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.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

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.

Improvement in radiation techniques for locally advanced cervical cancer during the last two decades.

Since the National Cancer Institute (NCI) alert of concurrent chemoradiotherapy, radiotherapy has been changed from external beam radiotherapy plus brachytherapy to platinum-based concurrent chemoradiotherapy. Therefore, concurrent chemoradiotherapy plus brachytherapy has become a standard treatment for locally advanced cervical cancer. Simultaneously, definitive radiotherapy has been changed gradually from external beam radiotherapy plus low-dose-rate intracavitary brachytherapy to external beam radiotherapy plus high-dose-rate intracavitary brachytherapy. Cervix cancer is uncommon in developed countries; hence, international collaborations have been critical in large-scale clinical trials. The Cervical Cancer Research Network (CCRN), created from the Gynecologic Cancer InterGroup (GCIG), has investigated various concurrent chemotherapy regimens and sequential methods of radiation and chemotherapy. Most recently, many clinical trials of combining immune checkpoint inhibitors with radiotherapy have been ongoing for sequential or concurrent settings. During the last decade, the method of standard radiation therapy has changed from three-dimensional conformal radiation therapy to intensity-modulated radiation therapy for external beam radiotherapy and from two-dimensional to three-dimensional image-guided approaches for brachytherapy. Recent improvements include stereotactic ablative body radiotherapy and MRI-guided linear accelerator (MRI-LINAC) using adaptive radiotherapy. Here we review the current progress of radiation therapy during the last two decades.

Mental health disorders are more common in patients with Hodgkin lymphoma and may negatively impact overall survival.

BACKGROUND: Long-term mental health outcomes were characterized in patients who were diagnosed with Hodgkin lymphoma (HL), and risk factors for the development of mental health disorders were identified. METHODS: Patients who were diagnosed with HL between 1997 and 2014 were identified in the Utah Cancer Registry. Each patient was matched with up to five individuals from a general population cohort identified within the Utah Population Database, a unique source of linked records that includes patient and demographic data. RESULTS: In total, 795 patients who had HL were matched with 3575 individuals from the general population. Compared with the general population, patients who had HL had a higher risk of any mental health diagnosis (hazard ratio, 1.77; 95% confidence interval, 1.57-2.00). Patients with HL had higher risks of anxiety, depression, substance-related disorders, and suicide and intentional self-inflicted injuries compared with the general population. The main risk factor associated with an increased risk of being diagnosed with mental health disorders was undergoing hematopoietic stem cell transplantation, with a hazard ratio of 2.06 (95% confidence interval, 1.53-2.76). The diagnosis of any mental health disorder among patients with HL was associated with a detrimental impact on overall survival; the 10-year overall survival rate was 70% in patients who had a mental health diagnosis compared with 86% in those patients without a mental health diagnosis (p < .0001). CONCLUSIONS: Patients who had HL had an increased risk of various mental health disorders compared with a matched general population. The current data illustrate the importance of attention to mental health in HL survivorship, particularly for patients who undergo therapy with hematopoietic stem cell transplantation.

Risk of secondary malignancies in ovarian cancer survivors: 52,680 patients analyzed with over 40 years of follow-up.

OBJECTIVE: Survivors of ovarian cancer are at risk of developing a secondary malignancy (SM). We sought to evaluate the risk of developing SM, stratified by treatment modality. METHODS: Standardized incidence ratios (SIR, observed-to-expected [O/E] ratio) were assessed in 52,680 patients diagnosed with ovarian cancer between 1975 and 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. RESULTS: Of the 52,680 patients, 3366 patients (6.4%) developed SM, which was more than the endemic rate (O/E 1.13; p < .05). Patients who received any radiation (RT) had an increased risk of overall SM compared to those who didn't (O/E 1.42 vs 1.11; p < .05), and specifically, in the bladder (O/E 2.81). Patients who received any chemotherapy (CT) had an increased risk of leukemia (O/E 3.06), and a similar risk of overall SM compared to those not treated with CT (O/E 1.11 vs 1.14; p < .05). The excess risk of developing a solid tumor SM was greatest at latencies of 10-20 years. Patients younger than 50 had the highest risk of developing SM. Non-White patients had a higher risk of SM compared to White patients. CONCLUSIONS: This is the largest study to examine the risk of SM in patients with ovarian cancer and has the longest follow-up. Risk of SM was increased after ovarian cancer and varied with treatment modality, race, latency, and age. These results may help inform SM screening protocols for women diagnosed with ovarian cancer.

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.

Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations.

OBJECTIVE: To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic. METHODS: An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel. RESULTS: Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended. CONCLUSIONS: The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19.

The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system.

OBJECTIVE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer changed from a clinical system to a clinical/pathologic/radiologic system with stages IIIC1 and IIIC2 indicating positive pelvic and para-aortic lymph nodes, respectively. We evaluated the National Cancer Database (NCDB) for the impact on survival of lymph node metastases (LNM). METHODS: The NCDB from 2004 to 2015 was queried for patients with cervical cancer, yielding 115,819 patients. Patients with FIGO IVB (22,569), non-adeno/squamous cell histologies (5,909), unknown nodal status (60,695), or unknown survival time (9,473) were excluded. Survival was compared using Cox proportional hazard model based on nodal status. Univariate (UVA) and multivariate analyses (MVA) were done for the overall cohort, followed by UVA by individual stage. RESULTS: In 17,173 eligible patients, LNM negatively affected survival (UVA IIIC1 Hazard Ratio [HR] 2.0, p < 0.001, IIIC2 HR 3.9, p < 0.001, MVA IIIC1 HR 1.36, p < 0.001, IIIC2 HR 2.14, p < 0.001). In T1B, the effect of IIIC2 was most pronounced (HR 5.38, p < 0.001 versus HR 1.5 p = 0.001 for IIIC1 disease). In T3, the effect of LNM was markedly less: (HR 1.7, p < 0.001 for IIIC2 versus HR 1.2 p = 0.02 for IIIC1). Within T1B, there was no difference in survival for IIIC1 for the smaller T stages (IB1-2). CONCLUSION: In this study, LNM negatively affects prognosis in cervical cancer. The impact on survival varies by T stage with the greatest effect seen in stage T1B with IIIC2 disease.

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

NCCN Guidelines Insights: Cervical Cancer, Version 1.2020.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.

Recurrent early stage endometrial cancer: Patterns of recurrence and results of salvage therapy.

OBJECTIVE: To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients. METHODS: We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR). Overall survival (OS) was assessed using Kaplan-Meier survival analysis. Univariate (UV) and multivariate (MV) Cox proportional hazards modeling was also used. RESULTS: A total of 2691 women were analyzed. The majority had endometrioid histology (91%), stage IA disease (61%), and were grade 1 (57%). With a median follow-up of 6.1 years, the overall rate of recurrence was 7.2%, and the rate of LRR was 3.7%. Women with vaginal-only recurrences had a longer median OS after recurrence (14.0 years) compared to both pelvic (1.2 years) and distant (1.0 year) failures. For women with vaginal-only recurrences, salvage radiotherapy (RT) was the only factor associated with improved OS on MVA (HR 0.1, p = .04). For women with pelvic recurrences, salvage surgery (HR 0.3, p = .01), salvage RT (HR 0.3, p < .01), and salvage chemotherapy (HR 0.4, p = .03) were associated with improved OS. CONCLUSIONS: Failure rates for women with early-stage endometrial cancer are low. Women with vaginal-only recurrences have improved OS compared to pelvic or distant recurrences. Salvage RT appears to be an important factor for treatment of women with vaginal-only recurrences. Aggressive multimodality treatment may be beneficial for women with pelvic recurrences.

Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.

OBJECTIVE: Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT. METHODS: In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed. RESULTS: Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT. CONCLUSION: Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.

Too many women are dying from cervix cancer: Problems and solutions.

One woman dies from cervix cancer every 2 min, adding up to over 270,000 deaths globally per year. This cancer affects a young population, and hence, the loss of life is staggering. There are many aspects of prevention, screening, and care that are suboptimal. A great deal is known about HPV induced carcinogenesis, yet clinical outcomes have been stagnant over decades. There has been no improvement in cervix cancer survival in the US since the mid-1970s [1]. With increased knowledge of the disease and greater worldwide resources including prevention, screening, and improved therapeutics, there is significant promise for fewer women to die from this virally induced cancer. We focus here on the major problems in prevention, screening, and delivery of care for cervix cancer and provide concrete solutions. With appropriate focus, a major improvement in survival from cervix cancer could be achieved in a short time span.

Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

Is radiation indicated for young women with early stage, node-negative breast cancer after mastectomy? A multi-institution, retrospective review.

The role of post-mastectomy radiation for women with node negative, early stage disease is not well-defined. The purpose of this study is to more clearly define a subset of women who are ≤40 years of age with T1-T2, node negative breast cancer who may benefit from post-mastectomy radiation. Using tumor registries at two institutions, we identified 219 women ≤40 years of age with T1-T2, node negative breast cancer treated with mastectomy. Of these 219 patients, 38 received post-mastectomy radiation and 181 did not. Kaplan-Meier methods and cox proportional-hazards regression models were employed for statistical analysis. There were no locoregional failures in the women receiving post mastectomy radiation, which lead to a nonsignificant increase in freedom from locoregional recurrence (P=.08). For women not receiving post-mastectomy radiation, freedom from locoregional recurrence was 94.7% and 89.7% at 5- and 10-years. Lymphovascular space invasion (LVSI) was the only factor predictive of locoregional recurrence. For women without LVSI, freedom from locoregional recurrence was 96.0% and 93.3% at 5- and 10-years respectively. For women with LVSI who did not receive post mastectomy radiation, freedom from locoregional recurrence was 89.1% at 5-years. There were no failures in the women with LVSI who received post mastectomy radiation. For women ≤40 years of age with T1-2, node negative breast cancer treated with mastectomy and no post-mastectomy radiation, locoregional control is excellent in the absence of LVSI, regardless of other risk factors. In the presence of LVSI (regardless of other risk factors), the risk of locoregional recurrence is high and appears to be decreased with post-mastectomy radiation.