ReviewEORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome☆
Introduction
Cutaneous lymphomas are a group of disorders characterised by localisation of malignant lymphocytes to the skin. Approximately two-thirds of these lymphomas are of T-cell origin, and the pathogenesis and management of both T- and B-cell cutaneous lymphomas have been recently reviewed.1, 2, 3, 4, 5, 6 The most common form of cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF), accounting for around 60% of new cases. Sézary syndrome (SS) is much rarer and accounts for only 5% of CTCL cases.3, 7, 8, 9 An analysis of US cancer registries showed that the incidence of MF/SS increased markedly from 1973 to 1984, with the highest incidence reported in the elderly. African-Americans had a twofold higher incidence than Caucasians: the incidence in men was more than twice than that observed in women.10 Since 1983 the incidence of MF/SS appears to have stabilised at 0.36 per 105 person-years, and the mortality rate has declined.11 Age-adjusted incidence, relative to Caucasians, is 1.7 for African-Americans and 0.6 for Asians.11 In Europe, according to the Finnish Cancer Registry Database, the incidence of cutaneous T-cell lymphoma has been reported for the Finnish population to be as high as 2.5 per 105 for men and 1.5 per 105 for women.12
There are many therapeutic options available for the management of CTCL, including MF/SS.7, 13 The choice of treatment is often determined by physician or patient preference, or institutional experience, particularly as there is a paucity of data from phase III trials and a lack of consensus concerning treatment for later stages of MF/SS.3, 14, 15, 16 However, a number of authors have published recommendations or reviews on the management of CTCL,1, 3, 7, 15, 17, and guidelines have been published jointly by the British Association of Dermatologists and the UK Cutaneous Lymphoma Group.16 Nonetheless, treatment choices vary across Europe and there are, as yet, no uniform European guidelines for the management of CTCL.
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Development process of recommendations
In September 2004, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force organised a Workshop meeting to establish a consensus for the development and implementation of European guidelines for the management of MF/SS.m At the meeting, ‘best practices’ from each national group were presented
Classification of CTCL
Primary cutaneous lymphomas often have a different clinical course to histologically similar systemic lymphomas. Therefore, the EORTC classification for primary cutaneous lymphomas was established in 1997: the World Health Organization (WHO) classification for tumours of haematopoietic and lymphoid tissues includes primary cutaneous lymphomas as separate entities. Remaining differences between the two classification systems have resulted in the recent publication of the WHO-EORTC classification
Levels of evidence
Much has been written in recent years on the need for clinical guidelines and the criteria they should meet for development and application, as well as evidence and recommendations to be used in their support.18, 19, 20 The levels of evidence used in this article will be as described by the Oxford Centre for Evidence-Based Medicine (Table 2a, Table 2b).20
Clinical presentation
The onset of MF is often insidious and initial cutaneous symptoms may be difficult to distinguish from other non-malignant pathologies of the skin.7 The median duration from the initial appearance of skin symptoms to a diagnosis of MF/SS is almost 6 years.7 Typically, the initial lesions in MF are flat and erythematous skin patches, which evolve over a variable period of time into palpable plaques characterised by well-demarcated edges.7 Patches and plaques may also exhibit hypopigmentation or
Staging
Staging of MF is based on a tumour–node–metastasis (TNM) system, originally published in 1979.1, 3, 7, 23 Numerous studies have shown that prognosis is dependent on the magnitude of the cutaneous tumour burden.1 Increased skin surface area involvement is also associated with a poorer prognosis, as is lymph node involvement and the appearance of clonal T cells in the peripheral blood.1, 7 Table 3a/b shows the TNM classification, the resulting stages, and the prognostic implications in terms of
Treatment modalities considered for inclusion in the consensus recommendations
The aims of treatment for CTCLs include clearance of lesions, that is, remission, in order to maintain or improve quality of life and prolong disease-free survival and overall survival.29, 30 However, assessing response to treatment is not necessarily straightforward. MF is an indolent condition with a long natural history and may not extend beyond the skin for many years.7 This finding has necessitated the use of surrogate markers, such as the tumour burden measurements described by Heald,
Skin-directed therapy
Skin-directed therapy (SDT) comprises one or more of the following: topical corticosteroids, topical nitrogen mustard (HN2), topical BCNU (carmustine), psoralen plus ultraviolet (UV)A, UVB, total skin electron beam therapy (TSEB), and superficial X-irradiation. These treatment options are described in the following sections.
Systemic therapies
Systemic therapies include the following modalities, which are summarized below: chemotherapy, biological response modifiers (BRMs), immunotherapy, and extra-corporeal photoimmunotherapy (ECP).
Immunotherapy
Alemtuzumab is a humanised recombinant IgG1κ monoclonal antibody with human Fc and V region framework sequences. The complementarity-determining regions are derived from rodent (rat) gene sequences.73 The antibody is specific for the CD52 cell surface glycoprotein, which is found at densities of up to 5 × 105 binding sites/cell on the surface of normal and malignant B and T cells. However, CD52 does not appear to be expressed by granulocytes or myeloid or erythroid bone marrow cells.73
Recommendations from the workshop meeting of the EORTC Cutaneous Lymphoma Task Force
These guideline recommendations are intended for MF/SS and may not be appropriate for other CTCLs. They are laid out by disease stage and subdivided by treatment stage (first- or second-line).
Expectant policy
Patients with stage IA disease have a normal life expectancy.78, 79 For this reason, ‘Expectant Policy’ is a legitimate management option for patients with this early disease stage. However, this strategy must incorporate careful monitoring. Kim and colleagues, in a retrospective cohort analysis, noted that long-term survival in 122 patients with stage IA disease was similar to that of an age-, sex- and racematched control population.78 The median survival of the cohort had not been reached
Summary and conclusion
In early-stage MF, SDT represents the most appropriate therapy. Most patients will be able to achieve a short-term clinical response with recurrent disease for many years and, in the majority of cases, a normal life expectancy. Therefore, potentially toxic and aggressive therapies should be avoided. Patients with more advanced stages of MF and patients with SS have a poor prognosis. In these patients, the absence of randomised, controlled trials results in a lack of sufficient evidence to
Conflict of interest statement
Robert Knobler has received consultant fees from Ligand and Sean Whittaker has received consultant fees from Astrella, Genmab, Ligand, Merck, and Zeneus.
Acknowledgement
Financial support for the making of this manuscript was provided by Zeneus Pharma GmbH, Munich.
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Disclaimer: These recommendations reflect the best data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from these recommendations in special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from them should not be necessarily deemed negligent.