Orchiectomy

Orchiectomy in treatment of metastatic prostate cancer

Posted Sep 17 2008 1:54pm

Introduction

Certainly until the mid- and perhaps even the late 1980s there was no doubt whatsoever that orchiectomy was the gold standard for the hormonal treatment of metastatic prostate cancer.
By carrying out the surgical removal of a man’s testes, the physician was able to completely shut down the synthesis of testosterone, thus removing testosterone stimulation of prostate cancer growth and alleviating (for a while) the symptoms of progression of the disease, particularly bone pain. However, orchiectomy, like other forms of hormone therapy, was never shown to extend survival of men with metastatic prostate cancer evident on a bone scan.

What Are the Advantages of Orchiectomy?

First, it is a single, simple, surgical procedure with a very low risk of problems and 100 percent efficacy.
Second, it can be carried out in ways which are not physically evident. In other words, it is possible to carry out what is known as a subcapsular orchiectomy, in which the cores of the two testes are removed while the capsules remain in the scrotum. This means that the man still appears to be an “intact” male.

What are the Side Effects of Orchiectomy?

The side effects of orchiectomy are limited to those resulting from the absence of testosterone. These include:

• Loss of sexual desire (treatable with hormone injections or gel preparations)
• Impotence
• Hot flashes similar to those in menopausal women, controllable by medication
• Weight gain of 10–15 lb (4.5–6.8 kg)
• Mood swings and/or depression
• Gynecomastia — tenderness and swelling of the breasts and nipples (also treatable)
• Fatigue
• A loss of sensation in the groin or the genitals
• Osteoporosis (treatable with bisphosphonates and similar agents)

What Are the Other Disadvantages of Orchiectomy?

The major disadvantage appears to be the psychological one associated with “loss of manhood.” For many men this loss appears to be all but unbearable. Interestingly, the loss of “manhood” is not usually a problem for the partners of most prostate cancer patients when compared to the possibility of loss of life. However, the male association between his theoretical ability to be able to have sexual intercourse and his sense of self worth appears to be astonishingly strong, regardless of the truth about his actual level of sexual activity and/or capability.
The other disadvantage is that the procedure is not reversible. However, since cases of complete remission of advanced prostate cancer are almost completely unheard of and certainly not well documented, it would appear that the need for reversing this operation is about as close to zero as one can get!

Is Orchiectomy Becoming More Common Again?

During the 1990s and the first few years of the 21st Century here in America, the use of orchiectomy declined precipitously compared to the use of other forms of hormone therapy (most notably the use of the LHRH agonists). However, in the last couple of years, there seems to have been a gradual increase in the use of orchiectomy again.
A variety of suggestions have been made as to why this is the case. Frankly, most of the likely reasons seem to revolve around financial issues:

• In the 1990s, urologists were able to bill Medicare for administering LHRH agonists at costs significantly higher than the office acquisition cost. In other words, they were able to make a significant profit each time they gave an LHRH agonist injection. This may well have encouraged them to preferentially recommend LHRH agonist treatment to their patients as compared to orchiectomy.
• In 2005 this practice came to an end when Medicare set a flat reimbursement rate for the LHRH agonists that no longer made it possible for urologicts to profit in this way. And the use of orchiectomy started to rise again.
• In addition, legal cases were brought against some physicians and two major pharmaceutical companies for defrauding Medicare in the way that the LHRH agonists were marketed and the physicians sought Medicare reimbursement for clinical use of free drug “samples.”
• Finally, as we have noted above, orchiectomy is simply less expensive than LHRH therapy. For many patients today the co-pay required for treatment with an LHRH agonist for a year is simply not worth the cost compared to the simplicity of orchiectomy.

Some Things to Think About

If you are unfortunate enough to have advanced prostate cancer, we know that at present there is no cure for your disease. Orchiectomy (especially subcapsular orchiectomy, which allows the patient to retain the appearance of complete maleness) is still a very reasonable option. It is noticeably lower in cost over time than monthly or even quarterly injections of LHRH agonists, and the patient can avoid the necessity of regular visits for injections of LHRH agonists. However, presented with the choice, about seven out of 10 men will still select “medical castration” with LHRH therapy rather than orchiectomy.
It also needs to be understood that there is a very real difference between an orchiectomy and complete emasculation. After an orchiectomy (even an orchiectomy in which the testes are completely removed), the patient still retains full use of his penis, the scrotum is still present, and to all but the closest scrutiny a man still looks completely “male.”
Interestingly, there are rare but well documented cases of patients who retained sexual potency even after orchiectomy. This would appear to be impossible to explain. However, it introduces a fascinating series of possible speculations on the nature of male sexual function.

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Urine Test May Identify Aggressive Prostate Cancer Nick Mulcahy Information from Industry Assess clinically focused product information on Medscape. Click Here for Product Infosites – Information from Industry. February 12, 2009 — An experimental urine test is "at least as good" as the prostate-specific antigen (PSA) test for predicting which men have aggressive prostate cancer, according to a University of Michigan researcher who participated in a new study published online in the February 12 issue of Nature. The urine test, which assesses levels of prostate-cancer-specific metabolites, could eventually be added to PSA and other tools for monitoring prostate cancer progression, said study coauthor John Wei, MD, at a press briefing. Dr. Wei is an associate professor of urology at the University of Michigan Medical School, in Ann Arbor. However, the new study had a small sample, and the scientific approach to analyze metabolites as prostate cancer biomarkers needs further validation and development, he added. Nonetheless, Dr. Wei and his colleagues believe that 1 of the metabolites, sarcosine, has the potential to differentiate between benign prostate tissue and localized/metastatic prostate cancer. "One of the main clinical issues in prostate cancer is distinguishing between aggressive [and] indolent slow-growing disease," said senior author Arul Chinnaiyan, MD, PhD, during the press briefing. The inability to do so leads to "overtreatment," added Dr. Chinnaiyan, who is director of the Michigan Center for Translational Pathology, in Ann Arbor. In the new study, the researchers identified at least 10 prostate-cancer-specific metabolites. Notably, sarcosine was increased "most robustly in metastatic prostate cancer," in comparison with the others, they write. It was also elevated in locally advanced prostate cancer, but less so, added Dr. Chinnaiyan. Dr. Chinnaiyan's lab has also developed urine tests to screen for prostate cancer that are more accurate than PSA tests, as reported by Medscape Oncology. But the tests employ genetic biomarkers and are for screening, not monitoring, the disease. The new study is the first time that "metabolomics," which surveys the metabolite composition of cells and tissues, akin to the way genetics surveys their genetic composition, has been shown "to solve a real-world problem," said the researchers at the press briefing. Why Prostate-Cancer-Specific Metabolites? In the study, the investigators examined 1126 metabolites across 262 samples of tissue, blood, or urine associated with benign prostate tissue, early-stage prostate cancer, and metastatic prostate cancer. Of the metabolites that were present more often in prostate cancer than in the benign cells, sarcosine appeared to be the strongest indicator of advanced disease. Levels of sarcosine, an amino acid, were elevated in 79% of the metastatic prostate cancer samples and in 42% of the locally advanced cancer samples. Sarcosine was not found in the cancer-free samples. In the study, sarcosine was a better indicator of advancing aggressive disease than the PSA test, which both monitors and screens for prostate cancer. "When we're looking at metabolites, we're looking several steps beyond genes and proteins. It allows us to look very deeply at some of the functions of the cells and the biochemistry that occurs during cancer development," added Dr. Chinnaiyan in a statement. The researchers also showed that adding sarcosine to cultures of benign prostate cells turned them into invasive cancer cells, suggesting that the molecule may have an important role in disease. "Components of the sarcosine pathway may have potential as biomarkers of prostate cancer prevention and serve as new avenues for therapeutic intervention," note the authors. The Future of Prostate Cancer Testing "Current biomarkers for detection or progression of prostate cancer are not as precise as we would like. Therefore, a more accurate indicator of cancer is of great interest," said Sudhir Srivastava, PhD, chief of the National Cancer Institute (NCI)'s Cancer Biomarkers Research Group, in a statement. "Sarcosine and some other select metabolites may be excellent indicators of cancer progression." The NCI Early Detection Research Network supported the study, but the Michigan researchers emphasized that their urine test is not a screening test. "We only examined sarcosine in the context of aggressive prostate cancer," noted Dr. Wei. "A lot more work has to be done before it can be used as a screening test." Sarcosine was detected in the urine, which makes researchers hopeful that a simple urine test could be used to monitor the disease. Dr. Wei imagined that the combination of the PSA test and new biomarkers, such as prostate-cancer-specific metabolites (including sarcosine and some of the others identified in the new study), will allow clinicians to eventually "individualize" the analysis of patients. "This may allow clinicians to determine — before biopsy — the severity of disease," he speculated. The study was funded by the National Cancer Institute Early Detection Research Network, National Institutes of Health, an MTTC grant, the Burroughs Welcome Foundation, and the Doris Duke Charitable Foundation. Nature. 2009.457:910-915, 799-800. Related Links News Urine Biomarker Test More Accurate in Detecting Prostate Cancer Than PSA Resource Centers Prostate Cancer Resource Center

New prostate cancer marker-Sarcosine

Survey of metabolites finds new prostate cancer marker

sarcosine in prostate cancer

February 11, 2009

Potential role for sarcosine in prostate cancer progression

A very interesting paper in Nature this week looked at a metabolite called sarcosine and how it's detection in urine may distinguish slow growing prostate cancers from aggressive ones. The paper, entitled "Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression", may well be a useful new marker in helping doctors decide when to stop 'watchful waiting' and treat prostate cancer patients more aggressively.

The researchers examined 1,126 metabolites from over 260 samples of blood, urine and tissue in benign prostate tissue, early stage prostate cancer and advanced or metastatic disease to enable them to map alterations in disease state.

Sarcosine molecule from: jchemed.chem.wisc.edu

They found 10 that were present more often in prostate cancer samples and one, sarcosine, appeared to offer the strongest indicator.

"... by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity."

Sarcosine is an amino acid and was found to be elevated in 79% of the metastatic prostate cancer samples and 42% of the early prostate cancer samples. None of the cancer-free samples had detectable levels of the metabolite.

So how does this happen? Is there an explanation for the phenomenon reported? The researchers went on to say that:

"Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway."

What was also interesting was the finding that:

"Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells."

In other words, they found a clear relationship between the sarcosine and the metastatic invasion. The study also found that sarcosine was a better indicator of advancing disease than the traditional measure, prostate specific antigen (PSA), which is currently used to monitor prostate cancer.

Sources:

Thanks to Prof Chris Beecher for kindly supplying a copy of the Nature reprint.

Arun Sreekumar, Laila M. Poisson, Thekkelnaycke M. Rajendiran, Amjad P. Khan, Qi Cao, Jindan Yu, Bharathi Laxman, Rohit Mehra, Robert J. Lonigro, Yong Li, Mukesh K. Nyati, Aarif Ahsan, Shanker Kalyana-Sundaram, Bo Han, Xuhong Cao, Jaeman Byun, Gilbert S. Omenn, Debashis Ghosh, Subramaniam Pennathur, Danny C. Alexander, Alvin Berger, Jeffrey R. Shuster, John T. Wei, Sooryanarayana Varambally, Christopher Beecher, Arul M. Chinnaiyan (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression Nature, 457 (7231), 910-914 DOI: 10.1038/nature07762