Can anything be done about oral mucositis?

J. P. Donnelly, N. M. A. Blijlevens and C. A. H. Verhagen

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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Table 1.  Agents that have been investigated for treating and preventing oral mucositis
 


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Figure 1. Phases of mucositis (adapted from Sonis [6]). CRP, C-reactive protein.

 
In this issue Dazzi et al. [7] report that granulocyte–macrophage colony-stimulating factor (GM-CSF), given as an oral rinse, neither reduces the frequency or duration of severe oral mucositis induced by high-dose chemotherapy given to recipients of an autologous peripheral blood haematopoietic stem cell transplant to treat solid tumours. The study meets the modern standards for evidence-based medicine as the drug was allocated randomly in a double-blind fashion to a large enough population to detect a difference of at least 25% between the placebo and the active treatment with a power of 90%. The authors also scored oral mucositis on a daily basis albeit with the NCI-CTC expanded toxicity criteria. This scoring system has been shown to be less than ideal since it is a composite of objectively verifiable signs such as ulceration and erythema, patient perception of discomfort and pain, and the need for intravenous hydration or parenteral or enteral nutrition, which is often a matter of policy or physician preference. Moreover, the inter and intra user reliability has never been formally determined [8]. However, the authors can be forgiven for this since the NCI-CTC scheme has the merit of being widely used and is practical. Moreover, they began their study in 1997 before there had been a concerted effort to validate a comprehensive scoring system based solely on ulceration and erythema, but none the less correlated well with the symptoms of oral mucositis such as pain and ability to swallow [9]. The authors also allowed patients to use a visual analogue scale to assess oral pain and asked them to keep a diary, which most did, thereby taking account of the patients own experience of oral mucositis. There were no significant differences between the active treatment group and the placebo group in terms of gender, age, underlying disease or risk for developing oral mucositis, so the failure to detect a significant difference in frequency, severity or duration of mucositis is likely to be true. Indeed, one other study among patients receiving an haematopoetic stem cell transplantation for haematological malignancies cited by the authors also failed to show that GM-CSF was effective [10]. There were minor differences in the daily dose of the growth factor which was 400 µg in the current study compared with 300 µg in the study of van der Lelie et al. [9], but the dose ranging study of Cartee et al. [11] failed to find a dose response, so the deficit is unlikely to be important. There were also no real differences in the use of opiates to manage pain nor in the patients own perception of mucositis. So the evidence is clear—GM-CSF used in this way has little to offer this patient population in the management of oral mucositis. What then, if anything, can be done to tackle this problem?

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)

References

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