No improvement in survival of older women with cervical cancer—A nationwide study

Aim: This study aims to report trends in primary treatment and survival in cervical cancer (CC) to identify opportunities to improve clinical practice and disease outcome. Methods: Patients diagnosed with CC between 1989 and 2018 were identified from the Netherlands Cancer Registry (N = 21,644). Trends in primary treatment and 5-year relative survival were analysed with the Cochran-Armitage trend test and multivariable Poisson regression, respectively. Results: In early CC, surgery remains the preferred treatment for ages 15–74. Overall, it was applied more often in younger than in older patients (92% in 15–44; 64% in 65–74). For 75+, surgery use was stable over time (38%–41%, p=0.368), wh

No improvement in survival of older women with cervical cancer—A nationwide study

Aim: This study aims to report trends in primary treatment and survival in cervical cancer (CC) to identify opportunities to improve clinical practice and disease outcome. Methods: Patients diagnosed with CC between 1989 and 2018 were identified from the Netherlands Cancer Registry (N = 21,644). Trends in primary treatment and 5-year relative survival were analysed with the Cochran-Armitage trend test and multivariable Poisson regression, respectively. Results: In early CC, surgery remains the preferred treatment for ages 15–74. Overall, it was applied more often in younger than in older patients (92% in 15–44; 64% in 65–74). For 75+, surgery use was stable over time (38%–41%, p=0.368), while administration of radiotherapy decreased (57%–29%, p < 0.001). In locally advanced CC, chemoradiation use increased over time (5%–65%, p < 0.001). It was applied least often for 75+, in which radiotherapy remains most common (54% in 2014–2018). In metastatic CC, chemotherapy use increased over time (11%–28%, p < 0.001), but varied across age groups (6%–40% in 2014–2018). In patients treated with primary chemoradiation, regardless of stage, brachytherapy use increased over time (p ≤ 0.001). Full cohort 5-year survival increased from 68% to 74% (relative excess risk 0.55; 95% confidence interval [0.50–0.62]). Increases were most significant in locally advanced CC (38%–60%; 0.55 [0.47–0.65]). Survival remained stable in 75+ (38%–34%; 0.82 [0.66–1.02]). Conclusion: Relative survival for cervical cancer increased over the last three decades. The proportion of older patients receiving preferred treatment lags behind. Consequently, survival did not improve in the oldest patients

Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth

Background Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased ri

Systemic adverse events in imiquimod use for cervical intraepithelial neoplasia – A case series

Treatment for cervical intraepithelial neoplasia (CIN) often consists of an excisional procedure. However, less invasive treatment methods have been explored, such as topical treatment with imiquimod cream. Imiquimod has been proven to be effective in the regression of vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN). Previous studies have investigated the effect of imiquimod in CIN and showed well tolerated adverse effects. During a current study in the Netherlands, a number of adverse events have occurred. This case series presents a selection of these. Gynaecologists should be aware of the possible adverse effects of topical treatment with imiquimod cream. Keywords: Imiquimod, Aldara, Side effects, HSIL, CIN, Nause

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

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 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

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

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. </p

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (PROHTECT-3B study). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for ≥CIN2 and ≥CIN3, and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV negative and cytology negative follow-up at 6 months was used as gold standard. Pap cytology (threshold atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93% (95% confidence interval: 85-98) with a specificity of 49% (95% confidence interval: 41-56) for ≥CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity with similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92% (95% confidence interval: 84-97) and a specificity of 61% (95% confidence interval: 54-69) for ≥CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92% (95% confidence interval: 84-97), with a specificity for ≥CIN3 of 64% (95% confidence interval: 56-71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96% (95% confidence interval: 89-99), and a specificity of 58% (95% confidence interval: 50-65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for ≥CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. Because the quality of Pap cytology worldwide varies, and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the most reliable strategy in triage of high-risk HPV-positive women with an increased specificity and similar sensitivity compared with Pap cytology triage