DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW Diabetes Metab Res Rev (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2582
ARTICLE
Diabetes mellitus is associated with elevated risk of mortality amongst patients with prostate cancer: a meta-analysis of 11 cohort studies Hongzhou Cai† Zicheng Xu† Ting Xu† Bin Yu Qing Zou* Department of Urologic Surgery, Nanjing Medical University Affiliated Cancer Hospital of Jiangsu Province, Nanjing, China *Correspondence to: Qing Zou, Department of Urologic Surgery, Nanjing Medical University Affiliated Cancer Hospital of Jiangsu Province, 42 Baiziting Road, Nanjing 210009, China. E-mail: [email protected] †
H. Cai, Z. Xu and T. Xu contributed equally to this work.
Abstract Purpose Diabetes mellitus is associated with a decreased risk of prostate cancer. However, previous studies examining the associations between diabetes mellitus and prostate cancer prognosis have produced mixed results. Here, we aim to summarize the effect of diabetes mellitus on prostate cancer prognosis. Methods We searched the database of PubMed from inception through 31 March 2014 for articles evaluating the effect of diabetes on outcome in prostate cancer patients, and a meta-analysis was conducted. Results A total of 11 cohort studies were included in this meta-analysis, of which seven studies were carried out to investigate whether diabetes mellitus is associated with all-cause mortality amongst those with prostate cancer, seven studies to investigate whether diabetes mellitus is associated with prostate cancer-specific mortality and two studies to investigate the relationship of diabetes mellitus and nonprostate cancer mortality. The meta-analysis results suggested that diabetes mellitus could significantly affect the incidence of all-cause mortality amongst those with prostate cancer (hazard ratio = 1.50, 95% confidence interval = 1.25–1.79). Besides, diabetes mellitus was also associated with prostate cancer-specific mortality (hazard ratio = 1.26, 95% confidence interval = 1.20–1.33) and nonprostate cancer mortality (hazard ratio = 1.83, 95% confidence interval = 1.33–2.52) separately. There was no obvious publication bias amongst the studies included. Conclusion The results of this meta-analysis reveal an association of diabetes mellitus with adverse prognosis amongst those with prostate cancer. The biological basis of the association of diabetes mellitus with prostate cancer incidence and prognosis remains unclear. Doctors could pay more attention to prostate patients with pre-existing diabetes mellitus, and more aggressive treatment regimens should be considered. Copyright © 2014 John Wiley & Sons, Ltd. Keywords
prostate cancer; diabetes mellitus; mortality; meta-analysis
Introduction
Received: 26 April 2014 Revised: 13 July 2014 Accepted: 14 July 2014
Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes mellitus (DM) is one of the most common chronic diseases. An estimated 285 million people worldwide had DM in 2010, and the global prevalence of DM is rapidly increasing [1]. DM has been reported to be associated with increased risk of numerous human cancers including cancers of the endometrium [2], pancreas [3], colon [4], thyroid [5] and so on. However, an inverse relationship has been reported between DM and prostate cancer risk [6].
H. Cai et al.
Approximately 63% of prostate cancers will be diagnosed in men age 65 years or older [7,8]. A recent study showed that DM was associated with a 28% reduced risk of high-grade prostate cancer [9]. Several meta-analyses also demonstrated a decreased risk of incident prostate cancer amongst men with DM [10–12]. Xu et al. found that the protective effect of DM was observed in different prostate cancer grade or stage, which further extended the evidence of the inverse relationship. It is worth noting that whether this protective effect extends to prognosis amongst men who do get prostate cancer. A recent meta-analysis found that pre-existing DM was associated with worse overall, long-term mortality in cancer patients generally [13]. However, the effect of DM varied across different cancer types. It is of interest to evaluate prostate cancer separately. As expected, there is rapidly growing interest in the association between DM and the prognosis of prostate cancer. Since 2006, some studies have been conducted to investigate the relationship, but the findings have continued to be somewhat inconclusive. Park et al. [14] used the Korean cancer registry to investigate the effect of glucose tolerance on survival amongst patients with prostate cancer. They found that men with fasting serum glucose (FSG) 126 or greater had a nonsignificantly increased risk compared with men with FSG 110 or lower. Two other studies also found nonsignificant relationships between pre-existing DM and overall mortality in prostate cancer patients [15,16]. Smith et al. [17] found that prevalent DM significantly associated with greater all-cause mortality but not prostate cancer mortality. Batty et al. [18] also demonstrated that there was no evidence that DM predicted the risk of death from the malignancy. However, Bensimon et al. [19] suggested that DM is associated with an increased risk of prostate cancer mortality and all-cause mortality. In 2010, a systematic literature review was conducted to summarize the influence of pre-existing DM on prostate cancer prognosis [20]. However, data from only four studies could be included in a preliminary meta-analysis for overall mortality and produced a pooled hazard ratio (HR) of 1.57 [95% confidence interval (CI): 1.12–2.20]. And there was insufficient evidence to conduct a formal meta-analysis of prostate cancer-specific mortality. Herein, we conducted this meta-analysis including studies up to 2014 to better assess the effect of pre-existing DM on prostate cancer-specific mortality, overall mortality and nonprostate cancer mortality.
Materials and methods Literature search strategy We searched the PubMed database from inception to 31 March 2014 for articles evaluating the effect of DM on prognostic outcome in prostate cancer patients. Search terms included ‘DM’ or ‘diabetes’ combined with ‘prostate cancer’ or ‘prostate neoplasms’. Two reviewers (Cai and Copyright © 2014 John Wiley & Sons, Ltd.
Xu) independently evaluated the titles and abstracts of the papers identified. The references in the identified articles were also reviewed for possible inclusions. Our overall research was limited to English language, human studies. No additional unpublished study was revealed.
Study inclusion criteria Studies were included if they met the following criteria: (1) case–control studies or cohort studies; (2) studies evaluating prostate cancer population; (3) studies evaluating prognostic outcome by DM; (3) studies that reported all-cause mortality or overall survival, prostate cancer mortality or nonprostate cancer mortality; (4) studies that had a follow-up period of 3 months or longer; and (5) studies that reported HR or relative risk relating pre-existing DM to prostate cancer outcome and the corresponding 95% CI; we also included studies that failed to report 95% CI directly but from which we could reconstruct an estimate of 95% CI using p-values and HR or relative risk. When two or more studies had overlapping study samples, the most recent article based on largest study population was selected.
Data extraction Two investigators (Cai and Xu) independently extracted the relevant data from all the eligible studies. Disagreements were settled by consensus or a third review for adjudication. The following item, if available, were extracted form the studies include: first author’s name, year of publication, data source, follow-up time, age of the subjects, sample size, effect estimates with 95% CIs for the association of DM and prostate cancer and statistical adjustments for confounding factors. The 95% CIs were recorded or calculated.
Statistical analysis The meta-analysis was conducted on published results instead of original data form the included studies. We calculated a pooled HR estimate across all studies. The association of pre-existing DM and all-cause mortality, prostate cancer mortality and nonprostate cancer mortality were considered in separate analyses. Publication bias was evaluated using funnel plots, the Begg–Mazumdar adjusted rank correlation test [21] and the Egger regression asymmetry test [22]. The p < 0.05 was considered statistically significant. Statistical heterogeneity amongst the studies was assessed using Q-statistic [23]. Heterogeneity was considered as p < 0.05. Two techniques were used to estimate the summary HR estimates. When there was no heterogeneity amongst studies, the fixed-effects model (the Mantel–Haenszel method) was used to calculate the pooled HRs [24]. Otherwise, a random-effects model (the DerSimonian and Laird method) was selected [25]. Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
DM and Prognosis of Prostate Cancer
All analyses were conducted using the software State version 11.0 (State Corporation, College Station, TX, USA). All the p-values were two sided.
Results Literature search Our initial search identified 1342 potentially relevant studies, of which we screened the titles and abstracts. After carefully evaluating the papers identified and reviewing the references for possible inclusions, our meta-analysis yielded a total of 11 articles on DM and mortality risk of prostate cancer patients (Figure 1).
mortality amongst those with prostate cancer. As shown in Figure 2, the pooled HR for the association of DM and the incidence of all-cause mortality amongst those with prostate cancer was 1.50 (95% CI: 1.25–1.79). Seven studies [17–19,26–28,30] were eligible for examining the relationship between DM is and the incidence of prostate cancer mortality. As shown in Figure 3, the pooled HR for the association of DM and the incidence of prostate cancer mortality was 1.26 (95% CI: 1.20–1.33). Two studies [17,30] were eligible for examining the relationship between DM is and the incidence for nonprostate cancer mortality amongst those with prostate cancer. As shown in Figure 4, the pooled HR for the association of DM and the incidence of nonprostate cancer mortality was 1.83 (95% CI: 1.33–2.52).
Publication bias analyses Characteristics of studies Descriptive data for the studies we identified are summarized in Table 1. A total of 11 studies [14,17–19,26–32] were included, which were published between 2006 and 2014. Of the 11 studies, seven studies [14,17,19,27,29,31,32] were carried out to determine whether DM is associated with the incidence of all-cause mortality amongst those with prostate cancer, seven studies [17–19,26–28,30] to determine whether DM is associated with the incidence of prostate cancer-specific mortality and only twos studies [17,30] to determine the relationship of DM and nonprostate cancer mortality. The duration of follow-up ranged from 3 to 40 years. The results of all the 11 studies were adjusted for several potential confounders, including age, body mass index, race, smoking, alcohol consumption and so on.
Results of the association between DM and the prostate cancer prognosis Seven studies [14,17,19,27,29,31,32] were included in the meta-analysis of DM and the incidence of all-cause
Figure 1. Flowchart representing the study selection process Copyright © 2014 John Wiley & Sons, Ltd.
Results from the Begg’s test and Egger’s test revealed that there was no obvious publication bias amongst either the studies eligible for all-cause mortality meta-analysed (pBegg’s = 0.764, pEgger’s = 0.067) nor amongst the studies eligible for prostate cancer mortality meta-analysed (pBegg’s = 0.764, pEgger’s = 0.147).
Discussion Diabetes mellitus and prostate cancer are both prevalent diseases amongst old men. It is reported that DM is associated with a decreased risk of developing prostate cancer, raising the question of whether this protective effect extends to prognosis amongst men with prostate cancer [10–12]. However, previous studies that have examined associations between DM and prostate cancer prognosis have produced somewhat mixed results. Our present meta-analysis sums up the previous studies on the effect of DM on the prognosis of prostate cancer. The results indicated a 50% increase in the incidence of all-cause mortality amongst prostate cancer patients with DM. As DM is associated with worse mortality in general (aside from any cancer diagnosis), it is particularly important to investigate the effect of DM on prostate cancer mortality. As speculated, the association of DM and prostate cancer-specific mortality risk also reached a statistical significance. Besides, result from two studies showed that DM also could increase the incidence of nonprostate cancer mortality. Wonderingly, what might explain the different effects of DM on prostate cancer incidence and outcomes? The biological basis of the contrasting association of DM on prostate cancer incidence and prognosis remain unclear. Several mechanisms have been proposed, including changes in hormonal environment, with reduced levels of insulin and testosterone in DM patients, and genetic factors related to DM and Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
Copyright © 2014 John Wiley & Sons, Ltd.
Liu X
Shetti MB
Batty GD
D’Amico AV
Smith MR
Van de Poll-Franse LV Merrick GS 2007
28
29
18
30
17
31
32
Yeh HC
27
2008 Radiation Therapy Oncology Group Protocol 92-02 2007 The Eindhoven Cancer Registry, the Netherlands
2010 The Chicago Prostate Cancer Center
2011 London (UK)
2012 The CLUE II (Give Us a Clue to Cancer and Heart Disease) cohort in Washington County and Maryland 2012 The Swedish Hospital Discharge Register and the nationwide Swedish Cancer Registry 2012 American Joint Committee on Cancer
2012 Primary care practices in the UK
Currie CJ
Data source
26
Year
Bensimon L 2014 Four databases from UK: NCDR, CPRD, HES and ONS
Author
19
Reference
Follow-up time (years)
1995–2003
1997–2007 Until 1 July 2008 or the date of death, whichever came first 1992–1995 Median: 8.1 (0.04–12.9) 1995–2002 3–10
1967–1970 Maximum: 40
1995–2006 Mean: 7.8, median 7.6
1961–2008 Mean: 8
1990–2009 Median: 2.0 for non-DM, 1.6 for DM 1989–2006 Maximum: 17
1998–2009 Mean: 4.7
Study recruitment years
Table 1. Characteristics of 11 cohort studies included in the meta-analysis Confounders adjusted
66.1 ± 7.4
Median 70 (43–88) 72.6 vs 70.3
68.9
40–69
66.6 ± 6.1 vs 65.2 ± 7.5
68 vs 72
61.8 ± 11.2 vs 51.5 ± 13.7
71.7 ± 9.5 vs 67.5 ± 13.0 NG
NG
Age, square of age, BMI, smoking, education level, hypertension treatment and high cholesterol treatment
530
5 478
1 520
5 279
17 934
1 624
64
468
210
608
NG
199
466
5 010
1 310
4 671
NG
1 425
Age, smoking, percent positive biopsies and BMI
Age, race, Gleason score, tumour stage, PSA, treatment arm and weight Age, gender, stage, treatment and cardiovascular disease
Age, PSA, Gleason score, percent positive biopsies, BMI, prostate volume, clinical stage, XRT, ADT, ADT duration, perineal invasion, hypertension, hypercholesteremia, CAD and tobacco use BMI, plasma cholesterol, physical activity, socioeconomic status, blood glucose, marital status, FEV1, height, age at risk, smoking and diastolic and systolic blood pressure A history of MI, treatment received, age, year of brachytherapy and prostate cancer aggressiveness
15 6687 2 217 15 4470 Age at diagnosis, period, obesity, alcohol, smoking, socio-economic status and diagnosis region
NG
11 920 1 132 10 788 Age, year of cohort entry, ethnicity, excessive alcohol use, BMI, smoking status, CKD, MI, ischemic stroke, transient ischemic attack, peripheral artery disease, previous cancer, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, diuretics, other antihypertensive drugs, aspirin, other nonsteroidal anti-inflammatory drugs, statins, 5-alpha reductase inhibitors and the following prostate cancer-related variables: PSA levels, Gleason score, radical prostatectomy, radiation therapy, chemotherapy and androgen deprivation therapy 17 264 2 008 15 256 Age at baseline, sex, smoking history, Charlison comorbidity index and year of diagnosis
NonDM (n)
73.4 vs 71.3
DM (n)
Sample size (n)
Age (years), mean ± SD (range)
H. Cai et al.
Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
Copyright © 2014 John Wiley & Sons, Ltd.
NCDR, National Cancer Data Repository; CPRD, Clinical Practice Research Datalink; HES, Hospital Episode Statistics; ONS, Office for National Statistics; BMI, body mass index; CKD, chronic kidney disease; MI, myocardial infarction; PSA, prostate-specific antigen; ADT, androgen deprivation therapy; ANOVA, analysis of variance; CAD, coronary artery disease; XRT, supplemental external beam radiation therapy; FEV1, forced expiratory volume in one second; NG, not given.
Age, alcohol consumption, BMI, fasting serum glucose level, cholesterol level, physical activity, food preference, blood pressure and other comorbidities (heart disease, liver disease and cerebrovascular disease) NG NG 256 50.8 (all participants) 14
Park SM
Schiffler Cancer Center, Mean: 6.0, Wheeling, WV median 5.7 2006 The National Health Insurance 1996–2002 Median: 3.86 Corporation Study (NHICS) and Korean Central Cancer Registry
Year Author Reference
Table r2582-tbl-0001. (continued)
Data source
Study recruitment years
Follow-up time (years)
Age (years), mean ± SD (range)
Sample size (n)
DM (n)
NonDM (n)
Confounders adjusted
DM and Prognosis of Prostate Cancer
prostate cancer [33]. It is suspected that the incidence effect may be driven dominantly by the relatively low levels of male hormones in DM patients compared with non-DM, while the prognosis effect may be driven by the proposed stimulatory effects of hyperinsulinemia on prostate cancer behaviour [34–36]. High levels of male hormones in tissue can explain the increased risk for prostate cancer [37]. Notably, low testosterone levels are common in men with DM [38]. Evidence from several studies further demonstrated that a lower testosterone level is the main cause of the lower prostate cancer risk amongst patients with DM [39,40]. On the other hand, it is suggested that cancer patients with DM may have increased tumour cell proliferation and metastases in a physiologic environment of hyperinsulinemia and hyperglycaemia [41]. Insulin could stimulate the growth of prostate cells [42]. An in vitro study showed that insulin is capable of increasing growth of rat prostate cancer cells. Another study discovered that insulin levels are associated with recurrence of prostate cancer after treatment [43]. Evidence from the intensive care literature indicates that achieving glucose control leads to better clinical outcomes. A possible explanation of this phenomenon is that DM might have a protective role in the initiation phase but not in the progression phase of prostate cancer, which may be a reason leading to contrasting association of DM on prostate cancer incidence and prognosis. As both prostate cancer and DM are common conditions amongst older men, more research is certainly needed to investigate how DM affects prostate cancer prognosis. Furthermore, it is of interest to demonstrate whether men with DM should receive different treatments from men without DM. If so, more attention should be paid to what the appropriate treatments are and how to improve the prognosis of prostate cancer patients with DM.
Study limitations We aimed to conduct a rigorous meta-analysis to investigate the effect of DM on prostate cancer outcome. However, several limitations should be acknowledged. First, our search was restricted to studies published in indexed journals. No additional unpublished studies or original data were revealed. Second, we did not consider the associations between prostate cancer prognosis and type 1 DM or type 2 DM separately because there was limited data on this in the included studies. Third, the results of all the 11 studies included were adjusted for potential confounders. However, a part of the studies were not able to adjust for tumour stage, which is considered to be associated with the mortality outcomes. Fourth, DM durations are much inconsistent in different studies. We cannot investigate whether DM duration could affect prostate cancer outcome. Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
H. Cai et al.
Figure 2. Forest plot of cohort studies examining the association between diabetes mellitus and all-cause mortality
Figure 3. Forest plot of cohort studies examining the association between diabetes mellitus and prostate cancer mortality
Figure 4. Forest plot of cohort studies examining the association between diabetes mellitus and nonprostate cancer mortality Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
DM and Prognosis of Prostate Cancer
Conclusion This meta-analysis strongly suggests that DM could inversely impact the prognosis of prostate cancer. Given the small number of studies included in this metaanalysis, especially studies focused on type 1 and type 2 DM separately, the present conclusion should be confirmed with additional experimental and prospective epidemiologic studies. If confirmed, doctors should pay
more attention to prostate patients with pre-existing DM, and more aggressive prostate cancer and DM treatment regimens should be required.
Conflicts of interest The authors have no conflicts of interest.
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27. Yeh HC, Platz EA, Wang NY, Visvanathan K, Helzlsouer KJ, Brancati FL. A prospective study of the associations between treated diabetes and cancer outcomes. Diabetes Care 2012; 35(1): 113–118. 28. Liu X, Ji J, Sundquist K, Sundquist J, Hemminki K. The impact of type 2 diabetes mellitus on cancer-specific survival: a follow-up study in Sweden. Cancer 2012; 118(5): 1353–1361. 29. Shetti MB, Merrick GS, Butler WM, et al. The impact of diabetes mellitus on survival in men with clinically localized prostate cancer treated with permanent interstitial brachytherapy. Am J Clin Oncol 2012; 35(6): 572–579. 30. D’Amico AV, Braccioforte MH, Moran BJ, Chen MH. Causes of death in men with prevalent diabetes and newly diagnosed high- versus favorable-risk prostate cancer. Int J Radiat Oncol Biol Phys 2010; 77(5): 1329–1337. 31. van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR. Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 2007; 120(9): 1986–1992. 32. Merrick GS, Galbreath RW, Butler WM, et al. Primary Gleason pattern does not impact survival after permanent interstitial brachytherapy for Gleason score 7 prostate cancer. Cancer 2007; 110(2): 289–296. 33. Rastmanesh R, Hejazi J, Marotta F, Hara N. Type 2 diabetes: a protective factor for prostate cancer? An overview of proposed mechanisms. Clin Genitourin Canc 2014. 34. Venkateswaran V, Haddad AQ, Fleshner NE, et al. Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. J Natl Cancer Inst 2007; 99(23): 1793–1800. 35. Lubik AA, Gunter JH, Hendy SC, et al. Insulin increases de novo steroidogenesis in prostate cancer cells. Cancer Res 2011; 71(17): 5754–5764. 36. Ma J, Li H, Giovannucci E, et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol 2008; 9(11): 1039–1047. 37. Hsing AW, Chu LW, Stanczyk FZ. Androgen and prostate cancer: is the hypothesis dead? Cancer Epidemiol Biomarkers Prev 2008; 17(10): 2525–2530.
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Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
ARTICLE
Diabetes mellitus is associated with elevated risk of mortality amongst patients with prostate cancer: a meta-analysis of 11 cohort studies Hongzhou Cai† Zicheng Xu† Ting Xu† Bin Yu Qing Zou* Department of Urologic Surgery, Nanjing Medical University Affiliated Cancer Hospital of Jiangsu Province, Nanjing, China *Correspondence to: Qing Zou, Department of Urologic Surgery, Nanjing Medical University Affiliated Cancer Hospital of Jiangsu Province, 42 Baiziting Road, Nanjing 210009, China. E-mail: [email protected] †
H. Cai, Z. Xu and T. Xu contributed equally to this work.
Abstract Purpose Diabetes mellitus is associated with a decreased risk of prostate cancer. However, previous studies examining the associations between diabetes mellitus and prostate cancer prognosis have produced mixed results. Here, we aim to summarize the effect of diabetes mellitus on prostate cancer prognosis. Methods We searched the database of PubMed from inception through 31 March 2014 for articles evaluating the effect of diabetes on outcome in prostate cancer patients, and a meta-analysis was conducted. Results A total of 11 cohort studies were included in this meta-analysis, of which seven studies were carried out to investigate whether diabetes mellitus is associated with all-cause mortality amongst those with prostate cancer, seven studies to investigate whether diabetes mellitus is associated with prostate cancer-specific mortality and two studies to investigate the relationship of diabetes mellitus and nonprostate cancer mortality. The meta-analysis results suggested that diabetes mellitus could significantly affect the incidence of all-cause mortality amongst those with prostate cancer (hazard ratio = 1.50, 95% confidence interval = 1.25–1.79). Besides, diabetes mellitus was also associated with prostate cancer-specific mortality (hazard ratio = 1.26, 95% confidence interval = 1.20–1.33) and nonprostate cancer mortality (hazard ratio = 1.83, 95% confidence interval = 1.33–2.52) separately. There was no obvious publication bias amongst the studies included. Conclusion The results of this meta-analysis reveal an association of diabetes mellitus with adverse prognosis amongst those with prostate cancer. The biological basis of the association of diabetes mellitus with prostate cancer incidence and prognosis remains unclear. Doctors could pay more attention to prostate patients with pre-existing diabetes mellitus, and more aggressive treatment regimens should be considered. Copyright © 2014 John Wiley & Sons, Ltd. Keywords
prostate cancer; diabetes mellitus; mortality; meta-analysis
Introduction
Received: 26 April 2014 Revised: 13 July 2014 Accepted: 14 July 2014
Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes mellitus (DM) is one of the most common chronic diseases. An estimated 285 million people worldwide had DM in 2010, and the global prevalence of DM is rapidly increasing [1]. DM has been reported to be associated with increased risk of numerous human cancers including cancers of the endometrium [2], pancreas [3], colon [4], thyroid [5] and so on. However, an inverse relationship has been reported between DM and prostate cancer risk [6].
H. Cai et al.
Approximately 63% of prostate cancers will be diagnosed in men age 65 years or older [7,8]. A recent study showed that DM was associated with a 28% reduced risk of high-grade prostate cancer [9]. Several meta-analyses also demonstrated a decreased risk of incident prostate cancer amongst men with DM [10–12]. Xu et al. found that the protective effect of DM was observed in different prostate cancer grade or stage, which further extended the evidence of the inverse relationship. It is worth noting that whether this protective effect extends to prognosis amongst men who do get prostate cancer. A recent meta-analysis found that pre-existing DM was associated with worse overall, long-term mortality in cancer patients generally [13]. However, the effect of DM varied across different cancer types. It is of interest to evaluate prostate cancer separately. As expected, there is rapidly growing interest in the association between DM and the prognosis of prostate cancer. Since 2006, some studies have been conducted to investigate the relationship, but the findings have continued to be somewhat inconclusive. Park et al. [14] used the Korean cancer registry to investigate the effect of glucose tolerance on survival amongst patients with prostate cancer. They found that men with fasting serum glucose (FSG) 126 or greater had a nonsignificantly increased risk compared with men with FSG 110 or lower. Two other studies also found nonsignificant relationships between pre-existing DM and overall mortality in prostate cancer patients [15,16]. Smith et al. [17] found that prevalent DM significantly associated with greater all-cause mortality but not prostate cancer mortality. Batty et al. [18] also demonstrated that there was no evidence that DM predicted the risk of death from the malignancy. However, Bensimon et al. [19] suggested that DM is associated with an increased risk of prostate cancer mortality and all-cause mortality. In 2010, a systematic literature review was conducted to summarize the influence of pre-existing DM on prostate cancer prognosis [20]. However, data from only four studies could be included in a preliminary meta-analysis for overall mortality and produced a pooled hazard ratio (HR) of 1.57 [95% confidence interval (CI): 1.12–2.20]. And there was insufficient evidence to conduct a formal meta-analysis of prostate cancer-specific mortality. Herein, we conducted this meta-analysis including studies up to 2014 to better assess the effect of pre-existing DM on prostate cancer-specific mortality, overall mortality and nonprostate cancer mortality.
Materials and methods Literature search strategy We searched the PubMed database from inception to 31 March 2014 for articles evaluating the effect of DM on prognostic outcome in prostate cancer patients. Search terms included ‘DM’ or ‘diabetes’ combined with ‘prostate cancer’ or ‘prostate neoplasms’. Two reviewers (Cai and Copyright © 2014 John Wiley & Sons, Ltd.
Xu) independently evaluated the titles and abstracts of the papers identified. The references in the identified articles were also reviewed for possible inclusions. Our overall research was limited to English language, human studies. No additional unpublished study was revealed.
Study inclusion criteria Studies were included if they met the following criteria: (1) case–control studies or cohort studies; (2) studies evaluating prostate cancer population; (3) studies evaluating prognostic outcome by DM; (3) studies that reported all-cause mortality or overall survival, prostate cancer mortality or nonprostate cancer mortality; (4) studies that had a follow-up period of 3 months or longer; and (5) studies that reported HR or relative risk relating pre-existing DM to prostate cancer outcome and the corresponding 95% CI; we also included studies that failed to report 95% CI directly but from which we could reconstruct an estimate of 95% CI using p-values and HR or relative risk. When two or more studies had overlapping study samples, the most recent article based on largest study population was selected.
Data extraction Two investigators (Cai and Xu) independently extracted the relevant data from all the eligible studies. Disagreements were settled by consensus or a third review for adjudication. The following item, if available, were extracted form the studies include: first author’s name, year of publication, data source, follow-up time, age of the subjects, sample size, effect estimates with 95% CIs for the association of DM and prostate cancer and statistical adjustments for confounding factors. The 95% CIs were recorded or calculated.
Statistical analysis The meta-analysis was conducted on published results instead of original data form the included studies. We calculated a pooled HR estimate across all studies. The association of pre-existing DM and all-cause mortality, prostate cancer mortality and nonprostate cancer mortality were considered in separate analyses. Publication bias was evaluated using funnel plots, the Begg–Mazumdar adjusted rank correlation test [21] and the Egger regression asymmetry test [22]. The p < 0.05 was considered statistically significant. Statistical heterogeneity amongst the studies was assessed using Q-statistic [23]. Heterogeneity was considered as p < 0.05. Two techniques were used to estimate the summary HR estimates. When there was no heterogeneity amongst studies, the fixed-effects model (the Mantel–Haenszel method) was used to calculate the pooled HRs [24]. Otherwise, a random-effects model (the DerSimonian and Laird method) was selected [25]. Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
DM and Prognosis of Prostate Cancer
All analyses were conducted using the software State version 11.0 (State Corporation, College Station, TX, USA). All the p-values were two sided.
Results Literature search Our initial search identified 1342 potentially relevant studies, of which we screened the titles and abstracts. After carefully evaluating the papers identified and reviewing the references for possible inclusions, our meta-analysis yielded a total of 11 articles on DM and mortality risk of prostate cancer patients (Figure 1).
mortality amongst those with prostate cancer. As shown in Figure 2, the pooled HR for the association of DM and the incidence of all-cause mortality amongst those with prostate cancer was 1.50 (95% CI: 1.25–1.79). Seven studies [17–19,26–28,30] were eligible for examining the relationship between DM is and the incidence of prostate cancer mortality. As shown in Figure 3, the pooled HR for the association of DM and the incidence of prostate cancer mortality was 1.26 (95% CI: 1.20–1.33). Two studies [17,30] were eligible for examining the relationship between DM is and the incidence for nonprostate cancer mortality amongst those with prostate cancer. As shown in Figure 4, the pooled HR for the association of DM and the incidence of nonprostate cancer mortality was 1.83 (95% CI: 1.33–2.52).
Publication bias analyses Characteristics of studies Descriptive data for the studies we identified are summarized in Table 1. A total of 11 studies [14,17–19,26–32] were included, which were published between 2006 and 2014. Of the 11 studies, seven studies [14,17,19,27,29,31,32] were carried out to determine whether DM is associated with the incidence of all-cause mortality amongst those with prostate cancer, seven studies [17–19,26–28,30] to determine whether DM is associated with the incidence of prostate cancer-specific mortality and only twos studies [17,30] to determine the relationship of DM and nonprostate cancer mortality. The duration of follow-up ranged from 3 to 40 years. The results of all the 11 studies were adjusted for several potential confounders, including age, body mass index, race, smoking, alcohol consumption and so on.
Results of the association between DM and the prostate cancer prognosis Seven studies [14,17,19,27,29,31,32] were included in the meta-analysis of DM and the incidence of all-cause
Figure 1. Flowchart representing the study selection process Copyright © 2014 John Wiley & Sons, Ltd.
Results from the Begg’s test and Egger’s test revealed that there was no obvious publication bias amongst either the studies eligible for all-cause mortality meta-analysed (pBegg’s = 0.764, pEgger’s = 0.067) nor amongst the studies eligible for prostate cancer mortality meta-analysed (pBegg’s = 0.764, pEgger’s = 0.147).
Discussion Diabetes mellitus and prostate cancer are both prevalent diseases amongst old men. It is reported that DM is associated with a decreased risk of developing prostate cancer, raising the question of whether this protective effect extends to prognosis amongst men with prostate cancer [10–12]. However, previous studies that have examined associations between DM and prostate cancer prognosis have produced somewhat mixed results. Our present meta-analysis sums up the previous studies on the effect of DM on the prognosis of prostate cancer. The results indicated a 50% increase in the incidence of all-cause mortality amongst prostate cancer patients with DM. As DM is associated with worse mortality in general (aside from any cancer diagnosis), it is particularly important to investigate the effect of DM on prostate cancer mortality. As speculated, the association of DM and prostate cancer-specific mortality risk also reached a statistical significance. Besides, result from two studies showed that DM also could increase the incidence of nonprostate cancer mortality. Wonderingly, what might explain the different effects of DM on prostate cancer incidence and outcomes? The biological basis of the contrasting association of DM on prostate cancer incidence and prognosis remain unclear. Several mechanisms have been proposed, including changes in hormonal environment, with reduced levels of insulin and testosterone in DM patients, and genetic factors related to DM and Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
Copyright © 2014 John Wiley & Sons, Ltd.
Liu X
Shetti MB
Batty GD
D’Amico AV
Smith MR
Van de Poll-Franse LV Merrick GS 2007
28
29
18
30
17
31
32
Yeh HC
27
2008 Radiation Therapy Oncology Group Protocol 92-02 2007 The Eindhoven Cancer Registry, the Netherlands
2010 The Chicago Prostate Cancer Center
2011 London (UK)
2012 The CLUE II (Give Us a Clue to Cancer and Heart Disease) cohort in Washington County and Maryland 2012 The Swedish Hospital Discharge Register and the nationwide Swedish Cancer Registry 2012 American Joint Committee on Cancer
2012 Primary care practices in the UK
Currie CJ
Data source
26
Year
Bensimon L 2014 Four databases from UK: NCDR, CPRD, HES and ONS
Author
19
Reference
Follow-up time (years)
1995–2003
1997–2007 Until 1 July 2008 or the date of death, whichever came first 1992–1995 Median: 8.1 (0.04–12.9) 1995–2002 3–10
1967–1970 Maximum: 40
1995–2006 Mean: 7.8, median 7.6
1961–2008 Mean: 8
1990–2009 Median: 2.0 for non-DM, 1.6 for DM 1989–2006 Maximum: 17
1998–2009 Mean: 4.7
Study recruitment years
Table 1. Characteristics of 11 cohort studies included in the meta-analysis Confounders adjusted
66.1 ± 7.4
Median 70 (43–88) 72.6 vs 70.3
68.9
40–69
66.6 ± 6.1 vs 65.2 ± 7.5
68 vs 72
61.8 ± 11.2 vs 51.5 ± 13.7
71.7 ± 9.5 vs 67.5 ± 13.0 NG
NG
Age, square of age, BMI, smoking, education level, hypertension treatment and high cholesterol treatment
530
5 478
1 520
5 279
17 934
1 624
64
468
210
608
NG
199
466
5 010
1 310
4 671
NG
1 425
Age, smoking, percent positive biopsies and BMI
Age, race, Gleason score, tumour stage, PSA, treatment arm and weight Age, gender, stage, treatment and cardiovascular disease
Age, PSA, Gleason score, percent positive biopsies, BMI, prostate volume, clinical stage, XRT, ADT, ADT duration, perineal invasion, hypertension, hypercholesteremia, CAD and tobacco use BMI, plasma cholesterol, physical activity, socioeconomic status, blood glucose, marital status, FEV1, height, age at risk, smoking and diastolic and systolic blood pressure A history of MI, treatment received, age, year of brachytherapy and prostate cancer aggressiveness
15 6687 2 217 15 4470 Age at diagnosis, period, obesity, alcohol, smoking, socio-economic status and diagnosis region
NG
11 920 1 132 10 788 Age, year of cohort entry, ethnicity, excessive alcohol use, BMI, smoking status, CKD, MI, ischemic stroke, transient ischemic attack, peripheral artery disease, previous cancer, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, diuretics, other antihypertensive drugs, aspirin, other nonsteroidal anti-inflammatory drugs, statins, 5-alpha reductase inhibitors and the following prostate cancer-related variables: PSA levels, Gleason score, radical prostatectomy, radiation therapy, chemotherapy and androgen deprivation therapy 17 264 2 008 15 256 Age at baseline, sex, smoking history, Charlison comorbidity index and year of diagnosis
NonDM (n)
73.4 vs 71.3
DM (n)
Sample size (n)
Age (years), mean ± SD (range)
H. Cai et al.
Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
Copyright © 2014 John Wiley & Sons, Ltd.
NCDR, National Cancer Data Repository; CPRD, Clinical Practice Research Datalink; HES, Hospital Episode Statistics; ONS, Office for National Statistics; BMI, body mass index; CKD, chronic kidney disease; MI, myocardial infarction; PSA, prostate-specific antigen; ADT, androgen deprivation therapy; ANOVA, analysis of variance; CAD, coronary artery disease; XRT, supplemental external beam radiation therapy; FEV1, forced expiratory volume in one second; NG, not given.
Age, alcohol consumption, BMI, fasting serum glucose level, cholesterol level, physical activity, food preference, blood pressure and other comorbidities (heart disease, liver disease and cerebrovascular disease) NG NG 256 50.8 (all participants) 14
Park SM
Schiffler Cancer Center, Mean: 6.0, Wheeling, WV median 5.7 2006 The National Health Insurance 1996–2002 Median: 3.86 Corporation Study (NHICS) and Korean Central Cancer Registry
Year Author Reference
Table r2582-tbl-0001. (continued)
Data source
Study recruitment years
Follow-up time (years)
Age (years), mean ± SD (range)
Sample size (n)
DM (n)
NonDM (n)
Confounders adjusted
DM and Prognosis of Prostate Cancer
prostate cancer [33]. It is suspected that the incidence effect may be driven dominantly by the relatively low levels of male hormones in DM patients compared with non-DM, while the prognosis effect may be driven by the proposed stimulatory effects of hyperinsulinemia on prostate cancer behaviour [34–36]. High levels of male hormones in tissue can explain the increased risk for prostate cancer [37]. Notably, low testosterone levels are common in men with DM [38]. Evidence from several studies further demonstrated that a lower testosterone level is the main cause of the lower prostate cancer risk amongst patients with DM [39,40]. On the other hand, it is suggested that cancer patients with DM may have increased tumour cell proliferation and metastases in a physiologic environment of hyperinsulinemia and hyperglycaemia [41]. Insulin could stimulate the growth of prostate cells [42]. An in vitro study showed that insulin is capable of increasing growth of rat prostate cancer cells. Another study discovered that insulin levels are associated with recurrence of prostate cancer after treatment [43]. Evidence from the intensive care literature indicates that achieving glucose control leads to better clinical outcomes. A possible explanation of this phenomenon is that DM might have a protective role in the initiation phase but not in the progression phase of prostate cancer, which may be a reason leading to contrasting association of DM on prostate cancer incidence and prognosis. As both prostate cancer and DM are common conditions amongst older men, more research is certainly needed to investigate how DM affects prostate cancer prognosis. Furthermore, it is of interest to demonstrate whether men with DM should receive different treatments from men without DM. If so, more attention should be paid to what the appropriate treatments are and how to improve the prognosis of prostate cancer patients with DM.
Study limitations We aimed to conduct a rigorous meta-analysis to investigate the effect of DM on prostate cancer outcome. However, several limitations should be acknowledged. First, our search was restricted to studies published in indexed journals. No additional unpublished studies or original data were revealed. Second, we did not consider the associations between prostate cancer prognosis and type 1 DM or type 2 DM separately because there was limited data on this in the included studies. Third, the results of all the 11 studies included were adjusted for potential confounders. However, a part of the studies were not able to adjust for tumour stage, which is considered to be associated with the mortality outcomes. Fourth, DM durations are much inconsistent in different studies. We cannot investigate whether DM duration could affect prostate cancer outcome. Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
H. Cai et al.
Figure 2. Forest plot of cohort studies examining the association between diabetes mellitus and all-cause mortality
Figure 3. Forest plot of cohort studies examining the association between diabetes mellitus and prostate cancer mortality
Figure 4. Forest plot of cohort studies examining the association between diabetes mellitus and nonprostate cancer mortality Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes Metab Res Rev (2014) DOI: 10.1002/dmrr
DM and Prognosis of Prostate Cancer
Conclusion This meta-analysis strongly suggests that DM could inversely impact the prognosis of prostate cancer. Given the small number of studies included in this metaanalysis, especially studies focused on type 1 and type 2 DM separately, the present conclusion should be confirmed with additional experimental and prospective epidemiologic studies. If confirmed, doctors should pay
more attention to prostate patients with pre-existing DM, and more aggressive prostate cancer and DM treatment regimens should be required.
Conflicts of interest The authors have no conflicts of interest.
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