The feasibility of folate receptor alpha- and HER2-targeted intraoperative fluorescence-guided cytoreductive surgery in women with epithelial ovarian cancer: A systematic review

Background: Epithelial ovarian cancer (EOC) is often diagnosed late, with a 5-year relative survival of 30.2% for patients with metastatic disease. Residual disease following cytoreductive surgery is an important predictor for poor survival. EOC is characterized by diffuse peritoneal metastases and depositions of small size, challenging a complete resection. Targeted fluorescence imaging is a technique to enhance tumor visualization and can be performed intraoperatively. Folate receptor alpha (FRα) and human epidermal growth factor receptor 2 (HER2) are overexpressed in EOC in 80% and 20% of the cases, respectively, and have been previously studied as a target for intraoperative imaging. Objective: To systematically review the literature on the feasibility of FRα and HER2 targeted fluorescence-guided cytoreductive surgery (FGCS) in women with EOC. Methods: PubMed and Embase were searched for human and animal studies on FGCS targeting either HER2 or FRα in either women with EOC or animal models of EOC. Risk of bias and methodological quality were assessed with the SYRCLE and MINORS tool, respectively. Results: All animal studies targeting either FRα or HER2 were able to detect tumor deposits using intraoperative fluorescence imaging. One animal study targeting HER2 compared conventional cytoreductive surgery (CCS) to FGCS and concluded that FGCS, either without or following CCS, resulted in statistically significant less residual disease compared to CCS alone. Human studies on FGCS showed an increased detection rate of tumor deposits. True positives ranged between 75%–77% and false positives between 10%–25%. Lymph nodes were the main source of false positive results. Sensitivity was 85.9%, though only reported by one human study. Conclusion: FGCS targeting either HER2 or FRα appears to be feasible in both EOC animal models and patients with EOC. FGCS is a promising technique, but further research is warranted to validate these results and particularly study the survival benefit

Lymphocele following lymph node dissection in cervical and endometrial cancer: A systematic review and meta-analysis

Objectives: The purpose of this systematic review and meta-analysis was to evaluate the proportion and risk factors of lymphoceles and symptomatic lymphoceles after PLND in early-stage cervical and early-stage high or high-intermediate risk endometrial cancer. Methods: Studies reporting on the proportion of lymphocele after PLND were conducted in PubMed, Embase and Cochrane Library. Retrieved studies were screened on title/abstract and full text by two reviewers independently. Quality assessment was conducted using the Newcastle Ottowa Scale and the Cochrane risk-of-bias tool. Proportion of lymphocele and possible risk factors were pooled through random-effects meta-analyses. Results: From the 233 studies retrieved, 24 studies were included. The pooled proportion of lymphocele was 14% and of symptomatic lymphocele was 3%. Routinely performing diagnostics was associated with a significantly higher proportion of lymphocele compared to diagnostics performed on indication (21% versus 4%, p 15% of the study population underwent additional paraaortic lymph node dissection (PAOLND) opposed to <15% (15% versus 3%, p < 0.01). A mean number of lymph nodes dissected of <21 resulted in a significantly higher pooled proportion of lymphoceles opposed to when the mean number was 21 or higher (19% versus 5%, p = 0.02). Other risk factors analysed were BMI, lymph node metastasis, adjuvant radiotherapy and follow up. There was no sufficient data to detect significant risk factors for the development of symptomatic lymphoceles. Conclusion: The pooled proportion of lymphocele was 14% of which symptomatic lymphoceles occurred in 3%. Significant risk factors for the total proportion of lymphoceles were laparotomic approach, decreased number of lymph nodes dissected and additional PAOLND

Fertility-sparing surgery and fertility preservation in cervical cancer: The desire for parenthood, reproductive and obstetric outcomes

Objective: To evaluate the desire for parenthood and reproductive outcomes of young cervical cancer survivors who underwent fertility-sparing surgery or fertility preservation procedures for invasive cervical cancer. Methods: All women <45 years who underwent fertility-sparing treatment for invasive cervical cancer in a tertiary referral center in the Netherlands between January 2009 and January 2020 were identified. Fertility-sparing treatment options included Vaginal Radical Trachelectomy (VRT) for patients with early-stage disease and fertility preservation techniques (FP) when requiring Radical Hysterectomy (RH) or chemoradiotherapy. Data on reproductive intentions – and outcomes were retrieved from medical files and questionnaires. Results: 75 patients were identified of whom 34 underwent VRT, 9 RH and 32 had (chemo)radiotherapy. 26 patients started FP of whom 23 (88.5%) successfully preserved fertility through cryopreservation of embryos, oocytes and ovarian tissue. After a median follow-up of 49 months, 5 patients developed recurrent disease and died. Reproductive outcomes were retrieved in 58 patients. 89.6% maintained their desire for parenthood after cancer treatment. Following VRT, we report a pregnancy rate of 61.9% among the patients attempting conception (n = 24). 15 patients conceived 21 pregnancies which resulted in 15 live-births, yielding a live-birth rate of 75.0%. Following RH or (chemo)radiotherapy, 3 surrogate pregnancies were established (21.4%) using frozen-thawed material with good neonatal outcomes. Conclusion: Many cervical cancer survivors maintain the desire to become parents eventually. In early-stage disease, VRT shows good reproductive outcomes without compromising oncological safety. For those requiring gonadotoxic treatment fertility preservation and gestational surrogacy provides a promising alternative for achieving a biological offspring

The influence of learning curve of robot-assisted laparoscopy on oncological outcomes in early-stage cervical cancer: an observational cohort study

OBJECTIVE: To investigate the learning curve of robot-assisted laparoscopy in early-stage cervical cancer and quantify impact on oncological outcomes. DESIGN: Observational cohort study. SETTING: Tertiary referral centre with one surgical team. POPULATION: All women with early-stage cervical cancer treated consecutively with robot-assisted laparoscopy between 2007 and 2017. METHODS: With multivariate risk-adjusted cumulative sum analysis (RA-CUSUM), we assessed the learning curve of robot-assisted laparoscopy of a single surgical team based on cervical cancer recurrence. Subsequently, a survival analysis was conducted comparing oncological outcomes of women treated during different phases of the learning curve. MAIN OUTCOME MEASURES: Surgical proficiency based on recurrence, survival rates in the different learning phases. RESULTS: One hundred and sixty-five women with cervical cancer underwent robot-assisted laparoscopy, with a median follow up of 57 months (range 3-132 months). The RA-CUSUM analysis demonstrated two phases of the learning curve: a learning phase of 61 procedures (group 1) and an experienced phase representing the 104 procedures thereafter (group 2). The 5-year disease-free survival was 80.2% in group 1 and 91.1% in group 2 (P = 0.040). Both the 5-year disease-specific survival and overall survival significantly increased after the learning phase. CONCLUSION: The learning phase of robot-assisted laparoscopy in early-stage cervical cancer in this institutional cohort is at least 61 procedures, with higher survival rates in the women treated thereafter. The learning curve of robot-assisted laparoscopy affects oncological outcomes and warrants more attention in the design of future studies. TWEETABLE ABSTRACT: The learning curve of robot-assisted laparoscopy in early-stage cervical cancer affects oncological outcomes and warrants more attention

The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia:A systematic review and meta-analysis

Objective: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. Methods: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. Results: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03–8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59–33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62–23.77). Conclusions: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.</p

Value of routine cytokeratin immunohistochemistry in detecting low volume disease in cervical cancer

Objective: In cervical cancer, sentinel lymph nodes (SLNs) are processed according to the pathological ultrastaging protocol. According to current guidelines, immunohistochemistry with pancytokeratin antibodies is performed in addition to step sectioning with hematoxylin and eosin (H&E), aiding the detection of low volume disease (micrometastasis and isolated tumor cells (ITC)). We studied the added clinical value, and costs, of routine immunohistochemistry (IHC). Methods: We retrospectively included all FIGO stage IA-IIA1 cervical cancer patients who had undergone SLN procedures at UMC Utrecht from 2008 to 2020. Pathological data were derived from the Dutch Pathology Registry (PALGA) including SLN tumor status and number of slides stained with IHC. Results: In total 234 cervical cancer patients were included. In the 516 surgically resected SLN specimens, 630 SLNs were discovered by the pathologist. Hereof, 579 SLNs from 211 patients were routinely processed with IHC. IHC identified three patients with micrometastasis and five patients with ITC undetected with H&E staining. Thereby, IHC significantly increased the number of patients with low volume disease from 11 (5.3%) to 19 patients (9.1%) (p = 0.04). To achieve this, 3791 slides were stained with IHC at an estimated additional cost of €94,775. In 1.4% (95% CI 0.3%–4.3%) of patients routine use of IHC adjusted the adjuvant treatment. Conclusions: Routine use of IHC increases detection of low volume disease in cervical cancer SLNs compared to step sectioning with H&E alone by nearly 4%, with an impact on therapeutic strategy-decisions in about 1% of patients. In view of the high associated costs, cost-effectiveness of routine IHC is questionable

Mainstream germline genetic testing for patients with epithelial ovarian cancer leads to higher testing rates and a reduction in genetics-related healthcare costs from a healthcare payer perspective

OBJECTIVE: Germline genetic testing is increasingly offered to patients with epithelial ovarian cancer by non-genetic healthcare professionals, so called mainstream genetic testing. The aim of this study was to evaluate the effect of implementing a mainstream genetic testing pathway on the percentage of newly diagnosed patients with epithelial ovarian cancer to whom genetic testing was offered and the genetics-related healthcare costs. METHODS: The possible care pathways for genetic counseling and testing and their associated costs were mapped. Patient files from all newly diagnosed patients with epithelial ovarian cancer before (March 2016 - September 2017) and after (April 2018 - December 2019) implementing our mainstream genetic testing pathway were analyzed. Based on this analysis, the percentage of newly diagnosed patients to whom genetic testing was offered was assessed and genetics-related healthcare costs were calculated using a healthcare payer perspective based on a Diagnosis-Related Group financing approach. RESULTS: Within six months after diagnosis, genetic testing was offered to 56% of patients before and to 70% of patients after implementation of our mainstream genetic testing pathway (p = 0.005). Genetics-related healthcare costs decreased from €3.511,29 per patient before implementation to €2.418,41 per patient after implementation of our mainstream genetic testing pathway (31% reduction, p = 0.000). CONCLUSION: This study shows that mainstream genetic testing leads to a significantly higher proportion of newly diagnosed patients with epithelial ovarian cancer being offered germline genetic testing. In addition, it significantly reduces genetics-related healthcare costs per patient

Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study

Contains fulltext : 108486.pdf (publisher's version ) (Open Access)BACKGROUND: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer. METHODS: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients. TRIAL REGISTRATION: Netherlands Trial Register number NTR2644

Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Patient Characteristics, Treatment, and Outcome-A Systematic Review

BACKGROUND: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor. The aim of this systematic review is to generate an overview of all reported patients with SCCOHT from 1990 onwards, describing the clinical presentation, genetic characteristics, treatment, and outcome. METHODS: A systematic search was performed in the databases Embase, Medline, Web of Science, and Cochrane for studies that focus on SCCOHT. Patient characteristics and treatment data were extracted from the included studies. Survival was estimated using Kaplan-Meier's methodology. To assess the difference between survival, the log-rank test was used. To quantify the effect of the FIGO stage, the Cox proportional hazard regression model was estimated. The chi-squared test was used to study the association between the FIGO stage and the surgical procedures. RESULTS: Sixty-seven studies describing a total of 306 patients were included. The median patient age was 25 years (range 1-60 years). The patients mostly presented with non-specific symptoms such as abdominal pain and sometimes showed hypercalcemia and elevated CA-125. A great diversity in the diagnostic work-up and therapeutic approaches was reported. The chemotherapy regimens were very diverse, all containing a platinum-based (cisplatin or carboplatin) backbone. Survival was strongly associated with the FIGO stage at diagnosis. CONCLUSIONS: SCCOHT is a rare and aggressive ovarian cancer, with a poor prognosis, and information on adequate treatment for this cancer is lacking. The testing of mutations in SMARCA4 is crucial for an accurate diagnosis and may lead to new treatment options. Harmonization and international collaboration to obtain high-quality data on diagnostic investigations, treatment, and outcome are warranted to be able to develop international treatment guidelines to improve the survival chances of young women with SCCOHT