SCIENTIFIC ARTICLE Abstract Chemoradiationtherapy used on pediatric oncologypatients often causes dental developmentalanomalies that affect future dental care. Defects noted include tooth and root agenesis, root thinning and shortening, and localiz¢¢l enamel defects. Histologically, these defects appear as osteoid-like niches in the developing dentin which alter the overlying enamel. Odontogeniccell sensitivity is dependent upon the position on the cell cycle and the mitotic activity at the time of chemoradiationtherapy. Knowledgeoj: the stage of dental developmentat the time of oncologytreatment and the type of therapy allows the clinician to predict dental effects of the chemoradiation.Representative cases illustrate the clinical manifestationsof chemoradiationon the developing dentition. (Pediatr Dent 15:6-12, 1993) Chemoradiationtherapy: effect on dental development Curt Goho,DDS Introduction Morethan half of the 5000 children whodevelop cancer Radiation effects are either lethal or sublethal, depend- each year survive because of improved treatment meth- ing upon the cumulative and per dose amount of radia- ods.1 A s patient lifespans increase, dental effects of oncology tion. If the radiation dose exceeds a certain level, cells treatment becomeclinically significant. Chemoradiation cannot repair the damageand the cell dies. Cells farther therapy is a major part of pediatric oncology treatment from the radiation target or protected by shielding receive and is implicated in causing tooth agenesis, microdontia, less radiation and show only limited damage. root shortening, early apical closure, and coronal hypocalcification.2, 3 Understanding the causes of these Dental Sequelaeto Radiation Therapy dental developmental changes is important for proper Amelogenesis and dentinogenesis are affected by ra- diagnosis, prognosis, and dental treatment of these pa- diation directed at or near the mouth. Teeth located along tients. This article overviewschemoradiation therapy, its the edge of a radiation exposure field receive up to 45%of effects on dental development, and presents cases associ- the administered dose.5 Radiation directed at distant areas ating chemoradiation therapy with dental developmental of the body has no effect on dental development. Some anomalies. oncologists deliver bilateral radiation to equalize facial skeletal growth disturbances and prevent hemifacial hy- Radiation Therapy poplasias. Radiation therapy effects maybe noted bilater- Radiation therapy attempts to destroy tumor cells with ally even if the tumor is unilateral. minimal damageto normal tissue. However, any cells in Sufficiently high radiation doses cause ameloblast and the path of an external radiation beamor near implanted odontoblast death regardless of their position in the cell radioisotopes maybe affected. External radiation creates cycle. Even nonproliferating odontogenic precursor cells deep penetrating gammaand X-ray photons, and internal radioisotopes create gammaand X-ray photons and beta IRadiationtherawI particles. These particles damageDNA and amino acids, I(;hem°therapyl CELL CYCLE either directly by ionizing critical structural molecules,or indirectly by first ionizing intracellular water. Cell sensitivity to radiation depends upon its location in the cell cycle during irradiation. Cells are most suscep- tible to damageduring increased mitotic activity in phase M, G1 and G2 (Fig 1). However, very high dose radiation affects even nonproliferating cells in phase G0.4 This article is a work of the United States Government and may be reprinted without permission. Opinions expressed therein, unless otherwise specifically indicated, are those of the author., and does not not purport to express views of the United States Armyor any other Fig 1. Cell cycle with radiation-specific and chemotherapy- Department or Agency of the United States Government. specific sites of action. 6 Pediatric Dentistry: January/February,1993 - Volume15, NumberI (second and third molars in an infant) are destroyed, re- Low-dose radiation effects noted in enamel appear to sulting in complete tooth agenesis. Partially formed teeth be due to damage to the underlying dentin and not to have remaining development halted, resulting in tooth direct ameloblast injury. Nucleation of enamel crystals and root agenesis.6'7 requires a properly mineralized dentin substrate. Enamel Lower radiation doses cause sublethal changes which crystals theoretically grow from existing dentin crystals at vary with both radiation amount and cellular mitotic ac- the dentinoenamel interface. Or, dentin crystals actually tivity. Minimal doses causing localized dental defects in may grow into the enamel matrix to induce enamel crystal animal models range from 200 R8 to 5000 R.9 Human formation.15~17 Abnormal osteodentin alters dentinogenesis, dental development shows localized damage at 400 R.10 which alters the mineralization of enamel. Enamel hypo- The radiation threshold at which odontogenic cell death plasias over the defective dentin are the result. instead of cell damage occurs is unknown. Odontoblasts are most susceptible to low-dose radia- Chemotherapy tion just before initiating dentin matrix formation.9"11 These Chemotherapy also attempts to destroy tumor cells, presecretory odontoblasts are proliferating rapidly and with minimal toxicity to normal cells. Chemotherapy is have increased mitotic activity.12 Mature secretory odon- selectively toxic to actively proliferating cells by interfer- toblasts and ameloblasts are not affected by low-dose ra- ing with DNA synthesis and replication, RNA transcrip- diation. Histologically, irradiated presecretory odonto- tion, and cytoplasmic transport mechanisms. Since tu- blasts change from columnar to cuboidal shape. Mitotic mors consist primarily of rapidly proliferating cells, they activity ceases, although the cells do not die." Osteodentin" are more susceptible to chemotherapy. forms between the arrested odontoblasts and the pulp. Chemotherapeutic agents are either cell cycle phase The osteodentin is secreted by osteoblast-like cells origi- specific or cell cycle phase nonspecific (Table). Phase-spe- nating from undifferentiated pulp mesenchyme. The pulp cific agents interfere with DNA synthesis (S phase) or cell mesenchyme forms these cells either due to direct radia- division (M phase). They include antimetabolites tion damage, or due to induction by the damaged odonto- (methotrexate, mercaptopurine, thioguanine, cytarabine, blasts.13 The osteodentin is visible microscopically as a azacytidine, fluorouracil, procarbazine, and hydroxyurea), " niche" in the dentin, or as a wavy, irregular dentinoenamel vinca alkaloids (vincristine and vinblastine) junction.8 It is delineated from normal dentin both apically podophyllotoxins (VP-16, VM-26), and asparaginase. and incisally, indicating that only presecretory odonto- Phase nonspecific drugs are toxic to cells in aU phases of blasts are damaged by low-dose radiation (Fig 2). the active cell cycle. The only cells not affected are Osteodentin also differs chemically from normal den- nonproliferating cells (G0 phase). These agents interfere tin. In normal dentin, phosphorylated phosphoprotein with DNA replication by cross Unking DNA bases.18 Non- (PP-H) is the predominant noncollagenous protein. PP-H specific agents include alkylators (nitrogen mustard, cy- initiates hydroxyapatite nucleation, an early step in clophosphamide, chlorambucil, busulfan, melphalan), dentinogenesis.14 PP-H is reduced significantly in nitrosureas (BCNU, CCNU), antibiotics (actinomycin D, osteodentin, altering its ability to initiate dentinogenesis doxorubicin), DTIC, and cisplatin.19 and resulting in shortened, thin, tapered roots. Since tumor cells replicate asynchronously, they are not all in susceptible phases during the initial chemo- therapy exposure. Chemotherapeutic agents are elimi- nated rapidly, and a single dose does not affect tumor cells entering a susceptible phase at a later time. Furthermore, chemotherapy works on first order kinetics, in which only a percentage of cells are killed with each dose, leaving some undamaged cells. Chemotherapeutic agents are therefore administered in multiple (fractionated) doses, so that tumor cells unaffected by the first dose are de- stroyed by following doses. Dental Sequelae to Chemotherapy Chemotherapy damage is related directly to the doses and repetition of the various agents. Odontoblasts and ameloblasts in susceptible phases of the cell cycle are dam- aged easily. Cells in nonproliferative, germinal stages (sec- ond or third permanent molars in the infant) are unaf- Fig 2. Radiation therapy-induced dentin niche. N = niche, D = fected and should develop normally. This differs from dentin, ES = enamel space, P = pulp mesenchyme. Osteodentin high-dose radiation therapy, in which even non-prolifer- visible in the niche defect (microphotograph couresy of Dr. ating dental cells maybe destroyed. Furthermore, although Hanna S. Koppang, University of Oslo). radiation only affects cells in its path, chemotherapy is Pediatric Dentistry: January/February, 1993 - Volume 15, Number 1 7 Table. Chemotherapeuticagents Some chemotherapeutic agents also affect mature secre- Cell CyclePhase Specific Cell CyclePhase Nonspecific tory odontoblasts and amelo- blasts. Vinblastine and vincris- Antimetabolites Alkylators ARA-C(Cytarabine) tine disrupt cytoplasmic Busulfan microtubulesof the intracellu- 5-Fluorouracil Chlorambucil lar transport system.~6,27 Inter- 6-Mercaptopurine Cytoxan