Granulocyte colony-stimulating factors (G-CSF) and granulocyte-macrophage colony-stimulating factors (GM-CSF) are substances that bind to hemopoietic stem cells, activating them to proliferate and differentiate into granulocytes and macrophages—the specific cell type of interest. Colony-stimulating factors administered in an oral rinse have been evaluated for effect to prevent and manage mucositis.
Clarkson, J.E., Worthington, H.V., Furness, S., McCabe, M., Khalid, T., & Meyer, S. (2010). Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews, 8, CD001973.
To assess the effectiveness of interventions for treatment of oral mucositis or its associated pain for patients receiving chemotherapy or radiation therapy
Databases searched were MEDLINE, CancerLIT, EMBASE, CINAHL, LILACS (Latin American and Caribbean Health Sciences Literature), Cochrane Oral Health Group and PaPaS Trials Registers, Cochrane Central Register of Controlled Trials (CENTRAL), OpenSIGLE, and Current Controlled Trials. Handsearching carried out by the Cochrane Collaboration was included. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.
Search keywords were (neoplasm* OR leukemia OR leukaemia OR lymphoma* OR plasmacytoma OR “histiocytosis malignant” OR reticuloendotherliosis OR “sarcoma mast cell” OR “LettererSiwe disease” OR “immunoproliferative small intestine disease” OR “Hodkin disease” OR “bone marrow transplant*” OR cancer* OR tumor* OR malignan* OR netropeni* OR carino* or Adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemo*) AND (stomatitis OR “Stevnes Johnson syndrome” OR “candidiasis oral” OR mucositis OR (oral AND (cand* OR mucos* OR fung*)) OR mycosis OR mycotic OR thrush. Extensive appendices are provided with specific search strategies used for each database.
Studies were included in the review if they
The final assessment incorporated 32 studies. Out of an initial 95 eligible studies, 64 were excluded because of study design issues, protocol violations, lack of useable data, or no relevant outcomes.
Treatment of mucositis
Summary of data from single trials showed the following interventions to demonstrate statistically significant benefit (p < 0.05).
Other interventions for treatment of mucositis evaluated included chlorhexadine versus salt and soda, Gelclair verus sucralfate and mucaine,”Magic” mouthwash versus salt and soda, sucralfate versus placebo and versus salt and soda, and tetrachlorodecaoxide.
Management of pain with mucositis
The following interventions demonstrated statistically significant benefit in managing pain (p < 0.05).
The lack of independent duplication of studies investigating the same intervention limits the strength of evidence and ability to generalize results.
Most studies reviewed had small sample sizes and may have been underpowered to demonstrate significant differences in outcomes.
Different scoring systems for mucositis were used, and, in some studies, the method of scoring was not defined.
The need for further well-designed trials to evaluate the effectiveness of interventions continues.
Adoption of standard clinical outcome measures should be considered, including patient-based measures and inclusion of the cost of interventions.
Qutob, A.F., Gue, S., Revesz, T., Logan, R.M., & Keefe, D. (2013). Prevention of oral mucositis in children receiving cancer therapy: A systematic review and evidence-based analysis. Oral Oncology, 49, 102–107.
To investigate, critically appraise, and rate the evidence regarding agents used for the prevention of mucositis in children
Databases searched included CINAHL, Cochrane library, Ovid MEDLINE, PubMed, BioMed Central, and other internet-based sources. A total of 19 databases were searched.
Search keywords were mucositis, stomatitis, oral inflammation, mouth mucosal inflammation, prophylaxis, management, and prevent; in addition to keywords to identify children and all types of cancer therapy.
Studies were included in the search if they
Studies were excluded if they
The authors concluded that oral care protocols should be used; oral sucralfate suspension, prostaglandin E2, and GM-CSF mouthwash should not be considered based on current evidence; and chlorhexidine (without use as part of an oral care protocol), laser therapy, and glutamine should not be considered because of conflicting evidence.
Findings provide further support for use of oral care protocols. Results provided no other useful recommendations for preventive therapies but identified the need for further research in this area.
Worthington, H.V., Clarkson, J.E., Bryan, G., Furness, S., Glenny, A.M., Littlewood, A., … Khalid, T. (2011). Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews (Online), 4(4), CD000978.
To evaluate the evidence for prophylactic agents in management of oral mucositis in patients with cancer receiving treatment
Databases searched were MEDLINE, CANCERLIT, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), System for Information on Grey Literature in Europe (SIGLE), and the Cochrane Database.
An extensive list of search terms and strategies used per database was provided in the article.
Studies were included in the review if they
A total of 383 references were retrieved. Risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were categorized as low, unclear, or high risk of bias. Studies were labeled using the GRADES system for evaluating quality of evidence.
Findings support the benefits of cryotherapy and keratinocyte growth factor. The low quality of evidence in most of the other interventions points to the need for ongoing, well-designed research in this area. The presentation of findings in many publications made meta-analysis impossible.
The rationale for the authors' summaries of findings was not entirely clear. Similar RR ratio results with similar evidence quality levels were identified differently in terms of potential benefit. Although the review was inclusive and extensive, interpretation of results was inconsistent. High heterogeneity existed in most interventions, and most studies were either at high or unclear risk of bias with low GRADES scoring. Studies did not always differentiate between mucositis and candidiasis, which would affect recommendations.
This article suggests strong support for use of cryotherapy and keratinocyte growth factor for mucositis prevention. It suggests possible benefit from aloe vera, amifostine, IV glutamine, G-CSF, honey, laser, and antibiotic lozenges. Sucralfate may reduce the severity of mucositis. These findings should be interpreted with caution, given the relatively low quality of overall evidence and high heterogeneity across studies included in meta-analysis, as well as the fact that treatments and sample characteristics were highly varied.
Dazzi, C., Cariello, A., Giovanis, P., Monti, M., Vertogen, B., Leoni, M. … Marangolo, M. (2003). Prophylaxis with GM-CSF mouthwashes does not reduce frequency and duration of severe oral mucositis in patients with solid tumors undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue: A double blind, randomized, placebo-controlled study. Annals of Oncology, 14, 559–563.
Patients were stratified on the basis of their conditioning treatment. Patients in the treatment group were given granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash, 150 mcg per day in 100 cm3 of sterile water. Patients in the control group received 100 cm3 of sterile water alone as placebo. Both groups were instructed to perform one-minute mouthwashes, four times per day. Treatment started the day after chemotherapy ended and continued until stomatitis resolution, neutrophil recovery, or both.
The study was conducted between July 1997 and February 2002.
This was a double-blind, randomized, placebo-controlled study.
The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) for mucositis was used.
The intervention was not effective.
Hejna, M., Kostler, W.J., Raderer, M., Steger, G.G., Brodowicz, T., Scheithauer, W., … Zielinski, C.C. (2001). Decrease of duration and symptoms in chemotherapy-induced oral mucositis by topical GM-CSF: Results of a prospective randomized trial. European Journal of Cancer, 37, 1971–1975.
Patients were randomized to one of two arms.
Both groups were instructed to continue using the respective mouthwashes until complete response (CR). A third, independent investigator randomized patients without knowing individual mucositis ratings.
The study was conducted between March 1998 and June 1999.
This was a prospective, randomized, controlled study.
Every three days, objective and subjective evaluations were conducted.
Mantovani, G., Massa, E., Astara, G., Murgia, V., Gramignano, G., Lusso, M.R., … Maccio, A. (2003). Phase II clinical trial of local use of GM-CSF for prevention and treatment of chemotherapy and concomitant chemoradiotherapy-induced severe oral mucositis in advanced head and neck cancer patients: An evaluation of effectiveness, safety and costs. Oncology Reports, 10, 197-206.
To evaluate a granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash in the prophylactic and curative settings of oral mucositis (OM)
All patients were given 300 mcg of granulocyte-macrophage colony-stimulating factor (GM-CSF) in 300 ml of water; patients were instructed to rinse and gargle with the mouthwash for as long as possible, three times daily (morning, midday, and before bedtime). Patients were instructed to not eat, drink, or rinse with another mouthwash for at least one hour afterward. Patients in the prophylactic group also received amifostine (500 mg IV). Patients in the curative group were treated from the appearance of mucositis until two days after clinical resolution.
This was an open, nonrandomized, phase II study.
Nicolatou-Galitis, O., Dardoufas, K., Markoulatos, P., Sotiropoulou-Lontou, A., Kyprianou, K., Kolitsi, G., … Velegraki, A. (2001). Oral pseudomembranous candidiasis, herpes simplex virus-1 infection, and oral mucositis in head and neck cancer patients receiving radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash. Journal of Oral Pathology and Medicine, 30, 471–480.
Patients were given a mouthwash of 400 mcg granulocyte-macrophage colony-stimulating factor (GM-CSF) dissolved in 1 mL sterile water, added to 200 mL drinking water, to treat grade II–IV mucositis. Patients were instructed to use the mouthwash once a day after the end of the second week of therapy. They were instructed to use as a mouthwash and then swallow in fragments within one hour.
Physicians used the following grading system.
Patients used the following grading system.
The authors stated that because 20 out of 46 patients with initial mucositis of grade II and III completed RT with grade I mucositis, the mouthwash was beneficial. However, additional research is needed.
Sprinzl, G.M., Glava, O., deVries, A., Ulmer, H., Gunkel, A.R., Lukas, P., et al. (2001). Local application of granulocyte-macrophage colony stimulating factor (GM_CSF) for the treatment of oral mucositis. European Journal of Cancer, 37, 2003-2009.
GM-CSF topically (Leukomax mouthwash)
Given in 250 ml 400 mcg recombinant Escherichia coli GMCSF once daily as soon as erythema was diagnosed, ordered to swish and swallow over period of 1 hr.
Control arm – conventional mouthwash (Hydrocortisone, Pantocain)
Patients also told to maintain strict oral hygiene using a soft toothbrush and fluoride toothpaste, and to avoid tobacco, alcoholic beverages, very hot and cold food, and spicy food.
Stratified for RT chem. Combination or RT alone.
All patients had daily rinses at least 3x/day. GM-CSF versus pantocain, hydrocortisone, cional kreussler, and bepathen (European product).
The study was comprised of 59 patients, recruited, 14 not randomized, patients = 45.
GMCSF group = 23, 21 control
18 and 17 completed trial
Jan 1997 – Oct 1998
Prospective, randomized, parallel grouped phase II clinical trial (non-blinded)
WHO scale for mucositis
No statistically significant evidence was reached in the grade of oral mucositis or the patient’s perception of oral pain.
Unable to determine therapeutic benefit of control arm product versus lack of effect of GM-CSF versus benefit of strict oral hygiene.
Authors conclude the agent cannot be recommended.
Intervention not effective
Valcarcel, D., Sanz, M.A., Sureda, A., Sala, M., Munoz, L., Subira, M., et al. (2002). Mouth-washings with recombinant human granulocyte-macrophage colony stimulation factor (rhGM-CSF) do not improve Grade III-IV oropharyngeal mucositis (OM) in patients with hematological malignancies undergoing stem cell transplantation. Results of a randomized, double-blind, placebo-controlled study. Bone Marrow Transplantation, 29, 783-787.
Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) mouthwash
400 mcg dissolved in 20 mL NS; control received 200 mL saline only
Mouthwashings 3 times a day for 30 min without swallowing, over a period of 5 days after inclusion in protocol. Avoid other oral intake for 1 hour.
Also standard protocol of mouth care – toothbrushing after each meal and rinsing oral cavity with 0.9% saline or in cases of inflammation, 0.12% chlorhexidine four times daily
Only MM patients received IV GCSF 5 mcg/kg from day +7 to neutrophil recovery.
The study was comprised of 41 patients (tx grp = 18, 23 placebo), with an age range of 16–69 years and a median age of 44.
All patients developed OM grade III-IV after auto- or allo-SCT.
Oct 1998 – Mar 2001
Prospective randomized, double-blind placebo-controlled study
WHO toxicity score grading mucositis from 0-4, EVA scale (visual analog) scoring swallowing induced pain from 0-10 3x a day, sleep quality evaluations as good, intermediate, and poor, and food intake, none, liquids, soft, regular
Also, infections, days with fever, fungal and viral oral infections, and need for broad spectrum antibiotics, TPN, and opioids were documented.
P < 0.05 = significant
No statistically significant differences in overall duration of mucositis or duration of maximum grade of OM. Mouth pain and sleep quality scores were similar.
More people in the rhGM-CSF group needed PCA morphine (50%, 8pts) versus the NS (10%, 2pts).
Also no significance in the use of TPN between the two groups.
Given cost, it appeared the results were not better than NS.
No benefit of GM-CSF mouthwash.
May actually show benefit of NS.
Schering-Plough supplied the rhGM-CSF.
Small diverse study group – long duration for study – other potential factors possibly change over time.
Study needs to be larger.
Only trialed with stem cell transplant recipients.
Patients were also rinsing with 0.9 NS and chlorhexidine as part of everyday mouth care (unable to determine number).
Study was from 1998-2001.
Study focused only on prevention after dev grade 3 – 4 OM.