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.

Combinatorial Approaches for Chemotherapies and Targeted Therapies With Radiation: United Efforts to Innovate in Patient Care.

Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.

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.

The American Brachytherapy Society and Indian Brachytherapy Society consensus statement for the establishment of high-dose-rate brachytherapy programs for gynecological malignancies in low- and middle-income countries.

PURPOSE: The global cervical cancer burden is disproportionately high in low- and middle-income countries (LMICs), and outcomes can be governed by the accessibility of appropriate screening and treatment. High-dose-rate (HDR) brachytherapy plays a central role in cervical cancer treatment, improving local control and overall survival. The American Brachytherapy Society (ABS) and Indian Brachytherapy Society (IBS) collaborated to provide this succinct consensus statement guiding the establishment of brachytherapy programs for gynecological malignancies in resource-limited settings. METHODS AND MATERIALS: ABS and IBS members with expertise in brachytherapy formulated this consensus statement based on their collective clinical experience in LMICs with varying levels of resources. RESULTS: The ABS and IBS strongly encourage the establishment of HDR brachytherapy programs for the treatment of gynecological malignancies. With the consideration of resource variability in LMICs, we present 15 minimum component requirements for the establishment of such programs. Guidance on these components, including discussion of what is considered to be essential and what is considered to be optimal, is provided. CONCLUSIONS: This ABS/IBS consensus statement can guide the successful and safe establishment of HDR brachytherapy programs for gynecological malignancies in LMICs with varying levels of resources.

A novel multi-modality imaging phantom for validating interstitial needle guidance for high dose rate gynecological brachytherapy.

PURPOSE: To design, manufacture, and validate a female pelvic phantom for multi-modality imaging (CT, MRI, US) to benchmark a commercial needle tracking system with application in HDR gynecological (GYN) interstitial procedures. MATERIALS AND METHODS: A GYN needle-tracking phantom was designed using CAD software to model an average uterus from a previous patient study, a vaginal canal from speculum dimensions, and a rectum to accommodate a transrectal ultrasound (TRUS) probe. A target volume (CTVHR ) was designed as an extension from the cervix-uterus complex. Negative space molds were created from modeled anatomy and 3D printed. Silicone was used to cast the anatomy molds. A 3D printed box was constructed to house the manufactured anatomy for structural integrity and to accommodate the insertion of a speculum, tandem, needles, and TRUS probe. The phantom was CT-imaged to identify potential imperfections that might impact US visualization. Free-hand TRUS was used to guide interstitial needles into the phantom. The commercial tracking system was used to generate a 3D US volume. After insertion, the phantom was imaged with CT and MR and the uterus and CTVHR dimensions were verified against the CAD model. RESULTS/CONCLUSIONS: The manufactured phantom allows for accurate visualization with multiple imaging modalities and is conducive to applicator and needle insertion. The phantom dimensions from the CAD model were verified with those from each imaging modality. The phantom is low cost and can be reproducibly manufactured with the 3D printing and molding processes. Our initial experiments demonstrate the ability to integrate the phantom with a commercial tracking system for future needle tracking validation studies.

Adaptive Positron Emission Tomography Radiation Therapy in Patients With Locally Advanced Vulvar Cancer: A Prospective Study.

Purpose: In this prospective trial, we aim to determine whether fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT)-based adaptive radiation therapy (ART) improves dosimetry outcomes for patients treated with definitive radiation for locally advanced vulvar cancer. Methods and Materials: Patients were enrolled in 2 sequential institutional review board-approved prospective protocols for PET/CT ART from 2012 to 2020. Patients were planned with pretreatment PET/CT to 45 to 56 Gy in 1.8 Gy/fraction, followed by a boost to gross disease (nodal and/or primary) to a total of 64 to 66 Gy. Intratreatment PET/CT was obtained at 30 to 36 Gy, and all patients were replanned to the same dose goals with revised organ at risk (OAR), gross tumor volume, and planned target volume contours. Radiation therapy consisted of either intensity modulated radiation therapy or volumetric modulated arc therapy. Toxicity was graded by Common Terminology Criteria for Adverse Events, version 5.0. Local control, disease-free survival, overall survival, and time to toxicity were estimated using the Kaplan-Meier method. Dosimetry metrics for OARs were compared using the Wilcoxon signed rank test. Results: Twenty patients were eligible for analysis. Median follow-up among surviving patients was 5.5 years. Local control, disease-free survival, and overall survival at 2 years were 63%, 43%, and 68%, respectively. ART significantly reduced the following OAR doses: bladder, maximum dose (Dmax; median reduction [MR], 1.1 Gy; interquartile range [IQR], 0.48-2.3 Gy; P < .001) and D2cc (MR, 1.5 Gy; IQR, 0.51-2.1 Gy; P < .001); bowel, Dmax (MR, 1.0 Gy; IQR, 0.11-2.9 Gy; P < .001), D2cc (MR, 0.39 Gy; IQR, 0.023-1.7 Gy; P < .001), and D15cc (MR, 0.19 Gy; IQR, 0.026-0.47 Gy; P = .002); and rectal, mean dose (MR, 0.66 Gy; IQR, 0.17-1.7 Gy; P = .006) and D2cc (MR, 0.46 Gy; IQR, 0.17-0.80 Gy; P = .006). No patients experienced any grade ≥3 acute toxicities. There were no reported late grade ≥2 vaginal toxicities. Lymphedema at 2 years was 17% (95% confidence interval, 0%-34%). Conclusions: Doses to bladder, bowel, and rectum were significantly improved with ART, though the median magnitudes were modest. Which patients benefit most from adaptive treatment is a matter for future investigation.

Estimating Carbon Dioxide Emissions and Direct Power Consumption of Linear Accelerator-Based External Beam Radiation Therapy.

Purpose: Climate change is one of the direst health threats that humanity faces. We aim to estimate the carbon dioxide (CO2) emissions associated with the energy usage from linear accelerator (LINAC)-based external beam radiation therapy (EBRT) for the most common cancer diagnoses. Methods and Materials: We identified patients with the 4 most common cancer types treated with curative-intent EBRT. Beam-on time for each fraction was extracted from the treatment planning system and averaged over each site and treatment modality. The power was multiplied by the beam-on time in hours to yield kilowatt hours (kWh). Using the US Environmental Protection Agency Greenhouse Gas Equivalencies calculator, we converted the kWh into estimates of CO2-equivalent emissions for the average US power grid. Idle time of the LINAC was estimated via Varian Medical Systems. Results: A total of 10 patients were included for each of the following modalities: conventionally fractionated for prostate cancer (28 fractions [fx]), prostate stereotactic body radiation therapy (SBRT) (5 fx), 15- and 5-fx regimens for early-stage breast cancer, 3- and 5-fx SBRT regimens for early-stage lung cancer, conventional EBRT (30 fx) for locally advanced lung cancer, and short- (5 fx) and long-course (25-28 fx) for rectal cancer. The modality with the lowest and highest carbon emissions per course, on average, was prostate SBRT (2.18 kg CO2; interquartile range, 1.92-2.30) and conventional treatment for prostate cancer (17.34 kg CO2; interquartile range, 10.26-23.79), respectively. This corresponds to CO2-equivalent emissions of driving an average of 5.4 miles and 41.2 miles in a standard vehicle, respectively. "Standby" mode for a LINAC TrueBeam and Clinac IX uses 112 kWh and 64.8 kWh per day, respectively. Conclusions: We have estimated CO2 emissions arising from direct energy usage of a LINAC for 4 common cancers treated with EBRT. "Standby" mode of a LINAC uses the most energy per day. Comprehensive studies are warranted to minimize the environmental effects of health and cancer care.

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.

Insurance Coverage and Forgoing Medical Appointments Because of Cost Among Cancer Survivors After 2016.

PURPOSE: The uninsured rate began rising after 2016, which some have attributed to health policies undermining aspects of the Affordable Care Act. Our primary objectives were to assess the changes in insurance coverage and forgoing medical care because of cost in cancer survivors from pre-enactment (2016) through postenactment of those policies (2019) and determine whether there were subgroups that were disproportionately affected. METHODS: The 2016-2019 Behavioral Risk Factor Surveillance System surveys were queried for 18- to 64-year-old cancer survivors. Survey-weighted logistic regression was used to assess temporal changes in (1) insurance coverage and (2) forgoing medical appointments because of cost in the preceding 12 months. RESULTS: A total of 62,669 cancer survivors were identified. The percentage of insured cancer survivors decreased from 92.4% in 2016 to 90.4% in 2019 (odds ratio for change in insurance coverage or affordability per one-year increase [ORyear], 0.92; 95% CI, 0.86 to 0.98; P = .01), translating to 161,000 fewer cancer survivors in the United States with insurance coverage. There were decreases in employer-sponsored insurance coverage (ORyear, 0.89) but increases in Medicaid coverage (ORyear, 1.17) from 2016 to 2019. Forgoing medical appointments because of cost increased from 17.9% in 2016 to 20.0% in 2019 (ORyear, 1.05; 95% CI, 1.01 to 1.1; P = .025), affecting an estimated 169,000 cancer survivors. The greatest changes were observed among individuals with low income, particularly those residing in nonexpansion states. CONCLUSION: Between 2016 and 2019, there were 161,000 fewer cancer survivors in the United States with insurance coverage, and 169,000 forwent medical care because of cost.

The Affordable Care Act and suicide incidence among adults with cancer.

BACKGROUND: Patients with cancer are at an increased suicide risk, and socioeconomic deprivation may further exacerbate that risk. The Affordable Care Act (ACA) expanded insurance coverage options for low-income individuals and mandated coverage of mental health care. Our objective was to quantify associations of the ACA with suicide incidence among patients with cancer. METHODS: We identified US patients with cancer aged 18-74 years diagnosed with cancer from 2011 to 2016 from the Surveillance, Epidemiology, and End Results database. The primary outcome was the 1-year incidence of suicide based on cumulative incidence analyses. Difference-in-differences (DID) analyses compared changes in suicide incidence from 2011-2013 (pre-ACA) to 2014-2016 (post-ACA) in Medicaid expansion relative to non-expansion states. We conducted falsification tests with 65-74-year-old patients with cancer, who are Medicare-eligible and not expected to benefit from ACA provisions. RESULTS: We identified 1,263,717 patients with cancer, 812 of whom died by suicide. In DID analyses, there was no change in suicide incidence after 2014 in Medicaid expansion vs. non-expansion states for nonelderly (18-64 years) patients with cancer (p = .41), but there was a decrease in suicide incidence among young adults (18-39 years) (- 64.36 per 100,000, 95% CI = - 125.96 to - 2.76, p = .041). There were no ACA-associated changes in suicide incidence among 65-74-year-old patients with cancer. CONCLUSIONS: We found an ACA-associated decrease in the incidence of suicide for some nonelderly patients with cancer, particularly young adults in Medicaid expansion vs. non-expansion states. Expanding access to health care may decrease the risk of suicide among cancer survivors.

What is appropriate target delineation for MRI-based brachytherapy for medically inoperable endometrial cancer?

PURPOSE: For medically inoperable endometrial cancer (MIEC), the volumetric target of image-guided brachytherapy (IGBT) techniques is not well established. We propose a high-risk CTV (HRCTV) concept and report associated rates of local control and toxicity. METHODS AND MATERIALS: For all MIEC patients receiving definitive external beam radiotherapy (EBRT) followed by MRI-based IGBT at a single institution, BT dose was prescribed to HRCTV defined as GTV plus endometrial cavity with a planning goal of a summed EQD2 D90 of ≥85 Gy. Freedom from local progression (FFLP) and overall survival (OS) were estimated via Kaplan Meier method. RESULTS: Thirty two MIEC patients received EBRT followed by MRI-based IGBT between December 2015 and August 2020. Median follow up was 19.8 months. A total of 75% of patients had FIGO stage I/II disease, 56% endometrioid histology, and 50% grade 3 disease. OS was 73.6% (95% CI 57.8%-89.3%) at 12 months and 65.8% (95% CI 48.4%-83.2%) at 24 months. FFLP was 93.8% (95% CI 85.3%-100%) at 12 months and 88.8% (95% CI 86.6%-91.0%) at 24 months. 23 (72%) patients experienced no RT-related toxicity, while 2 of 32 patients (6%) experienced late grade 3+ toxicities (grade 3 refractory vomiting; grade 5 GI bleed secondary to RT-induced proctitis). CONCLUSIONS: Patients with MIEC receiving definitive EBRT followed by MRI-based IGBT prescribed to the MRI-defined HRCTV demonstrated favorable long-term local control with an acceptable toxicity profile.