Oral Mucositis — The Search for a Solution
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《新英格兰医药杂志》
The oral cavity is a complex environment composed of tissues with different origins, structures, and functions. Moreover, a myriad of commensal bacteria, fungi, and viruses populate the mucosa, connective tissue, salivary glands, taste buds, bones, and teeth of the mouth. This environment is disrupted in oral mucositis (Figure 1), a serious complication of high-dose chemoradiotherapy that affects up to 75 percent of patients who undergo hematopoietic stem-cell transplantation1 and 77 percent of patients with head and neck cancer who receive such treatment.2
Figure 1. Oral Mucositis after Chemoradiotherapy in a Patient with Leukemia, Who Was Later Treated with Bone Marrow Transplantation.
Numerous studies in animals and humans have tried to find a means of preventing and treating oral mucositis. In this issue of the Journal, Spielberger and coworkers3 report the use of the recombinant keratinocyte growth factor palifermin for this purpose. Keratinocyte growth factor has a beneficial effect on mucositis in mice given chemoradiotherapy4 and in human recipients of hematopoietic stem cells who received etoposide, cytarabine, and melphalan.5 In these patients, pretreatment with keratinocyte growth factor reduced mucosal atrophy and weight loss, accelerated mucosal regeneration, decreased ulceration, and improved survival through a gene-mediated effect on growth and differentiation.6 In addition, it ameliorated graft-versus-host disease.7 The finding by Spielberger et al. that the incidence of febrile neutropenia was significantly lower in the palifermin group than in the group given a placebo (75 percent vs. 92 percent, P<0.001) is important and accentuates the key role played by the oral mucosal barrier in the prevention of sepsis. All the patients were given filgrastim, a recombinant granulocyte colony-stimulating factor that prevents bacteremia with gram-negative bacteria or -hemolytic streptococci that originate in the oral cavity; such organisms cause 25 to 50 percent of cases of septicemia in patients treated with chemotherapy.8
Spielberger et al. do not comment on the results of cultures of the oral mucosa or describe protocols used to reduce the population of local pathogens.9 Only prophylactic acyclovir was given to all patients. Since acyclovir is considered to be highly effective in preventing mucosal injury by herpes simplex virus 1 and reducing systemic infection with streptococci,10 it may well have increased the effect of palifermin. The World Health Organization laconically describes grade 4 oral mucositis as "ulcers" and an "inability to swallow fluids"; for patients, however, it causes excruciating pain, for which there is no objective means of measurement. The suffering caused by severe oral mucositis is a major problem that requires a better solution than treatment with opioid analgesics. The pain and dry mouth of oral mucositis should receive the same attention as the associated tissue changes and infections. One of the primary end points of phase 3 trials of the treatment of this complication should be a reduction in pain in the ulcerated area. Indeed, Spielberger et al. found that patients receiving palifermin used significantly lower cumulative doses of morphine equivalents and for fewer days than did placebo recipients and had only minor adverse effects, such as rash.
Studies of other treatments have provided only limited evidence of clinical improvement. Transforming growth factor and interleukin-11 have been shown to increase cell proliferation, an effect relevant to their antitoxic effects on the mucosa, but further studies of their efficacy and mechanism of action are needed. Glutamine decreased mucositis in animal models but failed to do so in a phase 3 trial.11 Cryotherapy and benzamidine seem to be effective in the prophylaxis of mucositis,12 but the question of whether they should be recommended in the foreseeable future has not been settled.
The various scales for grading mucositis do not take into account all the objective, reproducible features of the condition, nor are they universally accepted. The study by Spielberger et al. reflects the unavoidable limitations of using combinations of symptoms, signs, and functional changes in the assessment of mucositis.6 Their study showed an incidence of grade 3 or 4 mucositis of 63 percent in the palifermin group and 98 percent in the placebo group, with a median duration of six and nine days, respectively. The incidence of severe grade 4 mucositis was significantly reduced to only 20 percent in the palifermin group. Future studies of larger groups should allow more reliable analyses of the effect of palifermin on mucositis.
Salivary secretion should also be evaluated in the assessment of oral health. Salivary immunoglobulins produced by the mucosa-associated lymphoid tissue constitute the major immune defense system of the oral mucosa. Changes occur in the salivary secretion of IgA, IgM, and IgG after hematopoietic stem-cell transplantation. After the preparatory phase involving chemoradiotherapy, the levels of salivary immunoglobulins, already low, further decrease by as much as 40 percent on the day of transplantation and return to baseline four days later, probably owing to the immediate homing of donor B cells to the recipient's salivary glands.13 The reduction in the severity of mucositis after the administration of cell-stimulating factors is probably linked to this concordant improvement in salivary immunoglobulin levels.
Oral mucositis is the result of a complex process of interactive biologic phenomena that take place in both the epithelium and the submucosa. It results in severe pain, a reduced quality of life, prolonged hospitalization, and an increased risk of local and systemic infection and compromises our ability to treat the underlying cancer. For these reasons, the solution to oral mucositis cannot be monofactorial but must instead be a combination of the elements implicated in the pathogenesis of this complication of treatment. Recently, human keratinocyte growth factor 2 and glutamine were evaluated in a phase 2 trial and a phase 3 trial, respectively, and were found to reduce the incidence of grade 2, 3, or 4 mucositis.14 Preliminary studies suggest that the administration of granulocyte–macrophage colony-stimulating factor has the potential to decrease radiation-induced mucositis and promote healing.15 The results of a meta-analysis of randomized, controlled trials provided support for the prophylactic use of cytoprotectants (benzamidine in phase 3 trials and sucralfate), but they were not found to have a therapeutic effect.16 Thalidomide has also been used to prevent the deleterious effects of tumor necrosis factor on the oral mucosa, but such treatment has not yet been properly evaluated.
In conclusion, the pathogenesis, prevention, and treatment of mucositis are the focus of considerable interest, and rapid advances are being made. Basic-science studies are under way, and new concepts are evolving. Chemoradiotherapy-induced mucositis is not simply an epithelial process; rather, it involves microvascular injury resulting from endothelial-cell apoptosis, increased peripheral-blood levels of tumor necrosis factor and interleukin-6, and genetically induced differences in the rates of tissue apoptosis.17 Keratinocyte growth factor should be considered one component of the multidrug therapies.
The work by Spielberger et al., if supported by additional studies to determine the optimal dose and regimen, will fundamentally change targeted therapies for radiochemically induced mucositis. A combination of protocols could provide the much-needed solution.
Source Information
From the Oral Medicine Department, Hadassah University Hospital, Jerusalem, Israel.
References
Woo SB, Sonis ST, Monopoli MM, Sonis AL. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer 1993;72:1612-1617.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952.
Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004;351:2590-2598.
Farrell CL, Bready JV, Rex KL, et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 1998;58:933-939.
Durant JR. High-dose chemotherapy for breast cancer in USA. Lancet 1999;354:252-253.
Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100:Suppl:1995-2025.
Krijanovski OI, Hill GR, Cooke KR, et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999;94:825-831.
Wingard JR. Oral complications of cancer therapies: infectious and non-infectious systemic consequences. NCI monograph no. 9. Bethesda, Md.: National Cancer Institute, 1990:21-6.
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 1991;46:167-173.
Ringden O, Heimdahl A, Lonnqvist B, Malmborg AS, Wilcek H. Decreased incidence of viridans streptococcal septicaemia in allogeneic bone marrow transplant recipients after the introduction of acyclovir. Lancet 1984;1:744-744.
Peterson DE, Beck SL, Keefe DMK. Novel therapies. Semin Oncol Nurs 2004;20:53-58.
Scully C, Epstein J, Sonis S. Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy. 1. Pathogenesis and prophylaxis of mucositis. Head Neck 2003;25:1057-1070.
Garfunkel AA, Tager N, Chausu S, Chausu G, Haze C, Galili D. Oral complications in bone marrow transplantation patients: recent advances. Isr J Med Sci 1994;30:120-124.
Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100:Suppl:2026-2046.
Nicolatou O, Sotiropoulou-Lontou A, Skarlatos J, Kyprianou K, Kolitsi G, Dardoufas K. A pilot study of the effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients during X-radiation therapy: a preliminary report. Int J Radiat Oncol Biol Phys 1998;42:551-556.
Sutherland SE, Browman GP. Prophylaxis of oral mucositis in irradiated head and neck cancer patients: a proposed classification scheme of interventions and meta-analysis of randomized controlled trials. Int J Radiat Oncol Biol Phys 2001;49:917-930.
Sonis ST. Pathobiology of mucositis. Semin Oncol Nurs 2004;20:11-15.(Adi A. Garfunkel, D.M.D.)
Figure 1. Oral Mucositis after Chemoradiotherapy in a Patient with Leukemia, Who Was Later Treated with Bone Marrow Transplantation.
Numerous studies in animals and humans have tried to find a means of preventing and treating oral mucositis. In this issue of the Journal, Spielberger and coworkers3 report the use of the recombinant keratinocyte growth factor palifermin for this purpose. Keratinocyte growth factor has a beneficial effect on mucositis in mice given chemoradiotherapy4 and in human recipients of hematopoietic stem cells who received etoposide, cytarabine, and melphalan.5 In these patients, pretreatment with keratinocyte growth factor reduced mucosal atrophy and weight loss, accelerated mucosal regeneration, decreased ulceration, and improved survival through a gene-mediated effect on growth and differentiation.6 In addition, it ameliorated graft-versus-host disease.7 The finding by Spielberger et al. that the incidence of febrile neutropenia was significantly lower in the palifermin group than in the group given a placebo (75 percent vs. 92 percent, P<0.001) is important and accentuates the key role played by the oral mucosal barrier in the prevention of sepsis. All the patients were given filgrastim, a recombinant granulocyte colony-stimulating factor that prevents bacteremia with gram-negative bacteria or -hemolytic streptococci that originate in the oral cavity; such organisms cause 25 to 50 percent of cases of septicemia in patients treated with chemotherapy.8
Spielberger et al. do not comment on the results of cultures of the oral mucosa or describe protocols used to reduce the population of local pathogens.9 Only prophylactic acyclovir was given to all patients. Since acyclovir is considered to be highly effective in preventing mucosal injury by herpes simplex virus 1 and reducing systemic infection with streptococci,10 it may well have increased the effect of palifermin. The World Health Organization laconically describes grade 4 oral mucositis as "ulcers" and an "inability to swallow fluids"; for patients, however, it causes excruciating pain, for which there is no objective means of measurement. The suffering caused by severe oral mucositis is a major problem that requires a better solution than treatment with opioid analgesics. The pain and dry mouth of oral mucositis should receive the same attention as the associated tissue changes and infections. One of the primary end points of phase 3 trials of the treatment of this complication should be a reduction in pain in the ulcerated area. Indeed, Spielberger et al. found that patients receiving palifermin used significantly lower cumulative doses of morphine equivalents and for fewer days than did placebo recipients and had only minor adverse effects, such as rash.
Studies of other treatments have provided only limited evidence of clinical improvement. Transforming growth factor and interleukin-11 have been shown to increase cell proliferation, an effect relevant to their antitoxic effects on the mucosa, but further studies of their efficacy and mechanism of action are needed. Glutamine decreased mucositis in animal models but failed to do so in a phase 3 trial.11 Cryotherapy and benzamidine seem to be effective in the prophylaxis of mucositis,12 but the question of whether they should be recommended in the foreseeable future has not been settled.
The various scales for grading mucositis do not take into account all the objective, reproducible features of the condition, nor are they universally accepted. The study by Spielberger et al. reflects the unavoidable limitations of using combinations of symptoms, signs, and functional changes in the assessment of mucositis.6 Their study showed an incidence of grade 3 or 4 mucositis of 63 percent in the palifermin group and 98 percent in the placebo group, with a median duration of six and nine days, respectively. The incidence of severe grade 4 mucositis was significantly reduced to only 20 percent in the palifermin group. Future studies of larger groups should allow more reliable analyses of the effect of palifermin on mucositis.
Salivary secretion should also be evaluated in the assessment of oral health. Salivary immunoglobulins produced by the mucosa-associated lymphoid tissue constitute the major immune defense system of the oral mucosa. Changes occur in the salivary secretion of IgA, IgM, and IgG after hematopoietic stem-cell transplantation. After the preparatory phase involving chemoradiotherapy, the levels of salivary immunoglobulins, already low, further decrease by as much as 40 percent on the day of transplantation and return to baseline four days later, probably owing to the immediate homing of donor B cells to the recipient's salivary glands.13 The reduction in the severity of mucositis after the administration of cell-stimulating factors is probably linked to this concordant improvement in salivary immunoglobulin levels.
Oral mucositis is the result of a complex process of interactive biologic phenomena that take place in both the epithelium and the submucosa. It results in severe pain, a reduced quality of life, prolonged hospitalization, and an increased risk of local and systemic infection and compromises our ability to treat the underlying cancer. For these reasons, the solution to oral mucositis cannot be monofactorial but must instead be a combination of the elements implicated in the pathogenesis of this complication of treatment. Recently, human keratinocyte growth factor 2 and glutamine were evaluated in a phase 2 trial and a phase 3 trial, respectively, and were found to reduce the incidence of grade 2, 3, or 4 mucositis.14 Preliminary studies suggest that the administration of granulocyte–macrophage colony-stimulating factor has the potential to decrease radiation-induced mucositis and promote healing.15 The results of a meta-analysis of randomized, controlled trials provided support for the prophylactic use of cytoprotectants (benzamidine in phase 3 trials and sucralfate), but they were not found to have a therapeutic effect.16 Thalidomide has also been used to prevent the deleterious effects of tumor necrosis factor on the oral mucosa, but such treatment has not yet been properly evaluated.
In conclusion, the pathogenesis, prevention, and treatment of mucositis are the focus of considerable interest, and rapid advances are being made. Basic-science studies are under way, and new concepts are evolving. Chemoradiotherapy-induced mucositis is not simply an epithelial process; rather, it involves microvascular injury resulting from endothelial-cell apoptosis, increased peripheral-blood levels of tumor necrosis factor and interleukin-6, and genetically induced differences in the rates of tissue apoptosis.17 Keratinocyte growth factor should be considered one component of the multidrug therapies.
The work by Spielberger et al., if supported by additional studies to determine the optimal dose and regimen, will fundamentally change targeted therapies for radiochemically induced mucositis. A combination of protocols could provide the much-needed solution.
Source Information
From the Oral Medicine Department, Hadassah University Hospital, Jerusalem, Israel.
References
Woo SB, Sonis ST, Monopoli MM, Sonis AL. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer 1993;72:1612-1617.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952.
Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004;351:2590-2598.
Farrell CL, Bready JV, Rex KL, et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 1998;58:933-939.
Durant JR. High-dose chemotherapy for breast cancer in USA. Lancet 1999;354:252-253.
Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100:Suppl:1995-2025.
Krijanovski OI, Hill GR, Cooke KR, et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999;94:825-831.
Wingard JR. Oral complications of cancer therapies: infectious and non-infectious systemic consequences. NCI monograph no. 9. Bethesda, Md.: National Cancer Institute, 1990:21-6.
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 1991;46:167-173.
Ringden O, Heimdahl A, Lonnqvist B, Malmborg AS, Wilcek H. Decreased incidence of viridans streptococcal septicaemia in allogeneic bone marrow transplant recipients after the introduction of acyclovir. Lancet 1984;1:744-744.
Peterson DE, Beck SL, Keefe DMK. Novel therapies. Semin Oncol Nurs 2004;20:53-58.
Scully C, Epstein J, Sonis S. Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy. 1. Pathogenesis and prophylaxis of mucositis. Head Neck 2003;25:1057-1070.
Garfunkel AA, Tager N, Chausu S, Chausu G, Haze C, Galili D. Oral complications in bone marrow transplantation patients: recent advances. Isr J Med Sci 1994;30:120-124.
Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100:Suppl:2026-2046.
Nicolatou O, Sotiropoulou-Lontou A, Skarlatos J, Kyprianou K, Kolitsi G, Dardoufas K. A pilot study of the effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients during X-radiation therapy: a preliminary report. Int J Radiat Oncol Biol Phys 1998;42:551-556.
Sutherland SE, Browman GP. Prophylaxis of oral mucositis in irradiated head and neck cancer patients: a proposed classification scheme of interventions and meta-analysis of randomized controlled trials. Int J Radiat Oncol Biol Phys 2001;49:917-930.
Sonis ST. Pathobiology of mucositis. Semin Oncol Nurs 2004;20:11-15.(Adi A. Garfunkel, D.M.D.)