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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.
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.
Melanoma stage
Definition
I
Primary melanoma less than 1 mm in thickness with ulceration or less than 2 mm in thickness without ulceration. No involvement of local lymph nodes
II
Primary melanoma greater than 1 mm in thickness with ulceration or greater than 2 mm in thickness without ulceration. No involvement of local lymph nodes
III
Melanoma of any primary thickness with microscopic or macroscopic involvement of locoregional lymph nodes
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.
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).
Important outcomes
Mortality, quality of life, adverse effects
Number of studies (participants)
Outcome
Comparison
Type of evidence
Quality
Consistency
Directness
Effect size
GRADE
Comment
What are the effects of chemotherapy for metastatic melanoma?
7 (918)
Mortality
Combined cytotoxic chemotherapy v single agents
4
–1
–1
0
0
Low
Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
8 (1194)
Mortality
Different combination cytotoxic chemotherapy regimens v each other
4
–1
–1
0
0
Low
Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (305)
Mortality
Dacarbazine v temozolomide
4
0
0
–1
0
Moderate
Directness point deducted for restaging time differences
1 (305)
Quality of life
Dacarbazine v temozolomide
4
0
0
0
0
High
1 (229
Mortality
Dacarbazine v fotemustine
4
0
0
0
0
High
What are the effects of immunotherapy for metastatic melanoma?
2 (556)
Mortality
Interferon alfa plus cytotoxic chemotherapy v chemotherapy alone
4
–1
0
0
0
Moderate
Quality point deducted for incomplete reporting of results
3 (430)
Adverse effects
Interferon alfa plus cytotoxic chemotherapy v chemotherapy alone
4
–1
0
0
0
Moderate
Quality point deducted for incomplete reporting of results
2 (970)
Mortality
Interferon alfa plus interleukin plus cytotoxic chemotherapy v chemotherapy alone
4
–1
0
0
0
Moderate
Quality point deducted for incomplete reporting of results
2 (670)
Adverse effects
Interferon alfa plus interleukin plus cytotoxic chemotherapy v chemotherapy alone
4
–1
0
0
0
Moderate
Quality point deducted for incomplete reporting of results
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
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.
Malignant melanoma (non-metastatic)
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.
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.
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Cytotoxic chemotherapy plus supportive palliative care versus palliative care alone
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.
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.
Ref
Number of people
Comparison
Median progression-free survival (months)
Median overall survival (months)
132
TMZ plus CDDP v TMZ alone
Not reported
12 with TMZ plus CDDP v 11.5 with TMZ alone; P = 0.89
119
TMZ standard schedule plus Thal v TMZ every 8 hours for 5 doses (3-arm RCT, see table 3 for other comparisons)
Not reported
7.3 with TMZ standard schedule plus Thal v 5.3 with TMZ every 8 hours for 5 doses; significance between groups not assessed, results presented graphically
60
Dartmouth v DTIC alone
4 with Dartmouth v 2 with DTIC; significance between groups not assessed, results presented graphically
9 with Dartmouth v 7 with DTIC alone; significance between groups not assessed, results presented graphically
240
Dartmouth v DTIC alone
Not reported
7.7 with Dartmouth v 6.3 with DTIC alone; P = 0.52
119
DTIC plus Vind v DTIC alone
Not reported
5.8 with DTIC plus Vind v 4.7 with DTIC alone; significance between groups not assessed
131
DTIC plus Tam v DTIC alone (4-arm RCT, see table 3 for other comparisons)
Not reported
7.97 with DTIC plus Tam v 9.99 with DTIC alone; P = 0.85
117
DTIC plus Tam v DTIC alone
Not reported
11 with DTIC plus Tam v 6.75 with DTIC alone; P = 0.02
BCNU, carmustine; CDDP, cisplatin; Dartmouth, dacarbazine plus cisplatin plus carmustine plus tamoxifen; DTIC, dacarbazine; Ref, reference; Tam, tamoxifen; Thal, thalidomide; TMZ, temozolomide; Vind, vindesine
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.
Ref
Number of people
Comparison
Median progression-free survival (months)
Median overall survival (months)
56
DTIC plus Carbo plus Tam v DTIC plus Carbo
Not reported
4.6 with DTIC plus Carbo plus Tam v 7 with DTIC plus Carbo; P = 0.1377
184
Dartmouth v DTIC plus CDDP plus BCNU
3.1 with Dartmouth v 3.4 with DTIC plus CDDP plus BCNU; P = 0.429
6.8 with Dartmouth v 6.9 with DTIC plus CDDP plus BCNU; P = 0.545
211
Dartmouth v DTIC plus CDDP plus BCNU
Results presented graphically; P = 0.86
Absolute results presented graphically; P = 0.52
30
DTIC plus CDDP plus Vinb plus Tam v DTIC plus CDDP plus Vinb (3-arm RCT, see table 6 for other comparisons)
Not reported
12 with DTIC plus CDDP plus Vinb plus Tam v 11 with DTIC plus CDDP plus Vinb; significance not reported for this comparison
219
Standard-dose DTIC plus BCNU plus Vinc v high-dose DTIC plus BCNU plus Vinc v CDDP plus Bleo plus Vind v BCNU plus Procarb
Not reported
4 with standard-dose DTIC plus BCNU plus Vinc v 5 with high-dose DTIC plus BCNU plus Vinc; P = 0.98 4 with standard-dose DTIC plus BCNU plus Vinc v 6 with CDDP plus Bleo plus Vind; P = 0.17 4 with standard-dose DTIC plus BCNU plus Vinc v 4 with BCNU plus Procarb; P = 0.40 5 with high-dose DTIC plus BCNU plus Vinc v 6 with CDDP plus Bleo plus Vind; P = 0.17 5 with high-dose DTIC plus BCNU plus Vinc v 4 with BCNU plus Procarb; P = 0.64 6 with CDDP plus Bleo plus Vind v 4 with BCNU plus Procarb; P = 0.40
326
DTIC plus Vind plus CDDP v DTIC plus Vind
Not reported
7.2 with DTIC plus Vind plus CDDP v 5.9 with DTIC plus Vind; P = 0.22
125
Vind plus Tam v DTIC plus Tam
Not reported
10.5 with Vind plus Tam v 6 with DTIC plus Tam; P = 0.21
43
Vind plus CCNU plus Procarb v DTIC plus CCNU plus Procarb
Not reported
10 with Vind plus CCNU plus Procarb v 14 with DTIC plus CCNU plus Procarb; P greater than 0.05
BCNU, carmustine; Bleo, bleomycin; Carbo, carboplatin; CCNU, lomustine; CDDP, cisplatin; Dartmouth, dacarbazine plus cisplatin plus carmustine plus tamoxifen; DTIC, dacarbazine; Procarb, procarbazine; Ref, reference; Tam, tamoxifen; Vinb, vinblastine; Vinc, vincristine; Vind, vindesine
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.
Ref
Number of people
Comparison
Toxicity (grade 3 or 4 severity)
132
TMZ plus CDDP v TMZ alone
Nausea/vomiting: 10/66 (15%) with TMZ plus CDDP v 0/59 (0%) with TMZ alone; P = 0.002 Anaemia: 1/66 (2%) with TMZ plus CDDP v 2/59 (3%) with TMZ alone; P value not reported, reported as not significant Leukopenia: 3/66 (5%) with TMZ plus CDDP v 2/59 (3%) with TMZ alone; P value not reported, reported as not significant Thrombocytopenia: 9/66 (14%) with TMZ plus CDDP v with 8/59 (14%) TMZ alone; P value not reported, reported as not significant
119
TMZ standard schedule plus Thal v TMZ alone every 8 hours for 5 doses
Fatigue: 0% with TMZ standard schedule plus Thal v 16% with TMZ alone; P less than 0.05 Anaemia: 0% with TMZ standard schedule plus Thal v 8% with TMZ alone; P less than 0.05 Neutropenia: 2% with TMZ standard schedule plus Thal v 28% with TMZ alone; P less than 0.05 Thrombocytopenia: 0% with TMZ standard schedule plus Thal v 34% with TMZ alone; P less than 0.05 Infection: 16% with TMZ standard schedule plus Thal v 0% with TMZ alone; P less than 0.05 Absolute numbers not reported
60
Dartmouth v DTIC
Leukopenia: 33% with Dartmouth v 15% with DTIC Thrombocytopenia: 28% with Dartmouth v 5% with DTIC Anaemia: 28% with Dartmouth v 5% with DTIC Neutropenia: 16% with Dartmouth v 5% with DTIC Nausea/vomiting (grade 3): 15% with Dartmouth v 3% with DTIC Alopecia (grade 3): 58% with Dartmouth v 0% with DTIC Photosensitivity (grade 3): 0% with Dartmouth v 10% with DTIC Infection (grade 3): 10% with Dartmouth v 5% with DTIC Deep vein thrombosis: 8% with Dartmouth v 0% with DTIC Significance between groups not assessed for any adverse effect
240
Dartmouth v DTIC
Nausea/vomiting: 18% with Dartmouth v 5% with DTIC; P less than 0.01 Fatigue: 7% with Dartmouth v 0% with DTIC; significance between groups not assessed Anaemia: 32% with Dartmouth v 6% with DTIC; P less than 0.01 Leukopenia: 9% with Dartmouth v 1% with DTIC; P less than 0.01 Neutropenia: 39% with Dartmouth v 19% with DTIC; P less than 0.01 Thrombocytopenia: 57% with Dartmouth v 7% with DTIC; P less than 0.01 Absolute numbers not reported
119
DTIC plus Vind v DTIC alone
Anaemia (not graded): 37% with DTIC plus Vind v 22% with DTIC alone; absolute numbers not reported, reported as not significant Leukopenia (grade 4): 1/59 (2%) with DTIC plus Vind v 0/51 (0%) with DTIC alone; significance between groups not assessed Neurotoxicity (grade 1): 33% with DTIC plus Vind v 2% with DTIC alone; P less than 0.001, absolute numbers not reported Neurotoxicity (grade 2): 23% with DTIC plus Vind v 6% with DTIC alone; P less than 0.01, absolute numbers not reported Neurotoxicity (grade 3): 2% with DTIC plus Vind v 2% with DTIC alone; absolute numbers not reported, significance between groups not assessed Nausea/vomiting and alopecia: similar in both arms; absolute numbers not reported, significance between groups not assessed
131
DTIC plus Tam v DTIC alone (4-arm RCT, see table 6 for other comparisons)
Nausea/vomiting: 6/63 (10%) with DTIC plus Tam v 4/68 (6%) with DTIC alone Anaemia: 2/63 (3%) with DTIC plus Tam v 1/68 (2%) with DTIC alone Leukopenia: 0/63 (0%) with DTIC plus Tam v 1/68 (2%) with DTIC alone Thrombocytopenia: 0/63 (0%) with DTIC plus Tam v 3/68 (4%) with DTIC alone Significance between groups not assessed
117
DTIC plus Tam v DTIC alone
Reported as similar, no further information reported
CDDP, cisplatin; Dartmouth, dacarbazine plus cisplatin plus carmustine plus tamoxifen; DTIC, dacarbazine; Ref, reference; Tam, tamoxifen; Thal, thalidomide; TMZ, temozolomide; Vind, vindesine
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.
Ref
Number of people
Comparison
Toxicity (grade 3 or 4 severity)
56
DTIC plus Carbo plus Tam v DTIC plus Carbo
Vomiting: None reported in either group Anaemia: 9/28 (32%) with DTIC plus Carbo plus Tam v 3/28 (11%) with DTIC plus Carbo Leukopenia: 14/28 (50%) with DTIC plus Carbo plus Tam v 9/28 (32%) with DTIC plus Carbo Thrombocytopenia: 17/28 (61%) with DTIC plus Carbo plus Tam v 14/28 (50%) with DTIC plus Carbo Significance between groups not assessed
184
Dartmouth v DTIC plus CDDP plus BCNU
Thrombocytopenia: 65% with Dartmouth v 85% with DTIC plus CDDP plus BCNU Nausea/vomiting: 19% with Dartmouth v 12% with DTIC plus CDDP plus BCNU Fatigue: 12% with Dartmouth v 9% with DTIC plus CDDP plus BCNU
211
Dartmouth v DTIC plus CDDP plus BCNU
Leukopenia: 43% with Dartmouth v 44% with DTIC plus CDDP plus BCNU; P = 0.99 Thrombocytopenia (grade 4): 44/101 (44%) with Dartmouth v 43/98 (44%) with DTIC plus CDDP plus BCNU; P = 0.99 Neutropenia (grade 4): 32/101 (32%) with Dartmouth v 31/98 (32%) with DTIC plus CDDP plus BCNU; P = 0.99 Febrile neutropenia: 11/101 (11%) with Dartmouth v 5/98 (5%) with DTIC plus CDDP plus BCNU; P = 0.19 Deep vein thrombosis: 4/101 (4%) with Dartmouth v 6/98 (6%) with DTIC plus CDDP plus BCNU; P = 0.53
30
DTIC plus CDDP plus Vinb plus Tam v DTIC plus CDDP plus Vinb (3-arm RCT, see table 7 for other comparisons)
Nausea/vomiting: 3/15 (20%) with DTIC plus CDDP plus Vinb plus Tam v 2/15 (13%) with DTIC plus CDDP plus Vinb Anaemia: 0/15 (0%) with DTIC plus CDDP plus Vinb plus Tam v 1/15 (7%) with DTIC plus CDDP plus Vinb Leukopenia: 2/15 (13%) with DTIC plus CDDP plus Vinb plus Tam v 3/15 (20%) with DTIC plus CDDP plus Vinb Thrombocytopenia: 1/15 (7%) with DTIC plus CDDP plus Vinb plus Tam v 1/15 (7%) with DTIC plus CDDP plus Vinb Significance between groups not assessed
219
Standard-dose DTIC plus BCNU plus Vinc v high-dose DTIC plus BCNU plus Vinc v CDDP plus Bleo plus Vind v BCNU plus Procarb
Nausea/vomiting: 1/49 (2%) with standard-dose DTIC plus BCNU plus Vinc v 1/47 (2%) with high-dose DTIC plus BCNU plus Vinc v 3/63 (5%) with CDDP plus Bleo plus Vind v 0/60 (0%) with BCNU plus Procarb Anaemia: 5/49 (10%) with standard-dose DTIC plus BCNU plus Vinc v 7/47 (15%) with high-dose DTIC plus BCNU plus Vinc v 4/63 (6%) with CDDP plus Bleo plus Vind v 3/60 (5%) with BCNU plus Procarb Neutropenia: 11/49 (22%) with standard-dose DTIC plus BCNU plus Vinc v 15/47 (32%) with high-dose DTIC plus BCNU plus Vinc v 17/63 (27%) with CDDP plus Bleo plus Vind v 1/60 (2%) with BCNU plus Procarb Thrombocytopenia: 3/49 (6%) with standard-dose DTIC plus BCNU plus Vinc v 8/47 (17%) with high-dose DTIC plus BCNU plus Vinc v 0/63 (0%) with CDDP plus Bleo plus Vind v 0/60 (0%) with BCNU plus Procarb Significance between groups not assessed
326
DTIC plus Vind plus CDDP v DTIC plus Vind
Nausea/vomiting: 49/165 (35%) with DTIC plus Vind plus CDDP v 25/161 (17%) with DTIC plus Vind; P = 0.0011 Anaemia: 17/165 (11%) with DTIC plus Vind plus CDDP v 8/161 (5%) with DTIC plus Vind; significance between groups not assessed Leukopenia: 58/165 (38%) with DTIC plus Vind plus CDDP v 20/161 (13%) with DTIC plus Vind; P less than 0.0001 Thrombocytopenia: 17/165 (11%) with DTIC plus Vind plus CDDP v 10/161 (6%) with DTIC plus Vind; significance between groups not assessed
125
Vind plus Tam v DTIC plus Tam
Nausea/vomiting: 3% with Vind plus Tam v 2% with DTIC plus Tam Neurological toxicity: 7% with Vind plus Tam v 0% with DTIC plus Tam Anaemia: 0% with Vind plus Tam v 2% with DTIC plus Tam Leukopenia: 0% with Vind plus Tam v 5% with DTIC plus Tam Thrombocytopenia: 2% with Vind plus Tam v 0% with DTIC plus Tam Absolute numbers not reported, direct group comparisons not performed
43
Vind plus CCNU plus Procarb v DTIC plus CCNU plus Procarb
Leukopenia: 7/21 (32%) with Vind plus CCNU plus Procarb v 3/22 (14%) with DTIC plus CCNU plus Procarb Alopecia: 11/21 (52%) with Vind plus CCNU plus Procarb v 0/22 (0%) with DTIC plus CCNU plus Procarb Nausea/vomiting: similar in both groups Significance between groups not assessed
BCNU, carmustine; Bleo, bleomycin; Carbo, carboplatin; CCNU, lomustine; CDDP, cisplatin; Dartmouth, dacarbazine plus cisplatin plus carmustine plus tamoxifen; DTIC, dacarbazine; Procarb, procarbazine; Ref, reference; Tam, tamoxifen; Vinb, vinblastine; Vinc, vincristine; Vind, vindesine
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.
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.
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.
Ref
Number of people
Comparison
Progression-free survival
Overall survival or duration of survival
526
Cytotoxic chemotherapy plus IFNa v cytotoxic chemotherapy alone
Not reported
67/266 (25%) with chemotherapy plus IFNa v 52/260 (20%) with chemotherapy alone; Peto OR 0.74, 95% CI 0.49 to 1.12
30
DTIC plus CDDP plus Vinb plus IFNa v DTIC plus CDDP plus Vinb (3-arm RCT, see table 4 for other comparisons)
Not reported
8/15 (53%) with DTIC plus CDDP plus Vinb plus IFNa v 7/15 (47%) with DTIC plus CDDP plus Vinb; significance not reported for this comparison
73
DTIC plus IFNa v DTIC alone
Not reported
Duration of survival (months) 16.7 with DTIC plus IFNa v 8.0 with DTIC alone; P less than 0.01
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.
Ref
Number of people
Comparison
Toxicity (severity grade 3 or 4 unless otherwise specified)
332
Cytotoxic chemotherapy plus IFNa v cytotoxic chemotherapy alone
Non-haematological: 29/166 (17%) with chemotherapy plus IFNa v 10/166 (6% ) with IFNa alone; RR 2.89, 95% CI 1.46 to 5.73
30
DTIC plus CDDP plus Vinb plus IFNa v DTIC plus CDDP plus Vinb (3-arm RCT, see table 5 for other comparisons)
Nausea/vomiting: 3/15 (20%) with DTIC plus CDDP plus Vind plus IFNa v 2/15 (13%) with DTIC plus CDDP plus Vind Anaemia: 0/15 (0%) with DTIC plus CDDP plus Vind plus IFNa v 1/15 (7%) with DTIC plus CDDP plus Vind Leukopenia: 5/15 (30%) with DTIC plus CDDP plus Vind plus IFNa v 3/15 (20%) with DTIC plus CDDP plus Vind Thrombocytopenia: 5/15 (7%) with DTIC plus CDDP plus Vind plus IFNa v 1/15 (7%) with DTIC plus CDDP plus Vind Significance between groups not assessed
73
DTIC plus IFNa v DTIC alone
Nausea/vomiting (not graded): 32/34 (94%) with DTIC plus IFNa v 29/34 (85%) with DTIC alone Haematological toxicity (not graded): 28/34 (82%) with DTIC plus IFNa v 7/34 (21%) with DTIC alone Influenza-like symptoms (grade 3): 3/34 (9%) with DTIC plus IFNa v 0/34 (0%) with DTIC alone Significance between groups not assessed
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).
BMJ Clin Evid. 2008 Aug 22;2008:1718.
Adding interferon alfa plus interleukin-2 to chemotherapy
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.
Ref
Number of people
Comparison
Progression-free survival
Median overall survival (proportion)
819
Cytotoxic chemotherapy plus IFNa plus IL-2 v cytotoxic chemotherapy alone
17/213 (8%) with chemotherapy plus IFNa plus IL-2 v 10/211 (5%) with chemotherapy alone; Peto OR 0.76, 95% CI 0.57 to 1.02
95/417 (23%) with chemotherapy plus IFNa plus IL-2 v 69/412 (17%) with chemotherapy alone; Peto OR 0.89, 95% CI 0.72 to 1.11
151
DTIC plus CDDP plus Vind plus IFNa plus IL-2 v DTIC plus CDDP plus Vind
Not reported
43% with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 50%with DTIC plus CDDP plus Vind; absolute numbers not reported; significance between groups not assessed
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
Ref
Number of people
Comparison
Toxicity (severity grade 3 or 4 unless otherwise specified)
526
Cytotoxic chemotherapy plus IFNa plus IL-2 v cytotoxic chemotherapy alone
Non-haematological: 109/263 (41%) v 41/263 (16%); RR 2.63, 95% CI 1.78 to 3.90
151
DTIC plus CDDP plus Vind plus IFNa plus IL-2 v DTIC plus CDDP plus Vind
Nausea/vomiting: 22/72 (30%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 9/72 (13%) with DTIC plus CDDP plus Vind Fatigue: 14/72 (19%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 6/72 (8%) with DTIC plus CDDP plus Vind Anaemia: 8/72 (11%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 3/72 (4%) with DTIC plus CDDP plus Vind Neutropenia: 11/72 (15%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 9/72 (13%) with DTIC plus CDDP plus Vind Leukopenia: 4/72 (6%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 3/72 (4%) with DTIC plus CDDP plus Vind Thrombocytopenia: 6/72 (8%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 7/72 (10%) with DTIC plus CDDP plus Vind Fever: 26/72 (36%) with DTIC plus CDDP plus Vind plus IFNa plus IL-2 v 0/72 (0%) with DTIC plus CDDP plus Vind Significance between groups not assessed for any outcome
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).
