Oral mucositis continues to afflict most patients who are given chemotherapy with or without total body irradiation to prepare them for a haematopoietic stem cell transplant from peripheral blood or bone marrow. Besides the discomfort and pain caused, the intake of food and fluids can be severely curtailed, leading to dehydration and malnutrition, the risk of infection is increased, and there may even be a risk of other more serious complications such as hepatic veno-occlusion [1]. Throughout the last two decades there have been many attempts to identify remedies to prevent or at least ameliorate oral mucositis [2], but with mixed results. Moreover, the targets for these interventions have varied from bland rinses to growth factors (Table 1) indicating a clear need for something to deal with an intractable problem [35]. Meanwhile, the pathophysiology of mucositis was beginning to be unravelled to reveal a complex process involving four phases as proposed by Sonis [6] (Figure 1). Whether or not this model is correct remains to be seen, but it provides a biological basis for testing interventions. Importantly, the initial and final phases coincide with prevention and treatment, respectively, insofar as they imply some agents may prevent or minimise damage whilst others will foster healing.
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First, we must strive to identify the potential biological targets and the means for modulating them. This has been achieved for transforming growth factor ß3 and interleukin-11, which attenuate the ulcerative mucositis of hamsters exposed to 5-fluoruracil or radiation therapy [12, 13]. These results have yet to be replicated in humans. Secondly, it seems very unlikely that a single agent will be sufficiently pleiotropic to both prevent oral mucositis from starting and accelerate recovery of the oral mucosa. Indeed, a cursory glance at the model depicted in Figure 1 would instead suggest that there are windows of opportunity for different agents at different times. So, for instance, it might be more effective to initially use interleukin-11 in order to minimise mucositis and to use GM-CSF once maximum damage has occurred, e.g. the peak of mucositis to foster healing. Further investigation is clearly needed not only to identify potential agents, but also to determine the times required to start and stop using them. Thirdly, and crucially, there is now clear evidence that the choice of chemotherapeutic regimen is the most important factor in inducing oral mucositis [14]. Hence, agents must be tested on groups selected on the basis of a particular regimen rather than the transplant procedure or underlying disease. This will make it more difficult to undertake studies and it will take longer to recruit the necessary number of patients to meet the standards now set for randomised controlled trials. However, the result may well prove worth the wait, since some agents do appear to benefit some groups of patients; for instance, pilocarpine reduced mucositis amongst patients receiving chemotherapy mainly for breast cancer [15]. Interestingly, a quarter of the study population were actually being treated for haematological malignancies which would warrant further study amongst these patients. One elegant and efficient way of achieving this would be to incorporate a supplementary protocol into the type of study undertaken by the large co-operative groups, such as the European Organisation for Research and Treatment of Cancer and the European Group for Blood and Marrow Transplantation and their counterparts, since these groups evaluate particular chemotherapeutic regimens and recruit very large numbers of patients. The funding of such studies would need to be addressed since evaluating drug products for their efficacy and safety for unlicensed indications is very demanding. However, given the scale of the problem posed by oral mucositis and the costs associated with it, health care providers and government agencies might be persuaded that it would be worth the investment if effective prophylaxis could be achieved at a reasonable cost for those requiring high-dose chemotherapy with or without haematopoietic stem cell rescue.
J. P. Donnelly1*, N. M. A. Blijlevens1 & C. A. H. Verhagen2
Departments of Haematology1 and Oncology2, University Medical Centre St Radboud, 6500 HB Nijmegen, The Netherlands (*E-mail: p.donnelly@usa.net)
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