Increased Mortality from Testosterone Blockade

Gray1160_prostate_2Increased Mortality from Testosterone (Androgen) Blockade

by Jeffrey Dach MD

Diagnosis and Treatment of Prostate Cancer

Since the invention of the PSA test for prostate cancer, it is quite common to detect elevated PSA in the male population.  Mainstream medical practice for these patients with elevated PSA’s (prostate specific antigen) is to refer them to a urologist for evaluation and possible treatment.  Standard Urological practice is the trans rectal ultrasound guided biopsy of the prostate.  If prostate cancer is found on the biopsy, then the cancer is characterized according to aggressiveness and invasiveness (Gleason Score).

Above left image prostate gland courtesy of wikimedia.

Watchful Waiting

For the less aggressive prostate cancers, one option is “watch and wait”, another way of saying, do nothing.   The non-aggressive prostate cancers are detected fairly commonly now, and do not cause a clinical problem in the patient’s lifetime, so watchful waiting is a reasonable option. Another option is active surveillance.

More Aggressive Treatment Options

BrachytherapySeeds_sFor the aggressive or dangerous prostate cancers that do not fit into the watchful waiting category, treatment options include surgery with radical prostatectomy (surgical removal).  The major drawback of surgery is the possibility of post-op urinary and sexual  complications such as urinary incontinence and sexual dysfunction, which might dissuade one from chosing the surgical option.  An alternative to the surgical treatment option is radiation therapy which is administered either with radioactive seeds implanted into the prostate (left  image)  or by external beam radiation of some type.   Above left image: Radiation Seeds Courtesy of Wikimedia.

Testosterone Suppressive Hormone Therapy

Testosterone_smallFor the patients who choose to have radiation therapy, current practice before starting the course of radiation treatments is to “shrink the prostate” with hormonal therapy which suppresses testosterone to low levels.  In the old days of medicine, testosterone blockade was done with surgical castration, and I actually assisted in one of these during my training 30 years ago.  Removing testicles has fallen out of favor, as drugs such a Lupron are available that do the job easily.   Above left image: chemical structure of testosterone courtesy of wikimedia.

Lupron is given in the form of an injection which, in effect, produces a temporary chemical castration, as it knocks out testosterone production for three months. This has become the accepted standard of care before radiation therapy for prostate cancer.

Twenty Per Cent Increase in Mortality

However a recent study by Dr. Amy Dosoretz, a  radiation oncology resident with the Harvard Radiation Oncology Program in Boston has raised questions about the value of chemical castration.  Her study showed that patients treated with the hormone shot to  “knock out testosterone to shrink the prostate”  had a poor outcome.  They had a 20% increase in mortality.(1)(2)

A discovery such as this, that a treatment that carries a 20 per cent increase in mortality means the treatment is discredited and should be discarded, and should no longer be the “standard of care”.  Instead it should be considered “substandard care”. However, old habits in medicine have a way of lingering on, so it may take a few more years for this to change.

fda_2201FDA Approval Would Be Denied

FDA approval requires a drug to produce a benefit greater than placebo.  Had Amy Doseretz’ study been submitted to the FDA for drug approval, the FDA would never have been granted approval for the use of Lupron for prostate cancer.  A detrimental result of 20 per cent increased mortality would spell disaster, and the FDA approval would be denied.

Other Study Confirms Findings

Dr Amy Dosoretz was not the first to raise doubts about testosterone blockade for prostate cancer.  A previous study by Grace L. Lu-Yao was published JAMA 2008 showing that androgen deprivation therapy is not associated with improved survival. (3)

Low Testosterone Associated with Increased Mortality

Low testosterone in general (independent of underlying prostate cancer issues) is associated with increased mortality.  The recent EPIC study in Circulation 2007 found that,” In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.”(4)

Articles with Related interest:

Benefits of Testosterone Part One

Testosterone and PSA Part Two

Jeffrey Dach MD
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References and Links

(1) Hormone Therapy Not Best for Older Prostate Cancer Patients
Study found giving it before radiation raised death risk 20% in this group
By Alan Mozes HealthDay Reporter. Quote:TUESDAY, Sept. 23 (HealthDay News) — Older men with early-stage prostate cancer who are given hormone therapy before radiation seed implant therapy face a 20 percent greater risk of dying than those who get radiation treatment alone, new research suggests.

Focusing on men over the age of 70, the study summed up the risks of death from any cause linked to androgen-deprivation therapy. Such treatment is sometimes given before radiation treatment to lower male hormone levels, shrink the prostate, and retard cancer growth. Brachytherapy itself involves the insertion of small radioactive seeds into the prostate to destroy cancer cells.

We know that hormone therapy has a lot of side effects,” noted study author Dr. Amy M. Dosoretz, a radiation oncology resident with the Harvard Radiation Oncology Program in Boston. “Depression, fatigue and anemia, among others. Yet it can be worth it, because it has a significant benefit for many patients. But for some patients, the risks may outweigh the benefits. And here, we found that in this particular group of patients — early-stage prostate cancer patients over 70 — there was an increased risk for mortality.”

Dosoretz and her colleagues were expected to present their findings Tuesday at the American Society for Therapeutic Radiology and Oncology annual meeting, in Boston.

The team’s risk assessment is based on a mortality analysis involving more than 1,700 early-stage, localized prostate cancer patients. The men were between the ages of 70 and 91, and received either hormone and brachytherapy treatments or brachytherapy alone between 1991 and 2005.

For those who received hormone therapy, treatment lasted three and a half months on average.

The authors found that undergoing such hormonal intervention was associated with an increased risk of dying from all causes. Being older and having a more aggressive form of prostate cancer was similarly associated with an increased risk of dying from all causes.

“But we still don’t know exactly why there’s an increased risk for mortality for these patients,” Dosoretz cautioned. “So, we need to look into this important issue further, with randomized trials that take in all the bias. Meanwhile, when deciding about hormone therapy treatment, it’s important — especially among elderly men who have early-stage prostate cancer — to really weigh the benefits and risks.”

Dr. Charles J. Ryan, a urologic cancer specialist and an assistant clinical professor of medicine in the division of hematology/oncology at the University of California, San Francisco, agreed.

“We have a pretty good sense that hormone therapy can increase the relative risk for cardiac risk, diabetes and some of the major problems that are likely to kill patients with prostate cancer,” Ryan noted. “However, here, the researchers do not address prostate-cancer specific mortality but rather all-cause mortality. And it does a disservice to what hormone therapy can do well to ignore the fact that there have been several studies going back years that show that hormone therapy in addition to radiation improves survival for high-risk patients.”

“So, basically, the decision with what to do with hormone therapy needs to be taken in the context of risk,” Ryan said.

SOURCES: Amy M. Dosoretz, M.D., radiation oncology resident, Harvard Radiation Oncology Program, Boston; Charles J. Ryan, M.D., assistant clinical professor, medicine, division of hematology/oncology, University of California, San Francisco; Sept. 23, 2008, presentation, American Society for Therapeutic Radiology and Oncology meeting, Boston. Copyright © 2008 ScoutNews, LLC. All rights reserved. Last updated 9/23/2008  End Quote

(2) http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574CE006F3F4A    Hormone Therapy Before Brachytherapy May Increase Mortality in Prostate Cancer: Presented at ASTRO By Martha Kerr, BSN

BOSTON — September 24, 2008 — Neoadjuvant hormonal therapy given prior to brachytherapy is associated with increased all-cause mortality in elderly men with localised prostate cancer compared with brachytherapy alone, investigators reported here at the American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting.     In a presentation on September 23, lead investigator Amy M. Dosoretz, MD, Harvard Radiation Oncology Program, Boston, Massachusetts, reported results of a retrospective analysis including 1,709 men at least 70 years old with localised prostate cancer treated between 1991 and 2005.    The study evaluated 786 men who were treated with a short course of neoadjuvant hormone therapy for a median duration of 3.5 months before brachytherapy and 916 men with brachytherapy alone. None of the men received supplemental external beam radiation therapy.    After a median follow-up of 5 years and after adjusting for known prostate cancer prognostic factors and age, the researchers found that neoadjuvant hormone therapy was associated with a hazard ratio of 1.2 for all-cause mortality compared with brachytherapy alone (95% confidence interval, 1.0-1.4; P = .04), Dr. Dosoretz reported.

Increasing age and Gleason score of 7 or greater were also associated with a significantly increased risk of all-cause mortality.

“Our study shows that for men over 70 with early-stage prostate cancer, androgen deprivation therapy as a form of treatment may do more harm than good,” she said.

“It is currently unclear why hormone therapy before radiation seed implantation may increase the risk of death in older men with early-stage prostate cancer,” Dr. Dosoretz said. “It is possible that comorbid illness may raise the risk of treatment-related complications, including cardiovascular complications,” she postulated.

“Our message is that in older patients, it is very important to weigh the risks and benefits of hormone therapy when designing a treatment plan for these patients,” Dr. Dosoretz said.

The findings of this study are “potentially practice-changing,” commented Louis Harrison, MD, Beth Israel Medical Center, New York, New York, and moderator of a press briefing where the findings were released.

[Presentation title: Mortality in Men Age 70 or More With Localized Prostate Cancer Treated With Brachytherapy With or Without Neoadjuvant Hormonal Therapy. Abstract 84]

(3) http://jama.ama-assn.org/cgi/content/full/300/2/173
Survival Following Primary Androgen Deprivation Therapy Among Men With Localized Prostate Cancer. Grace L. Lu-Yao, MPH, PhD; Peter C. Albertsen, MD; Dirk F. Moore, PhD; Weichung Shih, PhD; Yong Lin, PhD; Robert S. DiPaola, MD; Siu-Long Yao, MD  JAMA. 2008;300(2):173-181.    ABSTRACT   Despite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management for the treatment of localized prostate cancer.      Objective  To evaluate the association between PADT and survival in elderly men with localized prostate cancer.    Design, Setting, and Patients  A population-based cohort study of 19 271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1-T2 prostate cancer. These patients were diagnosed in 1992-2002 within predefined US geographical areas, with follow-up through December 31, 2006, for all-cause mortality and through December 31, 2004, for prostate cancer–specific mortality. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables.   Main Outcome Measures  Prostate cancer–specific survival and overall survival.

Results  Among patients with localized prostate cancer (median age, 77 years), 7867 (41%) received PADT, and 11 404 were treated with conservative management, not including PADT. During the follow-up period, there were 1560 prostate cancer deaths and 11 045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer–specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03-1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96-1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer–specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70-1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84-1.01).

Conclusion  Primary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.

(4) http://circ.ahajournals.org/cgi/content/short/116/23/2694
Circulation. 2007;116:2694-2701.

Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men

European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Kay-Tee Khaw, MBBChir, FRCP; Mitch Dowsett, PhD; Elizabeth Folkerd, PhD; Sheila Bingham, PhD; Nicholas Wareham, MBBS, PhD; Robert Luben, BSc; Ailsa Welch, PhD; Nicholas Day, PhD

Methods and Results— We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003. Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths). Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 (0.55 to 1.00), 0.62 (0.45 to 0.84), and 0.59 (0.42 to 0.85), respectively (P<0.001 for trend after adjustment for age, date of visit, body mass index, systolic blood pressure, blood cholesterol, cigarette smoking, diabetes mellitus, alcohol intake, physical activity, social class, education, dehydroepiandrosterone sulfate, androstanediol glucuronide, and sex hormone binding globulin). An increase of 6 nmol/L serum testosterone (1 SD) was associated with a 0.81 (95% confidence interval 0.71 to 0.92, P<0.01) multivariable-adjusted odds ratio for mortality. Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years.

Conclusions— In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

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