Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma.

BACKGROUND: The objective was to compare sequencing strategies for treatment of advanced endometrial carcinoma. METHODS: Patients were eligible if they had FIGO 2009 Stage III or IVA endometrial carcinoma or Stage I or II serous or clear cell endometrial carcinoma and positive cytology. Patients were randomized to: Cisplatin 50 mg/m2 IV Days 1 and 29 plus radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles (chemoRT then chemo) vs. Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles followed by radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles (sandwich therapy). Futility analysis was planned. The primary objective was to determine if chemoRT then chemo improves recurrence-free survival (RFS) compared to sandwich therapy. RESULTS: Of the 48 patients enrolled at 8 sites, 42 patients were eligible for futility analysis, and the trial was closed early. The median follow-up was 30.9 months. The 3-year RFS was 85.7% (95% confidence interval [CI], 62 to 95) in the chemoRT then chemo arm and 73.4% (95% CI, 43 to 89) in the sandwich therapy group (p = 0.58). The 3-year overall survival (OS) was 88.4% (95% CI, 61 to 97) in the chemoRT then chemo arm and 80.9% (95% CI, 51 to 93) in the sandwich therapy group (p = 0.55). CONCLUSION: There was no observed significant difference between chemoRT then chemo compared to sandwich therapy in terms of RFS, OS, or adverse events, although the trial was underpowered and closed early due to low accrual.

Disparities in Diagnosis and Treatment of Cervical Adenocarcinoma Compared With Squamous Cell Carcinoma: An Analysis of the National Cancer Database, 2004-2017.

OBJECTIVES: The aim of the study are to compare trends in diagnosis and treatment of adenocarcinoma of the cervix (AC) to squamous cell carcinoma of the cervix (SCC) and to examine associations between stage at diagnosis and guideline-concordant treatment with race, age, and insurance type for AC and SCC. MATERIALS AND METHODS: We performed a retrospective cohort study of cervical AC ( n = 18,811) and SCC ( n = 68,421) from the 2004-2017 National Cancer Database. We used generalized linear models to evaluate trends in frequency of histologies and to evaluate associations between race, age, and insurance status with stage of diagnosis and receipt of National Comprehensive Cancer Network guideline-concordant treatment for AC and SCC. RESULTS: The proportion of AC relative to SCC increased from 19.4% (95% CI = 18.4-20.5) to 23.2% (95% CI = 22.2-24.2) from 2004 to 2017 ( p < .001). Compared with SCC, women with AC were younger, more likely to be White, and privately insured ( p < .001). Older women with AC were 44% less likely to be diagnosed with early-stage disease than younger women (adjusted relative risk = 0.56, 95% CI = 0.52-0.60); there was no significant difference for SCC. Black women with AC were 16% less likely to be diagnosed with early-stage disease (adjusted relative risk [aRR] = 0.84, 95% CI = 0.79-0.89) than White women. Women with public insurance were less likely to be diagnosed at an early stage for both AC (aRR = 0.81, 95% CI = 0.78-0.84) and SCC (aRR = 0.79, 95% CI = 0.77-0.81). Rates of guideline-concordant treatment were similar for AC and SCC, with minimal differences by age, race, and insurance. CONCLUSIONS: As the proportion of AC to SCC rises, important race and age-related disparities must be addressed to reduce unnecessary morbidity and death.

Epidemiology of Cervical Adenocarcinoma and Squamous Cell Carcinoma Among Women Living With Human Immunodeficiency Virus Compared With the General Population in the United States.

BACKGROUND: Although cervical cancer risk overall is elevated among women living with human immunodeficiency virus (HIV; WLH), it is unclear whether risks are similarly elevated across histologic subtypes. METHODS: Data from the HIV/AIDS Cancer Match Study, a linkage of 12 US HIV and cancer registries during 1996 -2016, were used. Cervical cancers were categorized as adenocarcinoma (AC), squamous cell carcinoma (SCC), or other histologic subtype. Standardized incidence ratios compared rates of AC and SCC in WLH to those in general population. For WLH, risk factors for AC and SCC were evaluated using Poisson regression. Five-year survival was estimated by HIV status and histology. RESULTS: Overall, 62 615 cervical cancers were identified, including 609 in WLH. Compared with the general population, incidence of AC was 1.47 times higher (95% confidence interval [CI]: 1.03-2.05) and SCC was 3.62 times higher among WLH (95% CI: 3.31-3.94). Among WLH, there was no difference in AC rates by race/ethnicity or HIV transmission group, although SCC rates were lower among White women (vs Black) and higher among women who inject drugs (vs heterosexual transmission). Among WLH, 5-year overall survival was similar for AC (46.2%) and SCC (43.8%) but notably lower than for women not living with HIV. CONCLUSIONS: Among WLH, AC rates were modestly elevated, whereas SCC rates were greatly elevated compared with the general population. These findings suggest there may be differences in the impact of immunosuppression and HIV in the development of AC versus SCC, given their common etiology in human papillomavirus infection.

Understanding cervical cancer after the age of routine screening: Characteristics of cases, treatment, and survival in the United States.

OBJECTIVE: Given that cervical cancer incidence rates do not decline in women >65, there is generally limited screening, and these women have a poor prognosis, it is imperative to better understand this population. We aim to describe the characteristics, treatment, and survival of women >65 diagnosed with cervical cancer. METHODS: SEER-Medicare 2004-2013 data was used to describe 2274 patients >65 diagnosed with cervical cancer. Five-year cancer-specific survival was estimated using the Kaplan-Meier method. Multivariable Poisson and Cox regression analyses identified characteristics associated with treatment and mortality. RESULTS: The median age was 76.1 years, with nearly one-third of cases occurring in women >80 years. Most patients were non-Hispanic White (64.8%), had comorbidity scores ≥ 1 (53.9%) and squamous histology (66.3%). Most women were diagnosed at stage II or higher (62.7%), including nearly one-quarter at Stage IV (23.1%). Nearly 15% of patients were not treated (14.6%). Lack of treatment was associated with oldest age (>80), comorbidity scores ≥3, and stage IV disease. Five-year cancer-specific survival was 50%. Increasing age and stage at diagnosis were significantly associated with lower cancer-specific survival whereas treatment was strongly associated with increased survival. CONCLUSION: Most women >65 with cervical cancer are diagnosed with locally advanced or metastatic disease and many do not receive treatment. Survival is improved with early-stage diagnosis and treatment. These findings, coupled with the fact that women >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in this population to detect cervical cancer at earlier stages and increase survival. NOVELTY AND IMPACT STATEMENT: In SEER-Medicare linked data from 2004 to 2013, most women >65 with cervical cancer were diagnosed with locally advanced or metastatic disease. Both receipt of treatment and survival decreased with increasing age. These findings, coupled with the fact that women aged >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in older women to detect cervical cancer at earlier stages and increase survival.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

PURPOSE: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment. METHODS: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk. RESULTS: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI. CONCLUSIONS: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.

Treatment of vulvar and vaginal dysplasia: plasma energy ablation versus carbon dioxide laser ablation.

OBJECTIVE: Plasma energy ablation vaporizes tissues similar to carbon dioxide laser ablation, but is not hindered by the unique hazards and regulation of laser technology. We aimed to evaluate the complication rate and effectiveness of plasma versus laser ablation in the treatment of vulvovaginal high-grade squamous intra-epithelial lesions (HSIL). METHODS: We performed a retrospective cohort study of women treated with plasma or carbon dioxide laser ablation for histologically proven HSIL of the vulva or vagina from January 2014 to October 2019 at a single institution. Demographic factors, surgical characteristics, and complications were compared by ablation type using Fisher's exact tests. Recurrence-free survival was evaluated by ablation type using Kaplan-Meier curves, weighted log-rank tests, and Cox proportional hazards ratio estimates. RESULTS: Forty-two women were included; 50% underwent plasma and 50% underwent carbon dioxide laser ablation. Demographic factors were similar between the groups. 50% (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most women (n=25, 59.5%) were treated for vulvar HSIL, 38.1% (n=16) for vaginal HSIL. Complication rates did not differ by treatment: 9.5% (n=2) for laser ablation versus 4.8% (n=1) for plasma ablation (p=1.0). Over a median follow-up time of 29.3 months (IQR 11.0-45.0 months), recurrence rates were similar: 28.6% in the laser ablation group versus 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month HR 0.54, 95% CI 0.15 to 2.01). CONCLUSION: Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.

The impact of an enhanced recovery after minimally invasive surgery program on opioid use in gynecologic oncology patients undergoing hysterectomy.

OBJECTIVES: To evaluate the effects of an enhanced recovery after minimally invasive surgery (MIS-ERAS) protocol on opioid requirements and post-operative pain in patients undergoing minimally invasive hysterectomy on a gynecologic oncology service. METHODS: For this retrospective study, opioid use (oral morphine equivalents (OME)) and post-operative pain scores were compared between patients undergoing minimally invasive hysterectomy pre and post MIS-ERAS protocol implementation. Patients with chronic opioid use or chronic pain were excluded. Opioid use and pain scores were compared between groups using Wilcoxon Rank Sum, Student's t-test, and multiple linear regression. Compliance and factors associated with opioid use and pain scores were assessed. RESULTS: The MIS-ERAS cohort (n = 127) was compared to the historical cohort (n = 99) with no differences in patient demographic, clinical or surgical characteristics observed between groups. Median intra-operative and inpatient post-operative opioid use were lower among the MIS-ERAS cohort (12.0 vs 32.0 OME, p < .0001 and 20.0 vs 35.0 OME, p = .02, respectively). Pain scores among MIS-ERAS patients were also lower (mean 3.6 vs 4.1, p = .03). After controlling for age, BMI, operative time, length of stay, cancer diagnosis, and surgical approach, the MIS-ERAS cohort used 10.43 fewer OME intra-operatively (p < .001), 10.97 fewer OME post-operatively (p = .019) and reported pain scores 0.56 points lower than historical controls (p = .013). Compliance was ≥81% for multimodal analgesia elements and ≥75% overall. CONCLUSIONS: Enhanced recovery after minimally invasive surgery protocol implementation is an effective means to reduce opioid use, both in the intra-operative and post-operative phases of care, among gynecologic oncology patients undergoing minimally invasive hysterectomy.

The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: Little impact on response and low live-birth rates.

OBJECTIVE: Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. METHODS: A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. RESULTS: Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. CONCLUSIONS: Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

Basic social resource needs screening in the gynecologic oncology clinic: a quality improvement initiative.

BACKGROUND: Social determinants of health are known to contribute to disparities in health outcomes. Routine screening for basic social needs is not a part of standard care; however, the association of those needs with increased healthcare utilization and poor compliance with guideline-directed care is well established. OBJECTIVE: In this study, we aimed to assess the prevalence of basic social resource needs identified through a quality improvement initiative in a gynecologic oncology outpatient clinic. In addition, we aimed to identify clinical and demographic factors associated with having basic social resource needs. STUDY DESIGN: We performed a prospective cohort study of women presenting to a gynecologic oncology clinic at an urban academic institution who were screened for basic social resource needs as part of a quality improvement initiative from July 2017 to May 2018. The following 8 domains of resource needs were assessed: food insecurity, housing insecurity, utility needs, financial strain, transportation, childcare, household items, and difficulty reading hospital materials. Women with needs were referred to resources to address those needs. Demographic and clinical information were collected for each patient. The prevalence of needs and successful follow-up interventions were calculated. Patient factors independently associated with having at least 1 basic social resource need were identified using multivariable Poisson regression. RESULTS: A total of 752 women were screened in the study period, of whom 274 (36%) reported 1 or more basic social resource need, with a median of 1 (range, 1-7) need. Financial strain was the most commonly reported need (171 of 752, 23%), followed by transportation (119 of 752, 16%), difficulty reading hospital materials (54 of 752, 7%), housing insecurity (31 of 752, 4%), food insecurity (28 of 752, 4%), household items (22 of 752, 3%), childcare (15 of 752, 2%), and utility needs (13 of 752, 2%). On multivariable analysis, independent factors associated with having at least 1 basic social resource need were being single, divorced or widowed, nonwhite race, current smoker, nonprivate insurance, and a history of anxiety or depression. A total of 36 of 274 (13%) women who screened positive requested assistance and were referred to resources to address those needs. Of the 36 women, 25 (69%) successfully accessed a resource or felt equipped to address their needs, 9 (25%) could not be reached despite repeated attempts, and 2 (6%) declined assistance. CONCLUSION: Basic social resource needs are prevalent in women presenting to an urban academic gynecologic oncology clinic and can be identified and addressed through routine screening. To help mitigate ongoing disparities in this population, screening for and addressing basic social resource needs should be incorporated into routine comprehensive care in gynecologic oncology clinics.

Gynecologic cancer in HIV-positive women: a systematic review and meta-analysis.

BACKGROUND: While there is a significant body of literature on cervical cancer in HIV-positive women, little is known about other gynecologic cancers in this population. OBJECTIVE: The objective of this systematic review and meta-analysis is to describe the incidence, presentation, treatment, and outcomes for HIV-positive women with non-acquired immunodeficiency syndrome-defining gynecologic cancers. STUDY DESIGN: We searched MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials for English-language studies published from 2000 to May 1, 2017. Studies containing 1 or more HIV-positive women with endometrial, ovarian, or vulvovaginal cancer and reporting incidence, treatment regimen, or survival were included. Two authors independently reviewed abstracts and full-text articles for inclusion and assessed study quality (details of the review protocol were registered as PROSPERO-CRD42017064525). Pooled estimates of incidence were calculated using random-effects models. Pooled estimates of cancer presentation and outcomes were averaged from case studies. RESULTS: Of 5744 abstracts screened, we identified 70 articles on 58 studies on 292,202 women with HIV and 528 women with HIV and gynecologic cancer for inclusion. Most articles (53%) focused on incidence, and only 3, 4, and 20 articles focused on treatment and outcomes of endometrial, ovarian, and vulvovaginal cancers, respectively. The standardized incidence ratios for endometrial, ovarian, and vulvovaginal cancers were 4.38 (95% confidence interval 0.26-8.49) for endometrial cancer, 3.21 (95% confidence interval 2.29-4.13) for ovarian cancer, and 21.93 (95% confidence interval 13.50-30.35) for vulvovaginal cancer. Fifty-seven percent of women were diagnosed at an early stage, and all received cancer treatment. CONCLUSION: In women with HIV, the incidence of ovarian and vulvovaginal cancer were higher than the general population, while incidence of endometrial cancer was similar. However, there was a paucity of data on treatment and outcomes for non-acquired immunodeficiency syndrome-defining gynecologic cancers. Given the increased incidence of gynecologic cancer, specific research on this population is essential to improve treatment and outcomes for HIV-positive women.

Minimally invasive hysterectomy surgery rates for endometrial cancer performed at National Comprehensive Cancer Network (NCCN) Centers.

OBJECTIVES: Minimally invasive surgery (MIS) is a quality measure for endometrial cancer (EC) established by the Society of Gynecologic Oncology and the American College of Surgeons. Our study objective was to assess the proportion of EC cases performed by MIS at National Comprehensive Cancer Network (NCCN) centers and evaluate perioperative outcomes. METHODS: A retrospective cohort study of women who underwent surgical treatment for EC from 2013 to 2014 was conducted at four NCCN centers. Multivariable mixed logistic regression models analyzed factors associated with failure to perform MIS and perioperative complications. RESULTS: In total 1621 patients were evaluated; 86.5% underwent MIS (robotic-assisted 72.5%, laparoscopic 20.9%, vaginal 6.6%). On multivariable analysis, factors associated with failure to undergo MIS were uterine size >12cm (Odds Ratio [OR]: 0.17, 95% CI 0.03-0.9), stage III (OR: 0.16, 95% CI 0.05-0.49) and IV disease (OR: 0.07, 95% CI 0.02-0.22). For stage I/II disease, complications occurred in 5.1% of MIS and 21.7% of laparotomy cases (p<0.01). Laparotomy was associated with increases in any complication (OR: 6.0, 95% CI 3.3-10.8), gastrointestinal (OR: 7.2, 95% CI 2.6-19.5), wound (OR: 3.7, 95% CI 1.5-9.2), respiratory (OR 37.5, 95% CI 3.9-358.0), VTE (OR 10.5, 95% CI 1.3-82.8) and 30-day readmission (OR: 2.6, 95% CI 1.4-4.9) compared to MIS. CONCLUSIONS: At NCCN-designated centers, the MIS hysterectomy rate in EC is higher than the published national average, with low perioperative complications. Previously identified disparities of age, race, and BMI were not observed. A proposed MIS hysterectomy benchmark of >80% in EC care is feasible when performed at high volume centers.

Narcotics reduction, quality and safety in gynecologic oncology surgery in the first year of enhanced recovery after surgery protocol implementation.

OBJECTIVES: Enhanced Recovery After Surgery (ERAS) programs are mechanisms for achieving value-based improvements in surgery. This report provides a detailed analysis of the impact of an ERAS program on patient outcomes as well as quality and safety measures during implementation on a gynecologic oncology service at a major academic medical center. METHODS: A retrospective review of gynecologic oncology patients undergoing elective laparotomy during the implementation phase of an ERAS program (January 2016 through December 2016) was performed. Patient demographics, surgical variables, postoperative outcomes, and adherence to core safety measures, including antimicrobial and venous thromboembolism (VTE) prophylaxis, were compared to a historical patient cohort (January 2015 through December 2015). Statistical analyses were performed using t-tests, Wilcoxon rank sum tests, and Chi squared tests. RESULTS: The inaugural 109 ERAS program participants were compared to a historical patient cohort (n=158). There was no difference in BMI, race, malignancy, or complexity of procedure between cohorts. ERAS patients required less narcotics (70.7 vs 127.4, p=0.007, oral morphine equivalents) and PCA use (32.1% vs. 50.6%, p=0.002). Despite this substantial reduction in narcotics, ERAS patients did not report more pain and in fact reported significantly less pain by postoperative day 3. There were no differences in length of stay (5days), complication rates (13.8% vs. 20.3%, p=0.17) or 30-day readmission rates (9.5 vs 11.9%, p=0.54) between ERAS and historical patients, respectively. Compliance with antimicrobial prophylaxis was 97.2%. However, 33.9% of ERAS patients received substandard preoperative VTE prophylaxis. CONCLUSIONS: ERAS program implementation resulted in reductions in narcotic requirements and PCA use without changes in length of stay or readmission rates. Compliance should be diligently audited during the implementation phase of ERAS programs, with special attention to adherence to pre-existing core safety measures.

Compliance with research standards within gynecologic oncology fellowship: A Gynecologic Oncology Fellowship Research Network (GOFRN) study.

OBJECTIVES: Participation in clinical and basic science research is emphasized in gynecologic oncology training. We sought to identify trends in adherence to expected research practices and reasons for non-adherence among gynecologic oncology fellows. METHODS: An anonymous 31-question online survey assessing academic behaviors, including IRB compliance, authorship assignment, data sharing, and potential barriers to non-adherence was distributed to all SGO gynecologic oncology fellow members in July 2016. Descriptive statistics and univariate analyses were performed. RESULTS: Of 190 members, 35.3% (n=67) responded. 73% (n=49) of respondents reported personal non-compliance and 79.1% (n=53) reported having witnessed others being non-complaint with at least one expected research practice. Areas of compliance failure included changing a research question without appropriate IRB amendment (20%; n=14), conducting research under a nonspecific IRB (13.9%; n=9), and performing research without IRB approval (6.1%; n=4). Longer institutional time for IRB approval was significantly associated with IRB non-adherence (p<0.05). First year fellows were more likely to use a nonspecific IRB (p=0.04) or expand a question without amending the IRB (p=0.04). When asked about storage of protected health information (PHI) for research, 53% reported non-secure storage with 17.1% (n=6) having done so for >1000 patients. Thirty respondents (45.5%) assigned authorship to someone who failed to meet ICMJE criteria and twelve (18.5%) accepted authorship without meeting ICMJE criteria. Most commonly cited reasons for non-adherence were: cumbersome IRB processes (80.3%), pressure from senior authors (78.8%), fear of someone else publishing first, (74.2%) and lack of support navigating appropriate research practices (71.2%). CONCLUSIONS: Fellow non-compliance with expected research practices is high, particularly with regards to secure storage of PHI and appropriate authorship assignment. Time-consuming and cumbersome IRB procedures, perceived pressure from senior authors, and lack of research support contribute to non-adherence. Further support and education of gynecologic oncology fellows is needed in order to help address these barriers.

Use of a novel sentinel lymph node mapping algorithm reduces the need for pelvic lymphadenectomy in low-grade endometrial cancer.

OBJECTIVES: To evaluate the capability of a novel sentinel lymph node (SLN) mapping algorithm to reduce the need for pelvic lymphadenectomy (PLND) in patients with low-grade (G1-2) endometrial cancer (LGEC). METHODS: Patients with LGEC underwent evaluation according to a novel lymphatic assessment algorithm during hysterectomy with SLN biopsy at two academic gynecologic oncology programs. Side-specific PLND was only performed if ipsilateral SLN mapping failed and high-risk uterine features were identified on frozen section (FS). Side-specific and PLND rates were compared to theoretical PLND rates based on the NCCN EC SLN mapping algorithm. RESULTS: Since 11/2015, 113 LGEC patients have been managed according to the algorithm. SLN mapping was bilateral (81%), unilateral (12%), or neither (6%). Nine patients (8.0%) had LN metastases identified. Of the 21 patients requiring intraoperative FS due to failed SLN mapping, high-risk uterine features were identified in eight (38%). These patients underwent either bilateral (2) or unilateral (6) PLND. Side-specific and overall PLND rates were 5.3% and 7.1%, respectively. If all patients with failed mapping had undergone PLND according to the NCCN algorithm, side-specific and overall PLND rates would have been higher, 12.4% and 18.6%, respectively (P=0.01). All patients who failed to map and did not undergo side-specific PLND had low-risk uterine features on final pathology. CONCLUSIONS: Lymphatic assessment using SLN mapping followed by selective FS to determine need for PLND is feasible. When compared to the NCCN algorithm, this novel "Reflex Frozen Section" strategy eliminates PLND in patients at lowest risk for metastasis without compromising identification of metastatic nodal disease.

Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival?

OBJECTIVES: Women with advanced-stage, low-grade serous ovarian carcinoma (LGSC) have low chemotherapy response rates and poor overall survival. Most LGSC tumors overexpress hormone receptors, which represent a potential treatment target. Our study objective was to determine the outcomes of patients with advanced-stage LGSC treated with primary cytoreductive surgery (CRS) and hormone therapy (HT). METHODS: A retrospective study was performed at two academic cancer centers. Patients with Stage II-IV LGSC underwent either primary or interval CRS followed by adjuvant HT between 2004 and 2016. Gynecologic pathologists reviewed all cases. Two-year progression-free (PFS) and overall survival (OS) were calculated. RESULTS: Twenty-seven patients were studied; primary CRS followed by HT were administered in 26, while 1 patient had neoadjuvant chemotherapy followed by CRS and HT. The median patient age was 47.5, and patients had Stage II (n=2), Stage IIIA (n=6), Stage IIIC (n=18), and Stage IV (n=1) disease. Optimal cytoreduction to no gross residual was achieved in 85.2%. Ninety six percent of tumors expressed estrogen receptors, while only 32% expressed progesterone receptors. Letrozole was administered post operatively in 55.5% cases, anastrozole in 37.1% and tamoxifen in 7.4%. After a median follow up of 41months, only 6 patients (22.2%) have developed a tumor recurrence and two patients have died of disease. Median PFS and OS have not yet been reached, but 2-year PFS and OS were 82.8% and 96.3%, respectively, and 3-year PFS and OS were 79.0% and 92.6%, respectively. CONCLUSIONS: Our series describes the initial experience with cytoreductive surgery and hormonal monotherapy for women with Stage II-IV primary ovarian LGSC. While surgery remains the mainstay of treatment, chemotherapy may not be necessary in patients with advanced-stage disease who receive adjuvant hormonal therapy. A cooperative group, Phase III trial is planned to define the optimal therapy for women with this ovarian carcinoma subtype.

The Utility of Sentinel Lymph Node Mapping in High-Grade Endometrial Cancer.

OBJECTIVE: The aim of this study was to report the utility and false-negative rates of sentinel lymph node (SLN) mapping during surgical staging of women with high-grade, apparent uterine-confined endometrial cancer. METHODS: This was a single-institution study performed at a high-volume academic center. From December 2012 to December 2015, women with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, and carcinosarcoma) underwent SLN mapping via cervical injection followed by robot-assisted total laparoscopic hysterectomy and completion lymphadenectomy. Ultrastaging of SLNs was performed in patients with tumors with any degree of myoinvasion. Patient demographics, SLN test characteristics, treatment, and recurrence outcomes were prospectively evaluated for analysis. RESULTS: Fifty-two patients with high-grade histologic findings underwent SLN mapping followed by completion lymphadenectomy. The median patient age was 64 years, and median body mass index was 31.8 kg/m2. Most patients had either serous (46%) or grade 3 endometrioid histology (27%) on preoperative biopsy. Nine patients had nodal metastases, 7 of whom had metastases identified in SLNs. No low-volume nodal metastases were identified on ultrastaging. Two patients had false-negative SLN mapping (22%). After a median follow-up of 15.6 months, 14 recurrences (27%) were diagnosed; all were distant or multisite relapses. Sentinel lymph node mapping did not impact the choice of adjuvant therapy or recurrence risk in node-positive patients. CONCLUSIONS: Sentinel lymph node detection of metastases in patients with high-grade endometrial cancer is high, but false-negative results were encountered. More research is needed to determine whether SLN mapping can safely replace systemic lymphadenectomy in women with high-risk histologic findings.

Preinvasive and Invasive Cervical Adenocarcinoma: Preceding Low-Risk or Negative Pap Result Increases Time to Diagnosis.

OBJECTIVES: The aims of the study were to investigate screening histories of women with adenocarcinoma in situ (AIS) and adenocarcinoma (AdCa) of the cervix and to further evaluate screening for glandular disease. MATERIALS AND METHODS: Screening histories were retrospectively collected for patients with AIS or AdCa at a single large-volume academic institution from 2005 to 2015. Fisher exact and Wilcoxon rank sum tests were used to compare AIS with AdCa patient characteristics, distribution of preceding Pap (i.e., trigger Pap) results, and high-risk human papillomavirus testing. The association between Pap result and time to diagnosis was evaluated. RESULTS: Eighty-seven cases, 50 AIS and 37 AdCa, met study criteria; median age was 31 and 43 years, respectively. Among the AIS cohort, 52.0% had a negative or low-risk trigger Pap result versus 24.3% of those with AdCa (p = .001). The time to diagnosis of AIS ranged from 8.4 to 18.8 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .002). The time to diagnosis of AdCa ranged from 14.6 to 44.7 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .003). Among those with high-risk human papillomavirus testing, 89.7% tested positive at the time of trigger Pap with 100% positivity among those with low-risk or negative trigger Pap results. CONCLUSIONS: Cervical AIS and AdCa affect many young nulliparous women and commonly preceded by low-risk or negative Pap testing. The interval to diagnosis increases with low-risk and negative Pap results, and therefore, further investigation into optimal screening for glandular lesions is needed.

Reducing overtreatment: A comparison of lymph node assessment strategies for endometrial cancer.

OBJECTIVES: To compare the utility of three lymph node (LN) assessment strategies to identify lymphatic metastases while minimizing complete lymphadenectomy rates in women with low-grade endometrial cancer (EC). METHODS: Using our institutional standard protocol (SP), patients with complex atypical hyperplasia (CAH) or grade 1/2 EC underwent sentinel lymph node (SLN) mapping, hysterectomy, and intraoperative frozen section (FS). Lymphadenectomy was performed if high-risk uterine features were identified on FS. Utilizing SP data, two alternative strategies were applied: a Universal FS Strategy (UFS), omitting SLN mapping and performing lymphadenectomy based on FS results, and a SLN-Restrictive FS Strategy (SLN-RFS) in which FS and lymphadenectomy are performed only if bilateral SLN mapping fails. RESULTS: Of 114 patients managed on the SP, SLNs were identified in 86%, with lymphatic metastases detected in eight patients. Six patients recurred after a median follow up of 15months. Most (83%) developed in those who had a negative systematic lymphadenectomy (n=4; mean LNs: 18) or no lymphadenectomy indication. When applying the alternative lymphatic assessment strategies, the SLN-RFS approach would theoretically result in lower lymphadenectomy rates compared to both the SP and the alternative UFS strategies (9.2% versus 36.8% and 36.8%, respectively; p=0.004), without a reduction in detection of LN metastases (8/8 versus 8/8 and 5/8, respectively). CONCLUSION: In this modeling analysis, an operative strategy omitting universal frozen section and restricting its use to cases with failed SLN mapping may result in lower lymphadenectomy rates and reduce the risk of overtreatment without compromising oncologic outcome for patients with EC.

Lymphopenia and its association with survival in patients with locally advanced cervical cancer.

OBJECTIVE: To evaluate the association between lymphopenia and survival in women with cervical cancer treated with primary chemoradiation. METHODS: A single institution, retrospective analysis of patients with stage IB2-IVA cervical cancer who received upfront chemoradiation from 1998 to 2013 was performed. Complete blood counts from pre-treatment to 36 months post-treatment were analyzed. Lymphopenia and known prognostic factors were evaluated for an association with progression-free (PFS) and overall survival (OS). RESULTS: Seventy-one patients met study criteria for whom 47 (66%) had a documented total lymphocyte count (TLC) two months after initiating chemoradiation. FIGO stage distribution was 6% Stage I, 46% Stage II, 45% Stage III and 3% Stage IV. Pre-treatment TLC was abnormal (<1000 cells/mm3) in 15% of patients. The mean reduction in TLC was 70% two months after initiating chemoradiation. Severe post-treatment lymphopenia (TLC <500 cells/mm3) was observed in 53% of patients; they experienced inferior median OS (21.2 vs. 45.0 months, P=0.03) and similar 25th percentile PFS (6.3 vs. 7.7 months, P=0.06) compared to patients without severe lymphopenia. Multivariate analysis demonstrated pre-treatment TLC ≥1000 cells/mm3 and post-treatment TLC >500 cells/mm3 had a 77% (HR: 0.23; 95% CI 0.05-1.03; P=0.053) and 58% decrease in hazards of death (HR: 0.42; 95%CI 0.12-1.46; P=0.17) respectively. CONCLUSION: More than half of cervical cancer patients treated with chemoradiation experienced severe and prolonged lymphopenia. Although statistical significance was not reached, the findings suggest that pre- and post-treatment lymphopenia may be associated with decreased survival. Further research is warranted, given that lymphopenia could be a reversible prognostic factor.