Colony Stimulating Factors: GCSF & GMCSF Mouth Rinse

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  

• Were randomized controlled trials using placebo, no treatment, or another active intervention.
• Involved patients with cancer receiving chemotherapy or radiotherapy and experiencing oral mucositis.
• Involved any intervention for the treatment of oral mucositis or its associated pain.
• Written in any languages. Papers not in English were translated by members of the Cochrane collaboration.

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.

• The final set of studies involved a total of 1,505 patients; 1,023 patients were involved in trials investigating the effectiveness of agents to treat mucositis, and 718 patients were involved in trials evaluating pain relief. 
• Sample sizes ranged from 6–71 patients per treatment or control group.
• Twenty-eight trials included only adult patients, and four included only children.
• Trials included patients treated for a combination of leukemia and solid tumors (n = 14), patients with head and neck cancer (n = 8), and patients who had received bone marrow or stem call transplant (n = 11).

Treatment of mucositis

Summary of data from single trials showed the following interventions to demonstrate statistically significant benefit (p < 0.05).

• Allopurinal mouthwash resulted in improvement in mucositis, eradication of mucositis in some cases, and reduction in time to healing.
• Granulocyte macrophage-colony stimulating factor (GM-CSF) demonstrated mixed results, with two trials showing improved time to healing versus use of providone iodine and antimycotic mouthwash and one trial showing improvement in mucositis by the end of radiotherapy.
• Human placental extract demonstrated improvement in mucositis in one trial.
• Phenytoin mouthrinse was associated with better quality of life than placebo in one trial, but no benefit for pain was found and healing was not evaluated.
• Polyvariant intramuscular immunoglobulin was associated with improvement in mucositis versus placebo in one trial.
• Topical vitamin E was associated with improvement in mucositis and eradication of mucositis compared to systemic vitamin E in one trial.
• Debridement was associated with fewer days to clinical resolution and decreased severity of mucositis, when compared to no debridement.
• Laser treatment was beneficial in management of mild to moderate mucositis compared to sham treatment.

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).

• Opiod use was associated with lower average pain scores when compared to antidepressant use.
• Morphine pharmacokinetically patient controlled analgesia (PKPCA) was associated with lower average pain score than morphine standard patient controlled analgesia (PCA).
• When morphine PCA was compared to continuous morphine infusion, meta-analysis showed no difference in mean pain scores; however, mean opiate intake was reduced with PCA, and PCA was associated with fewer days of pain.

Other findings

• Interventions reviewed that showed no statistical benefit for treatment of mucositis included chlorhexadine, Gelclair, “Magic” mouthwash, and sucralfate.
• Interventions reviewed for management of associated pain that demonstrated no statistical benefit included hydromorphone PCA versus morphine, Alfentanil versus morphine, Dicofenic versus placebo, PCA versus staff controlled, hypnosis, relaxation, and imagery.
• Out of 27 different interventions evaluated for treatment of mucositis, only one comparison was significant for one outcome: low level laser treatment reduced the severity of mucositis.
• No evidence was found to suggest a difference in pain control between continuous infusion and PCA; however, the PCA group required less morphine, and the pain lasted two less days.

• Some evidence exists that low level laser treatment may help reduce severity of mucositis.
• No evidence suggests that PCA is more effective than continuous infusion for controlling pain. Weak evidence is available to support that PCA is associated with less opiate used per hour and that the duration of pain may be reduced.
• No clear benefit appears to be associated with antimicrobial use and GM-CSF for prevention or management of mucositis.
• This review demonstrated weak and unreliable evidence of benefit for interventions for mucositis.

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.

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

• Involved English-speaking children.
• Were clinical trials conducted on the prevention of oral mucositis during cancer therapy.

Studies were excluded if they

• Were not in English
• Did not involve children
• Involved only gastrointestinal mucositis.
• Involved treatment of mucositis rather than prevention.
• Were case studies or pilot studies.
• Were commentaries or letters to the editor.
• Involved sample sizes of less than 20 patients.

• The total number of references retrieved was 16,471.
• The authors evaluated the references using the Canadian Task Force on Preventive Health Care evidence-based guidelines.

• The final number of studies was 27. The sample range across studies was not reported.
• Other than inclusion of pediatric cases, no other characteristics were described.

• Patients were undergoing the active antitumor treatment phase of care.
• The study has clinical applicability for pediatrics.

• The studies involved the following interventions.
  • Oral care protocols (n = 5)
  • Chlorhexidine mouthwash (n = 7) 
  • Benzydamine mouthwash (n = 1)
  • Iseganan mouthwash (n = 1),
  • Granulocyte macrophage-colony stimulating factor (GM-CSF) mouthwash (n = 2)
  • Oral glutamine (n = 2)
  • Enteral glutamine (n = 1)
  • Oral propantheline and cryotherapy (n = 1)
  • Oral cryotherapy (n = 1)
  • Oral sucralfate suspension (n = 1)
  • Prostaglandin E2 tablets (n = 1)
  • Chewing gum (n = 1)
  • Laser therapy (n = 3). 
• Good evidential support was found for the use of oral care protocols. Fair support was found for the use of chlorhexidine with some mixed results.
• Only one article was found that studied benzydamine, CSF, and iseganan. The evidence was deemed insufficient to make a recommendation. 
• Good evidential support was found against the use of sucralfate and prostaglandin E2 tablets.
• Evidence regarding laser use and oral and enteral glutamine were mixed.

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.

• No disease or treatment factors were reported or considered in the analysis. 
• Some interventions were evaluated in only one study.
• The quality of the evidence in general was highly variable.
• No information was provided on how the outcome for mucositis was measured in the included studies.
• The authors recommendations suggest no use of a specific intervention if findings were conflicting, which assumes that insufficient evidence of effectiveness is equivalent to ineffectiveness.

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.

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

• Were randomized controlled trials (RCTs).
• Compared an intervention to a placebo or no treatment.

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.

• The final number of studies included in the review was 131.
• The total sample size across all studies was 10,514 with an across-study sample range of 12–301. 
• Studies involved a variety of cancers and patients receiving chemotherapy, radiation therapy, or both.

• Patients were in the active antitumor treatment phase of care.
• This study has clinical applicability to pediatrics.

• Only 8% of studies included were seen to have a low risk of bias. 
• Studies included a variety of treatments such as acyclovir, allopurinol rinse, aloe vera, amifostine, antibiotic paste, systemic antibiotics, axulene, benzydamine, beta carotene, chamomile, chewing gum, Chinese herbs, chlorhezidine, cryotherapy, epidermal growth factor, glutamine, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enymes, indigo wood root, intestinal trefoil factor, keratinocyte growth factor, laser, anti-inflammatory drugs, oral care, pentoxifylline, pilocarpine, polymixin/tobramycin/amphotericin (PTA), traumeel, sucralfate, zinc sulphate, and povidone iodine. 
• From all analyses, at least moderately strong evidence of benefit was found for cryotherapy (RR = 0.74, 95% confidence interval [CI] 0.57–0.95, p = 0.02) for any mucositis and for keratinocyte growth factor (RR = 0.82, 95% CI 0.71–0.94, p = .0005) for any mucositis. 
• Weak and unreliable evidence for potential benefit was found with aloe vera, amifostine, glutamine, G-CSF, honey, laser, polymixin/tobramycin, amphotericin lozenges, and sucralfate.
• A substantial body of evidence showed no benefit of chlorhexidine.

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.

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 reported on 90 patients with lymphoma or solid tumors who were hospitalized and receiving high-dose chemotherapy and autologous stem cell transplant.
• The treatment group had 46 patients, and the control group had 44 patients. 
• Patients' ages ranged from 15–61 years, with a median age of 29 years.

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.

• Incidence of mucositis was similar in both groups with 87% in the treatment group and 95% in the control group experiencing mucositis.
• Grade 4 stomatitis was also similar with 33% in the treatment group and 34% in the control group.
• No significant difference was found in duration of symptoms.
• Median days with oral pain, maximum mucositis scores, and mean length of time with a mucositis score greater than 4, were all higher in the GM-CSF group than in the control group.

The intervention was not effective.

• All patients received subcutaneous G-CSF 300 mcg each day until hematopoietic reconstitution.
• Observers graded mucositis differently.
• Because 0.2% chlorhexidine solution and amphotericin B were also being used as a rinse, the effect of specific agents was not clear.
• The overall rate of oral mucositis was lower than expected, making the sample size insufficient.

Patients were randomized to one of two arms.

• Arm A was given topical granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leucomax) mouthwash three times per day. The mouthwash consisted of 400 mcg GM-CSF in 250 mL water. Patients were instructed to rinse with 25 mL for 3 minutes and repeat 10 times within 30 minutes. They were to repeat this process at three identical times each day.
• Arm B was given a solution of 4 mL povidone-iodine in 125 ml water with amphotericin B. They were to rinse with 10 mg four times per day according to the same instructions as Arm A.

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 reported on 31 patients, with 15 in Arm A and 16 in Arm B.
• Patients' ages ranged from 39–77 years, with a median age of 58 years.
• All patients had solid tumor diagnoses.
• The World Health Organization (WHO) oral mucositis scale was used to grade patients after they had received fluorouracil (5FU)-based chemotherapy. Two investigators independently rated mucositis severity.

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.

• Patients who received the GM-CSF treatment experienced shorter duration (5.3 versus 8.1 [p = 0.0008]) and quicker resolution (2.8 versus 4.1 [p = 0.0011]) of mucositis.
• No side effects were reported, and the treatment was well tolerated.

• The sample size was small.
• Application of mouthwash findings is complicated.
• The treatment has a high cost.

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.

• The study reported on 68 patients with 46 in the prophylaxis group and 22 in the curative group.
• All patients were treated with chemotherapy and radiation therapy. Most patients were diagnosed with advanced head and neck cancer.

This was an open, nonrandomized, phase II study.

• The National Cancer Institute (NCI) Common Toxicity Criteria for oral mucositis were used.
• The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)–Head and Neck (H&N) 35 was used.

• Duration of mucositis was 8.7 in the prophylaxis group and 11.5 in the curative group (p = 0.089).
• Patients had a lower mean grade of OM on day 3 (p = 0.012) and day 6 (p = 0.007).
• Only 50% of patients in the prophylaxis group developed mucositis.

• The QLQ was only administered to those in the prophylactic arm of study.
• Too many factors could have influenced patient outcomes. No control group was included.
• The  two groups had different sizes.
• Determining significance is difficult to based on the study design.

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.

• GM-CSF was given to 46 patients with radiation-induced ulcers.
• All patients were receiving radiation therapy (RT) for head and neck cancer. Some patients also received chemotherapy.

Physicians used the following grading system.

• 0 - None
• I - Diffuse erythema
• II - Erythema, small foci of ulcers
• III - Ulcers covered by pseudomembranes in more than half of mucosa
• IV - Necrotic ulcers and hemorrhage

Patients used the following grading system.

• 0 - none
• I - Mild soreness, solid diet
• II - Mild to moderate pain, soft diet
• III - Severe pain and dysphagia, liquids only
• IV - Severe pain, liquids only, and/or parenteral support

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.

• Mucositis grade 1 was NOT treated.
• The article did not include statistical evidence.
• The article assumes that the oral mucositis resolved as a result of the mouthwash and not spontaneously; however, no control group was included to validate that conclusion.
• The article focused on infection.

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
 

• Sample size small
• Selection of control arm agent
• \"Tremendous cost\" of agent

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.