.6; P = .025). Distant recurrence was the most common recurrence site, regardless of MMR status. Patients with MLH1ph had significantly higher proportion of vaginal (5% vs 0% vs 2%) and pelvic (5.3% vs 3.2% vs 0.5%) recurrences compared with sdMMR and pMMR, respectively (P = .038). Patients with MLH1ph had worse RFS, which may be attributed in part to a higher proportion of locoregional recurrences compared with the pMMR and sdMMR patients.

Can Immunotherapy Replace Radiation in Locally Advanced Endometrial Cancer?

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma

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 &gt;1 positive paraaortic lymph nodes compared with non-black patients (all P &lt;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 &lt;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.

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

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). 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. 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). 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.

Impact of the COVID-19 pandemic on brachytherapy and cancer patient outcomes: A systematic review

To assess the impact of the COVID-19 pandemic on the use of brachytherapy in patients with gynecologic and prostate cancers including treatment delays, increased burden of mortality, and associated clinical outcomes. A comprehensive search of PubMed, Cochrane Library, CINAHL, Scopus, and Web of Science was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases were searched for studies published through September 2023 using MeSH terms and keywords related to "COVID and brachytherapy." Inclusion criteria included all studies reporting on the impact of COVID-19 on treatment delay, treatment omission, recurrence rates, and clinical outcomes in patients requiring brachytherapy for prostate or gynecologic cancers from December 2019 to September 2023. Data were extracted by two independent reviewers (LH, IV). Of the 292 screened records, 10 studies (9 retrospective, 1 prospective single-arm exploratory noninferiority) were included. Hypofractioned regimens were the preferred approach in radiation treatment (RT) centers, with 6 of 10 studies noting shift towards hypofractionation. For cervical cancer, intracavitary brachytherapy was limited to 3-4 fractions, reducing personnel and patient exposure. Treatment delays influenced by COVID-19 ranged between 19% and 53% and treatment omissions ranged between 2% and 28%. These disruptions arose from factors such as patient fear of contracting COVID-19, COVID-19 infection, barriers to accessing care, and operating room closures. Three studies reported on a single-application (SA) rather than a multiple application (MA) approach for cervical cancer. They reported excellent local control, shorter overall treatment time at the expense of higher grade ≥2 vaginal, genitourinary, and gastrointestinal events. For cervical cancer patients, overall treatment time (OTT) was significantly impacted by COVID-19 as reported by 2 studies from India. OTT > 60 days occurred in 40-53% of patients. This is the first systematic review to assess the impact of the COVID-19 pandemic on brachytherapy in patients with gynecologic and prostate cancers. Although many expert consensus recommendations have been published during the pandemic regarding radiation therapy, few studies evaluated its clinical impact on brachytherapy delivery and patient outcomes. The COVID-19 pandemic resulted in treatment delays, omissions in brachytherapy, and further adoption of hypofractionated regimens. Early results demonstrate that despite increased toxicities, local control rates with hypofractionated treatment are similar to standard fractionation. The impact of the pandemic on gynecologic and prostate cancers is yet to be determined as well as the long-term outcomes on patients treated during the lockdown period.