WELCOME TO THE INTERACTIVE PROGRAM OF THE IGCS 2023 MEETING

Introduction

Purpose/Objective: To evaluate the association between regular vaginal dilation and/or sexual activity on vaginal stenosis in locally advanced cervical cancer patients after definitive radiochemotherapy and image-guided adaptive brachytherapy from the EMBRACE-I study.

Methods

Material/Methods: Physician-assessed vaginal stenosis (CTCAEv.3), vaginal dilation and patient-reported sexual activity (EORTC-QLQ-CX24) were prospectively assessed at baseline and during regular follow-up.

For this longitudinal analysis, a subgroup of patients was selected with at least 3 follow-ups with information on vaginal dilation and/or sexual activity. Vaginal penetration summarized either the use of vaginal dilators or sexual activity or both. Regular vaginal penetration was defined, if reported in ≥50%; no/infrequent penetration, if reported in <50% of follow-ups.

Results

Results: Of 1416 patients overall, the subgroup for this longitudinal evaluation included 882 patients, with a median follow-up of 60 months. Regular penetration was associated with a significantly lower 5-year actuarial risk estimate for vaginal stenosis G≥2, compared to reporting no/infrequent penetration (23% vs. 37%, p≤0.001, figure 1).

A multivariable Cox regression model confirmed this association (HR=0.630), adjusting for other known risk factors (table 1).

Conclusion/Implications

Conclusion: Regular dilation and/or sexual activity is associated with significantly lower risk for vaginal stenosis in cervical cancer patients. As a correlation does not justify any cause-effect relation, it cannot finally be concluded that regular penetration prevents vaginal stenosis or if the development of vaginal stenosis interferes with these activities.

However, as a randomized trial design is not appropriate in this context, the multivariable model supports the clinical observations and recommendations for prevention of vaginal stenosis.

Introduction

The accuracy of colposcopy depends on the skill and proficiency of the colposcopist. This study evaluated the feasibility of an artificial intelligence (AI) system as an assistive tool for diagnosing high-grade cervical intraepithelial neoplasia lesions compared to the human interpretation of cervical images

Methods

This two-centered, crossover, double-blind, randomized controlled trial included 886 randomly selected images. Four colposcopists (two proficient and two inexperienced) independently evaluated the cervical images once with and without the aid of the Cerviray AI® system (AIDOT, Seoul, Korea).

Results

The AI aid demonstrated improved areas under the curve on the localization receiver-operating characteristic curve compared with the colposcopy impressions of colposcopists (difference 0.12, 95% confidence interval [CI], 0.10 – 0.14, p-value < 0.001). Sensitivity and specificity also improved on using AI system (89.18% vs. 71.33%; p < 0.001, 96.68% vs. 92.16%; p < 0.001, respectively). Additionally, the classification accuracy rate improved with the aid of AI (86.40% vs. 75.45%; p < 0.001).

Conclusion/Implications

This study highlights the feasibility of using an AI system as an effective assistive tool for both proficient and inexperienced colposcopists in cervical cancer screening. AI interpretation can be used as an assisting tool in combination with human colposcopic evaluation of the exocervix.

Introduction

Immune checkpoint inhibitors are active in advanced cervical cancer. SKYSCRAPER-04 (NCT04300647) evaluated dual blockade with tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) (tira+atezo), an approach hypothesized to overcome immune suppression and restore immune response.

Methods

Eligible patients had measurable (per investigator assessment) PD-L1-positive recurrent/persistent cervical cancer after 1-2 prior chemotherapy lines (including ≥1 platinum-based regimen). Patients were randomized 3:1 to atezolizumab 1200mg with or without tiragolumab 600mg q3w until unacceptable toxicity/progression. Crossover to tira+atezo was permitted after unequivocal progression during single-agent atezolizumab. Stratification factors were ECOG PS, prior (chemo)radiotherapy, and disease status. The primary endpoint was independent review committee (IRC)-assessed confirmed objective response rate (ORR) per RECIST v1.1 in all treated patients randomized to tira+atezo. An ORR ≥21% (1-sample z-test p≤0.0245) was required to demonstrate statistically significant improvement versus a 14.6% historical reference [Chung, 2019]. Secondary endpoints included IRC-assessed progression-free survival, overall survival, and pre-crossover safety.

Results

Prior therapy in 171 treated patients included bevacizumab in 35%, (chemo)radiotherapy in 80%, and paclitaxel in 93%. IRC-assessed ORRs were 19.0% with tira+atezo and 15.6% with atezo alone (Table). In post hoc exploratory analyses of patients with measurable disease per IRC assessment, ORRs were 21.6% (tira+atezo) and 15.8% (atezo). There were no new safety signals. In a post hoc follow-up analysis, 15% of patients remained on treatment and 15/45 initially randomized to atezo had crossed over to tira+atezo.

Conclusion/Implications

The ORR with tira+atezo was numerically but not significantly higher than the historical benchmark. This is the first reported phase 2 cervical cancer trial targeting TIGIT and PD-L1 concurrently.

Introduction

Patients with gynecologic cancers are living longer after diagnosis, but the consequences of aggressive treatments may render them susceptible to future health concerns. The Canadian Longitudinal Study on Aging (CLSA) is a large population-based cohort of >50,000 individuals between the ages of 45-85 and provides a distinct opportunity to evaluate the impact of psychosocial and functional factors on health outcomes. We sought to examine the prevalence and impact of frailty among community-dwelling older individuals with a history of gynecologic cancer.

Methods

We performed a cross-sectional analysis of CLSA participants who self-identified as female. Frailty was operationalized using the deficit accumulation model (where frailty is defined as frailty index (FI) > 0.21). Associations were evaluated using multivariate regression analyses, adjusting for sociodemographic, lifestyle and social support factors.

Results

Datapoints to measure frailty were available for 15,149 of 15,320 (98.8%) female participants. The prevalence of frailty was 19.9% in those with a history of gynecologic cancer compared to 9.1% in those without (p<0.001; OR 2.2, 95%CI 1.6-2.9). Gynecologic cancer survivors classified as frail were more likely to require assistance from family members (OR 3.4, 95%CI 2.0-5.7) and professional community supports (OR 7.9, 95%CI 4.2-15.0) than those who were not frail.

Conclusion/Implications

In this large national prospective cohort study, frailty was found to affect approximately 20% of gynecologic cancer survivors. Further studies are required to evaluate the impact of frailty on oncologic outcomes and to elucidate strategies for early recognition and risk mitigation of frailty.

Introduction

The mental health of gynecologic cancer survivors is under investigated. The Canadian Longitudinal Study on Aging (CLSA) includes >50,000 individuals aged 45-85 for 20 years and contains important psychosocial and self-reported data. We sought to evaluate factors contributing to current mental health outcomes among gynecologic cancer survivors.

Methods

We performed a cross-sectional analysis of 26,155 female participants. Depression and psychological distress were measured using the Center for Epidemiological Studies Depression Scale (CES-D10) and the Kessler’s Psychological Distress Scale (K10), respectively. Self-rated mental health (SRMH) was measured using a five-point Likert scale. Regression analyses were performed, controlling for the complexity of the design and covariates.

Results

Participants with a history of gynecologic cancer (n=765, weighted prevalence 2.9%, 95%CI 2.4-3.3) were more likely to screen positive for depression (OR_CES-D10 1.6, 95%CI 1.1-2.5). Low income (OR_CES-D10 1.8, 95%CI 1.1-3.2; OR_K10 8.8, 95%CI 3.3-23.7) and smoking (OR_CESD-10 4.9, 95%CI 2.5-9.7; OR_K10 3.6, 95%CI 1.7-10.9) were predictors of screening positive for depression and psychological distress. Non-white ethnicity was predictive of psychological distress (OR_K10 5.9, 95%CI 2.0-17.0). Low income (OR_SRMH 5.2, 95%CI 2.1-12.8) and multimorbidity (OR_SRMH 18.5, 95%CI 2.2-153.3) were predictors for low SRMH. Education, marital status and alcohol consumption were not found to be predictive of mental health outcomes.

Conclusion/Implications

Participants with a history of gynecologic cancer are at increased risk of depression, particularly those faced with additional socioeconomic challenges and multimorbidity. Further research is required to address the mental health needs of patients with gynecologic cancers and to identify strategies towards sustained support throughout diagnosis and survivorship.

Introduction

Using the p53 immunohistochemical staining pattern (IHC) as a marker of TP53 gene mutation, IHC and next-generation sequencing (NGS) have a high agreement in ovarian cancer, but the agreement in endometrial cancer (EC) remains to be improved. In addition to overexpression, non-expression, and cytoplasmic expression, there is also subclonal abnormal expression pattern of p53 immunohistochemical abnormality in endometrial cancer. However, there are few studies on subclonal expression in endometrial cancer.

Methods

A total of 1869 patients who underwent surgical treatment for ECs between January 2019 and November 2022 were included in the study. Of these, 167 patients with both p53 immunohistochemistry and TP53 NGS results were further analyzed.

Results

Abnormal p53 subclonal staining was observed in 14 cases (8.4%) of ECs, and the agreement increased from 80.2% to 93.4% after the identification of subclonal types. IHC and NGS detected disagreement in 11 cases, all of which were missense mutations in the DBD (DNA binding domain). Among the 14 subclonal cases, 9 cases were POLEmut-p53abn or MMRd-p53abn multimolecular typing, and 5 cases were p53abn. Excluding the POLEmut/MMRd agreement reached 95.0%. The subclones had better prognosis compared with other p53 abnormal patterns and wild type (p<0.05).

Conclusion/Implications

Recognize the p53 subclonal staining pattern in EC is the main reason affecting agreement. Accurately identifying abnormal subclonal expression can improve the agreement of p53 IHC and TP53 NGS in endometrial cancer. The p53 IHC subclone is associated with POLEmut-p53abn or MMRd-p53abn multi-molecular typing and may have a good prognosis.

Introduction

HITEC (hyperthermic intrathoracic chemotherapy) is a method of delivering chemotherapeutic agents directly to the chest cavity, often by way of video-assisted thoracoscopic surgery (VATS). This therapy has been reported in non-gynecologic malignancies including breast, mesothelioma, and pseudomyxoma peritonei. Its use in ovarian cancer has been reported in less than 10 cases to our knowledge. Here we present the Cleveland Clinic gynecologic oncology approach to HITEC therapy.

Description

We demonstrate the use of HITEC for a 72yo female with recurrent high-grade papillary serous fallopian tube adenocarcinoma with persistent bilateral malignant pleural effusions and no other evidence of disease. In coordination with our cardiothoracic team, she underwent a left VATS and placement of chemotherapy tubing. She was premedicated with fosaprepitant, ondansetron, dexamethasone, potassium, magnesium, mannitol, and furosemide. Adriamycin (15mg/m2) was then introduced into the ThermoChem system and infused intrathoracically and heated to 40-42 degrees Celsius for 45 min. This was followed by Cisplatin (100mg/m2) in the same manner. Subsequently at her 6-month follow-up, imaging demonstrated resolution of her left sided pleural effusion. She then underwent HITEC of her right lung.

Conclusion/Implications

Given the success of HIPEC (hyperthermic intraperitoneal chemotherapy) in certain randomized controlled trials for ovarian cancer treatment, HITEC is a promising therapy option for symptom control and disease management in select patients. Further exploration and research on its therapeutic benefit in gynecologic malignancies is warranted.

Introduction

In this surgical film, we present a robot-assisted upper vaginectomy and partial cystectomy for resection of endometrial cancer recurrence at the vaginal cuff involving the bladder. We highlight the use of indocyanine green dye guidance to avoid ureteral injury and review techniques to prevent fistula formation.

Description

The patient was taken to the operating room for robot-assisted resection of vaginal cuff tumor. Cystoscopy was performed and revealed no mucosal invasion of the bladder. Bilateral ureteral stents were placed without difficulty and injected with indocyanine green dye for identification of the ureters during dissection. Exploratory laparoscopy revealed no gross carcinomatosis or distant metastasis. The vaginal cuff tumor was noted to be invading into the bladder muscularis posteriorly and partial cystectomy was performed to resect the mass margins in this area. Once the tumor was completely mobilized off the bladder anteriorly and rectum posteriorly, upper vaginectomy was performed with adequate margins. The cystotomy was repaired with a running 3.0 absorbable barbed suture horizontally and the vagina was closed with a running absorbable barbed suture vertically to avoid parallel friction with the cystotomy repair for prevention of fistula formation. A piece of omentum was mobilized and sutured over the vaginal closure as an additional step to prevent future fistula formation.

Conclusion/Implications

Locally recurrent vaginal cuff tumors can be safely resected with adequate margins robotically under indocyanine green dye guidance to avoid ureteral injury. Techniques to prevent future fistula formation include avoiding parallel suture friction between bladder, vagina or rectum and using omentum as a friction barrier.

Introduction

Cyclin E1 amplification and over-expression is associated with platinum resistance in high grade serous ovarian cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has activity in unselected women with recurrent ovarian and endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC (PR-HGSC) with cyclin E1 over-expression, with and without gene amplification.

Methods

IGNITE is a multicentre, Phase 2 trial with 2 cohorts of PR-HGSC patients. Cohort 1 were cyclin E1 amplified (≥8 copies by FISH) and over-expressed (H-score>50), and Cohort 2 were non-amplified. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 q21-day cycle (dose was reduced to 200mg after n=71 due to safety concerns). The primary endpoint was clinical benefit (CB) defined as no progression for ≥ 18 weeks. Here we present the 18-week CB rate (CBR) and overall response rate (ORR), with data cut-off of Apr-2023.

Results

From Jan-2020 to Oct-2022, 80 patients (Cohort 1 n=21; Cohort 2 n=59) were accrued. Median age was 64 years (range 42-84), 83% had ≥2 prior chemotherapy lines. For Cohort 1, ORR=38% and CBR=53%. For Cohort 2, ORR=45% and CBR=48%. Treatment related adverse events occurred in 78 patients (97%). Dose reduction was required in 36 (45%) patients, mostly for neutropenia or diarrhoea. Four patients (5%) died from treatment (sepsis n=3; thrombocytopenia n=1).

Conclusion/Implications

Adavosertib demonstrated activity in biomarker selected patients with PR-HGSC. Study accrual was halted early due to concern regarding rates of myelotoxicity.

Introduction

Transvaginal NOSES technique offers reduced postoperative pain and analgesia use, reduced length of hospital stays, faster return of bowel function, less chance of herniation, reduced skin surgical site infections and improved cosmesis. This case video demonstrates a laparoscopic radical hysterectomy bilateral salpingo-oophorectomy, pelvic lymphadenectomy, radical vaginectomy, ultra-low anterior resection using the Transvaginal NOSES technique for retrieval of the en bloc specimen in a 57-year-old with a 4cm high grade vaginal sarcoma in the post vaginal wall.

Description

Adhesiolysis performed then splenic flexure mobilization. Inferior mesenteric vein and artery are ligated and divided. Dissection is started medially then laterally to mobilize colon adequately. Mesorectal resection performed, pelvic spaces are opened bilaterally, ureters identified before dividing uterine arteries. Pelvic lymphadenectomy performed. Bladder dissected before performing anterior colpotomy to visualize the tumor and stitch placed a centimeter below tumor. Posterior colpotomy is performed and recto vaginal space is developed. Once total mesorectal resection complete, rectum is divided using an ENDO GIA Stapler. The specimen is retrieved through the vagina, resected and the anvil is placed in preparation for anastomosis. The vagina is then sutured. Rectal anastomosis is performed with EEA stapler. Abdomen inspected, drain inserted and a covering loop ileostomy is formed. Patient made a good post-operative recovery.

Conclusion/Implications

Transvaginal NOSES technique is safe and feasible to perform and offers additional benefits over traditional abdominal specimen retrieval.

Introduction

Determine whether molecular classification using mismatch repair (MMR) and p53 protein expression predictsRFS in EC patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT).

Methods

GOG-0258 was a phase III, randomized trial (NCT00942357) comparing CRT and CT with primary endpoint of RFS. Immunohistochemistry was performed to determine MMR and p53 status. Demographic variables were compared with chi-squared and Kruskal Wallis tests for categorical and continuous variables, respectively. Kaplan-Meier curves estimated RFS between sub-groups. Adjusted Cox proportional hazards models estimated hazard ratios and 95% confidence limits.

Results

Using a modified ProMiSe algorithm, 27.4% of EC classified as dMMR, 49% p53wt, and 23.6% p53abn. p53abn tumors were more frequent in older (p<0.001ADD p-value) and Black (p<0.001ADD p-value) patients, and those with serous histology (p<0.001ADD p-value). In contrast, dMMR was more common in Non-Hispanic patients (ADD p-valuep=0.025) and endometrioid cancers (p<0.001ADD p-value). 5-year RFS was significantly worse for those with p53abn [28.8% vs 68.9% vs 57.5%; HR=3.39 (2.34-4.91); p<0.001] compared to p53wt (referent) and dMMR ECs. After adjusting for age, gross residual disease, and treatment,p53wt was associated with improved RFS in the CRT compared to CT group [77.2% vs 59.7%; HR=0.54 (0.32-0.94); p=0.02]. The 5-year RFS with CRT versus CT were similar for those with p53abn [29.3% vs 29.4%; 0.76 (0.46-1.24)] and dMMR [52.5% vs 63.7% (0.70-2.57)] ECs.

Conclusion/Implications

Molecular classification is prognostic in EC, with worse RFS in p53abn tumors. In an exploratory analysis, p53wt appears to be predictive for treatment efficacy favoring CRT over CT. Further trials are warranted to confirm these findings.

Introduction

In patients who respond to neoadjuvant chemotherapy (NACT) for advanced-stage epithelial ovarian cancer (EOC), minimally invasive surgery (MIS) may reduce the morbidity of surgery. Studies evaluating oncologic outcomes of minimally invasive interval cytoreductive surgery are largely retrospective.

Methods

LANCE is a prospective, multicenter, international, randomized trial evaluating whether MIS is non-inferior to laparotomy in terms of disease-free survival, among patients with stage IIIC and IV EOC with normalization of CA125 after 3-4 cycles of NACT. The planned 100 patients were enrolled in a lead-in phase to assess the feasibility of the trial with respect to cross-over among those assigned to MIS, complete gross resection, and recruitment. Patients were randomized (1:1) to undergo open or MIS (laparoscopic or robotic) surgery. Surgeons applied maximal effort to resect all visible tumor, conversion to open surgery was performed when necessary to attain complete resection.

Results

From September 2020-February 2023, 100 patients were randomized (51 open, 49 MIS). The mean age was 62 years, 67% had stage IIIC, and 54% received 3 cycles of NACT. Six patients randomized to MIS (12.2%;95%CI: 4.6-24.8%) underwent conversion to open surgery. Surgeons achieved complete gross resection in 87.5% (95%CI: 74.8-95.3%) and 83% (95%CI: 69.2-92.4%) of patients assigned to MIS and open (p=0.6). There were three (6.3%) intraoperative complications in the MIS group and three (6.4%) in the open group. Two patients (4.1%) in the MIS group experienced grade 4-5 adverse events following surgery.

Conclusion/Implications

Evaluation of MIS interval cytoreductive surgery is feasible, enrollment is ongoing in a definitive trial.