|Year : 2019 | Volume
| Issue : 2 | Page : 47-53
Oral mucositis in children associated with hematopoietic stem cells transplant
Sarah A Mubaraki
Department of Preventive Oral Science, Division of Pediatric Dentistry, Riyadh Elm University, Riyadh, Saudi Arabia
|Date of Web Publication||19-Aug-2019|
Dr. Sarah A Mubaraki
Department of Preventive Oral Science, Division of Pediatric Dentistry, Riyadh Elm University, Riyadh
Source of Support: None, Conflict of Interest: None
Oral mucositis is one of the most common complication of Hematopoietic stem cell transplant. It is extremely painful and affect the quality of life. 67%–99% of the patients develop oral mucositis and they are at a high risk of developing various infections. Several methods was introduced aiming to reduce the incidence and severity of oral mucositis. The objective of this review is to summarize the different modalities to reduces the incidence and severity of oral mucositis. The review includes human clinical trails with or without randomization, meta-analysis and systematic review. The review suggests that proper oral hygiene, mouth lubricant and the epidermal growth factor can help to reduce the severity of oral mucositis.
Keywords: Hematopoietic stem cell transplant, oral complication, oral mucositis
|How to cite this article:|
Mubaraki SA. Oral mucositis in children associated with hematopoietic stem cells transplant. Saudi J Oral Sci 2019;6:47-53
| Introduction|| |
Hematopoietic stem cell transplant (HSCT) is defined as the infusion of multipotent stem cells, which are derived from the bone marrow, cord blood, or peripheral blood to reconstitute the hematopoietic system., This transplant is used to cure certain diseases and diverse hematopoietic disorders.,
Oral mucositis (OM), a common and an important complication of HSCT, is an inflammation of oral mucosa often extending to the oropharynx as a result of cancer therapy, typically manifesting as atrophy, swelling, erythema, and ulceration.,, It affects 67%–99% of patients receiving high-dose chemotherapy and/or total body irradiation (TBI) for HSCT , and usually occurs between 2 and 18 days following the initiation of the chemotherapy.
Moreover, OM may cause severe oral pain and may hamper the oral intake. It also facilitates the entry of pathogenic microorganisms leading to bacteremia and possible septicemia.
| Oral Mucositis Pathophysiology|| |
OM-related chemotherapy may result from direct effect on the mucosal tissue or indirectly from the consequences of chemotherapeutic drug-induced bone marrow myelosuppression., The mechanism has been studied extensively by several researchers, and presently, it is accepted that OM occurs in four phases.,, The first phase, that is, the inflammatory/vascular phase occurs after administering the chemotherapeutic agent, as the oral mucosa immediately releases cytokines, causing local tissue damage. The second phase commences when the mucosal turnover decreases and presents clinically as atrophy and ulceration. The first two phases occur within the first 5 days. The third phase occurs after the epithelial tissue rupture and ulcer development. The fourth and final phase is the healing stage between days 12 and 16 after the chemotherapy.
| Healing and Cellular Turnover in Oral Mucosa|| |
The oral mucosa is well adapted to protect the underlying tissues against mechanical damage and inhibits the entry of microorganisms and their toxic materials. Wounds and ulcers in the oral mucosa heal quickly and with improved scar quality than those on the skin due to high blood supply.
Saliva creates a humid environment, which is beneficial for wound healing,, by preventing tissue dehydration and cell death and accelerating angiogenesis and increasing the breakdown of dead tissue and fibrin.
Proteins within human saliva comprise classical growth factors, as well as deference, cathelicidin, and trefoil factors, which are known for their positive healing effects.,
The cellular turnover rate of the oral mucosa occurs between 7 and 14 days. The rapid basal cell turnover and resultant improvement in healing occur more rapidly in the younger age group.
| Clinical Implications of Oral Mucositis|| |
It has been reported that mucositis causes painful inflammation and ulcers that affect the mucosal membrane, from the oral cavity to the rectum. Nevertheless, the literature review states that OM refers to a particular inflammation and ulceration that affects only the oral cavity.,,,
The most common signs and symptoms of OM are erythema, edema, burning sensation, increased sensitivity to hot and spicy foods, and white patches on mucous membranes of the cheeks, lips, tongue, and palate [Figure 1].
OM is extremely painful and can cause a drastically reduced quality of life. Pain due to this ulceration can interfere with the patient's ability to eat and drink, thereby leading to weight loss and may necessitate total parenteral feeding. Documented evidence of OM have been found that suggest an increased need for narcotics to manage the pain.,
It has been reported that 75% of patients with OM are at a high risk of developing various infections including septicemia,, fungemia, and viral infections, in particular, herpes infections., It has been reported that neutropenia resulting from the chemotherapeutic treatment is the primary cause of these infections.
| Incidence and Severity of Oral Mucositis|| |
The occurrence of OM generally depends on several factors patient tolerance to the treatment, type of cytotoxic agent, dose, the application of TBI, disease severity and subtype, as well as the remission status.,,, Nevertheless, younger patients tend to develop OM more often than older patients who are being treated for the same malignancy.
OM occurs in 40% of the patients receiving chemotherapy without HSCT. The incidence is significantly increased to 67%–99% in patients receiving chemotherapy for HSCT.
Several risk factors such as tumor type, patient age, dental health, oral hygiene before and during the chemotherapy, and nutrition status are known to influence and substantially affect the OM severity.
The association between infection and the OM severity has been studied in detail. Carious teeth, periodontal diseases, and periradicular infection are associated with systemic complications. Previous studies reported that treating any odontogenic infection will decrease the risk of local and systemic infections. Before subjecting the patient to HSCT, prompt eradication of acute and chronic infections is necessary within the provided time limit. Hence, teeth with severe caries and dental infections are managed by extractions. The use of immunosuppressive drugs after the HSCT infusion can lead to infection in about 73% of the cases.
The overall impact of OM is enormous for patients, caregivers, and the medical system. Furthermore, it can be directly related to the reduced overall survival in patients, as well as increase in the medical costs ,, and hospitalization time.
| Oral Mucositis Interventions|| |
Studies related to OM in pediatric patients receiving HSCT are scarce; however, OM is of considerable clinical significance as it essentially facilitates the entry microorganisms, native to the oropharyngeal region, into the systemic circulation.
The OM incidence and severity for patients undergoing HSCT emphasize the importance of good prevention. Patient and parent's education about good oral hygiene to minimize the oral complication before, during, and after the treatment is crucial and important.
The incidence and severity of OM for patients undergoing HSCT underline the importance of good prevention. Patient and parent's education toward good oral hygiene in order to minimize the oral complication before, during, and after the treatment is very critical and important. Current literature on the different preventive methods agonist OM is reviewed below:
It is a harmless bland isotonic oral rinse, which is beneficial in maintaining appropriate oral hygiene due to its safety, low toxicity, and physiological properties. While it is not recognized as an effective intervention to alleviate the symptoms of OM, several studies have used it as a control for comparison with other regimens , or as a vehicle combined with other mouth rinses.,
While fluoride mouth rinses are less effective in reducing the OM incidence or severity, few studies have used fluoride mouth rinse in their control groups.,,
Banava et al. used a fluoridated paste of casein phosphopeptide-amorphous calcium phosphate (CPP-ACPF) on the oral cavity and salivary status of patients undergoing chemotherapy. On assessing the clinical effects, they found that although no change was observed on salivary signs, the resting and stimulated saliva rates and saliva buffering capacity significantly improved in patients using the CPP-ACPF paste.
Chlorhexidine gluconate mouthwash
Chlorhexidine gluconate (CHX) is a broad-spectrum antibacterial mouthwash present in a concentration of 0.12% and 0.2%. It is generally accepted that it prevents the buildup of dental plaque. It mechanically binds to the oral surface by reversible electrostatic bonds with salivary glycoproteins. While no concrete evidence exists regarding its beneficial effects on OM.
Several studies have tested CHX extensively in randomized trials to evaluate its effect in preventing OM in patients undergoing chemotherapy.,,,, CHX presented unfavorable characteristics such as a temporary alteration of taste, unpleasant sensation, staining of teeth and tongue, and soreness of the oral mucosa.,
Sodium bicarbonate mouthwash
Sodium bicarbonate is a bland mouthrinse that is harmless and beneficial for oral hygiene maintenance. There are a few published articles on the use of sodium bicarbonate mouthwash for preventing OM in patients undergoing chemotherapy., While Kenny (1990) suggested that it might be a valid aid to reduce the severity of OM, Dodd et al. 2000 reported that the evidence in this regard was inconclusive.
Standardized oral hygiene regimen
Since the 1980s, investigators have explored the link between oral hygiene and the OM incidence and severity. Bavier (1989) and Sampiano (2012) concluded that there was a well-known strong correlation between the OM severity and poor oral hygiene.
While there is no controversy in the literature about the need for oral hygiene, there is considerable debate about how best to achieve it. It is a well-documented fact that physical methods such as toothbrushes are far more effective than chemical methods alone. Several guidelines have addressed the use of soft toothbrush and parentally assisted brushing among children. The American Academy of Pediatric Dentistry 2013 recommended in their guidelines that patients should maintain good oral hygiene by brushing their teeth and tongue two to three times daily regardless of their hematological status.,,
Different Oral Hygiene Protocols developed for patients undergoing chemotherapy with or without HCST instruct the patients to brush their teeth to prevent gingival inflammation and bacterial colonization.
Supersaturated calcium phosphate rinse
The supersaturated calcium phosphate rinse (SCPR) has been introduced in oral health care management for oncology patients with the aim of lubricating the oral cavity, to minimize severe OM. SCPR is a natural electrolyte solution containing calcium and phosphate ions that resemble the ionic and pH balance of saliva.
Theoretically, the highly concentrated ions of Ca2+/PO43− diffuse into the intercellular spaces of the oral epithelium. The Ca2+ ions are crucial in the inflammatory process, the blood clotting cascade, fibrin production, and tissue repair. PO43− ions are important in facilitating intracellular signaling and regulating the voltage potential inside the cell; both mechanisms are important in repairing and protecting the damaged mucosal surfaces.
Although several studies in the literature reporting the positive effect of SCPR in reducing OM, peak, and duration of pain,, little is known about the efficacy of SCPR in pediatric patients undergoing HSCT.
In a study of 40 patients undergoing allogeneic transplants, Markiewicz et al(2010). have reported a significant reduction in the OM severity in patients using SPCR when compared to 20 patients of the control group. A pilot study reported that SCPR used for 34 adult patients undergoing HSCT from the initial step of conditioning resulted in a significant reduction in the OM severity.
In contrast, a study of 56 patients undergoing autologous or allogeneic HSCT revealed that OM developed in 19 patients using SCPR compared to 24 patients of the control group. Furthermore, the study found no significant difference in the OM severity between the two groups.
A more recent randomized control study by Markiewicz et al. (2012), testing the effect of SCPR found a reduction in the oral toxicity, mouth pain, and disease course duration compared to the control group.
A study by Lalioui et al. (2012) and Quinn (2013) in the pediatric patients undergoing autologous HSCT reported that half of the participants using SCPR developed OM.
Cryotherapy (CT) acts as vasoconstrictor and results in decreased toxicity of the chemotherapeutic agents associated with mucosal damage., In 1991, the first published report on CT and its effect on OM suggested that when applied during the time of peak serum 5FU levels, CT could cause vasoconstriction to oral mucous membranes and significantly lower intensity of OM.
It has been recommended by the Multinational Association of Supportive Care in the Cancer/International Society of Oral Oncology (MASCC/ISOO) in 2007, to use CT as a preventive measure.
Several studies have examined the effect of CT on OM and suggested the use of CT to prevent OM in patients receiving high-dose melphalan, with or without TBI, as conditioning for HSCT.,,
Few studies have been conducted on children. In 2006, a study was conducted for children aged between 2 and 16 years undergoing chemotherapy and autologous peripheral blood stem cells transplantation and found that combination of propantheline and oral CT may be feasible and effective for reducing the mucosal toxicity in patients with malignancy who are undergoing high-dose chemotherapy. A prospective randomized study found in that CT during methotrexate administration did not reduce severe OM in patients undergoing myeloablative allogeneic HSCT.
CT significantly affected OM in patients receiving short half-life chemotherapeutic agent., Nevertheless, some patients experienced uncomfortable sensation while holding ice in their mouth for 30 min.
This is a nonsteroidal anti-inflammatory mouthwash, which also possesses pain relieving, antimicrobial, antifungal, and anesthetic properties., Benzydamine is acceptable and well tolerated. Only few published articles are available on the use of benzydamine, and as a result, no guideline can be published for its use to prevent chemotherapy-induced mucositis. Nevertheless, in two studies, 0.15% benzydamine hydrochloride presented to be less effective than 0.2% CHX in the OM incidence and severity in a pediatric population.,
It is a well-known plant used for several medicinal purposes. It has anti-inflammatory, antibacterial, and antifungal properties., Few studies have tested the effect of chamomile drops mixed with water on OM. Fidler et al. (1996) conducted a randomized trial on 164 patients, and they reported that the solution was well tolerated by patients with OM.
Povidone–iodine a widely used antimicrobial solution. There is a significant reduction in the incidence, severity, and duration of OM in a group of patients using regular mouthwashes of povidone– iodine; however, no further studies were conducted on the use of povidone–iodine for treating OM.
Epidermal growth factor
The epidermal growth factor (EGF) regulates epithelial cell proliferation, growth, and migration. In addition, it enhances mucosal wound healing and tissue generation, which indicate that EGF may be effective in the treatment of ulcerative OM.
Since 1997, there is evidence suggesting that decreased salivary EGF is associated with more severe mucositis; however, no clinically applicable preparation of EGF is available for the management of OM.
Human keratinocyte growth factors
Human keratinocyte growth factors belong to the family of fibroblast growth factors. Palifermin is one of the most common human recombinant keratinocyte growth factors. It is mitogenic for epithelial and endothelial cells, fibroblast, and keratinocytes and supports the barrier integrity.
Animal studies suggested that KGF-1 decreased graft versus host disease associated with allogeneic HSCT.
The Mucositis Study Group of the MASCC/ISOO has published clinical practice guidelines for mucositis., These have resulted in a recommendation for the use of palifermin for 3 days before the conditioning treatment and for 3 days posttransplant to prevent OM.
Worthington et al., (2011) found a statistically significant result for palifermin in reducing the incidence of OM.
Morris et al., (2016) published the first clinical trial of palifermin for the treatment of OM in 27 children. The results revealed that there were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population, and no differences were observed between the three different age groups studied.
Granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor
These are specific hematopoietic growth factors needed for bone marrow progenitor cells to form mature blood cells. Granulocyte colony-stimulating factor (G-CSF) stimulates the development of neutrophils, eosinophils, and basophils; whereas, granulocyte–macrophage CSF (GM-CSF) stimulates the generation of cells belonging to the monocyte/macrophage lineage. Nevertheless, no guideline is available for using G-CSF due to insufficient evidence. Several studies concluded that GM-CSF mouthwashes are not effective in preventing OM in the HSCT.,,
| Conclusion|| |
The problem of OM in children who are undergoing HSCT is vital importance because of the morbidity and impact, it has on the quality of life of the patient.
The treatment of OM remains focused on symptomatic topical relief; different methods were introduced to reduce the incidence and severity of OM.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Appelbaum FR. The current status of hematopoietic cell transplantation. Annu Rev Med 2003;54:491-512.
Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004;4:277-84.
Nickel RS, Hendrickson JE, Haight AE. The ethics of a proposed study of hematopoietic stem cell transplant for children with “less severe” sickle cell disease. Blood 2014;124:861-6.
Bhatia M, Sheth S. Hematopoietic stem cell transplantation in sickle cell disease: Patient selection and special considerations. J Blood Med 2015;6:229-38.
Sonis ST, Fey EG. Oral complications of cancer therapy. Oncology (Williston Park) 2002;16:680-6.
Raber-Durlacher JE, Elad S, Barasch A. Oral mucositis. Oral Oncol 2010;46:452-6.
Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, et al.
Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100:1995-2025.
Bhatt V, Vendrell N, Nau K, Crumb D, Roy V. Implementation of a standardized protocol for prevention and management of oral mucositis in patients undergoing hematopoietic cell transplantation. J Oncol Pharm Pract 2010;16:195-204.
Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer 2007;15:491-6.
Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R, et al.
Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 2000;110:292-9.
Escoda-Francolí J, Rodríguez-Rodríguez A, Pérez-García S, Gargallo-Albiol J, Gay-Escoda C. Dental implications in oral cancer patients. Med Oral Patol Oral Cir Bucal 2011;16:e508-13.
Chaveli-López B. Oral toxicity produced by chemotherapy: A systematic review. J Clin Exp Dent 2014;6:e81-90.
Sonis ST. Oral mucositis in cancer therapy. J Support Oncol 2004;2:3-8.
Sonis ST. Pathobiology of oral mucositis: Novel insights and opportunities. J Support Oncol 2007;5:3-11.
Adamietz IA, Rahn R, Böttcher HD, Schäfer V, Reimer K, Fleischer W, et al.
Prophylaxis with povidone-iodine against induction of oral mucositis by radiochemotherapy. Support Care Cancer 1998;6:373-7.
Engeland CG, Bosch JA, Cacioppo JT, Marucha PT. Mucosal wound healing: The roles of age and sex. Arch Surg 2006;141:1193-7.
Jones V, Grey JE, Harding KG. Wound dressings. BMJ 2006;332:777-80.
Field FK, Kerstein MD. Overview of wound healing in a moist environment. Am J Surg 1994;167:2S-6S.
Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, et al.
Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol 2007;127:594-604.
Woo JS, Jeong JY, Hwang YJ, Chae SW, Hwang SJ, Lee HM, et al.
Expression of cathelicidin in human salivary glands. Arch Otolaryngol Head Neck Surg 2003;129:211-4.
López-Castaño F, Oñate-Sánchez RE, Roldán-Chicano R, Cabrerizo-Merino MC. Measurement of secondary mucositis to oncohematologic treatment by means of different scale. Review. Med Oral Patol Oral Cir Bucal 2005;10:412-21.
Harris DJ, Eilers J, Harriman A, Cashavelly BJ, Maxwell C. Putting evidence into practice: Evidence-based interventions for the management of oral mucositis. Clin J Oncol Nurs 2008;12:141-52.
Blijlevens N, Schwenkglenks M, Bacon P, D'Addio A, Einsele H, Maertens J, et al.
Prospective oral mucositis audit: Oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy – European blood and marrow transplantation mucositis advisory group. J Clin Oncol 2008;26:1519-25.
Yamagata K, Arai C, Sasaki H, Takeuchi Y, Onizawa K, Yanagawa T, et al.
The effect of oral management on the severity of oral mucositis during hematopoietic SCT. Bone Marrow Transplant 2012;47:725-30.
Kartin PT, Tasci S, Soyuer S, Elmali F. Effect of an oral mucositis protocol on quality of life of patients with head and neck cancer treated with radiation therapy. Clin J Oncol Nurs 2014;18:E118-25.
Rogers BB. Mucositis in the oncology patient. Nurs Clin North Am 2001;36:745-60, vii.
Markiewicz M, Dzierzak-Mietla M, Frankiewicz A, Zielinska P, Koclega A, Kruszelnicka M, et al.
Treating oral mucositis with a supersaturated calcium phosphate rinse: Comparison with control in patients undergoing allogeneic hematopoietic stem cell transplantation. Support Care Cancer 2012;20:2223-9.
Filicko J, Lazarus HM, Flomenberg N. Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: New approaches to prophylaxis and treatment. Bone Marrow Transplant 2003;31:1-0.
Akintoye SO, Brennan MT, Graber CJ, McKinney BE, Rams TE, Barrett AJ, et al.
A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:581-8.
Price A. Mucositis often overlooked and undertreated. Community Oncol 2008;5:173-4.
Bensinger W, Schubert M, Ang KK, Brizel D, Brown E, Eilers JG, et al.
NCCN task force report. Prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 2008;6 Suppl 1:S1-21.
Appelbaum FR. The use of bone marrow and peripheral blood stem cell transplantation in the treatment of cancer. CA Cancer J Clin 1996;46:142-64.
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al.
Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109:820-31.
Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infection in patients with acute nonlymphocyte leukemia. Prevalence of acute exacerbations. Arch Intern Med 1982;142:551-4.
Maxymiw WG, Wood RE. The role of dentistry in patients undergoing bone marrow transplantation. Br Dent J 1989;167:229-34.
Toljanic JA, Bedard JF, Larson RA, Fox JP. A prospective pilot study to evaluate a new dental assessment and treatment paradigm for patients scheduled to undergo intensive chemotherapy for cancer. Cancer 1999;85:1843-8.
Elting LS, Chang YC, Parelkar P, Boers-Doets CB, Michelet M, Hita G, et al.
Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: A meta-analysis. Support Care Cancer 2013;21:3243-54.
Pico JL, Avila-Garavito A, Naccache P. Mucositis: Its occurrence, consequences, and treatment in the oncology setting. Oncologist 1998;3:446-51.
Keefe DM. Mucositis management in patients with cancer. Support Cancer Ther 2006;3:154-7.
Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, et al.
Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001;19:2201-5.
McGuire DB, Fulton JS, Park J, Brown CG, Correa ME, Eilers J, et al.
Systematic review of basic oral care for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21:3165-77.
Vokurka S, Bystrická E, Koza V, Scudlová J, Pavlicová V, Valentová D, et al.
The comparative effects of povidone-iodine and normal saline mouthwashes on oral mucositis in patients after high-dose chemotherapy and APBSCT – Results of a randomized multicentre study. Support Care Cancer 2005;13:554-8.
Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1992;73:682-9.
Kim YH, Jun MH, Choi JS. Prevention of chemotherapy-induced oral mucositis in patients with acute leukemia by the two oral care protocols: The comparisons of sodium bicarbonate-normal saline gargling and chlorhexidine gargling. J Korean Acad Adult Nurs 1997;9:98-111.
Turhal NS, Erdal S, Karacay S. Efficacy of treatment to relieve mucositis-induced discomfort. Support Care Cancer 2000;8:55-8.
Pitten FA, Kiefer T, Buth C, Doelken G, Kramer A. Do cancer patients with chemotherapy-induced leukopenia benefit from an antiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study. J Hosp Infect 2003;53:283-91.
Rojas de Morales T, Zambrano O, Rivera L, Navas R, Chaparro N, Bernardonni C, et al.
Oral-disease prevention in children with cancer: Testing preventive protocol effectiveness. Med Oral 2001;6:326-34.
Papas AS, Clark RE, Martuscelli G, O'Loughlin KT, Johansen E, Miller KB, et al.
A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;31:705-12.
Banava S, Houshyari M, Safaie T. The effect of casein phosphopeptide amorphous calcium phosphate fluoride paste (CPP-ACPF) on oral and salivary conditions of patients undergoing chemotherapy: A randomized controlled clinical trial. Electron Physician 2015;7:1535-41.
Yates R, Shearer BH, Huntington E, Addy M. A method to compare four mouthrinses: Time to gingivitis level as the primary outcome variable. J Clin Periodontol 2002;29:519-23.
Davies A. The mode of action of chlorhexidine. J Periodontal Res Suppl 1973;12:68-75.
Rutkauskas JS, Davis JW. Effects of chlorhexidine during immunosuppressive chemotherapy. A preliminary report. Oral Surg Oral Med Oral Pathol 1993;76:441-8.
Dodd MJ, Larson PJ, Dibble SL, Miaskowski C, Greenspan D, MacPhail L, et al.
Randomized clinical trial of chlorhexidine versus placebo for prevention of oral mucositis in patients receiving chemotherapy. Oncol Nurs Forum 1996;23:921-7.
Dodd MJ, Dibble SL, Miaskowski C, MacPhail L, Greenspan D, Paul SM, et al.
Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat chemotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:39-47.
Marinone MG, Savoldi E. Chlorhexidine and taste. Influence of mouthwashes concentration and of rinsing time. Minerva Stomatol 2000;49:221-6.
Flötra L, Gjermo P, Rölla G, Waerhaug J. Side effects of chlorhexidine mouth washes. Eur J Oral Sci 1971;79:119-25.
Kenny SA. Effect of two oral care protocols on the incidence of stomatitis in hematology patients. Cancer Nurs 1990;13:345-53.
Glenny AM, Gibson F, Auld E, Coulson S, Clarkson JE, Craig JV, et al.
The development of evidence-based guidelines on mouth care for children, teenagers and young adults treated for cancer. Eur J Cancer 2010;46:1399-412.
Lalla RV, Brennan M, Schubert M. Oral complications of cancer therapy. In: Pharmacology and Therapeutics for Dentistry. 6th
ed.. St. Louis, Mo: Mosby Elsevier; 2011. p. 782-98.
Bavier AR. Nursing management of acute oral complications of cancer. NCI Monogr 1990;9:123-8.
American Academy of Pediatric Dentistry. Guideline on dental management of pediatric patients receiving chemotherapy, hematopoietic cell transplantation, and/or radiation. Pediatr Dent 2013;35:E185-93.
Yamagata K, Onizawa K, Yoshida H, Yamagata K, Kojima Y, Koike K, et al.
Dental management of pediatric patients undergoing hematopoietic stem cell transplant. Pediatr Hematol Oncol 2006;23:541-8.
Markiewicz M, Mietla MD, Zielinska P, Kruzel T, Czerw T, KyrczKrzemien S. Caphosol mouth rinse diminishes oral mucositis in allo-HSCT recipients. ASH Annual Meeting and Exposition. 2010.
Dłuz˙niewska A, Gozdzik J, Zygadlo D, Skoczen S, Krasowska-Kwiecien A, Czogala W, et al
. Supersaturated calcium phosphate rinse (Caphosol) in the management of mucositis after haematopoietic stem cell transplantation – Single-centre experience. 37th
Annual Meeting of the European Group for Blood and Marrow Transplantation. 2011.
Ambard N, Brechard C, Noyel J, Gourioud M, Michallet A, Bouafia F, et al
. Prospective evaluation of supersaturated calcium phosphate oral rinse for oral mucositis after autologous and allogeneic stem cell transplantation. 37th
Annual Meeting of the European Group for Blood and Marrow Transplantation. 2011.
Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, Therneau TM, et al.
Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991;9:449-52.
Aisa Y, Mori T, Kudo M, Yashima T, Kondo S, Yokoyama A, et al.
Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer 2005;13:266-9.
Ohbayashi Y, Imataki O, Ohnishi H, Iwasaki A, Ogawa T, Inagaki N, et al.
Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation. Ann Hematol 2008;87:837-45.
Sato A, Saisho-Hattori T, Koizumi Y, Minegishi M, Iinuma K, Imaizumi M, et al.
Prophylaxis of mucosal toxicity by oral propantheline and cryotherapy in children with malignancies undergoing myeloablative chemo-radiotherapy. Tohoku J Exp Med 2006;210:315-20.
Gori E, Arpinati M, Bonifazi F, Errico A, Mega A, Alberani F, et al.
Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: A prospective randomized study of the gruppo italiano trapianto di midollo osseo nurses group. Bone Marrow Transplant 2007;39:347-52.
Peterson DE, Ohrn K, Bowen J, Fliedner M, Lees J, Loprinzi C, et al.
Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer 2013;21:327-32.
Grant SC, Kris MG, Young CW, Sirotnak FM. Edatrexate, an antifolate with antitumor activity: A review. Cancer Invest 1993;11:36-45.
Cheng KK. Children's acceptance and tolerance of chlorhexidine and benzydamine oral rinses in the treatment of chemotherapy-induced oropharyngeal mucositis. Eur J Oncol Nurs 2004;8:341-9.
Hashemi A, Bahrololoumi Z, Khaksar Y, Saffarzadeh N, Neamatzade H, Foroughi E, et al.
Mouth-rinses for the prevention of chemotherapy-induced oral mucositis in children: A systematic review. Iran J Ped Hematol Oncol 2015;5:106-12.
Cheng KK, Chang AM. Palliation of oral mucositis symptoms in pediatric patients treated with cancer chemotherapy. Cancer Nurs 2003;26:476-84.
Cheng KK, Chang AM, Yuen MP. Prevention of oral mucositis in paediatric patients treated with chemotherapy; a randomised crossover trial comparing two protocols of oral care. Eur J Cancer 2004;40:1208-16.
Craker LE, Simon JE. Herbs, spices, and medicinal plants: Recent advances in botany, horticulture, and pharmacology. Herbs, spices, and medicinal plants: Recent advances in botany, horticulture, and pharmacology. 1987;2.
Aggag ME, Yousef RT. Study of antimicrobial activity of chamomile oil. Planta Med 1972;22:140-4.
Rahn R, Adamietz IA, Boettcher HD, Schaefer V, Reimer K, Fleischer W, et al.
Povidone-iodine to prevent mucositis in patients during antineoplastic radiochemotherapy. Dermatology 1997;195 Suppl 2:57-61.
Noguchi S, Ohba Y, Oka T. Effect of salivary epidermal growth factor on wound healing of tongue in mice. Am J Physiol 1991;260:E620-5.
Epstein JB, Emerton S, Guglietta A, Le N. Assessment of epidermal growth factor in oral secretions of patients receiving radiation therapy for cancer. Oral Oncol 1997;33:359-63.
Farrell CL, Rex KL, Chen JN, Bready JV, DiPalma CR, Kaufman SA, et al.
The effects of keratinocyte growth factor in preclinical models of mucositis. Cell Prolif 2002;35 Suppl 1:78-85.
Krijanovski OI, Hill GR, Cooke KR, Teshima T, Crawford JM, Brinson YS, et al.
Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999;94:825-31.
von Bültzingslöwen I, Brennan MT, Spijkervet FK, Logan R, Stringer A, Raber-Durlacher JE, et al.
Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis. Support Care Cancer 2006;14:519-27.
Raber-Durlacher JE, von Bültzingslöwen I, Logan RM, Bowen J, Al-Azri AR, Everaus H, et al.
Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21:343-55.
Dazzi C, Cariello A, Giovanis P, Monti M, Vertogen B, Leoni M, et al.
Prophylaxis with GM-CSF mouthwashes does not reduce frequency and duration of severe oral mucositis in patients with solid tumors undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue: A double-blind, randomized, placebo-controlled study. Ann Oncol 2003;14:559-63.
Cartee L, Petros WP, Rosner GL, Gilbert C, Moore S, Affronti ML, et al.
Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: A randomized, double-blind, dose-ranging study. Cytokine 1995;7:471-7.