Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

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.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

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.

Implementing a simulation-based curriculum for hybrid intracavitary/interstitial brachytherapy using a new, commercially available, US/MR/CT-compatible gynecologic phantom.

PURPOSE: To establish a simulation-based workshop for teaching hybrid intracavitary/interstitial (IC/IS) brachytherapy skills using a new, commercially available US/CT/MRI-compatible gynecologic phantom prototype. METHODS AND MATERIALS: The VIOMERSE gynecological trainer phantom consisted of tissue-like colloid material and was US, CT, and MRI-compatible. We designed a hands-on workshop incorporating the phantom prototype to teach skills for hybrid IC/IS brachytherapy including pre-implant planning, procedural steps of implant placement, and post-implant evaluation. The workshop impact was evaluated with pre- and post-workshop surveys and responses were analyzed with Wilcoxon matched-pairs signed-rank test. RESULTS: Thirteen residents, divided into small groups, attended one of three separate 1-h workshop sessions held during the gynecologic education block. Workshop steps included IC applicator placement, tumor mapping and pre-planning desired location and depth of needles for hybrid IC/IS application, IS needle labelling and insertion, image review of needle placements, comparison of IC-alone versus IC/IS brachytherapy plans. Responses to questions ascertaining knowledge, confidence, and ability in planning and executing hybrid IC/IS procedures all demonstrated significant improvement from pre- to post-workshop. In response to whether the session was an effective learning experience, all residents rated the workshop with a score of 9 (n = 1) or 10 (n = 12) out of 10, with a score of 10 indicating "strongly agree." CONCLUSIONS: Implementation of a hybrid IC/IS brachytherapy workshop utilizing a new, commercially-available phantom prototype was successful, with clear, subjective benefit for the residents in our program. This experience may inform continued efforts towards standardizing brachytherapy curricula across programs and increasing trainee exposure to interstitial procedures.

Brachytherapy impacts on sexual function: An integrative review of the literature focusing on cervical cancer.

There is growing awareness of the importance of sexual health in the quality of life of cancer patients and survivors. Brachytherapy, a vital component for the curative treatment of cervical cancer, leads to both direct and indirect sequelae that result in vaginal and sexual morbidity. The emergence of 3D image-guided adaptive brachytherapy has led to a better understanding of dose-and-effect relationships for critical organs-at-risk and there are new recommendations for vaginal dose reporting in the ongoing EMBRACE II study. An understanding of the vagina as an organ-at-risk and its dose-and-effect relationships can help brachytherapists limit dose to the vagina and improve sexual morbidity. Brachytherapists play a critical role in the primary and secondary prevention of vaginal and sexual sequelae resulting from treatment. Through close surveillance and recognition of common symptoms, brachytherapists can intervene with effective strategies to prevent and treat vaginal and sexual symptoms. This review summarizes the current literature on dosimetric factors that may predict for vaginal morbidity. It will focus on quantitative and qualitative reports of brachytherapy-related vaginal toxicity and sexual dysfunction. Lastly, it will review the available evidence supporting clinical interventions to mitigate the development and progression of vaginal and sexual sequelae to improve functional quality post-treatment.

Declining use of inguinofemoral lymphadenectomy in the treatment of clinically negative, pathologic node positive vulvar cancer.

PURPOSE: The management of vulvar cancer with clinically negative groin lymph nodes but with positive sentinel lymph node biopsy (SLNB) is controversial, with options including inguinofemoral lymphadenectomy (IFL) and/or adjuvant chemotherapy and radiotherapy. We used the National Cancer Database (NCDB) to examine trends in the management of clinically node negative, pathologically node positive (cN-/pN+) patients. METHODS: The NCDB was used to identify cN-/pN+ vulvar cancer patients. Demographic and clinical data were compared with chi-squared and Wilcoxon rank-sum tests. OS was analyzed with the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to determine factors associated with OS. RESULTS: A total of 885 cN-/pN+ vulvar cancer patients were identified between 2012 and 2016, during which the rate of SLNB alone increased from 3.6% to 11.7%, while the rate of IFL +/- SLNB decreased from 89.7% to 78.1% (p < 0.05). Radiation was used in 68.5% and 64.6% of the SLNB-alone and IFL +/- SLNB cohorts, respectively, with chemoradiation in 37.1% and 33.6%, respectively. OS was not different between patients who received SLNB-alone vs. IFL +/- SLNB (p = 0.644). Receipt of chemotherapy and radiation was associated with improved OS (p < 0.001). CONCLUSIONS: Among cN-/pN+ vulvar cancer patients in the NCDB, the practice of performing IFL decreased over time as SLNB-alone became more common and the majority received radiation +/- chemotherapy. There was no difference in OS between SLNB-alone vs. IFL +/- SLNB. Patients treated with adjuvant chemoradiation had improved survival. Whether the favorable outcomes in the SLNB-alone cohort may be attributed to radiotherapy dose escalation or use of chemotherapy warrants further study.

Single application hybrid interstitial brachytherapy for cervical cancer: an institutional approach during the COVID-19 pandemic.

PURPOSE: To ease anesthesia and inpatient strain during the COVID-19 pandemic, our institution's policy for hybrid intracavitary-interstitial brachytherapy (IC/ISBT) for cervical cancer (CC) was modified from multiple applications (MA) treated over 2 separate weeks (7 Gy × 4) to a single-application (SA), treated within 1 week (8 Gy × 3). Here, we assessed dosimetric quality of the SA hybrid IC/ISBT approach and report our early outcomes. MATERIAL AND METHODS: This was an IRB-approved retrospective review of CC patients treated with magnetic resonance imaging (MRI)-guided hybrid IC/ISBT between April 1, 2020 and December 31, 2020 (COVID cohort). Treatment parameters and quality indicators were compared to hybrid IC/ISBT cases treated in 2 years prior (pre-COVID cohort). Differences between cohorts were evaluated with the Mann-Whitney U-test. RESULTS: In the COVID compared to pre-COVID cohort, median high-risk clinical target volume (HR-CTV) was similar: 33.3 vs. 33.9 cc, as was cumulative HR-CTV D90%: 81.2 vs. 80.9 Gy. Organ-at-risk D2cc values and recto-vaginal point doses were similar. Median number of channels loaded was increased to 6 vs. 4 (p = 0.002), but percentage of total dwell time allocated to needles remained similar: 13% vs. 15%. Median implant HR-CTV D90% was higher: 107.8% vs. 98.4% (p = 0.001), and there was a trend toward reduced overall treatment time (OTT): 44 days vs. 53 days (p = 0.1). Local control was achieved in all patients, but mucosal toxicity was higher in the COVID group, with grade 2 or higher vaginal, genitourinary, or gastrointestinal events recorded in 56% of the patients. CONCLUSIONS: The SA hybrid IC/ISBT approach utilized during the COVID-19 pandemic maintained similar plan characteristics as pre-pandemic MA hybrid cases, while simultaneously reducing anesthesia, inpatient resources, and OTT. Local control outcomes demonstrate the regimen was effective; however, given the increased risk of mucosal toxicity, we conclude that the SA regimen should be considered only when a MA schedule is not feasible.

Radiation therapy in the definitive management of medically inoperable endometrial cancer.

The incidence of endometrial cancer continues to increase worldwide with growing life expectancy and rates of obesity. While endometrial cancer is primarily a surgical disease managed with hysterectomy, a small proportion of patients are deemed to be poor surgical candidates due to their co-morbidities. These medically inoperable patients should be considered for curative treatment with definitive radiation therapy, and brachytherapy is an integral component of their care. Referral to a high-volume center early on in the care of potentially inoperable patients is crucial to optimize their management. These patients should be evaluated by a high-risk surgical and anesthesia team to confirm their medical inoperability. For inoperable patients, use of image-guided brachytherapy is encouraged. Brachytherapy applicator selection is determined based on a patient's anatomy, uterine size, and extent of tumor. Advances in anatomic and functional imaging including multiparametric magnetic resonance imaging (MRI) have improved clinical staging of these patients and have also allowed for the delivery of three-dimensional image-guided brachytherapy with improved accuracy. With recent consensus guidelines to guide local computed tomography and/or MRI volume-based delineation of targets and organs-at-risk, local outcomes have improved and treatments are delivered with less acute and late morbidity. Ongoing trials are looking at novel systemic agents, such as immunotherapy, to induce a systemic anti-tumor immune response and improve outcomes in these patients.

Dosimetric study of Varian Universal Multi-Channel Cylinder System for High-Dose-Rate 192Ir Brachytherapy.

PURPOSE: Recently, the Varian multichannel vaginal cylinder (MCVC) set for high-dose-rate 192Ir brachytherapy was commercially released. This MCVC was distinct from our existing MCVC in its peripheral channel layout and tip design. This investigation sought to assess the dosimetric impact of these changes. METHODS AND MATERIALS: The dimensions of the virtual model for each applicator were compared against both physical and radiographic measurements. Volumetric dose distributions were generated in silico using a model-based dose calculation algorithm (MBDCA). To characterize the effects of the new peripheral channel layout on dose to adjacent areas ("dose-spill"), point doses were compared using two sets of applicator-based reference points: at surface or 5 mm radially from surface. To evaluate the dose-shaping capabilities, a dose distribution was generated for the new applicator and assessed against a representative dose distribution for a patient previously treated with existing equipment. RESULTS: Based on both physical and radiographic measurements, virtual models were representative of each applicator within ±1 mm. Commissioning of the MBDCA was benchmarked based on AAPM Working Group on Dose Calculation Algorithms in Brachytherapy. The layout of the new applicator reduced dose-spill to other reference points significantly, as much as a factor of 16.3, compared with the existing equipment. The rounded tip shape and curve of the peripheral channels in the new applicator produced more conformity to its HR-CTV than existing equipment. CONCLUSIONS: Compared with our existing equipment, the design changes in the new Varian MCVC set offered improved control of dose spill and better conformality to HR-CTV.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

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.

An evaluation of prognostic factors, oncologic outcomes, and management for primary and recurrent squamous cell carcinoma of the vulva.

OBJECTIVE: To evaluate prognostic factors, outcomes, and management patterns of patients treated for squamous cell carcinoma of the vulva. METHODS: One hundred sixty-four women were retrospectively identified with primary squamous cell carcinoma of the vulva treated at our institution between 1/1996-12/2018. Descriptive statistics were performed on patient, tumor, and treatment characteristics. The χ² tests and t-tests were used to compare categorical variables and continuous variables, respectively. Recurrence free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. RESULTS: Median follow-up was 52.5 months. Five-year RFS was 67.9%, 60.0%, 42.1%, and 20.0% for stage I-IV, respectively. Five-year DSS was 86.2%, 81.6%, 65.0%, and 42.9% for stage I-IV, respectively. On multivariate analysis, positive margins predicted overall RFS (hazard ratio [HR]=3.55; 95% confidence interval [CI]=1.18-10.73; p=0.025), while presence of lichen sclerosus on pathology (HR=2.78; 95% CI=1.30-5.91; p=0.008) predicted local RFS. OS was predicted by nodal involvement (HR=2.51; 95% CI=1.02-6.13; p=0.043) and positive margins (HR=5.19; 95% CI=2.03-13.26; p=0.001). Adjuvant radiotherapy significantly improved RFS (p=0.016) and DSS (p=0.012) in node-positive patients. Median survival after treatment of local, groin, and pelvic/distant recurrence was 52, 8, and 5 months, respectively. CONCLUSION: For primary treatment, more conservative surgical approaches can be considered with escalation of treatment in patients with concurrent precursor lesions, positive margins, and/or nodal involvement. Further studies are warranted to improve risk stratification in order to optimize treatment paradigms for vulvar cancer patients.

Prognostic impact of mismatch repair deficiency in high- and low-intermediate-risk, early-stage endometrial cancer following vaginal brachytherapy.

OBJECTIVES: To examine the impact of mismatch repair (MMR) status on prognosis among patients with high- and low-intermediate-risk endometrioid endometrial cancer (EEC) treated with vaginal brachytherapy (VBT). MATERIALS/METHODS: 198 stage I-II EEC patients with known MMR status treated with adjuvant VBT were identified. Both low-intermediate (LIR) and high-intermediate-risk (HIR) patients were included. Clinical characteristics were compared between patients with proficient and deficient mismatch repair (pMMR and dMMR) using Fisher's exact tests for categorical variables and t-tests for continuous variables. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression. RESULTS: Patients with dMMR compared to pMMR were more likely to have grade 2-3 tumors (75% vs. 57%, p = 0.006), lympho-vascular invasion (40% vs. 25%, p = 0.034), and HIR classification (65% vs. 49%, p = 0.011). Three-year RFS was inferior for dMMR compared to pMMR patients (75% vs. 96%, p = 0.001). dMMR patients compared to pMMR had similarly reduced 3-year RFS within the LIR (74% vs. 100%, p = 0.026) and HIR (75% vs. 91%, p = 0.038) subgroups. Three-year OS was not different between dMMR/pMMR patients (98% vs. 97%, p = 0.653) or HIR/LIR patients (97% vs. 97%, p = 0.999). On multivariable Cox regression, dMMR status was a significant prognostic variable for RFS (HR 3.774, CI 1.495-9.526, p = 0.005), though it was not significant for OS. CONCLUSION: Following VBT, patients with dMMR have poorer RFS compared to pMMR patients regardless of HIR/LIR risk classification. The prognosis of intermediate-risk EEC patients may lie more on a continuum dependent on molecular features rather than distinct clinicopathologic risk categories.

NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.