Women's Cancer Center of Nevada

IntroductionDysregulation of mTOR signaling is implicated in the pathology of endometrial carcinoma (EC), particularly in endometrioid EC (EEC) in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Crosstalk between mTOR and estrogen signaling pathways is associated with endocrine therapy resistance, and mTOR inhibition combined with endocrine therapy has shown benefit in patients with recurrent EC in previous phase 2 studies. nab-Sirolimus, an intravenous nanoparticle albumin-bound mTOR inhibitor (mTORi), is approved in the US for adults with advanced malignant perivascular epithelioid cell tumors. Preclinical data demonstrated improved tumor accumulation, mTOR target inhibition, and tumor growth suppression of nab-sirolimus versus other mTORis. This trial will evaluate the antitumor activity of combined mTOR and estrogen signaling pathway inhibition with nab-sirolimus and letrozole, respectively, in patients with advanced or recurrent EEC.MethodsIn this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8, 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~30 planned, Simon’s 2-stage design) with clinically confirmed, advanced or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemotherapy-based regimen in the advanced, metastatic, or recurrent setting (prior adjuvant chemotherapy additionally permitted), ECOG performance status 0 or 1, mTORi-naïve, and measurable disease. The primary endpoint is best overall response rate (per RECIST v1.1). Key secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of biomarkers with clinical outcomes.Current Trial StatusThe trial is currently open for enrollment.

ObjectivesOregovomab (O), a murine IgG? monoclonal antibody binds to tumor-associated antigen, CA125, rendering target CA125 more immunogenic through enhanced antigen processing and presentation to specific T cells, bypassing tumor-associated suppression and resulting in enhanced efficacy of chemotherapy. In a randomized phase II study, oregovomab in combination with paclitaxel and carboplatin (PC) demonstrated significant improvement in PFS (median (months) 41.8 PCO vs 12.3 PC, HR=0.46, p=0.0027 and OS median N.E. PCO vs 43.2 PC, HR=0.35, p=0.043. FLORA-5/GOG-3035 is the confirmatory global registration trial.MethodsOptimally debulked patients with FIGO III/IV epithelial ovarian cancer and serum CA125 > 50 U/ml randomized to PC ± oregovomab. Patients with BRCA1/2 mutations are excluded. Chemotherapy will be administered every 3 weeks in two cohorts. In Cohort 1 (adjuvant), oregovomab/placebo is administered at cycles 1, 3, and 5 of chemotherapy and at 12 weeks following cycle 5. In Cohort 2 (neoadjuvant), oregovomab/placebo will be administered at cycles 4 and 6 of chemotherapy, and at 6- and 18-weeks following cycle 6. No other post front-line maintenance therapy is permitted. The primary objective is PFS by RECIST 1.1 criteria. Cohort 1 will recruit 372 patients and Cohort 2 will recruit 230 patients. Secondary objectives include OS, frequency and severity of adverse events, and quality of life. 137 sites in US, Canada Asia, Europe and South American are actively enrolling. 324 patients have been randomized.ResultsTrial in progress: there are no available results at time of submission.ConclusionsTrial in progress: there are no available conclusions at time of submission.

TPS5606 Background: Oregovomab binds tumor-associated CA125 rendering the target antigen CA125 more immunogenic or “neoantigen-like” through altered and enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when administered in combination with chemotherapy. In a randomized phase II study, immunization with oregovomab in a schedule-dependent combination with paclitaxel and carboplatin induced tumor immunity and demonstrated significant improvement in PFS (median (months) 41.8 PCO vs 12.3 PCP, HR 0.44 p = 0.0027, and OS median N.E. PCO vs 43.2 PCP HR O.34 (p = 0.0077)) in patients with previously untreated EOC. The FLORA-5, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: The study is a phase 3, multicenter, double-blind, placebo-controlled clinical trial. Optimally debulked patients with FIGO III/IV EOC and serum CA125 > 50 U/ml receiving adjuvant (Cohort 1) or neoadjuvant (Cohort 2) chemotherapy will be randomized post-surgery to paclitaxel and carboplatin with or without oregovomab. Patients with germline BRCA1/2 mutations will be excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with a single maintenance dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients (Cohort 2) will be administered oregovomab/placebo post interval debulking surgery at cycles 4 and 6 with maintenance doses at 6- and 18-weeks following cycle 6. No other post front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1 criteria. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim analysis for futility will be performed. Secondary objectives include OS, frequency and severity of adverse events, and quality of life. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of potential biomarkers. The study is actively enrolling in the US with 9 patients enrolled at time of submission. Centers in Europe, South America and Asia are expected to begin accruing shortly. Clinical trial information: NCT04498117.

The primary objective was to determine if vaginal cuff brachytherapy and chemotherapy (VCB/C) increases recurrence-free survival (RFS) compared with pelvic radiation therapy (RT) in high-intermediate and high-risk early-stage endometrial carcinoma. A randomized phase III trial was performed in eligible patients with endometrial cancer. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with Gynecologic Oncology Group protocol 33-based high-intermediate-risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m2 (3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles. The median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months, the 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). The 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant recurrence rates were similar between arms. Pelvic or para-aortic nodal recurrences were more common with VCB/C (9% v 4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated. Superiority of VCB/C compared with pelvic RT was not demonstrated. Acute toxicity was greater with VCB/C; late toxicity was similar. Pelvic RT alone remains an effective, well-tolerated, and appropriate adjuvant treatment in high-risk early-stage endometrial carcinomas of all histologies.

ABC (argon beam coagulator) 52 abdomen access, laparoscopy 46 abdominal cavity opening/closing 33-44 Cherney incision 43 closure of the abdomen 39-40 draping 34 exploration 37 extending the wound 39 intestines, packing away 37-38 Joel-Cohen incision 42-43 Maylard incision 44 operative stance 33-34 peritoneal incision 35-36 Pfannenstiel incision 41-42 previous scars 38-39 rectus incision 35 subumbilical midline incision 34-36 transverse incisions 41-44 abdominal hysterectomy 128-130 abdominal sacrocolpopexy 183-184 ablative procedures cervix 90-94 complications 93-94 abscesses, vulval 64-66, 67 adhesion prevention/removal 31, 38-39, 77, 106 alcohol 11 anaesthesia laparoscopy 48 preparation for surgery 15-16 anaesthetist preoperative visit 12-13 antibiotics prophylactic antibiotics 14, 108, 263 urogenital fistulae 263 aortic injury, vascular surgery 332, 333 appendicectomy 349-350 variations in technique 350 argon beam coagulator (ABC) 52 Arista (Medafor Inc., Minneapolis, MN) 30 artery forceps 20 artificial urinary sphincter 224-225 augmentation cystoplasty, detrusor overactivity

Carcinoma of the cervix is the second most common female cancer worldwide and remains the most common in some developing countries. Cervical cancer can be treated with surgery, radiation or with chemoradiation. Radical hysterectomy for the treatment of cervical cancer consists of the removal of the uterus, approximately the upper one-third of the vagina and the parametrium and paracolpos to the pelvic sidewall. Small-volume disease is increasingly being managed by conservative surgical methods including cone biopsy or simple hysterectomy, often combined with laparoscopic pelvic lymph node dissection. The vaginal approach for radical hysterectomy was resurrected by Dargent in the 1980s as part of the laparoscopic-assisted radical vaginal hysterectomy or coelio-Schauta procedure. The chapter describes the laparoscopic element of lymphadenectomy and ligation of the uterine arteries. The vaginal radical trachelectomy begins with the laparoscopic pelvic lymph node dissection.

Uterine fibroids are the most common tumours in women but their true prevalence is unclear as the majority of fibroids are asymptomatic. The majority of fibroids are small and asymptomatic. Symptoms include heavy and painful periods, pelvic pain, urinary frequency and constipation. Ultrasound is useful in the detection and evaluation of uterine fibroids. Magnetic resonance imaging (MRI) has an increasing role in defining the anatomy of the uterus, in planning myomectomy and particularly in monitoring fibroid degeneration and for identifying sarcomatous changes. In the majority of women with asymptomatic fibroids management is conservative with no treatment required. There is an increasing use of medical and radiological treatments. Hysterectomy remains the most common surgical procedure for symptomatic uterine fibroids when retaining fertility is not an issue. For women wishing to conceive, myomectomy is the treatment of choice, with the laparoscopic approach being used for pedunculated and subserosal fibroids and the hysteroscopic approach for submucosal fibroids.