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## Complete Summary

#### GUIDELINE TITLE

Systemic adjuvant therapy for patients at high risk for recurrent
melanoma: a clinical practice guideline.

#### BIBLIOGRAPHIC SOURCE(S)

Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N, Melanoma
Disease Site Group. Systemic adjuvant therapy for patients at high risk
for recurrent melanoma: a clinical practice guideline. Toronto (ON):
Cancer Care Ontario (CCO); 2005 Aug 30. 39 p. (Evidence-based series;
no. 8-1). \[61 references\]

#### 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/pebc8-1f.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)

High-risk malignant melanoma

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Evaluation\
Treatment

#### CLINICAL SPECIALTY

Dermatology\
Internal Medicine\
Oncology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To evaluate systemic therapy for patients who have been rendered
disease-free following resection of cutaneous melanomas and who are at
high risk for subsequent recurrence

#### TARGET POPULATION

Adult patients with high-risk malignant melanoma who are rendered
disease-free following resection. High risk is defined as patients in
the following clinical states who have been rendered disease free by
surgery:

-   Primary melanoma with tumour thickness [\>]{.underline}4.0 mm or
    level V invasion

-   Primary melanoma with in-transit metastases

-   Primary melanoma with regional lymph node metastases that are
    clinically apparent or detected at elective lymph-node dissection

-   Regional lymph node recurrence

-   Involved nodes were excised but there was no known primary melanoma.

**Note**: The target population also includes those patients who would
now be classified as American Joint Committee on Cancer stage IIB, IIC,
and III.

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Adjuvant Therapy for High-Risk Melanoma**

High-dose interferon

Considered but not recommended: low-dose interferon, levamisole,
vaccines, and chemotherapy

#### MAJOR OUTCOMES CONSIDERED

-   Overall survival

-   Disease-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\
Searches of Unpublished Data

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

The MEDLINE (1980 through July 2005), CANCERLIT (1983 through 2004),
EMBASE (1980 to 2005 week 32) and Cochrane Library (2005, Issue 2)
databases were systematically searched. The search terms included the
Medical Subject Heading (MeSH) terms melanoma/th, melanoma/dt, and
clinical trial, and the text words random: and adjuvant. A search was
also done for published practice guidelines, meta-analyses, and reviews.
In addition, the Physician Data Query (PDQ) clinical trials database on
the Internet
([www.cancer.gov/search/clinical_trials/](http://www.cancer.gov/search/clinical_trials/))
and the proceedings of the 1996-2005 meetings of the American Society of
Clinical Oncology (ASCO) were searched for reports of new or ongoing
trials. Articles found by the searches, cited in the relevant papers, or
known to members of the Melanoma Disease Site Group were retrieved and
reviewed.

**Inclusion Criteria**

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

1.  Randomized controlled trials (RCT) of systemic therapies for the
    adjuvant treatment of patients with melanoma. Prior to the
    literature search, four types of treatments were identified as
    relevant to the guideline question: levamisole, interferon,
    vaccines, and chemotherapy.

2.  Trials had to include patients at high risk of recurrence, but the
    study population did not need to be restricted to that group of
    patients. For this report, high risk is defined by American Joint
    Committee on Cancer (AJCC) stages IIB and III (please see Appendix 1
    of the original guideline document for staging information) and
    includes primary tumours [\>]{.underline}4.00 mm thick, regional
    lymph-node metastases that are clinically apparent at presentation
    or are detected at lymph node dissection, and regional lymph node
    recurrence. All studies were conducted under the previous AJCC
    staging system. We attempt to define how patients under the new AJCC
    staging system should be considered, recognizing that the views
    expressed cannot be based on data but are the guideline developer\'s
    view of the information available.

3.  Practice guidelines, meta-analyses, and systematic reviews of
    adjuvant treatment of malignant melanoma were also eligible for
    review.

**Exclusion Criteria**

1.  Phase I and II studies were not considered for inclusion in this
    report because of the availability of randomized controlled trials.

2.  Papers published in a language other than English were not
    considered.

3.  Bacillus Calmette-Guérin (BCG), *Corynebacterium parvum*, transfer
    factor, vitamin A, and megestrol acetate have been investigated in
    the past as adjuvant therapy. However, there does not appear to be
    any ongoing interest in these agents. Trials involving these agents
    have been excluded in this systematic review.

#### NUMBER OF SOURCE DOCUMENTS

The following were eligible for inclusion in the systematic review of
the evidence on adjuvant therapy: 13 trials of interferon, four trials
of levamisole, nine trials of vaccines, and ten trials investigating
chemotherapy. In addition, one report of a consensus development
conference, two meta-analyses of interferon alpha therapy, one
systematic review of adjuvant interferon alpha therapy, and one trial of
chemotherapy plus interferon were reviewed.

#### 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

Meta-Analysis of Randomized Controlled Trials\
Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

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

Published guidelines for performing meta-analysis deal with issues
related to the comparability among studies of the questions being
addressed, the patient populations, the interventions, and the outcomes.
The majority of the trials selected for inclusion in this report
addressed a common question, namely: Does the therapy under
investigation, when given as adjuvant treatment, improve survival,
compared with no treatment? Similar patient groups, albeit with varying
risks of recurrence by virtue of entry criteria, participated in the
randomized trials. Few trials were restricted to patients at high risk
of recurrence (i.e., lesion depth 4.0 mm or greater or completely
resected regional nodal metastases). For trials enrolling patients with
a range of risks, survival results were not reported separately for the
high-risk subgroup. The treatments evaluated fall into the following
four distinct groups of interventions: interferons, levamisole,
vaccines, and chemotherapy. Dose or schedule varied within each type of
treatment. The majority of studies used an observation-only control arm
rather than a placebo control, while some compared two active
treatments.

In contrast to a published systematic review by Lens and Dawes, the
guideline developers pooled the results from the three published Eastern
Cooperative Oncology Group (ECOG) trials of high-dose interferon alpha
therapy. However, the most recent ECOG trial (1694) had a vaccine as the
intervention arm and interferon as the control arm. They pooled the
results with and without ECOG 1694 and discuss the advisability of this
approach in the Interpretive Summary section of the original guideline
document. Results were pooled across studies using the Review Manager
software (RevMan 4.1) provided by the Cochrane Collaboration (Metaview©
Update Software). Pooled results are expressed as relative risks (also
known as risk ratios) for mortality (with 95% confidence interval
\[CI\]) such that a relative risk less than 1.0 favours the active
treatment group. Data were analyzed using the random effects model. All
significance tests are two-sided. Ideally, a meta-analysis would be
restricted to high-risk patients as defined above. However, most of the
studies were not limited to that group of patients. Although attempts
were made to derive information for that group from the study reports or
to obtain results directly from investigators, limited relevant data
were available.

In addition, guideline developers were able to pool mortality data
within two of the other groups of therapies (levamisole and
chemotherapy). They did not pool results from trials of vaccines. The
vaccine trials studied a variety of vaccines that differed in the
postulated mechanisms by which they were hypothesized to exert their
immunomodulatory effects. Therefore, the guideline developers do not
believe that pooling the results from those trials is appropriate.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

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

**Guideline Development**

This practice guideline report was developed by the Program in
Evidence-based Care (PEBC) of Cancer Care Ontario, using the methods of
the Practice Guidelines Development Cycle. Evidence was selected and
reviewed by one member of the PEBC\'s Melanoma Disease Site Group (DSG)
and methodologists.

The practice guideline report is a convenient and up-to-date source of
the best available evidence on systemic adjuvant therapy for patients at
high risk for recurrent melanoma, developed through systematic reviews,
evidence synthesis, and input from practitioners in Ontario. The body of
evidence in this report is primarily comprised of mature randomized
controlled trial data; therefore, recommendations by the DSG are
offered. The report is intended to promote evidence-based practice. The
PEBC is editorially independent of Cancer Care Ontario and the Ontario
Ministry of Health and Long-Term Care.

A practice guideline report on systemic adjuvant therapy for patients at
high risk for recurrent melanoma was originally completed in 1998 and
published on the Web site. With the publication of further relevant
literature on adjuvant therapy and the adoption of a new staging system
for cutaneous melanoma, the Melanoma DSG has rewritten its 1998 report.
This document replaces that 1998 report.

**Disease Site Group Consensus Process**

The members of the Melanoma DSG reviewed the rewritten document at a
meeting held in September 2002. The group unanimously agreed that
interferon has activity in the adjuvant setting. However, one member of
the DSG objected to the word \"offered\" in the Key Recommendation,
pointing out that the issue of adjuvant interferon is controversial and
that the use of the word \"offered\" precludes further clinical trials
being undertaken. This member suggested alternate wording for the
recommendation: \"We recommend that interferon therapy be discussed with
the high risk patient. It may be used as adjuvant treatment, provided
that each patient has been made aware of the controversies, relative
risks, benefits, and costs of this therapy and wishes to proceed.\" The
group noted this objection but decided to let the Key Recommendation
stand as currently written, to be reviewed by practitioners in Ontario.

Another issue raised at the meeting of the Melanoma DSG concerned the
new American Joint Committee on Cancer (AJCC) staging system, which
highlights the presence of ulceration as an important prognostic factor.
Under the new staging system, patients with lesions between 2.0 and 4.0
mm with ulceration have the same prognosis as patients with lesions
greater than 4.0 mm without ulceration. None of the trials included in
this document were conducted under the new staging system. However, the
group felt that new trials based on the new staging criteria were
unlikely to be undertaken. For this reason, the Target Population has
been amended to include patients with shallower, ulcerated lesions. The
DSG sought input from Ontario practitioners about the appropriateness of
including these new patients when this document was circulated for
practitioner feedback.

#### 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

Following the review and discussion of Sections 1 and 2 of this
evidence-based series, the Melanoma Disease Site Group (DSG) circulated
the clinical practice guideline and systematic review to clinicians in
Ontario for review and feedback.

Practitioner feedback was obtained through a mailed survey of 91
practitioners in Ontario (50 general surgeons, 20 plastic surgeons, 18
medical oncologists, and three dermatologists). 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 November 11,
2002. Follow-up reminders were sent at two weeks (post card) and four
weeks (complete package mailed again). The Melanoma Disease Site Group
(DSG) reviewed the results of the survey. Forty-three responses were
received out of the 91 surveys sent (47% response rate).

The practice guideline report was circulated to members of the Practice
Guidelines Coordinating Committee (PGCC) for review and approval. Seven
of the 12 members of the PGCC returned ballots. Four PGCC members
approved the practice guideline report as written, two members approved
the report with suggestions for consideration by the Melanoma DSG, and
one member approved the report conditional on the Melanoma DSG
addressing specific concerns. The main suggestion of the PGCC member was
that the DSG outline the dose and schedule of high-dose interferon being
recommended.

Final approval of the original guideline report was obtained from the
Practice Guidelines Coordinating Committee.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

It is recommended that high-dose interferon alpha therapy (20 X10^6^
U/m^2^/d intravenously five days/week for four weeks, then 10 X 10^6^
U/m^2^ subcutaneously three times weekly for 48 weeks) be discussed and
offered to the high-risk group as defined in the guideline question (see
\"Target Population\" field). It may be used as adjuvant treatment,
provided that each patient has been made aware of the relative risks,
benefits, and costs of this therapy and wishes to proceed.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are supported by randomized controlled trials and
meta-analyses.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Familiarity with and appropriate use of systemic therapy options for
patients who have been rendered disease-free following resection of
cutaneous melanomas and who are at high risk for subsequent recurrence

#### POTENTIAL HARMS

Sixty-seven percent of patients who received high-dose interferon in the
Eastern Cooperative Oncology Group (ECOG) 1684 trial experienced severe
(grade 3 or greater) toxicity with 9% of patients having
life-threatening toxicity. Thirty-seven percent of patients on high-dose
interferon in ECOG 1684 and 59% in ECOG 1690 had dose reductions or
delays in treatment because of toxicity. Two deaths due to interferon,
linked to inadequate monitoring of liver function tests in those
patients, occurred early in ECOG 1684. No further treatment-related
mortality at this dose has been described in that or subsequent trials.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Patients and practitioners should be aware that there have been four
    randomized trials of high-dose interferon alpha in patients at high
    risk for recurrent melanoma. The evidence from the randomized trials
    is conflicting. The Eastern Cooperative Oncology Group (ECOG) 1684
    trial detected a significant improvement in overall survival, but a
    subsequent large randomized trial (ECOG 1690) failed to find any
    survival benefit for interferon compared with observation. Results
    from a third trial (ECOG 1694) that compared high dose interferon
    with a melanoma vaccine demonstrated a significant survival benefit
    for interferon. A fourth trial of high-dose interferon over a
    shorter treatment time failed to detect any benefit.

-   Practitioners should be aware that elderly patients (age 65 and
    older) were underrepresented in the high-dose interferon trials.
    Given the toxicities of interferon, particularly in the presence of
    other significant comorbidities, caution is advised.

-   The role of adjuvant interferon in patients with micrometastases as
    determined solely through sentinel lymph node dissection has not
    been defined and is the subject of ongoing trials. However, until
    such data is available, it is reasonable to discuss the benefits and
    risks of interferon therapy with such patients, particularly in
    those with more than one microscopically involved lymph node at the
    time of dissection, who would not be eligible for the ongoing
    randomized controlled trial.

-   Care has been taken in the preparation of the information contained
    in this document. Nonetheless, any person seeking to apply or
    consult the practice guidelines is expected to use independent
    medical judgment 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.

### 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

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N, Melanoma
Disease Site Group. Systemic adjuvant therapy for patients at high risk
for recurrent melanoma: a clinical practice guideline. Toronto (ON):
Cancer Care Ontario (CCO); 2005 Aug 30. 39 p. (Evidence-based series;
no. 8-1). \[61 references\]

#### ADAPTATION

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

#### DATE RELEASED

1998 May 27 (revised 2005 Aug 30)

#### GUIDELINE DEVELOPER(S)

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

#### GUIDELINE DEVELOPER COMMENT

The Program in Evidence-based Care (PEBC) is 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 Melanoma 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/melanoma-ebs/melanoma-dsg/).

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Melanoma Disease Site Group members were asked to disclose potential
conflict of interest information; no conflicts were declared.

#### 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/pebc8-1f.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/pebc8-1f.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Systemic adjuvant therapy for patients at high risk for recurrent
    melanoma: a clinical practice guideline. 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/pebc8-1s.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 summary was completed by ECRI on August 19, 1999. The information
was verified by the guideline developer as of September 17, 1999. The
summary was updated by ECRI on August 10, 2001 and verified by the
guideline developer as of August 22, 2001. This NGC summary was updated
by ECRI on March 20, 2003. The information was verified by the guideline
developer on May 8, 2003. This NGC summary was most recently updated on
September 27, 2004. The updated information was verified by the
guideline developer on October 20, 2004. This NGC summary was updated by
ECRI on June 29, 2006. The updated information was verified by the
guideline developer on July 7, 2006.

#### 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

#### NGC DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/10/2008