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Prostate cancer is the second-most-common cancer in men, with one in seven men diagnosed within their lifetimes.[1] In 2014, an estimated 233,000 men will be diagnosed, and over 29,000 will die from the disease, according to the American Cancer Society.[2]
Despite these sobering statistics, 80 percent of all cases of prostate cancer are diagnosed early, while the tumor is still “localized” to the prostate and has not spread to other parts of the body.[3] The recent proliferation of...
Prostate cancer is the second-most-common cancer in men, with one in seven men diagnosed within their lifetimes.[1] In 2014, an estimated 233,000 men will be diagnosed, and over 29,000 will die from the disease, according to the American Cancer Society.[2]
Despite these sobering statistics, 80 percent of all cases of prostate cancer are diagnosed early, while the tumor is still “localized” to the prostate and has not spread to other parts of the body.[3] The recent proliferation of early diagnoses — most cases diagnosed early never go on to kill or harm the patient — has presented physicians with a dilemma regarding what treatments, if any, to recommend in such cases.
A study published in July in the Journal of the American Medical Association (JAMA) Internal Medicine concluded that one widely used treatment, androgen deprivation therapy (ADT), does not seem to prolong the life of most men diagnosed with localized prostate cancer.[4] At least two other large studies also have demonstrated ADT’s lack of benefit in these patients.[5],[6]
Given the serious and often irreversible side effects of the therapy, its apparent lack of benefit in most patients has prompted concern among physicians treating otherwise healthy men with newly diagnosed localized prostate cancer.[7]
An ineffective treatment
ADT dramatically decreases the amount or activity of sex hormones known as androgens, primarily testosterone, in a patient. In the case of prostate cancer, this is accomplished by either removing the testicles or administering hormones that block the production or action of androgens in the body[8] (see table below, for a list of commonly used ADT drugs). When ADT is given without either radiation therapy or surgery, it is known as primary ADT.
The JAMA Internal Medicine study investigated whether primary ADT treatment improves survival in men with early-stage prostate cancer. To answer this question, the researchers collected data on over 66,000 Medicare enrollees age 66 and older who had been diagnosed with early-stage (stage 1 or 2) prostate cancer between 1992 and 2009.[9] The authors compared outcomes in men living in areas of the U.S. where ADT treatment was most frequently administered to treat prostate cancer patients (high-use areas) to those living in areas where such treatment was least frequently used (low-use areas).[10]
Evaluating the subjects up to 15 years after initial diagnosis, the study found that primary ADT did not lower overall death rates or deaths due to prostate cancer. This lack of benefit was apparent even in patients with “poorly differentiated” cancer, generally thought to be the most aggressive subtype.
The JAMA Internal Medicine study mostly confirmed the findings of a similarly designed 2008 analysis — conducted by several of the same researchers — that followed patients for shorter time periods.[11] For those with “moderately differentiated” prostate cancer, which is generally thought to be less aggressive, the results demonstrated no benefit of primary ADT on overall or prostate-cancer-specific death rates at five or 10 years after diagnosis.[12] However, unlike in the 2014 study, a modest but statistically significant benefit of primary ADT in reducing deaths related to prostate cancer was evident at five and 10 years after diagnosis for patients who had poorly differentiated prostate cancer.
A randomized, controlled clinical trial, the “gold standard” method for determining the benefits and harms of specific therapies, arrived at largely similar conclusions to these two studies. In the European Organisation for Research and Treatment of Cancer (EORTC) trial, published in 2013 in the journal European Urology, 985 subjects with newly diagnosed, localized prostate cancer were randomly assigned to receive primary ADT immediately or to receive no treatment unless their cancer caused serious symptoms or complications, such as spreading beyond the prostate (“deferred ADT”).[13] Subjects were followed for an average of 13 years. Those in the group immediately receiving primary ADT received an average of approximately seven years of treatment, compared with about two years for those in the deferred-ADT group.[14]
Neither deaths due to prostate cancer nor deaths from other causes were significantly different between the two groups by the end of the study. While subjects given deferred ADT had a significant, 21 percent higher overall death rate than the immediate therapy group, most of this difference was due to deaths that appeared unrelated to prostate cancer. However, the trial did reveal a spike in prostate cancer deaths in the deferred-ADT group from the third through the fifth year after initial diagnosis, indicating that subjects with more aggressive disease at the time of diagnosis may have benefited from receiving primary ADT immediately.[15]
Treatments Used In Androgen Deprivation Therapy for Prostate Cancer[16]*
| Treatments that lower androgen levels | Brand Name |
|---|---|
| Surgical castration (removal of testicles) | |
| goserelin* | ZOLADEX |
| abiraterone | ZYTIGA |
| degarelix | FIRMAGON |
| histrelin | SUPPRELIN LA; VANTAS |
| leuprolide | ELIGARD; LUPRON DEPOT; VIADUR |
| triptorelin | TRELSTAR |
| Treatments that block androgen activity | Brand Name |
| flutamide* | Only available as generic |
| bicalutamide | CASODEX |
| enzalutamide | XTANDI |
| nilutamide | NILANDRON |
*Only flutamide and goserelin are FDA-approved for use in localized prostate cancer. The other medications are approved only for more advanced prostate cancer.[17]
Harms of ADT
ADT is an irreversible treatment when done through surgical castration, and however it is administered, it involves profound changes to patients’ bodies and emotional well-being.[18] Early results of the EORTC trial revealed that hot flashes, enlarged breasts, headache and skin reactions were all significantly more common in subjects receiving immediate ADT than in those on deferred treatment.[19]
The authors of the 2014 JAMA Internal Medicine study identified osteoporosis and increased fracture risk, decreased libido and muscle tone, weight gain, and diabetes as additional adverse effects of ADT.[20]
Making sense of the studies
An editorial in the same issue of JAMA Internal Medicine that featured the 2014 study concluded that the evidence to date does not justify prescribing primary ADT for men with localized prostate cancer.[21] The evidence overwhelmingly demonstrates that primary ADT provides only harm and no survival benefit for most men with localized prostate cancer.
A notable exception may be found in men with more aggressive forms of localized cancer, in whom primary ADT might improve short-term survival. Signs of more aggressive disease include poorly differentiated subtypes, high prostate-specific antigen (PSA) levels at diagnosis and rapidly increasing PSA levels in the first two years following diagnosis. (PSA is a common blood test used to screen for and monitor prostate cancer.)[22],[23] The studies seem to indicate, however, that the potential benefit of primary ADT in patients with aggressive disease may be limited to the first few years following diagnosis, with death rates unaffected thereafter.
The JAMA Internal Medicine editorial pointed out that, despite the lack of evidence of any benefit of primary ADT in most men with localized prostate cancer, physicians and patients are opting for the therapy at alarming rates.[24] Approximately 29 percent of all men diagnosed with less aggressive (“well” or moderately differentiated) types of localized prostate cancer received primary ADT in the 2014 study.[25] The editorial’s authors estimated the annual cost of inappropriate ADT at $42 million for Medicare alone.[26]
What You Can Do
If you are diagnosed with localized prostate cancer, talk with your doctor about the studies discussed in this article and whether immediate ADT, more invasive surgery or radiation therapy, or watchful waiting with careful monitoring is the best option. Many factors must be weighed when deciding on an appropriate treatment plan — especially one such as ADT, which may be irreversible.
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Mass Screening for Prostate Cancer No Longer Recommended |
References
[1] American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Accessed August 4, 2014.
[2] Ibid.
[3] American Cancer Society. Survival rates for prostate cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates. Accessed August 4, 2014.
[4] Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.3028. [Epub ahead of print]
[5] Lu-Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA. July 9, 2008;300(2):173-81.
[6] Potosky AL, Haque R, Cassidy-Bushrow AE, et al. Effectiveness of primary androgen-deprivation therapy for clinically localized prostate cancer. J Clin Oncol. May 1, 2014;32(13):1324-30.
[7] Trinh QD, Schrag D. Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the Medicare population: Adequate data are neither the same as nor the enemy of perfect data. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.1107. [Epub ahead of print]
[8] Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.3028. [Epub ahead of print]
[9] Ibid.
[10] Ibid.
[11] Lu-Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA. July 9, 2008;300(2):173-81.
[12] Ibid.
[13] Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: Final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol. July 24, 2013. pii: S0302-2838(13)00739-2. doi: 10.1016/j.eururo.2013.07.024. [Epub ahead of print]
[14] Ibid.
[15] Ibid.
[16] American Cancer Society. Hormone (androgen deprivation) therapy for prostate cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy. Accessed August 18, 2014.
[17] FDA-approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 21, 2014.
[18] Cary KC, Singla N, Cowan JE, et al. Impact of androgen deprivation therapy on mental and emotional well-being in men with prostate cancer: analysis from the CaPSURE™ registry. J Urol. April 2014;191(4):964-70.
[19] Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol. April 20, 2006;24(12):1868-76.
[20] Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.3028. [Epub ahead of print]
[21] Trinh QD, Schrag D. Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the Medicare population: Adequate data are neither the same as nor the enemy of perfect data. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.1107. [Epub ahead of print]
[22] Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.3028. [Epub ahead of print]
[23] Studer UE, Whelan P, Wimpissinger F, et al. Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: Final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol. July 24, 2013. pii: S0302-2838(13)00739-2. doi: 10.1016/j.eururo.2013.07.024. [Epub ahead of print]
[24] Trinh QD, Schrag D. Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the Medicare population: Adequate data are neither the same as nor the enemy of perfect data. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.1107. [Epub ahead of print]
[25] Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.3028. [Epub ahead of print]
[26] Trinh QD, Schrag D. Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the Medicare population: Adequate data are neither the same as nor the enemy of perfect data. JAMA Intern Med. July 14, 2014. doi: 10.1001/jamainternmed.2014.1107. [Epub ahead of print]
[27] U.S. Preventive Services Task Force Recommendation Statement. Screening for Prostate Cancer. Release Date: May 2012. http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/draftrecprostate.htm. Accessed August 6, 2014.
[28] U.S. Preventive Services Task Force Recommendation Statement. Screening for Prostate Cancer. Release Date: May 2012. http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatefinalrs.htm#summary. Accessed August 6, 2014.
