An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG 275.

OBJECTIVES: Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about which is more effective, less toxic, and better tolerated. The primary trial objective was to test if treatment with multi-day methotrexate (MTX) was inferior to pulse actinomycin-D (ACT-D). Secondary objectives included evaluation of severity and frequency of adverse events, and impact on quality of life (QOL). METHODS: This was a prospective international cooperative group randomized phase III two arm non-inferiority study (Clinical Trials Identifier: (NCT01535053). The control arm was ACT-D; the experimental arm was multi-day MTX regimen (institutional preference of 5 or 8 day). Outcome measures included complete response rate, recurrence rate, toxicity, and QOL as measured by FACT-G and FACIT supplemental items. RESULTS: The complete response rates for multi-day methotrexate and pulse actinomycin-D were 88% (23/26 patients) and 79% (22/28 patients) (p = NS) respectively, there were two recurrences in each arm, and 100% of patients survived. Significant toxicity was minimal, but mouth sores (mucositis), and eye pain were significantly more common in the MTX arm (p = 0.001 and 0.01 respectively). Quality of life showed no significant difference in overall quality of life, body image, sexual function, or treatment related side effects. The study was closed for low accrual rate (target 384, actual accrual 57), precluding statistical analysis of the primary objective. CONCLUSIONS: The complete response rate for multi-day methotrexate was higher than actinomycin-D, but did not reach statistical significance. The multi-day MTX regimens were associated with significantly more mucositis and were significantly less convenient.

Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: An NRG Oncology/Gynecologic Oncology Group ancillary analysis.

OBJECTIVES: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. METHODS: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. CONCLUSIONS: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach.

Laparoendoscopic single-site radical hysterectomy with pelvic lymphadenectomy: initial multi-institutional experience for treatment of invasive cervical cancer.

STUDY OBJECTIVE: To describe the feasibility, safety, and outcomes of women with stage I cervical cancer treated with laparoendoscopic single-site surgery radical hysterectomy (LESS-RH). DESIGN: A retrospective descriptive study (Canadian Task Force classification III). SETTING: Multiple academic teaching hospitals. PATIENTS: Women with Fédération Internationale de Gynécologie et d'Obstétrique FIGO stage IA1 to IB1 cervical cancer. INTERVENTIONS: LESS-RH as the primary therapy for cervical cancer performed by a gynecologic oncologist with expertise in LESS. A multichannel, single-port access device; a flexible-tipped 5-mm laparoscope; and a multifunctional instrument were used in all cases. Clinicopathologic, surgical, and perioperative outcomes were analyzed. MEASUREMENTS AND MAIN RESULTS: Twenty-two women were identified in whom a LESS-RH was attempted; 20 (91%) successfully underwent the procedure, including 19 in whom pelvic lymphadenectomy (PLND) was completed. Of the 2 converted procedures, 1 patient underwent 2-port laparoscopy secondary to truncal obesity, and 1 patient underwent conversion to laparotomy secondary to external iliac vein laceration during PLND. The median age and body mass index were 46 years and 23.3 kg/m(2), respectively. The median number of pelvic lymph nodes removed was 22. One patient experienced an intraoperative complication, and no patient required reoperation. The margins of excision were negative. One patient with 2 positive pelvic nodes and 1 patient with microscopic parametrial disease received adjuvant chemosensitized radiation; 3 additional patients received adjuvant radiation therapy secondary to an intermediate risk for recurrence. After a median follow up of 11 months, no recurrences were detected. CONCLUSION: LESS-RH/PLND is feasible and safe for select patients with stage I cervical cancer. Larger studies are needed to confirm whether the increased technical difficulty of this procedure justifies its use in routine gynecologic oncology practice.

Radiation Therapy With or Without Cisplatin for Local Recurrences of Endometrial Cancer: Results From an NRG Oncology/GOG Prospective Randomized Multicenter Clinical Trial.

PURPOSE: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION: Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.

The use of argon beam coagulation in treating vulvar intraepithelial neoplasia III: a retrospective review.

UNLABELLED: Argon beam coagulation (ABC) has unique properties which make it suitable for the local treatment of superficial epithelial disorders such as vulvar intraepithelial neoplasia (VIN III). OBJECTIVE: To evaluate argon beam coagulation in treating multifocal VIN III. METHODS: Argon beam coagulation was used in twenty-nine patients. ABC was set at 80 W, 7 L/min. All patients were given 1% silvadene cream to apply to vulva. Patients had follow-up appointments two weeks and six weeks postoperatively. Patients were followed every three to six months for the subsequent year. RESULTS: 2 of 29 (6.8%) experienced moderate pain within the first two weeks postoperatively requiring prescriptions for perocet. 2 of 29 (6.8%) had yeast infection requiring diflucan. Mean follow-up time was 34.9 months (11.7-37.4). 15 of 29 (51.7%) had no recurrence within the follow-up period. 14 of 29 (48.3%) recurred within the follow-up period. The mean time to recurrence is 23.2 months. CONCLUSION: This small retrospective review is the first to evaluate argon beam coagulation in treating multifocal VIN III. This review indicates that ABC is comparable to other vulva organ conserving therapies. ABC retains cosmesis, and form of the vulva. This is a major advantage over surgery. Repeat treatments are also possible, which is important in a condition such as VIN, which tends to be multifocal and recurrent.

Evaluation of exposures to healthcare personnel from cisplatin during a mock demonstration of intra-operative intraperitoneal chemotherapy administration.

UNLABELLED: Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In 2006, the National Cancer Institute released an announcement supporting the use of intraperitoneal (IP) chemotherapy in advanced ovarian cancer. It remains unanswered how many cycles of IP chemotherapy are required to maintain a survival advantage. There may be a benefit with as few as three IP cycles and possibly as few as one IP chemotherapy cycle. OBJECTIVE: In preparation for a clinical trial in which chemotherapy would be administered intra-operatively, the question of exposure to healthcare personnel arose, therefore, the purpose of this study was to perform an evaluation of healthcare personnel exposure to cisplatin during a mock demonstration of intraperitoneal chemotherapy administration. MATERIALS AND METHODS: The National Institute of Occupational Safety and Health (NIOSH), the Women's Cancer Center of Nevada, and the staff of the University Medical Center, Las Vegas, participated in this mock demonstration. Employees wore personal protective equipment recommended by NIOSH. Wipe, area, and breathing zone air samples were taken from the pharmacy and operating room, and during sterilization of equipment. RESULTS: All samples were negative for cisplatin, except for one surface wipe from the floor of the operating room (OR) after the mock procedure. Upon sanitization of the OR, no cisplatin was detected on the floor. CONCLUSION: This was the first study evaluating the exposure of healthcare personnel to the administration of cisplatin intra-operatively. NIOSH endorsed this practice so long as the employees adhere to using the recommended personal protective equipment.

Comparison of current staging systems and a novel staging system for uterine leiomyosarcoma.

OBJECTIVES: Uterine leiomyosarcoma (LMS) was traditionally staged by modified 1988 International Federation of Gynecology and Obstetrics (FIGO) staging criteria for endometrial adenocarcinoma. Contemporary methods of staging include the 2009 FIGO system for uterine LMS and the 2010 American Joint Committee on Cancer (AJCC) soft tissue sarcoma system. The aim of this study was to compare the accuracy of these 3 staging systems and a novel system in predicting disease-specific survival for patients with uterine LMS. METHODS: Patients, evaluated at our institution with uterine LMS from 1976 to 2009, were identified. Stage was assigned retrospectively based on operative and pathology reports. Staging systems performance was compared using confidence indices. RESULTS: We identified 244 patients with uterine LMS with sufficient information to be staged by all 3 systems. For each staging method, lower stage was associated with significantly improved disease-specific survival, P < 0.001. Patients with 2010 AJCC stage IA disease (low-grade, ≤5 cm) experienced no disease-specific deaths. We created a novel staging system, which used size and grade to stratify patients with disease confined to the uterus and/or cervix and combined the remaining patients with extrauterine disease as stage IV. Based on confidence index, the 2010 AJCC system and our novel system provided more accurate prognostic information than either of the 2 FIGO systems. CONCLUSIONS: Uterine LMS remains a clinically aggressive malignancy. Size and grade provided accurate prognostic information for patients with disease confined to the uterus and/or cervix. Patients with small, low-grade uterine LMS do not benefit from adjuvant therapy.

Perioperative care in gynecologic oncology.

PURPOSE OF REVIEW: To review perioperative care in gynecologic oncology with special emphasis on areas of controversy. RECENT FINDINGS: Major gynecologic surgery still represents the cornerstone of management among women diagnosed with gynecologic malignancies. The implementation of clinical guidelines can significantly impact perioperative morbidity and mortality. Preoperative evaluation and preparation allows the surgeon to identify patient risks and develop risk factor modification strategies decreasing delays in preparation and cost and improving patient safety. Preoperative areas of controversy include preoperative testing and evaluation, use of mechanical bowel preparation, prophylactic antibiotics, and use of anticoagulants, and the timing of postoperative feeding. SUMMARY: In healthy women undergoing gynecologic cancer surgery preoperative evaluation requirements will be minimal. For women with extensive comorbid conditions a more detailed evaluation will be required to decrease perioperative morbidity and mortality. Mechanical bowel preparations should not be required preoperatively. Preoperative administration of antibiotics and anticoagulants should be provided to all patients undergoing major gynecologic cancer surgery.

Bilateral Ovarian Serous Borderline Tumor with Non-Invasive Endometrial Implants.

Herein, we are presenting a case of a 33-year-old woman who presented to the emergency department complaining of persistent lower abdominal pain of one-day duration. Physical examination revealed abdominal tenderness with right lower quadrant rebound tenderness. Computed tomography abdomen/pelvis showed a 6 cm possible necrotic mass of the left ovary with moderate amount of complex ascites. A laparoscopic left oophorectomy with bilateral salpingectomy, right ovarian biopsy, and appendectomy were performed without complications. The cut surface of the left ovary showed a 9.7 cm × 8 cm × 4 cm ovarian mass, and the cut surface revealed multiple gray-tan friable papillary excrescence. Microscopic evaluation showed findings consistent with left and right ovarian serous borderline tumor (SBT). Subsequently, a tumor staging was conducted with total laparoscopic hysterectomy, pelvic and periaortic lymph node dissection, and omentectomy. The endometrium sections showed several small foci of SBT within the endometrial stroma, consistent with non-invasive implants of the endometrium. The omentum and lymph nodes were all negative for malignancy. SBTs associated with endometrial implants are very rare with only one case reported in the literature. Their existence can cause diagnostic challenges, and they should be acknowledged for early diagnosis and to plan for patient's treatment and outcome.

Post fellowship training in "new-to-them" surgical techniques: assessment of learning curve characteristics.

OBJECTIVE: To evaluate surgically related quality outcomes during the learning curve for board-certified or board-eligible gynecologic oncologists developing "new-to-them" surgical techniques. METHODS: The study design was a retrospective review of patients with endometrial cancer clinically limited to the uterus and/or cervix undergoing TLH-BSO or TAH-BSO, aortic and pelvic lymphadenectomy(APLNDx), peritoneal washings with/without omentectomy from May 1996 to April /2006. A "senior" surgeon taught three board-certified or board-eligible gynecologic oncologists a "new-to-them" technique to perform both TLH-BSO and TAH-BSO with APLNDx using argon beam coagulation and endoscopic staplers in patients with early-stage endometrial cancer. The main outcome measures were: a) length of surgery; b) surgical measures, e.g. lymph node count; and c) peri-operative morbidity. A comparison of outcomes with the "senior" surgeon was undertaken. The learning curve characteristics were analyzed by ANOVA and curve estimate analysis. RESULTS: The mean operative times associated with learning a new technique to perform TLH-BSO with APLNDx and TAH-BSO with APLNDx were 155.39+/-26.32 and 102.28+/-34.22 min, respectively, with significant improvement after 20 cases (150.27+/-26.68 vs. 172.30+/-22.28, p=0.030) and 30 cases (93.30+/-24.97 vs. 124.63+/-29.73, p=0.030), respectively. Intra- and peri-operative morbidity and lymph node count were unaffected by experience. CONCLUSION: While mean operative times decreased, outcome measures of surgical quality were not adversely affected during the learning curve for post-fellowship training while acquiring "new-to-them" surgical techniques. This study emphasizes the need for "senior" surgical supervision during the initial training period. The results of this study are likely transferable to fellowship-trained gynecologic oncologists learning other "new-to-them" surgical techniques and procedures.

A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response.

PURPOSE: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. PATIENTS AND METHODS: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21-24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. RESULTS: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). CONCLUSIONS: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.

Virtual reality robotic surgical simulation: an analysis of gynecology trainees.

STUDY OBJECTIVE: To analyze the learning curves of gynecology trainees on several virtual reality da Vinci Skills Simulator exercises. DESIGN: Prospective cohort pilot study. SETTING: Academic hospital-based gynecology training program. PARTICIPANTS: Novice robotic surgeons from a gynecology training program. METHODS: Novice robotic surgeons from an academic gynecology training program completed 10 repetitions of 4 exercises on the da Vinci Skills Simulator: matchboard, ring and rail, suture sponge, and energy switching. Performance metrics measured included time to completion, economy of instrument movement, excessive force, collisions, master workspace range, missed targets, misapplied energy, critical errors, and overall score. Statistical analyses were conducted to define the learning curve for trainees and the optimal number of repetitions for each exercise. RESULTS: A total of 34 participants were enrolled, of which 9 were medical students, 22 were residents, and 3 were fellows. There was a significant improvement in performance between the 1st and 10th repetitions across multiple metrics for all exercises. Senior trainees performed the suture exercise significantly faster than the junior trainees during the first and last repetitions (p = 0.004 and p = 0.003, respectively). However, the performance gap between seniors and juniors narrowed significantly by the 10th repetition. The mean number of repetitions required to achieve performance plateau ranged from 6.4 to 9.3. CONCLUSION: Virtual reality robotic simulation improves ability through repetition at all levels of training. Further, a performance plateau may exist during a single training session. Larger studies are needed to further define the most high-yield simulator exercises, the ideal number of repetitions, and recommended intervals between training sessions to improve operative performance.

Extrauterine inflammatory myofibroblastic tumor: A case report.

•This is the first case report of inflammatory myofibroblastic tumor in the literature to present with extrauterine disease.•A prompt work-up of symptoms may have precluded a tumor debulking procedure.