ORAL AND GASTROINTESTINAL MUCOSITIS : NOVEL INSIGHTS INTO PATHOPHYSIOLOGY AND POTENTIAL THERAPIES —

Mucositis is a dose-limiting side effect of highdose chemotherapy and radiotherapy currently used in many cancer treatments and in the intensive conditioning that precedes hematopoietic stem cell transplantation (HSCT). Increasing awareness of the clinical and economic consequences of mucositis and ongoing research into the molecular and cellular mechanisms of mucositis have spurred development of novel strategies for the prevention or treatment of this debilitating disorder. In particular, the elucidation of 5 phases of mucositis pathophysiology—initiation, up-regulation and message generation, signaling, ulceration, and healing—has provided a road map for the development of several novel biologicals. After a summary of mucositis epidemiology and assessment methods, this article reviews the mechanism, administration, phase of drug development, and preliminary clinical data of several novel antimucositis agents, including palifermin (now approved), Aesgen-14 (L-glutamine in proprietary drug delivery system), low-energy laser therapy, benzydamine hydrochloride, and amifostine. It is likely that 1 or more new agents will emerge as a standard for preventing or treating mucositis in the next 1 to 5 years. Eventually, combination regimens will likely become available to reduce mucositis to a level at which high-dose chemotherapy and HSCT can achieve maximum anticancer outcomes. (Adv Stud Med. 2005;5(4B):S299-S310) T he scope of research related to oral and gastrointestinal (GI) mucositis secondary to high-dose chemotherapy has strategically expanded in recent years. Collectively, researchers have addressed several fundamental molecular mechanisms related to causation and potential novel therapies, in addition to previously unexamined aspects of mucositis related to epidemiology, clinical complications, objective assessments of mucosal injury, and economic impact. The current state of science is such that 1 or more of today’s mucositis investigational drugs will likely become available for clinical use within 1 to 5 years. This would represent a strategically important new opportunity in oncology practice. Until now, clinicians have dealt with chemotherapy-associated and radiation-associated mucositis through alteration in cancer therapy protocols (eg, using alternative regimens or reduced doses of radiation or chemotherapy) or by palliation with various techniques and agents for which use has been dictated more by empiricism than evidence. In coming years, if clinicians are instead able to administer therapies directed to molecular targets associated with mucosal injury, then improved efficacy is likely and better overall outcomes will follow. To reduce tissue injury and to enhance proliferative repair in this context of chemotherapy-induced epithelial cell damage, a variety of cytokines and growth factors have been tested, preclinically or clinically, including agents such as keratinocyte growth factor (KGF), interleukin (IL)-11, transforming growth factor beta, granulocyte macrophage colony-stimulating factor (GM-CSF), and RK-0202 (N-acetyl-L-cysteine) in thermosetting. Research aimed at identifying other new agents continues. To help clinicians prepare for an era of more targeted mucositis therapy, this article will review several novel mucositis therapies in various stages of clinical REVIEW