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BMJ Clin Evid. 2007; 2007: 1705.
Published online 2007 June 1.
PMCID: PMC2943794

Malignant melanoma (non-metastatic)

Philip Savage, PhD FRCP, Consultant in Cancer Medicine

Abstract

Introduction

The incidence of malignant melanoma has increased over the past 25 years in the UK, but death rates have remained fairly constant. Five-year survival ranges from 20% to 95% depending on disease stage. Risks are greater in white populations and in people with higher numbers of skin naevi.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent malignant melanoma? Is there an optimal surgical margin for the primary excision of melanoma? What are the effects of elective lymph node dissection in people with malignant melanoma with clinically uninvolved lymph nodes? What are the effects of sentinel lymph node biopsy in people with malignant melanoma with clinically uninvolved lymph nodes? What are the effects of adjuvant treatment for malignant melanoma? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (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 30 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: adjuvant vaccines; elective lymph node dissection; low-, intermediate-, and high-dose adjuvant interferon alfa; sentinel lymph node biopsy; suncreens; surveillance for early recurrence; and wide excisions.

Key Points

The incidence of malignant melanoma has increased over the past 25 years in the UK, but death rates have remained fairly constant. Five year survival ranges from 20% to 95% depending on disease stage.

  • Risks are greater in white populations and in people with higher numbers of skin naevi.
  • Prognosis depends on depth of tumour, ulceration, and number of lymph nodes involved. Survival may be better in women compared with men, and for lesions on the limbs compared with the trunk.
  • Lesions can recur after 5-10 years, so long term surveillance may be required.

Sunscreens have not been shown to reduce the risk of malignant melanoma, but sunscreen use does not necessarily correlate with reduced total ultraviolet light exposure.

Wide (3 cm) excision of lesions leads to reduced local recurrence compared with narrow (1 cm) excision in people with tumours greater than 2 mm Breslow thickness.

  • Wide (3-5 cm) excision is unlikely to be more beneficial than narrow (1-2 cm) excision in people with tumours of less than 2 mm Breslow thickness, and may increase the need for skin grafts.

Elective lymph node dissection is unlikely to increase survival in people without clinically detectable lymph node metastases.

We don't know whether adjuvant treatment with vaccines, high dose interferon alfa, or surveillance for early treatment of recurrence improve survival.

  • Low and intermediate dose interferon are unlikely to improve relapse rates or survival compared with no adjuvant treatment.
  • High dose interferon alfa may increase the time until relapse compared with no adjuvant treatment, but overall survival seems to be unchanged.
  • Severe adverse effects occur in 10-75% of people receiving interferon alfa treatment.

About this condition

Definition

Malignant melanoma is a tumour derived from melanocytes in the basal layer of the epidermis. After malignant transformation, the cancer cells become invasive and penetrate into and beyond the dermis. Malignant melanoma is described by stages (I-IV), which relate to the depth of dermal invasion and the presence of ulceration (see table 1 ). Metastatic spread can occur to the regional lymph nodes or to distant sites, particularly the lungs, liver, and central nervous system.

Table 1
Melanoma incidence and mortality in different populations (see text).

Incidence/ Prevalence

The incidence of melanoma varies widely in different populations and is about 10-20 times higher in white than non-white populations. Estimates suggest that the number of cases of melanoma in the UK has increased about fourfold over the past 25 years (see table 2 ). Despite this rising incidence, death rates have changed more modestly, and in some populations are now beginning to fall. The increased early diagnosis of thin, good prognosis melanoma and melanoma in situ are the main reasons for the divergent findings on incidence and death rates.

Table 2
Stage of malignant melanoma and 5 year survival (see text).

Aetiology/ Risk factors

The risk factors for the development of melanoma can be divided into genetic and environmental. Alongside the genetic risk factors of skin type and hair colour, the number of naevi a person has correlates closely with the risk of developing malignant melanoma. Although the risk of developing malignant melanoma is higher in fair skinned populations living in areas of high sun exposure, the exact relationship between sun exposure, sunscreen use, skin type, and risk is not clear. High total lifetime exposure to excessive sunlight, and episodes of severe sunburn in childhood, are both associated with an increased risk of developing malignant melanoma in adult life. However, people do not necessarily develop malignancy at the sites of maximum exposure to the sun.

Prognosis

The prognosis of early stage malignant melanoma, which is clinically limited to the primary skin site (stages I-II) is predominantly related to the depth of dermal invasion and the presence of ulceration (see table 1 ). In stage III disease, where disease is present in the regional lymph nodes, the prognosis becomes worse with the increasing number of nodes involved. For example, a person with a thin lesion (Breslow thickness < 1.0 mm) without lymph node involvement has a 95% chance of surviving 5 years. However, if the regional lymph nodes are macroscopically involved, the overall survival at 5 years is only 20-50%. In addition to tumour thickness and lymph node involvement, several studies have shown a better prognosis in women and in people with lesions on the limbs compared with those with lesions on the trunk. Lesions can recur after after 5-10 years, so long term surveillance may be required.

Aims of intervention

To reduce the risk of melanoma; to detect melanoma earlier; to minimise the adverse effects of surgical treatment while still achieving cure of local disease; to optimise quality of life and to eradicate occult metastatic disease, with acceptable adverse effects.

Outcomes

Prevention: Incidence of malignant melanoma; mortality from malignant melanoma; rates and severity of sunburn (proxy measure). Primary excision: Local recurrence, relapse; overall survival; requirement for skin grafting; adverse effects of treatment. Lymph node dissection and adjuvant treatment: Overall survival; disease free survival; quality of life; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal October 2006. The following databases were used to identify studies for this review: Medline 1966 to October 2006, Embase 1980 to October 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials, Issue 3, 2006. 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 National Institute for Health and Clinical Excellence (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 predetermined 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 if possible, 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 US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review 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 non-metastatic malignant melanoma

Glossary

Breslow thickness
The vertical depth (in mm) to which the tumour has penetrated.
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
Very low-quality evidence
Any estimate of effect is very uncertain

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.

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2007; 2007: 1705.
Published online 2007 June 1.

Sunscreens

Summary

INCIDENCE OF MALIGNANT MELANOMA Compared with no sunscreen use: The effects of sunscreen use compared with no use in the prevention of malignant melanoma are unclear ( very low-quality evidence ).

Benefits

We found no RCTs assessing the effects of sunscreen in preventing malignant melanoma (see comment below). However, we found four systematic reviews of case control studies. The reviews primarily identified the same studies, but had differing inclusion criteria, and differing methods of analysing the data. Two of the reviews performed a meta-analysis, and two did not because of perceived heterogeneity among the studies. We have therefore reported results from all reviews here; we will report the results of the most recent review first. The first systematic review (search date 2003) included 18 case control studies (about 5400 cases and about 7600 controls), including 11 of the studies identified by the second review and two excluded because of methodological problems, also including all 11 studies identified by the third review, and including 14 of the studies identified by the fourth review. The review found no significant difference in cases of melanoma between people who had “ever” used sunscreen compared with those who had “never” used sunscreen (OR 1.0, 95% CI 0.8 to 1.2). The authors of the review cautioned that data concerning modern sunscreens that have higher sun protection factor values and increased ultraviolet A blocking will not be available for several years. The second systematic review (search date not reported) identified 12 case control studies (4763 cases and 6663 controls), which found conflicting results. Two case control studies identified by the review (522 people with malignant melanoma, 1039 controls) found that people who “regularly” used sunscreen were less likely to develop melanoma than people who “never” used sunscreen. However, three case control studies (831 people with melanoma, 1550 controls) that adjusted for fair skin pigmentation, tendency to sunburn, and participation in water sports, found no association between sunscreen use and the development of melanoma. Another three case control studies found no significant difference between sunscreen use and no use in the risk of developing melanoma. Finally, three case control studies (1389 people with melanoma, 1991 controls) found that regular use of sunscreen may be associated with an increased risk of developing melanoma compared with no use. The third systematic review (search date 1999, 11 case control studies, including 8 studies identified by the second review and 2 excluded because of methodological problems; 3681 cases and 5386 controls) found no significant difference in the risk of developing melanoma between people who “regularly”, “often”, or “always” used sunscreen and people who “never” used sunscreen (RR 1.11, 95% CI 0.37 to 3.32). However, the authors of the review suggested that the results should be treated with caution because there was significant heterogeneity among studies, and eight of the 11 studies found that sunscreen use significantly increased the risk of melanoma compared with no sunscreen use. The fourth systematic review (search date not reported, 17 case control studies, including 11 studies identified by the second review and 2 excluded because of methodological problems, and including all 11 studies identified by the third review; 6045 cases and 8097 controls) stated that no firm conclusions could be drawn about the effects of sunscreen in preventing melanoma because of the heterogeneity of the studies identified.

Harms

Some of the individual case control studies identified by the reviews found an increased melanoma risk in regular sunscreen users compared with non-sunscreen users. The systematic reviews gave no other information on adverse effects.

Comment

Clinical guide:

It is difficult to obtain high quality prospective evidence about the effect of sunscreen usage on the risk of melanoma development. Sunscreens are widely used, and it would therefore be difficult to identify individuals who would consent to the possibility of being randomised to placebo. Placebo controlled RCTs are therefore unlikely to be conducted. By their nature, case control studies all have potential biases and confounding factors. However, these studies are the best evidence available, and have not shown any clear evidence that sunscreen use is associated with a reduction in melanoma risk. This finding is perhaps not surprising, as most sunscreen users employ them as a means to sunbathe for longer, and consequently they increase their total ultraviolet radiation doses. Although it is possible that the more modern sunscreens that filter out an increased proportion of the more harmful ultraviolet A radiation may be beneficial in reducing melanoma risk, at present there is no evidence to confirm this. The International Agency for Research on Cancer has issued a consensus statement saying that, although sunscreens reduce the likelihood of sunburn, and are therefore likely to reduce squamous cell carcinoma, the evidence regarding the effect of sunscreens on basal cell carcinoma or melanoma is inconclusive. This organisation warns that use of sunscreens to extend the period of intentional sun exposure may increase the risk of melanoma. The International Agency for Research on Cancer statement suggested that sunscreens of sun protection factor 15 or greater and a star rating for ultraviolet A light protection of 3–4 may have a role if used appropriately to reduce ultraviolet exposure, rather than being used to prolong the time spent in direct sunlight.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Wide (3 cm) excision in tumours greater than 2 mm Breslow depth

Summary

RECURRENCE AND RELAPSE Wider excision margins compared with narrower excision margins: Recurrence and relaspe rates after 5 years may be lower with a 3 cm excision margin compared with a 1 cm excision margin in people with thicker primary melanoma of greater than 2 mm Breslow depth ( moderate-quality evidence ). MORTALITY Wider excision margins compared with narrower excision margins: Wider (3 cm) excision margins are no more effective than narrower (1 cm) excision margins at reducing overall mortality or deaths from malignant melanoma (moderate-quality evidence). NOTE We found no direct evidence comparing 2 cm and 3 cm excision margins in this group of people.

Benefits

Local recurrence and relapse:

The RCT compared 1 cm and 3 cm excision margins. Over a median follow up of 60 months, a 1 cm excision margin increased the risk of locoregional recurrence compared with a 3 mm excision margin; this increase was of borderline significance (900 people with melanoma > 2 mm Breslow thickness; HR 1.26, 95% CI 1.00 to 1.59). The RCT found similar local recurrence rates and rates of distant metastases between wider (3 cm) and narrower (1 cm) excision margins; it did not assess the significance of the difference between groups for these outcomes (see table 3 ). Progression free and overall survival: The RCT found no significant difference in overall survival between the 1 cm and 3 cm excision margins over a median follow up of 60 months (see table 3 ). The RCT found that deaths from melanoma were increased in the 1 cm excision margin group compared with the 3 cm excision margin group (see table 3 ). Although this increase was not statistically significant, it may be clinically significant. Size of excision margins: We found no RCTs comparing 2 cm versus 3 cm excision margins in people with tumours greater than 2 mm in thickness.

Table 3
RCTs for assessing radical versus less radical local surgery for malignant melanoma (see text).

Harms

The RCT did not report on adverse effects.

Comment

Clinical guide:

For current recommended excision margins, see table 4 .

Table 4
Currently recommended excision margins for primary melanoma.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Wide excision in tumours less than 2 mm Breslow depth

Summary

RECURRENCE AND RELAPSE Wider excision margins compared with narrower excision margins: Wider excision margins (3–5 cm) do not reduce recurrence or relapse compared with narrower excision margins (1–2 cm) after 2–3 years in people with primary cutaneous melanoma of less than 2 mm Breslow depth ( high-quality evidence ). MORTALITY Wider excision margins compared with narrower excision margins: Wider excision margins (3–5 cm) do not reduce overall or progression-free mortality after 5–10 years compared with narrower excision margins (1–2 cm) in people with primary cutaneous melanoma of less than 2 mm Breslow depth (high-quality evidence). ADVERSE EFFECTS Wider excision has been associated with increased need for skin grafting and longer duration of hospital stay compared with narrower excision.

Benefits

Excision margins assessed:

Both reviews compared wider (3, 4, or 5 cm) versus narrower (1 or 2 cm) margins. The first subsequent RCT compared 2 cm versus 5 cm margins. Local recurrence and relapse: The first review (search date 2001, 2406 people) identified four RCTs, one of which was published only as an abstract, in people with stage I and II melanoma (see table 1 ) of less than or equal to 4 mm Breslow thickness). The second review (search date 2002) identified the same three RCTs (2087 people) as the first review but excluded the RCT which was only published as an abstract. The reviews differed in their decisions regarding whether or not to meta-analyse data on local recurrence, so we have reported results from both reviews here. The first review identified four RCTs that assessed local recurrence, but it did not perform a meta-analysis for this outcome because of the differing definitions of local recurrence and different durations of follow up among the trials. However, none of the RCTs found a significant difference between wider or narrower excision margins in local recurrence defined as a recurrence within the scar or transplant, a recurrence within 1 cm of the surgical scar, or a recurrence within 2 cm of the scar (see table 3 ). The second review found no significant difference in local recurrence at 48–72 months between wider (3–5 cm) and narrower (1–2 cm) excision margins (3 RCTs: RR 0.98, 95% CI 0.4 to 2.5). The first subsequent RCT also found no significant difference in recurrence rates between 2 cm and 5 cm margins (see table 3 ). Progression free and overall survival: The first review found no significant difference in overall survival at 5 years between narrower (1–2 cm) and wider (4–5 cm) excision margins (3 RCTs: 732/867 [84%] with narrower v 796/911 [87%] with wider; OR 0.79, 95% CI 0.61 to 1.04). The second review re-examined the three published RCTs and again found no significant difference in mortality at 4–6 years between wider (3–5 cm) and narrower (1–2 cm) excision margins (RR 0.93, 95% CI 0.73 to 1.19). The first subsequent RCT also found no significant difference in progression free or overall survival at 10 years between 2 cm and 5 cm excision margins (see table 3 ).

Harms

One RCT (486 people with 1–4 mm melanoma) identified by the reviews found that wider (4 cm) excision margins significantly increased skin grafting and inpatient stay compared with narrower (2 cm) margins (skin grafting: 11% with narrower v 46% with wider; P < 0.001; mean inpatient stay: 5.2 days with narrower v 7.0 days with wider; P = 0.001). However, it found no significant difference in wound infection or wound dehiscence between narrow and wider margins (wound infection: 4.6% with narrower v 5.4% with wider, reported as not significant, P value not reported; wound dehiscence: 4.2% with narrower v 4.6% with wider, reported as not significant, P value not reported). The other RCTs identified by the reviews and the subsequent RCT gave no information on adverse effects.

Comment

Clinical guide:

For current recommended excision margins, see table 4 .

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Elective lymph node dissection

Summary

MORTALITY Compared with surgery deferred to the time of clinical recurrence: Elective lymph node dissection does not reduce mortality after 5 years compared with deferring surgery to the time of clinical recurrence in people with malignant melanoma without clinically detectable lymph node metastases ( high-quality evidence ). ADVERSE EFFECTS Lymph node dissection has been associated with lymphoedema and wound-related adverse effects.

Benefits

We found one systematic review (4 RCTs, 1704 people with stage I and II melanoma without clinical evidence of lymph node metastases [see table 1 ; see comment below]) comparing elective lymph node dissection versus surgery deferred until the time of clinical recurrence. The review found no significant difference in survival at 5 years between elective lymph node dissection and delayed or no lymph node dissection (3 RCTs; AR for death: 197/768 [26%] with elective dissection v 219/765 [29%] with delayed or no dissection; OR for death 0.86, 95% CI 0.68 to 1.09). Retrospective subgroup analyses in the RCTs found non-significant trends in favour of elective lymph node dissection in certain groups of people (those with intermediate thickness tumours, especially those < 60 years of age), but such analyses are subject to bias.

Harms

The systematic review gave no information on adverse effects. One of the RCTs identified by the review found that lymphoedema developed in 32/110 (29%), seroma of the inguinal wounds of 11/110 (10%) and the axillary wounds of 3/110 (3%), significant haematoma in 1/110 (1%), delayed healing of the inguinal wound in 7/110 (6%), necrosis of the skin flaps in 1/110 (1%), and dehiscence and wound infection in 1/110 (1%). The other RCTs identified by the review gave no information on adverse effects.

Comment

Clinical guide:

Elective lymph node dissection has become a relatively unusual procedure in the management of stage I and II melanoma. Although subgroup analyses have suggested that some groups may potentially benefit, the lack of clear-cut benefit to most people, and the not inconsiderable complication rate, have led most surgeons to investigate the role of sentinel lymph node biopsy and dissection in suitable patients.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Sentinel lymph node biopsy

Summary

We found no clinically important results about the effects of sentinel lymph node biopsy on survival in people with malignant melanoma.

Benefits

We found no systematic review or RCTs that assessed survival (see comment below).

Harms

We found no RCTs.

Comment

Clinical guide:

Sentinel lymph node biopsy involves identification of the lymph node group that drains the primary tumour site, and then removing the first or sentinel node from this group. A full lymph node dissection is only performed if the node is shown to contain tumour. This procedure allows people with a negative sentinel node to avoid full lymph node dissection, and provides valuable prognostic information. The impact of sentinel lymph node biopsy on the natural history of the malignancy and overall survival is currently unclear, and is obviously an important question. Sentinel lymph node biopsy has recently been evaluated in RCTs, and the results of these RCTs should be available in 2007–2008.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Vaccines

Summary

MORTALITY Compared with no vaccine: Adjuvant vaccine plus surgery is no more effective than surgery alone at reducing mortality after 5–10 years ( moderate-quality evidence ). Compared with placebo vaccine: Melanoma vaccine does not reduce mortality after 3 years compared with placebo vaccine (moderate-quality evidence). Compared with high-dose interferon alfa: Ganglioside GM2 vaccine is less effective than high-dose interferon alfa at reducing mortality and increasing relapse-free survival after 16 months to 2 years ( high-quality evidence ).

Benefits

We found five RCTs comparing adjuvant vaccines versus no vaccine, placebo vaccine, or interferon alfa. Four RCTs found no significant difference in survival between adjuvant vaccines and surgery alone or surgery plus placebo vaccine. One RCT found that ganglioside GM2 vaccine was less effective than high dose interferon alfa in terms of relapse free and overall survival.A different vaccine preparation was used in each RCT, making it difficult to compare results from individual RCTs.

Vaccines versus no vaccine (surgery alone):

The first RCT (700 people with resected stage IIB or III [see table 1 ] primary or recurrent nodal involvement) compared adjuvant vaccine (prepared from vaccinia melanoma cell lysates) versus no vaccine. It found no significant difference between adjuvant vaccine and surgery alone in relapse free survival or overall survival at 5 years or 10 years (relapse free survival: 51% with adjuvant treatment v 47% with no adjuvant treatment; overall survival: 60% with adjuvant treatment v 55% with no adjuvant treatment; reported as not significant, CI not reported). The second RCT (689 people with completely resected stage II melanoma, primary tumour 1.5–4.0 mm Breslow thickness) found no significant difference in relapse free survival at 5 years between adjuvant vaccine (allogeneic melanoma cell lysate) and no vaccine (66% with vaccine v 62% with no vaccine; P = 0.17).

Vaccines versus surgery plus placebo vaccine:

The third RCT (217 people with resected stage III melanoma) compared adjuvant vaccinia melanoma oncolysate versus placebo vaccine (vaccinia virus). The RCT found no significant difference between melanoma vaccine and placebo vaccine in terms of disease free survival (P = 0.61) or overall survival (P = 0.79, absolute results presented graphically). The fourth RCT (38 people with resected stage III melanoma) compared polyvalent melanoma vaccine versus placebo vaccine (human albumin). It found that melanoma vaccine significantly increased time to recurrence compared with placebo vaccine (1.6 years with vaccine v 0.6 years with placebo vaccine; P = 0.03). It found no significant difference in overall survival at 3 years (53% with vaccine v 33% with placebo vaccine; reported as not significant, P value not reported).

Vaccines versus interferon alfa:

See benefits of high dose interferon alfa.

Harms

Vaccines versus no vaccine (surgery alone):

The first RCT found that melanoma vaccine was associated with erythema and ulceration at the injection site (47% of people), malaise (35%), and fever (20%). The second RCT found that most people receiving melanoma vaccine had mild to moderate adverse effects and that 9% of people had severe adverse effects, including malaise, fatigue, visual complaints, fever, diarrhoea, thrombocytopenia, or skin rash.

Vaccines versus surgery plus placebo vaccine:

The third RCT found that both melanoma vaccine and placebo vaccine were associated with headache, nausea, and fever. Erythema, swelling, and tenderness were also reported at the injection site (data not reported). The fourth RCT found that both vaccine and placebo vaccine were associated with skin reactions but found no other adverse effects (data not reported). One RCT found that injection site reactions were the most common grade 3 events in people receiving ganglioside GM2 vaccine, but no one discontinued because of the reaction (10/429 [2.3%] with vaccine v 1/440 [0.3%] with interferon alfa; significance not reported).

Vaccines versus interferon alfa:

See harms of high dose interferon alfa.

Comment

Clinical guide:

Cancer vaccines aim to enhance the ability of the immune system to recognise and attack the tumour cells. Although cancer vaccines are an attractive theoretical idea, in the treatment of melanoma they remain experimental. Owing to the complexity of the immune system, and the differing nature of the vaccine preparations used in each RCT, it is difficult to reach conclusions about vaccine effectiveness. Subgroup analysis of the allogeneic melanoma cell lysate vaccine study indicated a potential for activity in people with HLA-A2 and C3 tissue types, and this is being examined prospectively in a further study limited to people of these tissue types.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Surveillance for early treatment of recurrent melanoma

Summary

We found no clinically important results about the effects of more- or less-intensive follow-up or surveillance for early treatment of recurrent melanoma.

Benefits

We found no systematic review or RCTs (see comment below).

Harms

We found no RCTs.

Comment

Clinical guide:

Retrospective studies found that people presented with symptomatic recurrent malignant melanoma regardless of whether they were taking part in an intensive follow up programme. Thinner lesions (< 0.75 mm) may require longer surveillance because recurrence peaks at 5–10 years.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Interferon alfa (high dose)

Summary

MORTALITY Compared with observation alone: High-dose interferon alfa does not reduce mortality compared with observation alone after 4–7 years ( high-quality evidence ). Compared with ganglioside GM2 vaccine: High-dose interferon alfa reduces mortality and increases relapse-free survival after 16 months to 2 years compared with ganglioside GM2 vaccine (high-quality evidence). High-dose compared with low-dose interferon alfa: High-dose interferon alfa may increase relapse-free survival, but does not reduce overall mortality, compared with low-dose interferon alfa ( low-quality evidence ). RELAPSE Compared with observation alone: High-dose interferon alfa prolongs the time to relapse compared with observation alone after 4–7 years (high-quality evidence). ADVERSE EFFECTS High-dose interferon alfa is associated with high rates of toxicity (myelosuppression, hepatotoxicity, and neurotoxicity).

Benefits

High dose interferon alfa versus no adjuvant treatment (observation):

We found one systematic review, which found that high dose interferon alfa significantly reduced relapse rates compared with no adjuvant treatment (search date 2002, 3 RCTs, 978 people with stages I–III malignant melanoma; OR 0.70, 95% CI 0.54 to 0.91). However, it found no significant difference in overall survival over a median 4–7 years between high dose interferon alfa and no adjuvant treatment (3 RCTs, 978 people: OR 0.89, 95% CI 0.69 to 1.15).

High dose versus low dose interferon alfa:

We found one systematic review, which found that higher doses of interferon alfa significantly increased relapse free survival compared with lower doses (search date 2002, 2 RCTs; OR 0.68, 95% CI 0.50 to 0.92). It found no significant difference in overall survival between high and low doses (OR 0.90, 95% CI 0.66 to 1.21; absolute numbers not reported for either outcome).

High dose interferon alfa versus ganglioside GM2 vaccine:

We found one systematic review (search date not reported), which identified one RCT (880 people with resected stage IIB and III melanoma) comparing high dose interferon (20 MU/m2 iv 5 times/week for 4 weeks plus 10 MU/m2 sc 3 times/week for 48 weeks) versus ganglioside GM2 vaccine. The RCT found that high dose interferon alfa significantly improved relapse free survival (estimated relapse free survival at 2 years: 62% with interferon alfa v 49% with ganglioside; HR 1.47, 95% CI 1.14 to 1.90) and overall survival over a median follow up of 16 months (AR for death: 52/385 [14%] with interferon alfa v 81/389 [21%] with ganglioside; HR for survival 1.52, 95% CI 1.07 to 2.15) compared with ganglioside vaccine.

Harms

High dose interferon alfa versus no adjuvant treatment (observation):

The review did not report on harms. In the first RCT identified by the review, high dose interferon alfa caused severe toxicity — myelosuppression in 24% of people, hepatotoxicity in 15% (including 2 deaths), and neurotoxicity in 28%. During the year of treatment, 76% of people had severe grade 3 or 4 toxicity. At 11 months, only 25% of participants were receiving more than 80% of the planned dose. In the second RCT, high dose interferon alfa was associated with grade 3 influenza-like toxicity in 44% of people compared with 3% of people receiving no adjuvant treatment. In the third RCT, the most common toxicity grade 3 and 4 events were: granulocytopenia, liver toxicity, fatigue, neuroclinical toxicity, and myalgia (granulocytopenia: 85/212 [40%] grade 3 and 9/212 [4%] grade 4 with high dose v 0/207 [0%] grades 3 and 0/207 [0%] grade 4 with no adjuvant treatment; liver toxicity: 61/212 [29%] grade 3 with high dose v 6/207 [3%] with no adjuvant treatment; fatigue: 49/212 [23%] grade 3 and 2/212 [1%] grade 4 with high dose v 0/207 [0%] grades 3 and 0/207 [0%] grade 4 with no adjuvant treatment; neuroclinical toxicity: 42/212 [20%] grade 3 with high dose v 2/207 [1%] with no adjuvant treatment; myalgia: 35/212 [16%] grade 3 and 2/212 [1%] grade 4 with high dose v 0/207 [0%] grade 3 and 0/207 [0%] grade 4 with no adjuvant treatment).

High dose versus low dose interferon alfa:

The review did not report on harms.

High dose interferon alfa versus ganglioside GM2 vaccine:

In the RCT comparing high dose interferon alfa versus ganglioside GM2 vaccine, 45/440 (10%) people taking high dose interferon alfa discontinued treatment because of adverse effects (most commonly fatigue, cytopenias, elevation of liver enzymes, and neurological symptoms) compared with 0/440 (0%) with ganglioside GM2 vaccine.

Comment

The role of high dose interferon alfa as an adjuvant treatment for melanoma is uncertain at present. Further RCTs investigating high dose and sustained release polyethylene glycol conjugated (pegylated) interferon alfa have recently been completed, with results awaited (Savage P, personal communication, 2005). In this review, low and intermediate doses of interferon alfa generally range from 3 MU to 5 MU, and high doses generally range from 10 MU to 20 MU, but the dosing schedules vary considerably between studies in terms of initial and maintenance dose, and frequency and duration of treatment.

Substantive changes

No new evidence

2007; 2007: 1705.
Published online 2007 June 1.

Interferon alfa (low and intermediate dose)

Summary

MORTALITY Low-dose interferon alfa compared with no adjuvant treatment: Low-dose interferon alfa does not reduce mortality after 3–8 years compared with no adjuvant treatment ( high-quality evidence ). Intermediate-dose interferon compared with no adjuvant treatment: Intermediate-dose interferon alfa does not reduce mortality after 4–5 years compared with no adjuvant treatment ( moderate-quality evidence ). RELAPSE Low-dose interferon alfa compared with no adjuvant treatment: The effects of low-dose interferon alfa on relapse rates are unclear compared with no adjuvant treatment after 3–8 years (moderate-quality evidence). Intermediate-dose interferon alfa compared with no adjuvant treatment: Intermediate-dose interferon alfa does not reduce relapse rates after 4–5 years compared with no adjuvant treatment (moderate-quality evidence). ADVERSE EFFECTS Severe toxicity may occur in 10% of people taking low- or intermediate-dose interferon alfa.

Benefits

Low dose interferon alfa versus no adjuvant treatment:

We found one systematic review and two subsequent RCTs. The review found that low dose interferon alfa significantly reduced relapse rates compared with no adjuvant treatment (search date 2002, 7 RCTs, 2114 people with stages I–III malignant melanoma; OR 0.75, 95% CI 0.63 to 0.91). However, it found no significant difference between low dose interferon alfa and no adjuvant treatment in overall survival over a median 3–7 years' follow up (7 RCTs, 2114 people; OR 0.84, 95% CI 0.69 to 1.03). The first subsequent RCT (674 people with radically resected stage IIB and stage III malignant melanoma) compared low dose interferon (3 MU 3 times/week for 2 years or until recurrence) versus observation. It found no significant difference in relapse free survival (OR 0.91, 95% CI 0.75 to 1.10) or overall survival (OR 0.94, 95% CI 0.75 to 1.18) at 5 years' follow up. The second subsequent RCT (830 people with stage II or III melanoma, most with primary tumours > 3 mm or lymph node involvement) compared low dose interferon gamma or interferon alfa versus no adjuvant treatment for 12 months. It found no significant difference in disease free survival (HR interferon alfa v no treatment 1.04, 95% CI 0.84 to 1.30) or overall survival at 8 years (HR 0.96, 95% CI 0.76 to 1.21).

Intermediate dose interferon alfa versus no adjuvant treatment:

We found no systematic review but found one RCT. The RCT (1388 people with stage IIb or III melanoma) compared no adjuvant treatment with interferon alfa 10 MU five times a week for 4 weeks, followed by either 10 MU three times a week for 1 year (13 months total treatment) or 5 MU three times a week for 2 years (25 months total treatment). It found no significant difference between intermediate dose interferon alfa compared with no adjuvant treatment in the rate of disease free intervals at 4.5 years, although there was a trend towards improvement in the rate of disease free intervals for both treatment arms (13 months treatment: 43%, HR 0.93, 97.5% CI 0.75 to 1.16; 25 months treatment: 47%, HR 0.83, 97.5% CI 0.66 to 1.03; no treatment: 40% [absolute numbers not reported]). The RCT also found no significant difference between both treatment arms compared with no adjuvant treatment for overall survival rates at 4.5 years (13 months treatment: 48.3%, HR 0.97, 97.5% CI 0.77 to 1.21; 25 months treatment: 53.1%, HR 0.85, 97.5% CI 0.68 to 1.07; no treatment: 47.7% [absolute numbers not reported]).

High dose versus low dose interferon alfa:

See benefits of high dose interferon alfa.

Harms

Interferons commonly cause malaise, fevers, and influenza-like symptoms.

Low dose interferon alfa versus no adjuvant treatment:

The review did not report on adverse events. In one of the RCTs identified by the review, 10% of people taking low dose interferon alfa developed grade 3 or 4 toxicity. A second RCT identified by the review found that 5/154 (3%) of people taking low dose interferon alfa withdrew because of severe adverse effects, including leukopenia, thrombocytopenia, and cardiac arrhythmia. A third RCT identified by the review found that few people developed toxicity; 7% of people had a dose reduction because of adverse effects but none withdrew from treatment. A fourth RCT identified by the review found that 162/225 (72%) people taking low dose interferon alfa developed grade 1 toxicity, 54/225 (24%) grade 2 toxicity, and 9/225 (4%) no toxicity. In a fifth RCT, grade 3 and 4 toxicities associated with low dose interferon alfa included granulocytopenia, liver toxicity, fatigue, neuroclinical toxicity, and myalgia (granulocytopenia: 12/214 [6%] grade 3 with low dose interferon alfa v 0/207 [0%] with no adjuvant treatment; liver toxicity: 8/214 [4%] grade 3 and 1/214 [0.05%] grade 4 with low dose interferon alfa v 6/207 [3%] grade 3 and 0/207 [0%] grade 4 with no adjuvant treatment; fatigue: 7/214 [3%] grade 3 with low dose interferon alfa v 0/207 [0%] with no adjuvant treatment; neuroclinical toxicity: 14/214 [6%] grade 3 with low dose interferon alfa v 2/207 [1%] with no adjuvant treatment; myalgia: 18/214 [8%] grade 3 with low dose interferon alfa v 0/207 [0%] with no adjuvant treatment).

Intermediate dose interferon alfa versus no adjuvant treatment:

One RCT found that intermediate dose interferon alfa produced grade 3–4 toxicities in 131/1076 [12%] of people, which lead to interruption or stopping of treatment.

High dose versus low dose interferon alfa:

See harms of high dose interferon alfa. One RCT found that low dose interferon alfa significantly increased the proportion of people with grade 3 fatigue compared with no adjuvant treatment (22/137 [16%] with low dose interferon alfa v 4/133 [3%] with no adjuvant treatment; P < 0.05). Fifteen per cent of people withdrew because of adverse effects over a mean 6.9 months. In the second subsequent RCT, 5% of people taking low dose interferon alfa discontinued treatment because of grade 3–4 toxicity.

Comment

The role of interferon in the adjuvant treatment of melanoma has been an area of considerable research and much debate over the past 20 years. Several trials have used varying doses of interferon and differing schedules of administration. To simplify the reporting, we have classified the doses as low dose, intermediate dose, and high dose interferon alfa. In this review, low and intermediate doses of interferon alfa generally range from 3 MU to 5 MU, and high doses generally range from 10 MU to 20 MU, but the dosing schedules vary considerably between studies in terms of initial and maintenance dose, and frequency and duration of treatment. The systematic reviews in this area and meta-analyses have generally examined all the varying doses. In this review, we have reviewed the roles of low dose, intermediate dose, and high dose interferon in the adjuvant treatment of melanoma separately.

Clinical guide:

The routine use of low dose interferon in the adjuvant treatment of melanoma has now largely fallen from clinical practice. Without convincing data showing evidence of an increase in overall survival, it is difficult to recommend a lengthy course of treatment with considerable potential for adverse effects. In the UK, adjuvant treatment for melanoma is currently only offered in the context of clinical trials.

Substantive changes

No new evidence


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