The use of ice chips or ice-cold water has been studied for its efficacy in the prevention of oral mucositis. Patients suck on ice or hold ice-cold water in their mouths prior to, during, and after rapid infusions of mucotoxic agents with short half-lifes. Cryotherapy is based on the theory that vasoconstriction caused by cold temperatures decreases the exposure of the oral cavity mucous membranes to mucotoxic agents. Thirty minutes of oral cryotherapy is suggested for patients receiving bolus fluorouracil 5. Cryotherapy also has been used in patients receiving high-dose melphalan. Cryotherapy is not recommended for patients who also are receiving oxaliplatin because of the associated acute temperature sensitivity, which can cause severe discomfort (Lilleby et al., 2006; Tartarone, Matera, Romano, Vigliotti, & DiRenzo, 2005).
Lilleby, K., Garcia, P., Gooley, T., McDonnnell, P., Taber, R., Holmberg, L., . . . Bensinger, W. (2006). A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplantation, 37, 1031–1035. doi:10.1038/sj.bmt.1705384
Lalla, R.V., Bowen, J., Barasch, A., Elting, L, Epstein, J., Keefe, D.M., . . . Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology. (2014). MASCC/ISOO evidence based clinical practice guidelines for mucositis secondary to cancer therapy. Cancer, 120, 1453–1461. doi:10.1002/cncr.28592
Tartarone, A., Matera, R., Romano, G., Vigliotti, M.L., & Di Renzo, N. (2005). Prevention of high-dose melphalan-induced mucositis by cryotherapy. Leukemia and Lymphoma, 46, 633–634. doi:10.1080/10428190400029957
Kwong, K.K. (2004). Prevention and treatment of oropharyngeal mucositis following cancer therapy: Are there new approaches? Cancer Nursing, 27(3), 183–205.
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.
The author concluded that most agents require more study.
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.
de Melo Manzi, N., de Campos Pereira Silveira, R.C., & dos Reis, P.E. (2015). Prophylaxis for mucositis induced by ambulatory chemotherapy: Systematic review. Journal of Advanced Nursing, 72, 735–746.
STUDY PURPOSE: To systematically review evidence regarding interventions used to prevent chemotherapy-induced oral mucositis (OM)
PHASE OF CARE: Active antitumor treatment
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.
Migliorati, C.A., Oberle-Edwards, L., & Schubert, M. (2006). The role of alternative and natural agents, cryotherapy and/or laser for management of alimentary mucositis. Supportive Care in Cancer, 14, 533–540.
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.
Riley, P., Glenny, A.M., Worthington, H.V., Littlewood, A., Clarkson, J.E., & McCabe, M.G. (2015). Interventions for preventing oral mucositis in patients with cancer receiving treatment: Oral cryotherapy. Cochrane Database of Systematic Reviews, 12, CD011552.
STUDY PURPOSE: To evaluate the evidence to assess the effects of oral cryotherapy for the prevention of oral mucositis (OM)
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.
Tayyem, A.Q. (2014). Cryotherapy effect on oral mucositis severity among recipients of bone marrow transplantation: A literature review. Clinical Journal of Oncology Nursing, 18, E84–E87.
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.
Wang, L., Gu, Z., Zhai, R., Zhao, S., Luo, L., Li, D., . . . Gao, C. (2015). Efficacy of oral cryotherapy on oral mucositis prevention in patients with hematological malignancies undergoing hematopoietic stem cell transplantation: A meta-analysis of randomized controlled trials. PloS One, 10, e0128763.
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.
Worthington, H.V., Clarkson, J.E., Bryan, G., Furness, S., Glenny, A.M., Littlewood, A., … Khalid, T. (2011). Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews (Online), 4(4), CD000978.
To evaluate the evidence for prophylactic agents in management of oral mucositis in patients with cancer receiving treatment
Databases searched were MEDLINE, CANCERLIT, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), System for Information on Grey Literature in Europe (SIGLE), and the Cochrane Database.
An extensive list of search terms and strategies used per database was provided in the article.
Studies were included in the review if they
A total of 383 references were retrieved. Risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were categorized as low, unclear, or high risk of bias. Studies were labeled using the GRADES system for evaluating quality of evidence.
Findings support the benefits of cryotherapy and keratinocyte growth factor. The low quality of evidence in most of the other interventions points to the need for ongoing, well-designed research in this area. The presentation of findings in many publications made meta-analysis impossible.
The rationale for the authors' summaries of findings was not entirely clear. Similar RR ratio results with similar evidence quality levels were identified differently in terms of potential benefit. Although the review was inclusive and extensive, interpretation of results was inconsistent. High heterogeneity existed in most interventions, and most studies were either at high or unclear risk of bias with low GRADES scoring. Studies did not always differentiate between mucositis and candidiasis, which would affect recommendations.
This article suggests strong support for use of cryotherapy and keratinocyte growth factor for mucositis prevention. It suggests possible benefit from aloe vera, amifostine, IV glutamine, G-CSF, honey, laser, and antibiotic lozenges. Sucralfate may reduce the severity of mucositis. These findings should be interpreted with caution, given the relatively low quality of overall evidence and high heterogeneity across studies included in meta-analysis, as well as the fact that treatments and sample characteristics were highly varied.
Aisa, Y., Mori, T., Kudo, M., Yashima, T., Kondo, S., Yokoyama, A., … Okamoto, S. (2005). Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Supportive Care in Cancer, 13, 266–269.
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 sample size was small sample, and the control group was based on historical reports.
Batlle, M., Morgades, M., Vives, S., Ferra, C., Oriol, A., Sancho, J.M., ... Ribera, J.M. (2014). Usefulness and safety of oral cryotherapy in the prevention of oral mucositis after conditioning regimens with high dose melphalan for autologous stem cell transplantation for lymphoma and myeloma. European Journal of Haematology, 9(6), 487–491.
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.
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.
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.
Chen, J., Seabrook, J., Fulford, A., & Rajakumar, I. (2015). Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant. Journal of Oncology Pharmacy Practice. Advance online publication.
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.
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.
Cryotherapy has been shown to be effective in reducing the severity of mucositis in patients receiving chemotherapeutic agents with a short half-life.
Paula Eduardo, F., Bezinelli, L.M., Lopes, G., Marques, R., Nascimento Sobrinho, J.J., Hamerschlak, N., & Correa, L. (2015). Efficacy of cryotherapy associated with laser therapy for decreasing severity of melphalan-induced oral mucositis during hematological stem-cell transplantation: A prospective clinical study. Hematological Oncology, 33, 152–158.
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.
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.
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.
Karagozoglu, S., & Filiz Ulusoy, M.F. (2005). Chemotherapy: The effect of oral cryotherapy on the development of mucositis. Journal of Clinical Nursing, 14, 754–765.
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 was conducted at a respiratory disease clinic in Turkey from August 2000 to May 2001.
Katranci, N., Ovayolu, N., Ovayolu, O., & Sevinc, A. (2012). Evaluation of the effect of cryotherapy in preventing oral mucositis associated with chemotherapy: A randomized controlled trial. European Journal of Oncology Nursing, 16, 339–344.
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.
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.
Findings suggest that short-term cryotherapy may be beneficial for patients receiving bolus 5-FU; however, longer-term effectiveness may not be seen.
Lilleby, K., Garcia, P., Gooley, T., McDonnnell, P., Taber, R., Holmberg, L., … Bensinger, W. (2006). A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplantation, 37, 1031–1035.
This was a randomized trial.
Cryotherapy was associated with improved outcomes. Research is needed to determine the required length of cryotherapy.
Mori, T., Hasegawa, K., Okabe, A., Tsujimura, N., Kawata, Y., Yashima, T., … Okamoto, S. (2008). Efficacy of mouth rinse in preventing oral mucositis in patients receiving high-dose cytarabine for allogeneic hematopoietic stem cell transplantation. International Journal of Hematology, 88, 583–587.
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 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.
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.
Mori, T., Yamazaki, R., Aisa, Y., Nakazato, T., Kudo, M., Yashima, T., … Okamoto, S. (2006). Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer, 4, 392–395.
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.
Nikoletti, S., Hyde, S., Shaw, T., Myers, H., & Kristjanson, L.J. (2005). Comparison of plain ice and flavored ice for preventing oral mucositis associated with the use of 5-fluorouracil. Journal of Clinical Nursing, 14, 750–753.
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 was conducted in an outpatient, chemotherapy, acute care setting at a teaching hospital in Australia.
This was a randomized, controlled, crossover trial.
Papadeas, E., Naxakis, S., Riga, M., & Kalofonos. C. (2007). Prevention of 5-fluorouracil-related stomatitis by oral cryotherapy: A randomized controlled study. European Journal of Oncology Nursing, 11, 60–65.
Salvador, P., Azusano, C., Wang, L., & Howell, D. (2012). A pilot randomized controlled trial of an oral care intervention to reduce mucositis severity in stem cell transplant patients. Journal of Pain and Symptom Management, 44, 64–73.
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 was conducted at a single-site, inpatient setting in Ontario, Canada.
This was a prospective, pilot, randomized control trial with repeated measures.
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.
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.
Sharma, P., Vatsa, M., & Sharma, A. (2015). Effect of oral cooling on bolus 5-FUFA induced mucositis in cancer patients. International Journal of Nursing Education, 7, 249–255.
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.
PHASE OF CARE: Active antitumor treatment
Randomized, controlled trial
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.
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.
Sorensen, J. B., Skovsgaard, T., Bork, E., Damstrup, L., & Ingeberg, S. (2008). Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil–based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies. Cancer, 112(7), 1600–1606.
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.
Svanberg, A., Birgegard, G., & Ohrn, K. (2007). Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy—A randomized controlled trial. Supportive Care in Cancer, 15(10), 1155–1161.
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.
Svanberg, A., Öhrn, K., & Birgegård, G. (2010). Oral cryotherapy reduces mucositis and improves nutrition: A randomised controlled trial. Journal of Clinical Nursing, 19, 2146–2151.
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 was conducted at a single-site, inpatient setting in Uppsala, Sweden.
This was a randomized controlled trial.
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.
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.
Vokurka, S., Bystricka, E., Scudlova, J., Mazur, E., Visokaiova, M., Vasilieva, E., …Streinerova, K. (2011). The risk factors for oral mucositis and the effect of cryotherapy in patients after the BEAM and HD-l-PAM 200 mg/m2 autologous hematopoietic stem cell transplantation. European Journal of Oncology Nursing, 15, 508–512.
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.
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.
This was a multicenter, prospective, observational evaluation with oral cavity care.
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.
De Sanctis, V., Bossi, P., Sanguineti, G., Trippa, F., Ferrari, D., Bacigalupo, A., . . . Lalla, R.V. (2016). Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus statements. Critical Reviews in Oncology/Hematology, 100, 147–166.
No information is provided regarding the volume of evidence retrieved or quality ratings of studies included.
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.
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.
Edmonds, K., Hull, D., Spencer-Shaw, A., Koldenhof, J., Chrysou, M., Boers-Doets, C., & Molassiotis, A. (2012). Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular carcinoma: Recommendations from a European nursing task group. European Journal of Oncology Nursing, 16, 172–184.
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
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.
Lalla, R.V., Bowen, J., Barasch, A., Elting, L., Epstein, J., Keefe, D.M., ... Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). (2014). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 120, 1453–1461.
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.
Peterson, D.E., Bensadoun, R.J., & Roila, F. (2011). Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Annals of Oncology, 22(Suppl 6), vi78–vi84.
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.
This report contains few changes compared to previous versions published in 2008 and 2010. The oral mucositis (OM) guidelines are as follows.
Other recommendations are listed in the article for gastrointestinal mucositis prevention and treatment.
Peterson, D.E., Bensadoun, R.J., Roila, F., & ESMO Guidelines Working Group. (2010). Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Annals of Oncology, 21(Suppl. 5), v261–v265.
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
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.
Sung, L., Robinson, P., Treister, N., Baggott, T., Gibson, P., Tissing, W., . . . Dupuis, L.L. (2015). Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Supportive and Palliative Care. Advance online publication.
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.
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.