Skin Cancer & Melanoma Unit

Location: Royal Marsden

Section: NHS Clinical Research Programme

Head of Unit: Mr Meirion Thomas

Introduction

Skin cancer is the second most common cancer in both males and females. The most common types of skin cancer (squamous and basal cell) are readily curable by local treatments such as surgery and radiotherapy. The Unit has a large service commitment for these cases and its research effort is concentrated in two areas: melanoma and lymphoedema. The research strategy of the Unit in melanoma is focused on three major clinical problems:

• The optimal surgical management for locoregional disease
• The development of adjuvant treatments for patients who are at high risk of relapse
• The development of new treatments for patients with disseminated disease

The Unit also provides specialist treatment for lymphoedema, which can be a consequence of surgical treatment of skin cancer particularly melanoma. There is an active research programme for this distressing condition.

Relevance to the NHS Research and Development Programme

The incidence of melanoma is doubling every 10 years and it is the fastest increasing malignancy in the UK. The improved treatment of melanoma is a high priority of the NHS R&D programme The Unit's activities concern projects involved in early diagnosis, cost effectiveness, minimising the morbidity of surgical treatments for local and regional disease and improving the treatment of disseminated disease.

In addition, melanoma is increasingly recognised as a suitable target for novel biological therapies, such as virotherapy and gene therapy. The Unit has been involved in a number of study protocols in which patients with melanomatous and non-melanomatous skin tumours have been treated with viral therapeutics. A Phase II study of an oncolytic virus expressing an immunostimulatory cytokine has opened to recruitment in the melanoma unit.

The Unit continues to be a major force in the development of new agents that will hopefully result in improved outcomes for patients with melanoma in the future. The Unit continues to test new therapeutic agents for melanoma in patients with advanced disease and has been involved in a number of Phase I-III studies during the year. Amongst these include a Phase III first-line study of Temozolomide versus Dacarbazine (DTIC), Phase III study of DTIC with or without Ipilimumab (CTLA4 antibody), Phase III second-line study of anti CTLA4 antibody with or without a melanoma peptide vaccine, Phase I –II study of DTIC with or without a human anti-integrin receptor monoclonal antibody. The Unit will also be participating in a multi-centre study of the VEGF inhibitor Bevacizumab, as adjuvant therapy following resection of AJCC stage IIB (T4aN0M0), IIC(T4bN0M0) and III (TxN1-3M0) cutaneous melanoma which is scheduled to open in 2008. Some of the other planned studies include a Phase III front-line study of paclitaxel with or without STA-4783 (a novel small molecule), a Phase III study of Bcl-2 antisense when used in conjunction with standard treatment in patients with good prognosis advance disease.

Cancer-related lymphoedema remains a major interest of the Unit both clinically and through research. Professor Mortimer is Chief Medical Advisor to the Patients’ Association of the Lymphoedema Support Network (LSN) which has more than 3000 members. Professor Mortimer also holds a King’s Fund Grant which seeks to develop a National Service Framework for lymphoedema. The national framework project on lymphoedema, originally funded by the King’s Fund, has 19 PCTs as partners. The aim is to provide training and education for the management of all forms of lymphoedema, including cancer-related, in primary care.

 Highlights of 2007

• In 2007 Professor JM Thomas was awarded a personal Chair as Professor of Surgical Oncology by Imperial College London/The Royal Marsden Hospital.  This was as a direct consequence of his research in melanoma which focuses on minimizing treatment related morbidity  associated with melanoma surgery. Professor Thomas and Mr Andrew Hayes published widely in this area, and were invited Authors for in a 2007 Update of the definitive oncological text book “Principles and Practice of Oncology (eds DeVita, Hellman and Rosenberg)”. Professor Thomas has also published review articles on prognostic false positivity of microscopic disease in sentinel node biopsies for melanoma  in Nature Clinical Practice Oncology (with an accompanying Editorial by Professor Steven Rosenberg of the National Cancer Institute Bethesda USA), The British Journal of Surgery and The British Medical Journal ( In press)
• The Unit continues to be the only centre in the United Kingdom that offers the surgical procedure of Isolated Limb Perfusion with Tumour Necrosis Factor alpha for locally advanced regional melanoma, the Service being run by Mr Andrew Hayes and Mr J Meirion Thomas
• Professor Martin Gore, as well as maintaining an active clinical and research role in the Melanoma Unit has taken on the role of Medical Director of the Royal Marsden NHS Trust
• Dr Kevin Harrington co-authored a Phase I study of an oncolytic herpes simplex virus vector expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) in Clinical Cancer Research. This study has led directly to the instigation of a Phase II study of the same agent in patients with malignant melanoma
• Patients have been recruited in to two protocols (Phase I and Phase II) involving the use of intratumoural oncolytic reovirus in combination with external beam radiotherapy (P.I. Dr Kevin Harrington)
• Dr Harrington’s team has participated in a highly successful preclinical model for the treatment of melanoma affecting regional lymph nodes with oncolytic viruses linked to host T-cells, work that has been published in Nature Medicine in January 2008
• Dr Shaneen Sandhu has joined the Unit as Locum Consultant in Medical Oncology
• Professor Martin Gore was appointed Chairman of the Department of Health’s Gene Therapy advisory committee and became associate editor of Melanoma Research. He has been co-opted onto the  EMEA’s Gene therapy Working Party and was an invited speaker at the ICH workshop on oncolytic viruses
• The Andrew Quick Fellowship to fund a translational melanoma research in the development of new therapeutic targets was established.
• Close links with The Institute continue with joint projects in collaboration with Professor Richard Marais investigating the new therapeutic target B-RAF and Dr Ludovico Bruno investigating dendritic cell function in patients with melanoma

Future Aims

The Unit will continue its major lines of investigation into:

• The development of improved systemic therapies for disseminated melanoma - particularly in the context of antagonists to BRAF and other signalling pathways. We have a collaborative project with Professor Richard Marais (ICR) investigating the pathophysiological role of BRAF and its importance as a therapeutic target
• Clinically we are investigating the combination of drugs (kinase inhibitors such as sorafenib) which inhibit important kinases such as VEGFR, PDGFR and BRAF
• The development of 17-AAG in collaboration with The Institute’s Section of Drug Development and the National Cancer Institute in the US
• The further development of noninvasive methods of detecting micrometastases in local lymph nodes by ultrasonography. This work is in collaboration with the Department of Imaging (Dr Moskovic)
• The development of non-invasive methods for the assessment of melanoma so that secondary prevention in primary care can be improved
• The development of our model of in vivo human tumour microcirculation
• The understanding of mechanisms and the treatment of lymphoedema following cancer treatment
• The pursuit of the gene for lymphoedema by studying the pedigrees of families with multiple cases of lymphoedema. It is hoped to identify those at risk of lymphoedema, both primary forms and those patients undergoing cancer treatment
• To continue jointly with Dr Jeffrey Bamber, (from The Institute’s Joint Department of Physics), supervision of PhD students who are exploring aspects of elastography as a means of using functional high resolution ultrasound as a diagnostic and monitoring tool for lymphoedema
• To pursue studies of tumour lymphangiogenesis in melanoma
•  To pursue preclinical validation of novel prognostic markers in melanoma by analysing paraffin embedded tissue. Protocol is to be submitted to Committee for Clinical Research in early 2008