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## Complete Summary

#### GUIDELINE TITLE

Maximal androgen blockade for the treatment of metastatic prostate
cancer.

#### BIBLIOGRAPHIC SOURCE(S)

Genitourinary Cancer Disease Site Group. Maximal androgen blockade for
the treatment of metastatic prostate cancer \[full report\]. Toronto
(ON): Cancer Care Ontario (CCO); 2003 Feb 5 \[online update\]. 26
p. (Practice guideline; no. 3-1). \[73 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

The FULL REPORT, initially the full original Guideline or Evidence
Summary, over time will expand to contain new information emerging from
their reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc3-1f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Metastatic prostate cancer

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Treatment

#### CLINICAL SPECIALTY

Oncology\
Surgery\
Urology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To evaluate whether maximal androgen blockade (MAB) provides superior
overall survival or progression-free survival compared with castration
alone in previously untreated men with metastatic prostate cancer

#### TARGET POPULATION

Adult men with metastatic prostate cancer (D1 or D2, N+/M0 or M1)

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Maximal androgen blockade (MAB) consisting of orchiectomy or
    luteinizing hormone-releasing hormone (LHRH) agonist plus
    antiandrogen.

> Note: LHRH agonists considered included buserelin, goserelin, and
> leuprolide; Antiandrogens considered included flutamide, nilutamide,
> bicalutamide (Casodex), and cyproterone acetate. Maximum androgen
> blockade is not recommended as routine treatment.

2.  Castration alone (orchiectomy or LHRH agonist)

#### MAJOR OUTCOMES CONSIDERED

-   Survival

-   Disease-free/progression-free survival

-   Adverse effects

-   Quality of life

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

MEDLINE (1980 through February 2002), CANCERLIT (1980 through October
2001) and the Cochrane Library databases (2001, Issue 4) were
systematically searched. For the most recent searches (1998 through
February 2002 in MEDLINE and 1988 through October 2001 in CANCERLIT),
\"prostatic neoplasms\" (Medical subject heading \[MeSH\]) was combined
with \"gonadorelin\" (MeSH), \"androgen antagonists\" (MeSH),
\"diethylstilbestrol\" (MeSH), \"castration\" (MeSH), and each of the
following words or phrases used as text words: \"leuprolide\",
\"lupron\", \"goserelin\", \"zoladex\", \"buserelin\", \"suprefact\",
\"flutamide\", \"eulexin\", \"nilutamide\", \"anandron\", \"nilandron\",
\"bicalutamide\", \"casodex\", \"cyproterone acetate\", \"androcur\",
\"diethylstilbestrol\", \"DES\", \"castration\", \"orchidectomy\",
\"orchiectomy\", \"prostatic cancer\", \"prostate cancer\". These terms
were then combined with the search terms for the following study
designs: practice guidelines, systematic reviews or meta-analyses,
reviews, randomized controlled trials, and controlled clinical trials.
In addition, the Physician Data Query (PDQ) clinical trials database on
the Internet (<http://www.cancer.gov/search/clinical_trials/>) was
searched for reports of new or on-going trials. Relevant articles were
selected and reviewed by two reviewers, and the reference lists from
these sources were searched for additional trials, as were the reference
lists from relevant review articles. Genitourinary Disease Site Group
(GU DSG) members contributed papers from their personal reprint files.
The Canadian Medical Association Infobase
(<http://mdm.ca/cpgsnew/cpgs/index.asp>) and the National Guideline
Clearinghouse (<http://www.guideline.gov/>) were searched for existing
evidence-based practice guidelines.

**Inclusion Criteria**

Articles were selected for inclusion in this systematic review of the
evidence if they met the following criteria:

1.  Published reports of randomized controlled trials (RCTs) or
    meta-analyses comparing MAB (orchiectomy or luteinizing
    hormone-releasing hormone \[LHRH\] agonist plus administration of an
    antiandrogen) with castration alone (orchiectomy or administration
    of a luteinizing hormone-releasing hormone agonist) in previously
    untreated men with metastatic prostate cancer.

2.  Published reports providing data on overall survival and/or disease
    progression-related outcomes.

**Exclusion criteria**

1.  Phase I and phase II trials were excluded from this report due to
    the availability of randomized controlled trials and meta-analyses.

2.  Papers published in a language other than English, letters, and
    editorials were also excluded.

#### NUMBER OF SOURCE DOCUMENTS

Seven meta-analyses, 27 randomized controlled trials, an updated report
of a randomized trial that was originally published in 1993, and an
exploratory analysis of another trial were identified.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus (Committee)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

It was decided not to pool the results of trials of maximal androgen
blockade (MAB) therapy for metastatic prostate cancer due to the
availability of up-to-date, published meta-analyses that included recent
randomized controlled trials.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

In formulating a recommendation for the use of maximal androgen blockade
(MAB), the Genitourinary Cancer Disease Site Group (GU DSG) reviewed and
discussed the available data on survival, disease progression-related
outcomes, adverse effects, and quality of life as presented in the
Prostate Cancer Trialists\' Collaborative Group (PCTCG) meta-analysis
and the review by Aronson et al. Overall, the DSG weighed the evidence
of a small but non-significant difference in overall survival at five
years for MAB versus castration alone against the available information
on adverse effects and quality of life. Although the PCTCG meta-analysis
suggested an absolute survival difference of approximately two percent
in favour of MAB therapy and a difference of three percent if only
nonsteroidal antiandrogens are considered, the GU DSG questioned the
clinical significance of this benefit especially given the greater
toxicity profile associated with MAB. Faced with this scenario, the GU
DSG felt that the current evidence argued against the routine use of
MAB. Members of the GU DSG agreed that monotherapy, consisting of either
orchiectomy or the administration of a luteinizing hormone-releasing
hormone (LHRH) agonist should be recommended as standard treatment for
patients with metastatic prostate cancer.

In wording their recommendation, the GU DSG felt it was important to
make a distinction between the long-term use of MAB for treatment of
metastatic prostate cancer and the utility of short-term MAB in the
prevention of testosterone flare. In patients treated with medical
castration, initial treatment with an LHRH agonist is accompanied by a
surge in serum testosterone during the first week(s) of therapy,
followed by a decline. There is a concern that this surge may exacerbate
existing metastatic disease. In this clinical situation, short-term use
of an antiandrogen is indicated to prevent or block the flare
phenomenon. The GU DSG felt that in this clinical situation it was
reasonable for antiandrogens to be given to patients for a period of two
to four weeks following the first administration of an LHRH agonist.

While the GU DSG does not recommend the use of MAB as treatment for
patients with metastatic prostate cancer, they recognized that some
clinicians may choose to give MAB to individual patients for the purpose
of improving survival. Consequently, the GU DSG felt that their
recommendation should include a relatively strong statement against the
use of MAB therapy using cyproterone acetate due to the poorer survival
outcome associated with this MAB regimen. If MAB is to be administered
with the intent of improving survival, the GU DSG suggested that MAB
therapy contain a nonsteroidal antiandrogen, such as flutamide or
nilutamide. Although evidence from the Casodex Combination Study
suggests that MAB treatment containing the newer antiandrogen
bicalutamide is associated with lower toxicity, the GU DSG considered
this evidence to be preliminary. Before beginning treatment with MAB,
individual patients should be advised of the potential adverse effects
associated with combined treatment and the impact these adverse affects
could have on aspects of quality of life.

The GU DSG\'s final recommendation on MAB therapy applies to adult men
with documented metastatic prostate cancer. The recommendations do not
address the role of MAB in patients with a rising prostate specific
antigen (PSA) who have no evidence of metastatic disease or MAB as
neoadjuvant or adjuvant treatment in patients with non-metastatic
prostate cancer. The GU DSG believes that the available evidence on MAB
in these clinical situations is insufficient for formulating treatment
recommendations. The DSG commented that future research may one day
uncover molecular or other markers that may help in identifying
subgroups of patients who might benefit from MAB treatment.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Practitioner feedback was obtained through a mailed survey of 99
practitioners in Ontario (61 urologists, 15 medical oncologists, and 23
radiation oncologists). The survey consisted of items evaluating the
methods, results, and interpretive summary used to inform the draft
recommendations and whether the draft recommendations above should be
approved as a practice guideline. Written comments were invited. The
practitioner feedback survey was mailed out on June 4, 2002. Follow-up
reminders were sent at two weeks (post card) and four weeks (complete
package mailed again). The Genitourinary Disease Site Group (GU DSG)
reviewed the results of the survey.

The practice guideline report was circulated to members of the Practice
Guidelines Coordinating Committee (PGCC) for review and approval. Eight
of nine members of the PGCC returned ballots. Five PGCC members approved
the practice guideline report as written, and three members approved the
guideline and provided suggestions for consideration by the GU DSG. One
PGCC member commented that the guideline report was rather lengthy and
suggested the GU DSG consider streamlining the text for a shorter
report.

The GU DSG agreed that there were sections of the guideline report where
text could be streamlined without the loss of substantive content. The
guideline report was reviewed by the GU DSG and sections of the report
where text could be condensed were identified. All editorial changes
that were made were minor in nature and did not alter the substantive
content of the guideline report.

The practice guideline reflects the integration of the draft
recommendations with feedback obtained from the external review process.
It has been approved by the GU DSG and the Practice Guidelines
Coordinating Committee.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Maximal androgen blockade (MAB) should not be routinely offered as
treatment for patients with documented metastatic prostate cancer beyond
the purpose of blocking testosterone flare. Monotherapy, consisting of
orchiectomy or a luteinizing hormone-releasing hormone (LHRH) agonist,
is recommended as standard treatment for patients with metastatic
prostate cancer.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

Seven meta-analyses were identified by the literature search and search
of personal files. Since the publication of the Prostate Cancer
Trialists\' Collaborative Group (PCTCG) meta-analysis in 2000, three
reports have been published that compare relevant outcomes of maximal
androgen blockade (MAB) compared with castration alone. The literature
search identified one randomized controlled trial (RCT), an updated
report of a randomized trial that was originally published in 1993 and
included in the PCTCG meta-analysis, and an exploratory analysis of
another trial also included the PCTCG meta-analysis.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   The Genitourinary Cancer Disease Site Group (GU DSG) felt that the
    most compelling evidence upon which to base a recommendation on
    maximal androgen blockade (MAB) for the treatment of patients with
    metastatic prostate cancer, with survival as the endpoint, was the
    individual patient data meta-analysis published by the Prostate
    Cancer Trialists\' Collaborative Group (PCTCG) in 2000. This
    meta-analysis evaluated patients with advanced prostate cancer;
    however, 88% of the patients included in the meta-analysis had
    documented metastatic disease.

-   The PCTCG meta-analysis, which included 8275 patients from 27
    randomized controlled trials (RCTs), detected no significant
    improvement in overall survival with MAB therapy (orchiectomy or
    luteinizing hormone-releasing hormone \[LHRH\] agonist plus
    administration of either a steroidal or nonsteroidal antiandrogen)
    compared with castration alone (overall mortality rate ratio
    \[MRR\], 0.958; standard error \[SE\], 0.026; p=0.11). An analysis
    of survival at different follow-up periods indicated no significant
    difference in survival at two years and a small but non-significant
    difference at five years in favour of MAB versus castration alone
    (25.4% versus 23.6%), suggesting an absolute five-year survival
    difference of approximately two percent (1.8%; SE, 1.3).

-   A subgroup analysis performed on the 20 RCTs that included a
    nonsteroidal antiandrogen (flutamide or nilutamide) in the MAB arm
    indicated this form of MAB therapy was associated with a
    statistically significant improvement in five-year survival of
    approximately three percent compared with castration alone (27.6%
    versus 24.7%; SE, 1.3; p=0.005).

-   A subgroup analysis performed on the seven RCTs that included a
    steroidal antiandrogen (cyproterone acetate) in the MAB arm
    indicated this MAB regimen was associated with a statistically
    significant reduction in five-year survival of approximately three
    percent compared with castration alone (15.4% versus 18.1%; SE, 2.4;
    p=0.04).

-   A recent systematic review of the literature indicated that 19 of 23
    randomized trials that provided data on measures related to disease
    progression reported no significant differences between MAB and
    castration alone. Of the four trials that detected significant
    differences, three reported a statistically significant difference
    in favour of MAB with nonsteroidal antiandrogens. The other trial,
    which included cyproterone acetate in the MAB arm, reported a
    statistically significant advantage to castration alone over MAB for
    time to disease progression (median time to progression, 11.5 months
    for castration alone versus 10.8 months for MAB; progression-free
    survival at two years, 31% versus 21%; p=0.0160).

#### POTENTIAL HARMS

-   To date, only one randomized controlled trial has formally assessed
    quality of life outcomes associated with the use of maximum androgen
    blockade (MAB) in patients with metastatic prostate cancer. Measures
    of quality of life assessed in this trial included three
    treatment-related symptoms (diarrhea, gas pain, and body image),
    physical functioning, and emotional functioning. Compared with
    patients treated with castration alone, patients receiving maximum
    androgen blockade reported significantly more diarrhea at three
    months post-treatment (p\<0.001) and worse emotional functioning at
    three and six months post-treatment (p\<0.003).

-   The Casodex Combination Study did not meet the inclusion criteria of
    this review but was included because it provided data on the newer
    antiandrogen bicalutamide. Data from this study suggests that
    differences in toxicity might exist between different luteinizing
    hormone-releasing hormone (LHRH) agonists and nonsteroidal
    antiandrogens. In this trial, a greater number of patient
    withdrawals were observed among patients receiving MAB with
    flutamide compared to bicalutamide. While there is definitely the
    possibility of an improved toxicity profile with bicalutamide, this
    data should be interpreted with caution as the trial was not
    designed or powered to make comparisons among the four MAB treatment
    groups.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Care has been taken in the preparation of the information contained
    in this document. Nonetheless, any person seeking to apply or
    consult these guidelines is expected to use independent medical
    judgement in the context of individual clinical circumstances or
    seek out the supervision of a qualified clinician. Cancer Care
    Ontario makes no representation or warranties of any kind whatsoever
    regarding their content or use or application and disclaims any
    responsibility for their application or use in any way.

-   It is the opinion of the Genitourinary Cancer Disease Site Group (GU
    DSG) that the small statistically significant survival benefit found
    with maximal androgen blockade (MAB) using nonsteroidal
    antiandrogens (flutamide or nilutamide) is of questionable clinical
    significance and does not outweigh the negative side effects of MAB
    treatment. Patients to whom MAB may be offered should be advised of
    the small survival benefit and potential adverse effects associated
    with combined treatment and the impact these adverse effects could
    have on aspects of quality of life.

-   MAB containing the steroidal antiandrogen cyproterone acetate should
    not be used as this form of MAB treatment has been found to reduce
    survival compared with castration alone.

-   The current evidence does not permit a recommendation regarding the
    role of MAB in the following clinical situations beyond the purpose
    of blocking testosterone flare: MAB using the newer antiandrogen
    bicalutamide, MAB in patients with prostate-specific antigen relapse
    who have no documented evidence of metastatic disease, and MAB as
    neoadjuvant or adjuvant hormonal treatment for patients with
    non-metastatic prostate cancer.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Genitourinary Cancer Disease Site Group. Maximal androgen blockade for
the treatment of metastatic prostate cancer \[full report\]. Toronto
(ON): Cancer Care Ontario (CCO); 2003 Feb 5 \[online update\]. 26
p. (Practice guideline; no. 3-1). \[73 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2003 Feb

#### GUIDELINE DEVELOPER(S)

Program in Evidence-based Care - State/Local Government Agency
\[Non-U.S.\]

#### GUIDELINE DEVELOPER COMMENT

The Practice Guidelines Initiative (PGI) is the main project of the
Program in Evidence-based Care (PEBC), a Province of Ontario initiative
sponsored by Cancer Care Ontario and the Ontario Ministry of Health and
Long-Term Care.

#### SOURCE(S) OF FUNDING

Cancer Care Ontario, Ontario Ministry of Health and Long-Term Care

#### GUIDELINE COMMITTEE

Provincial Genitourinary Cancer Disease Site Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

For a current list of past and present members, please see the [Cancer
Care Ontario Web
site](http://www.cancercare.on.ca/english/toolbox/qualityguidelines/diseasesite/genito-ebs/genito-dsg/).

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Members of the Genitourinary Cancer Disease Site Group (GU DSG)
disclosed potential conflict of interest information.

#### GUIDELINE STATUS

This is the current release of the guideline.

The FULL REPORT, initially the full original Guideline or Evidence
Summary, over time will expand to contain new information emerging from
their reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc3-1f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc3-1f.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   Maximal androgen blockade for the treatment of metastatic prostate
    cancer. Summary. Toronto (ON): Cancer Care Ontario. Electronic
    copies: Available in Portable Document Format (PDF) from the [Cancer
    Care Ontario Web
    site](http://www.cancercare.on.ca/pdf/pebc3-1s.pdf).

-   Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni
    A, et al. The practice guidelines development cycle: a conceptual
    tool for practice guidelines development and implementation. J Clin
    Oncol 1995;13(2):502-12.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on July 21, 2003. The information
was verified by the guideline developer as of August 6, 2003.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions. Please refer to the
[Copyright and Disclaimer
Statements](http://www.cancercare.on.ca/ontariocancernews/copyright.html)
posted at the Cancer Care Ontario Web site.

### DISCLAIMER

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Date Modified: 11/3/2008