Randomised trial of HPV self-sampling among non-attenders in the Slovenian cervical screening programme ZORA: comparing three different screening approaches.

Background To overcome obstacles within the Slovenian organised cervical cancer screening programme, a randomised pilot study of human papillomavirus (HPV) self-sampling among non-attenders was performed, aiming to assess three different screening approaches. Participants and methods Non-attenders aged 30-64 years from two Slovenian regions were randomised to two HPV self-sampling groups-the opt-in (I1, n = 14.400) and the opt-out (I2, n = 9.556), with a control group (P, n = 2.600). Self-collected samples were analysed using the Hybrid Capture 2 assay. HPV-positive women were invited to a colposcopy. The overall and type-specific intention-to-screen response rates and histological outcomes with a positive predictive value (PPV) according to the women's age, the screening approach, the level of protection resulting from previous screening history, and the region of residence were assessed. Results Of the 26.556 women enrolled, 8.972 (33.8%) responded with self-sample for HPV testing and/or traditional cytology within one year of enrolment. Response rates were 37.7%, 34.0% and 18.4% (p < 0.050) for opt-out, opt-in and control groups. Cervical intraepithelial neoplasia (CIN)2+ was diagnosed in 3.9/1.000, 3.4/1.000, and 3.1/1.000 women (p > 0.050), respectively. PPV of the HPV self-sampling was 12.0% and 9.6% for CIN2+ and CIN3+. The highest PPV was obtained in non-attenders in screening programme for more than 10-years and concordant results of HPV testing with 40.8% for CIN2+ and 38.8% for CIN3+. Conclusions The results of our study show that a high response to HPV self-sampling can be achieved also in an opt-in approach, if women are encouraged to choose between self-sampling at home and screening with gynaecologist. In addition, clinically important risk difference for a high-grade cervical lesion exists in the case of a positive result of HPV testing on self-collected samples, depending on the length of the interval since last screening. Stratified management of these women should be strongly considered. Women who were not screened with cytology for at least 10 years should be referred to immediate colposcopy for histology verification instead to delayed re-testing.

A classification prognostic score to predict OS in stage IV well-differentiated neuroendocrine tumors.

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three 'field-practice' cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses.

Cancer Patients' Survival: Standard Calculation Methods And Some Considerations Regarding Their Interpretation: POPULACIJSKO PREZIVETJE BOLNIKOV Z RAKOM: UPORABA RAZLICNIH PRISTOPOV IN PROBLEMI INTERPRETACIJE REZULTATOV.

BACKGROUND: Cancer patients' survival is an extremely important but complex indicator for assessing regional or global inequalities in diagnosis practices and clinical management of cancer patients. The population-based cancer survival comparisons are available through international projects (i.e. CONCORD, EUROCARE, OECD Health Reports) and online systems (SEER, NORDCAN, SLORA). In our research we aimed to show that noticeable differences in cancer patients' survival may not always reflect the real inequalities in cancer care, but can also appear due to variations in the applied methodology for relative survival calculation. METHODS: Four different approaches for relative survival calculation (cohort, complete, period and hybrid) have been implemented on the data set of Slovenian breast cancer patients diagnosed between 2000 and 2009, and the differences in survival estimates have been quantified. The major cancer survival comparison studies have been reviewed according to the selected relative survival calculation approach. RESULTS: The gap between four survival curves widens with time; after ten years of follow up the difference increases to more than 10 percent points between the highest (hybrid) and the lowest (cohort) estimates. In population-based comparison studies, the choice of the calculation approach is not uniformed; we noticed a tendency of simply using the approach which yields numerically better survival estimates. CONCLUSION: The population-based cancer relative survival, which is continually reported by recognised research groups, could not be compared directly as the methodology is different, and, consequently, final country scores differ. A uniform survival measure would be of great benefit in the cancer care surveillance.

Microinvasive cervical squamous cell carcinoma in Slovenia during the period 2001-2007.

BACKGROUND: Microinvasive squamous cell carcinoma (MISCC) comprises a significant portion of all cervical cancers in Slovenia. Criteria of carcinomatous invasion are well described in the literature, however histopathological assessment of MISCC is difficult, because morphological characteristics can overlap with cervical intraepithelial neoplasia grade 3 (CIN 3) and other pathological changes. The aim of our study was to evaluate the reliability of the histopathological diagnosis of MISCC in Slovenia during the period from 2001 to 2007. MATERIALS AND METHODS: Data on patients with a histopathological diagnosis of cervical MISCC (FIGO stage IA) in the period of 2001 to 2007 were obtained from the Cancer Registry of Slovenia. Histological slides were obtained from the majority of pathology laboratories in Slovenia. We received 250 cases (69% of all MISCC) for the review; 30 control cases with CIN 3 and invasive squamous cell carcinoma FIGO stage IB were intermixed. The slides were coded and reviewed. RESULTS: Among 250 cases originally diagnosed as MISCC, there was an agreement with MISCC diagnosis in 184 (73.6%) cases (of these 179/184 (97.3%) cases were FIGO stage IA1 and 5/184 (2.7%) cases were FIGO stage IA2). Among 179 FIGO stage IA1 cases 117 (65.4%) showed only early stromal invasion. CONCLUSIONS: The retrospective review of cases diagnosed as MISCC during the period 2001-2007 in Slovenia showed a considerable number of overdiagnosed cases. Amongst cases with MISCC confirmed on review, there was a significant proportion with early stromal invasion (depth of invasion less than 1 mm).

Patterns of care for European colorectal cancer patients diagnosed 1996-1998: a EUROCARE high resolution study.

OBJECTIVE: To identify disparities in the management of colon and rectal cancer across Europe by assessing population-based information from 12 European cancer registries (CR) participating in EUROCARE, together with additional information obtained from individual clinical records. METHODS AND PATIENTS: We considered five indicators: (a) resection with curative intent; (b) post-operative mortality; (c) proportion of stage II/III colon cancer cases given adjuvant chemotherapy; (d) proportion of rectal cancer cases receiving radiotherapy; and (e) proportion of curative intent resections with 12 or more lymph nodes examined. RESULTS: A total of 6 871 colorectal cancer patients, diagnosed between 1996-1998, were examined. Overall 71% of patients received resection with curative intent, range 44-86% by CR; 46% of stage III colon cancer cases (range 24-73% by CR) and 22% of stage II cases (not then recommended) received adjuvant chemotherapy; 12% of rectal cancer cases received adjuvant radiotherapy, range < or =2% in five CRs to >51% in two CRs. For only 29% of curative intent resections were 12 or more lymph nodes examined. CONCLUSIONS: This study reveals that, although most patients received surgery with curative intent, disparities in treatment for colorectal cancer across Europe in the late 1990s were unexpectedly large, with many patients not receiving treatments indicated by published clinical trials. Consensus guidelines for CRC management are now becoming available and should be adopted across Europe. It is hoped that dissemination of guidelines will improve the use of scientifically proven treatments for the disease, but this should be monitored by further population-based studies.

Challenges in starting organised screening programmes for cervical cancer in the new member states of the European Union.

Following the 2003 Recommendation of the Council of the European Union on cancer screening, equal access to organised cervical cancer screening is supposed to be ensured for all women at risk in all member states. However, the first IARC report on the implementation of the Council Recommendation suggests that a remarkable proportion of women in the new member states are not yet covered with the free Pap tests offered either in organised or opportunistic manners. Cervical cancer incidence and mortality rates in most of these countries are among the highest in Europe. The purpose of this paper is to identify some common challenges and make further proposals in organising and implementing quality-assured cervical cancer screening programmes in these countries. Based on the responses to a corresponding questionnaire, a summary on cervical cancer prevention policies was established for the seven new European Union member states, Czech Republic, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia, and two candidate states, Croatia and Serbia. In most of these countries there are a lot of challenges to overcome before achieving the level of preventive services as seen in Finland and the Netherlands nowadays.

Process performance of cervical screening programmes in Europe.

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition. Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries. These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.

Incidence trends of adenocarcinoma of the cervix in 13 European countries.

Rapid increases in cervical adenocarcinoma incidence have been observed in Western countries in recent decades. Postulated explanations include an increasing specificity of subtype-the capability to diagnose the disease, an inability of cytologic screening to reduce adenocarcinoma, and heterogeneity in cofactors related to persistent human papillomavirus infection. This study examines the possible contribution of these factors in relation with trends observed in Europe. Age-period-cohort models were fitted to cervical adenocarcinoma incidence trends in women ages <75 in 13 European countries. Age-adjusted adenocarcinoma incidence rates increased throughout Europe, the rate of increase ranging from around 0.5% per annum in Denmark, Sweden, and Switzerland to >/=3% in Finland, Slovakia, and Slovenia. The increases first affected generations born in the early 1930s through the mid-1940s, with risk invariably higher in women born in the mid-1960s relative to those born 20 years earlier. The magnitude of this risk ratio varied considerably from around 7 in Slovenia to almost unity in France. Declines in period-specific risk were observed in United Kingdom, Denmark, and Sweden, primarily among women ages >30. Whereas increasing specificity of subtype with time may be responsible for some of the increases in several countries, the changing distribution and prevalence of persistent infection with high-risk human papillomavirus types, alongside an inability to detect cervical adenocarcinoma within screening programs, would accord with the temporal profile observed in Europe. The homogeneity of trends in adenocarcinoma and squamous cell carcinoma in birth cohort is consistent with the notion that they share a similar etiology irrespective of the differential capability of screen detection. Screening may have had at least some impact in reducing cervical adenocarcinoma incidence in several countries during the 1990s.