The mouth is a frequent site of complications arising from drug or radiation cancer therapy, with mucositis, xerostomia, osteoradionecrosis, and local infections being the most common. From the standpoint of dose limitation, treatment breaks, quality of life, and health economic outcomes, mucositis is the most significant acute oral toxicity. Xerostomia, a chronic side effect of radiation, involves the salivary gland tissue, and results in changes in taste, tissue resilience, and an increased risk of caries and periodontal disease. While the incidence of osteoradionecrosis seems to be decreasing, the chronicity and symptoms of this festering bony condition are especially difficult for patients. Local oral infections resulting from the overgrowth of opportunistic organisms or the activation of latent viruses are so common as to warrant a prophylactic approach in many cases. A surge of investigational interest has been directed at understanding the mechanisms of these stomatotoxicities and at developing treatment strategies to combat them. [ONCOLOGY 16:680-695, 2002]
The mouth is a frequent site of complications associated with drug and radiation therapy for cancer, and interest in these complications has increased precipitously. For example, a 40% rise in literature citations for mucositis was noted for 1996-2000 compared with 1991-1995. The increased importance of oral complications is attributable to at least four factors: First, the use of marrow-stimulating growth factors has made the management of neutropenia readily available, and has successfully reduced its impact as a dose-limiting toxicity. Second, the use of increasingly aggressive single-agent or multiagent drug therapy has resulted in increased oral toxicity. Third, the application of new radiation regimens, many including concomitant chemotherapy, has contributed to a marked increase in oral toxicity, such that optimal tumoricidal regimens are threatened. Finally, a series of studies have demonstrated that oral complications have a significant impact on nonoral health and economic outcomes.[5,6]
Oral mucositis is probably the most significant oral toxicity associated with cancer treatment. Its severity is often of such a magnitude as to require parenteral narcotic intervention, reduced drug dosing, or altered radiation schedules. The prevalence of clinically significant mucositis has become an important limitation to the introduction of innovative forms of concomitant or combination drug regimens. For many cancer patients, mucositis is the most notable side effect of treatment. However, the overall frequency of mucositis is dependent on a variety of patient- and regimen-related variables.
Certain populations are at exceptionally high risk, including patients receiving conditioning regimens for bone marrow transplant, particularly those including total-body irradiation; patients receiving induction therapy for leukemia; and patients who are being treated with fluorouracil (5-FU) infusional therapy for colorectal cancer. Patients who receive radiation therapy for tumors of the head and neck also demonstrate a high rate of clinically significant mucositis, especially if they are receiving concomitant chemotherapy.
Although the drug or radiation treatment regimen is probably the most noteworthy determinant of risk for mucositis, a number of other variables are also important. The presence of local mucosal irritation secondary to faulty dental appliances or trauma, secondary infection, and xerostomia all increase the risk of mucositis. Patients with hematologic malignancies develop more severe and more frequent mucositis than do comparable patients with other types of tumors. This observation is probably attributable to the tumor-induced functional neutropenia that these individuals develop. The effect of age as a risk factor is unresolved. It appears that younger populations are at increased risk, perhaps because of a greater epithelial rate of proliferation.
Patients with poor oral hygiene tend to have more, and longer lasting mucositis than do patients with clean mouths. The initiation of aggressive oral hygiene protocols has been shown to favorably affect the course of mucositis, probably by reducing the mouth’s bacterial load. Sloan et al recently reported a female predilection for mucositis induced by 5-FU. Finally, there could be genetic factors that influence the risk of mucositis. For example, because proinflammatory cytokines play a role in the pathogenesis of the condition, patients who express these proteins at high levels may be more likely to develop mucositis.
Mucositis represents a clinical continuum. Mild mucositis produces mucosal erythema that is accompanied by burning or soreness similar to that experienced following a food burn. In patients receiving radiation, the condition is usually first noted at cumulative doses of 20 Gy, after approximately 2 weeks of treatment with conventional radiation protocols of 2 Gy/d (5 d/wk). Mucositis worsens with accumulating radiation. By the time 30 Gy has been administered, breakdown of the mucosal surface is apparent, manifesting as pseudomembranes, or a fibrinous mass, overlying necrotic and ulcerated tissue. Ultimately, full-thickness mucosal ulceration develops and may persist for approximately 2 to 4 weeks after radiation ceases.
Chemotherapy-induced mucositis is more acute and is generally observed within 2 weeks of drug administration (usually between 1 to 2 weeks). In the case of chemotherapy-induced mucositis, a distinct erythematous stage may not be seen. Rather, after a brief, 1- or 2-day period of atrophy, superficial sloughing, and redness, the tissue becomes ulcerated and covered by necrotic tissue. This breakdown often precedes the nadir of neutropenia by 2 to 3 days. Ulceration persists for approximately 1 or 2 weeks, during which neutropenic patients are most susceptible to bacteremia and sepsis through mucosal breaks. In the absence of secondary infection, lesions resolve spontaneously.
Health and Economic Significance
It is becoming increasingly apparent that mucositis drives a number of health and economic outcomes. The strong relationship between mucositis, bacteremias, and sepsis is well established. Similarly, the trend toward an increasing frequency of viridans streptococcal infections in myeloablated patients is largely attributable to mucositis; the presence of mucositis confers a three- to fourfold greater probability of viridans streptococcal infection. Thus, the finding that mucositis is associated with increased use of health resources is not surprising. Reuscher et al found that among autologous bone marrow transplant recipients, mucositis was associated with a significant increase in the length of hospital stay.
In one recent study of hematopoietic stem-cell transplant recipients, Sonis, Oster, and colleagues explored the relationship between mucositis and selected clinical and economic outcomes. They found that the extent and severity of mucositis significantly contributed to the use of analgesics, total parenteral nutrition, injectable antibiotics, and to the risk of significant infection, prolonged hospital stay, and increased hospital charges. In the cohort studied, severe ulcerative mucositis resulted in hospital charges that were $43,000 greater than those for patients without the condition.
The pathogenesis of mucositis is more complex than was first envisioned. Challenge to mucosal tissue with stomatotoxic forms and doses of chemotherapy or radiation initiates a parallel and sequential series of events that result in injury. The generation of oxygen-free radicals and DNA damage are primary events in the process, triggering a variety of signal pathways that result in downstream events.
Although mucositis is generally considered an epithelial process, electron microscopic evidence suggests that early changes occur in both the endothelium of submucosal blood vessels and connective tissue. The nature of these changes is currently being defined, but they may stimulate additional molecular activity. For example, it seems probable that damage to connective tissue leads to a disruption of fibronectin. This breakup can result in stimulation of proinflammatory cytokines and production of potentially destructive metalloproteinases.
It appears that a number of genes in mucosal tissue are up-regulated almost immediately following exposure to radiation. Many of these genes, such as p53, are associated with the response of epithelial cells to injury. Others reflect an almost immediate attempt by the tissue to initiate healing. Of particular interest is the finding that genes controlling certain proinflammatory cytokines—in particular, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6—are up-regulated at a rate that parallels the development of mucositis. In contrast, no increase in the expression of genes for transforming growth factor (TGF)-beta or IL-2 has been demonstrated. Like TNF, submucosal cellular expression of IL-1b also increases during, and correlates with, the development of mucositis. A correlation between plasma levels of TNF-alpha and IL-6 and the severity of mucositis has been reported.
It also seems that the local oral environment and, in particular, the oral microbiota and saliva influence the course and severity of mucositis. The mouth’s microflora consists of bacteria, fungi, and viruses. The bacterial load of the mouth is among the greatest of any site in the body. Consequently, breaks in mucosal integrity caused by mucositis serve as a conduit for systemic influxes of bacteria, especially in neutropenic patients. Although the predominant bacteria in the mouths of healthy individuals are gram-positive streptococci, an increase in gram-negative organisms occurs during periods of myelosuppression.
During the 1970s, the frequency and sequelae of gram-negative sepsis led to the development and prophylactic use of quinolone antibiotics. The advent of these agents reduced the incidence of gram-negative infections but caused an increase in gram-positive infections, many of which were derived from the mouth. In addition to causing bacteremias and sepsis, the bacteria that secondarily colonize ulcerative lesions of mucositis spew out cell wall products and endotoxins into the underlying submucosa. These materials serve to amplify the production of proinflammatory cytokines with the consequence of producing worsening lesions of increased duration. Thus, one intervention strategy has been directed at lowering the local bacterial load.
Xerostomia appears to predispose for the development of mucositis. Desiccated tissue is more likely to break down than normal, moist mucosa. In addition, saliva plays an important role in controlling the level of local bacteria. Not only does saliva perform a washing function to clear microorganisms, but it is also rich in bactericidal enzymes and immunoglobulin A (IgA). The latter binds to bacteria and prevents their adherence to tissue.
1. Sonis ST: Oral complications, in Bast RC Jr, Kufe DW, Pollock RE, et al (eds): Holland-Frei Cancer Medicine, 5th ed. Hamilton, Ontario, BC Decker, 2000.
2. Dunn CJ, Goa KL: Lenogastim: An update of its pharmacological properties and use in chemotherapy-induced neutropenia and related clinical settings. Drugs 59:681-717, 2000.
3. Young A, Topham C, Moore J, et al: A patient preference study comparing raltitrexed (‘Tomudex’) and bolus and infusional 5-fluorouracil regimens in advanced colorectal cancer: influence of side effects and administration attributes. Eur J Cancer Care 8:154-161, 1999.
4. Colevas AD, Busse PM, Norris CM, et al: Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial. J Clin Oncol 16:1331-1339, 1998.
5. Rapoport AP, Miller Watelet LF, Linder T, et al: Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 17:2446-2453, 1999.
6. Sonis ST, Oster G, Bellm L, et al: Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J Clin Oncol 18(8):2201-2205, 2001.
7. Bellm LA, Epstein JB, Rose-Ped A, et al: Patient reports of complications of bone marrow transplantation. Support Care Cancer 8:33-39, 2000.
8. Trotti A: Toxicity in head and neck cancer: A review of trends and issues. Int J Radiat Oncol Biol Phys 47:1-12, 2000.
9. Dodd MJ, Miaskowski C, Shiba GH, et al: Risk factors for chemotherapy-induced oral mucositis: Dental appliances, oral hygiene, previous oral lesions, and history of smoking. Cancer Invest 17:278-284, 1999.
10. Sloan JA, Loprinzi CL, Novotny PJ, et al: Sex differences in fluorouracil-induced stomatitis. J Clin Oncol 18:412-420, 2000.
11. Kaanders JH, van der Kogel AJ, Ang KK: Altered fractionation: Limited by mucosal reactions? Radiother Oncol 50:247-260, 1999.
12. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11:261-266, 1999.
13. Marron A, Carratala J, Gonazalez-Barca E, et al: Serious complications of bacteremia caused by Viridans streptococci in neutropenic cancer patients. Clin Infect Dis 31:1126-1130, 2000.
14. Shenep JL: Viridans-group streptococcal infections in immunocompromised hosts. Int J Antimicrob Agents 14:129-135, 2000.
15. Ruescher TJ, Sodeifi A, Scrivani SJ, et al: The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 82:2275-2281, 1998.
16. Sonis ST: Mucositis as a biological process. Oral Oncol 34:39-43, 1998.
17. Sonis ST, Peterson RL, Edwards LJ, et al: Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters. Oral Oncol 36:373-381, 2000.
18. Ferra C, de Sanjose S, Gallardo D, et al: IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation. Hematologica 83:1082-1087, 1998.
19. Symonds RP, McIlroy P, Khorrami J, et al: The reduction of radiation mucositis by selective decontamination antibiotic pastilles: A placebo-controlled double-blind trial. Br J Cancer 74:312-317, 1996.
20. Meunier F: Prevention of infections in neutropenic patients with pefloxicin. J Antimicrob Chemother 26(suppl B):69-73, 1990.
21. Sriskandan S, Cohen J: Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis. Infect Dis Clin North Am 13:397-412, 1999.
22. Scully C, Epstein JB: Oral health care for the cancer patient. Eur J Cancer B Oral Oncol 32B:218-292, 1996.
23. Plevova P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: A review. Oral Oncol 35:453-470, 1999.
24. Lievens Y, Haustermans K, Van den Weyngaert D, et al: Does sucralfate reduce the acute side-effects in head and neck cancer treated with radiotherapy? A double-blind randomized trial. Radiother Oncol 47:149-153, 1998.
25. Etiz D, Erkal HS, Serin M, et al: Clinical and histopathological evaluation of sucralfate in prevention of oral mucositis induced by radiation therapy in patients with head and neck malignancies. Oral Oncol 36:116-120, 2000.
26. Rocke LK, Loprinzi CL, Lee JK, et al: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72:2234-2238, 1993.
27. Coghlin Dickson TM, Wong RM, Offrin RS, et al: Effect of glutamine supplementation during bone marrow transplantation. JPEN J Parenter Enteral Nutr 24:61-66, 2000.
28. Tilg H, Eibl B, Pichl M, et al: Immune response modulation by pentoxifylline in vitro. Transplantation 56:196-201, 1993.
29. Bianco JA, Appelbaum FR, Nemunaitis J, et al: Phase I-II trial of pentoxifylline for the prevention of treatment-related toxicities following bone marrow transplantation. Blood 78:1205-1211, 1991.
30. Attal M, Huguet F, Rubie H, et al: Prevention of regimen-related toxicities after bone marrow transplantation by pentoxifylline: A prospective, randomized trial. Blood 82:732-736, 1993.
31. Wadleigh RG, Redman RS, Graham ML, et al: Vitamin E in the treatment of chemotherapy-induced oral mucositis. Am J Med 92:481-484, 1992.
32. Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57:416-417, 1988.
33. Osaki T, Ueta E, Yoneda K, et al: Prophylaxis of oral mucositis associated with chemoradiotherapy for oral carcinoma by Azelastine hydrochloride with other antioxidants. Head Neck 16:331-339, 1994.
34. Capizzi RL, Oster W: Chemoprotective and radioprotective effects of amifostine: An update of clinical trials. Int J Hematol 72:425-435, 2000.
35. Tochner Z, Barnes M, Mitchell JB, et al: Protection by indomethacin against acute radiation esophagitis. Digestion 47:81-87, 1990.
36. Matejka M, Nell A, Kment G, et al: Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis. Br J Oral Maxillofac Surg 28:89-91, 1990.
37. Duenas-Gonzalez A, Sobrevilla-Calvo P, Frias-Mendivil M, et al: Misoprostol prophylaxis for high-dose chemotherapy-induced mucositis: A randomized double-blind study. Bone Marrow Transplant 17:809-812, 1996.
38. Hanson WR, Marks JE, Reddy SP, et al: Protection from radiation-induced oral mucositis by a mouth rinse containing the prostaglandin E1 analog, misoprostol: A placebo-controlled double blind clinical trial. Adv Exp Med Biol 400B:811-818, 1997.
39. Sironi M, Massimiliano L, Transidico P, et al: Differential effects of benzydamine on pro- vs anti-inflammatory cytokine production: Lack of inhibition of interleukin-10 and interleukin-1 receptor antagonist. Int J Clin Lab Res 30:17-19, 2000.
40. Turnbull RS: Benzydamine hydrochloride (Tantum) in the management of oral inflammatory conditions. J Can Dent Assoc 61:127-134, 1995.
41. Epstein JB, Silverman S Jr, Passiarino DA, et al: Benzydemine HCI for prophylaxis of radiation-induced oral mucositis: Results from a multicenter, randomized, double-blind, placebo-controlled clinical trial. Cancer 92:875-885, 2001.
42. Plevova P, Blazek B: Intravenous immunoglobulin as prophylaxis of chemotherapy-induced oral mucositis. J Natl Cancer Inst 89:326-327, 1997.
43. Dodd MJ, Dibble SL, Miaskowski C, et al: Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat chemotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:39-47, 2000.
44. Adamietz IA, Rahn R, Bottcher HD, et al: Prophylaxis with povidone-iodine against induction of oral mucositis by radiochemotherapy. Support Care Cancer 6:373-377, 1998.
45. Spijkervet FK, Van Saene HK, Van Saene JJ, et al: Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients. J Surg Oncol 46:167-173, 1991.
46. Okuno SH, Foote RL, Loprinzi CL, et al: A randomized trial of a nonabsorbable antibiotic lozenge given to alleviate radiation-induced mucositis. Cancer 79:2193-2199, 1997.
47. Vesole DH, Fuchs H, IB-367 Phase II Investigators: IB-367 reduces the number of days of severe oral mucositis complicating myeloablative chemotherapy. Poster presentation at the 41st Annual Meeting and Exposition of the American Society of Hematology, December 1999.
48. Farrell CL, Bready JV, Rex KL, et al: Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 58:933-939, 1998.
49. Spielberger RT, Stiff P, Emmanouilides C, et al: Efficacy of recombinant human keratinocyte growth factor (rhuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after radiation-based conditioning-results of a phase II trial (abstract 25). Proc Am Soc Clin Oncol 20:7a, 2001.
50. Sonis ST, Van Vugt AG, O’Brien JP, et al: Transforming growth factor-beta 3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis. Oral Oncol 33:47-54, 1997.
51. Wymenga AN, van der Graaf WT, Hofstra LS, et al: Phase I study of transforming growth factor beta-3 mouthwashes for prevention of chemotherapy-induced mucositis. Clin Cancer Res 5:1363-1368, 1999.
52. Foncuberta MC, Cagnoni P, Brandts CH, et al: Topical transforming growth factor—beta 3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors. J Immunother 24:384-388, 2001.
53. Berl T, Schwertschlag U: Preclinical pharmacologic basis for clinical use of rhIL-11 as an effective platelet-support agent. Oncology 14(suppl 8):12-20, 2000.
54. Trepicchio WL, Ozawa M, Walters IB, et al: Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 104:1527-1537, 1999.
55. Sonis ST, Van Vugt AG, McDonald J, et al: Mitigating effects of interleukin-11 on consecutive course of 5-fluorouracil-induced ulcerative mucositis in hamsters. Cytokine 9:605-612, 1997.
56. Crawford J, Tomita DK, Mazanet R, et al: Reduction of oral mucositis by filgrastim (r-met HUG-CSP) in patients receiving chemotherapy. Cytokines Cell Mol Ther 5:187-193, 1999.
57. Tejedor M, Valerdi JJ, Arias F, et al: Hyperfractionated radiotherapy concomitant with cisplatin and granulocyte colony-stimulating factor (Filgrastim) for laryngeal carcinomas. Cytokines Cell Mol Ther 6:35-39, 2000.
58. Taylor SE, Miller MG: Preemptive pharmacologic intervention in radiation-induced salivary dysfunction. Proc Soc Exp Biol Med 221:14-26, 1999.
59. O’Connell AC: Natural history and prevention of radiation injury. Adv Dent Res 14:57-61, 2000.
60. Wiseman LR, Faulds D: Oral pilocarpine: A review of its pharmacological properties and clinical potential in xerostomia. Drugs 49:143-155, 1995.
61. Capizzi RL, Oster W: Chemoprotective and radioprotective effects of amifostine: An update of clinical trials. Int J Hematol 72:425-435, 2000.
62. Chao KS, Majhart N, Huang C, et al: Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: A comparison with conventional techniques. Radiother Oncol 61:275-280, 2001.
63. Balogh JM, Sutherland SE: Osteoradionecrosis of the mandible: A review. J Otolaryngol 18:245-250, 1989.
64. Thorn JJ, Hansen HS, Specht L, et al: Osteoradionecrosis of the jaws: Clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 58:1088-1093, 2000.
65. Epstein JB, Wong FL, Stevenson-Moore P: Osteoradionecrosis: Clinical experience and a proposal for classification. J Oral Maxillofac Surg 45:104-110, 1987.
66. Nemeth Z, Somogyi A, Takacsi-Nagy Z, et al: Possibilities of preventing osteoradionecrosis during complex therapy of tumors of the oral cavity. Pathol Oncol Res 6:53-68, 2000.
67. Vanderpuye V, Goldson A: Osteoradionecrosis of the mandible. J Natl Med Assoc 92:579-584, 2000.
68. Curi MM, Dib LL, Kowalski LP: Management of refractory osteoradiovecious of the jaws with surgery and adjunctive hyperhasic oxygen therapy. Int J Oral Maxillofac Surg 29:430-434, 2000.