The new (Version 9) American Joint Committee on Cancer tumor, node, metastasis staging for cervical cancer.

The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging for all cancer sites has been periodically updated as a published manual for many years. The last update, the eighth edition AJCC Cancer Staging Manual went into use on January 1, 2018. The AJCC has since restructured and updated its processes, and all AJCC staging-related data are now housed on its new application programming interface. Consequently, the next AJCC TNM staging update, AJCC version 9 TNM staging, will be published electronically and will be released chapter by chapter. The first chapter of version 9 AJCC TNM staging is the updated cervical cancer staging, which is now published. This article highlights the changes to the AJCC TNM cervical cancer staging; these changes align with the International Federation of Gynecology and Obstetrics staging. The most important of the changes are: 1) the incorporation of imaging and surgical findings, 2) the elimination of lateral spread from T1a, 3) the addition of a subcategory to T1b (T1b3), and 4) histopathology is updated to reflect human papillomavirus-associated and human papillomavirus-independent carcinomas.

Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling.

BACKGROUND: There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery. METHODS: We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues. RESULTS: We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues. CONCLUSIONS: Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Intraluminal tumor cells and prognostic accuracy of endometrial cancer stage criteria: A multi-institution study.

OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.

Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers.

OBJECTIVE: To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic. METHODS: In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests. RESULTS: Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025). CONCLUSIONS: Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. METHODS: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual. FINDINGS: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group). INTERPRETATION: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. FUNDING: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.

Molecular profiles of endometrial cancer tumors among Black patients.

OBJECTIVES: Disparate outcomes exist between Black and White patients with endometrial cancer (EC). One contributing factor is the disproportionately low representation of Black patients in clinical trials and in tumor molecular profiling studies. Our objective was to investigate molecular profiles of ECs in a cohort with a high proportion of tumors from Black patients. METHODS: A total of 248 EC samples and self-reported race data were collected from 6 institutions. Comprehensive tumor profiling and analyses were performed by Caris Life Sciences. RESULTS: Tumors from 105 (42%) Black and 143 (58%) White patients were included. Serous histology (58% vs 36%) and carcinosarcoma (25% vs 16%), was more common among Black patients, and endometrioid was less common (17% vs 48%) (p < 0.01). Differences in gene mutations between cohorts corresponded to observed histologic differences between races. Specifically, TP53 mutations were predominant in serous tumors. In endometrioid tumors, mutations in ARID1A were the most common, and high rates of MSI-H, MMRd, and TMB-H were observed. In carcinosarcoma tumors, hormone receptor expression was high in tumors of Black patients (PR 23.4%, ER 30.8%). When stratified by histology, there were no significant differences between tumors from Black and White women. CONCLUSIONS: This cohort had a high proportion of tumors from Black women. Distinct molecular profiles were driven primarily by more aggressive histologic subtypes among Black women. Continued effort is needed to include Black women and other populations under-represented in EC molecular profiling studies as targeted therapies and personalized medicine become mainstream.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Impact of Ki-67 Labeling Index on Prognostic Significance of the Chemotherapy Response Score in Women With Tubo-ovarian Cancer Treated With Neoadjuvant Chemotherapy.

The chemotherapy response score (CRS) proposed by Bohm and colleagues in 2015 has been validated as a reproducible method for determining histopathologic response of tubo-ovarian carcinoma to neoadjuvant chemotherapy and stratifies tumor response into 3 groups: CRS1 is defined as minimal/no response, CRS2 as moderate response, and CRS3 as marked response. Although described as a 3-tiered system, it essentially works as a 2-tiered system (CRS1/CRS2 vs. CRS3) for assessing prognosis. Here, we analyzed the prognostic value of CRS in a large cohort of tubo-ovarian carcinomas at a tertiary care center and evaluated the potential for Ki-67 labeling index on post-neoadjuvant chemotherapy samples to provide additional prognostic information. We included 170 patients with tubo-ovarian carcinoma treated with neoadjuvant chemotherapy followed by interval debulking surgery. We determined CRS for each case by reviewing slides from the interval debulking surgery resection specimen and calculated progression-free survival and overall survival. For each case with residual disease (CRS1 and CRS2, n=123, 72%), we also performed Ki-67 antibody staining and determined both average and highest Ki-67 labeling index. Consistent with prior studies, patients in our cohort with CRS1 and CRS2 showed significantly shorter progression-free survival and overall survival compared with CRS3. Further, in the subset of cases with CRS1 and CRS2, Ki-67 labeling index was predictive of OS at multiple cutoff points. An average Ki-67 labeling index of 20% (log rank test P-value: 0.0004) or a highest Ki-67 labeling index of 50% (log rank test P-value: 0.0002) could provide a practically useful cutoff. Multivariable cox proportional hazard model showed worse overall survival with both, average Ki-67 >20% (hazard ratios: 2.02, P-value: 0.00422, confidence interval: 1.25-3.28) and highest Ki-67 >50% (hazard ratios: 1.88, P-value: 0.0205, confidence interval: 1.1-3.2). We propose adding Ki-67 labeling index to CRS to provide additional prognostic separation between patients with CRS1 and CRS2.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. METHODS: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. INTERPRETATION: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. FUNDING: US National Cancer Institute.

Dose-escalated intensity modulated radiation therapy in patients with locally-advanced vulvar cancer - does it increase response rate?

PURPOSE: GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) in locally-advanced vulvar cancer through dose escalation using three-dimensional radiotherapy (RT). The aim of this study is to assess the response of dose-escalated intensity modulated radiotherapy (IMRT) in locally-advanced vulvar cancer. METHODS: A retrospective review of patients treated with dose-escalated (≥ 55Gy) IMRT from 2012 to 2018 for locally-advanced vulvar cancer was performed. Patients treated with preoperative or definitive intent were included. Rates of cCR and pCR were assessed, and predictors of disease-free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox model. RESULTS: Median dose to the vulva was 66.0 Gy (Interquartile Range [IQR]: 66.0-68.0) for definitive and 59.4 Gy (IQR: 58.0-59.4) for preoperative IMRT. The overall rates of cCR and pCR were 76% and 70%, respectively. DFS at two years was 65% (95% Confidence Interval [CI] 50-80%) for all patients, 81% (95% CI 63% - 98%) for definitive IMRT, and 55% (95% CI 35% - 76%) for preoperative IMRT. On multivariate analysis, cCR predicted for disease-free survival (HR 0.21; 95% CI 0.06-0.76; p = 0.02), and pCR predicted for OS (HR 0.12; 95% CI 0.02-0.60; p = 0.01). Grade 3 acute and late RT toxicity was seen in 14 (29%) and 3 (6%) of patients, respectively. CONCLUSION: Dose-escalated IMRT for locally-advanced vulvar cancer is well tolerated, with rates of cCR and pCR that compare favorably with published data.

Race-driven survival differential in women diagnosed with endometrial cancers in the USA.

OBJECTIVE: African American women are increasingly being diagnosed with advanced and type II histology endometrial cancers. Outcomes have been observed to be worse in African American women, but whether or not race itself is a factor is unclear. We sought to evaluate the rates of diagnosis and outcomes on a stage-by-stage basis with respect to race using a large national cancer registry database. METHODS: The National Cancer Data Base was searched for patients with surgically staged non-metastatic endometrial cancer between 2004 and 2015. Women were excluded if surgical stage/histology was unknown, there was no follow-up, or no information on subsequent treatment. Pairwise comparison was used to determine temporal trends and Cox hazards tests with Bonferroni correction were used to determine overall survival. RESULTS: A total of 286 920 women were diagnosed with endometrial cancer and met the criteria for analysis. Median follow-up was 51 months (IQR 25.7-85.3). In multivariable models, in women with stage I disease, African American women had a higher risk of death than Caucasian women (HR 1.262, 95% CI 1.191 to 1.338, p<0.001) and Asian/Pacific Islander women had a lower risk of death than Caucasian women (HR 0.742, 95% CI 0.689 to 0.801, p<0.001). This held for African American women with stage II type I and type II disease (HR 1.26, 95% CI 1.109 to 1.444, p<0.001 and HR 1.235, 95% CI 1.098 to 1.388, p<0.001) but not for Asian/Pacific Islander women. African American women with stage IIIA-B disease also had a higher risk of death for type I and type II disease versus Caucasian women (HR 1.221, 95% CI 1.045 to 1.422, p=0.010 and HR 1.295, 95% CI 1.155 to 1.452, p<0.001). Asian/Pacific Islander women had a lower risk of death than Caucasian women with type I disease (HR 0.783, 95% CI 0.638 to 0.960, p=0.019) and type II disease (HR 0.790, 95% CI 0.624 to 0.999, p=0.05). African American women with stage IIIC1-2 had a higher risk of death with type I disease (HR 1.343, 95% CI 1.207 to 1.494, p<0.001) and type II disease (HR 1.141, 95% CI 1.055 to 1.233, p=0.001) whereas there was no significant difference between Caucasian women and Asian/Pacific Islander women. CONCLUSION: Race appears to play an independent role in survival from endometrial cancer in the USA, with African American women having worse survival on a stage-for-stage basis compared with Caucasian women.

Contemporary management of uterine clear cell carcinoma: A Society of Gynecologic Oncology (SGO) review and recommendation.

Uterine clear cell cancer (UCCC) is a rare but aggressive disease. Due to its rarity, large, prospective studies focused on UCCC are exceedingly difficult therefore available data are generally from small, retrospective studies. There is also pertinent information from subsection analysis of larger studies that include UCCC and other histotypes. In 2009, the clinical practice committee of the Society of Gynecologic Oncology (SGO) published a review on UCCC aimed at guiding management. Since that publication, there have been developments which are relevant to UCCC, these include availability of data from landmark trials regarding adjuvant therapy, increasing utilization of sentinel lymph node approach and availability of immunotherapy as a treatment option. This SGO review is updated with all relevant, published information since 2009 considered clinically important for management of UCCC. In addition, it follows the new SGO's style for this type of publication which includes utilization of the question and answer format.

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVES: The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients. METHODS: Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated. RESULTS: 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables. CONCLUSION: SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

Impact of histological grade on oncologic outcomes in clinical stage I patients with endometrial carcinoma patients after definitive primary radiation therapy.

OBJECTIVES: To determine the impact of histological grade on overall survival in patients with clinical stage I endometrioid endometrial adenocarcinoma when radiation therapy is used as primary definitive treatment. METHODS: Patients with stage I endometrioid endometrial adenocarcinomas who underwent definitive radiation therapy with brachytherapy ± external beam radiation therapy were identified from the National Cancer Database. Overall survival was estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed to determine factors affecting overall survival. Inverse probability of treatment weights were also used in multivariable analysis to estimate casual effects of external beam radiation therapy. RESULTS: A total of 947 patients were identified. Median overall survival for grade 1, grade 2, and grade 3 tumors was 62 months (95% CI 53.8 to 70.2), 48.5 months (95% CI 38.2 to 58.8), and 33.5 months (95% CI: 23.1 to 43.8), respectively. Grade, age, and insurance status were associated with overall survival in univariate analysis with only grade and age remaining significant in multivariate analysis. Brachytherapy with external beam radiation therapy was not associated with survival in comparison with brachytherapy alone. Compared with grade 1 tumors, patients with grade 3 (HR 1.4, 95% CI 1.15 to 1.89), but not grade 2 (HR 1.0, 95% CI 0.82 to 1.26), had an increased risk of death, which persisted in an inverse probability of treatment weights-adjusted model (HR 1.56, 95% CI 1.21 to 1.93). CONCLUSIONS: Patients with grade 3 stage I endometrioid endometrial adenocarcinoma treated with primary definitive radiation therapy have worse survival than those with lower grade tumors. Addition of external beam radiation therapy to brachytherapy did not affect survival.

International radical trachelectomy assessment: IRTA study.

BACKGROUND: Radical trachelectomy is considered a viable option for fertility preservation in patients with low-risk, early-stage cervical cancer. Standard approaches include laparotomy or minimally invasive surgery when performing radical trachelectomy. PRIMARY OBJECTIVE: To compare disease-free survival between patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy. STUDY HYPOTHESIS: We hypothesize that minimally invasive radical trachelectomy has similar oncologic outcomes to those of the open approach. STUDY DESIGN: This is a collaborative, multi-institutional, international, retrospective study. Patients who underwent a radical trachelectomy and lymphadenectomy between January 1, 2005 and December 31, 2017 will be included. Institutional review board approval will be required. Each institution will be provided access to a study-specific REDCap (Research Electronic Data Capture) database maintained by MD Anderson Cancer Center and will be responsible for entering patient data. INCLUSION CRITERIA: Patients with squamous, adenocarcinoma, or adenosquamous cervical cancer FIGO (2009) stages IA2 and IB1 (≤2 cm) will be included. Surgery performed by the open approach or minimally invasive approach (laparoscopy or robotics). Tumor size ≤2 cm, by physical examination, ultrasound, MRI, CT, or positron emission tomography (at least one should confirm a tumor size ≤2 cm). Centers must contribute at least 15 cases of radical trachelectomy (open, minimally invasive, or both). EXCLUSION CRITERIA: Prior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer at any time, prior lymphadenectomy, or pelvic retroperitoneal surgery, pregnant patients, aborted trachelectomy (intra-operative conversion to radical hysterectomy), or vaginal approach. PRIMARY ENDPOINT: The primary endpoint is disease-free survival measured as the time from surgery until recurrence or death due to disease. To evaluate the primary objective, we will compare disease-free survival among patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive radical trachelectomy. SAMPLE SIZE: An estimated 535 patients will be included; 256 open and 279 minimally invasive radical trachelectomy. Previous studies have shown that recurrence rates in the open group range from 3.8% to 7.6%. Assuming that the 4.5-year disease-free survival rate for patients who underwent open surgery is 95.0%, we have 80% power to detect a 0.44 HR using α level 0.10. This corresponds to an 89.0% disease-free survival rate at 4.5 years in the minimally invasive group.

Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm.

The treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy often includes the combination of gemcitabine and docetaxel with or without doxorubicin in first-line systemic therapy, but these cytotoxic agents only provide patients with advanced disease a 5-year survival <30%. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uLMS. Critical ongoing studies investigating novel approaches including immunotherapeutics and genetic alterations also will be discussed. IMPLICATIONS FOR PRACTICE: Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these compounds. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uterine leoimyosarcoma.

Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. METHODS: Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. RESULTS: A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19-1.72, P < 0.001) and 1.26 (95% CI, 1.04-1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51-5.26, P < 0.001) compared to dose-unmodified patients. CONCLUSION: Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.