Clinical Practice Guideline on the Use of 5-alpha Reductase Inhibitors for Prostate l h R d I hibi f P Cancer Chemoprevention American Society

of Clinical Oncology/American Urological Association O l /A i U l i lA i ti

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Introduction
ASCO Health Services Committee, ASCO Cancer Prevention Committee and the American Committee, Urological Association (AUA) Practice Guidelines Committee jointly convened a panel of experts American Urological Association (AUA) and ASCO commissioned a Systematic Review, Wilt et al. 5y , alpha reductase inhibitors for prostate cancer chemoprevention: a systematic review of the evidence regarding effectiveness and adverse effects. (Cochrane Database of Systematic Reviews)
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Guideline Methodology: Systematic Review

Wilt et al. completed a review and analysis of data published through December 2006 MEDLINE PreMedline Cochrane C ll b ti Lib C h Collaboration Library Reviews Personal files
*Additional search in April 2007 of MEDLINE/PreMEDLINE (yielded no relevant results)

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Guideline Methodology gy (contd): Panel Members

Barnett Kramer, MD, Co-Chair Paul Schellhammer, MD, Co-Chair Stewart Justman, Ph.D., Patient Representative Peter C. Albertsen, MD William J. Blot, PhD H. Ballentine Carter, MD p , Joseph P. Costantino, PhD Jonathan I. Epstein, MD National Institutes of Health Eastern Virginia Medical School University of Montana Liberal Studies University of Connecticut Health Center International Epidemiology Institute Johns Hopkins University National Surgical Adjuvant Breast and Bowel g j Project Johns Hopkins University

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Guideline Methodology gy (contd): Panel Members

Paul Godley, MD, PhD Russell P H i MD R ll P. Harris, Timothy J. Wilt, M.D., MPH Janet Wittes PhD Wittes, Robin Zon, MD University of North Carolina Chapel Hill University of North Carolina at Chapel Hill U i it f N th C li t Ch l University of Minnesota School of Medicine Statistics Collaborati e Collaborative Michiana Hematology Oncology

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2008 Recommendations for Use of 5- Reductase Inhibitors for Prostate Cancer Chemoprevention

Overarching C O Clinical Q Question

Should men routinely be offered a 5-Alpha Reductase I hibit f th R d t Inhibitor for the chemoprevention of prostate cancer?

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2008 Recommendations for Use of 5- Reductase Inhibitors for 5 Prostate Cancer Chemoprevention

Clinical Questions
A. What is the impact of 5--reductase inhibitors on the risk of incident prostate cancer, prostate cancer mortality, and overall mortality? Do benefits and harms of 5-reductase i hibit d t inhibitors vary among id tifi bl identifiable subpopulations (e.g., age, race/ethnicity, family history, p ) y yp baseline risk for prostate cancer) and by type of 5-reductase inhibitor?

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2008 Recommendations for Use of 5- Reductase Inhibitors for Prostate Cancer Chemoprevention

Clinical Questions
B. Do 5--reductase inhibitors have a differential effect on the development of different histologic grades or stages of prostate cancer? Are any such differences likely to modify th curability of prostate cancer when di dif the bilit f t t h diagnosed? d? Is the Gleason histologic grading system for prostate pp g cancer applicable to men who are receiving 5-reductase inhibitors or other interventions that target the androgen pathway?
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2008 Recommendations for Use of 5- Reductase Inhibitors for Prostate Cancer Chemoprevention

Clinical Questions
C. What is the impact of 5--reductase inhibitors on the need for treatment for benign prostatic disease? D. What is the impact of 5--reductase inhibitors on quality of life? What are other potential harms and side effects of 5--reductase inhibitors? What are other potential benefits of, and indications f 5 b fit f d i di ti for, 5--reductase inhibitor d t i hibit use (e.g., benign prostatic hyperplasia, male baldness)? E. How long should treatment continue for the best outcome (period vs. lifelong)? s F. What are the future directions of research regarding 5-reductase inhibitors for the prevention of prostate cancer?
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Primary Source of Evidence

Prostate Cancer P P C Prevention T i l (PCPT) i Trial N = 18,882 Design endpoint of period prevalence* Finasteride administered for 7 years Participant characteristics
No prior prostate cancer Asymptomatic or, at most, mild lower urologic symptoms PSA < 3 ng/ml / l Normal DRE
*the proportion of randomized population trial period identified as having the prostate cancer over trial period
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2008 Recommendations
Should Sh ld men routinely be offered a 5--reductase inhibitor ti l b ff d 5 d t i hibit for the chemoprevention of prostate cancer?
Asymptomatic men with a PSA 3.0 who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of the benefits of 5-ARIs for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer) to be able to make a betterinformed decision. Men who are taking 5--reductase inhibitors for benign conditions such as LUTS would benefit from a similar discussion.

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Findings
In a group of 1000 men, treatment with finasteride reduced cases of prostate cancer from 60 to 45; a decrease of 15 cases In a group of 1000 treatment with finasteride 1000, increased cases of high-grade (Gleason score 810) from 18 to 21; an increase of 3 cases Both courses above are seven years p prostate cancer by y NNT to prevent one case of p treating for 7 years with finasteride = 71

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Clinical Questions and Findings

Question A: What is impact on risk of incident prostate cancer, prostate cancer mortality, and/or overall mortality? A there li d/ ll li ? Are h differences by identifiable subpopulations? Response/Evidence: Decrease in risk of incident prostate cancer Relative decrease in period prevalence = 26% Absolute risk reduction = 1.4% Trials not powered to show mortality difference, no difference found No differences found among different races/ethnicities*, ages, N diff f d diff t / th i iti * baseline risks or family histories of prostate cancer

*The participants of the PCPT, however, were 92% non-Hispanic white The non Hispanic
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Clinical Questions and Findings

Question B: Are there differential effects on differences in grades/stages? What is applicability of Gleason histologic grading system?

Response/evidence:
Secondary analysis of PCPT found increase of 3 cases of high-grade p g g prostate cancer p 1000 men per Difference of opinion on explanation of this finding Until the explanation of finding known, decisions regarding the natural hi di h l history of the di f h disease and d decisions regarding treatment interventions should be based on the histologic information obtained on g biopsy regardless of 5-ARI status
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Clinical Questions and Findings

Question C: What is impact on treatment for benign prostatic disease Response/evidence:
5-ARIs are established, FDA-approved treatments for symptomatic benign prostatic hyperplasia (BPH). From PCPT
Reduces urinary retention RR = .67 Reduces transurethral resection of the prostate (TURP)

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Clinical Questions and Findings

Question D: What is impact on QOL? What are other potential benefits/harms, other indications Response/evidence: Potential Harms:

Erectile Dysfunction 2-4% increase Decreases in ejaculate volume 1.3-2.9% Gynecomastia 1.6-3.11% Decreased libido 1-4% Sexual dysfunction decreases over time

Decrease in PSA Male Pattern Baldness 50 years, 50% decrease in PSA and1 mg similar to 5 mgs at 1 year follow-up ( i l d1 i il t t f ll (single study).
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Clinical Questions and Findings

Question E: What is optimal treatment duration? Response/evidence:
Guideline recommends seven year duration for primary prevention for Finasteride (PCPT) Trial using four year administration of dutasteride is ongoing (REDUCE trial)

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Please note
All the men in the PCPT were receiving regular screening for prostate cancer. The impact of 5-alpha reductase inhibitors 5 alpha inhibitors, including finasteride, on the risk of developing prostate cancer in men who are not being actively screened is therefore not known. known

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Future Directions of Research on 5-ARIs 5 ARIs

Establish effect on prostate cancer morbidity and mortality Establishing optimal dose 1 mg versus 5 mg Find appropriate PSA cut-points for men taking 5cut points 5 ARIs which would trigger a biopsy Establish the role of 5-ARIs for men not actively receiving screening Establish the most effectivene means of communication f men considering th use of a 5 i ti for id i the f 5ARI Create risk stratification models incorporating molecular data
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Interpretive Summary
For the man who wishes periodic monitoring (opportunistic or organized screening), 5-ARI therapy over a 7-year period reduces the period prevalence of for cause cancer for-cause diagnoses by about 25% (relative risk reduction) for an absolute risk reduction of ) about 1.4%.

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Interpretive Summary, contd. cont d.

Although the majority of the Panel judged th t th Alth h th j it f th P l j d d that the observed higher incidence of high-grade (Gleason 8 10) 8-10) cancer in the finasteride group is likely due to confounding factors, the increased incidence of high-grade cancer as a result of induction by the drug cannot be excluded with certainty Further certainty. benefits accruing from the drug are reduction of the risk of urinary retention and need for surgical y g intervention. Harms include sexual side effects, which usually diminish with time.
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Strategies to Improve DoctorPatient Communication

1. 1 Inform the man who is considering a 5-ARI that 5 ARI these agents reduce the incidence of prostate cancer, and be sure to be clear that these , agents do not reduce the risk of prostate cancer to zero; 2. Discuss the elevated rate of high-grade cancer observed in the PCPT and inform men of the potential explanations;
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Strategies to Improve Doctorg p Patient Communication, contd.

3. 3 Communicate that no information on the longterm effects of 5-ARIs on prostate cancer incidence exists beyond about seven years and that whether or not a 5 ARI reduces 5-ARI prostate cancer mortality or increases life expectancy remains unknown; 4. Inform men of possible but reversible sexual side effects; and 5. Inform men of the likely improvement in lower urinary tract symptoms symptoms.
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Limitations in Current Literature

Only one large completed trial that was directly y g p y relevant to this guideline Prostate Cancer Prevention Trial (PCPT) PCPT powered to measure incidence, not mortality Proportion of prostate cancers decreased by finasteride that are clinically meaningful (i.e. morbid and/or life-threatening) is currently unknown 92% of PCPT participants were non-Hispanic white Changes that occur in standards for PSA thresholds, it i for biopsy, and bi th h ld criteria f bi d biopsy methods th d
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Additional ASCO Resources

Thi f ll text of the guideline, this slide set, and a d This full f h id li hi lid d doctorpatient discussion guide are available at: http://www.asco.org/guidelines/5ari/ Access the cancer.net website for a Patient Guide and other patient-friendly information at http://www.cancer.net

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ASCO Guidelines
It is im p o rta n t to re a lize th a t m a n y m a n a g e m e n t q u e stio n s h a ve n o t b e e n c o m p re h e n sive ly a d d re ss e d in ra n d o m ize d tria ls a n d g u id e lin e s ca n n o t a lw a ys a cc o u n t fo r in d ivid u a l va ria tio n a m o n g p a tie n ts. A g u id e lin e is n o t in te n d e d to s u p p la n t p h ysicia n ju d g m e n t w ith re s p e ct to p a rticu la r p a tie n ts o r sp e c ia l clin ic a l s itu a tio n s a n d c a n n o t b e co n sid e re d in c lu s ive o f a ll p ro p e r m e th o d s o f c a re o r e xclu s ive o f o th e r tre a tm e n ts re a so n a b ly d ire c te d a t o b ta in in g th e sa m e re s u lts . A c co rd in g ly, A S C O co n s id e rs a d h e re n ce to th is g u id e lin e to b e vo lu n ta ry, w ith th e u ltim a te d e te rm in a tio n re g a rd in g its a p p lic a tio n to b e m a d e b y th e p h ys ic ia n in lig h t o f e a c h p a tie n ts in d ivid u a l c ircu m s ta n ce s . In a d d itio n , th e gu id e lin e d e s c rib e s a d m in is tra tio n o f th e ra p ie s in c lin ica l p ra ctic e ; it ca n n o t b e a s su m e d to a p p ly to in te rve n tio n s p e rfo rm e d in th e co n te xt o f clin ic a l tria ls , g ive n th a t clin ic a l s tu d ie s a re d e s ig n e d to te s t in n o va tive a n d n o ve l th e ra p ie s in a d is e a s e a n d s e ttin g fo r w h ic h b e tte r th e ra p y is n e e d e d . B e c a u se g u id e lin e d e ve lo p m e n t in vo lve s a re vie w a n d s yn th e s is o f th e la te st lite ra tu re , a p ra c tic e g u id e lin e a lso s e rve s to id e n tify im p o rta n t q u e s tio n s fo r fu rth e r re s e a rc h a n d th o se s e ttin g s in w h i h i ve s ti a ti n a l th e ra p y s h o u ld b e c o n sid e re d . ic in tig tio id

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