MINI-REVIEW the Biological Basis for the Attenuation of Mucositis

The biological basis for the attenuation of mucositis: the example of interleukin-11 S Sonis, L Edwards and C Lucey

Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women’s Hospital; and Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, MA, USA

Oral mucositis is common, painful, dose-limiting toxicity of hospital stay which was 5 days longer than for patients with- drug and radiation therapy for cancer. In granulocytopenic out the condition.3 patients, the ulcerations which accompany mucositis are fre- quent portals of entry for indigenous oral bacteria often leading Despite its clinical significance, there is currently no ther- to bacteremias or sepsis. The complexity of mucositis as a bio- apy to prevent or treat mucositis predictably. A broad range logical process has only recently been appreciated. The con- of approaches and agents has been used in an attempt to mod- dition appears to represent a sequential interaction of the oral ify the course of mucositis. These have included compounds mucosal cells and tissues, pro-inflammatory cytokines, and that are strictly palliative, others which attempt to protect or local environmental factors in the mouth such as micro- modify tissue response to stomatotoxic insult and finally those organisms and saliva. The recognition that the pathophysiol- ogy of mucositis is a multifactorial process has presented for which alteration in the mouth’s microbial load is targeted. opportunities for intervention based on biological attenuation. Results from many studies have often been erratic and not Interleukin-11, a pleotropic cytokine, has a range of activities replicable. which is potentially relevant to mucositis. Consequently, it has A wide variety of topical palliative agents has been used to been used successfully to modify the development, severity treat mucositis. The most traditional is probably saline 0.9% and course of mucositis in an animal model which closely which has proven to be more effective than sodium hydrox- mimics the equivalent human condition. 4 Keywords: mucositis; stomatitis; toxicity; antineoplastic agents; ide. Some reports suggest that cryotherapy using ice chips is radiation therapy; interleukin-11 of some benefit in reducing chemotherapy-induced stomato- toxicity.5,6 Sucralfate, an ulcer-coating polysaccharide, when used to treat radiation-induced mucositis in double-blind ran- Introduction domized trials, failed to provide a statistically significant benefit compared to controls.7,8 Topical lidocaine and dyclonine Destruction of the oral mucosa as a consequence of myeloabl- HCl provide transient local pain control, but are generally not ative cancer chemotherapy results in full thickness epithelial sufficient for severe mucositis in which parenteral pain ulceration with consequent pain and loss of function. Muco- medications are indicated. sitis is common and occurs to some degree in more than one- Both GM-CSF and G-CSF have been proposed as inter- third of all patients receiving anti-neoplastic drug therapy.1 ventions for mucositis. Of the two, GM-CSF has been the more The frequency and severity are significantly greater among extensively studied. While the results of a number of unblinded, non-randomized pilot studies suggested that GM- patients who are treated with induction therapy for leukemia 9,10 or with many of the conditioning regimens for bone marrow CSF might be beneficial for treatment of mucositis, the transplant. Among these individuals, moderate to severe results of a randomized, double-blind, dose-ranging study in mucositis is not unusual in more than three-quarters of which the cytokine was administered topically failed to dem- onstrate efficacy.11 In an attempt to protect proliferating patients. In addition to severe pain, which routinely necessi- ␤ tates parenteral analgesic therapy, and loss of function of such mucosal basal cells, TGF- 3 was administered prior to severity as to require total parenteral nutrition, the areas of chemotherapy (5-FU) in an animal model and proved to successfully attenuate the course of mucositis.12 Both EGF13 and ulceration become sites of secondary infection. The absence 14 of an intact mucosal barrier provides a ready portal of entry KGF might have roles in effecting epithelial susceptibility to for oral microorganisms to such a degree that the mouth is a stomatotoxic therapy or in promoting healing following frequently identifiable site of origin for bacteremias and sepsis tissue damage. among granulocytopenic cancer patients.2 Still another approach has been to use compounds which are thought to be cytoprotective of normal cells. Among these With the availability of cytokine therapy to manage hemato- 15 16 logic toxicities, mucositis has become one of the most signifi- agents, amifostine, vitamins with antioxidant properties, and prostaglandins or prostaglandin analogs have been evalu- cant dose-limiting toxicities associated with cancer chemo- 17,18 therapy. Furthermore, the impact of mucositis on length of ated with mixed results. Pilot studies of two anticholinergic agents, pilocarpine and probanthine, suggest possible hospital stay, admissions for fluid support or treatment of 19,20 infection, and its causality as a reason to alter optimum anti- benefit, possibly through stimulation of the salivary flow. neoplastic treatment have significant economic conse- Direct manipulation of the superficial mucosa by helium-neon quences. For example, the presence of moderate to severe laser treatment has also been reported to favorably effect the course of mucositis.21 Finally, anti-inflammatory agents seem- mucositis among autologous bone marrow transplant recipi- 22 ents being treated for hematologic malignancies resulted in a ingly are of equivocal benefit. The oral cavity is rich in microorganisms which are thought to negatively affect the course of mucositis. Consequently, Correspondence: S Sonis, Brigham and Women’s Hospital, 75 Francis there has been a great deal of interest in evaluating the poten- Street, Boston, MA 02115, USA; Fax: 617 232 8970 tial of local antimicrobial therapy on the course of stomatotox- Received 20 January 1999; accepted 5 March 1999 icity. In general, the results of randomized, blinded trials with Mini-review S Sonis et al 832 such intervention have been variable. Results of studies using fected portion to determine the rate of recovery. An influx of single agent therapy in the form of chlorhexidine gluco- inflammatory cells expressing pro-inflammatory cytokines nate,23,24 or multiagent trouches,25,26 have been inconsistent, occurs during the breakdown of the mucosa and peaks just although there appear to be trends suggesting that a reduction prior to the acme of mucositis.33 Bacterial colonization of the in oral bacterial load favorably influences the course of damaged epithelium occurs and is accelerated by the patient’s mucositis.27,28 myelosuppressed state. Typically the nadir follows a day or so In reviewing attempts at mucositis intervention it seems after peak mucositis. Bacterial cell wall products from both clear that the rationale for therapy has been based on a num- gram-positive and gram-negative organisms likely then pen- ber of assumptions with respect to the development and physi- etrate the injured mucosa and further stimulate the release of ologic course of the condition, rather than on a sound under- damaging cytokines.34 Finally, the mucosa recovers, a process standing of its biological basis. Furthermore, the wide which takes about 3 weeks in the absence of secondary variability of results of clinical trials suggests a complexity infection. which has generally not been fully appreciated. Consequently, within the past few years, the need to define mucositis as a pathologic process has been recognized. Opportunities for intervention

The biologic complexity of mucositis may help to explain the Mucositis as a pathologic process variability of responses which have been observed among patients. Perhaps more importantly it provides a series of Historically, mucositis was viewed as the result of nonspecific opportunities for biologically-based intervention. Illustrative of toxicity of chemotherapy or radiation therapy directed against this have been the results of studies performed with interleu- the rapidly dividing cells of the oral-basal epithelium. It was kin-11 (IL-11). IL-11 is a multifunctional cytokine with hema- believed that drug or radiation exposure resulted in damage topoietic, epithelial and anti-inflammatory activities of poss- to the proliferating cells causing them to cease replication that ible relevance to mucositis. The naturally occurring mature resulted in atrophy which eventually led to ulcer formation. protein has 178 amino acids with a molecular mass of 19 kDa Clinical and experimental observations supported this hypoth- and is expressed by a wide range of mesenchymal tissues. esis: patients in whom epithelial proliferation was expected to Recombinant human IL-11 (rhIL-11) has multiple activities be rapid (youngsters) developed mucositis more frequently identified by in vitro and in vivo studies which may effect than did elderly patients in whom the rate of proliferation was mucositis. These activities include stimulation of myeloid pro- slower;29 second, exposure of animals to epidermal growth genitor cells,35 inhibition of proliferation of gastrointestinal factor, a cytokine which increased the rate of proliferation, epithelial cells,36 protection of connective tissues secondary prior to chemotherapy resulted in increased rates of muco- to modulation of extracellular matrix metabolism,37 reduction sitis;13 third, temporarily protecting the epithelium by of pro-inflammatory cytokine expression,38 and inhibition of inhibiting proliferation just before chemotherapy with TGF- apoptosis induction.39 ␤3 reduced experimental mucositis.12 However, a number of The modulation of chemotherapy-induced mucositis by clinical observations suggested that the mechanism of injury rhIL-11 has been studied using a hamster model which mimics was more complex than just involving the epithelium. In parti- the condition in humans.40 The hamster evolved as the animal cular, the results of the effects of agents with little or no of choice for a clinically relevant mucositis model for five reported epithelial activity contradicted a sole epithelial reasons: first, the cheek pouch provides an anatomic site mechanism. which is easily accessible and has a large mucosal surface We recently hypothesized that mucositis represents a clini- area; second, the cheek pouch has been well-studied, cal outcome due to a complex interaction of local tissue especially with respect to experimental carcinogenesis; third, (connective tissue, endothelium, epithelium) toxicity, the level the cheek pouch resembles similar human tissue; fourth, the of myelosuppression and the oral environment.30 The local oral bacterial flora of the hamster is remarkably similar to that tissue components include an oral mucosa of rapidly of humans; and fifth, the size of hamster peripheral blood cells renewing stratified squamous epithelium overlying a loose is like humans which makes automated analysis simple and and richly vascular connective tissue base and appear to be inexpensive. Earlier studies demonstrated that the hamster responsive to changes in patients’ bone marrow status and, mucosa and bone marrow were dose-responsive to chemo- particularly, the degree of granulocytopenia. The oral therapy and that the kinetics of both myelosuppression and microbial flora, saliva and functional trauma provide an mucositis paralleled that described for humans.41 Addition- indigenous environment which impacts on the frequency, ally, we confirmed the biological activity of rhIL-11 in ham- severity and course of chemotherapy-associated stomato- sters by demonstrating thrombopoiesis in response to cyto- toxicity. kine administration.42 It is quite likely that the initial oral tissue response to Subcutaneous administration of rhIL-11 effectively attenu- chemotherapy and radiation occurs at the endothelial and ated mucositis induced by 5-fluoruracil.42 Twice daily injec- connective tissue level. We believe that free radical formation tions of rhIL-11 started on the first day of chemotherapy and leads to the disruption of fibronectin with subsequent acti- continued for 14 days had a favorable impact on oral muco- vation of transcription factors, stimulation of pro-inflammatory sitis, weight loss and survival. The response was dose-depen- cytokine production and tissue damage. A relationship dent. Mucositis development, overall frequency and severity between the presence of tumor necrosis factor-alpha (TNF-␣) were significantly less in animals treated with therapeutic and IL-1 in serum correlates with the presence of non-hemato- doses of rhIL-11 compared to low-dose or placebo-treated logic toxicities.31 It is also likely that injury to endothelial cells hamsters. Survival in rhIL-11-treated animals was significantly occurs simultaneously.32 Concurrently, damage to the basal better than controls. epithelial cells prevents their replication. It is unclear whether That the favorable effects of rhIL-11 on mucositis were due many of these cells undergo apoptosis or necrosis; the unaf- to factors unrelated to its myeloproliferative activities was sug- Mini-review S Sonis et al 833 gested by three observations. First, whereas maximum throm- 16 Wadleigh RG, Redman RS, Graham ML, Krasnow SH, Anderson bopoiesis was noted 12 days after the initiation of rhIL-11 A, Cohen MH. Vitamin E in the treatment of chemotherapy- administration, mucositis suppression was seen by day 7. induced mucositis. Am J Med 1992; 92: 481–484. 17 Labar B, Mrsic M, Pavletic Z, Bogdanic V, Nemet D, Aurer I et Second, the favorable effect of rhIL-11 on weight loss pre- al. Prostaglandin E2 for prophylaxis of oral mucositis following ceded increases in peripheral platelet numbers. Finally, direct BMT. Bone Marrow Transplant 1993; 11: 379–382. observation of bone marrow cellularity failed to reveal differ- 18 Duenas-Gonzalez A, Sobrevilla-Calvo P, Frias-Mendivil M, Gal- ences between rhIL-11 and placebo-treated animals, although lardo-Rincon D, Lara-Medina F, Aguilar-Ponce L et al. Misoprostol peripheral white blood cell numbers were higher in hamsters prophylaxis for high-dose chemotherapy-induced mucositis. A which had received rhIL-11. randomized double-blind study. Bone Marrow Transplant 1996; Studies are currently underway to fully understand the 17: 809–812. 19 LeVeque F, Dansey R, Klein B. Use of concurrent oral pilocarpine mechanism(s) by which rhIL-11 modulates chemotherapy- to treat mucositis during bone marrow transplantation: a pilot induced mucositis. However, it seems likely that its beneficial study (Meeting abstract). 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