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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Background

Systemic glucocorticoids are potent immunosuppressants, potentially facilitating carcinogenesis. Studies examining glucocorticoids and colorectal cancer risk are few.

Aim

To investigate the association between use of systemic glucocorticoids and colorectal cancer risk, both overall and by cancer stage (localised versus metastatic).

Methods

We conducted a nested population-based case–control study in Northern Denmark (1.8 million people) using medical registries. The study included 14 158 patients with a first-time diagnosis of colorectal cancer from 1991 through 2010. Using risk set sampling, we identified 141 580 population controls, matched on age and gender. Logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates.

Results

Frequent use of systemic glucocorticoids (defined as >2 prescriptions) was not associated with overall colorectal cancer risk [adjusted OR (aOR) = 0.93 (95% CI: 0.85–1.00)], compared with never/rare use (≤2 prescriptions). Associations according to duration of use and doses (quartiles of cumulative prednisolone equivalents) were also near the null. Examining colorectal cancer by stage, no substantial associations were found between long-term use (>5 years) of high-dose (>5500 mg) systemic glucocorticoids and localised [aOR = 1.12 (95% CI: 0.81–1.55)] or metastatic [aOR = 0.82 (95% CI: 0.59–1.14)] cancer.

Conclusion

Despite immunological and metabolic effects of frequent use of systemic glucocorticoids, which would be expected to increase colorectal cancer risk, we found no substantial association between the two.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Colorectal cancer is the third most common malignancy worldwide[1] and the disease has a serious prognosis. Synthetic glucocorticoids are widely used in the treatment of chronic and acute inflammatory diseases due to their potent immunosuppressive effects. In Denmark, 3.3% of the population was treated with systemic glucocorticoids in 2010.[2] Concerns have been raised that prolonged therapy may increase cancer risk.[3-7] Use of glucocorticoids could possibly affect the risk of colorectal cancer through several mechanisms. Glucocorticoids are involved in the regulation of metabolism, cell growth, proliferation, apoptosis and immune function,[8] which all play major roles in the prevention of cancer development and spread.[9, 10] As glucocorticoids are potent inhibitors of immunosurveillance, they may facilitate carcinogenesis and rapid progression of colorectal cancer. Moreover, insulin resistance, a well-known side effect of glucocorticoids,[11] has been suggested to increase colorectal cancer risk.[12] In contrast, glucocorticoids exert antiproliferative and proapoptotic effects,[8] and could thereby even facilitate chemoprevention. In addition, glucocorticoids belong to the same steroid superfamily as oestrogen and progesterone, which appear inversely associated with risk of colorectal cancer.[13]

Although glucocorticoids are commonly prescribed in clinical practice, an association with colorectal cancer development is unclear and existing epidemiological data are few. Previous studies evaluating glucocorticoid therapy and colorectal cancer risk all were restricted to patients with inflammatory bowel disease, who a priori have an increased risk of cancer.[14] Moreover, glucocorticoid use was not the main exposure of interest in any of the studies, and their results were conflicting. We therefore conducted a large prospective population-based case–control study examining the association between glucocorticoid use and colorectal cancer risk, both overall and according to cancer stage.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Source population

We conducted this nested population-based case–control study in Northern Denmark, covering a population of 1.8 million inhabitants.[15] The Danish National Health Service guarantees free access to medical care provided by general practitioners and hospitals, and partial reimbursement of the costs of most prescribed drugs. Health-related services are recorded for individual patients using the unique civil registration number assigned to each Danish citizen at birth and to residents upon immigration. The civil registration number encodes age and gender, and allows unambiguous linkage of data from different medical registries. From the source population, we excluded persons with any cancer diagnosis (except for nonmelanoma skin cancer) before their index date (as defined below). Also, to ensure at least 2 years of prescription history for each case and control, we restricted the study to persons who resided in the study area for at least 2 years prior to the index date.

Patients with colorectal cancer

We used the Danish Cancer Registry to identify patients with a first-time colorectal cancer diagnosis between 1 January 1991 and 31 December 2010 (see Appendix S1 for diagnosis codes). The Danish Cancer Registry has recorded cases of incident cancer since 1943.[16, 17] During the 1991–2010 period, cancers were classified in this registry according to the 10th revision of the International Classification of Diseases. Recorded data include civil registration number, date of cancer diagnosis, cancer type and cancer stage at time of diagnosis [according to the Dukes classification system until the end of 2003 and the Tumor Node Metastasis (TNM) classification thereafter].[18] We defined localised cancer as Dukes A or B and associated TNM classification codes and metastatic cancer as Dukes C or D and associated TNM classification codes (see Appendix S1, published online).

Population controls

For each colorectal cancer case, we used the Danish Civil Registration System[19] to select 10 population controls matched on age and gender. Risk set sampling was applied, i.e. controls had to be alive and at risk of colorectal cancer at the time the corresponding case was diagnosed (index date). The Civil Registration System contains data on civil registration number, vital status, residence, migration, and date of death from 1968 onwards.

Prescription data

All pharmacies in Northern Denmark are equipped with an electronic accounting system that records the customer's civil registration number, type and amount of drug prescribed according to the Anatomical Therapeutic Chemical classification system, and the prescription redemption date. Prescription data on reimbursable medicines have been transferred from pharmacies in the study area to a research database at Aarhus University since 1989, with complete coverage from 1998 onwards.[20] In Denmark, glucocorticoids are dispensed by prescription only, except for a few nasal medications sold over the counter (see Appendix S2 published online for codes).

Use of systemic glucocorticoids

For each case and control, we identified all dispensed prescriptions of glucocorticoids prior to the index date. The exposure of interest was the use of systemic glucocorticoids. As a number of subjects were expected to use both systemic and locally acting glucocorticoids, we categorised exposure based on (i) never/rare use of systemic glucocorticoids (defined as two or fewer prescriptions filled prior to the index date); (ii) frequent use of systemic glucocorticoids (more than two prescriptions); and (iii) combined use (including systemic and locally acting or locally acting glucocorticoids alone, the latter including inhaled glucocorticoids and those acting locally in the intestines). For frequent systemic glucocorticoid use, we further defined subgroups based on timing of use, duration and dose. Time of treatment was categorised as recent use (most recent prescription filled 3 years or less prior to the index date) or former use (most recent prescription filled four or more years prior to the index date). Duration and dose were combined to identify the intensity of frequent systemic glucocorticoid use. The duration of use was grouped into short-term use (less than 5 years elapsing between the first and the most recent prescription) or long-term use (five or more years between the first and the most recent prescription) use. Within duration groups, we defined three categories according to cumulative prednisolone-equivalent doses [21, 22] used by cases and controls: low dose (lowest quartile), medium dose (middle quartiles) and high dose (highest quartile) (see Appendix S3, published online, for equivalence calculations). To minimise the risk of detection bias associated with glucocorticoid use due to regular medical follow-ups, we disregarded glucocorticoid prescriptions filled within 1 year prior to the index date in the main analysis. Also, glucocorticoid exposure during that period was unlikely to play an aetiological role in colorectal cancer incidence.

Potential confounders

A number of covariates were included in the study as potential confounders, based on their clinical relevance for, and known association with, both colorectal cancer risk and glucocorticoid exposure. To address the issue of confounders, we used the Danish National Registry of Patients. This registry contains records of nonpsychiatric discharges from Danish hospitals since 1977 and outpatient hospital contacts since 1995.[23] Data include the patient's civil registration number, dates of admission and discharge, surgical and diagnostic procedures and up to 20 discharge diagnoses, coded by physicians according to the 8th revision of the International Classification of Diseases until the end of 1993, and the 10th revision thereafter. We retrieved information from the Danish National Registry of Patients and the prescription database on diagnoses of diabetes/use of antidiabetic drugs, alcoholism/use of disulfiram, pulmonary diseases/use of beta-agonists, inflammatory bowel diseases and rheumatoid arthritis. In addition, we obtained information on use of prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (75 or 150 mg tablets), high-dose aspirin (500 mg tablets) and immunosuppressants. The corresponding codes are provided in Appendix S4 published online.

Statistical analysis

We calculated the frequency and proportion of colorectal cancer cases and population controls within categories of systemic glucocorticoid use, demographic variables and potential confounders. In addition, we calculated mean duration of frequent systemic glucocorticoid use (time between first and last prescription redemption) among cases and controls. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associating systemic glucocorticoid use and colorectal cancer risk. Given the risk set sampling of controls, these ORs represent unbiased estimates of the corresponding incidence rate ratios. As two outcomes were associated with cancer stage distribution, we estimated the ORs using unconditional polytomous logistic regression,[24] adjusting for potential confounding covariates. In all analyses, the reference category was never/rare use of systemic glucocorticoids.

Additional subanalyses were performed to explore observed associations. We examined the association between glucocorticoid use and colorectal cancer risk across strata of comorbidity and drug use. Also, we stratified by time period (1991–2002 and 2003–2010) to provide at least 5 years of prescription history for patients diagnosed during 2003–2010. For cases and controls in the 2003–2010 period, left truncation of prescription data thus would be less likely to influence the results. Furthermore, in a sensitivity analysis, we repeated all analyses, including prescriptions of glucocorticoids within the year before the index date to explore whether the most recent exposure would affect the risk estimates.

Statistical analyses were performed using stata 12.0 (StataCorp LP, College Station, TX, USA) and sas 9.2 (SAS Institute Inc., Cary, NC, USA). The study was approved by the Danish Protection Agency (record number 2011-41-6151).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

We identified 14 158 colorectal cancer cases and 141 580 population controls during the study period, of which 782 (5.5%) and 8434 (6.0%), respectively, were frequent users of systemic glucocorticoids (Table 1). More men (52.5%) than women (47.5%) had colorectal cancer, and most patients were diagnosed between the ages of 70 and 79 years (32.6%). The distribution of potential confounders was nearly the same for cases and controls.

Table 1. Characteristics of colorectal cancer cases and matched population controls, Northern Denmark, 1991–2010
CharacteristicsCases N (%)Controls N (%)
  1. NSAIDs, nonsteroidal anti-inflammatory drugs.

  2. a

    Systemic and locally acting or locally acting glucocorticoids alone.

  3. b

    Number of cases according to availability of prescription data.

  4. c

    Diabetes/antidiabetic agents (single variable).

  5. d

    Alcoholism/disulfiram (single variable).

  6. e

    Pulmonary diseases/beta-2 agonists (single variable).

  7. f

    75, 100 or 150 mg tablets.

  8. g

    500 mg tablets.

Glucocorticoid use
Never/rare systemic use12 122 (85.6)121 271 (85.7)
Frequent systemic use782 (5.5)8434 (6.0)
Combined usea1254 (8.9)11 875 (8.4)
Gender
Female6727 (47.5)67 270 (47.5)
Male7431 (52.5)74 310 (52.5)
Age at diagnosis, years
<50749 (5.3)7505 (5.3)
50–591910 (13.5)19 260 (13.6)
60–693668 (25.9)36 404 (25.7)
70–794596 (32.5)46 206 (32.6)
80+3235 (22.9)32 205 (22.8)
Time periodb
1991–19951391 (9.8)13 910 (9.8)
1996–20002672 (18.9)26 720 (18.9)
2001–20054777 (33.7)47 770 (33.7)
2006–20105318 (37.6)53 180 (37.6)
Diagnoses or related medication before index date
Diabetesc1203 (8.5)10 176 (7.2)
Obesity352 (2.5)3040 (2.2)
Alcoholismd366 (2.6)3398 (2.4)
Pulmonary diseasese2191 (15.5)20 868 (14.7)
Inflammatory bowel diseases107 (0.8)1036 (0.7)
Rheumatoid arthritis154 (1.1)1593 (1.1)
Medication before index date
NSAIDs8230 (58.1)83 257 (58.9)
Low-dose aspirinf4038 (28.5)40 180 (28.4)
High-dose aspirinb68 (0.5)942 (0.7)
Immunosuppressants176 (1.2)1727 (1.2)

Among frequent users of systemic glucocorticoids, each subject filled 11 prescriptions on average, ranging from 3 to 311, during a mean period of 4.4 years. The mean cumulative prednisolone-equivalent dose prescribed was 4295 mg, ranging from 75 to 87 550 mg. Grouped according to quartiles, low, medium and high doses were 75–350 mg, 350–5500 mg, and more than 5500 mg, respectively.

We found no association between frequent use of systemic glucocorticoids and overall risk of colorectal cancer [aOR = 0.93 (95% CI: 0.85–1.00)]. Recent vs. former use did not affect this overall OR (data not shown). Table 2 outlines the ORs according to duration of use and dose. The results are virtually identical to the overall OR, although short-term high-dose systemic glucocorticoid use was associated with a slightly lower aOR of 0.74 (95% CI: 0.59–0.94). In the analysis by colorectal cancer stage, associations between long-term use of medium-dose [aOR = 1.16 (95% CI: 0.89–1.53)] or high-dose [aOR = 1.12 (95% CI: 0.81–1.55)] systemic glucocorticoids and localised cancer were near the null (Table 3). Corresponding associations for metastatic cancer were also almost null [aOR = 0.79 (95% CI: 0.59–1.05) and aOR = 0.82 (95% CI: 0.59–1.14)].

Table 2. Associations between systemic glucocorticoid use and overall risk of colorectal cancer
 CasesControls  
Systemic glucocorticoidsN (%)N (%)OR (95% CI)aORa (95% CI)
  1. aOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio.

  2. a

    Adjusted for diabetes, obesity, alcoholism, pulmonary diseases, inflammatory bowel diseases, rheumatoid arthritis, and use of nonsteroidal anti-inflammatory drugs, low-dose aspirin, high-dose aspirin or immunosuppressants.

  3. b

    Systemic and locally acting or locally acting glucocorticoids alone.

  4. c

    Low dose: cumulative prednisone equivalent dose from 75 mg to 350 mg.

  5. d

    Medium dose: cumulative prednisone equivalent dose from 350 mg to 5500 mg.

  6. e

    High dose: cumulative prednisone equivalent dose more than 5500 mg.

Never/rare use12 122 (85.6)121 271 (85.7)1.0 (referent)1.0 (referent)
Combined useb1254 (8.9)11 875 (8.4)1.06 (0.99–1.12)1.02 (0.95–1.10)
Short-term use
Low dosec142 (1.0)1553 (1.1)0.91 (0.77–1.09)0.92 (0.78–1.10)
Medium dosed276 (2.0)2835 (2.0)0.97 (0.86–1.10)0.97 (0.85–1.10)
High dosee79 (0.6)1044 (0.7)0.76 (0.60–0.95)0.74 (0.59–0.94)
Long-term use
Low dose54 (0.4)666 (0.5)0.81 (0.61–1.07)0.81 (0.62–1.08)
Medium dose133 (0.9)1318 (0.9)1.01 (0.84–1.21)1.01 (0.84–1.21)
High dose98 (0.7)1018 (0.7)0.96 (0.78–1.19)0.95 (0.76–1.17)
Table 3. Associations between systemic glucocorticoid use and risk of colorectal cancer by stagea
Systemic glucocorticoidsLocalised colorectal cancerMetastatic colorectal cancer
NOR (95% CI)aORb (95% CI) N OR (95% CI)aOR (95% CI)
  1. aOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio.

  2. a

    1658 colorectal cancer patients were excluded due to missing stage. Including these patients did not change the estimates (data not shown).

  3. b

    Adjusted for diabetes, obesity, alcoholism, pulmonary diseases, inflammatory bowel diseases, rheumatoid arthritis, and use of nonsteroidal anti-inflammatory drugs, low-dose aspirin, high-dose aspirin or immunosuppressants.

  4. c

    Systemic and locally acting or locally acting glucocorticoids alone.

Never/rare use46351.0 (referent)1.0 (referent)61361.0 (referent)1.0 (referent)
Combined usec5421.19 (1.09–1.31)1.17 (1.04–1.31)5270.88 (0.80–0.96)0.88 (0.79–0.99)
Short-term use
Low dose450.76 (0.56–1.02)0.77 (0.57–1.03)801.02 (0.81–1.28)1.05 (0.84–1.32)
Medium dose1161.07 (0.89–1.29)1.09 (0.90–1.31)1160.81 (0.67–0.98)0.84 (0.70–1.02)
High dose300.75 (0.52–1.08)0.76 (0.53–1.10)390.74 (0.54–1.02)0.77 (0.56–1.07)
Long-term use
Low dose170.67 (0.41–1.08)0.70 (0.43–1.14)310.92 (0.64–1.32)0.96 (0.67–1.37)
Medium dose551.09 (0.83–1.43)1.16 (0.89–1.53)500.75 (0.56–1.00)0.79 (0.59–1.05)
High dose411.05 (0.77–1.44)1.12 (0.81–1.55)400.78 (0.57–1.07)0.82 (0.59–1.14)

Subanalyses across strata of comorbidities and drug use did not change the association between frequent use of systemic glucocorticoids and overall colorectal cancer risk, except for use of NSAIDs [aOR = 0.89 (95% CI: 0.81–0.97)]. The sensitivity analysis stratified by time period (1991–2002 and 2003–2010) also yielded results near the null (data not shown). Results of our sensitivity analyses, including glucocorticoid prescriptions filled within 1 year before the index date, were not substantially different from the results of the main analysis (data not shown).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

In this large population-based case–control study, we found no evidence of an overall association between frequent use of systemic glucocorticoids and colorectal cancer risk. Although results were close to null, long-term use of medium- or high-dose systemic glucocorticoids slightly increased risk of localised colorectal cancer, and decreased risk of metastatic cancer. We cannot exclude the possibility that this association was causal; however, it seems likely that increased surveillance influenced our findings. Systemic glucocorticoids are used for the treatment of various medical conditions and only by prescription. Thus, patients using these drugs may have frequent contacts with physicians. Moreover, glucocorticoids can cause serious side effects, including peptic ulcers, upper gastrointestinal bleeding, and anaemia,[25] which may lead to blood tests, diagnostic endoscopies and early detection of colorectal neoplasia. In this context, we would expect fewer metastatic colorectal cancers at the time of diagnosis. Our study findings supported this assumption.

To our knowledge, this is the first study to investigate the association between systemic glucocorticoid use and risk of colorectal cancer in the general population. Previous studies suggest that immune suppression by glucocorticoids increases the risk of non-Hodgkin lymphomas, and cancers of the skin, bladder and prostate.[3-7] Still, no association was found between glucocorticoid therapy and risk of breast cancer in a Danish population-based case–control study,[22] and an inverse association was reported for inhaled corticosteroids and lung cancer among patients with chronic obstructive pulmonary disease.[26] Differences in study results may indicate that associations between glucocorticoids and cancer risk depend on where the cancer is located.

Major strengths of our study include its population-based design, encompassing all incident colorectal cancers in the study period. Our study population was identified in registries with complete follow-up.[16, 19] In addition, accurate registry data on prescriptions and diagnoses eliminated recall bias and permitted adjustment for potential confounders.[20, 23]

Our study also has potential weaknesses.[27] Misclassification of both exposure and covariates is a major concern. First, filled prescriptions for medications were used to estimate actual intake, as we lacked information on adherence. However, a recent Danish study reported complete correspondence between corticosteroid treatment reported by general practitioners and time of prescription dispensation within 3 months of a set index date.[28] Second, we lacked data on glucocorticoids dispensed to hospital inpatients, thereby potentially underestimating the actual use of glucocorticoids. However, adjustment and stratification based on hospitalisations and corresponding diagnoses did not change the overall risk estimates. Third, the prescription database does not include over-the-counter NSAIDs, which account for 14% of total NSAID use in Denmark.[29] Also, low-dose aspirin is available without prescription. These drugs are inversely associated with colorectal cancer risk[30] and may also be related to glucocorticoid exposure. We assumed that these drugs were likely to be prescribed when used to treat chronic conditions, to allow patients to get reimbursed. Fourth, left truncation of prescription data could lead to misclassification of users as non-users. However, potential bias due to under-ascertainment of glucocorticoid exposure before establishment of the prescription database cannot explain our findings.

We had no information on the indication for prescription of systemic glucocorticoids. However, we adjusted for relevant diagnoses before the index date and included glucocorticoid dose and duration of use, which are surrogate markers of disease severity. Moreover, our definition of systemic glucocorticoids minimised confounding by the indication for concurrent use of either inhaled glucocorticoids or glucocorticoids acting locally in the intestines (i.e. related to severe underlying conditions).

Finally, unmeasured factors such as smoking, physical activity, and diet could affect colorectal cancer risk. However, confounding by lifestyle factors would have caused an overestimation of the ORs and thus cannot explain a null result or an inverse association.

In conclusion, despite immunological and metabolic effects of frequent use of systemic glucocorticoids, which would be expected to increase colorectal cancer risk, we found no overall association between the two. Associations between frequent use of systemic glucocorticoids and colorectal cancer stage are probably influenced by detection bias, due to increased medical surveillance among these patients.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Guarantor of the article: EBO takes the responsibility for the integrity of the work as a whole, from inception to published article.

Author contributions: All authors have made substantial contributions to the study design, analysis or interpretation of data, drafted the manuscript or critically revised it for important intellectual content. All authors approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Declaration of personal interests: None.

Declaration of funding interests: The study was supported by Manufacturer Einar Willumsen's Memorial Scholarship (to EBO); Dagmar Marshall's Foundation (to EBO); Director Jacob Madsen and wife Olga Madsen's Foundation (to EBO); the Else and Mogens Wedell-Wedellborg Foundation (to EBO); the Karen Elise Jensen Foundation (to HTS); and the Department of Clinical Epidemiology's Research Foundation (to EBO). The funding sources had no role in the design and conduct of the study; collection, management, analyses and interpretation of the data; or preparation, review or approval of the manuscript.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information
  • 1
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893917.
  • 2
    Danish Medicines Agency. Sales of Medicinal Products Within the Different ATC Groups in the Primary Healthcare Sector. Medicinal Product Statistics 2006–2010. Denmark Copenhagen: Danish Medicines Agency, 2011; 80.
  • 3
    Sorensen HT, Mellemkjaer L, Nielsen GL, Baron JA, Olsen JH, Karagas MR. Skin cancers and non-hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study. J Natl Cancer Inst 2004; 96: 70911.
  • 4
    Karagas MR, Cushing GL Jr, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer 2001; 85: 6836.
  • 5
    Jensen AO, Thomsen HF, Engebjerg MC, et al. Use of oral glucocorticoids and risk of skin cancer and non-Hodgkin's lymphoma: a population-based case-control study. Br J Cancer 2009; 100: 2005.
  • 6
    Dietrich K, Schned A, Fortuny J, et al. Glucocorticoid therapy and risk of bladder cancer. Br J Cancer 2009; 101: 131620.
  • 7
    Severi G, Baglietto L, Muller DC, et al. Asthma, asthma medications, and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2010; 19: 231824.
  • 8
    Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's the Pharmacological Basis of Therapeutics. New York: McGraw-Hill Medical Publishing Division, 2006; 1587612.
  • 9
    Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006; 6: 83648.
  • 10
    Fulop T, Larbi A, Kotb R, de Angelis F, Pawelec G. Aging, immunity, and cancer. Discov Med 2011; 11: 53750.
  • 11
    Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002; 96: 2343.
  • 12
    Siddiqui AA. Metabolic syndrome and its association with colorectal cancer: a review. Am J Med Sci 2011; 341: 22731.
  • 13
    Lin JH, Morikawa T, Chan AT, et al. Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression. Cancer Res 2012; 72: 30208.
  • 14
    Subramanian V, Logan RF. Chemoprevention of colorectal cancer in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2011; 25: 593606.
  • 15
    Statistics Denmark. StatBank Denmark. 2012. Available at: http://www.statistikbanken.dk/statbank5a/SelectVarVal/Define.asp?Maintable=FOLK1&PLanguage=1. Accessed September 20, 2012.
  • 16
    Storm HH, Michelsen EV, Clemmensen IH, Pihl J. The Danish Cancer Registry-history, content, quality and use. Dan Med Bull 1997; 44: 5359.
  • 17
    Gjerstorff ML. The Danish Cancer Registry. Scand J Public Health 2011; 39(Suppl.): 425.
  • 18
    Sobin LH. TNM: evolution and relation to other prognostic factors. Semin Surg Oncol 2003; 21: 37.
  • 19
    Pedersen CB. The Danish Civil Registration System. Scand J Public Health 2011; 39(Suppl.): 225.
  • 20
    Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical epidemiology: Aarhus University Prescription Database. Clin Epidemiol 2010; 2: 2739.
  • 21
    Jacobs JWG, Bijlsma JWJ. Glucocorticoid Therapy. In: Firestein GS, Budd RC, Harris ED, McInnes IB, Sergent JS, eds. Kelly's Textbook of Rheumatology. 8th ed. St. Louis, MO: W.B. Saunders Company, 2008; 863.
  • 22
    Sorensen GV, Cronin-Fenton DP, Sorensen HT, Ulrichsen SP, Pedersen L, Lash TL. Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study. Breast Cancer Res 2012; 14: R21.
  • 23
    Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999; 46: 2638.
  • 24
    Hosmer DW, Lemeshow S The Multinomal Logistic Regression Model. Applied Logistic Regression. 2nd ed. Hoboken NJ: John Wiley and Sons, Inc., 2000; 260.
  • 25
    Nielsen GL, Sorensen HT, Mellemkjoer L, et al. Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study. Am J Med 2001; 111: 5415.
  • 26
    Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 7129.
  • 27
    Sorensen HT, Lash TL, Rothman KJ. Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies. Hepatology 2006; 44: 107582.
  • 28
    Johannesdottir SA, Maegbaek ML, Hansen JG, Lash TL, Pedersen L, Ehrenstein V. Correspondence between general practitioner reported medication use and timing of prescription dispensation. Clin Epidemiol 2012; 4: 138.
  • 29
    Mellemkjaer L, Blot WJ, Sorensen HT, et al. Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark. Br J Clin Pharmacol 2002; 53: 17381.
  • 30
    Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 174150.

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information
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apt12115-sup-0001-AppendixS1-S4.docxWord document17K

Appendix S1. Colorectal cancer diagnosis codes and classification codes.

Appendix S2. Anatomical Therapeutic Chemical classification codes for glucocorticoids.

Appendix S3. Equivalency table presenting systemic glucocorticoids and corresponding prednisolone conversion factors.

Appendix S4. Diagnosis codes for potential confounders.

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