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BMJ Clin Evid. 2008; 2008: 1718.
Published online 2008 August 22.
PMCID: PMC2907961

Malignant melanoma (metastatic)

James Larkin# and Martin Gore, Professor#

Abstract

Introduction

Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide.

Key Points

There are 8100 new cases of malignant melanoma and 1800 deaths a year in the UK, largely as a result of metastatic disease.

  • The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years.
  • Chemotherapy is given with palliative rather than curative intent for metastatic disease.

Consensus is that it is reasonable to give chemotherapy to people with metastatic melanoma.

  • Chemotherapy for metastatic melanoma has been associated with serious adverse effects. However, these tend to be manageable, and it is reasonable to give chemotherapy to people with metastatic melanoma, although there are no good-quality studies to support this view, and only a small proportion of people may benefit.

Dacarbazine or temozolomide are the standard first-line chemotherapy.

  • Both dacarbazine and temozolomide are associated with similar progression-free survival and fewer adverse effects compared with other single-agent or combination chemotherapy.
  • Combination chemotherapy is no more effective than single-agent chemotherapy at increasing overall survival. Combination chemotherapy is associated with more adverse effects compared with single-agent chemotherapy.

Immunotherapy (interferon alfa or interferon alfa plus interleukin-2) is unlikely to increase survival when added to chemotherapy, and is associated with influenza-like symptoms and myelosuppression.

About this condition

Definition

Malignant melanoma is a tumour derived from melanocytes in the basal layer of the epidermis. The systemic treatment of malignant melanoma with distant metastases is reviewed here. For the purposes of this review, we will cover only cutaneous melanoma with distant metastases (stage IV, see table 1 ). Non-metastatic malignant melanoma is covered in a separate review (see review on malignant melanoma (non-metastatic).

Table 1
Staging of malignant melanoma.

Incidence/ Prevalence

There are 8100 new cases of malignant melanoma and 1800 deaths a year in the UK. Malignant melanoma accounts for 10% of all skin cancers, and is the primary cause of death from skin cancer. It occurs more frequently on exposed skin, such as men's backs, and women's lower legs.

Aetiology/ Risk factors

Environmental factors, such as exposure to ultraviolet light (especially episodes of severe sunburn in childhood), and genetic factors, such as a family history of the disease, are known to be risk factors for the development of melanoma. In addition, skin colour and the number of moles a person has correlate closely with the risk of developing malignant melanoma.

Prognosis

The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent in metastatic disease.

Aims of intervention

To palliate symptoms, maintain or improve quality of life, and prolong overall survival, with minimal adverse effects of treatment.

Outcomes

Quality of life, progression-free survival, overall survival, and adverse effects.

Methods

BMJ Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this review: Medline 1966 to September 2007, Embase 1980 to September 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for malignant melanoma (metastatic).

Glossary

Dartmouth regimen
A combined regimen of dacarbazine plus cisplatin plus carmustine plus tamoxifen.
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire.
Grading of toxicity of treatments
The Cancer Therapy Evaluation Program (CTEP) of the National Institutes of Health uses a 0–4 scale to grade adverse events related to cancer treatments: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening. These common toxicity criteria can be viewed at the National Cancer Institute website.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Progression-free survival (PFS)
Median survival from trial entry until disease progression or death. May also be expressed as proportion of participants who survived with no disease progression at the end of the trial.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Malignant melanoma (non-metastatic)

Contributor Information

James Larkin, Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London, UK.

Martin Gore, Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London, UK.

References

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26. Bajetta E, Del Vecchio M, Nova P, et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol 2006;17:571–577. [PubMed]
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2008; 2008: 1718.
Published online 2008 August 22.

Cytotoxic chemotherapy plus supportive palliative care versus palliative care alone

Summary

We found no clinically important results about palliative cytotoxic chemotherapy plus supportive palliative care compared with supportive palliative care alone in the treatment of people with malignant melanoma (metastatic). The current consensus, in view of the generally manageable adverse effects, and because a small proportion of people may experience benefit, is that it is reasonable to deliver single-agent treatment.

Benefits

We found no systematic review or RCTs assessing palliative cytotoxic chemotherapy plus supportive palliative care versus supportive palliative care alone.

Harms

We found no RCTs; however, the harms of chemotherapy are well documented (see harms of systemic chemotherapy).

Comment

Clinical guide:

Cytotoxic chemotherapy has not been compared with best supportive care in an RCT, but the current consensus is that it is reasonable to deliver single-agent treatment in view of the generally manageable adverse effects, and because a small proportion of people may experience benefit.

Substantive changes

No new evidence

2008; 2008: 1718.
Published online 2008 August 22.

Combination cytotoxic chemotherapy

Summary

MORTALITY Compared with single-agent chemotherapy: Combination cytotoxic chemotherapy may increase adverse effects compared with single-agent cytotoxic chemotherapy without increasing overall survival rates ( low-quality evidence ). Compared with each other: Different combination cytotoxic chemotherapy regimens have similar overall survival rates (low-quality evidence). NOTE The adverse-effect profile of a combination cytotoxic chemotherapy regimen depends on the agents given. The most common adverse effects of combination chemotherapy are nausea with or without vomiting, fatigue, and haematological adverse effects (neutropenia, anaemia, and thrombocytopenia). Current consensus is that combination cytotoxic chemotherapy may be considered when maximum chance of tumour shrinkage is required.

Benefits

Combination cytotoxic chemotherapy versus single agents:

We found one systematic review (search date 2003) that did not perform a meta-analysis. The review identified seven RCTs comparing combination cytotoxic chemotherapy versus single agents (5 RCTs comparing with dacarbazine, 2 RCTs comparing with temozolomide). The first RCT assessed the addition of a platinum compound (cisplatin) to temozolomide alone. The second RCT assessed the addition of thalidomide to temozolomide alone. Two RCTs compared the Dartmouth regimen versus dacarbazine alone. One RCT assessed the addition of vindesine to dacarbazine alone. Two RCTs assessed the addition of tamoxifen to dacarbazine alone (see table 2 ).

Table 2
Comparison of combination cytotoxic chemotherapy versus single agent: benefits.

Combined cytotoxic chemotherapy regimens versus each other:

We found one systematic review (search date 2003) which did not perform a meta-analysis. We found eight RCTs comparing combination cytotoxic chemotherapy regimens versus each other. A variety of regimens and drugs were used, including the Dartmouth regimen. Four RCTs assessed the addition of tamoxifen to combination cytotoxic chemotherapy. Two RCTs compared chemotherapy regimens containing platinum versus non-platinum regimens. One RCT compared vindesine plus tamoxifen versus dacarbazine plus tamoxifen. One RCT assessed the addition of vindesine to lomustine plus procarbazine. No RCTs reported progression-free survival (see table 3 ).

Table 3
Comparison of combination chemotherapy versus other combination chemotherapy: benefits.

Harms

Combined cytotoxic chemotherapy versus single agents:

Four RCTs found that combination cytotoxic chemotherapy increased adverse effects compared with single-agent chemotherapy (see table 4 ). In two RCTs, adverse effects were more common in the combination chemotherapy group compared with the single-agent group. However, the RCTs did not perform a direct group comparison. The most common adverse effects of cytotoxic chemotherapy were nausea with or without vomiting, and haematological adverse effects (neutropenia, anaemia, and thrombocytopenia).

Table 4
Comparison of combination chemotherapy versus single agent: harms.

Combined cytotoxic chemotherapy regimens versus each other:

The adverse-effect profile of a regimen depended on the agents given, but the most common adverse effects of combination cytotoxic chemotherapy were nausea with or without vomiting, fatigue, and haematological adverse effects (neutropenia, anaemia, and thrombocytopenia) (see table 5 ).

Table 5
Comparison of different combination cytotoxic chemotherapy regimens versus each other: harms.

Comment

Clinical guide:

Current consensus is that combination cytotoxic chemotherapy may be considered in situations where maximum chance of tumour shrinkage is required, such as in the palliation of locally advanced skin or subcutaneous metastases. Unresectable locally advanced melanoma can lead to ulceration, bleeding, or infection, which can be unpleasant for the person, and can be difficult to palliate; maximum tumour shrinkage reduces the risk of these complications. Combined chemotherapy causes considerably higher toxicity than single-agent chemotherapy, and, in the absence of a survival benefit, cannot be routinely recommended.

Substantive changes

No new evidence

2008; 2008: 1718.
Published online 2008 August 22.

Dacarbazine or temozolomide

Summary

MORTALITY Dacarbazine compared with temozolomide: Dacarbazine is less effective at increasing median progression-free survival rates, but not overall survival rates ( moderate-quality evidence ). Dacarbazine compared with fotemustine: Dacarbazine and fotemustine have similar survival rates ( high-quality evidence ). QUALITY OF LIFE Dacarbazine compared with temozolomide: Dacarbazine is less effective at 12 weeks at improving quality-of-life scores, such as physical functioning, fatigue, and sleep disturbances (high-quality evidence). ADVERSE EFFECTS Both dacarbazine and temozolomide may be associated with myelosuppression, nausea, and vomiting. Severe adverse effects, especially myelosuppression, may be more common in people treated with fotemustine.

Benefits

Dacarbazine versus temozolomide:

We found no systematic review. We found one RCT comparing dacarbazine versus temozolomide (305 people randomised to receive either oral temozolomide at a starting dose of 200 mg/m2/day for 5 days every 28 days or iv dacarbazine 250 mg/m2/day for 5 days every 21 days). The RCT found that, compared with dacarbazine, temozolomide non-significantly increased overall survival and significantly increased progression-free survival (overall survival: 7.7 months with temozolomide v 6.4 months with dacarbazine; HR 1.18, 95% CI 0.92 to 1.52; P = 0.20; progression-free survival: 1.9 months with temozolomide v 1.5 months with dacarbazine; HR 1.37, 95% CI 1.07 to 1.75; P = 0.012). In the RCT, restaging was performed at different time points in the two groups, as dacarbazine was given on a 3-weekly schedule and temozolomide on a 4-weekly schedule. This may account for the difference reported in progression-free survival. Quality of life, measured using EORTC QLQ-C30, was reported separately. The RCT found that, after 12 weeks, people who received temozolomide had significantly better physical functioning, and less fatigue and sleep disturbance, compared with people who received dacarbazine (mean EORTC QLQ-C30 score for physical functioning: 90.6 with temozolomide v 81.3 with dacarbazine; fatigue: 19.8 with temozolomide v 29.0 with dacarbazine; sleep disturbance: 11.8 with temozolomide v 23.7 with dacarbazine; P less than 0.05 for all comparisons). All other quality-of-life scores at 12 weeks and all scores at week 24 were higher in people treated with temozolomide compared with people treated with dacarbazine, but the differences did not reach significance.

Dacarbazine or temozolomide versus other single agent:

We found one RCT comparing dacarbazine versus fotemustine. The RCT (229 people randomised to receive 2 cycles of either dacarbazine 250 mg/m2 daily for 5 days every 4 weeks or fotemustine 100 mg/m2 weekly for 3 weeks) found no significant difference in overall survival time (5.6 months with dacarbazine v 7.3 months with fotemustine; P = 0.067).

Dacarbazine or temozolomide versus combination chemotherapy:

See benefits of combination chemotherapy.

Harms

Dacarbazine versus temozolomide:

The RCT reported that both dacarbazine and temozolomide caused mild to moderate myelosuppression (anaemia: 8% of people with temozolomide v 11% of people with dacarbazine; leukopenia: 2% of people with temozolomide v 1% of people with dacarbazine; thrombocytopenia: 9% of people with either drug; significance between groups not assessed). The RCT also reported moderate nausea and vomiting with both drugs (86% of people with temozolomide v 62% of people with dacarbazine; significance between groups not assessed).

Dacarbazine or temozolomide versus other single agent:

The RCT reported a higher incidence of grade 3 or 4 neutropenia and thrombocytopenia in people treated with fotemustine compared with people treated with dacarbazine (neutropenia: 6/112 [5%] with dacarbazine v 57/112 [51%] with fotemustine; thrombocytopenia: 7/112 [6%] with dacarbazine v 48/112 [43%] with fotemustine; significance between groups not assessed).

Dacarbazine or temozolomide versus combination chemotherapy:

See harms of combination chemotherapy.

Comment

Clinical guide:

Current consensus is that intravenous dacarbazine as a single agent is a standard first-line treatment for metastatic melanoma. Temozolomide is structurally related to dacarbazine — it is a prodrug that is converted to the active metabolite of dacarbazine. It is an alternative to dacarbazine with equivalent efficacy and toxicity. Temozolomide may be preferable as it is taken orally, whereas dacarbazine is given intravenously.

Substantive changes

No new evidence

2008; 2008: 1718.
Published online 2008 August 22.

Adding interferon alfa to cytotoxic chemotherapy

Summary

MORTALITY Adding interferon alfa to cytotoxic chemotherapy compared with chemotherapy alone: Adding interferon alfa to combination chemotherapy is no more effective at increasing overall survival ( moderate-quality evidence ). ADVERSE EFFECTS Adding interferon alfa to combination chemotherapy increases non-haematological adverse effects compared with chemotherapy alone (moderate-quality evidence).

Benefits

We found one systematic review (search date 2006, 11 RCTs, 1399 people) and two additional RCTs. The systematic review meta-analysed data from four RCTs (526 people) assessing overall survival at the end of the trial (time frame not specified), and found no significant difference between interferon alfa plus chemotherapy and chemotherapy alone.The first additional RCT found similar overall survival with chemotherapy plus interferon alfa and chemotherapy alone, but did not assess the significance of the difference between groups. The second additional RCT found that interferon alfa plus dacarbazine significantly increased length of overall survival compared with dacarbazine alone (see table 6 ).

Table 6
Adding interferon alfa to cytotoxic chemotherapy: benefits.

Harms

The review found that adding interferon alfa to chemotherapy significantly increased non-haematological toxicity compared with chemotherapy alone. The additional RCTs also found that adding interferon alfa to chemotherapy increased adverse effects, but the RCT did not perform a direct group comparison. The most common adverse effects were influenza-like symptoms, fatigue, myelosuppression, nausea, and vomiting (see table 7 ).

Table 7
Adding interferon alfa to cytotoxic chemotherapy: harms.

Comment

Clinical guide:

Combined immunotherapy plus chemotherapy may offer a greater chance of tumour shrinkage compared with chemotherapy alone, but overall survival is not prolonged. Until more data become available, immunotherapy should be added to chemotherapy in a clinical trial setting only.

Substantive changes

Adding interferon alfa to chemotherapy One systematic review added which found that adding interferon alfa to combination chemotherapy increased adverse effects without increasing overall survival. Categorisation unchanged (Unlikely to be beneficial).

2008; 2008: 1718.
Published online 2008 August 22.

Adding interferon alfa plus interleukin-2 to chemotherapy

Summary

MORTALITY Compared with chemotherapy alone: Adding interferon alfa plus interleukin-2 to combination chemotherapy is no more effective at increasing overall or progression-free survival ( moderate-quality evidence ). ADVERSE EFFECTS Adding interferon alfa plus interleukin-2 to combination chemotherapy increases non-haematological adverse effects compared with chemotherapy alone (moderate-quality evidence). NOTE We found no direct information about the effects of adding interferon alfa and interleukin-2 to single-agent chemotherapy.

Benefits

We found one systematic review (search date 2006, 7 RCTs, 1226 people) and one subsequent RCT. The systematic review meta-analysed data from four RCTs (819 people) assessing overall survival (time frame not specified), and found no significant difference between interferon alfa plus interleukin plus chemotherapy and chemotherapy alone. It also found no significant difference between groups in the proportion of people who were progression free (3 RCTs, 424 people). The subsequent RCT found similar rates of overall survival in people receiving interferon alfa plus interleukin plus chemotherapy and chemotherapy alone, but did not assess the significance of the difference between groups (see table 8 ).

Table 8
Adding interferon alfa plus interleukin-2 to cytotoxic chemotherapy: benefits.

Harms

The review found that adding interferon alfa plus interleukin-2 to chemotherapy significantly increased non-haematological adverse effects compared with chemotherapy alone. The subsequent RCT found that adding interferon alfa plus interleukin-2 to chemotherapy increased adverse effects, but did not perform a direct group comparison . The most common adverse effects were influenza-like symptoms, fatigue, myelosuppression, nausea, and vomiting (see table 9 ).

Table 9
Adding interferon alfa plus interleukin-2 to cytotoxic chemotherapy: harms

Comment

Clinical guide:

Combined immunotherapy plus chemotherapy may offer a greater chance of tumour shrinkage compared with chemotherapy alone, but overall survival is not prolonged. Until more data become available, immunotherapy should be added to chemotherapy in a clinical trial setting only.

Substantive changes

Adding interferon alfa plus interleukin-2 to chemotherapy One systematic review added which found that adding interferon alfa plus interleukin-2 to combination chemotherapy increased adverse effects without increasing overall survival. Categorisation unchanged (Unlikely to be beneficial).


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