A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status ≤ 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615].

Gynecologic melanomas: A clinicopathologic and molecular analysis.

OBJECTIVE: Melanoma originating from gynecologic sites (MOGS), including the vulva, vagina, and cervix, is a rare and aggressive form of melanoma with poor long-term clinical outcome. The clinicopathologic features of vulvar and non-vulvar tumors remain relatively understudied, and in contrast to cutaneous melanomas at non-sun-exposed sites, MOGS typically do not harbor BRAF mutations. Thus, we sought to analyze the clinicopathologic and molecular features of MOGS. METHODS: A large retrospective cohort of patients with MOGS (n=59) at a single large academic institution over a 28-year period was identified. Associations among clinicopathologic characteristics were assessed via standard statistical approaches, and clinical outcome was examined using Cox regression analysis. Sanger sequencing was utilized to identify mutations in hotspot regions of BRAF, KIT, NRAS, and CTNNB1. RESULTS: Tumors involving the vagina and/or cervix (non-vulvar) are significantly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, positive resection margins, lymph node metastasis, and poor long-term clinical outcome (with increased risk of death due to disease). The aggressive clinical behavior of non-vulvar tumors is independent of advanced clinical stage and lymph node metastasis in multivariate analysis. Targeted molecular analysis confirms an overall low rate of oncogenic mutations in our MOGS cohort, although KIT mutations (particularly in exon 11) are relatively enriched. CONCLUSIONS: Overall, our results show that non-vulvar MOGS are aggressive tumors with poor long-term clinical outcome and indicate that few targeted therapeutic options are currently available to patients with MOGS.

Incidence and Timing of Thromboembolic Events in Patients With Ovarian Cancer Undergoing Neoadjuvant Chemotherapy.

OBJECTIVE: To identify the incidence and timing of venous thromboembolism as well as any associated risk factors in patients with ovarian, fallopian tube, or primary peritoneal cancer undergoing neoadjuvant chemotherapy. METHODS: We conducted a retrospective cohort study of patients diagnosed with ovarian, fallopian tube, and primary peritoneal cancer and receiving neoadjuvant chemotherapy from January 2009 to May 2014 at a single academic institution. The timing and number of venous thromboembolic events for the entire cohort were categorized as follows: presenting symptom, during neoadjuvant chemotherapy treatment, after debulking surgery, and during adjuvant chemotherapy. RESULTS: Of the 125 total patients with ovarian cancer undergoing neoadjuvant chemotherapy, 13 of 125 patients (10.4%, 95% confidence interval [CI] 6.1-17.2%) had a venous thromboembolism as a presenting symptom and were excluded from further analysis. Of the 112 total patients at risk, 30 (26.8%, 95% CI 19.3-35.9%) experienced a venous thromboembolism. Based on the phase of care, 13 (11.6%, 95% CI 6.8-19.1%) experienced a venous thromboembolism during neoadjuvant chemotherapy, six (5.4%, 95% CI 2.4-11.5%) developed a postoperative venous thromboembolism, and 11 (9.9%, 95% CI 5.5-17%) developed a venous thromboembolism during adjuvant chemotherapy. Two of the four patients with clear cell histology developed a venous thromboembolism in this cohort. CONCLUSION: Overall new diagnosis of venous thromboembolism was associated with one fourth of the patients undergoing neoadjuvant chemotherapy for ovarian cancer with nearly half of these diagnosed during chemotherapy cycles before interval debulking surgery. Efforts to reduce venous thromboembolism so far have largely focused on the postoperative period. Additional attention to venous thromboembolic prophylaxis during chemotherapy (neoadjuvant and adjuvant) in this patient population is warranted in an effort to decrease the rates of venous thromboembolism.

Sister Society Meeting on Global Education Development and Collaboration: Meeting Report.

OBJECTIVES: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle- income countries. METHODS: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle- income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. RESULTS: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. CONCLUSIONS: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries.

Perioperative Laboratory Abnormalities in Gynecologic Oncology Surgical Patients.

Background: Laboratory blood testing incurs financial costs and the blood draws can increase discomfort, yet minimal data exists regarding routine testing in gynecologic oncology surgical patients. Additionally, an increasing number of gynecologic oncology surgeries are performed via a laparoscopic approach. Thus, further investigation into perioperative laboratory testing for gynecologic oncology patients is warranted. An increasing number of gynecologic oncology surgeries are performed via a laparoscopic approach. Thus, further investigation into perioperative laboratory testing for gynecologic oncology patients is warranted. Objective: The aims of this study were (1) to evaluate the frequency and etiology of perioperative laboratory test abnormalities in patients undergoing laparoscopic and laparotomy surgery in a gynecologic oncology service, and (2) to establish an evidence-based algorithm to reduce unnecessary laboratory testing. Materials and Methods: A single-institution retrospective study was completed, investigating laparoscopic and laparotomic surgeries over 4 years. Information on preoperative and postoperative laboratory data, surgical parameters, perioperative interventions, and patient demographics was collected. Quality-assurance data were reviewed. Data were tabulated and analyzed using Statistical Product and Service Solutions (SPSS) version 22. A Student's t-test was used to test for group differences for continuous variables with equal variance, the Mann-Whitney-U test for continuous variables when unequal variance was detected, and Pearson's χ2 was used to investigate categorical variables of interest. p-Values <0.05 were considered to be statistically significant. Logistic regression was performed to investigate the relationships among multiple predictors and each identified outcome. Results: The study included 481 subjects (168 laparoscopies, 313 laparotomies). Patients undergoing laparoscopy were, on average, younger (53.5 versus 57.4), with lower body mass indexes (29.7 versus 33.0) and lower rates of diabetes (10.7% versus 19.5%), compared to patients undergoing laparotomy. Overall, >98% of patients underwent at least one preoperative and postoperative laboratory test, totaling 8060 preoperative and 5784 postoperative results. The laparoscopy group was significantly less likely to have postoperative metabolic abnormalities or to undergo perioperative blood transfusion. Patients taking an angiotensin-converting-enzyme inhibitor, angiotensin-II-receptor blocker, or diuretic were significantly more likely to have elevated creatinine preoperatively (odds ratio [OR]: 5.0; p < 0.001) and postoperatively (OR: 7.1; p < 0.001), and this remained true for each group when divided by surgical approach. Perioperative complications meeting institutional quality assurance criteria occurred in 1.7% of laparoscopy patients compared to 11.8% of laparotomy patients (p < 0.001); perioperative laboratory testing was not a factor in the diagnosis of these complications. Conclusions: Clinically significant laboratory abnormalities are uncommon and are less likely to be found on routine perioperative testing in gynecologic oncology patients undergoing laparoscopy, compared to patients undergoing laparotomy. This suggests a role for limiting perioperative laboratory blood testing. (J GYNECOL SURG 32:111).

An assessment of gynecological cytology screening practices among health care providers nationwide.

CONTEXT: The Michigan Public Health Institute and the Michigan Cancer Consortium's Cervical Cancer Committee conducted a national survey of health care providers, thanks to funding from the Centers for Disease Control Cooperative Agreement 5U47CI000743-02. Papanicolaou test screening practices were examined, emphasizing the relationship between clinical and laboratory practices. This survey found differing screening practices among providers of women's health care. OBJECTIVES: To collect information from family medicine practitioners, women's nurse practitioners, obstetricians and gynecologists, and certified nurse-midwives on Papanicolaou and human papillomavirus testing; to discuss how those practices align with current cytology screening and follow-up recommendations from professional organizations (US Preventive Services Task Force, American Cancer Society, American College of Obstetricians and Gynecologists, and American Society for Colposcopy, and Cervical Pathology); and ultimately, to make recommendations aimed at standardizing practice performance. DESIGN: This survey was conducted in part to examine clinicians' practices and their perceptions of laboratory performance, to evaluate items that are known to enhance quality of care, and to examine factors that may prohibit universal implementation of best standards of care. The survey used a self-administered questionnaire, distributed to 9366 clinicians, with 1601 (17.1%) completed surveys. RESULTS: This assessment shows a clear lack of consensus among practitioners in performing Papanicolaou testing. It demonstrates how differently patients are tested, based on the providers' screening practices, and demonstrates specific cervical cancer screening practice disparities between and among the 4 provider groups, both in Papanicolaou testing and in the use of human papillomavirus testing. CONCLUSION: A unified mandate for screening is needed to standardize screening practices.

A phase II evaluation of selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer. METHODS: This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days. RESULTS: Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum). CONCLUSIONS: Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.

A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study.

BACKGROUND: Patients with recurrent ovarian cancer have limited options, especially in the context of relapse less than six months from primary platinum-based therapy. This Gynecologic Oncology Group (GOG) study was conducted to evaluate the impact of the histone deacetylase inhibitor, belinostat, in combination with carboplatin in women with platinum-resistant ovarian cancer. METHODS: Eligible patients had measurable, recurrent disease within six months of their last dose of a platinum-based combination. Belinostat was dosed at 1000 mg/m(2) daily for five days with carboplatin AUC 5 on day three of 21-day cycles. The primary endpoint was overall response rate (ORR), using a two-stage design. RESULTS: Twenty-nine women enrolled on study and 27 were evaluable. The median number of cycles given was two (range 1-10). One patient had a complete response and one had a partial response, for an ORR of 7.4% (95% CI, .9%-24.3%). Twelve patients had stable disease while eight had increasing disease. Response could not be assessed in five (18.5%). Grade 3 and 4 events occurring in more than 10% of treated patients were uncommon and limited to neutropenia (22.2%), thrombocytopenia (14.8%), and vomiting (11.1%). The median progression-free survival (PFS) was 3.3 months and overall survival was 13.7 months. PFS of at least six months was noted in 29.6% of patients. Due to the lack of drug activity, the study was closed after the first-stage. CONCLUSIONS: The addition of belinostat to carboplatin had little activity in a population with platinum-resistant ovarian cancer.

Perception and use of complementary and alternative medicine among gynecologic oncology care providers.

OBJECTIVE: To determine general attitudes and approaches to complementary and alternative medicine (CAM) among physicians who care for gynecologic oncology patients. METHODS: Surveys were mailed to members of the Society of Gynecologic Oncologists and the Michigan Oncology Group. Physicians were asked to rate their general attitude toward CAM. RESULTS: Surveys were obtained from 462 physicians. Gynecologic oncologists and female physicians were more likely to have positive attitudes toward CAM, and to believe that clinical care should integrate conventional and CAM practices, compared with other oncologists and male physicians. CONCLUSION: Discrepancies exist among oncologists regarding attitude and use of CAM in their practice. Education of physicians regarding the safety and efficacy of CAM modalities may ultimately improve patient care.

Postmenopausal hyperandrogenism caused by a benign cystic teratoma: a case report.

BACKGROUND: Mature, benign cystic teratomas of the ovary are common in reproductive-age women, but they are very rarely associated with androgen production and subsequent development of hirsutism or virilization. We describe a case of postmenopausal hirsutism and hyperandrogenism caused by a mature cystic teratoma as well as the 7 previously reported cases. CASE: A 55-year-old, postmenopausal woman presented with hirsutism and unilateral lower extremity edema. Pelvic ultrasound showed a complex cystic mass in the left ovary measuring 6.0 x 7.0 x 10 cm, and laboratory evaluations revealed progressively increasing testosterone levels. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, with resection of a large, complex mass originating in the left ovary. The pathology department found 2 left, mature ovarian cystic teratomas containing a layer of Leydig cells. Postoperatively the patient experienced rapid normalization of the elevated testosterone level. CONCLUSION: Although rare, ovarian production of androgens resulting in hirsutism or virilization can occur with a hormonally active mature cystic teratoma.

A phase II study of weekly docetaxel for patients with advanced or recurrent cancer of the cervix.

BACKGROUND/AIMS: A phase II study was conducted to assess the activity and toxicity of weekly docetaxel in patients with advanced or recurrent cancer of the cervix. METHODS: Eligible patients were required to have measurable disease with adequate performance status, bone marrow, renal and hepatic function. Patients were allowed to receive chemosensitization and not more than one prior chemotherapy regimen excluding taxanes. Docetaxel 35 mg/m2 was administered intravenously weekly for 3 weeks followed by 1 week off until disease progression or adverse effects prohibited further therapy. RESULTS: Ten patients were entered into this study, all of who were evaluable for toxicity and response. A median of 2 cycles (range 2-6) were administered. The most frequent drug-related toxicities were anemia and fatigue. There were no objective responses. Three patients had stable disease up to 6 cycles. One patient died of exsanguination from a known vaginal metastasis after completing her second cycle. The median progression-free interval was 1.7 months (range 0.9-5.8) and overall survival was 6.9 months (1.6-23.7). CONCLUSIONS: Docetaxel has limited activity in patients with recurrent cancer of the cervix at the dose and schedule tested.

Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide.

OBJECTIVE: To determine if the incidence of cervical intraepithelial neoplasia (CIN) is increased in immunosuppressed women with systemic lupus erythematosus (SLE). METHODS: Women with SLE were consecutively recruited from University of Michigan outpatient rheumatology clinics. Women with abnormal cervical smears at screening were excluded. Cervical smears were obtained at baseline and at 3 and 7 years. Cervical biopsies confirmed cytologic abnormalities (CIN I-III), and were scored by pathologists in blinded fashion. Data were analyzed according to treatment group: (1) prednisone; (2) azathioprine (AZA); (3) intravenous cyclophosphamide (IVCYC); and (4) IVCYC + AZA + prednisone. RESULTS: Sixty-one of 89 women screened were eligible for enrollment. The overall 3-year incidence of CIN was 9.8%. Stratified by treatment group, the 3-year incidence of CIN was 0/23 (0%) in prednisone treated patients, 0/4 (0%) in AZA treated patients, 2/8 (25%) in IVCYC treated patients, and 4/26 (15%) in CYC + AZA + prednisone treated patients. A dose relationship was observed between cumulative IVCYC exposure and CIN; each increase of 1 g of IVCYC exposure corresponded to a 13% increased risk of CIN (p = 0.04). At 7 years, 45 patients remained under followup and 6 patients had died of unrelated causes. No cases of CIN were observed at 7 years, although there were 2 cases of atypical squamous cells of unknown significance and one case of condyloma. CONCLUSION: IVCYC + prednisone therapy for SLE is significantly associated with development of CIN.

Vulvar melanoma: a report of 20 cases and review of the literature.

BACKGROUND: Vulvar melanoma is the second most common vulvar malignancy and represents a significant women's health issue. OBJECTIVE: To report experience with 21 cases of vulvar melanoma in 20 patients and to review the literature about the condition. METHODS: Parameters retrospectively reviewed included age at diagnosis, family history of melanoma, location on the vulva, atypical nevi, Breslow depth, ulceration status, histologic pattern, presenting signs and symptoms, and the results of sentinel lymph node biopsy. Molecular characterization of the melanocortin type 1 receptor was performed in 1 patient. RESULTS: A family history of cutaneous melanoma was present in 15% of cases. The mean Breslow depth was 2.8 mm (range, 0.0-11.0 mm). Ten patients successfully underwent sentinel lymph node biopsy, results of which were positive in 2 (20%). Reported for the first time is that one patient had a germline mutation in the melanocortin type 1 receptor. CONCLUSION: Vulvar and cutaneous melanoma behave similarly despite their unique pathogeneses. Sentinel lymph node biopsy can be performed successfully for vulvar melanoma.

Vulvar melanoma: review of diagnosis, staging, and therapy.

OBJECTIVES: To update, assimilate, and bridge the contemporary literature on vulvar and cutaneous melanoma regarding diagnosis, staging, and therapy to provide a useful clinical reference for managing and counseling for affected patients. MATERIALS AND METHODS: A computerized search for reports in the literature up to June 2003 was carried out using PubMed and MEDLINE databases. Multidisciplinary involvement was used in evaluating the available data and formulating conclusions. RESULTS: More than 300 reports were reviewed. Diagnosis, staging, and therapy aspects of vulvar melanoma are summarized. CONCLUSIONS: Vulvar melanoma represents a subtype of cutaneous melanoma, with similar prognostic and staging factors. The most recent American Joint Committee on Cancer staging system for cutaneous melanoma is applicable to vulvar melanoma. Sentinel lymph node biopsy is reliable for staging the regional lymph node basin for vulvar melanoma. Standardized documentation of clinical and histopathologic parameters is needed to standardize grouping of cases for future comparison studies.

Prognostic value of positron emission tomography using F-18-fluorodeoxyglucose in patients with cervical cancer undergoing radiotherapy.

OBJECTIVE: The purpose of this study was to determine whether positron emission tomography (PET) using F-18-fluorodeoxyglucose (FDG) before and after radiotherapy would predict whether local control of cervical cancer had been achieved. METHODS: FDG-PET scans were performed prior to therapy and at a mean of 4.6 months after radiation in 20 patients (pts) with histologically proven uterine cervical cancer who were undergoing a "curative" course of radiation therapy. FDG uptake was interpreted visually by two readers using a 5-point grading system (0 = normal, 1 = probably normal, 2 = equivocal, 3 = probably abnormal, and 4 = definitely abnormal). The standardized uptake values corrected by lean body mass (SUL) were calculated for suspicious areas. The percentage of residual activity (%RA) for the posttherapy SUL was also evaluated as a percentage of the pretherapy SUL. RESULTS: At baseline before irradiation, 17 of 20 (85.0%) primary tumors were detected. Following irradiation, no or low (grade 0-2) uptake was observed in 9 pts, and none of these had local recurrence. Among the remaining 11 pts with grade 3 or 4 uptake, the correct diagnosis was made for 5 pts with active tumor; SULs (mean +/- SD = 4.17 +/- 2.52) and %RAs (57.9 +/- 16.8). Six patients without active tumor showed relatively low SULs (2.67 +/- 0.69) and %RAs (43.0 +/- 18.3). No significant differences were observed between the recurrent and nonrecurrent groups for these parameters. Overall, sensitivity, specificity, and accuracy were 100, 60, and 70%, respectively. CONCLUSION: These preliminary data indicate that FDG-PET is a sensitive tool for detecting active cervical cancer after radiation, however, the method, without anatomic correlation had suboptimal specificity.