Initial investigation of using Norwegian health data for the purpose of external comparator arms - an example for non-small cell lung cancer.

BACKGROUND: Using real-world (RW) data from registries to mimic or substitute a comparator arm of clinical trials is increasingly investigated. The feasibility of using data sources for this purpose depends on the source's completeness of the wide spectrum of a disease characteristics and relevant endpoints, which could allow for proper matching of important variables. MATERIALS AND METHODS: This is a Norwegian study using data from three population-based registries, the Cancer Registry (CRN), the National Patient Registry (NPR), and the Norwegian Prescribed Drug Registry (LMR). We assessed if the registries contained the information necessary for selecting a RW cohort of patients with characteristics that mimicked the inclusion and exclusion criteria from the control arm of the phase 3 trial (KeyNote-407) on patients with stage IV, squamous NSCLC. We did this both on an aggregated - and individual data level. We also described the survival in the RW-cohorts and compared it with the survival in the control arm of the KN-407 trial. RESULTS: Using aggregated data from the CRN allowed us to find the patients based on some clinically relevant inclusion criteria, but only to a limited extent could we apply the exclusion criteria of KN-407. When we used individual data from the CRN, NPR and the LMR we could create a patient cohort that shared more criteria corresponding to the eligibility criteria from KN-407, including exclusion criteria. Compared to the 11.3 months (CI 95% 9.5, 14.8) median survival in the control arm of KN-407, both RW-cohorts had a shorter median survival, 7.07 months (CI 95% 6.7, 9.5) (individual) and 8.0 months (CI 95% 5.8, 10.5) (aggregated). CONCLUSION: Even if we demonstrated that the registries contain clinically relevant information necessary to mimic the eligibility criteria of a selected RCT, the survival is shorter for RW patients compared to their control arm counterpart in the RCT.

Incidence, mortality and relative survival of patients with cancer of the bladder and upper urothelial tract in the Nordic countries between 1990 and 2019.

PURPOSE: To understand the potential impact of new treatment options for urinary tract cancer, recent population trends in incidence, mortality and survival should be elucidated. This study estimated changes in the incidence, mortality and relative survival of urinary tract cancer in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) between 1990 and 2019. METHODS: Annual counts of incident cases and deaths due to urinary tract cancer (International Classification of Diseases, Tenth Revision, Clinical Modification codes C65-C68, D09.0-D09.1, D30.1-D30.9 and D41.1-D41.9) in Nordic countries were retrieved in 5-year age categories by sex during the study period. Country-specific time trends (annual rate ratios [RRs]) were estimated using Poisson regression, and RRs were compared between sexes. RESULTS: The incidence rate of bladder and upper urothelial tract cancer was >3-times lower in women than men in all countries across all age groups (incidence RR for women to men ranging from 0.219 [95% CI = 0.213-0.224] in Finland to 0.291 [95% CI = 0.286-0.296] in Denmark). Incidence rates were lowest in Finland and highest in Norway and Denmark. Age-adjusted mortality decreased in Finland, Denmark and Norway and in Swedish men, with the greatest decrease seen in Danish men (annual RR = 0.976; 95% CI = 0.975-0.978). In all countries and age groups, women had a lower relative survival rate than men. CONCLUSION: Between 1990 and 2019, the incidence of urinary tract cancer was stable in the Nordic countries, while mortality rates declined and relative survival increased. This could be due to earlier diagnosis and better treatment.

Improvements in survival for patients with stage IV adenocarcinoma in the lung, diagnosed between 2010 - 2020 - A population-based registry study from Norway.

Objectives: We investigated how the prognosis for Norwegian patients with stage IV, adenocarcinoma (NSCLC) has developed during the last decade, to observe if increased survival coincides with the introduction of immunotherapy at a population level. Materials and methods: Incidence data from the Cancer Registry of Norway are virtually complete and includes information about histological subtypes and biomarkers. The data was used to analyze median and relative survival for females and males diagnosed with stage IV NSCLC, divided by histological subgroups and age-groups. Results: During 2010 - 2020, 14472 patients were diagnosed with lung cancer in stage IV, in Norway. Among them 6351 patients (43%) were classified with adenocarcinoma. The median survival has increased for both sexes, but the largest increase is seen in females. From 2010 to 2020, median survival for females in the 0-69 group increased from 6.7 months to 12 months and from 3.7 months to 10 months for the 70+ age group. For the equivalent male age groups, we see an increase from 6.1 months to 7.7 months for the 0-69 group, and an increase from 3.8 months to 4.5 months for the 70+ group. When excluding patients with EGFR/ALK mutations from the survival analysis, the groups continue to display an increased survival from 2010 to 2020, although modest in the male 70+ group. The 1-year relative survival (RS) has increased for both sexes, from 32.4% to 51.2 in females and 25.4% to 44.5% in males. When EGFR/ALK positive patients were excluded from the analysis 1-year RS in females rose from 32.4% to 47.4% and for males from 25.4% to 41.8%. Conclusion: A real-world patient population of stage IV, NSCLC adenocarcinoma have had a clinically meaningful increase in both median and relative survival from 2010 - 2020. The steepest survival increase has taken place after 2016, the time point where immunotherapy was implemented as a treatment option for the stage IV, adenocarcinoma population not harboring targetable mutations (EGFR/ALK).

Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer.

BACKGROUND: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. METHODS: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. RESULTS: Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3). CONCLUSIONS: A large prospective study has assessed the role of different STIs in cervical cancer. IMPACT: Prospective evidence supports cofactor role of some STI in cervical cancer.

Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway.

BACKGROUND: Some studies have indicated that reproductive factors affect the risk of histological types of breast cancer differently. The long-term protective effect of a childbirth is preceded by a short-term adverse effect. Few studies have examined whether tumors diagnosed shortly after birth have specific histological characteristics. METHODS: In the present register-based study, comprising information for 22,867 Norwegian breast cancer cases (20-74 years), we examined whether histological type (9 categories) and grade of tumor (2 combined categories) differed by parity or age at first birth. Associations with time since birth were evaluated among 9709 women diagnosed before age 50 years. Chi-square tests were applied for comparing proportions, whereas odds ratios (each histological type vs. ductal, or grade 3-4 vs. grade 1-2) were estimated in polytomous and binary logistic regression analyses. RESULTS: Ductal tumors, the most common histological type, accounted for 81.4% of all cases, followed by lobular tumors (6.3%) and unspecified carcinomas (5.5%). Other subtypes accounted for 0.4%-1.5% of the cases each. For all histological types, the proportions differed significantly by age at diagnoses. The proportion of mucinous and tubular tumors decreased with increasing parity, whereas Paget disease and medullary tumors were most common in women of high parity. An increasing trend with increasing age at first birth was most pronounced for lobular tumors and unspecified carcinomas; an association in the opposite direction was seen in relation to medullary and tubular tumors. In age-adjusted analyses, only the proportions of unspecified carcinomas and lobular tumors decreased significantly with increasing time since first and last birth. However, ductal tumors, and malignant sarcomas, mainly phyllodes tumors, seemed to occur at higher frequency in women diagnosed <2 years after first childbirth. The proportions of medullary tumors and Paget disease were particularly high among women diagnosed 2-5 years after last birth. The high proportion of poorly differentiated tumors in women with a recent childbirth was partly explained by young age. CONCLUSION: Our results support previous observations that reproductive factors affect the risk of histological types of breast cancer differently. Sarcomas, medullary tumors, and possible also Paget disease, may be particularly susceptible to pregnancy-related exposure.

Improved breast cancer survival following introduction of an organized mammography screening program among both screened and unscreened women: a population-based cohort study.

INTRODUCTION: Mammography screening reduces breast cancer mortality through earlier diagnosis but may convey further benefit if screening is associated with optimized treatment through multidisciplinary medical care. In Norway, a national mammography screening program was introduced among women aged 50 to 69 years during 1995/6 to 2004. Also during this time, multidisciplinary breast cancer care units were implemented. METHODS: We constructed three cohorts of breast cancer patients: 1) the pre-program group comprising women diagnosed and treated before mammography screening began in their county of residence, 2) the post-program group comprising women diagnosed and treated through multidisciplinary breast cancer care units in their county but before they had been invited to mammography screening; and 3) the screening group comprising women diagnosed and treated after invitation to screening. We calculated Kaplan-Meier plots and multivariable Cox proportional hazard models. RESULTS: We studied 41,833 women with breast cancer. The nine-year breast cancer-specific survival rate was 0.66 (95%CI: 0.65 to 0.67) in the pre-program group; 0.72 (95%CI: 0.70 to 0.74) in the post-program group; and 0.84 (95%CI: 0.80 to 0.88) in the screening group. In multivariable analyses, the risk of death from breast cancer was 14% lower in the post-program group than in the pre-program group (hazard ratio 0.86; (95%CI: 0.78 to 0.95, P = 0.003)). CONCLUSIONS: After nine years follow-up, at least 33% of the improved survival is attributable to improved breast cancer management through multidisciplinary medical care.

Performance of human papillomavirus DNA and mRNA testing strategies for women with and without cervical neoplasia.

In the present study we investigated the cross-sectional positivity for DNA and E6/E7 mRNA from high-risk human papillomavirus (HPV) types in 643 women with high-grade cervical neoplasia (135 cases of cervical intraepithelial neoplasia grade 2 [CIN2], 495 cases of CIN3/adenocarcinoma in situ [ACIS], and 13 cases of invasive carcinoma) and in 736 women with normal cytology by using the Amplicor and PreTect HPV-Proofer assays. In addition, genotyping was performed using Linear Array for women with normal cytology and a positive HPV test and in all women with histologically confirmed CIN2+. In women with normal cytology, 8.3% (61/736) were Amplicor positive and 3.3% (24/736) were PreTect HPV-Proofer positive (P < 0.001). Concordant results between the Amplicor and PreTect HPV-Proofer tests were present in 90.3% (665/736). In women with CIN2+ lesions 96.4% (620/643) were positive by Amplicor, 98.4% (633/643) by linear array, and 64.1% (412/643) by PreTect HPV-Proofer. Concordant results for the three HPV assays were present in 63.8%. The genotype profile detected by linear array and PreTect HPV-Proofer showed substantial agreement for HPV types 16, 18, 33, and 45. HPV type 16 and/or 18 was detected in 58.8% (378/643) of the women with high-grade neoplasia. Detection of E6/E7 mRNA by PreTect HPV-Proofer increased with severity of the cervical lesion. Detection of HPV DNA, however, was not associated with histology grade. In conclusion, the detection of HPV varied according to the assay used, and the concordance between the tests was poor. Our results indicate that mRNA testing may be a biomarker for progression of cervical neoplasia, but the optimal genotype mix remains to be determined.

Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients.

AIMS: To determine the frequency and survival of the various types of uterine sarcoma in the total population of Norway and evaluate histopathological prognostic factors in order to identify risk groups. METHODS AND RESULTS: Histopathological review of all uterine sarcoma cases reported to the Norwegian Cancer Registry during 1970-2000 was undertaken. Survival dates were provided by The Cancer Registry. Kaplan-Meier survival curves were generated. The log rank test was used for univariate analysis and a Cox proportional hazards regression model for multivariate evaluation of survival. Stage of disease was the most important prognostic factor for all tumour types. Tumour size and the mitotic index (MI) were significant prognostic factors (P < 0.0001) in leiomyosarcomas confined to the uterus and allowed for separation into three risk groups with marked differences in prognosis. The prognosis of endometrial stromal sarcomas confined to the uterus was related to MI (P < 0.0001) and tumour cell necrosis (P < 0.004). Combining these parameters allowed for separation into three risk groups with marked difference in prognosis. In adenosarcomas, tumour cell necrosis was the only significant prognostic factor. CONCLUSIONS: There are marked differences in survival between uterine sarcoma types. Leiomyosarcomas and endometrial stromal sarcomas can be divided into different groups.

Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks.

The strong correlation between smoking and exposure to oncogenic human papillomaviruses (HPVs) has made it difficult to verify the independent role of smoking in cervical carcinogenesis. Thus, the authors evaluated this role. Five large Nordic serum banks containing samples from more than 1,000,000 subjects were linked with nationwide cancer registries (1973-2003). Serum samples were retrieved from 588 women who developed invasive cervical cancer and 2,861 matched controls. The samples were analyzed for cotinine (a biomarker of tobacco exposure) and antibodies to HPV types 16 and 18, herpes simplex virus type 2, and Chlamydia trachomatis. Smoking was associated with the risk of squamous cell carcinoma (SCC) among HPV16- and/or HPV18-seropositive heavy smokers (odds ratio=2.7, 95% confidence interval: 1.7, 4.3). A similar risk of SCC (odds ratio=3.2, 95% confidence interval: 2.6, 4.0) was found in heavy smokers after adjustment for HPV16/18 antibodies. The point estimates increased with increasing age at diagnosis and increasing cotinine level. This study confirms that smoking is an independent risk factor for cervical cancer/SCC in women infected with oncogenic HPVs. These findings emphasize the importance of cervical cancer prevention among women exposed to tobacco smoke.

Twin births, sex of children and maternal risk of endometrial cancer: a cohort study in Norway.

OBJECTIVE: To explore whether twin births and sex of children influenced maternal risk of endometrial cancer, possibly with effect modification by age. DESIGN: Population-based prospective study. STUDY POPULATION: A total of 1,094,017 parous Norwegian women aged 30-74 years, including 3,356 endometrial cancer cases. Among the 27,158 mothers of twins, 101 cases occurred. METHODS: Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated in Poisson regression analyses of person-years at risk. RESULTS: Women ever having experienced a twin birth had an overall higher risk of endometrial cancer than women with singleton births only (IRR=1.26, 95% CI=1.03-1.53). Women with twin boys appeared to be the main contributor to the overall elevated risk (IRR=1.57, 95% CI=1.15-2.14). The risk estimates for women with twin girls or sex-nonconcordant twins were close to unity (IRR of 1.09 and 1.12, respectively). However, age-specific analyses revealed an elevated risk also in women with twin girls, but only before age 55 years (IRR=1.92, 95% CI=1.27-2.89); a lower risk was seen at older ages (IRR=0.41, 95% CI=0.19-0.92). The risk estimates for twin boys and sex-nonconcordant twins were consistently observed across age groups. The effect modification by age was statistically significant (p=0.0024). No association was found with sex of children in singleton mothers. CONCLUSION: Mothers of twin boys had a significantly higher risk of endometrial cancer than women with singleton births only, whereas women with twin girls had an elevated risk before age 55 years. No significant association was seen with sex-noncordant twins, neither overall nor within age groups.

Pregnancy outcome in women before and after cervical conisation: population based cohort study.

OBJECTIVES: To examine the consequences of cervical conisation in terms of adverse outcome in subsequent pregnancies. DESIGN: Population based cohort study. DATA SOURCES: Data on cervical conisation derived from the Cancer Registry of Norway and on pregnancy outcome from the Medical Birth Registry of Norway, 1967-2003. 15 108 births occurred in women who had previously undergone cervical conisation and 57 136 who subsequently underwent cervical conisation. In the same period there were 2 164 006 births to women who had not undergone relevant treatment (control). RESULTS: The proportion of preterm delivery was 17.2% in women who gave birth after cervical conisation versus 6.7% in women who gave birth before cervical conisation and 6.2% in women who had not undergone cervical conisation. The relative risk of a late abortion (<24 weeks' gestation) was 4.0 (95% confidence interval 3.3 to 4.8) in women who gave birth after cervical conisation compared with no cervical conisation. The relative risk of delivery was 4.4 (3.8 to 5.0) at 24-27 weeks, 3.4 (3.1 to 3.7) at 28-32 weeks, and 2.5 (2.4 to 2.6) at 33-36 weeks. The relative risk of preterm delivery declined during the study period and especially of delivery before 28 weeks' gestation. CONCLUSION: Cervical conisation influences outcome in subsequent pregnancies in terms of an increased risk of preterm delivery, especially in the early gestational age groups in which the clinical significance is highest. A careful clinical approach should be taken in the selection of women for cervical conisation and in the clinical care of pregnancies after a cervical conisation.

[Cervical cancer after 10 years of nationally coordinated screening]. / Livmorhalskreft etter ti års offentlig koordinert screening.

BACKGROUND: A cervical cancer screening programme has been operating on a national level since 1995. Women aged 25-69 years who have not had a Pap smear in the previous 3-year period, are recommended by letter to contact a doctor and have a smear taken. The aims of the programme are a more rational use of tests and to decrease the incidence and mortality of the disease. MATERIAL AND METHODS: Trends in incidence and mortality of cervical cancer are studied by data from the national cancer registry, which also collects data on individual smears. RESULTS: From the period 1990-94 to the period 2000-04 the age-adjusted incidence rate per 1,000, 000 person-years decreased from 127 to 95, the corresponding rate for squamous carcinomas decreased from 102 to 70. The age-adjusted mortality rate decreased from 38 to 25. Number of tests decreased from 542,666 in 1994 to 486 118 in 2004. The proportion of women aged 25-69 years who had a test taken during the last four years, increased from 72.4% in 1995 to 78.3% in 2004. INTERPRETATION: Implementation of a nationally coordinated cervical cancer screening programme has contributed to a favourable development of the disease (lower incidence and mortality) and a more rational use of tests. Continued efforts are needed to achieve the goals of the programme.

Incidence and tumor characteristics of breast cancer diagnosed before and after implementation of a population-based screening-program.

BACKGROUND: Randomized controlled trials and service screening programs have shown that breast cancer screening reduces the mortality from the disease. Several years of monitoring are needed to prove such an effect. In the meantime attention should be paid to early surrogate measures, such as histopathological tumor characteristics. The Norwegian Breast Cancer Screening Program started November 1995. This study compares incidence, prognostic tumor characteristics and surgical treatment in breast cancer cases diagnosed in the pre-screening (1987-1995, n=2 618) and screening period (1996-2004, n=5 417), in women aged 50-69 years, residing in the first four counties implementing the screening program. The screening period is divided into those invited versus those not invited to the screening program, and those exposed (participants) versus those not exposed to the program (non-participants). RESULTS: The incidence of invasive breast cancer rose from 170 per 100 000 women years (wy) in 1987 to 355 per 100 000 wy in 1997. The proportion of DCIS was 5% in the pre-screening period, and 14% in the screening period. Tumors 20 mm or less were diagnosed in 56% of the invasive cases in the pre-screening period, in 74% of the invited, and in 77% of the exposed women. The relative risk of diagnosing breast cancer with metastases was 0.85 (95% CI 0.84-0.87) for invited and 0.82 (95% CI 0.81-0.84) for exposed women, relative to those diagnosed in the pre-screening period. Ablation was performed in 85% of the invasive cases diagnosed in the pre-screening period, and in 45% of the cases in the screening period. CONCLUSION: Breast cancer diagnosed in the screening period had prognostically favorable tumor characteristics compared to breast cancer diagnosed in the pre-screening period. Implementation of organized population based screening and the time trend are considered possible reasons.

Using the European guidelines to evaluate the Norwegian Breast Cancer Screening Program.

This is an evaluation of selected process indicators achieved during the first 10 years of performance of the Norwegian Breast Cancer Screening Program (NBCSP). The indicators are compared with the recommended levels given in the European Guidelines. The program invites all female residents aged 50-69 years old to two-view mammography biennially. The attendance rate was 76.2%. The recall rates due to positive mammography were 4.6% and 2.6%, and the detection rates were 6.4 and 4.9 per 1,000 screens, in prevalent and subsequent screens, respectively. Mean tumor size was 14.7 mm for screening detected and 21.2 mm for interval cancers. Axillary lymph node metastases were present in 25.4% and 43.8%, respectively. Detection mode (screening detected or interval cancer) was shown to be an independent predictor for axillary lymph node metastases and high-grade (Grade 3) tumors. The NBCSP meets the recommendations given in the European Guidelines for most of the process indicators evaluated in this study. Based on the results, we anticipate a future mortality reduction from breast cancer in women invited to the NBCSP.