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.

Can MRI Be Used as a Sole Diagnostic Modality in Determining Clinical Stage in Cervical Cancer?

OBJECTIVE: The objective of this study was to compare staging by MRI to clinical staging in patients with cervical cancer and to determine the histological accuracy of staging by MRI and examination under anesthesia (EUA) in early stage disease. METHODS: This was a retrospective cohort study of patients diagnosed with cervical cancer between 2010 and 2020 at the Radboud University Medical Centre, the Netherlands. Pretreatment stage (FIGO 2009) by MRI was compared with staging by EUA. Diagnostic accuracy in terms of sensitivity, specificity, positive, and negative predictive value was calculated for MRI and EUA in patients undergoing surgery (early stage disease) with histological results as a reference standard. RESULTS: A total of 358 patients were included in the study and MRI-based stage differed from EUA stage in 30.7%. In 12.3% this meant a discrepancy in treatment assignment between MRI and EUA. Diagnostic accuracy of MRI in terms of sensitivity and specificity for detecting early stage disease was comparable to EUA in surgical patients. Further analyses showed that premenopausal status, early stage disease and a tumor diameter of <2 cm were associated with improved comparability of MRI and EUA (98%). CONCLUSION: There is still a large discrepancy between MRI and EUA. In patients with suspected early stage disease, diagnostic accuracy of MRI is similar to EUA, especially for premenopausal women with early stage disease and a tumor diameter of <2 cm.

Finding the sentinel lymph node in early cervical cancer: When is unusual not uncommon?

OBJECTIVE: To report our institutional experience with sentinel lymph node (SLN) detection using indocyanine green for cervical cancer, in terms of detection rates, detection of SLN at unusual locations, and factors associated with unusual SLN locations. In addition, we performed a systematic review of the literature to identify factors associated with unusual SLN localizations. METHODS: This is a retrospective cohort study of women with early-stage cervical cancer undergoing sentinel lymph node mapping between 2015 and 2019. Outcome measures were SLN detection rates, detection rates of unusual locations for SLN and risk factors for aberrant lymphatic drainage pathways. In addition, studies evaluating factors associated with unusual SLN locations in cervical cancer were assessed in a systematic review. RESULTS: A total of 100 patients were included. The unilateral SLN detection rate was 88%, whereas the bilateral detection rate was 75%. In 37% of all patients, SLN were found in unusual locations, and in 10% of patients SLN were solely found in unusual locations. Body mass index (BMI) was associated with finding SLN in unusual locations, with unusual nodes detected in 52% of patients with BMI <25 kg/m2 and in 28% of patients with BMI ≥25 kg/m2. The systematic review identified three studies, identifying lower BMI, nulliparity and tumor size of >20 mm as factors associated with finding SLN at unusual locations. CONCLUSION: Aberrant drainage sites represent a significant proportion of SLN detected in cervical cancer. Factors associated with increased rates of unusual nodal locations are a lower BMI, with a possible association with nulliparity and tumor size of >20 mm.

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.

SUCCOR cone study: conization before radical hysterectomy.

OBJECTIVE: To evaluate disease-free survival of cervical conization prior to radical hysterectomy in patients with stage IB1 cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009). METHODS: A multicenter retrospective observational cohort study was conducted including patients from the Surgery in Cervical Cancer Comparing Different Surgical Aproaches in Stage IB1 Cervical Cancer (SUCCOR) database with FIGO 2009 IB1 cervical carcinoma treated with radical hysterectomy between January 1, 2013, and December 31, 2014. We used propensity score matching to minimize the potential allocation biases arising from the retrospective design. Patients who underwent conization but were similar for other measured characteristics were matched 1:1 to patients from the non-cone group using a caliper width ≤0.2 standard deviations of the logit odds of the estimated propensity score. RESULTS: We obtained a weighted cohort of 374 patients (187 patients with prior conization and 187 non-conization patients). We found a 65% reduction in the risk of relapse for patients who had cervical conization prior to radical hysterectomy (hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.16 to 0.75, p=0.007) and a 75% reduction in the risk of death for the same sample (HR 0.25, 95% CI 0.07 to 0.90, p=0.033). In addition, patients who underwent minimally invasive surgery without prior conization had a 5.63 times higher chance of relapse compared with those who had an open approach and previous conization (HR 5.63, 95% CI 1.64 to 19.3, p=0.006). Patients who underwent minimally invasive surgery with prior conization and those who underwent open surgery without prior conization showed no differences in relapse rates compared with those who underwent open surgery with prior cone biopsy (reference) (HR 1.94, 95% CI 0.49 to 7.76, p=0.349 and HR 2.94, 95% CI 0.80 to 10.86, p=0.106 respectively). CONCLUSIONS: In this retrospective study, patients undergoing cervical conization before radical hysterectomy had a significantly lower risk of relapse and death.

SUCCOR quality: validation of ESGO quality indicators for surgical treatment of cervical cancer.

OBJECTIVE: To evaluate whether compliance with European Society of Gynaecological Oncology (ESGO) surgery quality indicators impacts disease-free survival in patients undergoing radical hysterectomy for cervical cancer. METHODS: In this retrospective cohort study, 15 ESGO quality indicators were assessed in the SUCCOR database (patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage 2009 IB1, FIGO 2018 IB1, and IB2 cervical cancer between January 2013 and December 2014), and the final score ranged between 0 and 16 points. Centers with more than 13 points were classified as high-quality indicator compliance centers. We constructed a weighted cohort using inverse probability weighting to adjust for the variables. We compared disease-free survival and overall survival using Cox proportional hazards regression analysis in the weighted cohort. RESULTS: A total of 838 patients were included in the study. The mean number of quality indicators compliance in this cohort was 13.6 (SD 1.45). A total of 479 (57.2%) patients were operated on at high compliance centers and 359 (42.8%) patients at low compliance centers. High compliance centers performed more open surgeries (58.4% vs 36.7%, p<0.01). Women who were operated on at centers with high compliance with quality indicators had a significantly lower risk of relapse (HR=0.39; 95% CI 0.25 to 0.61; p<0.001). The association was reduced, but remained significant, after further adjustment for conization, surgical approach, and use of manipulator surgery (HR=0.48; 95% CI 0.30 to 0.75; p=0.001) and adjustment for adjuvant therapy (HR=0.47; 95% CI 0.30 to 0.74; p=0.001). Risk of death from disease was significantly lower in women operated on at centers with high adherence to quality indicators (HR=0.43; 95% CI 0.19 to 0.97; p=0.041). However, the association was not significant after adjustment for conization, surgical approach, use of manipulator surgery, and adjuvant therapy. CONCLUSIONS: Patients with early cervical cancer who underwent radical hysterectomy in centers with high compliance with ESGO quality indicators had a lower risk of recurrence and death.

A cost-effectiveness analysis of three approaches for lymph node assessment in patients with low- and intermediate-risk endometrial cancer.

OBJECTIVE: To assess the cost-effectiveness of sentinel lymph node mapping compared to risk factor assessment and routine full lymph node dissection for the assessment of lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer. METHODS: A decision-analytic model was designed to compare three lymph node assessment strategies in terms of costs and effects: 1) sentinel lymph node mapping; 2) post-operative risk factor assessment (adjuvant therapy based on clinical and histological risk factors); 3) full lymph node dissection. Input data were derived from systematic literature searches and expert opinion. QALYs were used as measure of effectiveness. The model was built from a healthcare perspective and the impact of uncertainty was assessed with sensitivity analyses. RESULTS: Base-case analysis showed that sentinel lymph node mapping was the most effective strategy for lymph node assessment in patients with low- and intermediate-risk endometrial cancer. Compared to risk factor assessment it was more costly, but the incremental cost effectiveness ratio stayed below a willingness-to-pay threshold of €20,000 with a maximum of €9637/QALY. Sentinel lymph node mapping was dominant compared to lymph node dissection since it was more effective and less costly. Sensitivity analyses showed that the outcome of the model was robust to changes in input values. With a willingness-to-pay threshold of €20,000 sentinel lymph node mapping remained cost-effective in at least 74.3% of the iterations. CONCLUSION: Sentinel lymph node mapping is the most cost-effective strategy to guide the need for adjuvant therapy in patients with low and intermediate risk endometrioid endometrial cancer.

Ultrastaging methods of sentinel lymph nodes in endometrial cancer - a systematic review.

OBJECTIVE: Sentinel lymph node mapping has emerged as an alternative to lymphadenectomy in evaluating the lymph node status in endometrial cancer. Several pathological methods to examine the sentinel lymph node are applied internationally. The aim of this study was to determine the value of ultrastaging and to assess the ultrastaging method with the highest detection rate of metastases. METHODS: A systematic review was conducted. Inclusion criteria were: pathologically-confirmed endometrial cancer with sentinel lymph node mapping, report of the histological outcomes, metastases found by hematoxylin and eosin staining and metastases found by ultrastaging were separately mentioned, and description of the ultrastaging method. The primary outcome was the detection of metastases found by ultrastaging that were not detected by routine hematoxylin and eosin staining. The secondary outcome was the difference in detection rate of metastases between several ultrastaging methods. Random effects meta-analyses were conducted. RESULTS: Fifteen studies were selected, including 2259 patients. Sentinel lymph nodes were examined by routine hematoxylin and eosin staining. Subsequently, multiple ultrastaging methods were used, with differences in macroscopic slicing (bread-loaf/longitudinal), number of microscopic slides, and distance between slides, but all used immunohistochemistry. A positive sentinel lymph node was found in 14% of patients. In 37% of these, this was detected only by ultrastaging. Using more ultrastaging slides did not result in a higher detection rate. Bread-loaf slicing led to a higher detection rate compared with longitudinal slicing (mean detection rates 53% and 33%, respectively). CONCLUSION: Pathological ultrastaging after routine hematoxylin and eosin staining in endometrial cancer patients has led to an increased detection rate of sentinel lymph node metastases. Different ultrastaging methods are used, with a preference for bread-loaf slicing. However, due to the large heterogeneity of the studies, assessing which ultrastaging method has the highest detection rate of sentinel lymph node metastases was not possible.

Radical hysterectomy in early cervical cancer in Europe: characteristics, outcomes and evaluation of ESGO quality indicators.

INTRODUCTION: Comprehensive updated information on cervical cancer surgical treatment in Europe is scarce. OBJECTIVE: To evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database. METHODS: The SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified. RESULTS: The mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) <2 cm was observed in 667 (57.7%) patients. The most frequent histology type was squamous carcinoma (794 (68.7%) patients), and positive lymph nodes were found in 143 (12.4%) patients. A total of 633 (54.8%) patients were operated by open abdominal surgery. Intra-operative complications occurred in 108 (9.3%) patients, and post-operative complications during the first month occurred in 249 (21.5%) patients, with bladder dysfunction as the most frequent event (119 (10.3%) patients). Clavien-Dindo grade III or higher complication occurred in 56 (4.8%) patients. A total of 510 (44.1%) patients received adjuvant therapy. After a median follow-up of 58 months (range 0-84), the 5-year disease-free survival was 88.3%, and the overall survival was 94.9%. In our population, 10 of the 11 surgical-related quality indicators currently recommended by ESGO were fully fulfilled 5 years before its implementation. CONCLUSIONS: In this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

Salvage surgery for patients with residual disease after chemoradiation therapy for locally advanced cervical cancer: A systematic review on indication, complications, and survival.

INTRODUCTION: Standard treatment for locally advanced cervical cancer is chemoradiation therapy. Treatment with chemoradiation therapy harbors a risk of local residual disease, which can be curatively treated with salvage surgery, but the risk of complications following surgical procedures in radiated tissue is not negligible. The presence of residual disease can be radiologically and/or histologically diagnosed. The objective of this study is to describe studies that report on salvage surgery for patients with locally advanced cervical cancer after primary treatment with chemoradiation therapy. Therefore, we assessed the method of determining the presence of residual disease, the risk of complications, and the survival rate after salvage surgery. MATERIAL AND METHODS: PubMed, EMBASE, and the Cochrane database were searched from inception up to 6 March 2020. Titles and abstracts were independently assessed by two researchers. Studies were eligible for inclusion when patients had locally advanced cervical cancer with radiologically suspected or histologically confirmed residual disease after chemoradiation therapy, diagnosed with a CT, MRI, or PET-CT scan, or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. Methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale. RESULTS: Of the 2963 screened articles, six studies were included, representing 220 women. A total of 175 patients were treated with salvage surgery, of whom 27%-100% had residual disease on the surgery specimen. Of the 161 patients treated with salvage surgery based on positive biopsy results, 72%-100% showed residual disease on the surgery specimen. Of the 44 patients treated with salvage surgery based on suspected residual disease on radiology, 27%-48% showed residual disease on the salvage surgery specimen. A total of 105 complications were registered in 175 patients treated with salvage surgery. The overall survival rate after salvage surgery was 69% (mean follow-up period of 24.9 months). CONCLUSIONS: It is necessary to confirm residual disease by biopsy before performing salvage surgery in patients with locally advanced cervical cancer primarily treated with chemoradiation therapy. Salvage surgery only based on radiologically suspected residual disease should be avoided to prevent unnecessary surgery and complications.

Neoadjuvant Chemotherapy Followed by Vaginal Radical Trachelectomy as Fertility-Preserving Treatment for Patients with FIGO 2018 Stage 1B2 Cervical Cancer.

BACKGROUND: Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (i.e., tumor size between 2 and 4 cm) is a radical hysterectomy (RH) with pelvic lymph node dissection (PLND). We evaluated the oncological and fertility outcomes treatment in patients receiving a fertility-sparing alternative consisting of neoadjuvant chemotherapy (NACT) followed by vaginal radical trachelectomy (VRT). METHODS: Patients with stage 1B2 cervical cancer who wished to preserve fertility were included from September 2009 to September 2018. NACT consisted of 6-week cycles of cisplatin or carboplatin with paclitaxel. If tumor size decreased to 2 cm or smaller, NACT was followed by a robot-assisted PLND and VRT. RESULTS: Eighteen patients were included. Median follow-up time was 49.7 months (range 11.4-110.8). Median tumor size was 32 mm (range 22-40 mm). Complete remission after NACT occurred in seven women. Four women had a poor response on NACT. Three underwent RH with PLND; one received chemoradiation after PLND instead of VRT because of positive lymph nodes. The remaining 14 patients received VRT 3-4 weeks after NACT. Four recurrences occurred: three after NACT and VRT and one after NACT and RH. Median time to recurrence was 20.8 months (range 17.0-105.7). Three recurrences occurred in women with adenocarcinoma with lymph vascular space invasion (LVSI). In four women fertility could not be preserved. To date, four women had six pregnancies, including three live births born at term, two first trimester miscarriages, and one currently ongoing pregnancy. CONCLUSION: NACT and VRT in women with stage 1B2 cervical cancer showed promising results. In 78% fertility was preserved. However, patients with poor response on NACT and with adenocarcinoma and/or LVSI were possibly at risk for recurrence. Long-term results in relation to fertility and oncological outcome are needed to corroborate these findings. IMPLICATIONS FOR PRACTICE: Standard treatment for women with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (tumor size 2-4 cm) is a radical hysterectomy and pelvic lymph node dissection (PLND). However, many of these women are young and wish to preserve fertility. Data on fertility-sparing treatment options are sparse, but neoadjuvant chemotherapy followed by a vaginal radical trachelectomy and PLND could be an alternative. Since 2009 we performed an observational cohort study in which 18 women opted for this treatment in our center. In 14 women fertility could be preserved. In four patients the tumor recurred. In four women six pregnancies occurred. After careful selection this treatment could be a good fertility-sparing treatment option.

Patients' and gynecologists' views on sentinel lymph node mapping in low- and intermediate-risk endometrial cancer: a Dutch vignette study.

OBJECTIVE: Sentinel lymph node (SLN) mapping in endometrial cancer is gaining ground. However, patient views on this new technique are unknown. The aim of this study was to determine factors important to patients and gynecologists when considering SLN mapping in low- and intermediate-risk endometrial cancer. METHODS: We performed a vignette study. Patients who underwent a total hysterectomy for low- or intermediate-risk endometrial cancer between 2012 and 2015 were invited. Dutch gynecologists specializing in gynecologic oncology were also invited. We based the selection for attributes in the vignettes on literature and interviews: risk of complications of SLN mapping; chance of finding a metastasis; survival gain; risk of complications after radiotherapy; operation time; and hospital of surgery (travel time). We developed a questionnaire with 18 hypothetical scenarios. Each attribute level varied and for each scenario, participants were asked how strongly they would prefer SLN on a scale from 1 to 7. The strength of preference for each scenario was analyzed using linear mixed effects models. RESULTS: A total of 38% of patients (41/108) and 33% of gynecologists (42/126) participated in the study. Overall, they had a preference for SLN. The mean preference for patients was 4.29 (95% CI 3.72 to 4.85) and 4.39 (95% CI 3.99 to 4.78) for gynecologists. Patients' preferences increased from 3.4 in the case of no survival gain to 4.9 in the case of 3-year survival gain (P<0.05) and it decreased when travel time increased to >60 min (-0.4, P=0.024), or with an increased risk of complications after adjuvant radiotherapy (-0.6, P=0.002). For gynecologists all attributes except travel time were important. CONCLUSIONS: Overall, patients and gynecologists were in favor of SLN mapping in low- and intermediate-risk endometrial cancer. Most important to patients were survival gain, travel time, and complication risk after adjuvant radiotherapy. These preferences should be taken into account when counseling about SLN mapping.

SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer.

BACKGROUND: Minimally invasive surgery in cervical cancer has demonstrated in recent publications worse outcomes than open surgery. The primary objective of the SUCCOR study, a European, multicenter, retrospective, observational cohort study was to evaluate disease-free survival in patients with stage IB1 (FIGO 2009) cervical cancer undergoing open vs minimally invasive radical hysterectomy. As a secondary objective, we aimed to investigate the association between protective surgical maneuvers and the risk of relapse. METHODS: We obtained data from 1272 patients that underwent a radical hysterectomy by open or minimally invasive surgery for stage IB1 cervical cancer (FIGO 2009) from January 2013 to December 2014. After applying all the inclusion-exclusion criteria, we used an inverse probability weighting to construct a weighted cohort of 693 patients to compare outcomes (minimally invasive surgery vs open). The first endpoint compared disease-free survival at 4.5 years in both groups. Secondary endpoints compared overall survival among groups and the impact of the use of a uterine manipulator and protective closure of the colpotomy over the tumor in the minimally invasive surgery group. RESULTS: Mean age was 48.3 years (range; 23-83) while the mean BMI was 25.7 kg/m2 (range; 15-49). The risk of recurrence for patients who underwent minimally invasive surgery was twice as high as that in the open surgery group (HR, 2.07; 95% CI, 1.35 to 3.15; P=0.001). Similarly, the risk of death was 2.42-times higher than in the open surgery group (HR, 2.45; 95% CI, 1.30 to 4.60, P=0.005). Patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse (HR, 2.76; 95% CI, 1.75 to 4.33; P<0.001) and those without the use of a uterine manipulator had similar disease-free-survival to the open surgery group (HR, 1.58; 95% CI, 0.79 to 3.15; P=0.20). Moreover, patients that underwent minimally invasive surgery with protective vaginal closure had similar rates of relapse to those who underwent open surgery (HR, 0.63; 95% CI, 0.15 to 2.59; P<0.52). CONCLUSIONS: Minimally invasive surgery in cervical cancer increased the risk of relapse and death compared with open surgery. In this study, avoiding the uterine manipulator and using maneuvers to avoid tumor spread at the time of colpotomy in minimally invasive surgery was associated with similar outcomes to open surgery. Further prospective studies are warranted.

MRI evaluation of vulvar squamous-cell carcinoma in fresh radical local excision specimens for cancer localization and prediction of surgical tumor-free margins.

In the surgical treatment of vulvar squamous-cell carcinoma (VSCC), tumor-free margins of 8 mm or more are considered adequate. However, limited perioperative information on the tumor-free margins other than the surgeon's own estimation is available. The purpose of this study was therefore to investigate the feasibility of ex vivo MRI in localizing VSCC and to assess the surgical tumor-free margins in fresh radical local excision (RLE) specimens to guide the surgeon during resections. Nine patients with biopsy-proven VSCC scheduled for RLE were prospectively included. Intact fresh specimens were scanned using a 7 T preclinical MR-scanner. Whole mount H&E-stained slides were obtained every 3 mm and correlated with ex vivo MRI. A pathologist annotated VSCC and minimal tumor-free margins (3 o'clock, 9 o'clock, basal) on the digitalized histological slides. An observer with knowledge of histology (the non-blinded annotation) and a radiologist blinded to histology (the blinded annotation) separately performed annotation of the same features on ex vivo MRI. Linear correlation and agreement of the ex vivo MRI measurements with histology were assessed. Diagnostic performance for VSCC localization and identification of margins less than 8 mm was expressed as positive and negative predictive values (PPV, NPV). In 153 matched ex vivo MRI slices, the observer correctly identified 79/91 margins as less than 8 mm (PPV 87%) and 110/124 margins as 8 mm or greater (NPV 89%). The radiologist correctly annotated absence of VSCC in 73/81 (NPV 90%) and presence in 65/72 (PPV 90%) slices. Sixty-four of 90 margins were correctly identified as less than 8 mm (PPV 71%) and 83/102 margins as 8 mm or greater (NPV 81%). Both non-blinded and blinded annotations were linearly correlated and demonstrated good agreement with histology. Accurate localization of VSCC and measurements of the surgical tumor-free margins in fresh RLE specimens using ex vivo MRI seems feasible. High diagnostic performance in VSCC localization and identification of margins less than 8 mm suggest ex vivo MRI to be clinically applicable.

HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients.

OBJECTIVE: To date, biomarkers are not routinely used in endometrial cancer diagnosis, prognosis, and follow-up. The purpose of this study was to evaluate whether serum HE4 was related to clinicopathological risk factors and outcome. Second, the role of serum HE4 and CA125 was assessed as indicator for recurrent disease during follow-up. METHODS: A total of 174 patients with endometrial cancer between 1999 and 2009 were selected for this retrospective study. Serum HE4 and CA125 were analyzed at primary diagnosis, during follow-up, and at the time of recurrence. Correlations with clinicopathological factors were studied by univariate and multivariate survival analyses. Lead time was calculated in order to determine which serum marker was elevated prior to clinical detection of recurrent disease. RESULTS: Serum levels of HE4 and CA125 were significantly associated with high tumor grade, myometrial invasion, lymph node involvement, and advanced stage (p < 0.01). HE4 was an independent prognostic factor for reduced disease-free survival and overall survival with hazard ratios of 2.96 (95% confidence interval: 1.18-7.99) and 3.27 (95% confidence interval: 1.18-9.02), respectively. At recurrence, 75% of the patients had an elevated HE4 compared to 54% with an elevated CA125. HE4 levels were more frequently elevated in patients with distant metastasis compared to local recurrences, 67% and 37%, respectively. Serum HE4 detected a recurrence with a median of 126 days earlier than clinical confirmation. CONCLUSION: Elevated serum HE4 is an independent risk factor for reduced disease-free survival and overall survival. HE4 seems to be superior to CA125 in the detection of recurrent disease during follow-up, mainly in high-risk endometrial cancer patients who are more prone to distant metastasis.

Different Lipid Regulation in Ovarian Cancer: Inhibition of the Immune System.

Lipid metabolism is altered in several cancer settings leading to different ratios of intermediates. Ovarian cancer is the most lethal gynecological malignancy. Cancer cells disperse in the abdominal space and ascites occurs. T cells obtained from ascites are unable to proliferate after an antigenic stimulus. The proliferation of ascites-derived T cells can be restored after culturing the cells for ten days in normal culture medium. No pathway aberrancies were detected. The acellular fraction of ascites can inhibit the proliferation of autologous as well as allogeneic peripheral blood lymphocytes, indicating the presence of soluble factors that interfere with T cell functionality. Therefore, we analyzed 109 lipid mediators and found differentially regulated lipids in suppressive ascitic fluid compared to normal abdominal fluid. Our study indicates the presence of lipid intermediates in ascites of ovarian cancer patients, which coincidences with T cell dysfunctionality. Since the immune system in the abdominal cavity is compromised, this may explain the high seeding efficiency of disseminated tumor cells. Further research is needed to fully understand the correlation between the various lipids and T cell proliferation, which could lead to new treatment options.

Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer.

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.

Measuring health-related quality of life in cervical cancer patients: a systematic review of the most used questionnaires and their validity.

BACKGROUND: Data on health-related quality of life (HRQoL) is paramount for shared and evidence based decision-making. Since an overview of cervical cancer HRQoL tools and their validity appears to be lacking, we performed a systematic review on usage of disease specific HRQoL instruments in cervical cancer patients and their psychometric properties to identify the most suitable cervical cancer specific HRQoL tool. METHODS: We searched Pubmed, EMBASE and PsycINFO from inception up to 18 October 2016 for studies on quality of life in cervical cancer patients. Data extraction and HRQoL identification was performed by two independent reviewers. Validation studies of the identified cervical cancer specific HRQoL tools were retrieved and assessed on psychometric properties using the COSMIN checklist. All used cervical cancer specific HRQoL instruments were scored and ranked according to their psychometric properties. RESULTS: We included 156 studies (20,690 patients) and identified 31 HRQoL tools. The EORTC QLQ-CX24 (35 studies; 5,556 patients) and FACT-Cx (22 studies; 4,224 patients) were the only cervical cancer specific tools. The EORTC QLQ-CX24 had 4 out of 9 positive rated psychometric properties; internal consistency, content and construct validity, and agreement. Criterion validity, reliability, and interpretability scored doubtful. Responsiveness and floor- and ceiling effects were not reported. The FACT-Cx had 2 out of 9 positive rated psychometric properties; internal consistency and agreement. Content validity, reliability, and interpretability scored doubtful while criterion and construct validity scored negative. Responsiveness and floor- and ceiling effects were not reported. CONCLUSION: The validity of the often used EORTC QLQ-CX24 questionnaire for cervical cancer patients remains uncertain as 5 out of 9 psychometric properties were doubtful or not reported in current literature. Cervical cancer specific HRQoL tools should therefore always be used in conjunction with validated generic cancer HRQoL tools until proper validity has been proven, or a more valid tool has been developed.

Prediction of incomplete primary debulking surgery in patients with advanced ovarian cancer: An external validation study of three models using computed tomography.

OBJECTIVE: To test the ability of three prospectively developed computed tomography (CT) models to predict incomplete primary debulking surgery in patients with advanced (International Federation of Gynecology and Obstetrics stages III-IV) ovarian cancer. METHODS: Three prediction models to predict incomplete surgery (any tumor residual >1cm in diameter) previously published by Ferrandina (models A and B) and by Gerestein were applied to a validation cohort consisting of 151 patients with advanced epithelial ovarian cancer. All patients were treated with primary debulking surgery in the Eastern part of the Netherlands between 2000 and 2009 and data were retrospectively collected. Three individual readers evaluated the radiographic parameters and gave a subjective assessment. Using the predicted probabilities from the models, the area under the curve (AUC) was calculated which represents the discriminative ability of the model. RESULTS: The AUC of the Ferrandina models was 0.56, 0.59 and 0.59 in model A, and 0.55, 0.60 and 0.59 in model B for readers 1, 2 and 3, respectively. The AUC of Gerestein's model was 0.69, 0.61 and 0.69 for readers 1, 2 and 3, respectively. AUC values of 0.69 and 0.63 for reader 1 and 3 were found for subjective assessment. CONCLUSIONS: Models to predict incomplete surgery in advanced ovarian cancer have limited predictive ability and their reproducibility is questionable. Subjective assessment seems as successful as applying predictive models. Present prediction models are not reliable enough to be used in clinical decision-making and should be interpreted with caution.

Surgery for Recurrent Epithelial Ovarian Cancer in the Netherlands: A Population-Based Cohort Study.

OBJECTIVE: The value of secondary cytoreductive surgery (SCS) in patients with recurrent epithelial ovarian cancer is controversial. The aim of this population-based study was to investigate the role of SCS in the Netherlands. METHODS: Data of 408 patients who underwent SCS between 2000 and 2013 were retrospectively collected from 38 Dutch hospitals. Survival after complete and incomplete SCS was estimated by Kaplan-Meier curves. Factors associated with overall survival (OS) were explored with Cox regression. RESULTS: Median OS after SCS was 51 months (95% confidence interval [95% CI], 44.8-57.2). Complete SCS was achieved in 295 (72.3%) patients, with an OS of 57 months (95% CI, 49.0-65.0) compared with 28 months (95% CI, 20.8-35.2) in patients with incomplete SCS (log-rank test; P < 0.001). Nonserous histology (HR 0.65; 95% CI 0.45-0.95), a long progression free interval (hazard ratio [HR], 0.29; 95% CI, 0.07-1.18), a good performance status (HR, 0.68; 95% CI, 0.49-0.94), SCS without preoperative chemotherapy (HR, 0.72; 95% CI, 0.51-1.01), and complete SCS (HR, 0.46; 95% CI, 0.33-0.64) were prognostic factors for survival. CONCLUSIONS: This population-based retrospective study showed that there might be a role for SCS in recurrent epithelial ovarian cancer especially when complete SCS can be accomplished. However, before adopting SCS as a standard treatment modality for recurrent epithelial ovarian cancer, results of 3 ongoing prospectively randomized trials are needed.