Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study

doi:10.1006/cyto.1995.0064

Cytokine

Volume 7, Issue 5, July 1995, Pages 471-477

https://doi.org/10.1006/cyto.1995.0064 Get rights and content

Abstract

Uncontrolled clinical trials have shown that parenteral administration of GM-CSF reduces the frequency of chemotherapy-induced mucositis. The mechanism of this effect could be related to acceleration of haematopoiesis and/or increase in functional activation of WBC. We conducted a double-blind, placebo-controlled, dose ranging study of GM-CSF (molgramostim) mouthwash in patients with breast cancer during the first treatment cycle of a combination chemotherapy regimen which has historically produced dose-limiting (grade ≥3) mucositis in approximately 39% of patients. Subjects were randomized to receive either placebo mouthwash (0.1 percent albumin) or one of four concentrations of GM-CSF mouthwash (0.01, 0.1, 1.0 or 10 mcg/ml). The primary endpoint was to evaluate the relationship between dose of GM-CSF mouthwash received and probability of grade ≥3 mucositis using a logistic model. Solutions were administered four times daily starting within 24 hours of chemotherapy initiation and continuing until the end of the cycle (day 21). Mucositis was assessed on days 1–6, 10, 15 and 21. Day 6 plasma samples were assayed for GM-CSF. Forty-five patients were evaluable for response (nine per dosing group). A 42% risk (15/36) of mucositis grade ≥3 was evident on day 15 in patients receiving GM-CSF compared to 2 of 9 patients on the placebo arm. No evidence of dose response was found by logistic regression. Five patients had a detectable plasma concentration of GM-CSF (56–209 pg/ml). A positive correlation between GM-CSF dose and leukocyte recovery was noted (P=0.04).

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Cited by (62)

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Both factors can improve the activity of peripheral neutrophils in the mucosal tissue, whereas GM-CSF can still stimulate the proliferation of keratinocytes [104,105]. A pro-healing wound effect has been observed and extensively studied [106-111], which led to the study of these glycoproteins or their PEGylated recombinant versions (e.g., filgrastim and pegfilgrastim) via systemic (parenteral or subcutaneous injections) [52,112–120] or topical (mouthwash or gel) [121–125] administration in OM prevention and healing. Results tend to be very conflicting, with studies indicating some promising results in OM prevention or regression, while others not showing any clinical benefits [9,24,55].
Oral mucositis, a common inflammatory side effect of oncological treatments, is a disorder of the oral mucosa that can cause painful ulcerations, local motor disabilities, and an increased risk of infections. Due to the discomfort it produces and the associated health risks, it can lead to cancer treatment restrains, such as the need for dose reduction, cycle delays or abandonment. Current mucositis management has low efficiency in prevention and treatment. A topical drug application for a local action can be a more effective approach than systemic routes when addressing oral cavity pathologies. Local delivery of growth factors, antibodies, and anti-inflammatory cytokines have shown promising results. However, due to the peptide and protein nature of these novel agents, and the several anatomic, physiological and environmental challenges of the oral cavity, their local action might be limited when using traditional delivering systems. This review is an awareness of the issues and strategies in the local delivery of macromolecules for the management of oral mucositis.
A Review of Clinical Radioprotection and Chemoprotection for Oral Mucositis
2018, Translational Oncology
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Methotrexate and etoposide, in particular, are secreted in saliva, which leads to an increased risk of direct mucositis [13]. While evidence of a direct causal link between mucositis and neutropenia is not definitive, the possibility that it is a contributory factor is suggested by a) reduced duration and severity of the OM with topical and systemic GM-CSF treatment (although this data is contradictory [14]) b) predisposition to mucositis with low neutrophil counts (<400 cells/μL) c) high incidence of microbial infections during neutropenia since perturbation of the mucosal barrier results in a portal of entry for pathogens and neutrophil-depleted patients are less able to clear these pathogens d) recovery of the mucosa in tandem with white cell recovery, all of which implies that depletion of neutrophils leads to impaired wound healing and that neutrophil repopulation particularly during the recovery phase accelerates repair [15]. Like macrophages, neutrophils are highly plastic cells, capable of dynamically switching between two main states, N1, inflammatory, and N2, pro-repair, in a context- and time-dependent manner.
The first tenet of medicine, “primum non nocere” or “first, do no harm”, is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and radiation, since they commonly result in significant toxicities. One of the more frequent and serious treatment-induced toxicities is mucositis and particularly oral mucositis (OM) described as inflammation, atrophy and breakdown of the mucosa or lining of the oral cavity. The sequelae of oral mucositis (OM), which include pain, odynodysphagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions and discontinuations that not only negatively impact quality of life but also tumor control and survivorship. One potential strategy to reduce or prevent the development of mucositis, for which no effective therapies exist only best supportive empirical care measures, is the administration of agents referred to as radioprotectors and/or chemoprotectors, which are intended to differentially protect normal but not malignant tissue from cytotoxicity. This limited-scope review briefly summarizes the incidence, pathogenesis, symptoms and impact on patients of OM as well as the background and mechanisms of four clinical stage radioprotectors/chemoprotectors, amifostine, palifermin, GC4419 and RRx-001, with the proven or theoretical potential to minimize the development of mucositis particularly in the treatment of head and neck cancers.
Topical use of systemic drugs in dermatology: A comprehensive review
2011, Journal of the American Academy of Dermatology
Citation Excerpt :
A recent study also revealed the beneficial effects of topical granulocyte-CSF in the treatment of oral and genital ulcers in Behçet disease.28 No cutaneous or systemic adverse effects were detected after the use of topical GM-CSF or granulocyte-CSF except for a burning sensation and allergic reaction in a minority of patients.28,29 Topical phenytoin has been shown to be effective in the treatment of ulcers in many RDBPCTs.
Topical use of systemic agents to treat cutaneous disorders is widely applied. However, there is a lack of articles summarizing the relevant literature in a systematic way.
We sought to review the published literature regarding topical use of systemic drugs that were categorized according to their mode of actions. Only drugs that are not yet commercially available in a topical preparation are included.
A PubMed search was performed, using as key words “topical,” “extemporaneous,” “compounding,” and names of each generic drug, to identify all clinical reports (1966-2009).
Although many systemic drugs are used topically, randomized controlled trials were limited to a few agents.
Many of the reports consist only of small case series or are anecdotal in nature. As the level of evidence is limited, larger prospective trials are needed before firm conclusions can be drawn.
Extemporaneous compounding helps physicians to individualize treatment to the patient’s specific needs and to create topical preparations that are not otherwise commercially available. However, comparative effectiveness studies are needed to determine whether or not topical use of systemic therapeutics is more beneficial than existing therapies.
Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms
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In a single-institution, double-blind, prospective, randomized trial, we determined whether oral aloe vera gel can reduce radiation-induced mucositis in head-and-neck cancer patients.
We randomized 58 head-and-neck cancer patients between oral aloe vera and placebo. To be included in this Phase II protocol, patients had to be treated with radiotherapy with curative intent at Stanford University between February 1999 and March 2002. We examined patients biweekly for mucositis at 15 head-and-neck subsites and administered quality-of-life questionnaires.
Patients in the aloe and placebo groups were statistically identical in baseline characteristics. By the end of treatment, the two groups were also statistically identical in maximal grade of toxicity, duration of Grade 2 or worse mucositis, quality-of-life scores, percentage of weight loss, use of pain medications, hydration requirement, oral infections, and prolonged radiation breaks.
In our randomized study, oral aloe vera was not a beneficial adjunct to head-and-neck radiotherapy. The mean quality-of-life scores were greater in the aloe vera group, but the differences were not statistically significant. Oral aloe vera did not improve tolerance to head-and-neck radiotherapy, decrease mucositis, reduce soreness, or otherwise improve patient well-being.
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Regular PaperEvaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study

Abstract

Regular Paper
Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study