In the cohort of 33 555 survivors of adolescent and young adult cancer, the standardized hospitalization rate ratios (RRs) and corresponding 95% CIs are shown for each of the 12 main diagnostic groups and the group of injuries and violence. Obs indicates observed.
In the cohort of 33 555 survivors of adolescent and young adult cancer, the standardized hospitalization rate ratio (RRs) and corresponding 95% CIs are shown for each of the 10 most common cancers among adolescents and young adults. Obs indicates observed.
eTable 1. Diseases included in the analyses, with corresponding ICD codes.
eTable 2. Characteristics of the cohort of 5-year survivors of adolescent and young adult cancer.
eTable 3: Standardized hospitalization rate ratios and absolute excess risks for all main diagnostic groups and disease categories.
eTable 4: Standardized hospitalization rate ratios and absolute excess risks for hospitalization for selected combinations of cancer type, main diagnostic groups and disease categories.
eFigure 1. Flowchart showing exclusions in the cancer survivor cohort and the comparison cohort.
eFigure 2. Hospitalization rates in survivors of adolescent and young adult cancer and population comparisons.
eFigure 3 (Parts A-K). Distribution of main diagnostic groups according to percentage of total absolute excess risk.
eFigure 4 (Parts A-M). Risks for hospitalization in each of the main diagnostic groups by cancer type.
eFigure 5 (Parts A-J). Risks for hospitalization for survivors of the 10 most common cancers by main diagnostic group.
eFigure 6. Cumulative risk (%) for selected combinations of cancer types and main diagnostic groups.
eFigure 7 (Parts A-B). Standardized bed day ratios by main diagnostic group and by type of cancer.
eFigure 8. Comparison of the results reported by Zhang et al. 2014 with those of the present study.
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Rugbjerg K, Olsen JH. Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer. JAMA Oncol. 2016;2(2):193–200. doi:10.1001/jamaoncol.2015.4393
Survivors of adolescent and young adult cancers are at risk for treatment-induced late adverse effects; however, to our knowledge, the long-term risk of hospitalization in this specific group of cancer survivors has not been thoroughly evaluated.
To examine relative and absolute excess risk for hospitalizations up to 34 years after diagnosis of adolescent and young adult cancer compared with population comparisons.
Design, Setting, and Participants
This was a cohort study, conducted in Denmark, of 33 555 five-year survivors of adolescent or young adult cancer, diagnosed from 1943 through 2004, when they were 15 to 39 years of age, and 228 447 population comparisons, matched to the survivors by sex and year of birth.
Main Outcomes and Measures
Cancer survivors and comparisons were followed up for hospitalizations in the Danish Patient Register through December 2010. Standardized hospitalization rate ratios (RRs) and absolute excess risks (AERs) were calculated.
After a median follow-up of 14 years, we identified 53 032 hospitalizations in cancer survivors, whereas 38 423 were expected, resulting in an overall RR of 1.38 (95% CI, 1.37-1.39). The data analysis was started in January 2015 and ended in June 2015. Additional data analyses requested by the reviewers were conducted in August 2015. The highest risks were found for the main diagnostic groups of diseases of blood and blood-forming organs (RR, 2.00; 95% CI, 1.87-2.14), infectious and parasitic diseases (RR, 1.69; 95% CI, 1.61-1.77), and malignant neoplasms (RR, 1.63; 95% CI, 1.59-1.68). The overall AER was 2803 (95% CI, 2712-2893) per 100 000 person-years; the highest AERs were found for malignant neoplasms, diseases of digestive organs, and diseases of the circulatory system (18%, 15%, and 14% of total AER, respectively). Survivors of the 10 most common cancers in adolescents and young adults were at significantly increased risk for diseases in the 12 main diagnostic groups. The highest risks were those of survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain cancer (RR, 1.93; 95% CI, 1.86-2.00), and Hodgkin lymphoma (RR, 1.87; 95% CI, 1.80-1.94).
Conclusions and Relevance
The large number of survivors and the use of hospital discharge diagnoses made it possible to draw a comprehensive picture of the complex inpatient disease burden experienced by survivors of adolescent and young adult cancer. The findings underscore a great diversity of cancer-related health problems that physicians and patients should be knowledgeable about.
Several large studies have been published on the general disease burden of survivors of childhood cancer1-6; however, the disease pattern of survivors of adolescent and young adult cancer is only incompletely described. Few studies conducted have focused mainly on risks for specific diseases7-10; only 1 Canadian study11 evaluated the risk for hospitalization for several diseases. That study,11 which included 902 five-year survivors of cancer diagnosed at ages 20 to 24 years, found a significantly increased risk for hospitalization of 1.4 relative to that of a matched comparison group. The small sample size, however, prevented formation of any firm conclusion when estimating risks for survivors of specific cancer types and for specific causes for hospitalization.11 Because the pattern of cancers in adolescents and young adults differs from that in children and middle-aged adults12 and the biology of adolescent and young adult cancers is suggested to be distinct,13 research on the disease burden of this particular group of cancer survivors is important for planning preventive initiatives.
In a nationwide cohort study with virtually no loss to follow-up and exclusive use of medically verified diagnostic information from individual inpatient records, we studied the full range of somatic diseases requiring hospitalization in 33 555 five-year survivors of cancer diagnosed when they were 15 to 39 years old.
A comprehensive picture of the risk of hospitalization in survivors of adolescent and young adult cancer is needed to identify survivors at high risk for serious late adverse effects.
In this cohort of 33 555 five-year survivors of adolescent and young adult cancer, we observed an overall increased relative risk for hospitalization of 1.38 (95% CI, 1.37-1.39) compared with population comparisons.
Highest relative risks were seen for diseases of blood and blood-forming organs (standardized hospital rate ratio [RR], 2.00; 95% CI, 1.87-2.14), infectious and parasitic diseases (RR, 1.69; 95% CI, 1.61-1.77), and malignant neoplasms (RR, 1.63; 95% CI, 1.59-1.68).
At highest risk for hospitalizations were survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain cancer (RR, 1.93; 95% CI, 1.86-2.00), and Hodgkin lymphoma (RR, 1.87; 95% CI, 1.80-1.94).
Clinicians and patients should be knowledgeable about this increased disease burden and preventive strategies should be developed considering the complex disease pattern among survivors of adolescent and young adult cancer.
The basic cohort comprised 53 482 patients with a first primary cancer (except nonmelanoma skin cancer) diagnosed when they were 15 to 39 years old and added to the Danish Cancer Registry in the period January 1, 1943, to December 31, 2009 (recruitment period), and who were alive on April 2, 1968, when the Danish civil registration system was started. The Danish Cancer Registry is nationwide, and cancer diagnoses are reported from several sources, ensuring virtually complete coverage. Cancers were classified according to the International Classification of Diseases, seventh revision (ICD-7) from 1943 to 1977; the ICD for Oncology (ICD-O) during 1978 to 2003; and the ICD-10 thereafter.14 From the Cancer Registry, we obtained information on type of cancer and date of diagnosis and assigned individuals to the main diagnostic groups of ICD-7. Since the start of the centralized civil registration in Denmark, all residents (5.5 million in 2009) have been assigned a unique personal identification number that allows accurate linkage between registers.15
To measure disease-specific hospitalization rates in the general Danish population, we established a comparison cohort from the files of Danish civil registration system. For each cancer survivor we randomly selected 5 comparisons who were matched to the survivor on sex and year of birth. Moreover, the comparisons had to be alive and free of cancer on the date of diagnosis of their respective survivor. Information about vital status and migration was obtained from the civil registration system for both cancer survivors and the comparison cohort.
Before linking survivors and population comparisons to the Danish Patient Register (see next subsection), we excluded those who had died or emigrated within 5 years of the date of cancer diagnosis, or an equivalent lag for the comparisons, and those who had died or emigrated before the start of the Danish Patient Register. These exclusions resulted in a cohort of 35 848 five-year survivors of adolescent or young adult cancer and 237 875 in the comparison cohort.
All statistical analyses were performed with SAS software (version 9.3; SAS Institute Inc). The study was approved by the Danish Data Protection Agency.
The Danish National Patient Register holds information on all nonpsychiatric hospital admissions in Denmark since January 1, 1977.16 Registration is mandatory, and diagnostic information is submitted electronically by the treating physician. Each admission to hospital initiates a medical record that includes the personal identification number of the patient, dates of admission and discharge, a primary discharge diagnosis, and supplementary diagnoses coded according to the ICD, eighth revision (ICD-8), until 1993 and according to ICD-10 thereafter.
Data on cancer survivors and comparisons were linked to the Patient Register, and a full hospital history with discharge diagnoses was established for each person with a previous hospital contact. On the basis of information in the Patient Register, we excluded cancer survivors and comparisons who had ever been hospitalized for a congenital malformation or chromosome abnormality (ICD-8 codes 740-759, ICD-10 codes Q00−Q99) because we judged that these disorders might confound any causal association between cancer treatment and chronic disorders. Thus, 33 555 five-year survivors of adolescent or young adult cancer and 228 447 population comparisons were left for the risk analyses (eFigure 1 in the Supplement).
To characterize and quantify the inpatient disease burden among study subjects in a comprehensible fashion we grouped their hospital discharge diagnoses into 12 main diagnostic groups and the group of injuries and violence; these groups were further categorized into 97 more specific disease categories; see eTable 1 in the Supplement for the detailed list of ICD-8 defined categories and the equivalent ICD-10 codes. Because the Patient Register does not reliably distinguish relapses from primary cancer, we used the Danish Cancer Registry for information on second primary cancers among cancer survivors and first primary cancers among comparisons. Hospitalizations due to injuries and violence accounting for 1 main diagnostic group were analyzed separately and not added to the total disease burden because these conditions are primarily of external origin. We did not include the ICD section on symptoms and ill-defined diseases in the present analysis because these were regarded as too unspecific for solid conclusions. (Mental disorders, child birth, and reproductive difficulties require special considerations and will be dealt with in separate publications.)
Follow-up for hospitalizations started 5 years after the date of cancer diagnosis for the survivors and on the corresponding date for the comparisons, at the earliest on January 1, 1977, when the Danish Patient Register was initiated. Follow-up ended at date of death, date of emigration, or end of study on December 31, 2010, which was the latest available update of the Patient Register. Only the primary diagnosis (ie, the main reason for hospitalization at each in-patient contact) was included in the analyses because primary diagnoses are judged to be more reliable than supplementary diagnoses. If participants had more than 1 hospital admission for a particular disease category, only the first medical record was retained. Risk was analyzed for each disease category, and the number of hospitalizations for different disease categories was added up for each of the 12 main diagnostic groups and the group of injuries and violence. For each person, the sum yielded the total number of different disease categories requiring hospitalization. The observed numbers of first hospital admissions of survivors of adolescent or young adult cancer for a given disease category were compared with expected numbers derived from the appropriate sex-, age-, and calendar period–specific hospitalization rates of the comparison cohort, and the standardized hospitalization rate ratio (RR), observed-to-expected hospital admissions for the defined disease categories) with corresponding 95% CIs, was estimated. The absolute excess risk (AER) (ie, the additional risk of survivors for hospitalization) was derived as the difference between the observed and expected first hospitalization rates for a particular disease category per 100 000 person-years of follow-up. For a selected set of cancers and main diagnostic groups we calculated the cumulative risk until age 70 years with death as competing risk.
To obtain an indication of the overall burden of disease, we generated the distributions of cancer survivors and comparisons for hospitalizations in 3 or more and 5 or more disease categories during follow-up before the age of 60 years. Furthermore, standardized bed day ratios (SBDRs) and corresponding 95% CIs were calculated; in this analysis, all hospitalizations were included. Hospitalizations for new malignant neoplasms were not included in the calculation of SBDRs since the information on new malignant neoplasms were obtained from the Danish Cancer Registry, which do not hold information on number of days at hospital. Expected bed day rates were calculated on the basis of the hospitalization pattern in the comparison group.
We included 33 555 five-year survivors of adolescent or young adult cancer (61% of whom were women) and 228 447 population comparisons in our risk analysis. During follow-up, 10 488 cancer survivors (31%) and 41 012 comparisons (18%) died. The survivors were followed in the Patient Register for 521 228 person-years (median follow-up, 14 years [range, 0-34 years]). Comparisons had a median follow-up of 18 years (range, 0-34 years). Additional selected key characteristics of the adolescent and young adult cancer survivor group are given in eTable 2 in the Supplement.
The 33 555 cancer survivors had 53 032 first admissions to hospital for 1 or more of the 97 disease categories listed in eTable 1 in the Supplement, with 38 423 expected, yielding a standardized hospitalization RR for a category-specific first hospitalization of 1.38 (95% CI, 1.37-1.39), which was slightly higher in men than in women (Table 1). The observed and expected category-specific first hospitalization rates of 10 174 and 7372 per 100 000 person-years, respectively, gave an AER of 2803 per 100 000 person-years (Table 1). Thus, for each additional year of follow-up, approximately 3 of 100 survivors of adolescent or young adult cancer were hospitalized for a new excess disease (ie, a disease attributable to the status as cancer survivor). Although the relative risk was significantly increased in all groups of attained age, the increase diminished with age, from a relative risk of 1.9 in the age group 20 to 29 years to 1.3 in the age group 70 to 79 years (Table 1; eFigure 2 in the Supplement). The AER did not vary similarly with attained age, ranging between 2 and 4 category-specific excess hospitalizations per 100 survivors for each year of follow-up, with the lowest number in the age group 40 to 49 years (Table 1).
Figure 1 shows the relative risk for all category-specific first hospitalizations in each of the main diagnostic groups. The highest relative risks were seen for diseases of blood and blood-forming organs, infectious and parasitic diseases, and malignant neoplasms. In general, men had higher risks than women; in particular, the risk of men for benign neoplasms was markedly higher (Figure 1) primarily owing to a substantially increased relative risk for benign bladder papilloma in male cancer survivors and a decreased relative risk for uterine leiomyoma in female survivors. The latter is likely due to a higher prevalence of hysterectomy among survivors of cervical cancer. Relative and absolute risk estimates for each of the 97 disease categories are listed in eTable 3 in the Supplement.
eFigure 3 in the Supplement shows the percentage distribution of the excess number of hospitalization for different disease categories belonging to each of the 12 main diagnostic groups for survivors of all cancers and for survivors of the 10 most common cancers in adolescents and young adults. The overall 18% excess risk for malignant neoplasms was mainly due to large excesses in survivors of Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer, and breast cancer with AERs of 1280, 711, 701, and 610 per 100 000 person-years, respectively.
Figure 2 gives the relative risks for the total sum of category-specific first hospitalizations in survivors of the 10 most common cancers among adolescents and young adults. Survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain cancer (RR, 1.93; 95% CI, 1.86-2.00), and Hodgkin lymphoma (RR, 1.87; 95% CI, 1.80-1.94) were at highest risk for subsequent hospitalizations; however, survivors of all 10 cancer types were hospitalized significantly above expected rates.
In a further analysis we calculated the relative risk for all first hospitalizations for different disease categories belonging to each of the 12 main diagnostic groups and for the group of injuries and violence stratified by type of cancer; these risk estimates are presented by main diagnostic group (eFigure 4 in the Supplement) and by type of cancer (eFigure 5 in the Supplement). While the relative risks for the groups of endocrine diseases and other related diseases and diseases of the nervous system and sense organs were particularly high among survivors of brain cancer (RRs, 5.5 and 5.5, respectively), risks for diseases of the blood and blood-forming organs and respiratory system were highly increased among survivors of leukemia (RRs, 6.3 and 4.9, respectively). Also, relative risks for infectious and parasitic diseases were notably high among survivors of leukemia and of non-Hodgkin lymphoma (RRs, 6.3 and 3.5, respectively), while survivors of Hodgkin lymphoma were affected by high risk for malignant neoplasms (RR, 3.7) (eFigure 5 in the Supplement).
Although survivors of cancers of the testis, thyroid, breast, cervix, and ovary experienced increased risks for a broad range of diseases, the extent of the increase was generally smaller. In particular, the observed increased risks among survivors of malignant melanoma were modest (Table 2).
Table 2 gives the overall risk estimates for hospitalizations in survivors of the 10 most common cancer types, and for a selected set of combinations of type of cancer and main diagnostic groups for which the RRs, the AERs, or the number of disease outcomes were particularly high. Survivors of leukemia, brain cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma were affected by highest AERs for subsequent hospitalizations equivalent to 49% of the hospitalizations per 100 000 person-years among all survivors. Table 2 also shows that the group of survivors of cancers of the cervix, testis, and breast account for most hospitalizations number-wise, owing to a substantially higher prevalence of these cancers in the present cohort. In eTable 4 in the Supplement, the information of Table 2 is further extended with the inclusion of pairs of cancer and specific disease categories worthy of note. This selected set of combinations of cancer type and disease category reveals a disproportionally large number of high-risk combinations among survivors of leukemia, brain cancer, and Hodgkin lymphoma (eTable 4 in the Supplement).
eFigure 6 in the Supplement shows the cumulative risks until age 70 years for diseases belonging to 2 main diagnostic groups among survivors of leukemia, brain cancer, and Hodgkin lymphoma, respectively; combining the 2 main diagnostic groups constitutes approximately half of the total AER for these cancer survivors (Table 2).
Cancer survivors experienced more comorbid conditions than comparisons; for example, 11.6% of cancer survivors (3750) and 8.4% of the comparisons (18 523) were hospitalized for diseases in at least 3 disease categories at any time before the age of 60 years. Hospitalization for diseases in at least 5 disease categories was experienced by 3.3% of cancer survivors (1071) and 1.9% of comparisons (4104) during the same age range. Also, cancer survivors spent more days in hospital than comparisons; the SBDR was 1.49 (95% CI, 1.49-1.50), and the corresponding absolute excess bed days were 40.6 per 100 cancer survivors per year. The highest SBDRs were those of survivors of leukemia (SBDR, 2.7), brain cancer (SBDR, 2.7), and Hodgkin lymphoma (SBDR, 2.3). The SBDRs for each of the 10 most common cancers in adolescents and young adults and for 11 main diagnostic groups (hospitalizations for malignant neoplasms were not included) and for the group of injuries and violence are shown in eFigure 7 in the Supplement.
Most of the current follow-up guidelines for adolescents and young adults are based on knowledge from studies on childhood cancer survivors.17 In the present report, we provide risk estimates for hospitalization in cancer survivors diagnosed at age 15 to 39 years, including survivors of types of cancers that are uncommon or nonexistent in children. The 33 555 five-year survivors of adolescent or young adult cancer had an overall 38% increased risk for being hospitalized during follow-up for 1 or more of the defined disease categories. The increased risk persisted throughout life, with 2 to 4 excess disease-specific first hospitalizations per 100 survivors each year (ie, hospitalizations for diseases attributable to their status as cancer survivors).
It is clear that the highest overall risks for diseases requiring treatment at hospital were seen in survivors of leukemia, brain cancer, and Hodgkin and non-Hodgkin lymphoma (ie, cancers often characterized by particularly intensive and lengthy treatments).
Hospitalizations among survivors of leukemia were predominated by a broad spectrum of infectious diseases, which is likely the result of the common use of intensive treatments with agents possessing immunosuppressive properties. Hospitalizations among brain cancer survivors were primarily due to dysfunction of the neurological and endocrine systems induced by surgical interventions and radiation treatments directed toward the brain, whereas hospitalizations among Hodgkin lymphoma survivors mostly were characterized by new malignant neoplasms and heart diseases. However, survivors of all the 10 most common cancers had significantly increased risk of hospitalization when compared with that of population comparisons.
Not only are the survivors affected by an increased risk for chronic disease but they also experience more chronic comorbid conditions than the comparison cohort and spent, on average, 50% more days in hospitals. A Scottish study1 of hospital admissions among 5-year survivors of cancers diagnosed before age 25 years reports a SBDR of 3.7, which is markedly higher than our finding; however, this is likely due to the younger age composition of survivors at diagnosis and during follow-up with lower hospitalization rates of the background population.
To our knowledge, only 1 previous study11 has assessed the disease burden of survivors of adolescent and young adult cancer from inpatient data. In the files of the British Columbia Cancer Registry, the authors11 identified 902 five-year survivors of cancer diagnosed in people ages 20 to 24 years during 1980 to 1999, who were subsequently followed up for hospitalizations from health insurance inpatient data for an average of 6.1 years. Seventeen diagnostic groups were defined from ICD-9, and a first hospitalization for any disease in a given group was counted as a new disease in the analysis. The authors11 reported a significant, 1.4-fold increased risk (95% CI, 1.2-1.5) for any hospitalization when compared with 10 times as many matched individuals who were free of cancer at baseline. When we restricted our analysis to survivors with cancer diagnosed in the same age range and shortened follow-up accordingly, we observed a relative risk for overall hospitalization of 1.6 (95% CI, 1.5-1.6), somewhat higher than that observed in the Canadian study11 (eFigure 8 in the Supplement). This is likely a consequence of inclusion of a larger number of more specific disease categories in our study.
In a recent cross-sectional survey18 in the United States of general health and quality of life among 8375 survivors of cancer diagnosed at ages 15 to 39 years and 334 759 cancer-free controls in the same age range, 30% of the survivors and less than 20% of controls in their 40s, 50s, and early 60s were reported to be in poor general health.18 Another cross-sectional survey in the United States of 4054 survivors of cancer diagnosed at ages 15 to 29 years of age and 345 592 cancer-free respondents, with a median age at interview of 40 and 42 years, respectively, showed that survivors had a significantly higher prevalence of chronic health conditions, including cardiovascular disease (14% vs 7%), hypertension (35% vs 29%), disability (36% vs 18%), and asthma (15% vs 8%).19 These increases in a broad range of self-reported health problems are reasonably in line with the hospitalization pattern seen in our study.
We observed a 1.6-fold increased risk for a new primary cancer in the entire cancer survivor cohort. The highest risks were those of survivors of Hodgkin lymphoma, with a relative risk of 3.7 (95% CI, 3.4-4.1). This is markedly lower than the relative risk of 7.0 (95% CI, 5.9-8.3) reported in a Dutch study20 of 1253 survivors of Hodgkin lymphoma diagnosed at ages up to 40 years. We were unable to explain this difference.
The size of the present study, with 33 555 survivors of adolescent and young adult cancer and 5 times as many individuals in the comparison cohort, made it possible not only to measure the burden of hospitalization accurately but also to assess comprehensively the extent and range of chronic diseases experienced by this somatically disadvantaged subgroup of the population. Moreover, the unique personal identifiers and the early start of the inpatient register in 1977 ensured both random selection of a population comparison cohort and virtually complete long-term follow-up for chronic comorbidity. We used hospital-based diagnoses by physicians as markers of disease outcome. While this increased the validity of the diagnostic information, we could not include less severe conditions and often more easily compensational conditions treated by the survivors’ general practitioners because no register data on such activities are available. Accordingly, we acknowledge that the study does not give the full picture of the survivors’ disease burden. Thus, the absolute level of the somatic disease burden is underestimated to an unknown extent; however, because this limitation also applies to the population comparisons, the validity of the relative risk estimates is probably little affected. The testing in this descriptive study of the individual associations for statistical significance should not be considered as hypothesis testing. Given the unusually large number of estimate rate ratios and our practice of establishing significance with 95% CIs, chance alone might result in some false-positive findings.
The usefulness of the Danish Cancer Registry for research on late adverse effects in survivors of cancer is limited by insufficient information about cancer treatment. Thus, we were unable to specify the fraction of total disease burden attributable directly or indirectly to the various treatment modalities used. The primary aim of the present study, however, was to measure the frequency and distribution of somatic diseases serious enough to require hospitalization rather than to disentangle the complex causal relations between specific treatments for a defined type of cancer and late adverse effects.
Survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases requiring hospitalization. The morbidity pattern which—as described herein—is highly dependent on the type of cancer being treated, underscores the need for further implementation of strict evidence-based sex-, age-, and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities.
Corresponding Author: Kathrine Rugbjerg, PhD, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark (firstname.lastname@example.org).
Accepted for Publication: September 14, 2015.
Published Online: November 19, 2015. doi:10.1001/jamaoncol.2015.4393.
Author Contributions: Dr Rugbjerg had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Both authors.
Drafting of the manuscript: Rugbjerg.
Critical revision of the manuscript for important intellectual content: Both authors.
Statistical analysis: Both authors.
Obtained funding: Rugbjerg,
Administrative, technical, or material support: Olsen.
Study supervision: Olsen.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Rugbjerg received an individual postdoctoral stipend from the Danish Council for Independent Research in Medical Science.
Role of the Funder/Sponsor: The Danish Council for Independent Research in Medical Science had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Additional Contributions: We thank Andrea Bautz, data manager at the Danish Cancer Society Research Center, for her thorough work with the programming and the analyses of the data used in this article and for her expertise in handling and analyzing data from the Danish registries. She was supported through the core budget of the Danish Cancer Society Research Center. We thank Nick Martinussen, data manager at the Danish Cancer Society Research Center, for sharing his program for creation of the forest plots. He received no compensation from the present project since the program was already developed for other projects. Written permission has been obtained from all persons named in the acknowledgment section. We confirm that all information and materials in the article are original.