Oncologic outcomes after Total Mesometrial Resection (TMMR) or treatment according to current international guidelines in FIGO (2009) stages IB1-IIB cervical cancer: an observational cohort study.

Background: According to international guidelines, standard treatment (ST) with curative intent in cervical cancer (CC) comprises radical hysterectomy and pelvic lymphadenectomy in early stages (International Federation of Gynecology and Obstetrics (FIGO) 2009 IB1, IIA1), adjuvant chemoradiation is recommended based on risk factors upon final pathology. Definitive chemoradiation is recommended in locally advanced stages (FIGO 2009 IB2, IIA2, IIB). Total mesometrial resection (TMMR) with therapeutic lymph node dissection (tLND) without adjuvant radiation has emerged as a promising treatment. Here we compare oncologic outcome by TMMR + tLND or ST. Methods: In this observational cohort study, women treated according to international guidelines were identified in the population-based registries from Sweden and women treated with TMMR were identified in the Leipzig Mesometrial Resection (MMR) Study Database (DRKS 0001517) 2011-2020. Relevant clinical and tumour related variables were extracted. Recurrence-free survival (RFS) and overall survival (OS) by ST or TMMR was analysed with log-rank test, cumulative incidence function and proportional hazard regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for relevant confounders. Findings: Between 2011 and 2020, 1007 women were included in the final analysis. 733 women were treated according to ST and 274 with TMMR. RFS at five years was 77.9% (95% CI 74.3-81.1) and 82.6% (95% CI 77.2-86.9) for the ST and TMMR cohorts respectively (p = 0.053). In early-stage CC, RFS was higher after TMMR as compared to ST, 91.2% vs 81.8% (p = 0.002). In the adjusted analysis, TMMR was associated with a lower hazard of recurrence (HR 0.39; 95% CI 0.22-0.69) and death (HR 0.42; 95% CI 0.21-0.86) compared to ST. The absolute difference in risk of recurrence at 5 years was 9.4% (95% CI 3.2-15.7) in favor of TMMR. In locally advanced CC, no significant differences in RFS or OS was observed. Interpretation: Compared to ST, TMMR without radiation therapy was associated with superior oncologic outcomes in women with early-stage cervical cancer whereas no difference was observed in locally advanced disease. Our findings together with previous evidence suggest that TMMR may be considered the primary option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment. Funding: This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden).

Accuracy of colposcopy in the Swedish screening program.

INTRODUCTION: Sensitivity and specificity of colposcopy vary greatly between studies and efficacy in clinical studies seldom corresponds with effectiveness in a real-life setting. It is unclear whether colposcopists' experience affects assessment; studies show divergent results. The study's objective was to investigate the accuracy of colposcopies in the Swedish screening program, the variability in colposcopists' assessments and whether degree of experience affects accuracy in a routine setting. MATERIAL AND METHODS: Cross-sectional register study. All colposcopic assessments with a concomitant histopathological sample from women aged at least 18 years, performed between 1999 and September 2020 in Sweden. The main outcome measure was accuracy. The accuracy of colposcopic assessments was calculated as overall agreement with linked biopsies, with three outcomes: Normal vs Atypical, Normal vs Low-Grade Atypical vs High-Grade Atypical, and Non-High-Grade Atypical vs High-Grade Atypical. A time-trend analysis was performed. The accuracy of identifiable colposcopists related to experience was analyzed. RESULTS: In total, 82 289 colposcopic assessments with linked biopsies were included for analysis of the outcome Normal vs Atypical; average accuracy was 63%. Overrating colposcopic findings was four times more common than underrating. No time trend in accuracy was noted during the study period. Accuracy in distinguishing High-Grade from Non-High-Grade lesions was better: 76%. Among identifiable colposcopists, overall accuracy was 67%. Some had significantly better accuracy than others, but no correlation with experience was found. CONCLUSIONS: Colposcopy, including in a referral setting, has low accuracy in distinguishing Normal from Atypical. Increased experience alone does not lead to improvement. This is supported by the substantial differences in performance between colposcopists.

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.

Colposcopic assessment by Swedescore, evaluation of effectiveness in the Swedish screening programme: a cross-sectional study.

OBJECTIVE: To evaluate the effectiveness and performance of Swedescore in the Swedish screening programme. DESIGN: Cross-sectional register study. SETTING AND POPULATION: All Swedish women aged over 18 years with a colposcopic assessment linked to a biopsy in the Swedish National Cervical Screening Registry, 2015-20. METHODS: Colposcopies with Swedescore were compared with the histopathological diagnosis of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). The respective influence of cytology and human papillomavirus (HPV) testing, at referral for colposcopy and concurrently with colposcopy, were investigated in regression models. MAIN OUTCOME MEASURES: CIN2+. RESULTS: A total of 11 317 colposcopic assessments with Swedescore were included. Odds ratios for CIN2+ increased for every step in the Swedescore scale. At Swedescore ≥0-1, the proportion of CIN2+ was 9.8%. At Swedescore ≥8, the specificity was 93.3% and the positive predictive value was 60.1%, Area under the receiver operating characteristics curve (AUC) was 0.71. If the smear had been abnormal at referral, a normal colposcopy (Swedescore 0-1) was still associated with a CIN2+ risk of more than 5%. In the regression model, cytology and HPV had higher odds ratio for CIN2+ than colposcopy; the combination resulted in an AUC of 0.88. CONCLUSIONS: Swedescore works well in a routine clinical setting but colposcopy assessed with Swedescore was inferior to that reported in previous clinical studies. No safe cutoff level was identified for refraining from biopsy. See-and-treat at Swedescore 8-10 is feasible only if referral cytology showed high-grade squamous intraepithelial lesion. TWEETABLE ABSTRACT: No safe cutoff level for refraining from biopsy nor for see-and-treat with Swedescore.

Increased Institutional Surgical Experience in Robot-Assisted Radical Hysterectomy for Early Stage Cervical Cancer Reduces Recurrence Rate: Results from a Nationwide Study.

The aim of this study was to evaluate the impact of institutional surgical experience on recurrence following robotic radical hysterectomy (RRH) for early stage cervical cancer. All women in Sweden who underwent an RRH for stage IA2-IB1 cervical cancer at tertiary referral centers from its implementation in December 2005 until June 2017 were identified using a Swedish nationwide register and local hospital registers. Registry data were controlled by a chart review of all women. Recurrence rates and patterns of recurrence were compared between early and late (≤50 vs. >50 procedures) institutional series. Six hundred and thirty-five women were included. Regression analysis identified a lower risk of recurrence with increased experience but without a clear cut off level. Among the 489 women who did not receive adjuvant radio chemotherapy (RC-T), the rate of recurrence was 3.6% in the experienced cohort (>50 procedures) compared to 9.3% in the introductory cohort (p < 0.05). This was also seen in tumors < 2 cm regardless of RC-T (p < 0.05), whereas no difference in recurrence was seen when analyzing all women receiving RC-T. In conclusion, the rate of recurrence following RRH for early stage cervical cancer decreased with increased institutional surgical experience, in tumors < 2 cm and in women who did not receive adjuvant RC-T.

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population-based national cohort study.

OBJECTIVE: To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN). DESIGN: Population-based national cohort study. SETTING AND POPULATION: All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries. METHODS: The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised. MAIN OUTCOME MEASURE: Vaginal cancer. RESULTS: We identified 898 incident cases of vaginal cancer. Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100 000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15 years of follow up: 65.7 (95% CI 21.2-203.6). CONCLUSIONS: Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening. TWEETABLE ABSTRACT: High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery.

No survival difference between robotic and open radical hysterectomy for women with early-stage cervical cancer: results from a nationwide population-based cohort study.

PURPOSE: The aim of the study was to compare overall survival (OS) and disease-free survival (DFS) after open and robotic radical hysterectomy for early-stage cervical cancer. PATIENTS AND METHODS: This was a nationwide population-based cohort study on all women with cervical cancer stage IA1-IB of squamous, adenocarcinoma or adenosquamous histological subtypes, from January 2011 to December 2017, for whom radical hysterectomy was performed. The Swedish Quality Register of Gynaecologic Cancer was used for identification. To ensure quality and conformity of data and to disclose patients not yet registered, hospital registries were reviewed and validated. Cox and propensity score regression analysis and univariable and multivariable regression analysis were performed in regard to OS and DFS. RESULTS: There were 864 women (236 open and 628 robotic) included in the study. The 5-year OS was 92% and 94% and DFS was 84% and 88% for the open and robotic cohorts, respectively. The recurrence pattern was similar in both groups. Using propensity score analysis and matched cohorts of 232 women in each surgical group, no significant differences were seen in survival: 5-year OS of 92% in both groups (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.50-2.01) and DFS of 85% vs 84% in the open and robotic cohort, respectively (HR, 1.08; 95% CI, 0.66-1.78). In univariable and multivariable analysis with OS as the end-point, no significant factors were found, and in regard to DFS, tumour size (p < 0.001) and grade 3 (p = 0.02) were found as independent significant risk factors. CONCLUSION: In a complete nationwide population-based cohort, where radical hysterectomy for early-stage cervical cancer is highly centralised, neither long-term survival nor pattern of recurrence differed significantly between open and robotic surgery.

Effect of Fee on Cervical Cancer Screening Attendance--ScreenFee, a Swedish Population-Based Randomised Trial.

BACKGROUND: Attendance in the cervical cancer screening programme is one of the most important factors to lower the risk of contracting the disease. Attendance rates are often low in areas with low socioeconomic status. Charging a fee for screening might possibly decrease attendance in this population. Screening programme coverage is low in low socio-economic status areas in Gothenburg, Sweden, but has increased slightly after multiple interventions in recent years. For many years, women in the region have paid a fee for screening. We studied the effect of abolishing this fee in a trial emanating from the regular cervical cancer screening programme. METHOD: Individually randomised controlled trial. All 3 124 women in three low-resource areas in Gothenburg, due for screening during the study period, were randomised to receive an offer of a free test or the standard invitation stating the regular fee of 100 SEK (≈11 €). The study was conducted during the first six months of 2013. Attendance was defined as a registered Pap smear within 90 days from the date the invitation was sent out. RESULTS: Attendance did not differ significantly between women who were charged and those offered free screening (RR 0.93; CI 0.85-1.02). No differences were found within the districts or as an effect of age, attendance after the most recent previous invitation or previous experience of smear taking. CONCLUSION: Abolishment of a modest screening fee in socially disadvantaged urban districts with low coverage, after previous multiple systematic interventions, does not increase attendance in the short term. Other interventions might be more important for increasing attendance in low socio-economic status areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT02378324.