Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study.

OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

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.

Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209).

PURPOSE: Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS: GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS: From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION: With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

Neuropathic uterine pain after hysterectomy. A case report.

BACKGROUND: Neuropathic pain arises when there is damage to or dysfunction of the nervous system. Diabetic neuropathy, postherpetic neuralgia and phantom limb pain are common types of neuropathic pain. It is not commonly recognized in gynecologic practice. CASE: A patient underwent a hysterectomy for a tuboovarian abscess and underlying endometriosis. Despite maximal dosing with conventional pain medications, she continued to have significant pain that had not been present following prior surgeries. Use of low-dose amitriptyline successfully treated the pain, with no sequelae. CONCLUSION: Persistent pain following gynecologic surgery that does not respond to conventional therapy may have a neuropathic origin. Attention to appropriate history and physical examination may lead to an increase in the diagnosis of neuropathic pain in gynecology patients. This may have implications for persistent pain in other gynecologic diseases.

Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study.

PURPOSE Ixabepilone (BMS-247550) is a microtubule-stabilizing epothilone B analog with activity in taxane-resistant metastatic breast cancer. The Gynecologic Oncology Group conducted a phase II evaluation of the efficacy and safety of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant primary ovarian or peritoneal carcinoma. PATIENTS AND METHODS Patients with measurable platinum- and taxane-resistant ovarian or peritoneal carcinoma, defined as progression during or within 6 months of one prior course of treatment with each agent, received intravenous ixabepilone 20 mg/m(2) administered over 1 hour on days 1, 8, and 15 of a 28-day cycle. Results Of 51 patients entered, 49 were eligible. The objective response rate was 14.3% (95% CI, 5.9% to 27.2%), with three complete and four partial responses. Twenty patients (40.8%) had stable disease, whereas sixteen (32.7%) had increasing disease. The median time to progression was 4.4 months (95% CI, 0.8 to 32.6+ months); median survival was 14.8 months (95% CI, 0.8 to 50.0) months. Patients received a median of two treatment cycles (range, 1 to 29 cycles), and 18.4% of patients received > or = six cycles. Adverse effects included peripheral grade 2 (28.5%) and grade 3 (6.1%) neuropathy, grades 3 to 4 neutropenia (20.4%), grade 3 fatigue (14.3%), grade 3 nausea/emesis (22%), grade 3 diarrhea (10%), and grade 3 mucositis (4%). CONCLUSION Ixabepilone 20 mg/m(2) over 1 hour on days 1, 8, and 15 of a 28-day cycle demonstrates antitumor activity and acceptable safety in patients with platinum- and taxane-resistant recurrent or persistent ovarian or primary peritoneal carcinoma.

Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group.

OBJECTIVES: This trial was conducted to evaluate the safety and efficacy of cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix. SUBJECTS AND METHODS: All women had measurable histologically confirmed squamous cell cervical cancer and a GOG performance status less than or equal to 2. The women were to receive cisplatin at 30 mg/m(2) plus gemcitabine at 800 mg/m(2) day 1 and day 8 every 28 days. RESULTS: Between February 2001 and May 2002, 32 eligible patients were entered. All women had received prior chemotherapy and 29 had received radiation. Twenty patients received platinum previously twice. The median time from primary treatment to recurrence was 21 months, but the median time from last prior chemotherapy was less than 2 months. A second phase of accrual was not indicated per the established stopping rules. There were 7 (21.9%) partial responses and median response duration was 2.1 months. Twelve additional women (37.5%) had stable disease. Nine women (28.1%) had increasing disease. Median time to progression was 3.5 months. There were no treatment-related deaths. Six women had grade 4 neutropenia, three had grade 4 anemia, and two had grade 4 thrombocytopenia. Grade 4 gastrointestinal toxicity occurred in two women and grade 4 anorexia occurred in one. CONCLUSIONS: This study suggests modest activity for the gemcitabine plus cisplatin doublet in previously treated squamous cell carcinoma of the cervix. The objective response rate of 22% is comparable to that of other active agents and combinations tested in this setting. Toxicities were primarily hematologic and generally manageable with dose reductions.

Primary angiosarcoma of the ovary: a case report of Stage I disease.

BACKGROUND: There are 20 documented cases of primary ovarian angiosarcoma. Most patients present with metastatic disease and respond poorly to chemotherapy. There is little information available to counsel early-staged patients on the need for or efficacy of adjuvant chemotherapy. CASE: We present a case of Stage Ic primary ovarian angiosarcoma treated with 3 cycles of adjuvant MAID chemotherapy. The patient is without evidence of disease 10 months post-operatively. CONCLUSION: A review of the literature indicates a potential role for MAID chemotherapy in the treatment of ovarian angiosarcomas. Detection of Stage I disease appears to confer a better prognosis regardless of the utilization of adjuvant chemotherapy.

Differences in symptoms between patients with benign and malignant ovarian neoplasms.

OBJECTIVE: The purpose of this study was to determine the symptoms that are experienced by patients who receive a diagnosis of early ovarian cancer and to compare those symptoms with the symptoms that are experienced by patients with late ovarian cancer, borderline ovarian cancer, and benign ovarian neoplasms. STUDY DESIGN: This study used a retrospective case-control design. Cases of invasive and borderline ovarian cancer (n=147 patients) were compared with 76 patients with benign ovarian neoplasms. RESULTS: Patients with early ovarian cancer were significantly more likely to have symptoms of mass effect (urinary frequency, constipation, palpable mass, pelvic pressure) compared with patients with benign ovarian neoplasms (67% vs 15%; P <.001), late stage disease (67% vs 40%; P =.008), and borderline cancer (67% vs 33%; P =.007). CONCLUSION: Mass effect symptoms were the only symptoms that differentiated patients with early-stage ovarian cancer from all other groups of patients. However, one third of the patients with early ovarian cancer did not report any of these symptoms.