Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales.
Forty years ago the causes, incidence and natural history of melanoma were still poorly understood. Little was known about prognostic factors, and radical surgery was routine for all melanomas. However, dedicated melanoma treatment centres had been established in Sydney and Brisbane and Australians were at the forefront of early epidemiological research into melanoma. Today, the natural history of melanoma is much better understood, and a detailed staging system has been developed. Great prognostic accuracy can now be achieved, based on the histological features of the primary melanoma (particularly Breslow thickness, ulcerative state and mitotic rate), and knowledge of whether or not there is metastatic disease in a ‘sentinel’ lymph node. The extent of surgery is now based on the staging, with 1cm excision margins for ‘thin’ invasive melanomas (≤1mm), and 1-2cm margins for thicker tumours. Sentinel node biopsy is routinely offered for melanomas ≥1mm in thickness, and for thinner melanomas with adverse prognostic features. In recent times, huge advances have been made in the medical management of systemic melanoma metastases, with the introduction of signal pathway inhibitors (BRAF and MEK inhibitors) and effective immunological agents (anti-CTLA4 and anti-PD1 antibodies). In parallel, the roles of surgery and radiation therapy in the treatment of metastatic melanoma have become much better defined. As a result, the importance of multidisciplinary care for all patients with metastatic melanoma has become apparent.
When the Clinical Oncological Society of Australia (COSA) was formed 40 years ago, the causes, incidence and natural history of melanoma were still poorly understood and little was known about prognostic factors. As a result, very radical skin and lymph node surgery was routinely undertaken whenever the diagnosis was made, even for tumours that would today be treated as an outpatient procedure by simple wide local excision with 1cm margins. At this time, Australia had led the world by establishing dedicated melanoma treatment centres, notably the Sydney Melanoma Unit in Sydney, led by Gerald Milton, and the Queensland Melanoma Project in Brisbane, led by Neville Davis.1 Australians had also been at the forefront of epidemiological research into melanoma, which had established clearly that exposure to solar ultraviolet radiation was one of the principal factors leading to melanoma development.2 Over subsequent decades, a more comprehensive understanding of all aspects of melanoma has been obtained, and there have been dramatic changes in its treatment. Over this period, the incidence of melanoma has continued to rise, not only in Australia, but also in fair-skinned populations around the world.3
Staging and prognosis
It is now clear that the outlook for a patient who presents with a primary cutaneous melanoma can be predicted with considerable accuracy on the basis of the pathology of the primary tumour, and the knowledge of whether metastatic spread to regional lymph nodes has occurred. The principal determinant of outcome is the Breslow thickness of the melanoma, but other factors such as ulceration and mitotic rate are also of great importance.4 Tumours ≤1mm in Breslow thickness are classified as ‘thin’, are treated by simple wide excision with 1cm minimum clearance margins, and are associated with an excellent prognosis. Tumours 1-4mm in Breslow thickness are classified as ‘intermediate thickness’, have a 15-25% risk of metastatic spread to regional lymph nodes, and in most melanoma treatment centres worldwide are now treated not only by wide excision with 1-2cm clearance margins, but also with sentinel node biopsy.5 The latter is a very accurate staging procedure introduced in the early 1990s, involving lymphatic mapping to identify ‘sentinel’ lymph nodes receiving direct lymphatic drainage from a primary melanoma, which are then removed and sent for detailed histological assessment.6 Primary melanomas >4mm in Breslow thickness are classified as ‘thick’, and have a much more serious prognosis, with five year survival rates of the order of 50%. This is because the risk of systemic metastasis is much higher, and until recently there were no satisfactory systemic treatment options available once spread to internal organs had occurred. These patients are nevertheless treated by wide excision, usually with 2cm minimum clearance margins, and sentinel node biopsy, which is still of important prognostic value even in patients with thick melanomas, and permits much better regional node field control, if immediate complete lymph node dissection is performed in those found to be sentinel node positive.
Sentinel node biopsy
In patients with intermediate thickness melanomas (1-4mm), there is emerging evidence that the sentinel node biopsy procedure not only provides accurate staging (as already described), but also provides a substantial survival advantage in those who are found to be sentinel node positive and have an immediate completion lymphadenectomy. This evidence comes from a large international randomised trial, the first Multicentre Selective Lymphadenectomy Trial (MSLT-I). The results of the third interim analysis of MSLT-I were published in 2006,7 and the results of the final analysis of the trial are expected to be published by mid-2013. Australia made a huge contribution to this important study, randomising more than half the total number of patients (2001) who entered the trial.
Systemic therapy for metastatic melanoma
While the major changes in surgical melanoma management occurred 20 years ago, with very wide excision of primary tumours and highly morbid elective regional lymph node dissections being abandoned, it has only been in the last few years that significant changes have occurred in the systemic treatment of metastatic melanoma. Several decades of clinical trials with chemotherapy, immune therapy (interferon, vaccines), and combinations of these did not achieve effective systemic treatment options for most patients with melanoma. Dacarbazine was generally considered to be the best systemic therapy for patients with metastatic melanoma, despite low response rates and no proven overall survival advantage over placebo. Similarly, interferon became the chosen adjuvant (post-operative) therapy for high-risk early melanoma, based upon a relapse-free survival advantage, despite no overall survival advantage over placebo. Many argued that supportive care was the best treatment for all patients with Stage IV disease when surgical resection of metastases was not possible. Over the last decade however, improvements in the understanding of molecular biology and immune regulation have led to the development of systemic treatments that have dramatically changed the treatment landscape for patients with melanoma.
Signal pathway inhibitors
Ten years ago, a driver oncogene (BRAF) was discovered that regulates a critical growth and survival signalling pathway in melanoma cells. Mutations in BRAF result in uncontrolled pathway activation and cell growth, and are found in approximately 50% of melanomas. Drugs designed to inhibit the mutant BRAF kinase (BRAF inhibitors) include vemurafenib and dabrafenib. Patients with BRAF mutant metastatic melanoma have high response rates (approximately 50%), a rapid onset of action, achieve dramatic improvements in symptoms, and have a significant survival benefit compared to patients treated with chemotherapy.8,9 They have therefore become the new standard of care. Median duration of benefit is only six months however, and toxicities, although mild and rarely requiring permanent drug cessation, include low grade cutaneous squamous cell carcinomas. Trametinib, an inhibitor of MEK kinase situated downstream of BRAF, also has activity in BRAF mutant metastatic melanoma patients, but is less effective than the BRAF inhibitors.10 Regimens that combine BRAF and MEK inhibitors are currently being assessed, with the aim of improving benefit while reducing toxicity. The first combination in trials, dabrafenib and trametinib, has early data suggesting a higher response rate (75%), prolonged duration of benefit (9-10 months) and a much improved toxicity profile than either drug given alone.11 Phase 3 trials are in progress, as are trials of several other combinations of pathway inhibitors, and adjuvant studies in patients with high-risk early melanoma have commenced.
New immunological therapies
The other breakthrough in melanoma treatment has been in the area of immune therapy. Drugs designed to prevent the inhibition of activated T cells in order to promote sustained anti-tumour immunity appear superior to older immunotherapies such as interferon. Two classes currently exist, anti-CTLA4 and Anti-PD-1 antibodies. Ipilimumab, an anti-CTLA4 antibody, is the first immune therapy to improve overall survival in phase 3 randomised control trials in patients with metastatic melanoma.12,13 While the majority of patients do not benefit from treatment, and the onset of action is slow, ipilimumab has a sustained effect on tumour control in a subgroup of patients, resulting in a 10% increase in patient survival each year. It has however, become another standard therapeutic option, particularly in patients without mutated BRAF. Dermatologic, gastrointestinal and endocrine immune-related toxicities are common with ipilimumab, and can be severe if not managed appropriately. An adjuvant trial has completed recruitment and results are eagerly anticipated. Several anti-PD-1 antibodies are in early clinical development, with phase 1 data suggesting response rates higher than with ipilumumab (approximately 50%), and also with less frequent and less severe toxicity. Trials using combinations of ipilimumab and anti-PD-1 antibodies, as well as combinations of immune therapies with kinase inhibitors, are in progress.
Prospects for the next 40 years
Despite the advances in treatment for melanoma in the last 40 years, significant further improvements are clearly required. In 2013, the best treatment option for many patients with melanoma may be participation in a clinical trial. Modern melanoma management requires a multi-disciplinary approach, involving a team of clinicians who understand clinical, pathological and molecular factors. Australian clinicians and researchers continue to play an important role in improving the management of patients with melanoma through basic and applied research and the conduct of clinical trials.