IJC International Journal of Cancer

Variation in general practice prostate-specific antigen testing and prostate cancer outcomes: An ecological study Peter Hjertholm1,2,3, Morten Fenger-Grïn1,2, Mogens Vestergaard2,3, Morten B. Christensen1,2, Michael Borre4, Henrik Mïller1,2,5 and Peter Vedsted1,2 1

Research Center for Cancer Diagnosis in Primary Care, Aarhus University, Aarhus C, Denmark Research Unit for General Practice, Aarhus University, Aarhus C, Denmark 3 Section for General Medical Practice, Aarhus University, Aarhus C, Denmark 4 Department of Urology, Aarhus University Hospital Skejby, Aarhus N, Denmark 5 King’s College London, Cancer Epidemiology and Population Health, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, United Kingdom 2

Most Western countries have seen an increase in prostate cancer incidence during the last 25 years. This is temporally linked with the introduction of the prostate-specific antigen (PSA) test in the different countries.1 Differences among countries in prostate cancer incidence, stage distribution, and survival are predominantly induced by differences in the use of PSA testing and to policies and recommendations regarding its use.2 However, the question remains whether these associations also exist within countries due to variations among individual practitioners and general practices. Public healthcare in Denmark is tax-funded and free at the point of care. General practices act as gatekeepers to sec-

ondary care by managing referrals to specialists, hospital admission and diagnostic and therapeutic services. Almost all Danish citizens (99%) are listed with a general practice, which they must seek for medical advice.3 Danish guidelines for PSA testing recommend against screening of asymptomatic men (Fig. 1),4 but PSA testing remains an issue for discussion. The resulting variable frequency of PSA testing provides a suitable study population for investigating effects of PSA testing in a primary health care setting. The aim of this study was to investigate the association between variations in the use of PSA tests among general practices in the Central Denmark Region in 2004–2009 and prostate cancer-related outcomes.

Material and Methods Key words: neoplasm, primary health care, general practice, prostate-specific antigen, prostate neoplasms Additional Supporting Information may be found in the online version of this article. DOI: 10.1002/ijc.29008 Revised 29 Apr 2014; Accepted 20 May 2014; Online 6 June 2014 Correspondence to: Peter Hjertholm, Research Centre for Cancer Diagnosis in Primary Care, Aarhus University, Research Unit for General Practice, Aarhus University, Bartholins Alle 2, DK-8000 Aarhus, Denmark, Tel.: 145-8716-8043, Fax: 145-8612-4788, E-mail: [email protected]

C 2014 UICC Int. J. Cancer: 136, 435–442 (2015) V

Study population

We conducted a population-based ecological study with a well-defined cohort of all men aged 40 years or more listed at a general practice in the Central Denmark Region (1.2 million inhabitants, corresponding to 20% of the Danish population) between January 1, 2004 and December 31, 2009. Only general practices which remained active during the entire study period were included. Prostate cancer-free men were included from January 1, 2004, when turning 40 years old or when moving to the Central Denmark Region, whichever occurred last. Individuals

Epidemiology

Knowledge is sparse about the consequences of variation in prostate-specific antigen (PSA) testing rates in general practice. This study investigated associations between PSA testing and prostate cancer- related outcomes in Danish general practice, where screening for prostate cancer is not recommended. National registers were used to divide general practices into four groups based on their adjusted PSA test rate 2004–2009. We analysed associations between PSA test rate and prostate cancer-related outcomes using Poisson regression adjusted for potential confounders. We included 368 general practices, 303,098 men and 4,199 incident prostate cancers. Men in the highest testing quartile of practices compared to men in the lowest quartile had increased risk of trans-rectal ultrasound (incidence rate ratio (IRR): 1.20, 95% CI, 0.95–1.51), biopsy (IRR: 1.76, 95% CI, 1.54–2.02), and getting a prostate cancer diagnosis (IRR: 1.37, 95% CI, 1.23–1.52). More were diagnosed with local stage disease (IRR: 1.61, 95% CI, 1.37–1.89) with no differences regarding regional or distant stage. The IRR for prostatectomy was 2.25 (95% CI, 1.72–2.94) and 1.28 (95% CI, 1.02–1.62) for radiotherapy. No differences in prostate cancer or overall mortality were found between the groups. These results show that the highest PSA testing general practices may not reduce prostate cancer mortality but increase the downstream use of diagnostic and surgical procedures with potentially harmful side effects.

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PSA testing and prostate cancer outcomes

What’s new? The impact of PSA testing on diagnosis and mortality of prostate cancer is not yet clear. In this study, the authors found that patients of general practitioners (GPs) with high rates of PSA testing had a significantly increased incidence of prostate cancer, as well as greater use of diagnostic and surgical procedures. However, the mortality rate due to prostate cancer was similar to patients of GPs with low rates of PSA testing. This indicates that routine PSA testing may increase the use of diagnostic and surgical procedures with potentially harmful side effects, without actually reducing prostate cancer mortality.

were censored at the end of the study period, upon death, when moving out of Central Denmark Region or when leaving the list system, whichever occurred first. The study cohort was established using the Danish Civil Registration System where all Danish citizens are assigned a unique personal identification number. The system also contains data on emigration, immigration and vital status.5 The identification number was used as a key to allow accurate linkage of information from different registries on the individual level. Information about any citizen’s general practice is registered in the Patient Lists Register. All changes of practice are noted here with a specific date and any citizen’s general practice can be identified at any given time.

Epidemiology

Exposure PSA tests rates.

PSA tests were identified in the clinical laboratory information system (“LABKA”) for all laboratories in the Central Denmark Region.6 Results of biochemical analyses are electronically transferred directly to this database, and it holds information on all PSA tests (including test date, test requestor and test result). We calculated the overall test rate for each general practice in the study period as the number of PSA tests ordered in the practice divided by the sum of person-years contributed by all eligible men listed in the practice up to the point of prostate cancer diagnosis, leaving the region, leaving the list system, death or end of study.

National Patient Register using a register-specific procedure code.7 Prostate cancers (International Classification of Diseases, ICD-10 code C61)8 were identified in the Danish Cancer Registry.9 This registry holds information on all incident cancer cases in Denmark since 1943, including date of diagnosis, age at diagnosis, cancer type and Tumor-Node-Metastasis (TNM) stage. Disease stage at diagnosis was categorised based on the TNM classification using the clinical categories local, regional, distant and unknown as proposed by NguyenNielsen et al. (Supporting Information Table 1).10 Radical prostatectomy and radiotherapy were identified in the Danish National Patient Register. Radiotherapy was counted as number of prostate cancer patients who received radiotherapy within six months after diagnosis and who had not been treated with prostatectomy. Relative survival was calculated as the survival of prostate cancer patients relative to the survival expected had they been subject to the background mortality given the same demographic factors (year of birth, calendar time). Information on the general population mortality was collected from national life tables available from Statistics Denmark. Mortality was calculated separately as prostate cancerspecific and all-cause deaths in the entire study population per person-years. Information on date of death was retrieved from the Civil Registration System and cause of death was retrieved from the Danish Register of Causes of Death.11

Outcome measures

Trans-rectal ultrasound of the prostate and biopsy of the prostate on all included men were identified in the Danish

Background variables

The Charlson Comorbidity Index was computed for each man, and data were used in a comparison of four groups of practices.12,13 All available primary and secondary diagnoses in the Danish National Patient Register were included (both inpatient and outpatient hospital diagnoses) from 1994 until date of censoring. Included diagnoses are listed in Supporting Information Table 2. The men were divided into three groups based on their individual score (0, 1–2 and 3 or higher). Information from January 2004 on education and marital status was obtained from Statistics Denmark.

Statistical methods Figure 1. Danish guidelines for PSA testing, 2012.

The analyses consisted of two main steps; (i) categorisation of general practices into four groups (quartiles) based on C 2014 UICC Int. J. Cancer: 136, 435–442 (2015) V

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Table 1. Characteristics of men aged 40 years or more according to PSA test rate in the four practice groups (group 1 lowest rate of PSA testing, group 4 highest rate of PSA testing) Total

Group 1

Group 2

Group 3

Group 4

No. practices

368

92

92

92

92

No. men1

303,098

70,491

87,915

88,608

74,795

Person-years

1,471,869

317,601

400,504

410,397

343,368

Observation time per practice, mean (sd), person-years

4,000 (2,683)

3,452 (2,350)

4,353 (2,989)

4,461 (3,053)

3,732 (2,130)

Number

106,882

11,401

21,511

29,984

43,986

Crude rate, mean tests/1,000 person-years

72.6

35.9

53.7

73.1

128.1

1 (Reference)

1.50 (1.46–1.53)

2.04 (1.99–2.08)

3.57 (3.50–3.64)

PSA tests

IRR, unadjusted (95% CI) IRR, adjusted (95% CI)

1 (Reference)

1.52 (1.49–1.56)

2.02 (1.98–2.06)

3.56 (3.48–3.63)

PSA value, mean, mg/L2,3

5.37

5.17

4.53

3.97

Proportion of PSA tests >4 mg/L, %3

27.3

30.5

31.0

27.2

24.6

Age, mean (sd), yrs

57.9 (12.1)

58.2 (12.4)

57.6 (12.1)

58.0 (12.0)

58.0 (12.0)

12 yrs (higher education)

22.1

21.2

23.4

22.3

21.3

4

Educational level (%)

Marital status5 (%) Married/cohabitating

76.7

75.0

77.2

77.5

76.7

Single

23.3

25.0

22.8

22.5

23.3

Danish

95.1

94.5

95.1

95.3

95.4

Western immigrant

1.8

1.8

1.8

1.8

1.7

Non-western immigrant

2.9

3.4

2.9

2.6

2.7

0

72.0

71.2

72.2

72.6

71.6

1–2

20.1

20.5

19.9

19.7

20.4

3 or more

8.0

8.3

7.9

7.7

8.0

Ethnicity5 (%)

1

Sum of groups adds to more than total because men can change practice One-way analysis of variance shows that values are statistically significantly different between the groups, except groups 1 and 2 3 Only values less than 200 mg/L were included (99.1% of the tests) 4 Information missing in 4.7%. Men with missing educational level were included in the lowest educational level 5 Information missing in 0.4%. Persons were excluded from analyses. Abbreviations: sd: standard deviation, IRR: incidence rate ratio, CI, confidence interval. 2

their adjusted PSA test rates, (ii) computation of associations between PSA test rate groups and outcomes. First step. PSA test rates at practice level were calculated using a Poisson regression adjusting for calendar-year in 2year periods (2004–2005, 2006–2007, 2008–2009), age in 10-year age groups (40–49, 50–59. . . 90–99, >100), educational level (12 years), ethnic origin (Danish, western immigrant, and non-western immigrant) and marital status (married/cohabitating or living alone).

C 2014 UICC Int. J. Cancer: 136, 435–442 (2015) V

Second step. Age at prostate cancer diagnosis and mean

PSA values were compared among groups using one-way analysis of variance. Incidence rate ratios in the period 2004 to 2009 of trans-rectal ultrasound and biopsy of the prostate, prostate cancer, different disease stages at diagnosis, prostatectomy, radiotherapy and mortality among all included men were calculated using Poisson regressions with male personyears in the four groups as the denominator. The practice group with least testing (group 1) was chosen as the reference group. Adjusted models included calendar year, age group, educational level, ethnic origin and marital status as

Epidemiology

Charlson Comorbidity Index (%)

2.46

n 5 3,801 71.5 (8.8)

IRR, only men aged 60 yrs

Age at diagnosis (sd), mean

1.19 (1.03–1.38)

18 (2.3)

Number (%)

723 (17.2)

137 (17.6)

1 (Reference)

Radiotherapy

IRR, adjusted

104 (13.3) 1 (Reference)

846 (20.1)

IRR, unadjusted

Number (% of cancer patients)

Prostatectomy

1 (Reference)

217 (27.8)

IRR unknown, adjusted

0.99 (0.80–1.23)

1 (Reference) 1,022 (24.3)

IRR distant, adjusted

Number with unknown stage (%)

177 (16.8)

1.41 (1.08–1.83)

1.41 (1.09 (1.85)

186 (17.7)

1.05 (0.85–1.30)

263 (25.0)

174 (16.5)

150 (19.2)

651 (15.5)

Number with distant disease (%)

1.70 (0.94–3.07)

1 (Reference)

IRR regional, adjusted

38 (3.6)

1 (Reference)

IRR local, adjusted

Number with regional disease (%)

105 (2.5)

1.11 (1.00–1.24) 70.9 (8.6)

578 (54.9)

72.9 (9.2)

1.28 (0.93–1.78)

1.12 (1.02–1.25)

1.07 (0.96–1.19)

2.63

1,053

1.13 (1.00–1.28)

1.11 (0.98–1.27)

1,463

1.05 (0.83–1.33)

1.03 (0.81–1.30)

1,870

Group 2 (95% CI)

395 (50.6)

2,421 (57.7)

Number with local disease (%)

Stage at diagnosis

1 (Reference)

IRR, only men aged

Variation in general practice prostate-specific antigen testing and prostate cancer outcomes: an ecological study.

Knowledge is sparse about the consequences of variation in prostate-specific antigen (PSA) testing rates in general practice. This study investigated ...
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