Cryotherapy

Database searched was MEDLINE (1993–2003) for randomized, controlled trials evaluating mucositis interventions.

A total of 50 randomized controlled trials were presented. Other trials and papers were referenced.

• Sample sizes ranged from 10–222.
• Patients were treated with chemotherapy, radiotherapy, and bone marrow transplantation.

The author concluded that most agents require more study.

• Evidence for cryotherapy and bolus 5-fluorouracil was strong.
• Sucralfate studies produced conflicting results and included varying doses and administration frequencies, making comparisons difficult. Most studies indicated no difference in severity or duration. The validity and reliability of the data were questioned because of the measurement scales used.
• Similarly, studies of cytokine-like agents used different doses, making comparisons difficult.
• Moderate evidence suggested that benzydamine is effective in relieving mouth pain caused by radiation-induced mucositis in patients with head and neck cancer. The agent requires additional investigation and study for chemotherapy-induced mucositis.
• Large studies of chlorhexidine mouthwashes have failed to show significant findings; however, the studies may have had inadequate sample sizes, as power analyses were not performed.
• Povidone-iodine showed significant reduction in onset, incidence, total duration, and worst grade of mucositis for patients with head and neck cancer undergoing radiation with carboplatin in two studies. Both studies had sample sizes of 40. Given these sample sizes and specific populations, generalizability of the findings was restricted.
• Oral hygiene protocols were shown to reduce the duration and severity of mucositis; however, the content of the protocols was not proven.

The author noted the problem of variation in study protocols, insufficient sample sizes, and a lack of consensus regarding the scoring system for mucositis.

The author noted the need to include psychotherapeutic interventions and management and pointed out the lack of a quality-of-life tool for mucositis.

STUDY PURPOSE: To systematically review evidence regarding interventions used to prevent chemotherapy-induced oral mucositis (OM)

• FINAL NUMBER STUDIES INCLUDED = 20
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,626
• SAMPLE RANGE ACROSS STUDIES: 16–326 patients
• KEY SAMPLE CHARACTERISTICS: Various patient types

PHASE OF CARE: Active antitumor treatment

• Cryotherapy was evaluated in four studies. Cryotherapy reduced the seriousness and incidence of OM. Three of these were among patients receiving 5-fluorouracil (5-FU).   
• Limited research evidence for oral care in general and lack of consistent definition and components of oral care
• Two palifermin studies were included, showing its effectiveness for the prevention of OM; however, they were of small sample sizes.
• Two studies looked at allopurinol and had mixed results.
• Two studies examined the use of chlorhexidine and had mixed results.

Based on this review, the strongest evidence was in favor of cryotherapy in patients receiving 5-FU. The evidence was insufficient in other interventions to demonstrate a benefit.

Very few studies were included, and why this search did not yield a larger number of studies for some of these interventions was unclear. Exclusion criteria may have eliminated many. Most included studies had small sample sizes.

The findings support the use of cryotherapy for the prevention of OM in patients receiving 5-FU. Although not studied extensively, this intervention should have benefit in patients receiving any agent with a short half-life. The amount of ice chips, etc. used and the duration of the cryotherapy varied. Multinational Association of Supportive Care in Cancer guidelines recommend a 30-minute duration and an amount of ice that can easily be moved around in the mouth.

The process began with a MEDLINE search of research articles from 2002–May 2005. Authors also examined abstracts from American Society of Clinical Oncology, American Society of Hematology, and the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology, as well as the bibliographies of the articles from the MEDLINE search. Articles were included if they involved the use of alternative or natural agents, ice, or laser therapy in the prevention and management of alimentary mucositis.

The initial search identified 167 articles. Of these, 14 were selected and reviewed. These involved one preclinical study on alternative/natural therapy, four clinical studies on cryotherapy, two studies on laser therapy, and seven studies on alternative and natural therapy. The studies were randomized, controlled, and determined to have a low bias potential.

The sample characteristics varied across studies.

Major and minor design flaws prevented the recommendation of scientifically based guidelines. Strong evidence exists for the use of cryotherapy in patients receiving high-dose melphalan (140 mg/m²) as part of the conditioning regimen for hematopoietic stem cell transplantation. Cryotherapy is not appropriate for use with agents with a longer half-life such as methotrexate or doxorubicin. Laser therapy seems promising.

To date, clinical studies with laser therapy have been small, protocols are not standardized, laser devices are different, parameters are varied, and assessment tools are not uniform.

The authors recommended further investigation of the agents and noted the lack of standardized assessment instruments.

STUDY PURPOSE: To evaluate the evidence to assess the effects of oral cryotherapy for the prevention of oral mucositis (OM)

• DATABASES USED: MEDLINE, EMBASE, CINAHL, CANCERLIT, Cochrane Collaboration, National Institutes of Health (NIH) health trials registry, World Health Organization (WHO) clinical trials registry
• KEYWORDS: Explicit search terms per database are provided.
• INCLUSION CRITERIA: Randomized controlled trails comparing oral cryotherapy against any other treatment or no treatment; OM caused by chemotherapy, radiotherapy, or combination therapy
• EXCLUSION CRITERIA: Crossover design trials, interventions involving other approaches in addition to cryotherapy

• FINAL NUMBER STUDIES INCLUDED = 14 in qualitative review, 11 in meta-analysis
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,316
• SAMPLE RANGE ACROSS STUDIES: 20–206 patients
• KEY SAMPLE CHARACTERISTICS: One study included a small number of children, one study involved patients with head and neck cancer receiving radiation therapy, and the rest involved patients receiving chemotherapy. Five studies involved treatment with high-dose melphalan.

PHASE OF CARE: Active antitumor treatment

Insufficient evidence exists to evaluate the effect of cryotherapy in patients receiving radiation therapy alone for head and neck cancer. Five studies in which 5-fluorouracil (5-FU) was administered showed that oral cryotherapy reduced the risk of OM development (RR = 0.61; 95% CI [0.52, 0.72]; p < 0.00001). Five studies involving treatment with high-dose melphalan risk of OM was also reduced (RR = 0.59; 95% CI [0.35, 1.01]; p = 0.05). OM risk was reduced in mild, moderate, and severe OM cases. Insufficient evidence existed to determine whether 30 minutes or 60 minutes of cryotherapy was more effective. One study with a high risk of bias showed no difference between oral cryotherapy and the use of prophylactic chlorhexidine.

Oral cryotherapy is effective in reducing OM in patients receiving 5-FU and high-dose melphalan.

Studies were of moderate quality based on the risk of bias assessment.

Strong evidence existed in support of effectiveness of oral cryotherapy to reduce the OM risk in patients receiving 5-FU treatment and moderately strong evidence of efficacy in patients given high-dose melphalan. Very limited evidence existed in children. This intervention is very low risk, so nurses can advocate for the use of oral cryotherapy for patients receiving chemotherapeutic agents with a short half-life. Ice chips could create a potential choking hazard for children; therefore, the use of iced drinks or popsicles may be better approaches to use in this population. Future research of head and neck trials of cryotherapy versus other effective interventions would be useful to further inform clinical practice.

STUDY PURPOSE: To determine the effectiveness of cryotherapy on oral mucositis in patients receiving myeloablative conditioning followed by bone marrow transplantation (BMT)

TYPE OF STUDY: Systematic review

PHASE OF CARE: Active antitumor treatment

Oral cryotherapy before, during, and after chemotherapy infusion reduced oral mucositis incidence, severity, and pain.  

Small number of studies was looked at. Three of the six studies were greater than five years old.

Cryotherapy is a simple, low-cost, effective way of decreasing mucositis in some patients. The proper administration of cryotherapy is important for the best results possible. Nurses need to understand the instructions of how and when to administer cryotherapy and enlist the patient's and caregivers' help in administering it.

• FINAL NUMBER STUDIES INCLUDED = 8 (with one study used twice) 
• TOTAL PATIENTS INCLUDED IN REVIEW = 458
• SAMPLE RANGE ACROSS STUDIES: 23–122 patients
• KEY SAMPLE CHARACTERISTICS: Patients with hematologic malignancies     

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care

Oral cryotherapy for patients with hematologic malignancies receiving HSCTs with high-dose melphalan decreased the incidence of severe OM. Cryotherapy also may be helpful for patients receiving other preparative regimens. Cryotherapy may decrease the duration of TPN usage and shorten hospital stay. Oral cryotherapy did not appear to affect on the length of analgesic use.

Limitations of this study included the small number of RTCs and the small sample sizes of those RCTs. The methodologic quality of the studies might have resulted in bias.

Oral cryotherapy is a low-cost, easy modality that demonstrated efficacy in decreasing the severity of OM in patients with hematologic malignancies receiving HSCTs. Additional studies on the efficacy of cryotherapy with other conditioning regimens are needed.

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 kept ice chips and ice-cold water in their mouths for 15 minutes before and during as well as for an additional 90 minutes after melphalan infusion. Patients were advised to continue swirling ice chips around in their mouths and to gargle and swallow ice-cold water every 10–20 minutes throughout oral cryotherapy. Patients were consecutively compared with a historical control group (no cryotherapy). Fludarabine was administered at 25 mg/m² daily for five days; melphalan was administered at 70 mg/m² daily for 15 minutes for two days.

The sample consisted of 18 patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) receiving fludarabine and high-dose melphalan (140 mg/m²).

Common toxicity criteria (CTC) grading of stomatitis (0–4) was done every day from the first day of HSCT to day 28. The maximum grade recorded for each participant was considered that patient's grade.

• The cryotherapy group reported less moderate to severe mucositis with 2 out of 18 patients (11.1%) in the cryotherapy experiencing moderate to severe mucositis (grade 2 or 3) and 6 out of 7 patients (85.7%) in the historical control group experiencing grade 2 or 3 mucositis (p = 0.001).
• No patients in the cryotherapy or control group developed grade 4 mucositis.
• Side effects included chills (n = 7; 39%) and nausea (n = 4; 22%), and one patient discontinued cryotherapy.

The sample size was small sample, and the control group was based on historical reports.

To compare the effectiveness of oral cryotherapy (OC) to room temperature saline rinses in prevention of oral mucositis (OM) in patients with multiple myeloma (MM) and lymphoid neoplasias (NHL, HL) for autologous stem cell transplantation (ASCT)

An oral care protocol with sodium bicarbonate mouthwash from day 7 of ASCT until hospital discharge was implemented for all patients in the study. The intervention group received oral cryotherapy before infusion for 10 minutes, during infusion for 15 minutes, and after HDmel for 15 minutes. The control group received saline salt rinses at room temperature, but the schedule was not described in the study. Nurses assessed for oral mucositis on the day before ASCT and on days 3, 6, 9, and 12 after infusion. 

• N = 134  
• MEDIAN AGE = 55-56 years (range = 23–70 years)
• MALES: 64%, FEMALES: 35%
• KEY DISEASE CHARACTERISTICS: MM = 58%, NHL = 41%
• OTHER KEY SAMPLE CHARACTERISTICS: Conditioning regimens: MM = HD melphalan, NHL = BEAM (carmustine, etoposide, cytarabine, melphalan)

• SITE: Single site, 0
• SETTING TYPE: Inpatient  
• LOCATION: Instituto Carlos III, Spain

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS:  Elder care  

• Retrospective

• Primary outcome measurement was development of OM (time to onset, severity/duration, and resolution), on the World Health Organization (WHO) mucositis grading scale.
• OM assessed by nursing team on day 1 prior to ASCT and days 3, 6, 9 and 12 after ASCT.

Oral mucositis was significantly lower in the intervention group (44%) compared to the control group (82%) (p < 0.001). Grades III and IV oral mucositis were also lower in the intervention group (15%) compared to the control group (31%) (p = 0.031). There was no difference between groups in the onset or duration of mucositis.

OC is more effective than oral saline rinses in the prevention of OM, including grades III-IV OM in patients receiving conditioning regimens.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results 
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Other limitations/explanation: Conditioning regimens were not homogeneous.

OM can interfere with nutrition and quality of life and can lead to secondary infections. Effective prophylaxis is needed to have good outcomes. Although this study had limitations, OC reduced severity of OM, is cost effective, and is well tolerated by patients. Therefore, it does offer an effective and inexpensive supportive measure.

To evaluate the effectiveness of a cryotherapy protocol in patients undergoing hematopoietic cell transplantation (HCT)

Medical records of patients undergoing autologous HCT for multiple myeloma were used to obtain data. All received high-dose melphalan as part of the conditioning regimen. Patients who were treated prior to the implementation of the cryotherapy protocol were compared to those who received cryotherapy in terms of the incidence, severity, and duration of mucositis. Data were collected to also compare the use of parenteral narcotics, use of parenteral nutrition, and hospital stay.

• N = 140
• MEAN AGE = 55 years
• MALES: 44%, FEMALES: 56%
• KEY DISEASE CHARACTERISTICS: All had multiple myeloma and received autologous HCT.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Canada

• PHASE OF CARE: Active antitumor treatment

• Retrospective cohort comparison

• World Health Organization (WHO) mucositis severity scale

Overall incidence of oral mucositis was 95.7% of those with no cryotherapy compared to 71.4% of those who received cryotherapy (p < 0.001). Median severity without cryotherapy was 2.5 compared to 2 with cryotherapy (p = 0.03). More patients without cryotherapy needed parenteral narcotics for pain control (p = 0.02), and duration of mucositis was about two days less with cryotherapy (p = 0.02). No differences existed in parenteral nutrition use or length of hospital stay.

The use of cryotherapy was associated with lower incidence, severity, and duration of mucositis among patients undergoing HCT receiving high-dose melphalan.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Cryotherapy has been shown to be effective in reducing the severity of mucositis in patients receiving chemotherapeutic agents with a short half-life.

To verify the efficacy of cryotherapy plus low level laser therapy (LLLT) on oral mucositis (OM) in patients receiving high-dose melphalan chemotherapy

Prior to chemotherapy, patients were examined by a dentist who performed prophylaxis, eliminated any oral infections, and provided oral hygiene instructions. All patients received basic oral care, consisting of gargling with alcohol-free mouthwash and brushing of teeth. Daily LLLT was given from the day after chemotherapy was begun until engraftment. Study group patients also received cryotherapy in addition to LLLT with ice chips for five minutes before infusion, during melphalan infusion, and then for 30 minutes after infusion. Mucositis was evaluated daily. Patients who received cryotherapy were compared to historical controls who received only oral hygiene and historical controls who received hygiene plus LLLT.

• N = 104
• MEAN AGE = 56.3 years
• AGE RANGE = 6–73 years
• MALES: 70.2%, FEMALES: 29.8%
• KEY DISEASE CHARACTERISTICS: Patients had multiple tumor types, most had multiple myeloma, and all were undergoing ablative chemotherapy for HCT.
• OTHER KEY SAMPLE CHARACTERISTICS: The majority had autologous HCT.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Brazil

• PHASE OF CARE: Active antitumor treatment

• Prospective with historical cohort comparisons

• World Health Organization (WHO) oral mucositis scale

Fifty-four patients had LLLT plus cryotherapy, 17 had LLLT, and 33 had only oral hygiene. All patients had some degree of OM. Those who received LLLT plus cryotherapy had the highest prevalence of grade 1 mucositis and lowest prevalence of grade 2 or greater (p < 0.001). The duration of OM was highest in the control group, who had only oral hygiene (p < 0.001).

The combination of LLLT and cryotherapy was associated with the lowest severity of OM compared to controls and patients receiving LLLT alone.

• Baseline sample/group differences of import
• Risk of bias (no random assignment)
• Risk of bias (sample characteristics)
• Significant group differences in age, chemotherapy regimens used, and diagnoses, which could have influenced results

The addition of oral cryotherapy to LLLT for patients undergoing ablative chemotherapy with melphalan prior to HCT demonstrated greater efficacy in reducing the severity of OM. Both LLLT and cryotherapy have demonstrated efficacy for preventing severe OM. This study shows that the addition of oral cryotherapy with melphalan infusions can further reduce this complication. Nurses should employ cryotherapy in appropriate patients such as those receiving high-dose melphalan, and advocate for the concomitant use of LLLT.

The study group used oral cryotherapy, via ice cubes “at a size that could be moved easily in the mouth and whose corners have been smoothed in order that they will not cause irritation in the mouth,\" beginning five minutes before chemotherapy initiation and maintained use during IV infusions of etoposide, platinol, mitomycin, and vinblastin. For random allocation, patients were assigned to the study group or a control group in sets of five.

• The study involved 60 patients, with 30 in the study group and 30 in the control group.
• The majority of patients (66.7%) were older than 60 years of age.
• Patients were excluded from the study if they
  • Had previously undergone their first chemotherapy.
  • Were not receiving combined courses.
  • Were given chemotherapy agents other than etoposide, platinol, mitomycin, or vinblastine.
  • Had malignancy in the oral cavity. Five of the patients had oral infection findings in the oral cavity prior to study.
• Cancer diagnoses were epidermoid (43.3%), small cell (28.3%), adenocarcinoma (11.7%), and mesothelioma (16.7%).
• Chemotherapy regimens were one-day etoposide-platinol (43.3%); three successive days of etoposide-platinol (28.3%); one-day mitomycin, vinblastin, platinol (11.7%); and one-day mitomycin-platinol (16.7%).

The study was conducted at a respiratory disease clinic in Turkey from August 2000 to May 2001.

• A data collection form and patient-judged 0–4 mucositis grading scale were used on days 1–21. A 0–4 physician-judged mucositis grading scale was used on day 21 for patients receiving single-day protocols and on days 2, 3, and 21 for patients receiving three-day protocols. The mucositis grading scales were based on the Mucositis Grading System of the World Health Organization (WHO).
• An oral pH measurement scale was used before and after single-day chemotherapy regimens, before and after each day of chemotherapy for multiday chemotherapy regimens, and on day 21 for all subjects.

• The study group experienced a decrease in the severity and duration of mucositis and in oral pH values.
• Rates of mucositis were lower in the study group.
  • Patient-judged mucositis was 36.7% in the study group and 90.0% in the control group (p < 0.05).
  • Physician-judged mucositis was 10.0% in the study group and 50.0% in the control group (p < 0.05).

• The sample size was small.
• Physicians only assessed mucositis on days 1, 2, 3, and 21, but not during the entire chemotherapy course.
• Application to other chemotherapy agents is not known.

To assess the effect of oral cryotherapy on development of oral mucositis associated with infusion of fluorouracil (5-FU) with leucovorin

Patients were randomized to cryotherapy or usual care. Prior to randomization, patients completed a study questionnaire, and 60 patients, who had similar characteristics, were selected for randomization. Ice chips were given to patients in the treatment group 5 minutes before and throughout treatment for a total of 30 minutes of continuous use. Mucositis assessment was done on days 7,14, and 21 after chemotherapy.

• The study reported on 60 patients. Ages were not stated.
• The sample was 50% male and 50% female.
• More than 70% in each group did not brush their teeth, and none had gone to a dentist. All were receiving bolus 5-FU treatment. Patients with oral problems at baseline or head and neck cancer were excluded. Gastric and colon cancers were most common in the sample.
• Just more than half (53.3%) of patients were elementary school graduates. 

This was a single-site study conducted in an outpatient setting in Turkey.

Patients were undergoing the active antitumor treatment phase of care.

This was a randomized controlled trial (RCT).

The World Health Organization (WHO) mucositis grading scale was used to assess mucositis severity.

On days 7 and 14, more patients in the experimental group did not have mucositis (p < 0.05). On day 21, patients in the experimental group tended to have lower-grade or grade 0 mucositis, but the difference was not significant.

Findings demonstrated a short-term benefit of cryotherapy in patients receiving 5-FU.

• The sample size was small, with fewer than 100 patients.
• A risk of bias exists because of the lack of blinding and no appropriate attentional control condition.
• The findings are not generalizable as no information about usual care was provided. Investigators selected the group of patients for randomization, which could have biased results. This was a group of patients who did not have any normal oral care, such as routine toothbrushing or ongoing dental prophylaxis. Findings may not be applicable to other groups. No information on oral pain, use of pain medication, or use of other interventions for oral care were included.

Findings suggest that short-term cryotherapy may be beneficial for patients receiving bolus 5-FU; however, longer-term effectiveness may not be seen.

• Patients were randomly assigned to use either ice chips or room-temperature normal saline (NS) rinses before, during, and after melphalan infusion, two days before peripheral blood stem cell transplantation (PBSCT).
• Patients in the ice chips group were instructed to place approximately 1 oz of crushed ice in the mouth. Ice was allowed to melt and was replenished as soon as it was completely melted. Patients were instructed to start 30 minutes before and continue for 6 hours after the end of the 30-minute melphalan infusion.
• Patients in the saline rinse group were instructed to swish 1 oz of room-temperature normal saline in the mouth and spit it out every 30 minutes.   
• Patients were instructed not to eat or drink anything extremely hot or cold during this period.
• The sample size was set at 40 to provide 91% power at a 0.05 significance level.

• The study reported on 41 randomized patients with 21 assigned to receive ice chips and 20 assigned to receive NS. One patient in the NS group withdrew because the patient wanted ice chips. Therefore, data was collected for 21 patients in the ice chips group and 19 in the NS group.
• Patients had to be 18 years or older with multiple myeloma scheduled to receive single-agent melphalan at 200 mg/m² followed by autologous PBSCT.
• Patients were stratified by age less than or greater than 60 years.

This was a randomized trial.

• Patients completed questionnaires that addressed overall health as well as mouth and throat soreness.
• Patients rated difficulties swallowing, drinking, eating, talking, sleeping, and tasting on a 0–4 scale with 0 = no difficulty and 4 = unable to perform.
• Patients rated mouth and throat soreness on a 0–10 scale.  
• Clinical providers and nurses conducted oral assessments as part of routine care using National Cancer Institute (NCI) common toxicity criteria.

• Fewer patients in the ice chips group (14%) experienced grade 3–4 mucositis than in the NS group (75%) (p = 0.0005).
• Patients in the ice chips group required fewer days of total parenteral nutrition (TPN) than the NS group (2 versus 5.5; p = 0.04).
• Patients in the ice chips group also required fewer days of IV narcotics than the NS group (0 versus 5.5; p = 0.0003).
• No significant difference was found in days of hospitalization.
• Patients in the ice chips group experienced significantly less difficulty with activities of eating, talking, sleeping, and tasting.

• The sample size was small.  
• Some inconsistencies occurred with protocol compliance such as variations in the length of time that ice was used and lack of reporting how long ice was used. Some patients complained of coldness and stopped using the ice chips. Additionally, four patients did not fill out any pain reports or record other activities.

Cryotherapy was associated with improved outcomes. Research is needed to determine the required length of cryotherapy.

To determine efficacy of an icy mouth rinse during the administration of cytarabine

Patients were instructed to rinse the mouth with ice-cold water every 10 minutes during the two-hour cytarabine infusion and for one hour after completion of cytarabine infusion. At each time, patients were instructed to rinse the mouth three times. Oral mucositis grading was evaluated daily from the day treatment began to day 28 post-transplant or until complete resolution of mucositis. Maximum grades were used in analysis.

• The study reported on 15 patients. These patients were compared to 35 historical controls.
• Median age of patients was 50 years, with a range of 31–57 years. In the historical control group, the median age of patients was 40 years, with a range of 20–56.
• The sample was 46% female and 54% male.
• All were patients undergoing allogeneic stem cell transplant with a conditioning regimen of total body irradiation and high-dose cytarabine.

The study was conducted at a single-site inpatient setting in Tokyo, Japan.

This was a prospective trial with comparison to historical controls.

The National Cancer Institute common toxicity criteria grading for mucositis was used.

Incidence of grade 2 mucositis  (p = 0.009) and grade 3 mucositis (p = 0.02) was significantly lower in patients who used the mouth rinse compared to the historical controls.

Findings suggest that the cytarabine excreted into saliva contributes to high-dose, cytarabine-induced oral mucositis. Approaches such as mouth rinsing may remove this from the oral cavity and help in the prevention of severe mucositis. How the temperature of the rinse may influence effects is not known.

• The sample size was small with fewer than 30 patients.
• This was not a prospective study.
• No appropriate control or comparison group was included.

Use of ice water rinses during chemotherapy infusion is a simple intervention that might be helpful for prevention of oral mucositis. Well-designed research in this area is warranted, and application and timing of use with other chemotherapeutic agents needs to be examined.

To determine if shorter duration of cryotherapy would minimize side effects without affecting efficacy

Patients were instructed to use cryotherapy 15 minutes before, for 15 minutes during, and for an additional 30 minutes after receiving high-dose melphalan infusion (140 mg/m²). The cryotherapy consisted of continuously swirling ice chips in the mouth and gargling with and swallowing ice-cold water every 10-20 minutes throughout a total of 60 minutes. These patients were compared to 18 historical controls who used cryotherapy for 120 minutes. The 17 patients in the study received fludarabine 25 mg/m² daily for five days and melphalan 70 mg/m² per day over 15 minutes for two days, two days prior to hematopoietic stem cell transplantation (HSCT). Some patients received additional chemotherapy or radiation therapy.

The National Cancer Institute (NCI) common toxicity criteria (CTC) were used to evaluate stomatitis.

Two of the 17 patients in the study (11.1%) developed grades 2–3 oral mucositis, compared to two out of 18 historical controls (11%) who used cryotherapy for a longer time period. Although this is not a statistically significant difference, patients in the study group did report significantly lower incidence of unpleasant symptoms compared to those in the historical control group (p < 0.001).

This article provided an interesting discussion and rationale for adjusting the length of oral cryotherapy to relieve patient discomfort.

The sample size was small, and this was not a controlled study.

To evaluate the use of plain ice, flavored ice, and standard care in the management of oral mucositis

Patients receiving 5-fluorouracil (5-FU) were randomized to receive standard care plus plain ice, standard care plus flavored ice, or standard care alone. Standard care alone consisted of mouthwashes of plain or salty water four times daily plus use of a soft toothbrush and nonabrasive toothpaste. Patients who were assigned to one of the cryotherapy arms were instructed to swirl the ice around the mouth for five minutes prior to, five minutes during, and 20 minutes after the injection. Patients who used plain ice were instructed to do so three times daily. Flavored ice was in the form of a purchased product called \"icy poles.\" Nurses assessed mucositis prior to each chemotherapy cycle and 15 days after each intervention. The sequencing of the interventions was random.

• The study reported on 79 patients across three cycles of chemotherapy.
• The majority of patients were male (67%) and had colorectal cancer (92%).

The study was conducted in an outpatient, chemotherapy, acute care setting at a teaching hospital in Australia.

This was a randomized, controlled, crossover trial.

• Investigators used an Oral Assessment Guide (OAG) and the Western Consortium Cancer Nursing Research (WCCNR) scale to assess mucositis.
• A patient questionnaire was used to gather information regarding comfort, satisfaction, and factors affecting compliance.

• Data analysis of 67 patients were provided as 12 patients were unable to complete the first intervention.
• The reported odds ratio (odds of symptoms increasing versus not increasing) were as follows.
  • Standard care versus ice: OAG 3.26, p = 0.002; WCCNR 3.23, p = 0.021
  • Standard care versus flavored ice: OAG 3.50, p = 0.003; WCCNR 4.00, p = 0.012
  • Ice versus flavored ice OAG 1.07, p = 0.872; WCCNR 1.20, p = 0.774
  • Leucovorin versus no leucovorin: 4.46, p = 0.050
• Pain scores were only available for analysis on 28 data sets because of incomplete data. Ice chips were found to be more effective than standard care in reducing pain (p = 0.009). Flavored ice did not differ from either of the other two treatments (p = 0.152, p = 0.581).
• The taste of the flavored ice and the time required to complete either form of oral cryotherapy were the two main concerns.

• Both forms of cryotherapy were effective in reducing the severity of oral mucositis after each cycle.
• The use of leucovorin appeared to increase the odds of patients experiencing mucositis at least fourfold.
• Use of crossover design is a strength of this study.

• The sample size was small.
• Only conducting oral assessment prior to chemotherapy initiation and on day 15 may not have provided a complete picture of the differences across groups.
• The study was not able to be blinded because of the nature of the intervention.

• Patients were instructed to swish around crushed ice cubes in their oral cavity from 5 minutes before until 30 minutes after IV administration of 5-fluorouracil (5-FU).
• Physician evaluators were blinded.
• Patients received five consecutive days of leucovorin (20 mg/m² per day) plus 5-FU (600 mg/m² per day) administered over a few minutes (Mayo regimen).
• Patients were evaluated for three consecutive cycles.

• The cryotherapy group consisted of 36 patients. Mean age was 62.6 years, with a range of 50–82 years. 
• The control group consisted of 40 patients. Mean age was 61 years, with a range of 42–78 years.
• Patients with head and neck cancer were excluded.
• Nine patients were unwilling to join the cryotherapy group because of tolerance to oral ice.

• Patients were instructed to complete a questionnaire one month after cryotherapy prior to the following course.
• Two blinded otorhinolaryngologists graded patients on a 0–4 scale.

• The percentage of patients free from oral toxicity was significantly higher in the cryotherapy arm (p < 0.01) based on physician evaluations.
• The percentage of patients not suffering from mucositis was significantly higher in the cryotherapy arm following the first and third cycles (p < 0.05) but also after the second chemotherapy cycle (p < 0.01).

• Researchers were unable to double blind cryotherapy.
• The sample size was small.
• Results depended on assessment at completion of cycles, so some changes may have been missed. This study would have benefited from having additional, earlier assessment times.

To assess the effectiveness and feasibility of implementing an oral cryotherapy plus oral care protocol to reduce oral mucositis (OM) severity in patients with multiple myeloma undergoing autologous stem cell transplant (ASCT)

Participants were randomized into an oral cryotherapy study group or a standard oral care control group. Patients in the oral cryotherapy study group received verbal and written instructions on oral cryotherapy plus an oral care protocol in place at the study site. Oral cryotherapy consisted of sucking on ice chips five minutes before, during, and after melphalan administration for a total of 60 minutes. The standard oral care protocol included education regarding oral self care, brushing with Toothette® brushes dipped in sodium bicarbonate, mouth rinsing with sodium bicarbonate mouthwash, and applying moisturizer to lips or the oral cavity. Patients were permitted to floss until their platelet counts fell below 50,000. Patients in the standard oral care control group received only the instructions on the oral care protocol (no cryotherapy). Outcomes were evaluated on days 3, 6, 9, and 12 after stem cell rescue. A research assistant who was blinded to group assignment assessed each participant and recorded the results of the assessment on data collection forms.

• The study reported on 46 patients aged 18 years and older.
• Patients' ages ranged from 43–72 years.
• The sample was 58% male and 42% female.
• Patients had been diagnosed with multiple myeloma and were undergoing ASCT. They were scheduled to receive 200 mg/m² high-dose melphalan. Additionally, they were scheduled to receive growth factors. They had no preexisting oral disease.
• Statistically significant differences existed between the study group and the control group related to age and education.

The study was conducted at a single-site, inpatient setting in Ontario, Canada.

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

This was a prospective, pilot, randomized control trial with repeated measures.

• The World Health Organization (WHO) mucositis grading scale was used.
• Pain was assessed using a 100-mm visual analog scale.
• Opioid use was assessed quantiatively by converting into morphine-equivalent units.
• A nutritional assessment form was used to record functional intake of food and fluids.
• Lengths of stay were recorded from medical records.
• An oral therapy questionnaire was used to assess the tolerability of cryotherapy.

• All participants were free of OM symptoms on days -1 and +3. Signs and symptoms of OM were observed on day +6 and were most pronounced on day +9. Symptoms of OM began to resolve on day +12.
• The overall mean severity scores for OM on the WHO scale were statistically significant (0.43 to 1.14, p < 0.001) on days +9 and +12 (p = 0.03), both in favor of the study group. On day +6, the statistically significant difference (p = 0.02) favored the control group.
• Pain scores were lower for the study group (p  < 0.01), and more participants in the control group used opioid analgesics than in the experimental group (41% versus 13%).
• No significant differences were found related to functional intake of food and fluids.
• The study group experienced a one-day decrease in length of stay, but this was not statistically significant.
• Cryotherapy was somewhat or well tolerated by 87% of patients. Side effects of teeth sensitivity and chills were reported by 17.4% of participants in the study group.

Cryotherapy in addition to an oral care protocol (as described above) is likely to be beneficial in reducing the severity of OM as well as decreasing pain and the need for opioid analgesics. In terms of lengths of stay, cryotherapy offered a clinical benefit, although not statistically significant.

• The sample size was small with fewer than 100 patients.
• Some data collection required patients to self-report.
• The study observed only adult patients diagnosed with multiple myeloma and undergoing stem cell tranplant.
• The study was limited in that the only OM-causing agent was melphalan.
• The study was not blinded.

Cryotherapy is inexpensive, and the protocol is relatively simple. In conjunction with an oral care protocol, this is a reasonable approach to take. A larger trial would be helpful.

To evaluate the effect of oral cooling using ice-rolls on chemotherapy-induced mucositis in patients administered bolus 5-FUFA

Randomized, control trial of 53 patients with gastroinstenal tract cancer receiving 5-fluorouracil (5-FU) in an outpatient clinic either daily for three, four, or five days (n = 22) or weekly (n = 31). The intervention group (n = 27) was asked to do oral cooling using ice-rolls in and out of oral cavity for the following schedule (10 minutes before administration, 5 minutes during administration, and 15 minutes after the administration of 5-FU). Patients used oral cooling for a total of 30 minutes (SD = 5 minutes). Assessment of oral cavity was conducted every week for three weeks.

• N = 53 patients
• AGE = 18–73 years
• MALES: 53.7%, FEMALES: 52.3%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Gastrointestinal tract cancer

• SITE:Single site
• SETTING TYPE:Outpatient
• LOCATION: New Delhi

PHASE OF CARE: Active antitumor treatment

Randomized, controlled trial

• World Health Organization (WHO) Oral Toxicity Scale 
• Patient-judged mucositis grading

A significanct decrease in oral mucositis incidence was noted in the experimental group in week 1 (p = 0.001), week 2 (p = 0.014), and week 3 (p = 0.05) compared to the control group. Descriptive statistics showed only mild oral mucositis in the experimental group, whereas moderate and severe oral mucositis was reported in the control group.

Oral cooling was effective in reducing oral mucositis in patients receiving 5-FU.

• Small sample (< 100)
• Findings not generalizable
• Only one type of medication—5-FU—included

Oral cooling was 100% accepted as an intervention to reduce the incidence of oral mucositis induced by chemotherapy. Nurses need education on proper assessment tools for oral mucositis. Educational materials should also be given to patients and their families to enhance the proactivity of preventing mucositis induced by chemotherapy.

Randomized after consent to one of three arms (A, B, or C)

A = chlorhexidine mouthwash (0.1% without alcohol, 10 ml) with taste additives

B = placebo mouthwash (normal saline) with taste additives  

C = crushed ice

Participants were stratified according to age (older than 40 versus younger than 40), smoking or nonsmoking, and use of dental prosthesis. Patients and the physician were blinded with respect to mouthwash versus placebo.

Both rinses were administered for 1 minute TID on days 1–21; crushed ice was administered from 10 minutes before until 35 minutes after the start of chemotherapy.

Study sample included patients with gastric or colorectal cancer receiving bolus 5-FU 425 mg/m² and bolus leucovorin 20 mg/m² (Mayo regimen) for five days every four weeks.

Exclusion criteria were head and neck radiotherapy and symptoms of infections.

 
Arm A: n = 73
Arm B: n = 66
Arm C: n = 67

 

Patients were evaluated when they returned for the second round of treatment on day 28.
 
Patients were evaluated on days 14 and 28. Signs and symptoms from the oral cavity were observed and registered on a daily basis and written into the questionnaires on days 14 and 28.

The treating physician evaluated patients on days 14 and 28 using the NCI Common Toxicity Criteria (CTC).
 

No differences were observed in compliance with regimen or side effects (e.g., headache, taste disturbances).
 
Twenty-three percent of patients in arm B and 43% of patients in arms A and C had no mucositis.

Of the three arms, only one patient had grade 4 mucositis (arm A).
The frequency of grades 3 and 4 were 12% in arm A, 32% in arm B, and 10% in arm C. Frequency was significantly lower in arm A (p < 0.01) and arm C (p < 0.005) compared with arm B. Arms A and C were similar.

No differences were observed between patient or physician scoring.

Median duration of oral mucositis was 3 days (arm A), 5 days (arm B), and –1 day (arm C). Duration was significantly shorter in arm B than in arm A (p = 0.035) and arm C (p = 0.003). No differences were observed between arms A and C.

Neither smoking nor performance status predicted severity of oral mucositis.

Ages were unequal across arms but not statistically different.
 

Power analysis of 15%; decreased CTC mucositis grade 3–4; 75 patients in each arm. The study had 225 evaluable participants, but not all participants returned forms.

Two arms were double blinded. Cryotherapy could not be double blinded but was blind to MD assessment.
 

Patients sucked on ice chips or rinsed with ice cold water during administration of chemotherapy. Treatment started in direct connection with and lasted until the end of the chemotherapy session.

Patients were randomized to oral cryotherapy or standard oral care. Stratified randomization was used with regard to type of BMT.

Eighty patients aged 18 and older scheduled for bone marrow transplantation (BMT). Two patients refused.

Two patients had testicular cancer; all others had hematologic malignancies (11 diagnoses evenly distributed).

Occurred from January 2002 to August 2004

Pain intensity was rated from 0–10.

Mucositis index scores  

Modified version of the Oral Mucositis Assessment Scale (OMAS)

Morphine equivalent of pain medication and duration of medications
 

Of the patients, 71%–100% managed to keep their oral cavity constantly cooled more than half the time, 58%–75% managed to keep their oral cavity constantly cooled all the time, and 7 (18%) found oral cryotherapy unpleasant. Among those seven, four (10%) found oral cryotherapy very unpleasant.

Calculated power analysis was based on days of opioids.

The experimental group had significantly fewer days with IV opioids (0.77 +/– 2.3) and complete treatment response (CTR) (2.44+/– 4.6) t = –2.053; df = 76, p = 0.045. No other differences in opioid use were observed.

Autologous BMT highest mucositis was days 9–11 (days start with chemotherapy)

Allogeneic and unrelated donor transplants peak was days 16–18

Autologous BMT experimental group (n = 62) had significantly lower mucositis score on day 10 (1.6 +/–1.9 versus 4.3 +/–5.7; t = 2.1; df = 45; p = 0.042). The experimental group also had significantly fewer days (0.06 +/– 0.25 versus 1.71 +/– 3.22, p = 0.008) and lower total dose IV opioids.

The allogenic and URD BMT group (n = 16) had significantly lower mucositis scores on day 16 (3.7 +/– 1.8 versus 11.6 +/– 6.8; t = 2.9; df = 11; p = 0.021) but  no different opioid use.

Compliance with regimen (dose of cryotherapy)

Unable to blind cryotherapy; no indication if mucositis assessors were blinded.
 

To investigate if oral cryotherapy during myeloablative therapy may influence frequency and severity of mucositis, nutritional status, and infection rate after bone marrow transplant

Patients were randomly assigned to the cryotherapy treatment group or the usual care control group. A stratified randomization technique was used in regard to the type of transplant. Patients in the cryotherapy treatment group were instructed to suck on ice chips or rinse with ice-cold water during chemotherapy administration. The control group followed usual care without cryotherapy.

• The study reported on 78 patients aged 18 years or older.
• The mean age of the cryotherapy treatment group was 49.8 years (SD = 14.4 years), and the mean age of the usual care control group was 54.3 years (SD = 11.0 years).
• The sample was 58% male and 42% female.
• All patients had been diagnosed with hematologic or oncologic malignances. A total of 11 different diagnoses were represented.
• No significant differences existed between the cryotherapy treatment group and the usual care control group regarding age, gender, or tobacco use; the types of conditioning regimens; or the use of total body irradiation.

The study was conducted at a single-site, inpatient setting in Uppsala, Sweden.

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

This was a randomized controlled trial.

• Investigators used an Oral Mucositis Assessment Score (OMAS), which was converted into the World Health Organization (WHO) scale.
• Infection rates were assessed based on neutropenic fever and use of IV antibiotics.
• Nutrition was assessed based on rate of total parenteral nutrition (TPN) and serum albumin.

• Fewer patients in the cryotherapy treatment group experienced grade 3–4 oral mucositis (OM) than in the control group (p < 0.05). However, no statistical difference was found in the severity of mucositis in the subgroup of patients receiving unrelated donor bone marrow transplant.
• No significant differences were found in weight loss between the cryotherapy treatment group and the control group.
• Fewer patients in the cryotherapy treatment group needed TPN and the number of days of TPN were fewer than in the control group. However, these differences were not statistically significant.
• The cryotherapy treatment group maintained better serum albumin levels on days 1–6 (p < 0.01) and days 7–13 (p < 0.009). 
• The cryotherapy treatment group had significantly fewer days of hospitalization (p < 0.05) in the subgroup of patients receiving unrelated donor bone marrow transplant.
• No statistical significance was found between groups related to the number of days with fever, number of positive blood cultures, or use of IV antibiotics.

Oral cryotherapy may be helpful in reducing the severity of mucositis, particularly in patients receiving autologous stem cell transplant (ASCT). Decreasing the severity of mucositis may lead to decreases in the need for TPN and better maintenance of serum albumin levels. Limited statistically significant findings were found in this study; however, it supports positive trends that favor cryotherapy use. Larger, prospective trials need to be completed.

• The sample size was small with fewer than 100 patients.
• The investigators did not clearly describe how the OMAS scale translated into the WHO scale.
• The compliance rate for using the oral cryotherapy for the unrelated  bone marrow transplant group was only three out of eight patients or less than half of the time.

Mucositis carries a high symptom burden for patients undergoing stem cell transplant. Cryotherapy may be one way to curb the effects of oral mucositis. However, this study provided no evidence to suggest that cryotherapy is the definitive way to prevent mucositis or to lessen the intensity of mucositis for all patients across the board.

To evaluate the characteristics of oral mucositis in autologous hematopoietic stem cell transplantation (HSCT) after HD-L-PAM (high-dose [HD] methotrexate plus vincristine, HD-doxorubicin, cisplatin, and HD-melphalan) 200 mg/m² and BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) conditioning regimens and to analyze the impact of simple and basic clinical and laboratory factors on oral mucositis incidence

Patients who were admitted to a transplant hospital to receive BEAM or HD-L-PAM 200 mg/m² chemotherapy followed by autologous HSCT were recruited to the study. To be included, patients had to have healthy oral mucosa without symptoms of inflammation or local infection at baseline and signed informed consent. Patients were excluded from the study if they had a history of head or neck or total body radiotherapy, received keratinocyte growth factors or amifostine for oral mucositis prophylaxis, or participated in any other trial comparing any new drugs for oral mucositis prophylaxis or treatment. 

Oral cavity monitoring began on the first day of admission and continued throughout the inpatient stay. Beginning on the first day of chemotherapy administration, patients used mouthwash after main meals, before sleep, and as desired. Patients could use their mouthwash of choice, selecting from chlorhexidine, salvia officinalis, providone-iodine, normal saline, Listerine^®, benzydamine, or water. Patients were instructed to gargle for two minutes with the solution of choice. Patients were instructed to use soft toothbrushes. Cryotherapy with lollipops, ice-cold water, or crushed ice was added to the protocol in 2008.

Basic clinical and laboratory data representing individual variables, tested as oral mucositis risk factors, were recorded. Basic statistical univariate analyses were performed using statistical software with Mann-Whitney. The p values comparing the presence and absence of the characteristics and p values < 0.05 were considered indicative of statistically significant differences in relation to mucositis occurrence. 

• The study reported on 126 patients with a median age of 57 years and a range of 8–67 years.
• The sample was 57% male and 43% female.
• Patient diagnoses were chronic lymphocytic leukemia (2%), Hodgkin lymphoma (13%), non-Hodgkin lymphoma (31%), and multiple myeloma (54%).
• In all, 40% of patients were in complete remission and 60% were in partial remission.
• The median number of days since last chemotherapy administration was 72 with a range of 15–560.
• Additional patient data were as follows.
  • Diagnosed with diabetes mellitus, 7%
  • Wore removable dentures (prosthesis), 12%
  • Had a history of oral mucositis, 13%
  • Used cryotherapy of the oral cavity, 29%
• Laboratory values were as follows.
  • Absolute neutrophil count at baseline (x10 - 9/l = 2.3 [1.2–10.0])
  • Serum bilirubin level at baseline (umol/l = 11 [3–42])
  • Creatinine clearance at baseline (ml/min) = 102 (28-181)
  • Number of CD34+ cells in the graft (x10-6/kg) = 4.6 (1.4-17.9)

This was a multisite study conducted in the inpatient setting at the University Hospital in Pilsen, Czech Republic;  University Hospital in Olomouc, Czech Republic;  University Hospital in Kosice, Slovak Republic; Silesian Medical Academy in Katowice, Poland; and Pavlov Medical University in St. Petersburg, Russia.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability to end-of-life and palliative care.

This was a multicenter, prospective, observational evaluation with oral cavity care.

• The World Health Organization (WHO) 0–4 mucositis grading scale was used.
• Oral cavity monitoring was stated on the first day of the conditioning and covered the whole inpatient stay.
• Oral mucositis was assessed daily by nurses who had attended a specific training course before data collection started. Interrater reliability testing was not performed. With 7% of patients, nurses assessing oral mucositis had not attended any specific oral mucositis training courses.
• Patients evaluated the tolerability of oral cryotherapy once daily using a 1–5 visual analog scale (VAS) with 1 = tolerable without any problems and 5 = intolerable.

• Overall, 62% of patients developed oral mucositis.
• Patients experienced the following grades of oral mucositis.
  • Grade 1: 31%
  • Grade II: 13.5%
  • Grade III: 16%
  • Grade IV: 1.5%
• Oral mucositis incidence was significantly lower in the cryotherapy group (22%) compared to the noncryotherapy group (78%).
• Univariate analysis of the noncryotherapy group (n = 90) found no significant differences between patients with respect to age, gender, performance status, body mass index (BMI), neutrophil count, bilirubin levels, creatinine clearance, number of CD34+ cells in the graft, number of days since the last chemotherapy, presence of removable dentures (prosthesis), or diabetes mellitus. 
• Oral mucositis occurred more often in patients receiving the BEAM conditioning regimen (86% versus 68%, p = 0.04) and in patients with a history of oral mucositis (100% versus 73%, p = 0.0182). 
• The fact that oral cryotherapy was not provided in some patients was the most significant and independent factor for oral mucositis development.

This observational study verified the potential efficacy and feasibility of oral cryotherapy in melphalan short-infusion administration with HD-L-PAM and multidrug BEAM conditioning regimens. Much larger and more homogenous cohorts of patients are needed for future research on the oral mucositis risk factors.

The study findings are limited because of the lack of random assignment, blinding, and an appropriate control group.

Based on the results of this observational trial, the nonprovision of oral cryotherapy is a risk for the development of oral mucositis in patients after autologous HSCT with BEAM or HD-L-PAM conditioning regimens. Maximum effort should be targeted toward the education of medical and nursing teams to implement cryotherapy as a standard prophylactic approach in melphalan regimens.

• RESOURCE TYPE: Evidence-based guideline

• PHASE OF CARE: Active antitumor treatment

No information is provided regarding the volume of evidence retrieved or quality ratings of studies included.

• Oral hygiene
• Pretreatment control of preexisting periodontal and dental disease with professional cleaning
• Routine use of palifermin is not recommended.

• Regular oral care with use of nonalcohol-containing mouthwashes
• At least weekly assessment

All specific interventions had either recommendations against use or no ability to provide a recommendation. Cryotherapy even with bolus 5-FU was not recommended due to lack of evidence in the setting of RT for patients with head and neck cancer. The guideline provides a listing of numerous interventions that have been examined with no recommendations for use.

• Limited search and no clear study quality rating
• Unclear if the panel reviewed all the evidence or just statements created by an individual facilitator

This review provides a comprehensive list of interventions, none of which can be recommended for practice. This article does provide a good overview of assessment instruments and provides some information on probable risk factors.

PURPOSE: To review effective strategies to assist nurses in caring for patients receiving sorafenib, with the focus on those adverse effects the group felt were most difficult to manage—hand-foot syndrome, diarrhea, fatigue, and oral complications

TYPES OF PATIENTS ADDRESSED: Patients receiving sorafenib for renal cell or hepatocellular cancer

RESOURCE TYPE: Evidence-based guideline

DATABASES USED: PubMed, Cochrane Library, and hand-searching of the Clinical Journal of Oncology Nursing and American Society of Clinical Oncology website     

KEYWORDS: Side effect general terms, and specific terms for each side effect (e.g., altered taste, hand-foot syndrome); disease-related search terms included renal cancer, cancer of the kidneys, hepatocellular carcinoma, and liver cancer

INCLUSION CRITERIA: Evidence base included wider literature regarding the management of similar adverse events in patients with other types of cancer and other types of antitumor therapy. No other specific criteria were stated.

EXCLUSION CRITERIA: Not stated
 

• PHASE OF CARE: Active antitumor treatment            
• APPLICATIONS: Late effects and survivorship

Out of 2,469 initial citations retrieved, 37 were included for review. No specific quality evaluation of citations was done due to the nature of the literature, with few clinical trials. No description of the group process used is provided. Findings from citations reviewed were outlined and a review of the literature was provided, but no actual synthesis of evidence exists. Noted is that most evidence in this area is from experience.

Recommendations for mucositis include oral care, amifostine, and antibiotic paste for prophylaxis. For symptom management, recommendations include ice chips, topical lidocaine solutions, sage tea and baking soda oral rinses, and topical solution containing aloe vera, and advising patient to avoid tobacco, alcohol, and spicy foods, mucosal coating agents (e.g., Gelclair®), hydrolytic enzymes, and treatment interruption. For diarrhea, recommendations are patient education, loperamide, diphenoxylate, cholestyramine, probiotics, tincture of opium, and antidiarrheal agents, and avoidance of lactose, high roughage, fatty and spicy foods, fruit juice, and caffeine. For hand-foot syndrome, recommendations include use of emollients, wearing gloves, and avoiding constrictive footwear, hot water, urea- or salicylate-containing creams, and treatment interruptions. For fatigue, recommendations include encouraging activity, maintaining normal work and social schedules, providing supportive care, and considering antidepressants, methylphenidate, sleep medication, and treatment-free intervals.

This review adds nothing new to the limited body of evidence in this area, and does not include a huge body of literature related to the management of fatigue and diarrhea symptoms. Most evidence reviewed was of low quality and expert opinion. No process by which the group evaluated the evidence strength in order to make full recommendations is described, and the result is generally a listing of previously documented opinions related to the management of these symptoms.

This review provides recommended assessments and management approaches that are at the level of expert opinion only.

570 articles were included in this literature review. Literature contained prevention and/or treatment methods for mucositis. Interventions for treatment of mucositis were given, recommendations against an intervention were provided, suggestions in favor of an intervention were supplied, and suggestions against an intervention were given.

Recommendations included a combination of teeth brushing, flossing, mouth rinsing, and use of growth factors and cytokines in treatment of mucositis. The use of anti-inflammatory agents was also recommended. Low level laser therapy was recommended in prevention of mucositis with specific types of cancer treatment. Cryotherapy was also recommended for patients receiving chemotherapy. A list of natural and miscellaneous agents was recommended for treatment and prevention of mucositis.

Limitations of this study include clinical situations that were not seen in the literature review or that are rare in clinical settings. These limitations occur because of conflicting evidence or not enough evidence provided.

Nurses should be assessing patients' pain control, nutritional support, ability to eat, and oral hygiene practices, and should be teaching on the use of oral care products that are essential for prevention.

To summarize the oral and gastrointestinal mucositis guidelines developed by the Mucositis Study Group of Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) for patients receiving high-dose chemotherapy, standard-dose chemotherapy, radiation therapy, and combination chemotherapy/radiation therapy

The resource type is guidelines. The process of development was not explained.

Patients were undergoing the active treatment phase of care.

This study has clinical applicability for the following.

• High-dose (HD) head and neck radiation
• Hematopoietic stem cell transplant (HSCT)
• Standard multicycle chemotherapy
   

This report contains few changes compared to previous versions published in 2008 and 2010. The oral mucositis (OM) guidelines are as follows.

• Basic oral care and good clinical practice
  • ​Multidisciplinary development and evaluation of oral care protocols that include frequent use of nonmedicated oral rinses (e.g., saline mouth rinses 4–6 times per day) is recommended. Patient and staff education in the use of such protocols is recommended.
  • Alcohol-based mouth rinses should be avoided.
  • Interdisciplinary development of systemic oral care protocols is suggested. The protocol should include the use of a soft toothbrush that is replaced on a regular basis.
  • Patient-controlled analgesia with morphine is recommended as the treatment of choice for OM pain in patients undergoing HSCT. Regular oral pain assessment using validated instruments for self-reporting is essential.
  • All patients should be screened for nutritional risk, and early enteral nutrition should be started if patients cannot swallow.
  • Topical anesthesia can provide short-term pain relief for OM on an empiric basis.
• ​Prevention of OM associated with radiotherapy (RT)
  • ​Use of midline radiation blocks and three-dimensional RT to reduce mucosal injury is recommended.
  • Benzydamine oral rinse for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose RT is recommended. (This is not available in the United States.) 
  • Chlorhexidine is not recommended for patients with head and neck cancer.
  • Antimicrobial lozenges are not recommended
• ​Prevention of OM for patients receiving standard-dose (SD) chemotherapy
  • ​Oral cryotherapy recommended for prevention of OM in patients receiving bolus 5-FU and reduction of OM with bolus edatrexate.
  • Including granulocyte-colony stimulating factor (G-CSF) in Taxotere^®, Adriamycin, cyclophosphamide (TAC) breast cancer regimens has been associated with significant reduction in toxicities, including OM.
  • IV acyclovir and its analogs are not recommended to prevent OM in SD chemotherapy. However, antivirals may be indicated to treat viral infections that may coexist with OM.
  • IV palifermin in solid tumors needs additional research.
• Prevention of OM in patients receiving HD chemotherapy with or without total body irradiation (TBI) plus HSCT
  • Palifermin is recommended.
  • Oral cryotherapy is recommended with HD melphalan.
  • Topical pentoxifylline is not recommended.
  • Granulocyte macrophage-colony stimulating factor (GM-CSF) mouthwashes are not suggested.
  • Low-level laser therapy (LLLT) is suggested to reduce OM and pain associated with OM, if available.
• Treatment of OM associated with RT
  • Oral sucralfate is not recommended.
• Treatment of OM with SD chemotherapy
  • Chlorhexidine oral rinses are not recommended.
  • Approved devices for OM, including Gelclair^®, Caphasol^TM, and Biotene^®, have a limited research evidence base but are safe and may offer some benefit for some patients.

Other recommendations are listed in the article for gastrointestinal mucositis prevention and treatment.

• Few changes were made from previously published guidelines.
• Revisions to these guidelines are expected in the next 2–5 years because of newer technology, better understanding of the clinical impact of OM, molecular pathobiology, and emerging targeted cancer therapy.
• Oncology nurses should recommend evidence-based management for prevention and treatment of OM because some therapies may be expensive and have not been proven effective. For example, “magic mouthwash” continues to be prescribed without evidence to support its use.    
• Consistent oral care with bland rinses continues to be recommended, is easy to use, and is inexpensive.

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

• Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
• Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

• Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
• Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
• Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
• Chlorhexidine rinses are not recommended to treat established mucositis but may be an option to enhance treatment of oral infection.
• Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
• For prevention of mucositis in patients receiving standard-dose chemotherapy,
  • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
  • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
• For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
  • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
  • Cryotherapy in high-dose melphalan
  • Low-level laser therapy (LLLT) before HSCT

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.

PHASE OF CARE: Active antitumor treatment

Cryotherapy or low-level laser therapy may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. Keratinocyte growth factor (KGF) may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there was a lack of efficacy and significant toxicity data as well as a lack of long-term follow-up data in pediatric cancers. No other interventions were recommended for oral mucositis prevention in children.

• Cryotherapy: Weak recommendation with moderate to quality evidence
• Low-level laser therapy: Weak recommendation with high-quality evidence
• KGF: Weak recommendation with high-quality evidence

No keywords, inclusion criteria, or exclusion criteria were stated in the article.

Although some information was missing in this study, the decision making process and results of the evidence review were well-described. The inclusion of a description of research gaps, summarized in a table, showed the comprehensiveness of this review.