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decision of whether or not to undergo definitive treatment for his prostate cancer resembles that of a man who discovers a ‘bomb’ ticking beneath his bed. Of six such bombs, only one will explode; the rest are decoys. The dilemma is he cannot distinguish the live bomb from the duds.”
Gary G Schwartz Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, USA n Tel.: +1 336 716 7446 n Fax:+1 336 716 5687 n
[email protected]
‘The great imposter’
Syphilis is known as ‘the great pretender’, because the symptoms of this condition mimic the symptoms of many other diseases. Prostate cancer could justly be called ‘the great imposter’, because the microscopic appearance of prostate cancers that are clinically insignificant mimics those of prostate cancers that are potentially lifethreatening. In the post-prostate-specific antigen (PSA) era, only a minority of the 187,000 prostate cancers that are newly diagnosed annually in the USA are potentially fatal. Unfortunately, there is no way to reliably distinguish the potentially fatal cancers from the fakes [1] . This imposture causes many men to receive treatment that is both unnecessary and harmful [2,3] . Data from the US Surveillance Epidemiology and End Results (SEER) Program indicate that the case-fatality rate from prostate cancer – that is to say, the proportion of men who die from prostate cancer following a diagnosis of prostate cancer – is 17.5%, or approximately one in six. Thus, if six men receive a diagnosis of prostate cancer today and none are treated, only one would eventually die of his cancer (the others would die of unrelated causes, principally cardiovascular disease [4]). Conversely, if all six received definitive treatment (radical prostatectomy or external beam radiation therapy), five would be treated unnecessarily, and at considerable cost. The costs are not merely economic; they include incalculable costs to quality of life, as definitive treatment causes impotence in most men, urinary and bowel incontinence (at least temporarily) of a small percentage, and death in approximately 1% of men who are treated by surgery [5] . The conundrum facing a man wrestling with the decision of whether or not to undergo definitive treatment for his prostate cancer resembles 10.2217/FON.09.37 © 2009 Future Medicine Ltd
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“The conundrum facing a man wrestling with the
Future Oncology
Is serum calcium a biomarker of fatal prostate cancer?
that of a man who discovers a ‘bomb’ ticking beneath his bed. Of six such bombs, only one will explode; the rest are decoys. The dilemma is he cannot distinguish the live bomb from the duds. Should he ignore the ticking, but risk losing his entire house, or should he deactivate the bomb, knowing that the procedure will likely destroy the bedroom and may wreck the bathroom? It is in the context of this dilemma that our recent findings on serum calcium may be especially informative. Total & ionized serum calcium predict fatal prostate cancer
We examined differences in the characteristics of men who subsequently developed fatal prostate cancer and men who did not using two of the National Health and Nutrition Examination Surveys (NHANES), large public health surveys that collected health information on representative samples of the US population. Because the vitamin D–endocrine system is increasingly implicated in prostate cancer, we focused our attention on serum calcium levels at the baseline exam [6] . We then followed these men over time for their experience of prostate cancer. In the first NHANES and in the NHANES Epidemiologic Follow-up Study, 85 incident cases of prostate cancer and 25 prostate cancer deaths occurred over 46,188 person-years of follow-up. Serum calcium was measured an average of 9.9 years prior to the diagnosis of prostate cancer. When we compared men in the top tertile to men in the bottom tertile of total serum calcium, the multivariable-adjusted relative hazard for fatal prostate cancers was 2.68 (95% CI: 1.02–6.99; p = 0.04). For incident prostate cancer, the relative risk for the same comparison was not significantly elevated, at 1.31 (95% CI: 0.77–2.20). These results suggest Future Oncol. (2009) 5(5), 577–580
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that high serum calcium or a factor strongly associated with it (e.g., high serum parathyroid hormone) increases the risk for fatal prostate cancer. Our finding of a greater than 2.5-fold increased risk for men in the highest tertile of serum calcium is comparable in magnitude to the risk associated with family history [7] .
“Increases in extracellular serum calcium cause a decrease in apoptosis and an increase in proliferation and migration of metastatic prostate cancer cells. Thus, high levels of calcium in serum may promote the growth of potentially fatal cancers.”
In order to confirm the association between high serum calcium and fatal prostate cancer, we examined prostate cancer mortality in NHANES III. A unique feature of NHANES III is that it included measurements of ionized serum calcium, the biologically active fraction of total serum calcium. A total of 25 prostate cancer deaths occurred over 56,625 person-years of follow-up. Serum calcium was measured an average of 5.3 years prior to death from prostate cancer. Compared with men in the lowest tertile of total serum calcium, the multivariate-adjusted relative risk for death from prostate cancer for men in the highest tertile was 2.07 (95% CI: 1.06–4.04). For ionized serum calcium, men in the highest tertile had a relative risk of 3.18 (95% CI: 1.09–9.28). These results confirm the prospective association between serum calcium and prostate cancer mortality, and support the hypothesis that serum calcium is a prospective biomarker of fatal prostate cancer [8] . As these are observational studies, it is important to consider possible noncausal explanations for these associations. These studies were prospective and men with prevalent cancer were excluded. Although it is possible that some men may have had occult, pre-existing prostate cancer, this is an unlikely explanation for the findings, because advanced prostate cancer is associated with hypocalcemia (i.e., the reverse of our findings) caused by the diversion of calcium from serum into bony metastases [12] . In fact, when we controlled for this possibility by removing men in NHANES III who developed cancer in the first 3 years after the baseline exam, the relative hazard for men in the highest tertile of ionized serum calcium was 4.65 (95% CI: 1.40–15.49). 578
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If these associations are valid, what is the underlying biology? There are several compelling possibilities. Prostate cancer cells express the calciumsensing receptor, a G-protein-coupled receptor that is activated by extracellular calcium [9] . Prostate cancer cells also express calcium-dependent potassium channels that regulate prostate cancer cell proliferation via the control of calcium entry into the cells [10] . Increases in extracellular serum calcium cause a decrease in apoptosis and an increase in proliferation and migration of metastatic prostate cancer cells. Thus, high levels of calcium in serum may promote the growth of potentially fatal cancers [11] . How can these findings be used?
These findings have applications for both theory and practice. Their use for theory is that they can help explain some puzzling findings in nutritional epidemiology. Many epidemiologic studies have found increases in risk for advanced or fatal prostate cancer associated with diets high in calcium [13,14] . These findings have been difficult to understand, in part because the increased risk was generally seen at high levels of calcium intake, but not at more moderate levels, and because a mechanism for this effect was not clear. These findings may now be more understandable. Because calcium levels in serum are under tight homeostatic control, calcium levels in the diet over a large range of calcium intakes are not correlated with calcium levels in serum [15] . However, diets that are very high in calcium, such as those associated with the use of calcium supplements, can override normal homeostatic controls and cause elevations in calcium levels in blood [16] . As levels of calcium in serum are remarkably constant within a given individual, but vary considerably between individuals, serum calcium levels can function like a genetic marker [17] . If we know nothing else regarding an individual case, the risk that a man with an incident prostate cancer has a cancer that is potentially lethal is one in six. However, data on levels of serum calcium can refine these odds. Compared with a man in the middle tertile of ionized serum calcium, the risk for a man whose ionized serum calcium is in the upper tertile is 50% greater – that is to say, it is one in four. Similarly, for a man in the lowest tertile of ionized calcium, the risk is almost 50% lower than one in six, that is to say, one in 11. Such information could provide practical guidance to men regarding whether or not to undergo therapy. For example, many men might be future science group
Is serum calcium a biomarker of fatal prostate cancer?
inclined to defer therapy if they learned that the risk that their cancer was potentially fatal was approximately 9%. Serum calcium levels might also have utility in the setting of prostate cancer screening. Recent findings from a large randomized trial showed that men who are screened for prostate cancer using PSA are not less likely to die of prostate cancer [18] . These findings cast doubt on the desirability of using PSA for population-based screening. The finding that men with serum calcium in the upper tertile are significantly more likely to die of prostate cancer suggests that these men might benefit from PSA screening. Men in the lowest risk group might opt to delay or forego screening, potentially sparing themselves the consequences of overdiagnosis and unnecessary treatment.
“Why do some bombs explode and others do not? We speculate that a bomb’s explosive potential depends upon characteristics of the explosive per se (the tumor), and on characteristics of the fuse (the microenvironment that transmits energy into it).”
Finally, if levels of calcium in serum predict fatal prostate cancer, then interventional trials that lower serum calcium in men with prostate cancer would be indicated [19] . It is intriguing in Bibliography 1.
Agrawal S, Dunsmuir WD: Molecular markers in prostate cancer. Part I: predicting lethality. Asian J. Androl. 11, 14–21 (2009).
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Schwartz GG: Vitamin D and the epidemiology of prostate cancer. Sem. Dialysis 18, 276–289 (2005).
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this regard that a recent clinical series of men with advanced prostate cancer found a significantly shorter survival for men with hypercalcemia [20] . In conclusion, much remains to be learned regarding the role of serum calcium and its apparent ability to predict mortality from prostate cancer. Returning to our explosive metaphor: why do some bombs explode and others do not? We speculate that a bomb’s explosive potential depends upon characteristics of the explosive per se (the tumor), and on characteristics of the fuse (the microenvironment that transmits energy into it). Bombs with ‘fast’ fuses are more likely to detonate than are bombs with ‘slow’ fuses. We hypothesize that the effects of high levels of calcium in the serum microenvironment are to create a faster fuse. This hypothesis suggests numerous testable predictions for prostate cancer prevention and control. Financial & competing interests disclosure
Dr Gary Schwartz has no industry affiliations relevant to this editorial. He is an inventor on a pending patent concerning calcium and risk prediction in prostate cancer that is assigned to Wake Forest University. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Skinner HG, Schwartz GG: Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey. Cancer Epidemiol. Biomarkers Prev. 17, 2302–2305 (2008).
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Skinner HG, Schwartz GG: A prospective study of total and ionized serum calcium and fatal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 18, 575–578 (2009).
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Lin KI, Chattopadhyay N, Bai M et al.: Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor. Biochem. Biophys. Res. Commun. 249, 325–331 (1998).
10. Lallet-Daher H, Roudbaraki M, Bavencoffee A
et al.: Intermediate-conductance Ca 2+ -activated K+ channels (IKca1) regulate human prostate cancer cell proliferation through a close control of calcium entry. Oncogene 28(15), 1792–1806 (2009). 11. Liao J, Schneider A, Datta NS, McKauley LK:
Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res. 77, 9065–9073 (2006).
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12. Schwartz GG: Prostate cancer, serum
parathyroid hormone and the progression of skeletal metastases. Cancer Epidemiol. Biomarkers Prev. 17, 478–483 (2008). 13. Tseng M, Breslow R A, Graubard BJ,
Ziegler RG: Dairy, calcium, and vitamin D intakes and prostate cancer risk in the National Health and Nutrition Examination Expidemiologic Follow-up Study cohort. Am. J. Clin. Nutr. 81, 1147–1154 (2005). 14. Gao X, LaValley MP, Tucker KL:
Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J. Natl Cancer Inst. 97, 1768–1777 (2005). 15. Jorde R, Sundsfjord J, Bønaa KH:
Determinants of serum calcium in men and women. The Tromsø Study. Eur. J. Epidemiol. 17, 117–1123 (2001). 16. Muldowney WP, Mazbar SA: Rolaids-yogurt
syndrome: a 1990s version of milk-alkali syndrome. Am. J. Kidney Dis. 27, 270–272 (1996).
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17. Ladenson JH, Bowers GN Jr: Free calcium in
serum. II. Rigor of homeostatic control, correlations with total serum calcium, and review of data on patients with disturbed calcium metabolism. Clin. Chem. 19, 575–582 (1973). 18. Andriole GL, Grubb RL 3rd, Buys SS et al.:
Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319 (2009).
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trials in prostate cancer: From theory to therapy. Ann. Epidemiol. 19, 96–102 (2009). 20. Tucci M, Mosca A, Lamanna G et al.:
Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease. Prostate Cancer Prostatic Dis. 12, 94–99 (2009).
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Affiliation n
Gary G Schwartz, PhD, MPH, PhD Associate Professor of Cancer Biology and Epidemiology & Prevention, Wake Forest University Health Sciences, Comprehensive Cancer Center, Medical Center Blvd, Winston-Salem, NC 27157, USA Tel.: +1 336 716 7446 Fax: +1 336 716 5687
[email protected]
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