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Testicular germ cell tumor (TGCT) patients and survivors have excess mortality compared to the general male population, but relative survival (RS) has been scarcely studied. We investigated causes of excess mortality and their impact on RS among men diagnosed with TGCT in Norway, 1953-2015. Using registry data (n = 9541), standardized mortality ratios (SMRs) and RS were calculated. By December 31st, 2015, 816 testicular cancer (TC) and 1508 non-TC deaths had occurred (non-TC SMR: 1.36). Within five years of TGCT diagnosis, 80% were TC deaths. Non-TC second cancer (SC) caused 65% of excess non-TC deaths, of which 34% from gastric, pancreatic or bladder cancer. SC SMRs remained elevated ≥26 years of follow-up. In localized TGCT diagnosed >1979, SC SMRs were only elevated after seminoma. Cardiovascular disease caused 9% and other causes 26% of excess non-TC deaths, of which 58% from gastrointestinal and genitourinary disorders. RS continuously declined with follow-up. TGCT patients diagnosed >1989 had superior five-year TC-specific RS (98.3%), lower non-TC SMR (1.21), but elevated SMRs for several SCs, infections, Alzheimer's disease, genitourinary disease and suicide. A limitation was lack of individual treatment data. RS declines mainly from TC deaths <5 years after TGCT diagnosis. Later, excess SC mortality becomes particularly important, reducing RS even ≥26 years. Radiotherapy; standard adjuvant seminoma treatment 1980-2007, is likely an important contributor, as are chemotherapy and possibly innate susceptibilities. Vigilant long-term follow-up, including psychosocial aspects, is important. Further research should focus on identifying survivor risk groups and optimizing treatment.

Background Neoadjuvant chemotherapy (NAC) before radical cystectomy is associated with pathological downstaging (DS) and improved overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC). Population-based studies have not unequivocally shown improved survival. The aim of this population-based study was to evaluate the effect of NAC on DS and OS in Norwegian patients with MIBC. Methods Patients in the Cancer Registry of Norway undergoing radical cystectomy (2008–2015) with or without NAC diagnosed with MIBC between 2008 and 2012 were included. Follow-up data were available until 31 December 2019. Logistic regression estimated the odds of DS with NAC, and a Cox model investigated the effect of DS on OS. Cox models, a mediator analysis and an instrumental variable approach were used to investigate the effect of NAC on OS. Results A total of 575 patients were included. NAC was administered to 82 (14%) patients. Compared to cystectomy only, NAC increased the proportion (43% vs. 22%) and the odds of DS (OR 2.51, CI 1.37–4.60, p  = 0.003). Independent of NAC, the proportion of pN0 was higher in patients with DS (89% vs. 60%) and DS yielded a 78% mortality risk reduction (HR 0.22, CI 0.15–0.34, p  = 1.9∙10–12), compared to patients without DS. We did not find an association between NAC and OS, neither by Cox regression (HR 1.16, CI 0.80–1.68, p  = 0.417) nor by an instrumental variable approach (HR = 0.56, CI = 0.07–4.57, p  = 0.586). The mediation analysis ( p  = 0.026) confirmed an indirect effect of NAC on OS through DS. Limitations include limited information of the primary tumour, details of NAC treatment and treatment indications. Conclusions NAC increases the probability of DS and is indirectly associated to OS. DS is related to the absence of regional lymph node metastases and is associated with an OS benefit. Improved staging and biomarkers are needed to identify patients most likely to achieve DS and to benefit from NAC.

Depressive symptoms are associated with higher cancer mortality, whereas anxiety symptoms are associated with lower than expected risk. This study aimed to investigate the prospective association between depressive/anxiety symptoms and the extent of disease (EOD) of first cancer at diagnosis. Prospective population-based study conducted from the second wave of the Nord-Trøndelag Health (HUNT) study. Of 65 000 residents comprehensively interviewed and examined for health status, 407 received first lifetime cancer diagnoses 1-3 years later, ascertained from the Cancer Registry of Norway, and had EOD recorded. Patients with localised disease or regional/distant spread at cancer diagnosis were analysed for earlier depressive/anxiety symptoms ascertained by the Hospital Anxiety and Depression Scale in HUNT. Beyond-local EOD was present in 59.8% of those with neither anxiety nor depression, in 76.6% of those with depression alone (odds ratio, 2.20; 1.08-4.49), in 39.3% of those with anxiety alone (odds ratio, 0.44; 0.20-0.96) and in 57.7% of those with both anxiety and depression (odds ratio, 0.92; 0.41-2.06). After adjustment for demographic and health status, and cancer type, these associations were marginally stronger, but no longer statistically significant (odds ratios, 2.26; 0.84-6.11; 0.43; 0.15-1.26; and 1.00; 0.98-1.03, respectively). In people who develop cancer, beyond-local EOD at diagnosis was more common in people with previous depression and less common in people with previous anxiety; however, independence from confounding factors could not be concluded.

ObjectivesTo examine age at diagnosis, prognostic factors and survival of prostate cancer (PCa) in Norwegian firefighters and three other occupations undergoing occupational health check-ups, and comparing with PCa cases in the general population.MethodsAll PCa cases diagnosed in 1960–2017 were extracted from the Cancer Registry of Norway. Firefighters, military employees, pilots and police officers were identified through occupational data from Statistics Norway. Age at diagnosis, clinical stage, prostate-specific antigen (PSA), Gleason score, performance status and overall survival and PCa-specific survival in cases in these occupations were compared with cases in the general population.ResultsFirefighters were significantly younger at PCa diagnosis than cases in the general population in 1960–1993 (mean difference: 2.1 years) and 2007–2017 (mean difference: 4.3 years). At diagnosis, firefighters had significantly lower PSA values, Gleason scores and performance status scores than the general population. Firefighters diagnosed in 2007–2017 had lower risk of all-cause death than the general population (crude HR 0.71 (0.53–0.95)). No difference remained after adjusting for age at diagnosis (HR 1.03 (0.77–1.37)). Firefighters were older at diagnosis in 1994–2006 (mean difference: 3.0 years), but showed no other significant differences in age at diagnosis, PSA values, Gleason scores or performance status compared with military employees, pilots and police officers.ConclusionsYounger age and better prognostic factors at PCa diagnosis among firefighters and other occupations with requirements for health check-ups than cases in the general population may indicate an increased diagnostic intensity, likely contributing to elevated PCa incidence in such occupations.

Background The association between curative treatment (CurTrt) and mortality in senior adults (≥70 years) with high‐risk prostate cancer (PCa) is poorly documented. In a population‐based cohort we report temporal trends in treatment and PCa‐specific mortality (PCSM), investigating the association between CurTrt and mortality in senior adults with high‐risk PCa, compared to findings in younger men (<70 years). Methods Observational study from the Cancer Registry of Norway. Patients with high‐risk PCa were stratified for three diagnostic periods (2005‐08, 2009‐12 and 2013‐16), age (<70, vs ≥70) and primary treatment (CurTrt: Radical prostatectomy (RP), Radiotherapy (RAD) vs no curative treatment (NoCurTrt)). Competing risk and Kaplan‐Meier methods estimated PCSM and overall mortality (OM), respectively. Multivariable logistic regression models estimated odds for CurTrt, and multivariable Fine Gray and Cox regression models evaluated the hazard ratios for PCSM and OM. Results Of 19 763 evaluable patients, 54% were aged ≥70 years. Senior adults had more unfavorable PCa characteristics than younger men. Across diagnostic periods, use of CurTrt increased from 15% to 51% in men aged ≥70 and 65% to 81% in men aged < 70 years. With median five years follow‐up, PCSM decreased in all patients (P < .05), in the third period restricted to senior adults. In all patients NoCurTrt was associated with three‐fold higher 5‐year PCSM and two‐fold higher OM compared to CurTrt. Conclusions In high‐risk PCa patients, increased use of CurTrt, greatest in senior men, was observed along with decreased PCSM and OM in both senior and younger adults. CurTrt should increasingly be considered in men ≥70 years. Curative treatment in senior adults with high‐risk prostate cancer is associated with decreased prostate cancer‐specific and overall mortality

PurposeDeclining response rates threaten the generalizability of health surveys. We investigate (1) the effect of item order on response rate; (2) characteristics of early , late and non-responders; and (3) potential non-response bias in a population-based health survey of childhood, adolescent and young adult cancer survivors (CAYACS).MethodsWe mailed a questionnaire survey to 5361 eligible CAYACS identified by the Cancer Registry of Norway (CRN), representing a range of cancer diagnoses. The 302-item questionnaire included a range of survivorship-related questions and validated patient-reported outcome measures. To investigate item-order effects on response rates, we constructed two versions of the questionnaire presenting cancer-related or socio-demographic items first. The CRN provided demographic and clinical information for the total population. Risk of non-response bias was estimated by (1) comparing outcomes between early and late responders (answered after a reminder), and (2) by applying inverse probability of participation weights to construct a total population (with 100% response) and then compare 21 a priori selected outcomes between early responders, all responders (early + late) and the total population (all eligible).ResultsSurvey item order did not affect response rates (cancer first 49.8% vs socio-demographic first 50.2%). Shorter time since diagnosis, male gender and a malignant melanoma diagnosis remained significant predictors of non-response in a multivariable multinomial regression model. There were no significant differences on 16/21 survey outcomes between early and late responders, and 18/21 survey outcomes between early responders, all responders and the total population.ConclusionDespite a modest response rate, we found little evidence for a response bias in our study.Implications for Cancer SurvivorsSurveys of survivor-reported outcomes with low response rates may still be valuable and generalizable to the total survivor population.

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5–18·0] vs 9·8 months [7·3–23·7]; hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Algeta and Bayer HealthCare Pharmaceuticals.

Purpose Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors’ annual expenses for dental treatment compared to reference data. Methods This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey ( n  = 555). Results The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age ( B  = −9.6, p  < 0.001) and a cumulative dose of anthracyclines >120 mg/m 2 ( B  = 11.5, p  < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p  = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p  = 0.02). Conclusions The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.

Background and purpose : The aim of this controlled cross-sectional, and population-based study was to evaluate adverse health outcomes (AHOs) 3 years after curative radiotherapy (RT) + androgen deprivation therapy (ADT). We also assessed Global Health/Quality of Life (QoL). Patients/material and methods: The Cancer Registry of Norway (CRN) provided data on prostate cancer (PCa) patients diagnosed in 2017-2019. All had been treated with RT+ ADT. All had completed EPIC-26 and EORTC QLO-C30 about 3 years after RT start (n = 663). ADT duration was stratified: Short (< 9 months), intermediate (9-18 months) and long ADT (18-24 months). A group of controls were established from the general population (п = 1,817). Outcome measures were the urinary irritative/obstructive domain summary score (DSS), the bowel and sexual DSSs (EPIC-26) and QoL (EORTC QLQ-C30). Results: Compared to controls, patients had clinically important lower bowel, and sexual mean scores. Urinary irritative/obstructive DSS levels were similar. Overall, 43% (PCa patients) and 20% (controls) reported major sexual problems. In patients aged < 75 years, longer than short ADT duration significantly decreased sexual DSS. QoL was relatively unaffected. Low response rates, selection bias and a lack of pre-treatment data represent the studys\" limitations. Conclusion and Interpretation: Three years post-RT+ADT, PCa patients describe clinically important lower EPIC-26 bowel and sexual DSS compared to controls. Sexual domain levels decreased with increasing ADT duration, particularly in patients < 75 years. Our observations indicate worse AHOs than previously reported and should be considered during pre-treatment counselling of PCa patients.

Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.