Palifermin and Chemotherapy-Induced Oral Mucositis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In the editorial by Garfunkel (Dec. 16 issue),1 which accompanies the report by Spielberger et al.2 about the action of palifermin in oral mucositis, Garfunkel cites other approaches but does not mention that low-level laser therapy might be useful in decreasing the severity of chemotherapy-associated oral mucositis.3 We believe that low-level laser therapy should be included in a randomized trial of palifermin in patients with oral mucositis.
Ahmad Awada, M.D., Ph.D.
Marie-Thérèse Genot, M.D.
Jean Klastersky, M.D., Ph.D.
Jules Bordet Institute
B-1000 Brussels, Belgium
ahmad.awada@bordet.be
References
Garfunkel AA. Oral mucositis -- the search for a solution. N Engl J Med 2004;351:2649-2651.
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.
Genot M-T, Klastersky J. Low level laser for prevention and therapy of oral mucositis induced by chemotherapy and/or radiotherapy. Curr Opin Oncol (in press)
To the Editor: The study by Spielberger et al. of palifermin is a hallmark trial for the prevention of severe oral mucositis due to myeloablative treatment. Stratification was performed according to the type of hematologic cancer and the treatment center, respectively, and treatment groups were compared by means of the generalized Cochrane–Mantel–Haenszel method stratified according to the study center. However, there are risk factors that may influence both the incidence and the severity of oral mucositis.1 These factors include smoking, malnutrition, poor oral hygiene, xerostomia, and other underlying oral disorders — none of which have been reported. Because these factors may have an important role in the development of mucositis and its subsequent course, the analysis of the outcome should have been adjusted for them.
Wolfgang J. K?stler, M.D.
Michael Hejna, M.D.
Christoph C. Zielinski, M.D.
Medical University of Vienna
1090 Vienna, Austria
wolfgang.koestler@meduniwien.ac.at
References
Kostler WJ, Hejna M, Wenzel C, Zielinski CC. Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2001;51:290-315.
To the Editor: A number of questions remain regarding the safe use of recombinant human keratinocyte growth factor to decrease oral mucosal damage after total-body irradiation and high-dose chemotherapy in patients with hematologic cancers. Spielberger et al. simply list the overall incidence of adverse events, without grading their severity using the World Health Organization (WHO) toxicity scale or Common Toxicity Criteria.1 Meropol and coworkers previously observed severe dose-limiting cutaneous toxic effects that were associated with recombinant human keratinocyte growth factor.2 Given that recombinant human keratinocyte growth factor is being used as supportive care to ameliorate the adverse effects of cytotoxic drugs and radiation therapy, we believe it is vital to demonstrate that this agent itself does not cause unacceptable toxic effects. In addition, there is concern that recombinant human keratinocyte growth factor may stimulate the proliferation of tumor cells.3 The safety of recombinant human keratinocyte growth factor must be properly evaluated in ongoing clinical trials4 before it can be accepted into routine clinical practice.
Carlo Palmieri, M.B., B.S., Ph.D.
David Vigushin, M.B., B.Ch., Ph.D.
Imperial College London
London W12 0NN, United Kingdom
c.palmieri@imperial.ac.uk
References
Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-181.
Meropol NJ, Somer RA, Gutheil J, et al. Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol 2003;21:1452-1458.
Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000;7:165-197.
Clarke SJ, Abdi A, Davies ID, et al. Recombinant human keratinocyte growth factor (rHuKGF) prevents chemotherapy-induced mucositis in patients with advanced colorectal cancer: a randomized phase II trial. Proc Am Soc Clin Oncol 2001;20:383a. abstract.
The authors reply: Drs. Palmieri and Vigushin refer to the study by Meropol et al.,1 which was a phase 1 trial of a fluorouracil-based regimen for metastatic colorectal cancer.1 In that study, one patient of eight treated with palifermin at a dose of 60 μg per kilogram of body weight (the dose used in our study) had grade 3 skin toxic effects that required discontinuation of the drug. In our study, adverse events were mild to moderate (equivalent to WHO Common Toxicity Criteria grade 1 or 2), transient, and not a cause for discontinuation of the study drug. We found that there were no secondary cancers related to keratinocyte growth factor and that the rates of progression-free survival at approximately one year of follow-up were identical in the two groups.
In regard to the comments by K?stler and colleagues, our study was randomized, and patients were balanced between the study groups with regard to baseline demographic and clinical characteristics. The primary analysis was prospectively defined and presented in our article. Additional analyses were not included because of space constraints and because the primary analysis showed unequivocal efficacy. Analysis of covariates indicated that patients received a benefit from palifermin in all subgroups analyzed. Although data on oral hygiene, presence or absence of underlying oral disorders, and smoking status were not collected, we examined the remaining potential prognostic factors associated with the incidence and severity of oral mucositis. The incidence of severe oral mucositis (WHO grade 3) was lower among patients who received palifermin, regardless of whether the patient had undergone radiotherapy. This difference was also seen regardless of baseline performance status, age, and weight. The management of oral hygiene and oral disease before the start of the treatment protocol was specific to the standard of care in each study center, and the results of primary analyses were similar across centers. In addition, the use of antiviral drugs was well balanced between the study groups.
We agree with Awada and colleagues that low-level laser therapy has not been fully evaluated,2 and we would welcome continued exploration of its use and mechanism of action. Investigators who support further development of low-level laser therapy might find it helpful to compare this approach with the standard of care, palifermin, or both in a randomized trial.
Ricardo Spielberger, M.D.
City of Hope National Medical Center
Duarte, CA 91010
Patrick Stiff, M.D.
Loyola University Medical Center
Maywood, IL 60153
William Bensinger, M.D.
Fred Hutchinson Cancer Research Center
Seattle, WA 98109
References
Meropol NJ, Somer RA, Gutheil J, et al. Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol 2003;21:1452-1458.
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 9:2026-2046.
Ahmad Awada, M.D., Ph.D.
Marie-Thérèse Genot, M.D.
Jean Klastersky, M.D., Ph.D.
Jules Bordet Institute
B-1000 Brussels, Belgium
ahmad.awada@bordet.be
References
Garfunkel AA. Oral mucositis -- the search for a solution. N Engl J Med 2004;351:2649-2651.
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.
Genot M-T, Klastersky J. Low level laser for prevention and therapy of oral mucositis induced by chemotherapy and/or radiotherapy. Curr Opin Oncol (in press)
To the Editor: The study by Spielberger et al. of palifermin is a hallmark trial for the prevention of severe oral mucositis due to myeloablative treatment. Stratification was performed according to the type of hematologic cancer and the treatment center, respectively, and treatment groups were compared by means of the generalized Cochrane–Mantel–Haenszel method stratified according to the study center. However, there are risk factors that may influence both the incidence and the severity of oral mucositis.1 These factors include smoking, malnutrition, poor oral hygiene, xerostomia, and other underlying oral disorders — none of which have been reported. Because these factors may have an important role in the development of mucositis and its subsequent course, the analysis of the outcome should have been adjusted for them.
Wolfgang J. K?stler, M.D.
Michael Hejna, M.D.
Christoph C. Zielinski, M.D.
Medical University of Vienna
1090 Vienna, Austria
wolfgang.koestler@meduniwien.ac.at
References
Kostler WJ, Hejna M, Wenzel C, Zielinski CC. Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2001;51:290-315.
To the Editor: A number of questions remain regarding the safe use of recombinant human keratinocyte growth factor to decrease oral mucosal damage after total-body irradiation and high-dose chemotherapy in patients with hematologic cancers. Spielberger et al. simply list the overall incidence of adverse events, without grading their severity using the World Health Organization (WHO) toxicity scale or Common Toxicity Criteria.1 Meropol and coworkers previously observed severe dose-limiting cutaneous toxic effects that were associated with recombinant human keratinocyte growth factor.2 Given that recombinant human keratinocyte growth factor is being used as supportive care to ameliorate the adverse effects of cytotoxic drugs and radiation therapy, we believe it is vital to demonstrate that this agent itself does not cause unacceptable toxic effects. In addition, there is concern that recombinant human keratinocyte growth factor may stimulate the proliferation of tumor cells.3 The safety of recombinant human keratinocyte growth factor must be properly evaluated in ongoing clinical trials4 before it can be accepted into routine clinical practice.
Carlo Palmieri, M.B., B.S., Ph.D.
David Vigushin, M.B., B.Ch., Ph.D.
Imperial College London
London W12 0NN, United Kingdom
c.palmieri@imperial.ac.uk
References
Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-181.
Meropol NJ, Somer RA, Gutheil J, et al. Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol 2003;21:1452-1458.
Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000;7:165-197.
Clarke SJ, Abdi A, Davies ID, et al. Recombinant human keratinocyte growth factor (rHuKGF) prevents chemotherapy-induced mucositis in patients with advanced colorectal cancer: a randomized phase II trial. Proc Am Soc Clin Oncol 2001;20:383a. abstract.
The authors reply: Drs. Palmieri and Vigushin refer to the study by Meropol et al.,1 which was a phase 1 trial of a fluorouracil-based regimen for metastatic colorectal cancer.1 In that study, one patient of eight treated with palifermin at a dose of 60 μg per kilogram of body weight (the dose used in our study) had grade 3 skin toxic effects that required discontinuation of the drug. In our study, adverse events were mild to moderate (equivalent to WHO Common Toxicity Criteria grade 1 or 2), transient, and not a cause for discontinuation of the study drug. We found that there were no secondary cancers related to keratinocyte growth factor and that the rates of progression-free survival at approximately one year of follow-up were identical in the two groups.
In regard to the comments by K?stler and colleagues, our study was randomized, and patients were balanced between the study groups with regard to baseline demographic and clinical characteristics. The primary analysis was prospectively defined and presented in our article. Additional analyses were not included because of space constraints and because the primary analysis showed unequivocal efficacy. Analysis of covariates indicated that patients received a benefit from palifermin in all subgroups analyzed. Although data on oral hygiene, presence or absence of underlying oral disorders, and smoking status were not collected, we examined the remaining potential prognostic factors associated with the incidence and severity of oral mucositis. The incidence of severe oral mucositis (WHO grade 3) was lower among patients who received palifermin, regardless of whether the patient had undergone radiotherapy. This difference was also seen regardless of baseline performance status, age, and weight. The management of oral hygiene and oral disease before the start of the treatment protocol was specific to the standard of care in each study center, and the results of primary analyses were similar across centers. In addition, the use of antiviral drugs was well balanced between the study groups.
We agree with Awada and colleagues that low-level laser therapy has not been fully evaluated,2 and we would welcome continued exploration of its use and mechanism of action. Investigators who support further development of low-level laser therapy might find it helpful to compare this approach with the standard of care, palifermin, or both in a randomized trial.
Ricardo Spielberger, M.D.
City of Hope National Medical Center
Duarte, CA 91010
Patrick Stiff, M.D.
Loyola University Medical Center
Maywood, IL 60153
William Bensinger, M.D.
Fred Hutchinson Cancer Research Center
Seattle, WA 98109
References
Meropol NJ, Somer RA, Gutheil J, et al. Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol 2003;21:1452-1458.
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 9:2026-2046.