25 augustus 2023: 

Uit een groot Zweeds onderzoek bij ruim een miljoen mannen die in militaire dienst waren geweest blijkt Cardiorespiratoire fitness (CRF) veel vormen van kanker met solide tumoren te hebben voorkomen. Zoals al in 2013 een andere grote studie liet zien bij longkanker en prostaatkanker, zie ook verderop in dit artikel. Uit deze neiuwe Zweedse studie blijkt dat mannen met goede Cardiorespiratoire fitness (CRF) veel minder nagenoeg alle vormen van kanker ontwikkelden met solide tumoren. 

Aron Onerup, M.D., Ph.D., en collega's van de Universiteit van Göteborg in Zweden, onderzochten de associaties tussen cardiorespiratoire fitheid en de incidentie van plaatsspecifieke kanker met behulp van gegevens van 1,078 miljoen mannen die militaire dienstplicht ondergingen (in de periode van 1968 tot 2005) met een gemiddelde follow-up van 33 jaar.

De onderzoekers ontdekten dat een hogere cardiorespiratoire conditie lineair geassocieerd was met een lager risico op het ontwikkelen van kanker in het hoofd en de nek (hazard ratio , 0,81), slokdarm (HR, 0,61), maag (HR, 0,79), alvleesklier - pancreas (HR, 0,79), 0,88), lever (HR, 0,60), darm (HR, 0,82), nier (HR, 0,80) en longen (HR, 0,58). Een hogere cardiorespiratoire fitheid ging gepaard met een hoger risico op de diagnose prostaatkanker (HR, 1,07) en kwaadaardige huidkanker - melanomen (HR, 1,31).

"Onze studie suggereert dat cardiorespiratoire fitheid lineair geassocieerd is met een lager risico op het ontwikkelen van de meeste plaatsspecifieke kankers die hier worden beoordeeld, waarvan sommige nog niet eerder zijn gerapporteerd in relatie tot cardiorespiratoire fitheid of fysieke activiteit", schrijven de auteurs. "Deze resultaten versterken de prikkel voor het bevorderen van interventies gericht op het vergroten van de cardiorespiratoire fitheid bij jongeren."

Het abstract van deze nieuwe studie staat onderaan dit artikel: Associations between cardiorespiratory fitness in youth and the incidence of site-specific cancer in men: a cohort study with register linkage 

21 mei 2013: Bron: ASCO 2013

Cardiorespiratoire fitness (CRF) heeft grote invloed op risico voor mannen op ontwikkelen van darmkanker en longkanker en beinvloed ook sterk de overlevingstijd als mannen eenmaal kanker hebben.

Cardiorespiratoire fitness (CRF) (lees onder Wikipedia wat CRF precies inhoudt  en hoe dit gemeten wordt) blijkt een sterke onafhankelijke voorspeller van de kansen op het ontwikkelen van darmkanker en longkanker  voor mannen van 50 jaar of ouder. Voor risico op prostaatkanker werd geen significant verschil gevonden.  Ook blijkt Cardiorespiratoire fitness (CRF) een goede onafhankelijke voorspeller hoe een eenmaal ontwikkelde kanker zal verlopen, bv. hoe beter de Cardiorespiratoire fitness (CRF) hoe beter de overlevingstijd en minder kans op sterven aan kanker.  Dit gold voor alle drie de vormen van onderzochte vormen van kanker.

Het risico op het ontwikkelen van zowel longkanker en darmkanker namen af met respectievelijk 68% en 38% bij mannen met het hoogste niveaus van fitheid, in vergelijking met degenen met de minste fitheid, volgens de studiegegevens van een langjarige studie bij 17.049 mannen met een gemiddelde leeftijd van 50 jaar. "Fitness zou niet significant het risico op prostaatkanker beïnvloeden," aldus Dr Lakoski. Een hoog niveau van fitheid werd ook geassocieerd met een vermindering van 14% in kanker specifieke mortaliteit (hazard ratio , 0.86, P <.001), en een vermindering van 23% in cardiovasculaire (hart- en vaatziekten specifieke mortaliteit (HR, 0.77; P < .001).

"Het is algemeen geaccepteerd dat een bepaalde fitheid een goede manier is om de overleving aan hart- en vaatziekten te kunnen voorspellen, zelfs waardevoller dan andere risico factoren waaronder zelf gerapporteerde fysieke activiteiten," zegt auteur Susan Lakoski, MD, van de Universiteit van Vermont, in Burlington .

Dr Lakoski presenteerde de resultaten van haar onderzoek op een persconferentie vooraf aan ASCO 2013.
"Helaas is er weinig bekend over fitheid - cardiorespiratoire fitness (CRF) -  als een voorspeller van de incidentie van kanker en de daaropvolgende prognoses hoe de ziekte zal verlopen bij patiënten die kanker ontwikkelen.""Dit is wel belangrijk te weten omdat voorspellende markers steeds meer noodzakelijk zullen zijn omdat de incidentie van kanker naar verwachting zal toenemen in de komende 2 decennia," aldus Dr Lakoski.

De studie resultaten:

Weinig studies hebben het prognostisch belang van cardiorespiratoire fitness (CRF) onderzocht in relatie tot de incidentie van kanker of in relatie tot een oorzaak specifieke sterfte na een diagnose van kanker bij mannen. In deze studie, Dr Lakoski en collega's evalueerden het verband tussen Cardiorespiratoire fitness (CRF)  en de incidentie van prostaatkanker, longkanker of darmkanker bij mannen, en de daaropvolgende oorzaak specifieke sterfte onder mannen die een diagnose van kanker hadden gekregen.

Deze studie volgde 17.049 mannen (gemiddelde leeftijd, 50 jaar) die een eerste cardiovasculaire conditie test hadden gekregen als onderdeel van een bezoek aan een gespecialiseerde preventieve gezondheids check-up, dat werd aangeboden door het Cooper Instituut, in Dallas, Texas. Prestaties werd opgenomen in vastgelegde eenheden van fitness genaamd metabole equivalenten (METs). De deelnemers werden vervolgens gescheiden in 5 kwintielen / groepen op basis van hun fitness prestaties.

Medische begeleiding en resultaten daarvan werden dan vervolgens geanalyseerd om de deelnemers die toch longkanker, darmkanker of prostaatkanker hadden ontwikkeld te evalueren.  De gemiddelde tijd vanaf hun eerste CRF beoordeling tot aan de diagnose van kanker en/of het overlijden daaraan waren respectievelijk 20,2  ± 8,2 jaar en 24,4 ± 8,5 jaar. Gedurende deze periode werden in totaal 2885 mensen gediagnosticeerd met prostaatkanker (n=2332), longkanker (n=277), of darmkanker (n=276)

Binnen de onderzoeksperiode, stierven totaal 769 mensen aan alle oorzaken. 347 patiënten daarvan stierven als gevolg van kanker en 159 aan hart- en vaatziekten.Gegevens werden gecorrigeerd voor risicofactoren zoals lichaamsgewicht en leeftijd. 

Vergeleken met mannen in het laagste kwintiel CRF en onder mannen in het hoogste kwintiel CRF, de gecorrigeerde hazard ratio voor longkanker, darmkanker en prostaatkanker incidentie was respectievelijk. 0.32 (95 betrouwbaarheidsinterval , 0,20-0,51; P <.001), 0.62 (95% BI, 0,40-0,97, p = 0,05) en 1,13 (95% BI, 0,97-1,33; P = 0,14).
Voor mannen die kanker ontwikkelden en kanker specifieke mortaliteit en cardiovasculaire specifieke mortaliteit daalde in relatief gelijke mate in relatie tot het verhogen van de CRF in alle kwintielen (P-waarden <.001)

Bijvoorbeeld, zelfs een kleine verbetering in de fitness niveaus (1-MET toename van CRF) werd geassocieerd met een vermindering van 14% in kanker specifieke mortaliteit (HR, 0.86, 95% CI, 0,81-0,91, p <.001) en een 23% vermindering van de cardiovasculaire specifieke mortaliteit (HR, 0,77, 95% CI, 0,69-0,85; P <.001).

Iedereen kan profiteren

De studie auteurs vonden ook dat zelfs bij de mannen die niet zwaarlijvig waren maar die een lage fitness meting hadden, een verhoogd risico hadden op kanker en hart- en vaatziekten. Fitness is een sterke onafhankelijke voorspeller van specifiek longkanker en  darmkanker bij mannen en een krachtige voorspeller van specifieke mortaliteit op middelbare leeftijd en oudere mannen gediagnosticeerd met longkanker, prostaatkanker en darmkanker, "Deze bevindingen bieden ondersteuning voor het nut van fitness testen in de preventieve gezondheidszorg instellingen om het risico op kanker en de prognose na een diagnose van kanker te bepalen,"  aldus Dr Lakoski.

Dit is een van de eerste studies naar Cardiorespiratoire fitness (CRF) als een onafhankelijke en sterke voorspeller van het risico op kanker en prognose, becommentarieerde ASCO President Sandra M. Swain, MD, FACP. "Een heel interessante bevinding is dat zelfs als mensen niet zwaarlijvig zijn, ze nog steeds een verhoogd risico op kanker hebben, zelfs als ze niet passen in het beeld van een hoog risico groep" "Dit suggereert dat iedereen kan profiteren van de verbetering van hun conditie," aldus Dr Swain, die als een comoderator van de persbriefing optrad.

Het abstract van de studie:  Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study  is te vinden op de website van ASCO 2013 en zal worden gepresenteerd 2 juni 2013.

Hier is ook het abstract:

Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung cancer, prostate cancer, or colorectal cancer

Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study.

Meeting:
2013 ASCO Annual Meeting

Abstract No:
1520

Citation:
J Clin Oncol 31, 2013 (suppl; abstr 1520)

Author(s): Susan G. Lakoski, Carolyn Barlow, Ang Gao, Laura DeFina, Nina Radford, Steve Farrell, Benjamin Willis, Jeffrey M. Peppercorn, Pamela S. Douglas, Jarett Berry, Lee Jones; University of Vermont, Colchester, VT; The Cooper Institute, Dallas, TX; UT Southwestern Medical Center, Dallas, TX; The Cooper Clinic, Dallas, TX; Duke Cancer Institute, Durham, NC; Duke University, Durham, NC; Duke University Medical Center, Durham, NC.

Abstract:

Background: Few studies have examined the prognostic importance of cardiorespiratory fitness (CRF) to predict cancer incidence or cause-specific mortality following a cancer diagnosis in men. Accordingly, we examined the relationships between baseline CRF and incidence of prostate, lung, or colorectal cancer in men at Medicare age and subsequent cause-specific mortality among men diagnosed with cancer.

Methods: The Cooper Center Longitudinal Study (CCLS) is a prospective observational cohort study of participants undergoing a preventive health examination including CRF assessment at the Cooper Clinic in Dallas, Texas. We studied 17,049 men with a complete CCLS medical exam and cardiovascular risk factor assessment at a mean age of 50± 9 years. Cancer incidence was defined using Medicare claims data. Cox proportional models were used to estimate the risk of adjusted primary cancer incidence and cause-specific mortality after cancer according to baseline age-specific CRF quintiles (Q).

Results: The mean times from CRF assessment to cancer incidence and death were 20.2 ± 8.2 years and 24.4 ± 8.5 years, respectively. During this period, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. Compared with men in lowest CRF quintile, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer incidence among men in the highest CRF quintile was 0.32 (95% CI: 0.20 to 0.51, p<0.001), 0.62 (95% CI: 0.40 to 0.97, p=0.05), 1.13 (95% CI: 0.97 to 1.33, p=0.14), respectively. In men developing cancer, both cancer-specific mortality and cardiovascular-specific mortality declined across increasing CRF quintiles (p’s <0.001). A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality (HR 0.86, 95% CI: 0.81-0.91, p<0.001), and 23% reduction in cardiovascular-specific mortality (HR 0.77, 95% CI: 0.69-0.85, p<0.001).

Conclusions: Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung, prostate, or colorectal cancer.

We report a number of protective associations between higher CRF in healthy young men and the subsequent hazard of site-specific cancers. These results have implications for public health policymaking, strengthening the incentive to promote health through improving CRF in youth.

  1. Aron Onerup1
  2. Kirsten Mehlig2
  3. Agnes af Geijerstam2
  4. Elin Ekblom-Bak3
  5. Hans Georg Kuhn4
  6. Lauren Lissner2
  7. Maria Åberg2
  8. Mats Börjesson5
  1. Correspondence to Dr Aron Onerup, Department of Pediatrics, University of Gothenburg Institute of Clinical Sciences, Goteborg, 413 90, Sweden; aron.onerup@gu.se

Abstract

Objectives To assess the associations between cardiorespiratory fitness (CRF) in young men and the incidence of site-specific cancer.

Methods A Swedish population-based cohort study with register linkage of men who underwent military conscription in 1968–2005 was undertaken. CRF was assessed by maximal aerobic workload cycle test at conscription. Cox regression models assessed linear associations and included CRF, age, year and site of conscription, body mass index and parental level of education. CRF was also categorised into low, moderate and high for facilitated interpretation and results comparing high and low CRF are reported.

Results Primary analyses were performed in 1 078 000 men, of whom 84 117 subsequently developed cancer in at least one site during a mean follow-up of 33 years. Higher CRF was linearly associated with a lower hazard ratio (HR) of developing cancer in the head and neck (n=2738, HR 0.81, 95% CI 0.74 to 0.90), oesophagus (n=689, HR 0.61, 95% CI 0.50 to 0.74), stomach (n=902, HR 0.79, 95% CI 0.67 to 0.94), pancreas (n=1280, HR 0.88, 95% CI 0.76 to 1.01), liver (n=1111, HR 0.60, 95% CI 0.51 to 0.71), colon (n=3222, HR 0.82, 95% CI 0.75 to 0.90), rectum (n=2337, HR 0.95, 95% CI 0.85 to 1.05), kidney (n=1753, HR 0.80, 95% CI 0.70 to 0.90) and lung (n=1635, HR 0.58, 95% CI 0.51 to 0.66). However, higher CRF predicted a higher hazard of being diagnosed with prostate cancer (n=14 232, HR 1.07, 95% CI 1.03 to 1.12) and malignant skin cancer (n=23 064, HR 1.31, 95% CI 1.27 to 1.36).

Conclusion We report a number of protective associations between higher CRF in healthy young men and the subsequent hazard of site-specific cancers. These results have implications for public health policymaking, strengthening the incentive to promote health through improving CRF in youth.

Data availability statement

No data are available. The data in this study are not available for data sharing.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://bjsm.bmj.com/content/early/2023/08/17/bjsports-2022-106617  

Discussion

This large population-based study of Swedish men presents novel results on the associations between CRF in youth and 18 site-specific cancers in men. To our knowledge, we show for the first time that higher CRF is associated with a lower hazard for cancer in the head and neck, oesophagus, stomach, pancreas, liver, colon, rectum and kidney. The results indicate a 20–40% lower hazard for men with high versus low CRF for several gastrointestinal sites, which would be clinically relevant.

Previous studies have looked at the association between CRF and the risk of developing colorectal cancer.2 Our study showed that CRF was associated with a reduced hazard of colon cancer, with a hazard reduction of 21% for high CRF. However, the association was weaker for rectal cancer. The novel reports of associations between CRF and cancer in the oesophagus, stomach, colon, liver and kidney in our study are supported by similar associations previously reported for PA.1 There are site-specific cancers for which previous studies have been unable to conclude whether there is an association for either CRF or PA. We can report dose-dependent associations between CRF and cancer in the head and neck and pancreas. For lung cancer, a systematic review reported a 50% reduced risk for high versus low CRF,2 while the WHO concluded that the associations for PA might be confounded by smoking.1 Our results confirmed a hazard reduction which seemed to be confounded by smoking.

For prostate cancer and malignant skin cancer, higher CRF was associated with a higher hazard. For prostate cancer, this is in line with previous studies, one of which was performed on the same registers.3 15 The authors of the previous study reported that the association between CRF and prostate cancer only occurred for any cancer diagnosis and did not apply to aggressive prostate cancer nor prostate cancer mortality. They concluded that this was probably explained by increased prostate cancer screening.3 In our study we show that the association was not confounded by smoking. For malignant skin cancer, the increase with higher CRF could possibly be due to a higher UV exposure for those with higher CRF. Our data did not allow adjustment for UV exposure.

Previous studies have shown a lower hazard across all cancer sites for individuals with higher CRF, with a HR of 0.86 in a 2019 systematic review.2 In our study we report a higher hazard with higher CRF. This is explained by higher hazard for the two major cancer sites, prostate and malignant skin cancer, with the probable confounding previously discussed. This confounding might explain the differences in results between different populations and time periods, with varying associations between CRF and UV exposure and cancer screening. Combined, the results for overall cancer highlight the need for analyses of site-specific cancers, since specific residual confounding may exist for specific site-specific cancers, as shown for lung cancer, malignant skin cancer and prostate cancer in the current study. The interaction analysis between CRF and BMI showed that the protective associations between CRF and site-specific cancers were generally not dependent on BMI, indicating that increasing CRF is beneficial, regardless of body weight. For bladder cancer and non-Hodgkin’s lymphoma, the preventive association with CRF was only seen in participants with overweight/obesity. This is in line with the fat but fit paradigm,16 indicating that maintaining a healthy CRF could be of even more importance for individuals with overweight/obesity.

This study has a number of strengths, including the population-based approach, the use of prospectively registered data with high validity, the large sample size and the long follow-up. These strengths increase both internal validity and generalisability and contribute to the novel results for several site-specific cancers. A limitation is the observational design, limiting conclusions on causality. The sensitivity analyses showed that the associations between CRF and site-specific cancers were robust to excluding pre-existing chronic disease, to adjusting for muscle strength and for cognitive ability and that participants missing information on parental education were similar to the analytical sample at baseline and had similar associations between CRF and site-specific cancer. The major limitation of this study is the lack of full data on other known lifestyle risk factors, especially smoking, which increases the risk of confounding. There is also a possibility of measurement error in smoking, with the relatively crude assessment. We have used the information on smoking habits from a subpopulation of more than 20 000 individuals for which this information was available to see how adjusting for smoking changed the estimates. This approach detected the anticipated confounding for lung cancer and partial confounding for cancers in the liver and oesophagus. Thus, we believe that this sensitivity analysis helps inform about cancer sites where confounding from smoking is probable and that our study improves the evidence compared with previous studies where information on smoking has been lacking.3 4 Furthermore, smoking declined dramatically in Sweden during the study period. Hence, confounding from smoking in the full population should be lower than that observed in the 1968–70 cohort where smoking was frequent. Our study is limited by a lack of information on other lifestyle risk factors such as alcohol and diet as well as other unmeasured confounding. The use of a 9-grade scale rather than widely accepted measures of CRF such as Wmax or VO2max is also a limitation. However, the CRF measure used comes from a maximal ergometer test and has been shown to predict several other health outcomes. Another limitation is the lack of data on changes in exposure during the long follow-up period, despite CRF being a time-varying exposure. While CRF decreases through life, it generally tracks stronger than PA.17 18 There is also a possible feedback between CRF and BMI over time. Hence, studies assessing the effect of CRF at different ages on site-specific cancers are warranted. The fact that CRF testing was only performed for men without underlying disease makes our results valid only for young men without chronic disease. Our sensitivity analysis showed that the results did not change when excluding participants, indicating that men with chronic disease could also have cancer protective effects from CRF. We did not perform any specific handling of competing events.19 However, since we did not estimate any cumulative incidence and the HR from Cox regression is robust to competing events,20 our results should be valid despite probable differences in the risk of death from, for example, cardiovascular disease between the groups. The HRs in our study do not account for possible time-dependent differences in hazard during follow-up, which is a limitation.21

This study has public health implications. While the CRF response to exercise (trainability) has a relatively strong genetic component,22 it is also correlated with the amount of PA of sufficient intensity.23 It is possible that part of the associations in our study could be explained by shared genetic variation, previously reported for cardiovascular disease.24 To our knowledge, shared genetic variations between CRF and cancer are yet to be reported. Since PA is an established risk factor for several site-specific cancers according to the WHO,1 we consider it reasonable to hypothesise that the associations between CRF and site-specific cancers in our study are mainly explained by a difference in underlying PA. While the reported risk reductions for PA are 10–20% for most cancers where there is an association, our study showed 20–30% hazard reductions for several site-specific cancers. One explanation for this could be that most studies on PA use self-reported doses of PA, which has a relatively low sensitivity. However, CRF is improved mainly by aerobic PA of moderate to high relative intensity and less by low intensity PA.25 Thus, our results may indicate that public health efforts aimed at reducing cancer should focus on aerobic PA of sufficient relative intensity to increase CRF. This has been suggested in studies on all-cause mortality,25 and is also reflected in the American Society of Clinical Oncology guidelines on exercise during cancer treatment,26 focusing on aerobic exercise training.

Our results indicate the following future research directions: (1) to confirm the results for cancer sites that have not been previously reported; (2) to clarify the effect of fitness on cancer in various periods of life; and (3) to establish whether a reduced hazard of developing cancer also translates into increased survival after being diagnosed with cancer.

Conclusion

This study shows that higher fitness in healthy young men is associated with a lower hazard of developing 9 out of 18 investigated site-specific cancers, with the most clinically relevant hazard rates in the gastrointestinal tract. These results could be used in public health policymaking, further strengthening the incentive for promoting interventions aimed at increasing CRF in youth.

Data availability statement

No data are available. The data in this study are not available for data sharing.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved bythe ethics committee. Ethical permission for conducting the study was obtained 2021-11-16 from the Swedish authority for ethical permissions, EPN Dnr 462-14 and an addendum covering the present project Dnr 2021-05638-02. Data were obtained from national registers and no informed consent could practically be obtained.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

  • Supplementary Data

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Footnotes

  • Correction notice This article has been corrected since it published Online First. The fourth author's name has been corrected.

  • Contributors AO, AG, KM, LL, MÅ and MB planned the study. MÅ and HGK collected data from Statistics Sweden and the Swedish National Board of Health and Welfare. KM and AO performed data managing. AO performed the statistical analyses with support from KM. AO wrote the first draft of the report with input from AG, EEB, HGK, KM, LL, MÅ and MB. All authors reviewed and approved the manuscript for submission. KM verified the underlying data. MB is the guarantor of the study. The guarantor accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding This work was supported by grants from the Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement (ALFGBG-813511, ALFGBG-965149, ALFGBG-30411, and ALFGBG-720691), Assar Gabrielsson’s Foundation (FB-2021), the Swedish Research Council (VRREG 2022-00166 and 2019-00193) and the Heart and Lung Foundation (20180379). The funders had no role in planning, interpreting or reporting the results of the study.

  • Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: EEB, MÅ, KM, AG, HGK and LL declare no support from any organisation for the submitted work. AO reports grants from Assar Gabrielsson’s Foundation and the Swedish Research Council during the conduct of the study. MB reports grants from the Swedish State under the LUA/ALF agreement and from the Heart and Lung Foundation during the conduct of the study. AO, EEB, MÅ, KM, AG and MB declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. HGK and LL report grants from the Swedish State under the LUA/ALF agreement and the Swedish Research Council (Vetenskapsrådet) outside the submitted work. HGK reports grants from the Swedish Childhood Cancer Foundation outside the submitted work. LL reports roles in the International Scientific Committee of Choices international, the board of Parker Institute, and the Scientific Advisory Committee of BIPS-Leibniz Institute. All authors report no other relationships or activities that could appear to have influenced the submitted work. All authors confirm that they had full access to all the data in the study and accept responsibility to submit for publication.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.


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