Effects of a combined exercise and dietary intervention on body composition, physical functioning and fatigue in patients with ovarian cancer: results of the PADOVA trial.

BACKGROUND: Guidelines recommend to include exercise and dietary advice in standard care for patients with cancer, based on evidence primarily derived from patients with breast cancer. Its applicability to patients with ovarian cancer is uncertain due to differences in patient characteristics and treatments. The PADOVA trial examined the effectiveness of a combined exercise and dietary intervention on fat-free mass (FFM), physical functioning, and fatigue. METHODS: In total, 81 patients with ovarian cancer were randomised to the exercise and dietary intervention (n = 40) or control (n = 41) group. Measurements were performed before chemotherapy, after chemotherapy, and 12 weeks later. FFM was assessed by bioelectrical impedance analysis, and physical functioning and fatigue were assessed using questionnaires. Intervention effects were assessed on an intention-to-treat basis using linear mixed models. RESULTS: FFM and physical functioning increased, and fatigue decreased significantly over time in both groups. No significant difference between the groups were found for FFM (ß = -0.5 kg; 95% CI = -3.2; 2.1), physical functioning (ß = 1.4; 95% CI = -5.4; 8.3) and fatigue (ß = 0.7; 95% CI = -1.5; 2.8). CONCLUSIONS: During treatment, both groups improved in FFM, physical functioning, and fatigue. The intervention group, however, did not demonstrate additional benefits compared to the control group. This highlights the need for caution when extrapolating findings from different cancer populations to patients with ovarian cancer.

Demographic, clinical, and sociocognitive determinants related to physical activity and dietary intake in patients with ovarian cancer: A cross-sectional study.

OBJECTIVE: To study physical activity and dietary intake among patients with ovarian cancer and to examine which demographic, clinical, and sociocognitive determinants are associated with these behaviours. METHODS: This cross-sectional study included 139 patients with ovarian cancer scheduled for (neo)adjuvant chemotherapy. Physical activity was measured with the Physical Activity Scale for the Elderly questionnaire (PASE). Dietary intake was measured with a questionnaire assessing energy and protein intake and a questionnaire assessing adherence to the World Cancer Research Fund (WCRF) lifestyle recommendations. Demographic, clinical, and sociocognitive (e.g., self-efficacy) determinants of physical activity and dietary intake were examined using backward linear regression analyses. RESULTS: Patients reported a median PASE score of 50 (IQR 24-94), a mean ± SD dietary intake of 1831 ± 604 kcal/day and 76 ± 27 g protein/day. Patients adhered to 3 out of 5 WCRF lifestyle recommendations. The absence of comorbidities, lower physical outcome expectations, and higher cancer specific outcome expectations were independently associated with higher physical activity levels. Higher age, lower cancer specific outcome expectations, and higher diet-related self-efficacy were significantly associated with adhering to more WCRF lifestyle recommendations, whilst no variables associated with total caloric or protein intake were identified. CONCLUSIONS: Patients with ovarian cancer have low physical activity levels and a suboptimal diet, particularly low fruit and vegetable consumption and dietary fibre intake. Interventions aiming to improve physical activity and dietary intake could focus on increasing self-efficacy and outcome expectations, and should consider age and comorbidity as factors that may impact behaviour. TRIAL REGISTRATION: Netherlands Trial Registry NTR6300.

Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer - a nationwide Dutch cohort study.

OBJECTIVES: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. METHODS: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. RESULTS: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. CONCLUSIONS: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. CRITICAL RELEVANCE STATEMENT: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. KEY POINTS: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach.

Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients: The STAPOVER study protocol.

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype-guided targeted therapy to improve survival without compromising quality of life. Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.

Abnormal preoperative haematological parameters in Endometrial cancer; reflecting tumour aggressiveness or reduced response to radiotherapy?

BACKGROUND: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC. METHODS: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 109 platelets/L, leucocytosis - leukocytes >10 × 109/L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy. RESULTS: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P = 0.002 and P = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy (n = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival (P = 0.005 and P = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy (n = 74), anaemia was associated with reduced disease-specific survival (P = 0.041). CONCLUSIONS: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy.What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome.What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients.What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.

In this study we focused on three specific blood values before surgery to predict survival outcomes in endometrial cancer patients: low haemoglobin (anaemia), high platelet count (thrombocytosis) and high white blood cell count (leucocytosis). We studied 894 patients with endometrial cancer over about 4.5 years, in which 11.5% had anaemia, 8.8% thrombocytosis and 12.7% leucocytosis. Anaemia was linked to a lower chance of surviving endometrial cancer, even after we considering patients' age, thrombocytosis, leucocytosis and the endometrial cancer risk classification groups. In patients who received radiotherapy after surgery (293 patients), anaemia was linked to a lower change of surviving and cancer coming back within 5 years. In patients within the intermediate endometrial cancer risk classification group who only received specific radiotherapy (74 patients), anaemia was even linked with lower chance of survival. In conclusion, anaemia is an important factor in predicting endometrial cancer outcomes, and it might also make radiotherapy less effective for some patients.

Optimising follow-up strategy based on cytology and human papillomavirus after fertility-sparing surgery for early stage cervical cancer: a nationwide, population-based, retrospective cohort study.

BACKGROUND: The optimal follow-up strategy to detect recurrence after fertility-sparing surgery for early stage cervical cancer is unknown. Tailored surveillance based on individual risks could contribute to improved efficiency and, subsequently, reduce costs in health care. The aim of this study was to establish the predictive value of cervical cytology and high-risk human papillomavirus (HPV) testing to detect recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+; including recurrent cervical cancer) after fertility-sparing surgery. METHODS: In this nationwide, population-based, retrospective cohort study, we used data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. All patients aged 18-40 years with cervical cancer of any histology who received fertility-sparing surgery (ie, large loop excision of the transformation zone, conisation, or trachelectomy) between Jan 1, 2000, and Dec 31, 2020, were included. Pathology data from diagnosis, treatment, and during follow-up were analysed. The primary and secondary outcomes were the cumulative incidence of recurrent CIN2+ and recurrence-free survival, overall and stratified by results for cytology and high-risk HPV. FINDINGS: 1548 patients were identified, of whom 1462 met the inclusion criteria. Of these included patients, 19 568 pathology reports were available. The median age at diagnosis was 31 years (IQR 30-35). After a median follow-up of 6·1 years (IQR 3·3-10·8), recurrent CIN2+ was diagnosed in 128 patients (cumulative incidence 15·0%, 95% CI 11·5-18·2), including 52 patients (cumulative incidence 5·4%, 95% CI 3·7-7·0) with recurrent cervical cancer. The overall 10-year recurrence-free survival for CIN2+ was 89·3% (95% CI 87·4-91·3). By cytology at first follow-up visit within 12 months after fertility-sparing surgery, 10-year recurrence-free survival for CIN2+ was 92·1% (90·2-94·1) in patients with normal cytology, 84·6% (77·4-92·3) in those with low-grade cytology, and 43·1% (26·4-70·2) in those with high-grade cytology. By high-risk HPV status at first follow-up visit within 12 months after surgery, 10-year recurrence-free survival for CIN2+ was 91·1% (85·3-97·3) in patients who were negative for high-risk HPV and 73·6% (58·4-92·8) in those who were positive for high-risk HPV. Cumulative incidence of recurrent CIN2+ within 6 months after any follow-up visit (6-24 months) in patients negative for high-risk HPV with normal or low-grade cytology was 0·0-0·7% and with high-grade cytology was 0·0-33·3%. Cumulative incidence of recurrence in patients positive for high-risk HPV with normal or low-grade cytology were 0·0-15·4% and with high-grade cytology were 50·0-100·0%. None of the patients who were negative for high-risk HPV without high-grade cytology, at 6 months and 12 months, developed recurrence. INTERPRETATION: Patients who are negative for high-risk HPV with normal or low-grade cytology at 6-24 months after fertility-sparing surgery, could be offered a prolonged follow-up interval of 6 months. This group comprises 80% of all patients receiving fertility-sparing surgery. An interval of 12 months seems to be safe after two consecutive negative tests for high-risk HPV with an absence of high-grade cytology, which accounts for nearly 75% of all patients who receive fertility-sparing surgery. FUNDING: KWF Dutch Cancer Society.

Impact of Sepsis on the Oncologic Outcomes of Advanced Epithelial Ovarian Cancer Patients: A Multicenter Observational Study.

OBJECTIVE: The sepsis-induced inflammatory response may potentially affect malignant cells. Recently, a case of spontaneous regression of a histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IIIC epithelial ovarian cancer (EOC) following sepsis was reported. The aim of our study was to assess the impact of sepsis on the oncologic outcomes of advanced-stage EOC patients. METHODS: Gynecologic oncologic patients admitted to the Intensive Care Unit of three oncologic centers between 2006 and 2019 were identified and patients who experienced sepsis following advanced-stage EOC diagnosis were selected. Survival outcomes were compared with advanced-stage EOC patients from the Netherlands Cancer Registry (NCR). To correct for case-mix differences, propensity score matching using 1:3 nearest neighbor matching was conducted after which survival analyses were repeated. RESULTS: A total of 18 of 215 patients with advanced-stage EOC experienced sepsis. Sepsis patients had similar distributions of patient, tumor, and treatment characteristics to 3988 patients from the NCR cohort. A total of 3 of 18 patients died from the complications of sepsis. While the remaining patients initially responded to treatment, 14/15 patients relapsed. The median (IQR) overall survival was 31 (24-44) and 35 (20-60) months for the sepsis and unmatched NCR cohort (p = 0.56), respectively. The median (IQR) progression-free survival was 16 (11-21) and 16 (11-27) months (p = 0.90), respectively. Survival outcomes did not differ following propensity matching (overall survival of 31 (24-44) vs. 36 (20-56) months, p = 0.40; progression-free survival of 16 (11-21) and 16 (12-21) months, p = 0.72). CONCLUSION: In this observational study, the occurrence of sepsis did not affect the oncologic and survival outcomes of advanced-stage EOC patients.

Acceptability of risk-based triage in cervical cancer screening: A focus group study.

BACKGROUND: Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30-60 years) eligible for cervical cancer screening. OBJECTIVE: The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening. DESIGN: A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences. APPROACH: The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis. PARTICIPANTS: A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result. KEY RESULTS: In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention). CONCLUSION: The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted by the target group. These challenges include dealing with sensitive topics and a transparent communication strategy.

Evaluation of DNA methylation biomarkers ASCL1 and LHX8 on HPV-positive self-collected samples from primary HPV-based screening.

BACKGROUND: Host-cell DNA methylation analysis can be used to triage women with high-risk human papillomavirus (HPV)-positive self-collected cervicovaginal samples, but current data are restricted to under-/never-screened women and referral populations. This study evaluated triage performance in women who were offered primary HPV self-sampling for cervical cancer screening. METHODS: Self-collected samples from 593 HPV-positive women who participated in a primary HPV self-sampling trial (IMPROVE study; NTR5078), were tested for the DNA methylation markers ASCL1 and LHX8 using quantitative multiplex methylation-specific PCR (qMSP). The diagnostic performance for CIN3 and cervical cancer (CIN3 + ) was evaluated and compared with that of paired HPV-positive clinician-collected cervical samples. RESULTS: Significantly higher methylation levels were found in HPV-positive self-collected samples of women with CIN3 + than control women with no evidence of disease (P values <0.0001). The marker panel ASCL1/LHX8 yielded a sensitivity for CIN3 + detection of 73.3% (63/86; 95% CI 63.9-82.6%), with a corresponding specificity of 61.1% (310/507; 95% CI 56.9-65.4%). The relative sensitivity for detecting CIN3+ was 0.95 (95% CI 0.82-1.10) for self-collection versus clinician-collection, and the relative specificity was 0.82 (95% CI 0.75-0.90). CONCLUSIONS: The ASCL1/LHX8 methylation marker panel constitutes a feasible direct triage method for the detection of CIN3 + in HPV-positive women participating in routine screening by self-sampling.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma.

BACKGROUND: Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. METHODS: Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. RESULTS: Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. CONCLUSIONS: Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

A federated approach to identify women with early-stage cervical cancer at low risk of lymph node metastases.

OBJECTIVE: Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection. METHODS: Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+. RESULTS: We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59-5.79), tumour size 21-40 mm (OR 2.14, 95% CI, 1.89-2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59-2.08). A group of 1469 women (41%)-with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm-had a very low risk of pN+ (2.4%, 95% CI, 1.7-3.3%). CONCLUSION: Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection.

Identification of over- and undertreatment in the Dutch national cervical cancer screening program: A data linkage study at the hospital level.

Research into the quality of cancer screening programs often lacks the perspective of clinicians, missing insights into the performance of individual hospitals. This retrospective cohort study aimed to identify guideline deviation (specifically, overtreatment and undertreatment) related to the cervical cancer screening program in Dutch hospitals by deterministically linking nationwide insurance data with pathology data for cervical intraepithelial neoplasia (CIN). We then constructed quality indicators using the Dutch CIN guideline and National Health Care Institute recommendations to assess compliance with CIN management, treatment outcomes, and follow-up, using an empirical Bayes shrinkage model to correct for case-mix variation and hospitals with few observations. Data were linked for 115,899 of 125,751 (92%) eligible women. Overtreatment was observed in the see-and-treat approach (immediate treatment) for women with low-grade referral cytology (4%; hospital range, 0%-25%), CIN ≤ 1 treatment specimens (26%; hospital range, 10%-55%), and follow-up cervix cytology ≥2 months before the guideline recommendation after treatment for CIN 2 (2%; hospital range, 0%-9%) or CIN 3 (5%; hospital range, 0%-19%). By contrast, undertreatment was observed for treatment within 3 months after a CIN 3 biopsy result (90%; hospital range 59%-100%) and follow-up ≥2 months beyond the guideline recommendation after treatments for CIN 2 (21%, hospital range 7%-48%) and CIN 3 (20%, hospital range 7%-90%). In conclusion, we found evidence of CIN overtreatment and undertreatment in all measured domains at the hospital level. Guideline adherence could be improved by implementing the developed indicators in an audit and feedback instrument for use by healthcare professionals in routine practice.

The added value of digital imaging to reflex cytology for triage of high-risk human papillomavirus positive self-sampled material in cervical cancer screening: A prospective cohort study.

OBJECTIVE: Cytology performed directly on hrHPV-positive self-samples (reflex cytology) is feasible and for women with abnormal cytology, an additional cytology test at the general practitioner could be omitted. The aim of this study is to assess the added value of digital imaging (ThinPrep® Imaging System) on the clinical utility of reflex cytology by reducing screening error. DESIGN: A secondary analysis of a prospective cohort study. SETTING: One of five Dutch screening laboratories. POPULATION: Women tested hrHPV-positive on self-samples between December 2018 and August 2019. METHODS: Self-samples were used for reflex cytology with and without digital imaging. The follow-up data (cytological and histological results within 1 year of follow-up) were obtained through the Dutch Pathology Registry (PALGA). MAIN OUTCOME MEASURES: Test performance of the reflex cytology was determined by comparing it with physician-collected follow-up results. RESULTS: The sensitivity for detecting abnormal cells by reflex cytology on self-samples increased significantly from 26.3% (42/160; 95% confidence interval [CI] 19.6-33.8) without digital imaging to 35.4% (56/158; 95% CI 28-43.4) with digital imaging (P < 0.05) without compromising specificity. Importantly, 41.7% of women with ≥CIN2 (35/84) and 45.6% with ≥CIN3 (26/57) were detected by reflex cytology with digital imaging on hrHPV-positive self-samples. CONCLUSION: Digital imaging is of added value to reflex cytology on hrHPV-positive self-samples with a 9% increase in sensitivity. If reflex cytology on self-samples analysed with digital imaging had been implemented in the screening programme, 35.4% of the hrHPV-positive women with abnormal cytology on additional physician-collected samples could have been referred directly for colposcopy.

Comparing Methods to Determine Complete Response to Chemoradiation in Patients with Locally Advanced Cervical Cancer.

OBJECTIVES: There is no consensus on the most reliable procedure to determine remission of cervical cancer after chemoradiotherapy (CRT). Therefore, this study aims to assess the diagnostic performance of two different imaging techniques, MRI and 18F[FDG]-PET/CT, in determining the presence of locoregional residual disease after CRT in patients with locally advanced cervical cancer. METHODS: Patients diagnosed with locally advanced cervical cancer (FIGO 2009) treated with CRT were retrospectively identified from a regional cohort. The accuracy of MRI and 18F[FDG]-PET/CT in detecting locoregional residual disease was assessed with histology as the reference standard. RESULTS: The negative predictive value (NPV) and positive predictive value (PPV) for locoregional residual disease detection of MRI and 18F[FDG]-PET/CT combined were 84.2% (95% CI 73.2-92.1), and 70.4% (95% CI 51.8-85.2), respectively. The NPV and PPV of MRI alone were 80.2% (95% CI 71.2-87.5) and 47.7% (95% CI 35.8-59.7), respectively, and values of 81.1% (95% CI 72.2-88.3) and 55.8 (95% CI 42.2-68.7), respectively, were obtained for 18F[FDG]-PET/CT alone. CONCLUSION: In this study, the reliability of MRI and 18F[FDG]-PET/CT in detecting locoregional residual disease was limited. Combining MRI and 18F[FDG]-PET/CT did not improve predictive values. Routine use of both MRI and 18F[FDG]-PET/CT in the follow-up after CRT should be avoided. MRI during follow-up is the advised imaging technique. Pathology confirmation of the presence of locoregional residual disease before performing salvage surgery is warranted.

Feasibility and Effectiveness of the Exercise Program in Endometrial Cancer; Feasibility and Acceptability Survivorship Trial (EPEC-FAST).

To evaluate the feasibility of an individualized exercise program in the standard care for endometrial cancer patients aimed to improve quality of life and other health outcomes. This was a single-arm prospective intervention trial to assess the feasibility of an individualized exercise intervention in endometrial cancer patients after treatment. The exercise intervention consisted of weekly individualized training sessions, for 10 weeks, at a local gym facility. The program started six weeks post-operatively. Primary outcomes were feasibility aspects including number of eligible patients, recruitment and adherence rates. Secondary outcomes included quality of life outcomes and anthropometric measures. A total of 54 women were eligible for participation, of which 22 (41%) consented to the study. Overall attendance was 86%, and there were no adverse events. There was a significant improvement in quality of life outcomes, including role (p = 0.02), emotional (p = 0.02) and cognitive functioning (p = 0.04). In addition, there was a significant improvement in visceral fat percentage (p = 0.039) and physical fitness (six-minute walk test p < 0.001). The maximum weight loss achieved was 6.0 kg after 3 months and 8.4 kg after 6 months. An individualized one-to-one exercise intervention in endometrial cancer patients is feasible in terms of recruitment, adherence and safety.

Adjunctive use of p16 immunohistochemistry for optimizing management of CIN lesions in a high-risk human papillomavirus-positive population.

INTRODUCTION: Immunostaining with p16INK4a (p16), a tumor-suppressor surrogate protein biomarker for high-risk human papillomavirus (hrHPV) oncogenic activity, may complement standard hematoxylin and eosin (H&E) histology review, and provide more objective criteria to support the cervical intraepithelial neoplasia (CIN) diagnosis. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting. MATERIAL AND METHODS: In this post-hoc analysis, 326 histology follow-up samples from a group of hrHPV-positive women were stained with p16 immunohistochemistry. All H&E samples were centrally revised. The pathologists reported their level of confidence in classifying the CIN lesion. RESULTS: Combining H&E and p16 staining resulted in a change of diagnosis in 27.3% (n = 89) of cases compared with the revised H&E samples, with a decrease of 34.5% (n = 18) in CIN1 and 22.7% (n = 15) in CIN2 classifications, and an increase of 18.3% (n = 19) in no CIN and 20.7% (n = 19) in CIN3 diagnoses. The level of confidence in CIN grading by the pathologist increased with adjunctive use of p16 immunohistochemistry to standard H&E. CONCLUSIONS: This study shows that adjunctive use of p16 immunohistochemistry to H&E morphology reduces the number of CIN1 and CIN2 classifications with a proportional increase in no CIN and CIN3 diagnoses, compared with standard H&E-based CIN diagnosis alone. The pathologists felt more confident in classifying the material with H&E and p16 immunohistochemistry than by using H&E alone, particularly during assessment of small biopsies. Adjunctive use of p16 immunohistochemistry to standard H&E assessment of CIN would be valuable for the diagnostic accuracy, thereby optimizing CIN management and possibly decreasing overtreatment.

The added value of SLN mapping with indocyanine green in low- and intermediate-risk endometrial cancer management: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). METHODS: A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. RESULTS: Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%-97.9%) and 76.5% (95% CI=68.1%-84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%-15.2%) in patients with grade 1-2 endometrial cancer and 11.8% (95% CI=8.1%-16.1%) in patients with grade 1-3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%-100%) in studies that included grade 1-2 endometrial cancer and 99.2% (95% CI=97.9%-99.9%) in studies that also included grade 3. CONCLUSION: SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediate-risk endometrial cancer.

Does the New FIGO 2018 Staging System Allow Better Prognostic Differentiation in Early Stage Cervical Cancer? A Dutch Nationwide Cohort Study.

The FIGO 2018 staging system was introduced to allow better prognostic differentiation in cervical cancer, causing considerable stage migration and affecting treatment options. We evaluated the accuracy of the FIGO 2018 staging in predicting recurrence free (RFS) and overall survival (OS) compared to FIGO 2009 staging in clinically early stage cervical cancer. We conducted a nationwide retrospective cohort study, including 2264 patients with preoperative FIGO (2009) IA1, IA2 and IB1 cervical cancer between 2007-2017. Kaplan-Meier analyses were used to assess survival outcomes. Logistic regression was used to assess risk factors for lymph node metastasis and parametrial invasion. Stage migration occurred in 48% (22% down-staged, 26% up-staged). Survival data of patients down-staged from IB to IA1/2 disease were comparable with FIGO 2009 IA1/2 and better than patients remaining stage IB1. LVSI, invasion depth and parametrial invasion were risk factors for lymph node metastases. LVSI, grade and age were associated with parametrial invasion. In conclusion, the FIGO 2018 staging system accurately reflects prognosis in early stage cervical cancer and is therefore more suitable than the FIGO 2009 staging. However subdivision in IA1 or IA2 based on presence or absence of LVSI instead of depth of invasion would have improved accuracy. For patients down-staged to IA1/2, less radical surgery seems appropriate, although LVSI and histology should be considered when determining the treatment plan.

Targeted RNA next generation sequencing analysis of cervical smears can predict the presence of hrHPV-induced cervical lesions.

BACKGROUND: Because most cervical cancers are caused by high-risk human papillomaviruses (hrHPVs), cervical cancer prevention programs increasingly employ hrHPV testing as a primary test. The high sensitivity of HPV tests is accompanied by low specificity, resulting in high rates of overdiagnosis and overtreatment. Targeted circular probe-based RNA next generation sequencing (ciRNAseq) allows for the quantitative detection of RNAs of interest with high sequencing depth. Here, we examined the potential of ciRNAseq-testing on cervical scrapes to identify hrHPV-positive women at risk of having or developing high-grade cervical intraepithelial neoplasia (CIN). METHODS: We performed ciRNAseq on 610 cervical scrapes from the Dutch cervical cancer screening program to detect gene expression from 15 hrHPV genotypes and from 429 human genes. Differentially expressed hrHPV- and host genes in scrapes from women with outcome "no CIN" or "CIN2+" were identified and a model was built to distinguish these groups. RESULTS: Apart from increasing percentages of hrHPV oncogene expression from "no CIN" to high-grade cytology/histology, we identified genes involved in cell cycle regulation, tyrosine kinase signaling pathways, immune suppression, and DNA repair being expressed at significantly higher levels in scrapes with high-grade cytology and histology. Machine learning using random forest on all the expression data resulted in a model that detected 'no CIN' versus CIN2+ in an independent data set with sensitivity and specificity of respectively 85 ± 8% and 72 ± 13%. CONCLUSIONS: CiRNAseq on exfoliated cells in cervical scrapes measures hrHPV-(onco)gene expression and host gene expression in one single assay and in the process identifies HPV genotype. By combining these data and applying machine learning protocols, the risk of CIN can be calculated. Because ciRNAseq can be performed in high-throughput, making it cost-effective, it can be a promising screening technology to stratify women at risk of CIN2+. Further increasing specificity by model improvement in larger cohorts is warranted.

Treatment of bulky lymph nodes in locally advanced cervical cancer: boosting versus debulking.

OBJECTIVE: Treatment strategies for bulky lymph nodes in patients with locally advanced cervical cancer scheduled for definitive chemoradiation include nodal boosting with radiotherapy, surgical debulking, or both. The aim of this retrospective cohort study was to compare survival and toxicity in patients receiving these treatments and to compare them with a group that received neither form of treatment. METHODS: Women diagnosed between January 2009 and January 2017 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2, IIA2-IVA cervical cancer with lymph nodes ≥1.5 cm without upper limit on pretreatment imaging and treated with definitive chemoradiation were selected from the Netherlands Cancer Registry. Patients were categorized by intention-to-treat strategy: boosting, debulking, or neither treatment, with subgroup analysis for patients receiving both treatments, that is, debulking with boosting. Overall and relapse-free survival outcomes were compared by Kaplan-Meier and Cox regression analyses and toxicity by logistic regression analysis. RESULTS: Of 190 patients, 101 (53%) received only nodal boosting, 31 (16%) debulking alone, 29 (15%) debulking combined with boosting, and 29 (15%) received neither treatment. The 5 year overall and relapse-free survival for the treatment groups were 58%, 45% and 45% (p=0.19), and 47%, 44% and 46% (p=0.87), respectively. Multivariable Cox regression analyses demonstrated no differences in overall and relapse-free survival. Combination of debulking with boosting was associated with decreased overall and relapse-free survival compared with debulking alone (HR 2.47, 95% CI 1.22 to 5.00; and HR 2.37, 95% CI 1.14 to 4.93). Nodal boosting was independently associated with a decreased toxicity risk compared with debulking strategy (OR 0.37, 95% CI 0.16 to 0.83). CONCLUSIONS: This study showed no survival benefit from either nodal boosting or debulking strategy in patients with suspicious bulky nodes. Nodal boosting might, however, be associated with less toxicity. Dual treatment with debulking and boosting showed a worse survival outcome because this group probably represents patients with poor prognostic factors.