Oral and Dental Considerations in the Management of ...

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Applied Clinical Research, Clinical Trials & Regulatory Affairs, 2014, 1, 118-122

Oral and Dental Considerations in the Management of Leukemic Children Eman H. Alnuaimi*, Manal El-Halabi, Mawlood B. Kowash Department of Pediatric Dentistry, Dubai College of Dental Medicine, Dubai Healthcare City, PO Box 505097, Dubai, United Arab Emirates Abstract: An incidence of overall oral sequelae in leukemic children of 54% has been reported in the literature. Oral complications include mucositis, fungal and viral infections, salivary gland hypofunction, dental caries, and others. Mucositis accounts for the most common complication followed by fungal infections and viral infections. It has also been reported that the quality of life of these children is affected. Dental healthcare professionals play a very important role in assessing the patient’s oral health needs before, during, and after cancer therapy. A multidisciplinary approach between the medical and dental team will help prevent, stabilize, and treat the oral and dental problems at an early stage. This paper reviews briefly the oral health problems in leukemic children as well as dental considerations and recommendations for optimal oral health care.

Keywords: Cancer therapy, childhood cancer, dental problems, leukemia, oral complications, oral health. INTRODUCTION

Table 1. Risk factors for leukemia in children.

The WHO states that “Cancer is a generic term for a large group of diseases that can affect any part of the body. It is characterized by rapidly growing abnormal cells, which can invade adjoining parts and organs in the body. This invasion is referred to as metastasis” [1]. Childhood cancers often differ from adulthood cancers. They usually occur as a result of DNA changes that occur early in life of an unknown cause, unlike adulthood cancers that are highly linked to lifestyles and environmental factors [2]. The most common type of childhood cancer is leukemia. Leukemia is a heterogenous group of hematological malignancies caused by clonal proliferation of primitive white blood cells [3]. It accounts for 34% of all childhood cancers among children below 15 years of age [4]. Leukemias are classified as acute versus chronic and lymphoid versus myeloid. The most common subtype is acute lymphocytic leukemia (ALL), which accounts for 75%-80% of all childhood cases. Another subtype is acute myeloid leukemia (AML) that makes up about 20%. By contrast, chronic myeloid leukemia (CML) represents only approximately 2% and chronic lymphocytic leukemia (CLL) is reported very rarely in children. Finally, myelodysplastic syndrome (MDS) designates a heterogenous group of clonal diseases related to a subset of AML [5]. Figliola et al. suggested that “the etiology of most leukemias is uncertain although the occurrence has been associated with predisposing cytogenic abnormalities, environmental, and viral factors. Currently, evidence suggests that chromosomal alterations and mutations during embryogenic *Address correspondence to this author at the Department of Pediatric Dentistry, Dubai College of Dental Medicine, Dubai Healthcare City, PO Box 505097, Dubai, United Arab Emirates; Tel: +971 4 424 8777; Fax: +971 4 424 8686; E-mail: [email protected] 2213-4778/14 $58.00+.00

Environmental factors: •

Ionizing radiation

•

Chemicals (hydrocarbons and pesticides)

•

Alcohol, cigarette, and illicit drug use (marijuana)

Genetic factors: •

Identical twins

•

Leukomogenic translocations or clonotypic gene fusion sequences

Infectious agents and the population mix theory: •

Peak incidence early years of life with immature immune system (susceptibility to infections)

•

Viral infections (Epstein-Barr virus for Burkitt lymphoma)

•

Population mixing theory (the introduction of a highly infectious but not highly pathogenic agent in a previously non-infected population)

Other: •

Maternal reproductive history and birth weight (fetal loss, increased maternal age, and increased birth weight)

development are frequently the initial event of pediatric leukemia. In addition, certain syndromes and chromosomal abnormalities including Down Syndrome, Fanconi’s anemia, Bloom syndrome, and ataxia-telangiectasia have been linked with an increased risk of developing ALL” [6]. Belson et al. suggested “other risk factors (Table 1) that may contribute to childhood cancers, which include environmental, genetic, and infectious factors” [7]. In general, treatment modalities include chemotherapy alone, chemotherapy with radiation and/or hematopoietic cell transplantation (HCT). “Chemotherapeutic protocols include four main components: (1) induction phase: aimed at initial remission induction within one month through the use of multiple che© 2014 Bentham Science Publishers

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motherapeutic agents; (2) a consolidation phase: to eradicate residual leukemic blasts in patients who are in remission according to morphological criteria; (3) extra-compartment therapy: such as central nervous system directed therapy; and (4) a maintenance phase: to further stabilize remission by suppressing re-emergence of a drug resistant clone through continuing reduction of residual leukemic cells” [8]. Chemotherapy and radiotherapy cause alterations in the DNA and RNA. “Radiotherapy when used in conjunction with chemotherapy during the above treatment phases may damage DNA and amino acids directly or indirectly by ionization, while chemotherapy can interfere with DNA synthesis and replication, and RNA transcription, and cytoplasmic transport mechanisms in actively proliferating cells” [8].

Fig. (1). Oral mucositis lesion on the dorsum of the tongue [14].

This paper briefly reviews the oral health problems and recommendations for oral care in leukemic children. ORAL HEALTH PROBLEMS IN LEUKEMIC CHILDREN “Acute oral sequelae as a result of cancer therapy and HCT regimens are common in children as reported by the American Academy of Pediatric Dentistry (AAPD). Oral and associated systemic complications may include mucositis, secondary infections (e.g., candidiasis, herpes simplex virus), salivary gland dysfunction (e.g., xerostomia), dental caries, neurotoxicity, post-radiation osteonecrosis, temporomandibular dysfunction (e.g., trismus), and craniofacial and dental developmental anomalies. Oral graft versus host disease (GVHD) can result from HCT. Oral cultures and/or biopsies are recommended for all suspicious oral lesions” [9].

Fig. (2). Erythematous oral mucositis lesion on the buccal mucosa* [15].

Fig. (3). Ulcerative oral mucositis lesion on the labial mucosa* [15].

ORAL MUCOSITIS The most prevalent oral sequelae in leukemic children is mucositis. Mucositis, or inflammation of the mucosal surfaces, is usually a complication that occurs as a result of chemotherapy. The incidence and severity depends on the treatment regimen employed, and those containing high dose methotrexate and cytarabine are particularly damaging to the mucosae. Rask and colleagues documented a 52% incidence of oral mucositis in children treated with methotrexate (5000-8000 mg/m2) given as 24-hour infusion. They also found that higher methotrexate plasma concentration and delayed clearance were risk factors [5]. “Chemotherapeutic agents result in the elevation of the levels of proinflammatory cytokines including Tumor Necrosis Factor (TNF-alpha) and Interleukin (IL)-1 and IL-6 in blood and saliva” [10]. “This in turn leads to apoptosis of submucosal endothelial cells and fibroblasts” [11]. Oral mucositis can also be seen during the induction phase when combined with radiotherapy (34%) and during the maintenance phase (39%) [12]. Poor oral hygiene has been found to play a very critical role in determining the severity of oral mucositis [13]. The most common sites of oral mucositis are the dorsum of the tongue in 72.5% of the cases (Fig. 1) followed by buccal (Fig. 2) and labial mucosa (Fig. 3) in 48.75% of the cases. Other sites include the palate, oropharynx, gingiva, floor of the mouth & ventral surface of the tongue (Fig. 4) [13].

Fig. (4). Ulcerative oral mucositis lesion on the lateral and ventral surface of the tongue* [15]. *Image reprinted with permission from Medscape Reference (http://emedicine.medscape.com/), 2014, available at: http://emedicine.medscape.com/article/1079570-overview.

The basis for prevention and management of oral mucositis is the maintenance of optimum oral health even if bleeding occurs as a result of thrombocytopenia. The use of a soft toothbrush can help reduce discomfort. However, sponges, foam brushes, and super-soft toothbrushes can be used in cases of severe mucositis [16]. Other preventive measures have been suggested in the literature as part of preventive protocols or treatment regimens (Table 2) [11]. Table 2. Oral mucositis preventive/treatment regimens. • • • • • •

Cryotherapy Low level laser therapy Amifostine Chlorhexidine Gelclair Benzydamine

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SECONDARY ORAL INFECTIONS Oral mucosal infections such as fungal and viral infections are also reported secondary to the immunosuppressive status in these children.

Alnuaimi et al.

related to the gingivae in leukemic children include bruising, petechiae, and bleeding. These occur as a result of reduced production of megakaryocytes in the bone marrow and thrombocytopenia [25].

Fungal Infections

TOOTH SURFACE LOSS

Fungal infections are prevalent during periods of severe immunosuppression and neutropenia. Oral candidiasis accounts for almost 15% of the cases [6]. Initially, Candida (C.) albicans are the most prevalent microorganisms. In few cases, it is replaced by non-albicans species (C. kefyr, C. lusitaniae, C. sake, C. tropicalis) [17]. In children and adolescents, the clinical presentation of candidiasis with C. albicans is either pseudomembranous or erythematous with 29.78% and 12.77% respectively. The most common site of infection is the dorsal surface of the tongue [18]. It is therefore advised to limit the use of antibiotics because the longterm use of antibiotics leads to immunosuppression creating a favorable environment for multiplication and proliferation of candidal microorganisms [19]. Antifungal prophylaxis is no more recommended [9].

Patients receiving chemotherapy can experience nausea and vomiting. Acidic products of the stomach can cause tooth surface loss due to erosion and improper oral hygiene measures [27]. It is important to determine whether the patient’s case requires monitoring or treatment [28]. The patient can be advised to rinse after vomiting to reduce the acidity in the oral cavity [16].

Viral Infections Viral infections are not uncommon in leukaemic children. Herpes simplex virus and varicella-zoster virus are the most common viral pathogens [20]. They account for 8% and 2% respectively [6]. Infection rates are highest during induction phase and relapse [20]. SALIVARY GLAND XEROSTOMIA

HYPOFUNCTION

AND

“Saliva plays a very important role in the oral cavity. Salivary gland hypofunction and xerostomia are most frequent after radiotherapy to the head and neck. Concomitant chemotherapy and radiotherapy may have an additive effect on salivary gland hypofunction” [21]. Chewing gums, frequent sipping of water, and salivary substitutes can help reduce discomfort associated with xerostomia [9].

PERIPHERAL NEUROPATHY Neuropathies occur either due to direct leukemic infiltration or as a complication of chemotherapy. One of the most common neuropathies is the cranial neuropathy that involves the numb chin syndrome, in which leukemic infiltration affects the mental nerve. Uncommon cranial neuropathies may affect the trigeminal or facial nerves and are manifested as jaw pain or facial paralysis [29]. GRAFT VERSUS HOST DISEASE (GVHD) “GVHD is a complication that occurs after allogenic HCT in which the newly transplanted donor cells attack the transplant recipient's body. It is classified into acute and chronic GVHD. Acute GVHD occurs within 3 months after the transplant while chronic GVHD occur more than 3 months after transplantation” [30]. GVHD is more common in adults than in children [31]. In children, the most common type is Chronic GVHD with an incidence of 46%. “Clinical signs and symptoms include lichen-type features, hyperkeratotic plaques, restriction of mouth opening from sclerosis, xerostomia, mucocele, mucosal atrophy, and pseudomembranes” [32]. GVHD lesions should be followed up closely for the potential of malignant transformation of the oral mucosa into oral squamous cell carcinoma. Discussion of the case with the patient’s physician is recommended [9].

DENTAL CARIES “Leukemic children may be at higher risk due to the diet that is rich in carbohydrates (to maintain or gain weight), medications containing sucrose, and salivary gland hypofunction and xerostomia” [22]. The incidence of dental caries when the DMFT (an index that measures the average number of decayed, missing, and filled teeth in the permanent dentition) was measured in children with ALL was 2.7 new carious lesions annually [23]. To ovoid osteoradionecrosis after radiotherapy, extraction is preferred for primary teeth for cases with poor prognosis and permanent teeth when definitive treatment cannot be guaranteed [9].

HEALTH-RELATED QUALITY OF LIFE

GINGIVAL PROBLEMS

RECOMMENDATIONS FOR ORAL AND DENTAL CARE WHEN MANAGING LEUKEMIC CHILDREN

Gingival hyperplasia is commonly seen in children with AML but uncommon in children with ALL [24]. It occurs due to abnormal proliferation and infiltration of leukemic cells [25]. Increased keratinization of the gingival epithelium has been observed in some cases of AML in conjunction with gingival hyperplasia [26]. Other oral manifestations

The Center for Disease Control and Prevention defined the health-related quality of life (H-RQL) as a broad multidimensional concept that usually includes subjective evaluations of both positive and negative aspects of life [33]. Children with ALL experience declining levels of H-RQL during active treatment [34]. It has been proposed that H-RQL is predicted by the degree of confidence and trust of the parents in the medical staff, child’s age and his/her coping abilities [35]. Pediatric cancer patients with mucositis and dental caries reported poor oral H-RQL [36].

The AAPD provides thorough guidelines on the Dental Management of Patients Receiving Chemotherapy. These guidelines were last reviewed by the Council on Clinical Affairs in 2013. The Royal College of Surgeons of England (RCSEng) also provides clinical guidelines on The Oral

Oral and Dental Considerations in the Management


Management of Oncology Patients Requiring Radiotherapy, Chemotherapy, and / or Bone Marrow Transplantation. These guidelines were updated in 2012 by the British Society for Disability and Oral Health. The following is a very brief summary on recommendations for dental and oral care adopted from the AAPD and the RCSEng guidelines [9, 37]. Before Initiation of Cancer Therapy The objectives of this assessment are to identify and manage potential sources of infection, patient/parent education, and the establishment of a preventive program that ensures optimum oral and dental health. An initial assessment should include a detailed review of the medical and dental history. This should be followed by a thorough oral and dental assessment. Hospitalization should be considered for children with absolute neutrophil count (ANC) of