Many cancers that affect children also affect adults, including acute lymphoblastic leukemia (ALL), which is by far the most prevalent, followed by tumors of the central nervous system (CNS), lymphomas, and bone cancers such as osteosarcoma and Ewing sarcoma (1). Neuroblastoma, Wilms tumor, rhabdomyosarcoma, and retinoblastoma are cancers that only affect children.
Leukemia is the most common cancer in children younger than 15 years old, and it is a hematological malignant disorder that arises from uncontrolled and excessive proliferation of hematopoietic stem cells in the bone marrow (2–6). The neoplastic cells inhibit cell differentiation and apoptosis, leading to disruption of normal marrow function and marrow failure (2, 5–7). Failure of precursor cells to mature results in the accumulation of lymphoid blasts in the bone marrow, which replace normal bone marrow cells (8). Suppression of physiological hematopoiesis, results in a shortage of red and white mature cells in the blood, such as leukocytes, erythrocytes, and platelets (9).
Leukemia is classified according to the cell involved and the duration and characteristics of the disease (3, 4, 10, 11). According to clinical behavior, leukemia is distinguished into acute and chronic (1, 11). Acute leukemia constitutes approximately 40% of all childhood cancers. Chronic leukemias are more common in adults than in children (7). Depending on the blast cell line of origin (myeloid or lymphoid), leukemia may be classified as lymphoblastic or myelogenous. In particular acute lymphoblastic leukemia (ALL) is the most common childhood malignancy accounting for 25% of all childhood cancers and 75% of all newly diagnosed patients with acute leukemia (5, 6, 12–15). Acute myeloid leukemia (AML), is the second most common subtype of leukemia in children, accounting for 15–20% of leukemia in children (7).
The standard chemotherapeutic treatment regimen for ALL and AML currently consists of 4 phases: induction (i), CNS (central nervous system) preventive therapy (ii), consolidation (iii) and maintenance (iv) (10, 16). Bone marrow transplantation (BMT), is performed only in patients who have abnormal cytogenetic, or high-risk ALL features in first or second remission (7, 17, 18).
For ALL, the pharmacological protocol during the induction phase (i), to date, includes vincristine, prednisone, L-asparaginase and an anthracycline (7, 19). Due to severe collateral effects related to anthracyclines, some regimens use a four drug induction for high risk patients only (7). Some protocols also use a seven day prednisolone prophase along with intrathecal methotrexate (7).
Consolidation therapy (iii) consists of a period of intensified treatment in which different chemotherapeutic agents are administered to overcome the problem of drug resistance (20). Commonly used agents include high dose methotrexate, 6-mercaptopurine, cyclophosphamide and cytarabine (21).
The goal of maintenance therapy (iV) is to eliminate the leukemic cell burden remaining following the first two phases of chemotherapy. Thus, continuous administration of weekly oral methotrexate and daily oral 6-mercaptopurine is needed for 2–3 years, to prevent relapse (21).
For AML, the main drugs used for the induction phase (i) are combination of cytosine arabinoside and an anthracycline (doxorubicin or daunorubicin) with or without additional drugs (etoposide, thioguanine) (7). Consolidation therapy (iii) consists of high dose chemotherapy including cytosine arabinoside and etoposide (7).
Chemotherapy acts on poorly differentiated or high-metabolism cells, affecting not only cancer cells, but also normal body cells (10, 11). As a consequence, there are several side effects that may be divided into immediate and late signs of chronic toxicity (22). Immediate effects include hair loss, nausea, vomiting, diarrhea, bleeding, anemia, neutropenia and neurotoxicity (eg. somnolence, paresthesia, paralysis, ataxia, spasms and coma) (22). Late effects of chemotherapy are drug resistance and carcinogenicity (22).
Oral mucositis is one of the most common side effects of pediatric cancer treatment because chemotherapeutic drugs are often secreted through saliva, which exposes their toxicity to the oral cavity (23). Oral mucositis consists of oral mucosal damage and inflammation described as a five-phase process: initiation, primary damage response, signaling and amplification, ulceration and healing (24, 25). The World Health Organization (WHO), has introduced a system that grades oral mucosal lesions, with a 0 to 4 scale, based on clinical parameters: grade 0, no change; grade 1, soreness/erythema; grade 2, erythema, ulcers, can eat solid diet; grade 3, ulcers, can eat liquid diet only; grade 4, oral alimentation not possible (26, 27).
The incidence rate of oral mucositis ranges from 52–100% when young patients are submitted to standard chemotherapeutic protocols, however it becomes 100% when they receive high-dose chemotherapy (28). The frequency rate of oral mucositis may range from 40–76% in young patients receiving chemotherapy (29).
The etiology of oral mucositis is poorly known. Sonis hypothesized a pathophysiologic process consisting of a cascade of biological and immunological events, causing cell apoptosis and damaging connective tissue, followed by a series of signaling inflammatory pathways sparked by the presence of cytotoxic chemicals and worsened by systemic and local factors (30–32). Local causes include changes in salivary flow, local tissue damage, and oral dysbiosis, whereas systemic factors include chemotherapeutic drugs, inflammatory cytokines (interleukin-1 and tumor necrosis factor), and immunosuppression (32, 33). Due to the damaged oral epithelial cells, the process progresses to the ulceration phase (34). Important variables influencing the severity of mucosal injury include the type of chemotherapy medicines used, their dosage, and the schedule of administration. Among the drugs most often associated with mucositis are alkylating agents (busulfan, cyclophosphamide, procarbazine, thiotepa), anthracyclines (daunorubicin, doxorubicin, and epirubicin), platinum compounds (cisplatin, carboplatin, oxaliplatin), antimetabolite agents (cytosine arabinoside, hydroxyurea, 5-flurouracil, methotrexate, 6-mercaptopurine, and 6-thioguanide), antibiotics (actinomycin D, bleomycin, mitomycin), vinca alkaloids (vinblastin and vincristine) and taxanes (docetaxel) (28, 35, 36).
Oral mucositis has been linked to patient-associated risk factors including malnutrition, comorbidities, changes in salivary production and composition, and preexisting dental disease (37). The oral microbiota, which is considered to be a mucositis modifying factor, is another significant host component. The microflora colonizes the ulcerative lesions and makes them worse, although it is yet unknown what role specific bacterial species have in the development of ulcerative mucositis (38). It is widely acknowledged that a change in the balance of the oral microbiome components might result in modifications at various signaling pathway levels, which would then start pathological processes that would affect the host's oral health (32, 39). The oral microbiota composition and homeostasis are modified by altered salivary production and composition, increased oral granulocyte presence, and chemotherapy's antimicrobial activity, promoting the predominance of gram-negative anaerobes over oral streptococci (34). Gram-negative bacteria can worsen or accelerate the development of ulcers by releasing endotoxins called lipopolysaccharides (LPS), which induce macrophages to produce inflammatory molecules such as TNF-, IL-6, and IL-1 (32). This chain of events results in oral mucositis (32).
Systemic antineoplastic treatments such as chemotherapy, may influence changes in the oral microbiome of patients and dysbiosis might be responsible for the development of oral mucositis (39). To the best of authors knowledge, only a few studies have investigated the role of the oral flora in the development of oral mucositis in patients undergoing chemotherapy, especially in the pediatric population. In this regard, the goal of this systematic review was to assess the role of oral dysbiosis associated with antineoplastic drugs in the development of oral mucositis in young oncology patients (< 18 years old).