Pathogenesis of Mucositis

It is now understood that following the insult of chemotherapy or radiotherapy, the development of overt mucositis is the result of a complex interplay between all levels of the epithelium and sub-epithelial tissues. Generation of reactive oxygen species (ROS) seems to be a key event, leading to direct damage of cells, tissues and blood vessels. The direct cell damage, however, is not sufficient to lead to the severity of mucosal damage that is later seen. Rather, ROS also lead to stimulation of various transcription factors, such as nuclear factor (NF)-kappa B, and activation of pro-inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6. There is also activation of the cyclo-oxygenase-2 pathway, and consequent angiogenesis, as well as activation of the ceramide pathway and macrophages. Following on from this, there develops a feedback loop leading to amplification of the response, probably mediated by the pro-inflammatory cytokines. It is important to note that all this occurs within hours of the insult, and thus days before any overt damage is visible.

After several days, ulcers do develop, but not uniformly over the mucosa – the reason for this is not clear. Also unknown is why some people suffer from mucositis limited to one area of the alimentary canal, whereas others develop generalised damage. Bacterial colonisation is possible during the ulcerative phase, and can lead to systemic infection. Eventually, signalling from the extracellular matrix leads to increased epithelial proliferation and healing. However, even when the mucosa again appears normal, it is possible to measure residual angiogenesis, and the patient remains at risk of further mucositis with on-going anti-cancer therapy.

Guidelines for Prevention and Treatment of Mucositis

The Mucositis Study Group of MASCC/ International Society for Oral Oncology (ISOO) reviewed the literature relating to mucositis from 1966 to 2002 in its initial guidelines. One of the major findings was that while many different agents had been tried, the quality and size of the published studies was such that, often, no recommendation for treatment could be made. However, one great benefit that did come out of the process was the forging of cross-discipline and international collaborations that have led to faster advances in understanding the patho-biology of mucositis, the ability to develop prospective clinical trials to look at the burden of illness and the more rational targeting of treatment. A summary of the guidelines that were possible is shown in Table 2.

Future Directions

Since the publication of the MASCC/ISOO mucositis guidelines, the FDA has approved the use of Palifermin1 for the reduction of oral mucositis in patients with haematological malignancies undergoing high dose chemotherapy and total body irradiation (TBI) with autologous stem cell transplant. Palifermin is a keratinocyte growth factor. It acts by stimulation of epithelial cell proliferation, leading to enhanced epithelial cell survival, maintenance of intracellular junctions, desmosomal attachments, and epithelial barrier integrity. It is a member of the fibroblast growth factor family, and several other members of this family are in various stages of development for the treatment of mucositis.

There is a theoretical risk with all the targeted growth factors that they may cause tumour protection, but there is currently no clinical evidence to support this.

Summary

For the first time, there are now agents available that can alleviate this distressing side effect of anticancer therapy. This will have the effect of improving quality of life for patients with cancer, reducing costs and possibly improving patient survival by reducing treatment reductions and delays. However, there is much more work to be undertaken to completely solve this problem.