Tor Åge Myklebust

Nationwide improvement of rectal cancer treatment outcomes in Norway, 1993–2010

Background. The Norwegian Rectal Cancer Project was initated in 1993 with the aims of improving surgery, decreasing local recurrence rates, improving survival, and establishing a national rectal cancer registry. Here we present results from the Norwegian Colorectal Cancer Registry (NCCR) from 1993 to 2010. Material and methods. A total of 15 193 patients were diagnosed with rectal cancer in Norway 1993–2010, and were registered with clinical data regarding diagnosis, treatment, locoregional recurrences and distant metastases. Of these, 10 796 with non-metastatic disease underwent tumour resection. The results were stratified into five time periods, and the treatment outcomes were compared. Recurrence rates are presented for the 9785 patients who underwent curative major resection (R0/R1). Results. Among all 15 193 patients, relative five-year survival increased from 54.1% in 1993–1997 to 63.4% in 2007–2010 (p < 0.001). Among the 10 796 patients with stage I–III disease who underwent tumour resection, from 1993–1997 to 2007–2010, relative five-year survival improved from 71.2% to 80.6% (p < 0.001). An increasing proportion of these patients underwent surgery at large-volume hospitals; and 30- and 100-day mortality rates, respectively, decreased from 3.0% to 1.4% (p < 0.001) and from 5.1% to 3.0% (p < 0.011). Use of preoperative chemoradiotherapy increased from 6.5% in 1993 to 39.0% in 2010 (p < 0.001). Estimated local recurrence rate after major resection (R0/R1) decreased from 14.5% in 1993–1997 to 5.0% in 2007–2009 (p < 0.001), and distant recurrence rate decreased from 26.0% to 20.2% (p < 0.001). Conclusion. Long-term outcomes from a national population-based rectal cancer registry are presented. Improvements in rectal cancer treatment have led to decreased recurrence rates of 5% and increased survival on a national level.

Risk of Cancer in Children Conceived by Assisted Reproductive Technology.

BACKGROUND AND OBJECTIVE: An increasing number of children are born after assisted reproductive technology (ART), and monitoring their long-term health effects is of interest. This study compares cancer risk in children conceived by ART to that in children conceived without. METHODS: The Medical Birth Registry of Norway contains individual information on all children born in Norway (including information of ART conceptions). All children born between 1984 and 2011 constituted the study cohort, and cancer data were obtained from the Cancer Registry of Norway. Follow-up started at date of birth and ended on the date of the first cancer diagnosis, death, emigration, or December 31, 2011. A Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of overall cancer risk between children conceived by ART and those not. Cancer risk was also assessed separately for all childhood cancer types. RESULTS: The study cohort comprised 1 628 658 children, of which 25 782 were conceived by ART. Of the total 4554 cancers, 51 occurred in ART-conceived children. Risk of overall cancer was not significantly elevated (HR 1.21; 95% CI 0.90–1.63). However, increased risk of leukemia was observed for children conceived by ART compared with those who were not (HR 1.67; 95% CI 1.02–2.73). Elevated risk of Hodgkins lymphoma was also found for ART-conceived children (HR 3.63; 95% CI 1.12–11.72), although this was based on small numbers. CONCLUSIONS: This population-based cohort study found elevated risks of leukemia and Hodgkins lymphoma in children conceived by ART.

Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study

PURPOSE Regular use of aspirin (acetylsalicylic acid) is associated with reduced incidence and mortality of colorectal cancer (CRC). However, aspirin as primary prevention is debated because of the risk of hemorrhagic adverse effects. Aspirin as secondary prevention may be more justified from a risk-benefit perspective. We have examined the association between aspirin use after the diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS An observational, population-based, retrospective cohort study was conducted by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with data on their aspirin use (The Norwegian Prescription Database). These registries cover more than 99% of the Norwegian population and include all patients in an unselected and consecutive manner. Exposure to aspirin was defined as receipt of aspirin prescriptions for more than 6 months after the diagnosis of CRC. Multivariable Cox-proportional hazard analyses were used to model survival. The main outcome measures of the study were CSS and OS. RESULTS A total of 23,162 patients diagnosed with CRC were included, 6,102 of whom were exposed to aspirin after the diagnosis of CRC (26.3%). The median follow-up time was 3.0 years. A total of 2,071 deaths (32.9%, all causes) occurred among aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01). CONCLUSION Aspirin use after the diagnosis of CRC is independently associated with improved CSS and OS.

Risk of breast cancer following fertility treatment – A registry based cohort study of parous women in Norway

Despite increasing numbers of women availing themselves of assisted reproductive technology (ART), effects on cancer risk remain unresolved. Given hormonal exposures, breast cancer risk is of particular concern. The aim of this study is to investigate breast cancer risk amongst women giving birth following ART as compared to that amongst women who gave birth without ART. Data on all women who gave birth in Norway with or without ART, between 1984 and 2010 were obtained from the Medical Birth Registry of Norway (MBRN). 808,834 women eligible for study were linked to the Cancer Registry of Norway. Cox proportional models computed hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer between the two groups, adjusting for age, parity, age at first birth, calendar period and region of residence. In total, 8,037 women were diagnosed with breast cancer during the study period, 138 ART women and 7,899 unexposed. Total follow‐up time was 12,401,121 person‐years (median 16.0); median age at entry was 32.5 years (range18.6–49.9) for ART women and 26.3 (range 10.5–54.6) for unexposed. Women exposed to ART had an elevated risk of breast cancer (adjusted HR 1.20, 95% CI 1.01–1.42). Subgroup analyses gave an HR of 1.30 (95% CI 1.07–1.57) for women treated with IVF and 1.35 (95 % CI 1.07–1.71) for women with follow‐up >10 years, compared with controls. Our findings of increased risk in the study population warrant continued monitoring of women treated with ART as this population advances into more typical cancer age ranges.

Cancer risk among parous women following assisted reproductive technology

STUDY QUESTION Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? SUMMARY ANSWER Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. WHAT IS KNOWN ALREADY Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. STUDY DESIGN, SIZE, DURATION A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. MAIN RESULTS AND THE ROLE OF CHANCE A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03– 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22–2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04–1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08–3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04–3.11). However, all findings became non-significant after correcting for multiple analyses. LIMITATIONS, REASONS FOR CAUTION The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. WIDER IMPLICATIONS OF THE FINDINGS In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. STUDY FUNDING/COMPETING INTEREST The study was funded by the Norwegian National Advisory Unit on Womens Health. All authors claim no competing interests.

Utilization of Radiation Therapy in Norway After the Implementation of The National Cancer Plan—A National, Population-Based Study

PURPOSE To estimate actual utilization rates of radiation therapy (RT) in Norway, describe time trends (1997-2010), and compare these estimates with corresponding optimal RT rates. METHODS AND MATERIALS Data from the population-based Cancer Registry of Norway was used to identify all patients diagnosed with cancer and/or treated by RT for cancer in 1997-2010. Radiation therapy utilization rates (RURs) were calculated as (1) the proportion of incident cancer cases who received RT at least once within 1 year of diagnosis (RUR1Y); and (2) the proportion who received RT within 5 years of diagnosis (RUR5Y). The number of RT treatment courses per incident cancer case (TCI) was also calculated for all cancer sites combined. The actual RURs were compared with corresponding Australian and Canadian epidemiologic- and evidence-based model estimates and criterion-based benchmark estimates of optimal RURs. The TCIs were compared with TCI estimates from the 1997 Norwegian/National Cancer Plan (NCP). Joinpoint regression was used to identify changes in trends and to estimate annual percentage change (APC) in actual RUR1Y and actual TCI. RESULTS The actual RUR5Y (all sites) increased significantly to 29% in 2005 but still differed markedly from the Australian epidemiologic- and evidence-based model estimate of 48%. With the exception of RUR5Y for breast cancer and RUR1Y for lung cancers, all actual RURs were markedly lower than optimal RUR estimates. The actual TCI increased significantly during the study period, reaching 42.5% in 2010, but was still lower than the 54% recommended in the NCP. The trend for RUR1Y (all sites) and TCI changed significantly, with the annual percentage change being largest during the first part of the study period. CONCLUSIONS Utilization rates of RT in Norway increased after the NCP was implemented and RT capacity was increased, but they still seem to be lower than optimal levels.

Long-term Relative Survival after Diagnosis of Testicular Germ Cell Tumor

Background: Long-term relative survival (RS) data for testicular germ cell tumor (TGCT) patients are scarce. We aimed to analyze long-term RS among TGCT patients diagnosed in Norway, between 1953 and 2012. Methods: Data sources were the Cancer Registry of Norway and the Norwegian Cause of Death Registry. TGCT patients diagnosed during 1953 to 2012 were classified by time of diagnosis, histology, age, and disease extent at diagnosis. Estimates for RS were obtained, and a test comparing overall RS was performed. Corresponding data were obtained for men diagnosed with localized malignant melanoma before age 50. Results: A total of 8,736 TGCT patients were included. RS generally continued to decline with increasing follow-up time, particularly beyond 15 to 30 years, unlike in localized malignant melanoma. Although RS was generally higher for seminomas, the continuing decline was more pronounced than for nonseminomas, even when diagnosed with localized disease. TGCT patients diagnosed before 1980 or after age 40 had lower RS. Conclusions: Although TGCT RS has improved in recent decades, it continues to decline even beyond 30 years of follow-up, regardless of disease extent at diagnosis. The main cause is probably treatment-induced late effects, particularly affecting seminoma patients. The continued use of adjuvant radiotherapy in seminomas until year 2000 is suspected as a culprit. Impact: Long-term TGCT survivors should be closely monitored for the development of late comorbidity. The challenge is to reduce negative consequences of previous and current TGCT treatment on RS while maintaining the excellent cure rates. Further research on causes of long-term morbidity and mortality among TGCT survivors is warranted. Cancer Epidemiol Biomarkers Prev; 25(5); 773–9. ©2016 AACR.

Cancer risk in women treated with fertility drugs according to parity status- A registry-based cohort study

Background: Long-term safety of assisted reproductive techniques (ART) is of interest as their use is increasing. Cancer risk is known to be affected by parity. This study examined the risk of cancer after fertility treatment, stratified by womens parity. Methods: Data were obtained from all women (n = 1,353,724) born in Norway between 1960 and 1996. Drug exposure data (2004–2014) were obtained from the Norwegian Prescription Database (drugs used in ART and clomiphene citrate). The Medical Birth Registry of Norway provided parity status. HRs were calculated for all site cancer, breast, cervical, endometrial, ovarian, colorectal, central nervous system, thyroid cancer, and malignant melanoma. Results: In 12,354,392 person-years of follow-up, 20,128 women were diagnosed with cancer. All-site cancer risk was 1.14 [95% confidence interval (95% CI), 1.03–1.26] and 1.10 (95% CI, 0.98–1.23) after clomiphene citrate and ART exposure, respectively. For ovarian cancer, a stronger association was observed for both exposures in nulliparous (HR, 2.49; 95% CI, 1.30–4.78; and HR, 1.62; 95% CI, 0.78–3.35) versus parous women (HR, 1.37; 95% CI, 0.64–2.96; and HR, 0.87; 95% CI, 0.33–2.27). Elevated risk of endometrial cancers was observed for clomiphene citrate exposure in nulliparous women (HR, 4.49; 95% CI, 2.66–7.60 vs. HR, 1.52; 95% CI, 0.67–3.42). Risk was elevated for breast cancer in parous women exposed to clomiphene citrate (HR, 1.26; 95% CI, 1.03–1.54) for thyroid cancer and among nulliparous women after ART treatment (HR, 2.19; 95% CI, 1.08–4.44). Conclusions: Clomiphene citrate appears associated with increased risk of ovarian and endometrial cancer. Elevations in risks of breast and thyroid cancer were less consistent across type of drug exposure and parity. Impact: Continued monitoring of fertility treatments is warranted. Cancer Epidemiol Biomarkers Prev; 26(6); 953–62. ©2017 AACR.

National Early Rectal Cancer Treatment Revisited

BACKGROUND: Treatment of early stage rectal cancer has excellent oncological results. To reduce treatment-related mortality and morbidity and improve functional results, a focus on local resections is increasingly important. OBJECTIVE: The purpose of this study was to compare outcomes after transanal endoscopic microsurgery and total mesorectal excision for early stage rectal cancer (T1 + T2) in Norway. DESIGN: This was an observational study based on prospective data from the Norwegian Colorectal Cancer Registry. SETTINGS: The study was conducted as a national, population-based study. PATIENTS: All 543 patients with T1 and 1593 patients with T2 rectal cancer without distant metastases that was treated by transanal endoscopic microsurgery or total mesorectal excision without radiochemotherapy during 2000–2009 were included. MAIN OUTCOME MEASURES: The primary outcomes were 5-year relative survival and 5-year local recurrence rate. RESULTS: Among 543 patients with T1 cancer, the 5-year overall survival rate was 65.3% after transanal endoscopic microsurgery versus 81.5% after total mesorectal excision (p = 0.012). Adjusted for age and sex there was no excess mortality for transanal endoscopic microsurgery (HR = 1.28 (95% CI, 0.8–1.9); p = 0.22). The 5-year relative survival rate was 96.8% after transanal endoscopic microsurgery versus 98.2% after total mesorectal excision (p = 0.603), and the 5-year local recurrence rate was 14.5% versus 1.4% (p < 0.001). Among 1593 patients with T2 cancer, 5-year overall survival was 42.1% versus 76.1% (p < 0.001), 5-year relative survival was 65.4% versus 93.9% (p < 0.001), and 5 year local recurrence rate was 11.4% versus 4.4% in the 2 groups. LIMITATIONS: The study is limited by its observational design and that the 2 groups were different according to patient and tumor characteristics. Another limitation was the low number of transanal endoscopic microsurgery procedures. CONCLUSIONS: Transanal endoscopic microsurgery had comparable 5-year relative survival to total mesorectal excision in T1 rectal cancer but inferior 5-year relative survival in T2 rectal cancer. Transanal endoscopic microsurgery was associated with higher local recurrence rates for both T1 and T2 tumors.

Preoperative chemoradiotherapy for rectal cancer and impact on outcomes – A population-based study

BACKGROUND AND PURPOSE Preoperative (chemo)radiotherapy ((C)RT) for rectal cancer is, in Norway, restricted to patients with cT4-stage or threatened circumferential resection margin. This nationwide population-based study assessed the use of preoperative (C)RT in Norway and its impact on treatment outcomes. PATIENTS AND METHODS Data from The Norwegian Colorectal Cancer Registry were used to identify all stage I-III rectal cancers treated with major resection (1997-2011: n=9193). Cumulative risk of local recurrence, distant metastasis, and relative survival was estimated for patients in 2007-2011 (n=3179). Multivariate regression-models were used to compare outcomes following preoperative (C)RT and surgery versus surgery alone. RESULTS The proportion of patients given preoperative (C)RT increased from 5% to 49% during 1997-2011. Preoperative (C)RT was associated with reduced risk of local recurrence (hazard ratio (HR)=0.55; 95% CI=0.29-1.04) and a tendency of improved survival (excess HR=0.75; 95% CI=0.52-1.08) with significant effects in patients aged ≥70years (local recurrence: HR=0.35; 95% CI=0.13-0.91; survival: excess HR=0.58; 95% CI=0.35-0.95). CONCLUSIONS This study indicates that when use of preoperative (C)RT is restricted to selected high-risk rectal cancers, preoperative (C)RT is associated with improved local recurrence, and possibly improved survival, when studied on a population-based level.