Efficacy of a nurse-led sexual rehabilitation intervention for women with gynaecological cancers receiving radiotherapy: results of a randomised trial.

BACKGROUND: The multicentre randomised SPARC trial evaluated the efficacy of a nurse-led sexual rehabilitation intervention on sexual functioning, distress, dilator use, and vaginal symptoms after radiotherapy for gynaecological cancers. METHODS: Eligible women were randomised to the rehabilitation intervention or care-as-usual. Four intervention sessions were scheduled over 12 months, with concurrent validated questionnaires and clinical assessments. Primary outcome was the Female Sexual Function Index (FSFI). A generalised-mixed-effects model compared groups over time. RESULTS: In total, 229 women were included (n = 112 intervention; n = 117 care-as-usual). No differences in FSFI total scores were found between groups at any timepoint (P = 0.37), with 12-month scores of 22.57 (intervention) versus 21.76 (care-as-usual). The intervention did not significantly improve dilator use, reduce sexual distress or vaginal symptoms compared to care-as-usual. At 12 months, both groups had minimal physician-reported vaginal stenosis; 70% of women were sexually active and reported no or mild vaginal symptoms. After radiotherapy and brachytherapy, 85% (intervention) versus 75% (care-as-usual) of participants reported dilation twice weekly. DISCUSSION: Sexual rehabilitation for women treated with combined (chemo)radiotherapy and brachytherapy improved before and during the SPARC trial, which likely contributed to comparable study groups. Best practice involves a sexual rehabilitation appointment 1 month post-radiotherapy, including patient information, with dilator guidance, preferably by a trained nurse, and follow-up during the first year after treatment. CLINICAL TRIAL REGISTRATION: NCT03611517.

Long-term outcome of high-grade serous carcinoma established in risk-reducing salpingo-oophorectomy specimens in asymptomatic BRCA1/2 germline pathogenic variant carriers.

OBJECTIVE: The aim of this study was to describe the long-term outcome of asymptomatic BRCA1/2 germline pathogenic variant (GPV) carriers with high-grade serous carcinoma (HGSC) in their risk-reducing salpingo-oophorectomy (RRSO) specimen. METHODS: In a previously described cohort of asymptomatic BRCA1/2 GPV carriers derived from the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) study, women with HGSC at RRSO were identified. Main outcome was ten-year disease-free survival (DFS). Secondary outcomes were time to recurrence, ten-year disease-specific survival (DSS), ten-year overall survival (OS). Patient, disease and treatment characteristics associated with recurrence were described. RESULTS: The 28 included women with HGSC at RRSO were diagnosed at a median age of 55.3 years (range: 33.5-74.3). After staging, eighteen women had (FIGO) stage I, three stage II and five had stage III disease. Two women did not undergo surgical staging and were classified as unknown stage. After a median follow-up of 13.5 years (range: 9.1-24.7), six women with stage I (33%), one woman with stage II (33%), two women with stage III (40%) and none of the women with unknown stage developed a recurrence. Median time to recurrence was 6.9 years (range: 0.8-9.2 years). Ten-year DFS was 68%, ten-year DSS was 88% and ten-year OS was 82%. CONCLUSION: Most asymptomatic BRCA1/2 GPV carriers with HGSC at RRSO were diagnosed at an early stage. Nevertheless, after a median follow-up of 13.5 years, nine of the 28 women with HGSC at RRSO developed a recurrence after a median of 6.9 years.

Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC-2): A randomised controlled trial.

OBJECTIVE: To investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ). DESIGN: Randomised controlled non-inferiority trial. SETTING: One academic and one regional hospital in the Netherlands. POPULATION: Thirty-five women with rrCIN were included in the study between May 2016 and May 2021. METHODS: Women were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment). MAIN OUTCOME MEASURES: The primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high-risk human papilloma virus (hr-HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored. RESULTS: Treatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow-up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow-up. CONCLUSIONS: This is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr-HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

APOLLO: neo-adjuvant pembrolizumab for primary vulvar squamous cell carcinoma-a multicenter, single-arm, phase II, clinical proof-of-concept study.

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) is a rare cancer for which the cornerstone of treatment is surgery with high complication rates. The unmet need is a less radical and more effective treatment for VSCC. PRIMARY OBJECTIVES: To investigate the impact of mono-immunotherapy pembrolizumab as neoadjuvant treatment for primary resectable VSCC patients. STUDY HYPOTHESIS: Some primary VSCC patients display a specific immune profile which is associated with better survival. In other tumors, this profile is associated with a better response to programmed cell death protein 1 (PD-1) checkpoint blockade which may reinvigorate tumor-specific T cells. This potentially results in a reduced tumor load and less radical surgery and/or adjuvant treatment in patients with this immune profile. TRIAL DESIGN: This is an investigator-initiated, prospective, single arm, multicenter, phase II clinical trial. INCLUSION CRITERIA: Patients with VSCC clinical stage International Federation of Gynecology and Obstetrics (FIGO) I-III (2021) eligible for primary surgery, with at least one measurable lesion of at least one dimension ≥10 mm in the largest diameter, are included in this study. MAIN EXCLUSION CRITERIA: Patients not suitable for surgery and/or previously treated with immunomodulatory agents, and/or who suffer from comorbidities that may interfere with PD-1 blockade, are excluded from the study. ENDPOINTS: The clinical efficacy of neoadjuvant pembrolizumab in VSCC is measured by an objective change in tumor size according to the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) and documented by calipers using standardized digital photography with a reference ruler. In addition, the activation, proliferation, and migration of T cells in the tumor will be studied. The secondary endpoints are pathological complete responses at the time of surgery, feasibility, and safety. SAMPLE SIZE: 40 patients with FIGO I-III (2021) primary VSCC will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The intervention phase started in July 2023 and will continue until July 2025. The expected completion of the entire study is July 2026. TRIAL REGISTRATION NUMBER: NCT05761132.

Recurrent postmenopausal bleeding: Pathological findings and predictive factors. A multicenter, prospective, observational study.

INTRODUCTION: Recurrent postmenopausal bleeding (PMB) occurs in 6%-25% of postmenopausal women who have experienced a previous episode of PMB. The question of whether recurrent PMB leads to a higher risk of endometrial cancer (EC) in comparison to a single episode of PMB is, however, controversial. Furthermore, little is known about predictive factors for recurrent PMB. MATERIAL AND METHODS: A multicenter prospective cohort study was conducted over a 5-year period in four hospitals in the Netherlands. Women with PMB undergoing endometrial sampling and aged 40 years and older were included. Occurrence of recurrent PMB was retrospectively determined. Primary outcomes included (1) the incidence of recurrent PMB and (2) differences in pathological findings between patients with a single episode vs recurrent PMB. Secondary outcomes included (1) the association between diagnosis of benign polyps at first PMB and pathological findings at recurrent PMB and (2) factors predictive for recurrent PMB. RESULTS: A total of 437 women with PMB were included, of whom 360 were at risk of recurrent PMB. With a median follow-up of 61 months (IQR (Interquartile range) 44-73), 26.4% experienced recurrent PMB. Patients with recurrent PMB were more often diagnosed with benign polyps (34.7% vs. 25.1%, p-value 0.015) and less frequently with a malignancy (5.3% vs. 17.8%, p-value 0.015), compared to patients with a single episode of PMB. Benign polyps at initial PMB were not associated with a (pre)malignancy at recurrence (OR 4.16, 95% CI 0.75-23.03). Predictive factors for recurrent PMB included use of hormone replacement therapy (HRT) (OR 3.32, 95% CI 1.64-6.72), and benign polyps at initial PMB (OR 1.80, 95% CI 1.07-3.04). CONCLUSIONS: Recurrent PMB is common in women with a previous episode of PMB. Compared to patients with a single episode of PMB, patients with recurrent PMB and benign histological outcomes at accurate workup during their first episode were less often diagnosed with malignancies and more frequently with benign polyps. Benign polyps at first PMB are predictive for recurrent PMB, but not for a higher risk of (pre)malignancy.

Incidence of inguinofemoral lymph node metastases at the first local recurrence of vulvar cancer: a Dutch nationwide study.

BACKGROUND: Up to 40% of vulvar cancer patients present with local recurrence within 10 years of follow-up. An inguinofemoral lymphadenectomy (IFL) is indicated if not performed at primary treatment. The incidence and risk factors for lymph node metastases (LNM) at first local recurrence, however, are unclear. Our aim was to determine the incidence of LNM at first local recurrence, in relation to previous groin treatment and clinicopathological factors. METHODS: A multicenter cohort study including vulvar cancer patients with a first macroinvasive local recurrence after primary surgical treatment between 2000 and 2015 was conducted in the Netherlands. Groin status at local recurrence was defined as positive (N+), negative (N-) or unknown (N?) and based on histology, imaging and follow-up. Patient-, tumour- and treatment characteristics of primary and recurrent disease were analysed. RESULTS: Overall, 16.3% (66/404) had a N+ groin status at first local recurrence, 66.4% (268/404) N- and 17.3% (70/404) N? groin status. The incidence of a N+ groin status was comparable after previous SLN and IFL, 11.5% and 13.8%, respectively. A N+ groin status was related to tumour size (25 vs.12 mm; P < 0.001), depth of invasion (5 vs. 3 mm; P < 0.001) and poorly differentiated tumours (22.9 vs. 11.9%; P = 0.050) at local recurrence. CONCLUSIONS: The incidence of LNM at first local recurrence in vulvar cancer patients was 16.3%, and independent of previous type of groin surgery. In accordance with primary diagnosis, tumour size, depth of invasion, and tumour grade were significantly associated with a positive groin status.

Sexual functioning more than 15 years after premenopausal risk-reducing salpingo-oophorectomy.

BACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown. OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy. STUDY DESIGN: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years. CONCLUSION: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity.

Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on cognition in women with high familial risk of ovarian cancer: A cross-sectional study.

OBJECTIVE: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. DESIGN: A cross-sectional study with prospective follow-up, nested in a nationwide cohort. SETTING: Multicentre in the Netherlands. POPULATION OR SAMPLE: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment. METHODS: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. MAIN OUTCOME MEASURES: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO. RESULTS: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). CONCLUSIONS: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Clinical validation and comparison of the Comprehensive Complication Index and Clavien-Dindo classification in predicting post-operative outcomes after cytoreductive surgery in advanced ovarian cancer.

OBJECTIVE: The Comprehensive Complication Index (CCI) is an instrument used to measure cumulative post-operative complications. Our study aimed to validate the CCI after cytoreductive surgery for primary advanced-stage epithelial ovarian cancer, and to compare its diagnostic performance with the Clavien-Dindo classification. METHODS: This prospective cohort study classified post-operative complications according to the Clavien-Dindo classification and the CCI. Logistic regression was used to determine the association between both classifications with intensive care unit admission, prolonged length of hospital stay (defined as stays longer than the 75th percentile of all stays in this study), 30-day readmission, and time to initiating chemotherapy after surgery >42 days. Area under the receiver operating characteristic curves (AUC) were used to assess the discriminative performance of each classification. RESULTS: A total of 300 patients were included in the analysis. Most patients (n=255, 85%) underwent interval cytoreductive surgery. Complete cytoreduction was achieved in 235 (78%) patients. Overall, 30-day post-operative complications classified by the Clavien-Dindo classification occurred in 147 (49%) patients. Severe complications (grade ≥3a) occurred in 51 (17%) patients. Approximately 30% (n=82) had multiple complications. The CCI showed an excellent correlation with the Clavien-Dindo classification (r=0.906, p<0.001). In comparison with the Clavien-Dindo classification, the proportion of patients classified with severe complications increased from 17% to 30% when stratified with the CCI, and 20% of patients were diagnosed with a CCI score that correlated with a higher Clavien-Dindo classification grade. On regression analysis, both Clavien-Dindo classification and CCI had associations with intensive care unit admission, prolonged length of hospital stay, 30-day readmission, and time to chemotherapy >42 days (all p<0.05). AUC demonstrated that CCI (0.842, 95% CI 0.792 to 0.893) and Clavien-Dindo classification (0.813, 95% CI 0.762 to 0.864, p<0.001) had a good diagnostic performance for prolonged length of hospital stay. CONCLUSIONS: Both the Clavien-Dindo classification and CCI showed significant associations with all surgical outcomes. However, the cumulative complications score of the CCI demonstrated a more superior discriminative performance than the Clavien-Dindo classification for prolonged length of hospital stay in advanced-stage epithelial ovarian cancer.

Sentinel lymph node procedure in patients with recurrent vulvar squamous cell carcinoma: a proposed protocol for a multicentre observational study.

BACKGROUND: Standard groin treatment in recurrent vulvar cancer consists of uni- or bilateral inguinofemoral lymphadenectomy (IFL), whereas in the primary setting women with selected unifocal tumours will undergo a sentinel lymph node (SLN) procedure. The SLN procedure results in fewer short and long-term sequelae compared to IFL, but some concerns must first be considered. Lymph drainage of the vulvar region can be affected by a previous surgery, which might reduce the number of detectable SLN nodes (feasibility) but increase the chance of encountering aberrant lymph drainage patterns such as bilateral SLNs in lateral tumours or SLNs at unexpected locations. Therefore, the SLN procedure potentially carries a higher risk of groin recurrence if a tumour positive node is not retrieved, but may also improve outcomes for women with aberrant drainage patterns. Since the relative benefits and drawbacks of the SLN procedure are still unclear we will investigate the safety of the SLN procedure in women with a first recurrent vulvar cancer. In a simultaneously started registration study we prospectively gather information on women with a first recurrence of vulvar cancer ineligible for the SLN procedure. METHOD: In this prospective multicentre observational study all women with a first recurrence of vulvar cancer will be asked to consent to the collection of information on their diagnostics, treatment and outcome, and to complete quality of life and lymph oedema questionnaires. Women with unifocal tumours smaller than 4 cm and unsuspicious groin nodes will be offered the SLN procedure, with follow-up every 3 months together with imaging at 6 and 12 months when the SLN is tumour negative. The primary outcome is groin recurrence within 2 years of initial surgery. A total of 150 women with negative SLNs will be required to demonstrate safety, a stopping rule will apply and an extensive statistical analysis has been designed. DISCUSSION: Should the SLN procedure prove feasible and safe in recurrent vulvar cancer, it will be available for implementation in clinics worldwide. The inclusion of women ineligible for the SLN procedure in the current prospective study will help to bridge knowledge gaps and define future research questions. TRIAL REGISTRATION: Medical Ethical Committee approval number NL70149.078.19 (trial protocol version 2.0, date March 2nd, 2020). Affiliation: Erasmus Medical Centre. Dutch trial register NL8467 . Date of registration 19.03.2020.

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors.

OBJECTIVE: High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. METHODS: Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. RESULTS: Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. CONCLUSIONS: Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. CLINICAL TRIAL REGISTRATION: The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

A sexual rehabilitation intervention for women with gynaecological cancer receiving radiotherapy (SPARC study): design of a multicentre randomized controlled trial.

BACKGROUND: Sexual problems are frequently reported after treatment with radiotherapy (RT) for gynaecological cancer (GC), in particular after combined external beam radiotherapy and brachytherapy (EBRT+BT). Studies demonstrate that psychosexual support should include cognitive behavioural interventions and involvement of the patient's partner, if available. Therefore, we developed a nurse-led sexual rehabilitation intervention, including these key components. The intervention was previously pilot-tested and results demonstrated that this intervention improves women's sexual functioning and increases dilator compliance. The objective of the current study is to investigate the (cost-)effectiveness of the intervention compared to optimal care as usual (CAU). We expect that women who receive the intervention will report a statistically significant greater improvement in sexual functioning and - for women who receive EBRT+BT - higher compliance with dilator use, from baseline to 12 months post-RT than women who receive optimal care as usual (CAU). METHODS/DESIGN: The intervention is evaluated in the SPARC (Sexual rehabilitation Programme After Radiotherapy for gynaecological Cancer) study, a multicentre, randomized controlled trial (RCT). The primary endpoint is sexual functioning. Secondary outcomes include body image, fear of sexual activity, sexual-, treatment-related- and psychological distress, health-related quality of life and relationship satisfaction. A cost-effectiveness analysis (CEA) will be conducted in which the costs of the intervention will be related to shifts in other health care costs and the impact on patient outcome. The study sample will consist of 220 women with GC treated with RT in specialized GC treatment centres (N = 10). Participants are randomized to either the intervention- or CAU control group (1:1), and within each centre stratified by type of radiotherapy (EBRT+BT vs. EBRT only) and having a partner (yes/no). All women complete questionnaires at baseline (T1) and at 1, 3, 6, and 12 months post-RT (T2, T3, T4 and T5, respectively). DISCUSSION: There is a need to improve sexual functioning after RT for GC. This RCT will provide evidence about the (cost-)effectiveness of a nurse-led sexual rehabilitation intervention. If proven effective, the intervention will be a much needed addition to care offered to GC survivors and will result in improved quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03611517 . Registered 2 August 2018.

Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy.

OBJECTIVE: Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. METHODS: Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA-study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). RESULTS: 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would recommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and cancer worry were similar in both cohorts. CONCLUSIONS: The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly appreciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy.

Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes.

OBJECTIVE: There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations. METHODS: A large retrospective cohort of surgically treated women with primary VSCC was used. VSCC were classified into three subtypes: HPV-positive (HPVpos), HPV-negative/p53 mutant (HPVneg/p53mut), and HPV-negative/p53 wildtype (HPVneg/p53wt). Overall survival (OS), relative survival (RS), and recurrence-free period (RFP) were depicted using the Kaplan-Meier method and survival curves for relative survival; associations were studied using univariable and multivariable Cox proportional hazard models. RESULTS: Of the 413 VSCCs, 75 (18%) were HPVpos, 63 (15%) HPVneg/p53wt, and 275 (66%) HPVneg/p53mut VSCC. Patients with HPVneg/p53mut VSCC had worse OS and RS (HR 3.43, 95%CI 1.80-6.53, and relative excess risk (RER) of 4.02; 95%CI 1.48-10.90, respectively, and worse RFP (HR 3.76, 95%CI 2.02-7.00). HPVpos VSCC patients showed most favorable outcomes. In univariate analysis, the molecular subtype of VSCC was a prognostic marker for OS, RS and RFP (p = 0.003, p = 0.009, p < 0.001, respectively) and remained prognostic for RFP even after adjusting for known risk factors (p = 0.0002). CONCLUSIONS: Stratification of VSCC by p16- and p53-IHC has potential to be used routinely in diagnostic pathology. It results in the identification of three clinically distinct subtypes and may be used to guide treatment and follow-up, and in stratifying patients in future clinical trials.

Near-infrared fluorescence imaging compared to standard sentinel lymph node detection with blue dye in patients with vulvar cancer - a randomized controlled trial.

OBJECTIVE: The aim of this study was to assess the superiority of ICG-99mTc-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using 99mTc-nanocolloid with blue dye. METHODS: In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-99mTc-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications. RESULTS: Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-99mTc-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041). CONCLUSIONS: Intraoperative visual detection of SLNs in patients with VSCC using ICG-99mTc-nanocolloid was superior compared to 99mTc-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register (Trial ID NL7443).

Vulvar Paget disease: A national retrospective cohort study.

BACKGROUND: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant. OBJECTIVE: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD. METHODS: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves. RESULTS: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005]). LIMITATIONS: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment. CONCLUSIONS: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly.

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies.

PURPOSE: Hyperthermia (40-44 °C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumours. EXPERIMENTAL DESIGN: Cells from four established cell lines and from freshly biopsied material of cervical (15), head- and neck (9) or bladder tumours (27) were heated to 42 °C for 60 min ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumour: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting. RESULTS: We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumours treated ex vivo. For tumours treated with hyperthermia in vivo, technical issues and intra-tumour heterogeneity prevented obtaining interpretable results. CONCLUSIONS: This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumour material directly derived from patients. Although BRCA2-degradation may not be a practical biomarker for heat deposition in situ, it does suggest that application of hyperthermia could be an effective method to expand the patient group that could benefit from PARP-inhibitors.

A patient decision aid for risk-reducing surgery in premenopausal BRCA1/2 mutation carriers: Development process and pilot testing.

BACKGROUND: BRCA1/2 mutation carriers' choice between risk-reducing salpingo-oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. DESIGN: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. SETTING AND PARTICIPANTS: Pre-menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. MAIN OUTCOME MEASURES: IPDAS quality criteria, relevance, usability, clarity. RESULTS: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step-by-step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. DISCUSSION AND CONCLUSIONS: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk-reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making.

Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics.

Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.

Outcome of ovarian cancer after breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. METHODS: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. RESULTS: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). CONCLUSIONS: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy.