Survival in the Prostate Cancer Prevention Trial

To the Editor:

In their article on long-term survival in the Prostate Cancer Prevention Trial (PCPT), Thompson et al. (Aug. 15 issue)1 comment on the aggressiveness of high-grade disease (which they defined as a tumor having a Gleason score of 7 to 10). These authors have always argued that the increase in high-grade disease in men receiving finasteride was an artifact.2 If this were true, men with high-grade disease who are treated with finasteride should have a better survival rate than men in the placebo group. However, the survival rates in these groups were virtually the same. This finding indicates that the increase in high-grade disease is not an artifact but is real. The Food and Drug Administration rejected the use of finasteride for the prevention of prostate cancer on the basis of a related increase in the most aggressive, potentially lethal form of high-grade disease (Gleason score, 8 to 10), excluding the less aggressive pattern of disease (Gleason score of 7).3,4 In another recent report, the PCPT investigators stated that tumors with a Gleason score of 8 to 10 may cause “a small increase in prostate cancer mortality.”5 In the study published in the Journal, which defined a high-grade tumor as one having a Gleason score of 7 to 10, there is no report on prevalence or mortality for cancers with Gleason scores of 8 to 10. What are they?

Patrick C. Walsh, M.D.
Johns Hopkins Medical Institutions, Baltimore, MD
pwalsh@jhmi.edu

No potential conflict of interest relevant to this letter was reported.
5 References

To the Editor:

The 5-α reductase inhibitor finasteride has found considerable clinical use, not only in the treatment of prostate disease but also as a treatment for male-pattern alopecia. Concerns have been raised about the potential for an increased risk of male breast cancer among patients receiving finasteride.1,2 Given that the PCPT involved a very large sample of more than 18,000 men, the investigators have the opportunity to study the incidence patterns of male breast cancer among the patients enrolled in the trial.

Swaroop Revannasiddaiah, M.D.
Swami Rama Cancer Hospital and Research Institute, Haldwani, India
swarooptheone@gmail.com
Sridhar P. Susheela, M.D.
Bangalore Institute of Oncology, Bengaluru, India

No potential conflict of interest relevant to this letter was reported.
2 References

The authors reply: In response to Walsh: the outcomes according to Gleason score in our recent report, with scores of 2 to 6 indicating low-grade tumors and scores of 7 to 10 indicating high-grade tumors, were consistent with those in our initial 2003 report.1 Table 1Table 1Estimates of Postdiagnostic Survival for Men with Tumors with Gleason Scores of 8 to 10 in the Prostate Cancer Prevention Trial. shows postdiagnostic Kaplan–Meier survival estimates for patients with Gleason scores between 8 and 10. In this small subset of men from the PCPT, confidence intervals are wide and overlap. Modeling the time from randomization to death with the use of time-dependent covariates to account for the time at which the diagnosis of prostate cancer occurred (an approach that is less biased than one incorporating postdiagnostic survival), we calculated the between-group difference in the hazard ratios for death when Gleason scores of 8 to 10 rather than 7 to 10 were used to indicate high-grade cancer. After adjusting for age and race, we found that the P value for the comparison was 0.59, indicating that there was no statistically significant difference in survival. However, this test is also underpowered and represents another reason why we chose not to highlight this subset in our article.
Revannasiddaiah and Susheela ask about the incidence of male breast cancer in the PCPT trial. With 141,009 person-years of follow-up, there have been two cases, one in each of the two study groups.

Catherine M. Tangen, Dr.P.H.
Phyllis J. Goodman, M.S.
Fred Hutchinson Cancer Research Center, Seattle, WA
Ian M. Thompson, Jr., M.D.
Cancer Therapy and Research Center, San Antonio, TX
thompsoni@uthscsa.edu

Since publication of their article, the authors report no further potential conflict of interest.
1 Reference

Related Article
 

Long-Term Survival of Participants in the Prostate Cancer Prevention Trial

August 15, 2013 | I.M. Thompson and Others

New drugs for prostate cancer

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By ANDREW POLLACK

Published: June 27, 2011

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A group of new drugs is promising to prolong the lives and relieve the symptoms of men with advanced prostate cancer, but could also add billions of dollars to the nation’s medical bills.

Bone-scan images before and after treatment with Cabozantinib. The dark spots are where cancer had spread to bones.

Multimedia

Interactive Feature

Promising Treatments for Prostate Cancer Patients

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Jenny Mass

Mark Moldanado, a retired postal worker in Omaha, said that Jevtana had helped keep his cancer in check.

In the last 15 months, three new drugs that extended the lives of prostate cancer patients in clinical trials have been approved by the Food and Drug Administration and several other promising medicines are in clinical trials. Before last year, only one drug had been shown to improve survival — docetaxel, which was approved in 2004.

“What a great time it is in prostate cancer,” Dr. Daniel J. George of the Duke Cancer Institute proclaimed earlier this month at the annual meeting of the American Society of Clinical Oncology.

And it’s a great time for the drug makers, with several drugs competing to fill a niche for longer-term survival. Analysts estimate that some of the new drugs, particularly Dendreon’s Provenge and Johnson & Johnson’s Zytiga, could reach annual sales of $1 billion or even much more.

The recently approved drugs and most of those in development are for cases in which the disease has spread beyond the prostate gland and is no longer held in check by hormone therapy.

Men with that late-stage cancer had a median survival of about a year and a half using docetaxel. The new drugs each added two to five months to median survival when tested in clinical trials. Doctors say that men taking more than one of the drugs in succession would be expected to live more than two years.

But the price of these drugs has already stirred concerns about the costs of care among patients, providers and insurers. For example, Provenge costs $93,000 for a course of treatment, while Zytiga costs about $5,000 a month. Another of the new drugs, Sanofi’s Jevtana, costs about $8,000 every three weeks.

With other pricey drugs on the way, said Joel Sendek, an analyst at Lazard, “We could be talking easily $500,000 per patient or more over the course of therapy, which I don’t think the system can afford, especially since 80 percent of the patients are on Medicare.”

5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer

5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer

Drugs in the 5-ARI class include finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn

AUDIENCE: Urology, Family Medicine, Internal Medicine

ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).

BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Proscar, Avodart, and Jalyn are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Propecia is approved to treat male pattern hair loss.

RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information.

Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online:www.fda.gov/MedWatch/report.htm1
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm

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Finasteride for benign prostatic hyperplasia.

Image via Wikipedia

by: James Tacklind, Howard A. Fink, Roderick Macdonald, Indy Rutks, Timothy J. Wilt

Tacklind J, Fink HA, Macdonald R, Rutks I, Wilt TJ. Finasteride for benign prostatic hyperplasia. Cochrane database of systematic reviews (Online). 2010;10. Available from: http://dx.doi.org/10.1002/14651858.CD006015.pub3.

Abstract

BACKGROUND: Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH. OBJECTIVES: To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS). SEARCH STRATEGY: We searched The Cochrane Library (which includes CDSR (Cochrane Database of Systematic Reviews), DARE (Database of Abstracts of Reviews of Effects), HTA (Heath Technology Assessments), and CENTRAL (Cochrane Central Register of Controlled Trials, and which includes EMBASE and MEDLINE), LILACS (Latin American and Caribbean Center on Health Sciences Information) and Google Scholar for randomized, controlled trials (RCTs). We also handsearched systematic reviews, references, and clinical-practice guidelines. SELECTION CRITERIA: Randomized trials in the English language with placebo and/or active arms with a duration of at least 6 months. DATA COLLECTION AND ANALYSIS: JT extracted the data, which included patient characteristics, outcomes, and harms. Our primary outcome was change in a validated, urinary symptom-scale score, such as the AUA/IPSS. A clinically meaningful change was defined as 4 points. We also categorized outcomes by trial lengths of ≤ 1 year (short term) and > 1 year (long term). MAIN RESULTS: Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, ≥ 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more likely than finasteride to improve peak urine flow and nocturia, versus finasteride. Versus tamsulosin, peak urine flow and QoL improved equally well versus finasteride. However, finasteride was associated with a lower risk of surgical intervention compared to doxazosin, but not to terazosin, while finasteride and doxazosin were no different for risk of acute urinary retention. Two small trials reported no difference in urinary symptom scores between finasteride and tamsulosin. Finasteride + doxazosin and doxazosin monotherapy improved urinary symptoms equally well (≥ 4 point improvement).For finasteride, there was an increased risk of ejaculation disorder, impotence, and lowered libido, versus placebo. Versus doxazosin, finasteride had a lower risk of asthenia, dizziness, and postural hypotension, and versus terazosin, finasteride had a significant, lower risk of asthenia, dizziness, and postural hypotension. AUTHORS' CONCLUSIONS: Finasteride improves long-term urinary symptoms versus placebo, but is less effective than doxazosin. Long-term combination therapy with alpha blockers (doxazosin, terazosin) improves symptoms significantly better than finasteride monotherapy. Finasteride + doxazosin improves symptoms equally - and clinically - to doxazosin alone. In comparison to doxazosin, finasteride + doxazosin appears to improve urinary symptoms only in men with medium (25 to < 40 mL) or large prostates (≥ 40 mL), but not in men with small prostates (25 mL).Comparing short to long-term therapy, finasteride does not improve symptoms significantly better than placebo at the short term, but in the long term it does, although the magnitude of differences was very small (from < 1.0 point to 2.2 points). Doxazosin improves symptoms better than finasteride both short and long term, with the magnitude of differences ∼2.0 points and 1.0 point, respectively. Finasteride + doxazosin improves scores versus finasteride alone at both short and long term, with mean differences ∼2.0 points for both time points. Finasteride + doxazosin versus doxazosin improves scores equally for short and long term.Drug-related adverse effects for finasteride are rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo. Versus doxazosin, which has higher rates of dizziness, postural hypotension, and asthenia, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder. Finasteride significantly reduces asthenia, postural hypotension, and dizziness versus terazosin. Finasteride significantly lowers the risk of asthenia, dizziness, ejaculation disorder, and postural hypotension, versus finasteride + terazosin.

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El finasteride no provoca efectos oseos a largo plazo

Aunque se ha sugerido que la disminución de los niveles plasmáticos de la dihidrotestosterona que se produce en los pacientes tratados con finasterida podría traducirse a largo plazo en alteraciones óseas, los estudios realizados hasta la fecha, no han mostrado efectos en la densidad mineral ósea o los marcadores de formación y de resorción ósea.
Según un estudio de casos y controles publicado en JAMA no se ha encontrado que finasterida, utilizada en la hiperplasia benigna de próstata, incremente el riesgo de fractura de cadera (OR 0.77, IC95% 0.29-1.00, p=0.04). Se incluyeron 7076 casos (varones mayores de 45 años y con fractura de cadera) y un número igual de controles emparejados por edad y centro médico.
El estudio mostró un riesgo superior de fractura de cadera entre los pacientes con una prescripción reciente de alfa-bloqueantes (en los primeros 30 días: OR 2.04; IC95% 1.19-3.49) que los autores atribuyen al efecto adverso de hipotensión ortostática causado por estos fármacos al inicio del tratamiento.
Fuente: Hemos leido.

El finasteride no provoca efectos oseos a largo plazo

Aunque se ha sugerido que la disminución de los niveles plasmáticos de la dihidrotestosterona que se produce en los pacientes tratados con finasterida podría traducirse a largo plazo en alteraciones óseas, los estudios realizados hasta la fecha, no han mostrado efectos en la densidad mineral ósea o los marcadores de formación y de resorción ósea.
Según un estudio de casos y controles publicado en JAMA no se ha encontrado que finasterida, utilizada en la hiperplasia benigna de próstata, incremente el riesgo de fractura de cadera (OR 0.77, IC95% 0.29-1.00, p=0.04). Se incluyeron 7076 casos (varones mayores de 45 años y con fractura de cadera) y un número igual de controles emparejados por edad y centro médico.
El estudio mostró un riesgo superior de fractura de cadera entre los pacientes con una prescripción reciente de alfa-bloqueantes (en los primeros 30 días: OR 2.04; IC95% 1.19-3.49) que los autores atribuyen al efecto adverso de hipotensión ortostática causado por estos fármacos al inicio del tratamiento.
Fuente: Hemos leido.