Malignant Melanoma: Biology, Diagnosis, and Therapy
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Integration and sequencing of treatments for unresectable melanoma. Education and training of patient and healthcare professionals.
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Role of screening, surveillance and follow-up strategies. Biology of melanoma guiding treatment decisions. Melanoma is responsible for only 2.
The vast majority of melanomas arise in the skin. Cutaneous melanoma is currently a major public health concern, due to rising incidence rates worldwide. The rate of increase is higher than for any other cancer and has been likened to an epidemic. Some of the increase may be due to improvements in surveillance and early detection as well as changes in diagnostic criteria, but most is considered to be real and linked to exposure to sun and sunbeds. This therefore argues for a high proportion of melanomas being preventable. European age-standardized incidence rates increased 4-fold for women and 7-fold for men over the last 30 years.
Incidence rates are higher for females than for males in the younger age groups, while males have higher incidence rates from age 55—59 years onwards. Mortality rates have also increased, but at a rate disproportionately less than incidence, such that the ratio of deaths to patient cases has fallen steadily over the last 50 years or more.
Independent risk factors for developing melanoma include the presence of benign melanocytic naevi moles , multiple dysplastic naevi and a history of sunburn causing peeling or blistering. In general, melanoma incidence correlates with total exposure to direct sunlight, especially during childhood and adolescence. Prevention of cancer includes primary and secondary interventions. Primary prevention is a set of interventions that keeps a cancerous process from ever developing and includes health counselling and education, environmental controls and product safety, as examples.
Secondary prevention is a set of interventions leading to the discovery and control of cancerous or precancerous processes while localized, i. The best way to prevent melanoma is to protect skin from the sun. Ultraviolet radiation from the sun is generally grouped into bands A and B. Both contribute to the development of skin cancer and protection from both is needed. Australia has the highest incidence of melanoma in the world and has led the world with primary prevention strategies and sun awareness programmes.
The rise in melanomas in young women under 35 years has been attributed, at least in part, to increasing popularity of sunbed salons over the last 30 years. Most primary melanomas can be successfully removed by surgery, while the chance of cure decreases with thickness of the tumour and the extent to which it invades surrounding tissue.
Therefore, there is a need to identify melanomas early to secure the highest chance of cure. In the UK, general practitioners GPs are likely to encounter melanoma perhaps once every 2 years, although patients seek advice about skin lesions far more frequently. A key challenge is for primary care clinicians to differentiate the vast majority of benign lesions from the few potentially malignant lesions requiring specialist advice.
The seven-point checklist was first published in and still remains a valuable diagnostic aid for both healthcare professionals and the public alike. Suspicion is greater for lesions scoring three points or more. However, not all melanomas conform to these criteria.
Furthermore, the possibility of skin cancer does not always generate an urgency often associated with other types of cancer. A recent UK cancer patient survey reported that patients with melanoma wait longer before consulting with their GPs than patients with all other cancers except head and neck cancer. The outcomes of dermoscopy is highly dependent on the skills and experience of the examiner and requires training and regular use.
New diagnostic tools are being developed for use in the community, but few have been rigorously tested. Computer-aided diagnostics CAD to assist with the classification of lesions have been applied to dermoscopy and spectroscopy. It is not clear yet that they improve diagnostic accuracy. Spectrophotometric intracutaneous analysis SIAscopy is a commercially available spectroscopic CAD method, which is one of the very few methods to have been tested in a randomized controlled trial.
The trial compared GPs using best practice following national management guidelines and the seven-point checklist with GPs using the same best practice plus SIAscopy using the MoleMate system.
Malignant Melanoma: Biology, Diagnosis, and Therapy | Larry Nathanson | Springer
The researchers concluded that best practice is not always used as regularly or systematically as it should be. Computerized or electronic diagnostic tools are increasing in popularity among both patients and GPs. Teledermatology is a complementary diagnostic approach using telecommunications to transmit visual images of skin lesions from primary to secondary care teams with the potential to improve diagnostic services. Despite skin cancer being the most common of all cancers, routine screening is not established practice across Europe, with one notable exception being Germany.
To date, evidence suggests that the numbers of melanomas as well as other non-melanoma skin cancers being diagnosed have increased, although it is too early to know whether there will be an impact on survival rates. A randomized trial to formally evaluate skin cancer screening would be extremely challenging.
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However, in common with the MoleMate trial, high quality, specialist education of primary care teams in diagnosing malignant skin cancer appears to be a key factor contributing to increased detection of malignancy. The clinical implications of this screening policy have not been determined. In England and Wales, national guidelines require referral for complete excision in secondary care on identification of a skin lesion suspicious for melanoma. Wide excision margins are advocated to reduce risk of local recurrence.
Malignant Melanoma: Biology, Diagnosis, and Therapy
Depth of excision is down to muscle fascia, but the optimal radial excision width remains controversial in spite of six randomized controlled trials undertaken to address this question. In the UK, just under half of all melanoma patients present with intermediate to high-risk primaries, which are generally resected with 2—3 cm margins.
However, many surgeons suspect that 1 cm may be adequate. There is growing interest to pursue a large-scale, international trial to establish optimal excision margins in this patient group and provide a definitive recommendation based on clinical, health-economic and quality of life outcomes. Pathological assessment of the primary melanoma Breslow thickness, mitotic index, ulceration and involvement of regional lymph nodes provides important prognostic information, which is incorporated into the international AJCC melanoma staging system.
SLNB is recognized to provide the most accurate prognostic information. However, evidence for a therapeutic benefit remains limited and interpretation of the MSLT-1 trial reported to show a survival benefit from SLNB compared with observation of the nodal basin in patients with resected intermediate thickness 1.
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The extent to which patients should undergo assessment for distant metastatic spread at the time of presentation with a primary melanoma is evidence poor. To date, there is no convincing evidence that melanoma genotype predicts for outcome. Early suggestions that BRAF mutant melanoma was associated with a more aggressive phenotype have not been borne out in larger datasets, although there does appear to be a higher rate of BRAF mutations in younger versus older people. Up until , no systemic therapy had convincingly been shown to improve survival of patients with metastatic melanoma.
In the last decade, scientific advancements have led to an unprecedented paradigm shift in management of advanced melanoma. They represent two very distinctive classes of agents: small molecule inhibitors of the MAP kinase signalling pathway and monoclonal antibodies against immune checkpoint molecules. Outcomes from modern melanoma systemic therapy reported in key published clinical trials: MAPkinase pathway targeted treatment.
Outcomes from modern melanoma systemic therapy reported in key published clinical trials: immunotherapy. Main vemurafenib side effects include photosensitivity occurring within days of starting the drug , rash starting within the first few weeks of treatment , myalgia, arthralgia, fatigue and occurrence of other skin lesions, ranging from benign e.
The skin lesions, being visible, can be treated locally or removed and to date, no patient deaths have arisen due to this drug effect. On the other hand, vemurafenib can be given to patients with extensive disease burden including brain metastases, see Fig. Most common melanoma systemic therapy adverse events reported in key published clinical trials: MAPkinase pathway targeted treatment.
Modern systemic therapy is active against melanoma brain metastases. Case 1: a year-old man who progressed with symptomatic multiple brain metastases A after two lines of prior systemic therapy was treated with four cycles of ipilimumab. Response to treatment was maintained 7 months later B. Case 2: a year-old man presenting with brain metastasis C and multiple extra-cranial metastases not shown was treated with vemurafinib and continues in virtual complete remission 9 months later D.
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Drug resistance to BRAF inhibitor monotherapy has been studied and several mechanisms of acquired resistance have been reported. The outcomes of several large-scale, multi-centre phase 3 combination regimen trials will report in Although offering life extension, these combinations of targeted agents also appear to be limited by the same problem of acquired resistance.