1 Oncology and Hematology Department, 2 Istituto Oncologico Romagnolo Unit of Biostatistics and 3 Pharmacy Unit, City Hospital, Ravenna, Italy
Received 29 November 2002; revised 7 January 2003; accepted 27 January 2003
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Abstract |
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The aim of this study was to evaluate the effectiveness of granulocytemacrophage colony-stimulating factor (GM-CSF) mouthwashes in the prevention of severe mucositis induced by high doses of chemotherapy.
Patients and methods:
Ninety consecutive patients affected by solid tumors and undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue were randomized to receive placebo versus GM-CSF mouthwash 150 µg/day. Patients were stratified on the basis of the conditioning treatment and the consequent different risk of severe oral mucositis. Treatment was administered from the day after the end of chemotherapy until the resolution of stomatitis and/or neutrophil recovery.
Results:
The statistical analyses were intention-to-treat and involved all patients who entered the study. The severity of stomatitis was evaluated daily by the physicians according to National Cancer Institute Common Toxicity Criteria. Both study and control groups were compared with respect to the frequency [30% versus 36%, 2 exact test, not significant (NS)] and mean duration (4.8 ± 4.7 versus 4.4 ± 2.7 days, t-test, NS) of severe stomatitis (grade
3). Oral pain was evaluated daily by patients themselves by means of a 10 cm analog visual scale: the mean (± standard error of the mean) maximum mucositis scores were 4.8 ± 3.5 versus 4.2 ± 3.5 cm (t-test, NS). Furthermore, 15/46 patients in the study group (33%) and 19/44 patients in the control group experienced pain requiring opioids (
2 exact test, NS).
Conclusion:
We did not find any evidence to indicate that prophylaxis with GM-CSF mouthwash can help to reduce the severity of mucositis in the setting of the patients we studied.
Key words: GM-CSF, mouthwash, mucositis, prophylaxis
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Introduction |
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On the basis of such considerations, we designed a randomized, placebo-controlled clinical study to evaluate the efficacy of prophylaxis with GM-CSF mouthwash in reducing the incidence and severity of oral mucositis in patients undergoing high-dose chemotherapy and peripheral blood stem cell transplantation (PSCT) rescue for solid tumors.
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Patients and methods |
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Results |
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Discussion |
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All things considered, we have seen few randomized studies with too few patients so far. Our trial does not show any advantage for the group receiving GM-CSF mouthwashes in terms of the incidence, severity and duration of oral mucositis. It is well known that healing of mucositis is associated with neutrophil recovery. In our series the duration of absolute neutropenia was the same in both the treatment and control group. We administered subcutaneous G-CSF to all patients, and this could have mitigated the impact of topical GM-CSF. The sample size was calculated on a theoretical 90% incidence of grade 34 chemotherapy-induced stomatitis. In fact, the rate of severe oral mucositis was lower than expected (33%), which was probably due to the abandonment of autologous bone marrow transplantation with the definitive use of PSCT rescue, and to the unforeseeable new scenario of transplantation implying the progressive reduction of request for treatment of patients with advanced breast cancer, usually subjected to highly stomatotoxic treatments. Nevertheless stomatitis as a whole was documented in 82 out of 90 patients (91%) without any difference between the two groups.
To evaluate the severity of stomatitis we used the NCI-CTC. Interobserver variability remains the greatest problem in the routine use of this grading system, as well of the others, but the randomized, double-blind design of our study should have overcome this concern. Furthermore, the evaluation was completed by patient self-assessment. Every day each patient judged his oral pain and put a mark on a subjective visual analogic scale. We could not demonstrate any difference between the two groups either in terms of pain score or in terms of opiate consumption. All our patients underwent prophylactic daily mouthwashes with a 0.2% chlorhexidine solution. This has been tested as prophylaxis for mucositis in standard and high-dose chemotherapy and showed encouraging results in some studies [21, 22], but it failed to evidence benefit in larger series [23, 24]. Therefore, it seems unlikely that the use of chlorhexidine in our series would have contributed to lowering the incidence of stomatitis and hiding the possible beneficial effect of GM-CSF. We administered GM-CSF at a concentration of 1.5 µg/ml for a total daily dose of 150 µg. A previous study did not show any evidence of a doseresponse relationship [19], even if a deleterious effect was achieved with a GM-CSF dose <0.1 µg/ml, and no differences were seen escalating GM-CSF concentration from 1 to 10 µg/ml.
In conclusion, our study is large enough, randomized and placebo controlled, and could contribute to the final answer on the utility of prophylaxis with GM-CSF mouthwashes in the setting of myeloablative chemotherapy, at least for patients scheduled to receive subcutaneous growth factors. We believe that future efforts should be concentrated in other directions. Some approaches seem promising, such as the employment of amifostine [25], oral pilocarpine [26], topical tretinoin [27] and oral glutamine [28]. Keratinocyte growth factor and interleukin-11 achieved interesting results in preclinical and phase I trials [29, 30]; however, since oral mucositis represents a major dose-limiting toxicity, large randomized trials are needed to better evaluate the activity of such promising agents.
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Acknowledgements |
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Footnotes |
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References |
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