2 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

2.1 Techniques for confirming a diagnosis in people with suspected atypical spitzoid melanocytic lesions

In people with reported atypical spitzoid lesions, how effective are fluorescence in‑situ hybridization (FISH), comparative genomic hybridization (CGH) and tests to detect driver mutations compared with histopathological examination alone in predicting disease‑specific survival?

This should be investigated in a prospective diagnostic study. Secondary outcomes should include sensitivity, specificity, accuracy, positive predictive value, disease‑specific survival and progression‑free survival.

Why this is important

Atypical spitzoid lesions continue to be diagnostically challenging. There are no reliably reproducible histological, immunohistochemistry or molecular features that allow exact typing and prognostic assessment of these lesions. The current 'gold standard' is histological examination with expert review, but it is not always possible to distinguish spitzoid melanoma from benign spitzoid melanocytic lesions.

Current molecular technologies such as FISH and CGH provide some help, but the results are difficult to interpret and may not be conclusive. Understanding and mapping changes in molecular pathways could predict outcome and inform individual treatment planning.

2.2 Surgical excision for people with lentigo maligna

For people with lentigo maligna (stage 0 in sun‑damaged skin, usually on the face) how effective is Mohs micrographic surgery, compared with excision with a 0.5 cm clinical margin, in preventing biopsy‑proven local recurrence at 5 years?

This should be investigated in a randomised controlled trial. Secondary outcomes should include cosmetic and functional outcomes.

Why this is important

Mohs micrographic surgery is a microscopically controlled surgical technique designed to allow complete excision of the tumour with minimal tissue loss. The technique can be useful for people with lentigo maligna because their lesions can be very large and located in a cosmetically sensitive site where surgery may cause significant scarring. However, the histological detection of small numbers of melanocytes at the edge of a sample is difficult, and can lead to false negative results. In addition, lentigo maligna may occur in an area of field change with a risk of skip lesions at the edge. Therefore, although Mohs micrographic surgery may ensure complete excision of lentigo maligna, it can be accompanied by the recurrence of a similar lesion in adjacent skin.

2.3 Follow-up surveillance imaging

In people treated for high‑risk stage II and III melanoma, does regular surveillance imaging improve melanoma‑specific survival compared with routine clinical follow‑up alone?

This should be investigated in a randomised controlled trial. Secondary outcomes should include time to recurrence, site of recurrence, proportion of people receiving active therapy at recurrence, cost effectiveness and quality of life.

Why this is important

Until recently there have been no effective therapies for metastatic melanoma and no strong rationale for early detection of relapse through surveillance imaging. However, new, effective targeted treatments and immunotherapy agents are now available and further treatments are likely to become available in the near future. In particular, immunotherapy can offer long‑term disease‑free survival but takes a number of months to take effect. In this situation, early detection of relapse may identify people likely to be fit enough to receive the treatment for long enough to benefit.

Although early detection of relapse through surveillance imaging might appear likely to improve outcomes, there is no evidence to confirm this. In addition, routine imaging has resource implications and involves more hospital visits and increased radiation exposure for the person.

2.4 Vitamin D supplementation

In people with stage I–III melanoma does vitamin D supplementation improve overall survival?

This should be investigated in a placebo‑controlled randomised trial. Secondary outcomes should include disease‑specific survival and toxicity, including the development of renal stones and hypercalcaemia.

Why this is important

It has been reported that suboptimal levels of vitamin D at diagnosis are common in people with melanoma from the north of England and that higher levels are associated with lower melanoma‑related mortality. However, vitamin D levels are higher in leaner, fitter people and the nature of the relationship between vitamin D levels and melanoma survival is unclear.

There are 2 adjuvant trials of vitamin D supplementation listed as active currently, 1 in Italy and 1 in Australia. However, there are many uncertainties about the design of vitamin D trials, which might become clearer in the next few years. These include the dose of vitamin D, use of concurrent aspirin therapy and the baseline level at which vitamin D supplementation would be started.

2.5 The effect of drug therapy for concurrent conditions on melanoma survival

In people diagnosed with melanoma what is the effect of drug therapy to treat concurrent conditions on disease‑specific survival?

This should be investigated in a national prospective cohort study. Secondary outcomes should include overall survival and quality of life.

Why this is important

Drugs such as immunosuppressants and those used to treat conditions such as diabetes have effects that may affect survival in people with melanoma. For example metformin, the most frequently prescribed drug for type 2 diabetes, is thought to reduce overall cancer rates in people with diabetes but to increase mortality from melanoma in the approximately 40% of these people who have a somatic BRAF mutation.

There is a need to balance the risk of melanoma deaths with the benefits from the most effective treatment of the concurrent conditions. But there is currently no evidence to inform this decision.

  • National Institute for Health and Care Excellence (NICE)