The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: Pathobiology, animal models and cytotoxic drugs

Summary

Alimentary tract (AT) mucositis can be a major problem for patients undergoing cancer treatment. It has significant clinical and economic consequences and is a major factor that can compromise the provision of optimal treatment for patients. The pathobiology of AT mucositis is complex and the exact mechanisms that underlie its development still need to be fully elucidated. Current opinion considers that there is a prominent interplay between all of the compartments of the mucosa involving, at a molecular level, the activation of transcription factors, particularly nuclear factor-κB, and the subsequent upregulation of pro-inflammatory cytokines and inflammatory mediators. The purpose of this review is to examine the literature relating to what is currently known about the pathobiology of AT mucositis, particularly with respect to the involvement of pro-inflammatory cytokines, as well as currently used animal models and the role of specific cytotoxic chemotherapy agents in the development of AT mucositis.

Introduction

Mucositis is a major problem for patients undergoing treatments such as chemotherapy and radiotherapy. Mucositis occurs throughout the alimentary tract (AT)1, 2 and causes a spectrum of clinical signs and symptoms ranging from intractable and debilitating oral pain as a result of ulceration through to, and including, gastrointestinal symptoms such as abdominal bloating, vomiting and diarrhoea.3, 4 It has recently also been suggested that other mucosal surfaces throughout the body, such as the genitourinary and respiratory mucosae, may also be affected.⁵

Other side effects of cancer treatment, such as severe nausea or potentially life threatening events, such as neutropenia, are now relatively well managed.⁶ Mucositis however, remains an important dose-limiting factor in a patient’s cancer treatment.6, 7 The debilitating effects of mucositis can result in unplanned treatment interruptions or even premature cessation of treatment. The risk of systemic infections and even death is increased in patients with mucositis. For patients undergoing radiotherapy, doses of treatment are limited by the proximity of the mouth to critical anatomical structures such as the brain and spinal cord and therefore increases in dose may not be feasible. However with respect to chemotherapy, effective treatment of mucositis may lead to increased maximum tolerated doses of treatment and improved quality of life for cancer patients during and after treatment. Conceivably, this would also translate to an increased likelihood for cancer remission.

Mucositis increases the morbidity of patients undergoing cancer treatment, results in extended hospital stays, and increases re-admission rates.4, 8 Hospitalisation of patients for supportive care and pain management due to mucositis has significant economic consequences.8, 9 As well as being important clinically and economically, patient perceptions of mucositis and its impact on their treatment and quality of life are also important. A study investigating patient reported complications of bone marrow transplantation clearly identified mucositis as the single most debilitating side effect of treatment.⁶ Furthermore, opioid analgesics used the management of mucositis had secondary effects on the quality of life of patients because of adverse drug reactions such as decreased mental acuity and hallucinations.⁶

The prevalence of mucositis is variable and appears to be dependent on the type of treatment given as well as the disease that is being treated. For example, mucositis occurs in 80–100% of patients undergoing so-called “high-risk” regimens such as radiotherapy to the head and neck or high dose chemotherapy and stem cell (or bone marrow) transplantation.3, 4 Furthermore, specific cytotoxic chemotherapy agents, such as 5-fluorouracil (5-FU), are associated with more severe mucositis.¹⁰ In regimens considered to be “low-risk” for the development of mucosal toxicity, the prevalence of mucositis may be as low as 10–15%, however given the numbers of people receiving chemotherapy, this still represents a significant number of patients that are affected by mucositis.¹⁰

It is important, therefore, that the pathobiology of mucositis is determined and fully described so that effective targeted treatment strategies can be developed. The most recent hypothesis for the pathogenesis of mucositis has implicated an important role for transcription factors and pro-inflammatory cytokines in the development of mucositis.11, 12 The focus of this review is to examine the literature relating to the role that pro-inflammatory cytokines might play in the pathobiology of mucositis, particularly in the context of chemotherapy-induced mucositis (radiation-induced mucositis has been adequately reviewed elsewhere¹³). The review will also examine animal models that are currently used to study mucositis pathobiology and, finally, discuss the role of specific chemotherapy drugs in the pathobiology of mucositis.