Vitamin D Deficiency May Be Linked With Aggressive Prostate Cancer

Vitamin D may be a biomarker of more aggressive prostate cancer, particularly in African American men. (Image: ©

Vitamin D may be a biomarker of more aggressive prostate cancer, particularly in African American men. (Image: ©

Vitamin D deficiency may increase the odds that some men who already are at high risk for prostate cancer will have an aggressive form of the disease, according to new research.

The study, published online today in Clinical Cancer Research, is the first to evaluate whether vitamin D deficiency might be associated with prostate cancer based on biopsy results from men who had abnormal findings on a prostate-specific antigen (PSA) test or digital rectal examination. Previous studies compared vitamin D levels only in men with or without prostate cancer.

Investigators enrolled 667 men aged 40 to 79 years who had their first prostate biopsy at 1 of 5 urology clinics in Chicago. About half were African American and the other half were European American. Their blood levels of 25-hydroxyvitamin D (25-OH D) were measured at enrollment to determine vitamin D deficiency.

European American men had higher 25-OH D levels (19.3 nanograms per milliliter [ng/mL] of blood) than African American men (16.7 ng/mL). Dark skin has more melanin, which blocks ultraviolent rays that trigger vitamin D production. The Institute of Medicine has concluded that a 25-OH D level below 12 ng/mL puts a person at risk for vitamin D deficiency and levels from 12 ng/mL to 20 ng/mL indicate insufficiency. But 20 ng/mL is considered adequate for most people.

Overall, 383 men in the study received a prostate cancer diagnosis. Among African American men, those with a 25-OH D level below 20 ng/mL were 2.4 times more likely to be diagnosed with prostate cancer than those with higher levels. African American men with 25-OH D levels below 12 mg/mL were nearly 5 times more likely to have aggressive prostate cancer and 4.2 times more likely to have a tumor stage T2b or higher, meaning that cancer is present in more than half of either the left or right side of the prostate.

Among European American men, 25-OH D levels weren’t related to overall prostate cancer risk. But those with levels below 12 ng/mL were 3.7 times more likely to have aggressive prostate cancer and 2.4 times more likely to have a tumor stage T2b or higher.

In both groups, low 25-OH D levels were linked with aggressive prostate cancer even after investigators accounted for diet, smoking habits, obesity, family medical history, and calcium intake.

“The stronger associations in African American men imply that vitamin D deficiency is a bigger contributor to prostate cancer in African American men compared with European American men,” lead author Adam Murphy, MD, said in a statement.

Murphy, an assistant professor of urology at Northwestern University’s Feinberg School of Medicine in Chicago, said vitamin D supplements may help prevent tumor progression in some men with prostate cancer. “It would be wise to be screened for vitamin D deficiency and treated,” he added.

Improved end-of-life care, limited use of imaging, and reduced drug costs could reduce the increasing costs of cancer care, according to 2 oncology experts. (Image: fluxfoto/

Improved end-of-life care, limited use of imaging, and reduced drug costs could reduce the increasing costs of cancer care, according to 2 oncology experts. (Image: fluxfoto/

Oncologists could cut the ever-increasing cost of cancer care by improving end-of-life care, limiting the use of expensive imaging, and using cancer drugs more cost-effectively, according to experts at the Johns Hopkins Medical Institutions in Baltimore, Maryland.

“We need to find the best ways to manage costs effectively while maintaining the same, if not better, quality of life among our patients,” Thomas Smith, MD, coauthor of the article released online today in The Lancet Oncology, said in a statement.

Smith and coauthor Ronan Kelly, MD, noted that the number of new cancer cases diagnosed annually is projected to increase to 21.4 million in 2030. In the United States the cost of care is expected to rise 39% by 2020, to $173 billion. But that cost isn’t driven only by the aging population and an increased demand for services. “In the [United States], 91% of the rise in costs was due to price increases,” they wrote.

The best opportunities for safe, ethical cost reductions are in caring for patients with metastatic cancer, not new surgical or radiation treatments, clinical trials, curative care, or pediatric care, according to Smith and Kelly, both oncologists at Hopkins’ Sidney Kimmel Comprehensive Cancer Center.

Their article notes that among Medicare’s cancer patients, 60% are hospitalized in the last year of their life, 30% die in a hospital, and only 54% ever use hospice care. However, “hospice and palliative care provide better overall care at a smaller cost than hospital care,” they wrote. “Hospice care also improves symptoms, reduces caregiver distress, and saves $2700 to $6500 per person as compared with care that does not actively involve a hospice.”

They cited a 2012 study indicating that of 608 deaths at a tertiary care center, 229 of the patients were eligible for hospice care at their second to last visit, but only 17 were informed about it. Additional studies show that hospice or palliative care may reduce costly hospital readmissions, they added.

The US cost of cancer imaging has increased by about 5% to 10% annually between 1996 and 2006 “without attendant changes in mortality from metastatic disease,” the authors wrote. They noted that the cure rate from salvage chemotherapy for lymphoma is the same regardless of whether a recurrence is diagnosed clinically or by a routine surveillance positron emission tomography scan.

The American Society of Clinical Oncology addressed appropriate imaging use in its Choosing Wisely recommendations. “Clinicians explaining the truth to patients about curability [and imaging] will allow most patients to choose wisely,” Smith and Kelly wrote.

The high cost of new drugs—sipuleucel-T, used to treat advanced prostate cancer, costs $93 000 per course of treatment and prolongs survival for a median 4.3 months—should motivate clinicians to clearly define “meaningful clinical benefit” when they make treatment decisions, the pair added. “There does seem to be some recent enthusiasm to establish thresholds,” they wrote.

Their article explains how several approaches, including accountable care organizations, competitive bidding for drug prices, and shared decision making with patients may reduce cancer care costs.

“The oncology community should do its part to limit itself to use of evidence-based treatments, standardize care with pathways, transition away from fee-for-service to alternative payment methods, and change communication with patients about reasonable end-of-life care,” Smith and Kelly wrote.

“We need political leadership working together with oncologists and patients to explicitly address the issue of what value is needed to justify expensive treatments.”

JAMA Forum: Pushback Against Covering Proton Beam Therapy

Austin Frakt, PhD

Austin Frakt, PhD

Because new and expensive treatments for medical conditions have substantial implications for cost, outcomes, and access, the extent to which insurers can and will resist covering such therapies is a perennially important question. Last month brought some interesting news on this front:

As hospitals race to offer the latest in high-tech care, a major health insurer, Blue Shield of California, is pushing back and refusing to pay for some of the more expensive and controversial cancer treatments….

… Blue Shield began notifying doctors statewide of its new policy for early-stage prostate cancer patients, effective in October. The San Francisco insurer says there’s no scientific evidence to justify spending $30 000 more for proton beam treatment compared with the price it pays for other forms of radiation that deliver similar results.

Blue Shield of California is not alone, according to a story in the Wall Street Journal (pay wall). Aetna has also stopped covering proton beam therapy for prostate cancer, and Cigna will review its policy for such coverage later this year, the story notes.

Indeed, recent studies have failed to find evidence of benefit from proton beam therapy relative to other, cheaper ways to treat prostate cancer. For instance, a retrospective study of more than 50 000 Medicare beneficiaries published early this year in the Journal of the National Cancer Institute found that 1 year after treatment with either proton beam or intensity-modulated radiation therapy (IMRT), there was no difference in the radiation toxicity experienced by patients. A study in JAMA last year by Sheets et al found that proton therapy was associated with more gastrointestinal morbidity than IMRT. However, IMRT costs slightly more than half the cost of proton beam therapy.

Not surprisingly, some dispute the allegation that proton beam therapy for prostate cancer provides no incremental benefit over other treatments for the condition. According to the Los Angeles Times, officials at Scripps Health in San Diego, which would be directly affected by Blue Shield’s new coverage policy, say that

the benefits of proton beam therapy are well established and that some of the research cited by critics is seriously flawed. Scripps says the limits imposed by insurers such as Blue Shield are troubling because they fail to recognize the long-term benefits from proton beam therapy and the savings that can be achieved over time.

Therefore, expect a vigorous fight over whether Blue Shield’s coverage policy should stand. Who will win, the insurer or those who offer proton beam therapy for treating prostate cancer?

The historical record provides some clues. In general, there is a strong bias in the United States in favor of covering new technology. This is among the reasons why technology is one of the leading drivers of health care spending growth. We pay for it—a lot.

One reason why new technologies are often covered is that insurers face a lot of pressure from clinicians, health care organizations, and patients when they try to limit coverage. Don Taylor, PhD, an associate professor of public policy at Duke University, reminds us of an attempt by Blue Cross Blue Shield of North Carolina to limit spinal fusion surgery. Facing resistance from the American Association of Neurological Surgeons and the North Carolina Spine Society, the coverage limitations were lifted in January 2011, just 6 weeks after Blue Cross Blue Shield tried to implement them.

Another reason new technologies are covered is that support for coverage is enshrined in law. Health economists Katherine Baicker, PhD, and Amitabh Chandra, PhD, wrote,

US corporate laws also make it difficult for individual insurers and hospitals to reduce the use of technologies with variable payments: insurers and hospitals are not permitted to interfere with the medical judgment of physicians. State laws also require insurers to pay for any service deemed medically necessary by a physician.

Health legal scholar Einer Elhauge, JD, concurs, writing in a Virginia Law Review article that “studies find, not just legally but in actual practice, that ‘hospitals must cater to physicians’ desire for new technology.’” But it’s not just hospitals that are pressured to do so; insurers are, too.

Take the story of bone marrow transplantation for breast cancer, as told by Gilbert Welch, MD, MPH, and Juliana Mogielnicki. Although the costly therapy was later found to be no better than alternatives, courts ruled in favor of plaintiffs who sued for damages when coverage was denied. One reason, among others, that courts rule against insurers who deny coverage for a new therapy or physicians who don’t provide it is that it is often possible to find evidence that the new and questionable technology is the accepted standard of care. If physicians provide it and if other insurers cover it, it’s harder to argue it’s reasonable not to.

And guess what? The biggest insurer of them all, Medicare, covers proton beam therapy for prostate cancer. As Katharine Cooper Wulff, MPH; Franklin Miller, PhD; and Steven Pearson, MD, MSc, wrote about vertebroplasty in Health Affairs,

Some private payers thought that if Medicare moved first to use the new evidence as the basis for different coverage policies, then private payers could follow. But without action from Medicare, many private payers believed that they lacked the legitimacy to lead in adjusting coverage; “their hands were tied,” as one put it.

Perhaps Blue Shield’s proton beam coverage policy will stand, but its action is an unusual one. As Pearson commented, it is uncommon for an insurer to stop covering a procedure without overwhelming evidence of harm. Instead, Blue Shield is resisting proton beam coverage largely because of its price. Noble or not, given the historical record and Medicare’s stance, do not be surprised if it succumbs to pressure and reverses course.


About the author: Austin B. Frakt, PhD, is a health economist and an associate professor at Boston University’s School of Medicine and School of Public Health. He blogs about health economics and policy at The Incidental Economist and tweets at @afrakt. The views expressed in this post are that of the author and do not necessarily reflect the position of Boston University. 

About The JAMA Forum: JAMA has assembled a team of leading scholars, including health economists, health policy experts, and legal scholars, to provide expert commentary and insight into news that involves the intersection of health policy and politics, economics, and the law. Each JAMA Forum entry expresses the opinions of the author but does not necessarily reflect the views or opinions of JAMA, the editorial staff, or the American Medical Association. More information is available here and here.

Author Insights: Men Who Are Unlikely to Die of Prostate Cancer Undergoing Aggressive Treatment

Brent K. Hollenbeck, MD, MS, of the University of Michigan, Ann Arbor, and colleagues found that advanced treatments for prostate cancer are becoming more common among men who are not likely to experience a life-extending benefit. Image: University of Michigan Health System

Brent K. Hollenbeck, MD, MS, of the University of Michigan, Ann Arbor, and colleagues found that advanced treatments for prostate cancer are becoming more common among men who are not likely to experience a life-extending benefit. Image: University of Michigan Health System

Expensive, advanced treatments for prostate cancer are increasingly being used on men who are unlikely to die of the disease, despite growing recognition that these men are unlikely to benefit from such procedures and may suffer harm, according to a study published in JAMA today.

Evidence that most prostate cancers grow so slowly that many men with such tumors will die of other causes has led to support for more conservative approaches to managing the disease, such as watchful waiting. Many guidelines now recommend against treating men who have low-risk cancers or who have a life expectancy of less than 10 more years by virtue of their age or other health conditions.

But an analysis of Medicare data for more than 55 000 men aged 66 years or older diagnosed with prostate cancer between 2004 and 2009 found that the use of newer advanced treatment technologies increased from 32% to 44% for men with prostate tumors that are classified as low risk; use of such treatments increased from 36% to 57% among men who were at high risk of death from a cause other than prostate cancer. Intensity-modulated radiotherapy accounted for most of the advanced treatments in the study, but rates of robotic prostatectomy also increased.

Brent K. Hollenbeck, MD, MS, associate professor of urology and director of the Dow Division of Health Services Research at the University of Michigan, Ann Arbor, discussed the findings with news@JAMA.

news@JAMA: Why did you decide specifically to look at men with low-risk cancers or a high likelihood of dying from something else?

Dr Hollenbeck: There is increasing recognition that some prostate cancers are really indolent and may not have an effect on life expectancy and that for some men, observation may be a better option.

news@JAMA: You found that it appeared that these new technologies are replacing standard prostate cancer treatments. Is there a good rationale for this shift?

Dr Hollenbeck: These technologies were introduced in the early part of the last decade. In health care, a lot of technology is introduced in the absence of a large amount of information about its effectiveness. Robotic prostatectomy was adopted as less invasive, which was appealing to patients, and because it offered more magnification for physicians and less bleeding. The intensity-modulated radiotherapy approach allowed higher doses of radiation. Theoretically, there are advantages to each for physicians and patients.

news@JAMA: Have data supported the potential benefits of these advanced therapies?

Dr Hollenbeck: There haven’t been randomized studies to verify the benefits of either therapy. Most physicians would say that they can do a better job surgically with robotic procedures and that higher-dose radiation is more likely to kill the tumor. But the data so far have been mixed.

news@JAMA: Your finding seems to suggest that observation is not gaining steam, despite evidence and recommendations in favor of this approach. Why?

Dr Hollenbeck: I don’t think our study can answer that. The answer lies at the intersection of patient preferences for treatment and physician advice. It would be valuable to gain insight on patient preferences regarding treatment vs observation.

news@JAMA: What should clinicians know about your findings?

Dr Hollenbeck: They should know that treatment among patients at low risk of dying using advance technology has grown despite our recognition of the indolent nature of many prostate cancers. If you have a patient at high risk of dying of another disease or at low risk of dying from prostate cancer because of the biological features of the tumor, it’s important to have a good discussion with the patient about what the benefits of treatment are.

news@JAMA: What about patients?

Dr Hollenbeck: If you have low-risk prostate cancer or a lot of other medical problems, you need to have a clear understanding of what the benefits of treatment are. There are potential adverse effects with all treatments for prostate cancer that can affect quality of life, including sexual, urinary, and bowel function.

Age, General Health of Men Diagnosed With Localized Prostate Cancer May Determine Treatment Strategies

Knowing a man’s risks of dying of localized prostate cancer and his risk of dying of other coexisting health problems can help inform decisions about whether to aggressively treat the cancer. (Image: murat sarica/

Knowing a man’s risks of dying of localized prostate cancer and his risk of dying of other coexisting health problems can help inform decisions about whether to aggressively treat the cancer. (Image: murat sarica/

For men newly diagnosed with localized prostate cancer, estimated life expectancy is a key factor in choosing from treatment options that range from surgery and radiation to watchful waiting. For men with low- or intermediate-risk prostate cancer (based on tumor characteristics) whose life expectancy is less than 10 years, guidelines recommend against aggressive therapy because such treatment is unlikely to further extend their lives but it does have significant risk of treatment-associated effects such as erectile dysfunction, urinary incontinence, and bowel problems.

The problem with this strategy is that estimating life expectancy is not an exact science. However, research findings appearing today in the Annals of Internal Medicine offer new tools for improving such estimates.

Researchers followed up 3183 men in the United States with localized prostate cancer at diagnosis for 14 years. They also asked the men if they had any of 12 major health conditions in addition to prostate cancer: diabetes, bleeding gastrointestinal ulcer, chronic lung disease, congestive heart failure, stroke, heart attack, angina, cirrhosis or liver disease, arthritis, inflammatory bowel disease, hypertension, or depression.

The researchers found that older men with low- or intermediate-risk prostate cancer who also have multiple major coexisting conditions are at high risk for dying from a cause other than prostate cancer within 10 years. Risk of death resulting from a condition other than prostate cancer within 10 years was 40% among men aged 61 to 74 years who had 3 or more additional health problems and 70% among similar men aged 75 years or older; the 14-year risk of dying of prostate cancer in these 2 groups was 3% and 7%, respectively. The risk of death from high-risk prostate cancer was 18% over 14 years and did not vary by the number of coexisting conditions.

The findings suggest that knowing a patient’s risks of dying of prostate cancer and of other coexisting conditions can help inform decisions about whether to aggressively treat localized prostate cancer. The authors said their findings should not be applied to decisions on whether to screen for prostate cancer. The US Preventive Services Task Force does not recommend screening for prostate cancer in the general asymptomatic population.

Before Prostate Cancer Screening, Men Should Know Harm Is More Likely Than Benefit

Men should know that they are more likely to be harmed than to benefit from prostate cancer screening and should only be screened if they have a strong preference for screening, a new guideline states. Image: scibak/

Men should know that they are more likely to be harmed than to benefit from prostate cancer screening and should only be screened if they have a strong preference for screening, a new guideline states. Image: scibak/

Men should be fully informed that they’re unlikely to benefit from prostate cancer screening and may face a substantial risk of various harms, such as complications from biopsy or treatment that may include infection, incontinence, or impotency, according to a new guideline from the American College of Physicians (ACP) published today in the Annals of Internal Medicine.

One in 6 men will be diagnosed as having prostate cancer in his lifetime, but only 3 of 100 men who are diagnosed as having the disease will die of it, according to the guideline. In other words, 97 of 100 men with prostate cancer will die of some other cause. In addition, most men who die of prostate cancer are older than 75 years. Yet despite the low risk of death from prostate cancer, especially among younger men, screening—using either the prostate-specific antigen (PSA) tests or a digital rectal examination—continues to be commonplace.

Thus, the likelihood of a man benefiting from prostate cancer screening is quite limited; about 1000 men would have to be screened to save 1 life, the guideline notes. Harm resulting from testing, however, is far more common. The false-positive rate for these tests is high and men who receive a positive result may undergo further invasive tests, such as a prostate biopsy, which can lead to infection, bleeding, or hospitalization. In addition, men who are diagnosed as having prostate cancer are likely to undergo radiation or surgery. Prostate cancer surgery is associated with a small increased risk of death, a 37% increased risk of sexual dysfunction, and an 11% increased risk of urinary incontinence.

Based on these risks and the fact that few men are likely to benefit, the US Preventive Services Task Force has recommended against prostate cancer screening with the PSA test. Other guidelines reviewed by the ACP as part of their own guideline-producing process recommend that physicians talk with patients about the risks and the patient’s preferences.

The ACP recommends that physicians fully inform patients aged 50 to 69 years that they are unlikely to benefit and face a substantial risk of harm from prostate cancer screening. The group also says that screening with the PSA test should be carried out only after such disclosure has occurred and the patient has expressed a clear preference for screening.

The authors conclude that “each man should have the opportunity to decide for himself whether to have the PSA screening test.”

Moreover, the ACP advises against prostate cancer screening with a PSA test for men younger than 50 years, older than 69 years, or with a remaining life expectancy of less than 10 to 15 years.

Whatever Health Risks May Be Associated With Workplace Stress, Increased Risk for Cancer Appears Unlikely, Study Says

New research could find no association between workplace stress and increased risk for cancer. (Image: Otmar Winterleitner/

New research could find no association between workplace stress and increased risk for cancer. (Image: Otmar Winterleitner/

People worried about the effects of workplace stress on their health can probably relax on one count: research appearing today in BMJ suggests that work-related stress is unlikely to be an important risk factor for cancer.

About 90% of cancers have been linked to nongenetic factors—environmental exposures and lifestyle choices such as smoking—but the evidence that psychosocial factors such as stress might increase cancer risk is tentative. In theory, stress could play a role in increasing cancer risk through its association with the physiological stress response, which is characterized by increased secretion of hypothalamic and pituitary stress hormones. These hormones can trigger and maintain chronic inflammation, which has been shown to play various roles in cancer promotion and progression. Continue reading