Inversely and adaptively planned interstitial brachytherapy: A single implant approach.

OBJECTIVE: To evaluate the efficacy, feasibility and safety of image-based, inversely and adaptively planned high-dose rate interstitial brachytherapy (HDR-ISBT) to treat advanced primary or recurrent gynecologic malignancy in a single implant, three-consecutive-day regimen. METHODS: Clinical demographics and outcome data were abstracted from all patients with primary and recurrent gynecologic malignancies who received HDR-ISBT boost from 2014 to 2017. Treatment consisted of a single implant (~7 Gy × 4 fractions) of interstitial needles using the Syed-Neblett template over a three-day hospital admission. CT-based (3D) simulation with inverse and adaptive planning was utilized for each fraction. MR prior to and MR immediately after external beam therapy were fused for HDR-ISBT target delineation. RESULTS: Forty women with an overall median follow-up of 18 months (range: 6-54 months) received an HDR-ISBT boost. Of the 30 primary cases (83% cervix, 10% vaginal, 7% uterine), 44% had organ invasion (bladder, rectal or both) on MRI. Median coverage and dose are reported (V100: 98%, HR-CTV EQD2: 85.1 Gy, D90: 92 Gy). A significant association existed between rectal doses exceeding GEC-ESTRO recommendations (D2cc < 75 Gy) and the development of grade 3 gastrointestinal toxicity with a relative risk of 1.4 [1.1-1.8] (p = .046). Actuarial two-year overall survival (OS), local control (LC) and progression-free survival (PFS) were 81%, 81% and 64%, respectively. CONCLUSIONS: A four fraction, inversely and adaptively planned, single-implant approach of image-based HDR-ISBT provides excellent coverage, minimal toxicity and effective local control in patients with advanced and recurrent disease.

The Role of Routine Peritoneal and Omental Biopsies at Risk-Reducing Salpingo-Oophorectomy.

STUDY OBJECTIVE: To assess the potential role of peritoneal and omental biopsies in women undergoing risk-reducing salpingo-oopherectomy (RRSO) for prophylactic management of hereditary breast/ovarian cancer (HBOC) syndromes. DESIGN: A retrospective observational cohort (Canadian Task Force classification II.1). SETTING: An academic gynecology practice. PATIENTS: All women who underwent RRSO for a high-risk BRCA1/2 mutation or deletion at a single institution between January 2003 and June 2016. INTERVENTIONS: After obtaining institutional review board approval, patient demographics, types of surgical intervention, histopathology reports, and outcomes were abstracted. Bilateral fallopian tubes were histologically evaluated using the "sectioning and extensively examining of the fimbriated end" protocol. Descriptive statistics were used to summarize findings. MEASUREMENTS AND MAIN RESULTS: Seventy women underwent RRSO within the study window; 60% (n = 42) carried a high-risk mutation in BRCA1, 37.1% (n = 26) carried a high-risk mutation in BRCA2, and 2.9% (n = 2) had a high-risk BRCA deletion identified by BRAC analysis rearrangement testing (BART). Serous tubal intraepithelial carcinomas were identified in the distal fallopian tube of 3 subjects. In addition to RRSO, subjects underwent pelvic washings (n = 58, 82.9%), omental biopsy (n = 44, 62.9%), peritoneal biopsies of the bilateral paracolic gutters (n = 51, 72.9%), anterior and posterior cul-de-sac (n = 53, 75.7%), and rectosigmoid mesentery (n = 11, 15.7%). Rare atypical cells favoring reactive cells were identified in pelvic washings of 1 subject (1.7%) with histologically normal fallopian tubes. No evidence of atypical mesothelial proliferations or carcinoma was identified in any omental or peritoneal biopsies. The mean duration of follow-up was 32.5 ± 24.7 months. At the last contact, 3 women (4.3%) had died of metastatic breast cancer, whereas another 3 (4.3%) had been diagnosed with a recurrence of their breast cancer. All other subjects were alive and well (n = 64, 91.4%). CONCLUSION: The routine use of peritoneal and omental biopsies for women undergoing RRSO does not appear to improve detection of occult malignancy.

Neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

The historical standard treatment paradigm for advanced epithelial ovarian cancer is surgical staging followed by adjuvant platinum- and taxane-based chemotherapy. It is well established that patients gain a survival advantage when optimal surgical debulking is achieved; surgical intervention that leaves bulky disease does not confer the same advantage. Thus, when optimal cytoreductive surgery is not possible or would lead to excessive morbidity, neoadjuvant chemotherapy followed by interval cytoreductive surgery is employed. There currently is no externally validated predictive model or consensus regarding which patients should be selected for primary debulking surgery vs neoadjuvant chemotherapy. This article reviews the current literature on the use of neoadjuvant chemotherapy as a treatment strategy for patients with advanced epithelial ovarian cancer.

Gynecologic Oncologist as surgical consultant: intraoperative consultations during general gynecologic surgery as an important focus of gynecologic oncology training.

OBJECTIVE: The aim of this study is to explore the previously unexamined role of the Gynecologic Oncologist as an intraoperative consultant during general gynecologic surgery. METHODS: Demographic and clinical data were collected on 98 major gynecologic surgeries that included both a general Gynecologist and a Gynecologic Oncologist between October 2010 and August 2014. Data were analyzed using XLSTAT-Prov2014.2.02. RESULTS: Of 794 major gynecologic surgeries, 98 (12.3%) cases that involved an intraoperative consultation were identified. There were 36 (37%) planned consults and 62 (63%) unplanned consults. Significantly more planned consults were during laparoscopy (100% v 58%; p<0.01) and significantly more unplanned consults were during laparotomy (42% v 0%; p<0.01). The majority of planned consults were for surgical training (86%) and the most common reasons for unplanned consults were adhesions (40%), bowel injury (19%), inability to identify ureter (19%), and cancer (11%). The most common interventions performed during unplanned consults were identification of anatomy (55%), lysis of adhesions (42%), and retroperitoneal dissection (27%). Average surgeon years in practice were significantly lower for unplanned consults (9 v 15; p<0.01). A total of 25 major adverse events occurred in 15 cases with the majority occurring in cases with unplanned consults (23% v 3%; p<0.01). After controlling for laparotomy, unplanned consultation was not significantly associated with major events (OR=6.67, 95%CI 0.69-64.39; p=0.10). CONCLUSIONS: Gynecologic Oncologists play a pivotal role in the support of generalist colleagues during pelvic surgery. In this series, Gynecologic Oncologists were consulted frequently for complex major benign surgeries. It is important to incorporate the skills required of an intraoperative consultant into Gynecologic Oncology fellowship training.

Trends in Treatment of Uterine Serous Cancer in the Medicare Population.

OBJECTIVE: The objectives of this study were to evaluate the rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma in the Medicare population and to compare clinical outcomes in treated and untreated patients. METHODS: The linked Surveillance, Epidemiology, and End Results and Medicare databases were queried to identify patients with a diagnosis of uterine serous carcinoma between 1992 and 2009. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: A total of 2188 patients met study eligibility criteria. Stages I, II, III, and IV diseases accounted for 890 (41%), 174 (8%), 470 (21%), and 654 (30%) of the study population, respectively. Chemotherapy, radiotherapy, both, or none, were administered as adjuvant therapy in 635 (29%), 536 (24%), 308 (14%), and 709 (32%) of the study population, respectively. Use of chemotherapy became more frequent over time. Over the study period, and after adjusting for race, time of diagnosis, SEER registry, marital status, stage, age, surgery, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between receipt of radiotherapy alone (hazard ratio [HR], 1.3; 95% CI, 1.04-1.67) and not receiving any treatment (HR, 1.5; 95% CI, 1.2-2.01) and worst survival. Survival was not improved over time. CONCLUSION: Although adjuvant chemotherapy and combination treatment with chemotherapy and radiation were associated with improved survival in our model, there was no significant improvement in survival over time.

Adnexal masses in the premenopausal patient.

Practitioners may frequently encounter adnexal masses in premenopausal women. Adnexal masses can represent a wide variety of etiologies, and therefore they can represent a diagnostic dilemma. When an adnexal mass is found the initial work up must focus on identifying acute pathology followed by determining the risk of a malignancy. Pelvic ultrasound remains the mainstay for evaluation of adnexal masses in premenopausal patients. If ultrasounds findings are indeterminate magnetic resonance imaging (MRI) is the next imaging modality of choice. The evaluation for malignancy should include serum marker screening. Aspiration of adnexal masses is generally avoided, due to the lack of therapeutic benefit and risk of seeding a tumor. When ultrasound findings are suggestive of benign disease, conservative management, including repeat imaging, should be considered. If the clinical suspicion for malignancy is high referral to a gynecologic oncologist is warranted. In other patients whom the evaluation of their adnexal mass remains unclear surgical excision with care not to disrupt the integrity of the mass should be performed for pathologic diagnosis.

Inhibition of gamma-secretase activity impedes uterine serous carcinoma growth in a human xenograft model.

OBJECTIVE: Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. METHODS: Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods. RESULTS: High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. CONCLUSIONS: Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.

Impact of hematologic toxicities during concurrent chemoradiation for cervical cancer.

OBJECTIVE: To evaluate the prognostic significance of hematological toxicities during cervical cancer treatment. METHODS: Patients treated for cervical carcinoma with definitive chemoradiation were identified. Toxicities were assessed during weeks 1 to 6 of concurrent external beam radiation and chemotherapy. Outcomes were analyzed using Cox regression analysis. RESULTS: One hundred twenty-one patients with Federation of Gynecology and Obstetrics stage I-III disease were eligible for analysis. Median age at diagnosis was 45 years (interquartile range, 40-52) with median follow-up time of 34 months (95% confidence interval, 30.8-37.2). All patients experienced some grade of hematologic toxicity. The most common grade 3+ toxicities were low absolute lymphocyte count (n=115, 95%), low white blood cell count (n=21, 17%), and anemia (n=11, 9%). The most common grade 4 toxicity was lymphopenia, experienced by 36% of patients (n=44). Grade 4 lymphopenia was associated with reduced overall survival (hazard ratio [HR], 4.5; P=0.005), progression-free survival (HR, 3.4; P=0.001), and local control (HR, 4.1; P=0.047). Anemia grade 3, 4 was also associated with reduced overall survival (HR, 4.1; P=0.014). After controlling for disease and treatment variables, grade 4 lymphopenia remained significantly associated with reduced overall survival (HR, 9.85; P=0.007). The association with grade 4 lymphopenia only remained significant in women of Hispanic ethnicity. CONCLUSION: Severe lymphopenia was associated with reduced overall survival and progression-free survival in Hispanic women undergoing definitive chemoradiation for cervical cancer, but not associated with outcomes in non-Hispanic women.

Predictors of follow-up non-compliance after definitive radiotherapy for locally advanced cervical cancer at a community cancer center.

Introduction: Non-compliance to post-treatment cancer surveillance can lead to late detection of recurrence. This study aims to identify patients at high risk for loss of follow-up after radiotherapy for locally advanced cervical cancer. Methods: Consecutive patients with locally advanced cervical cancer treated with definitive chemoradiotherapy (2013-2020) at a community cancer center were retrospectively reviewed. The main outcome was overall follow-up compliance rate over time. Additionally, specialist-specific follow-up times, reasons for discontinuation and predictors of loss of follow-up events were evaluated. Results: The median age of the 154 patients included was 46.5 years (range: 26-84). The 6-month, 1-, 3-, and 5-year overall loss of follow-up rates were: 5.3%, 15.3%, 33.6%, and 48.2%, respectively. After a median overall follow-up time of 21.0 months, the median specialist-specific surveillance times were 17 months and 6 months with gynecologic and radiation oncologists, respectively (p < 0.01). Overall, the most common reasons for loss of follow-up were financial (21.7%) and relocation to another city (28.3%). By specialty, the most common reasons were relocation of care (56.5%, gynecologic oncologist) and disease progression (31.3%, radiation oncologist). In the multivariable analysis, older age (continuous, OR: 0.96; p < 0.01) and Hispanic ethnicity (OR: 0.39; p < 0.01) were protective against loss of follow-up, while increased number of gestations (continuous, OR: 1.23, p = 0.01) and living farther from the cancer center (continuous, OR: 1.002; p = 0.03) increased the chance of loss of follow-up. Conclusion: Younger, non-Hispanic, multiparous women that live far from the community cancer center have an increased chance of follow-up discontinuity, which are attributed to financial reasons in more than 20% of the cases.

Association Between Metabolic Syndrome and Endometrial Cancer Survival in a SEER-Medicare Linked Database.

BACKGROUND: Metabolic syndrome has previously been linked to increased risk of endometrial cancer. This study examines the association between metabolic syndrome and cancer-specific survival (CSS) in early stage and locoregionally advanced endometrial cancer. METHODS: The SEER-Medicare linked database was used to identify a cohort of patients with endometrial cancer between 1992 and 2011 who underwent hysterectomy. Patients with incomplete stage or grade information were excluded. Patients were stratified into early stage (stage I to II) or locoregionally advanced (stage III to IVa) disease. Metabolic syndrome status was determined through Medicare claims 1 year before diagnosis. The relationship between metabolic syndrome and CSS was evaluated using univariable and multivariable Cox proportional hazards regression analyses. RESULTS: A total of 10,090 patients with endometrial cancer were identified. The mean age was 75 and the majority (91.5%) were white. At diagnosis, 86.6% of patients were early stage and 13.4% were locoregionally advanced. Sixteen percent of patients had metabolic syndrome. On stage stratified multivariable analysis, race, income quartile, year of diagnosis, histopathology, and adjuvant treatment were associated with CSS in early stage disease. Presence of metabolic syndrome was associated with worse CSS in early stage disease (hazard ratio=1.28, 95% confidence interval: 1.09-1.53); this difference did not exist for locoregionally advanced disease (hazard ratio=1.18, 95% confidence interval: 0.93-1.49). CONCLUSIONS: In elderly early stage endometrial cancer patients, metabolic syndrome is associated with worse CSS. Control of metabolic syndrome through lifestyle and pharmacologic therapies may improve cancer prognosis in this population.

Changing Trends in Lymphadenectomy for Endometrioid Adenocarcinoma of the Endometrium.

OBJECTIVE: To describe trends in the use of lymphadenectomy for endometrioid adenocarcinoma of the endometrium between 1998 and 2012. METHODS: A time-trend analysis was conducted using a population-based cancer registry covering 28% of the population of the United States. To quantify differences over the study period time, the frequency of lymphadenectomy and nodal metastasis among women who underwent surgical treatment of endometrioid endometrial adenocarcinoma was compared among consecutive 3- to 4-year periods. Biannual frequency of lymphadenectomy was modeled with Joinpoint regression to identify when potential changes in trends occurred and calculate annual percentage change. RESULTS: A total of 74,365 women who underwent surgery between 1998 and 2012 were analyzed. Frequency of lymphadenectomy increased by 4.2% annually (95% confidence interval [CI] 3.7-4.6) from 1998 to 2007, after which the frequency declined by 1.6% per year (95% CI 0.9-2.2). Between 1998-2000 and 2007-2009, the frequency of lymphadenectomy rose from 48.7% to 65.5% (risk difference 16.8%, 95% CI 15.4-18.1), the proportion of women found to have nodal metastasis increased by 1.1% (95% CI 0.4-1.7), and the frequency of negative lymphadenectomy increased by 15.7% (95% CI 14.3-17.1). The decline in frequency of lymphadenectomy after 2007 was associated a 3.1% (95% CI 2.1-4.1) decline in the rate of negative lymphadenectomy, but no change in the proportion of women found to have nodal metastasis (P=.17). CONCLUSION: The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012. LEVEL OF EVIDENCE: II.