|Year : 1998 | Volume
| Issue : 1 | Page : 37-43
Effect of granulocyte-macrophage colony-stimulating factor on chemotherapy-induced oral mucositis in non-neutropenic cancer patients
Ezzeldin M Ibrahim1, Fatma A Al-Mulhim2, Fahd A Al-Muhanna1, Ali Al-Amri1
1 Department of Internal Medicine, College of Medicine and Medical Sciences, King Faisal University, Saudi Arabia
2 Department of Radiology, College of Medicine and Medical Sciences, King Faisal University, Saudi Arabia
|Date of Web Publication||31-Jul-2012|
Ezzeldin M Ibrahim
Professor of Medicine and Oncology, King Fahd Hospital of the University, P.O. Box 40004, Al-Khobar 31952
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: The study was designed to assess prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the management of chemotherapy-induced oral mucositis in non-neutropenic cancer patients.
Material and Methods: In a prospective open study, adult cancer patients with chemotherapy-induced, neutropenia-independent oral mucositis were treated with GM-CSF (Schering Plough Corporation, Kenilworth, NJ) prepared as mouthwash solution (5 to 10 μgm /ml). GM-CSF was administered within 24 hours of occurrence of oral mucositis at a frequency of 4 to 6 times daily. Systemic GM-CSF was not permissible. Oral mucositis was graded according to the modified Radiation Therapy Oncology Group criteria.
Results: Forty-nine patients were recruited but nine were subsequently excluded as they experienced neutropenia during GM-CSF therapy. The remaining 40 patients were all evaluable. Most patients had either Grade 3 or 4 gross (71%) or functional (70%) mucositis. The mean ± SEM gross oral mucositis scores for all 40 patients combined decreased from 3.3 ± 0.11 at baseline to 2.1 ± 0.12 (p<0.0001) after 2 days, 0.95 ± 0.11 (p<0.0001) after 5 days and 0.23 ± 0.07 (p <0.0001) after 10 days of therapy. Likewise, the mean ± SEM functional oral mucositis scores decreased from 3.03 ± 0.13 at baseline to 1.58 ± 0.13 (p<0.0001) after 2 days, 0.68 ± 0.11 (p<0.0001) after 5 days, and 0.15 ± 0.06 (p<0.0001) after 10 days of therapy. The duration of severe oral mucositis was also shortened as Grade 0 or 1 (gross mucositis grading score) was evident in 12 (30%), 29 (73%), and 40 (100%) patients by the 2 nd , 5 th and 10 th day of therapy, respectively. Similarly, Grade 0 or 1 (functional mucositis grading score) reported in 19 (48%), 31 (78%), and 40 (100%) patients by the 2 nd , 5 th and 10 th day of therapy, respectively. The use of GM-CSF mouthwash was not associated with any apparent ill effect.
Conclusion: GM-CSF mouthwash as used in this study has a significant recuperative efficacy on the severity, morbidity, and duration of chemotherapy-induced oral mucositis. A large randomized, placebo-controlled study is warranted to ascertain that benefit and determine the optimal dosage and schedule.
Keywords: Chemotherapy, mucositis, G-CSF, GM-CSF
|How to cite this article:|
Ibrahim EM, Al-Mulhim FA, Al-Muhanna FA, Al-Amri A. Effect of granulocyte-macrophage colony-stimulating factor on chemotherapy-induced oral mucositis in non-neutropenic cancer patients. J Fam Community Med 1998;5:37-43
|How to cite this URL:|
Ibrahim EM, Al-Mulhim FA, Al-Muhanna FA, Al-Amri A. Effect of granulocyte-macrophage colony-stimulating factor on chemotherapy-induced oral mucositis in non-neutropenic cancer patients. J Fam Community Med [serial online] 1998 [cited 2020 Jul 12];5:37-43. Available from: http://www.jfcmonline.com/text.asp?1998/5/1/37/98390
| Introduction|| |
Oral mucositis as a consequence of cytotoxic therapy is a major cause of morbidity and dose-limiting toxicity in cancer patients. It was reported in up to 90% of patients after somatotoxic chemotherapy.  Moreover, the duration and severity of that complication is strikingly associated with high-dose chemoradiotherapy and hematopoietic stem-cell transplantation. ,, The pain in mucositis is usually intensively excruciating and may lead to weight loss from odynodysphagia. Furthermore, the breakdown of the mucosal epithelium barrier exposes cancer patients to infection and subsequent septicemia particularly in association with chemotherapy-induced neutropenia. , On the other hand, neutropenia and local secondary infection can also aggravate oral mucositis after chemotherapy. Moreover, severe sloughing of the oral mucosa may lead to airway compromise and may necessitate parenteral nutrition.
The efficacy of recombinant human hematopoietic growth factors in improving the neutropenic state is well documented. ,,,, Recently, a coincidental 75% decrease in oral mucositis associated with granulocyte colony-stimulating factor (G-CSF) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy of genitourinary cancer was first reported by Gabrilove et al.  The mucosal protection effects of G-CSF of granulocyte-macrophage colony-stimulating factor (GM-CSF) were also observed in other chemotherapy regimens. ,,, One report showed a lowered incidence of oral mucositis when GM-CSF was given after 5-FU/leucovorin chemotherapy of low myelotoxicity.  In most of these reported studies, however, the effect of hematopoietic growth factors on oral mucositis was not the primary end point.
Systemic administration of G-CSF or GM-CSF is effective in both reducing the severity and shortening the duration of neutropenia after chemotherapy. There is still some uncertainty as to whether GM-CSF has a direct salutary effect on the oral mucosal healing process independent of the improvement of neutropenia. However, a recently published crossover study has demonstrated the prophylactic efficacy of GM-CSF in head and neck cancer patients receiving a somatotoxic chemotherapy combination.  In this study, the reduction of the severity and duration of oral mucositis, that was the primary study goal, was independent of chemotherapy dose-intensity, myelotoxicity, or median leukocyte nadirs.
On the other hand, data that advocate the therapeutic efficacy of hematopoietic growth factors are very limited and only anecdotal.  We theorized that GM-CSF could have an advantageous therapeutic effect on oral mucositis that may be shown best if the agent is used as mouthwash. Our preliminary data on a small number of patients supported that concept.  Therefore, the present larger study was designed to assess the healing effect of GM-CSF mouthwash on oral mucositis independent of the confounding effect of neutropenia or its correction. The therapeutic strategy also eliminates the variability in somatotoxic potential of various chemotherapeutic agents.
| Patients and Methods|| |
Eligibility criteria: In a prospective, open label study, adult patients seen at King Fahd Hospital of the University, Al-Khobar, with chemotherapy induced oral mucositis without neutropenia (neutrophilic count > 2.0 x 10  /l) were eligible. Patients were enrolled between July 1996 and June 1997. Patients who developed neutropenia during GM-CSF mouthwash were excluded from the main analysis. Patients could not have concurrent fungal or bacterial infection (as proven by culture), and no local radiotherapy to the oropharynx region within 3 months. Any agent that may ameliorate or worsen the mucositis was not permitted. Systemic GM-CSF was not routinely given, and rendered enrolled patients non-evaluable if required.
Treatment plan: GM-CSF(Schering Plough Corporation, Kenilworth, NJ) was prepared as a mouthwash solution with concentrations of 5 to 10 μgm/ml. The preparation was administered within 24 hours of occurrence of oral mucositis. Patients were instructed to use the solution 4 to 6 times daily and to retain and gargle the fluid for as long as possible. Therapy continued until complete resolution of the mucositis or if no benefit was achieved for 10 days. Informed written consent was obtained from each patient.
Evaluation methods: Patients were assessed daily and mucositis was graded according to modified Radiation Therapy Oncology Group criteria [Table 1].  The duration of mucositis was also determined. Complete blood cell counts were performed every other day or more frequent if indicated.
Statistical analysis: Mucositis scores are expressed as the mean ± SEM. The 't' test was used to compare the mean severity scores at entry for all patients combined against that at 2 nd , 5 th , and 10 th day of therapy. As multiple comparisons were used (6 for each type of mucositis score), based on the Bonferroni method, a conservative p value less than 0.008 was considered significant.
| Results|| |
Forty-nine patients entered onto the trial. All patients had received somatotoxic chemotherapeutic agents mainly 5-flurouracil, methotrexate, and anthracylines. Nonetheless, neutropenia developed in 9 patients 4 of whom experienced febrile episodes that required institution of systemic GM-CSF. All patients were analyzed separately. The remaining 40 patients were evaluable and constituted the basis of this report. [Table 2] depicts the clinical characteristics of those patients. There were 24 men and 16 women with a median age of 41 years (range, 18 to 75). Seventy-one percent and 70% of patients had either Grade 3 or 4 of the gross and functional mucositis grading scores, respectively.
[Table 3] depicts the mean mucositis scores of all 40 patients combined at baseline and at the 2 nd , 5 th , and 10 th day. The table shows that the mean mucositis scores, both gross and functional, decreased significantly as compared with estimates at entry.
The duration of severe oral mucositis was also shortened as Grade 0 or 1 (gross mucositis grading score) was evident in 12 (30%), 29 (73%), and 40 (100%) patients by the 2 nd , 5 th , and 10 th day of therapy, respectively. Likewise, Grade 0 or 1 (functional mucositis grading score) reported in 19 (48%), 31 (78%), and 40 (100%) patients by the 2 nd , 5 th , and 10 th day of therapy, respectively. The use of GM-CSF mouthwash was not associated with any apparent ill effect.
|Table 3: Mean mucositis grading scores for all 40 patients combined at baseline and com-pared to that at the 2PndP, 5PthP and 10PthP day|
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As for the 9 patients excluded from the analysis due to neutropenia, subjective and objective improvement was demonstrated within 3 to 4 days of therapy.
| Discussion|| |
Reduction of chemotherapy-induced oral mucositis was first observed coincidentally with amelioration of neutropenia after chemotherapy in clinical trials of G-CSF or GM-CSF in cancer patients.  A decreased incidence of oral mucositis was also observed in bone marrow transplant patients given G-CSF or GM-CSF. ,,,, The results from the first randomized, prospective controlled clinical study to evaluate the effect of GM-CSF versus no treatment indicated that GM-CSF was effective in the reduction of the severity and duration of chemotherapy-induced oral mucositis. 
Preliminary data on a small number of patients supported the therapeutic efficacy of GM-CSF on oral mucositis.  The present larger study confirmed the earlier conclusion as it showed a significant expeditious lowering of the severity, morbidity, and duration of oral mucositis independent of an effect of granulocyte stimulatory effect of GM-CSF. The mean mucositis grading scores, both gross and functional, decreased significantly as compared with estimates at base level. Moreover, the duration of severe oral mucositis was also shortened as Grade 0 or 1 (gross mucositis grading score) was apparent in 30%, 73% and 100% of patients by the 2 nd , 5 th and 10 th day of therapy, respectively. Similarly, Grade 0 or 1 (functional mucositis grading score) reported in 48%, 78%, and 100% of patients by the 2 nd , 5 th , and 10 th day of therapy, respectively.
The mechanism of reduction of chemotherapy-induced oral mucositis by G-CSF or GM-CSF is uncertain. One plausible reason may be that chemotherapy-induced neutropenia may predispose the patient to oral infections, which may initiate or aggravate the severity or prolong the duration of oral mucositis. Therefore, G-CSF or GM-CSF may be able to reduce chemotherapy-induced oral mucositis by shortening the duration of neutropenia after chemotherapy or by benefiting the oral neutrophil level recovery.  Nevertheless, the benefit shown in our study and that of Chi et al  was independent of systemic or local neutrophil recovery effect.
Another mechanism of the beneficial effect of GM-CSF on chemotherapy-induced mucositis may be a direct stimulatory effect of GM-CSF on the growth or regeneration of the oral mucosa. GM-CSF may stimulate the oral mucosal cells to proliferate by enhancing interleukin-1 transcription and translation.  The latter mechanism is connoted by the increase in oral mucositis and more myelotoxicity when chemotherapy and G-CSF were given concurrently. , The elucidation for the increase in myelotoxicity when G-CSF and GM-CSF are given concurrently with chemotherapy is attributed to the stimulation of bone marrow progenitor cells and the increased pool of precursors responsive to chemotherapy.  In another study, concurrent administration of GM-CSF mouthwash with chemotherapy produced more oral mucositis as compared with placebo (42% vs 22%). 
In conclusion, therapeutic GM-CSF mouthwash can significantly reduce morbidity, severity, and duration of chemotherapy-induced oral mucositis. The effect is presumably related to its favorable acceleration of mucosal cells regeneration. The role of G-CSF or GM-CSF on chemotherapy-induced oral mucositis warrants a large, randomized, placebo-controlled clinical trial.
| References|| |
|1.||Chi KH, Chan WK, Cooper DL, Yen SH, Chen KY. A phase II study of outpatient chemotherapy with cisplatin, fluorouracil, and leucovorin in nasopharyngeal carcinoma. Cancer 1994; 73: 247-52. |
|2.||Seto BG, Kim M, Wolinsky L, Mito RS, Champlin R. Oral mucositis in patients undergoing bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1985; 60: 493-7. |
|3.||Kolbinson DA, Schubert MM, Flournoy N, Truelove EL. Early oral changes following bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1988; 66: 130-8. |
|4.||Berkowitz RJ, Strandjord SE, Jones P, Hughes C, Barsetti J, Gordon EM, et al. Stomatologic complications of bone marrow transplantation in a pediatric population. Pediatr Dentistry 1987; 9: 105-10. |
|5.||Bergmann OJ. Oral infections and septicemia in immunocompromised patients with hematologic malignancies. J Clin Microbiol 1988; 26: 2105-9. |
|6.||Greenberg MS, Cohen SG, McKitrick JC, Cassileth PA. The oral flora as a source of septicemia in patients with acute leukemia. Oral Surg 1982; 53: 32-6. |
|7.||Groopman JE, Molina JM, Scadden DT. Hematopoietic growth factors: Biology and clinical applications. N Engl J Med 1989; 321: 1449-59. |
|8.||Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, et al. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 1988; 319: 593-8. |
|9.||Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M, et al.. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988; 1: 667-72. |
|10.||Sheridan WP, Morstyn G, Wolf M, Dodds A, Lusk J, Maher D, et al. Granulocyte colony stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 1989; 2: 891-5. |
|11.||Brandt SJ, Peters WP, Atwater SK, Kurrtzberg J, Borowitz MJ, Jones RB, et al. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 1988; 318: 869-76. |
|12.||Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, et al. Effect of granulocyte colony stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med 1988; 318:1414-22. |
|13.||Nemunaitis J, Rosenfeld CS, Ash R, Freedman, Deeg HJ, Appelbaum F, et al. Phase II randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 15: 949-54. |
|14.||Taylor KM, Jagannath S, Spitzer G, Spinolo JA, Tucker SL, Fogel B, et al. Recombinant human granulocyte colony-stimulating factor hastens granulocyte recovery after high-dose chemotherapy and autologous bone marrow transplantation in Hodgkin's disease. J Clin Oncol 1989; 7: 1791-9. |
|15.||Herrmann F, Schulz G, Wieser M, Kolbe K, Nicolay U, Noack M, et al. Effect of granulocyte-macrophage colony stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy. Am J Med 1990; 88: 619-24. |
|16.||Ho AD, Del Valle F, Haas R, Engelhard M, Hiddemann W, Ruckle H, et al. Sequential studies on the role of mitoxantrone, high-dose cytarabine and recombinant human granulocyte-macrophage colony stimulating factor in the treatment of refractory non-Hodgkin's lymphoma. Semin Oncol 1990; 17:, (Suppl 10):14-19. |
|17.||Grem JL, McAtee N, Murphy RF, Hamilton JM, Steinberg S, Arbuck SG, et al. Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma. J Clin Oncol 1994; 12: 560-8. |
|18.||Chi KH, Chen CH, Chan WK, Chow KC, Chen SY, Yen SH, et al. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer in patients after cisplatin, flurorouracil, and leucovorin chemotherapy. J Clin Oncol 1995; 13: 2620-8. |
|19.||Katano M, Nakamura M, Matsuo T, Iyama A, Hisatsugu T. Effect of granulocyte colony-stimulating factor (G-CSF) on chemotherapy-induced oral mucositis. Surg Today 1995; 25: 202-6. |
|20.||Ibrahim EM, Al-Mulhim FA. Effect of granulocyte-macrophage colony-stimulating factor on chemotherapy-induced oral mucositis in non-neutropenic cancer patients. Medical Oncology 1997; 14:47-51. |
|21.||Lieschke GJ, Ramenghi U, O'Conner MP, Sheridan W, Szer J, Morstyn G. Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation. Br J Haematol 1992; 82: 589-95. |
|22.||Dinarello CA. Interleukin 1 and interleukin 1 antagonism. Blood 1991; 77: 1627-52. |
|23.||Meropol NJ, Miller LL, Korn EL, Braitman LE, MacDermott ML, Schuchter LM. Severe myelosuppression resulting from concurrent administration of granulocyte colony stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst 1992; 84:1201-3. |
|24.||Cartee L, Petros WP, Rosner GL, Gilbert C, Moore S, Affronti ML, et al. Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study. Cytokine 1995; 7: 471-7. |
[Table 1], [Table 2], [Table 3]