Dental abnormalities in children after chemotherapy treatment for acute lymphoid leukemia

Leukemia Research 27 (2003) 45–50

Dental abnormalities in children after chemotherapy treatment for acute lymphoid leukemia Eliana Maria Minicucci a,∗ , Luiz Fernando Lopes b , Adalberto José Crocci c a

Department of Pathology, School of Medicine of Botucatu, São Paulo State University, São Paulo, SP, Brazil b Department of Pediatrics of the Cancer Hospital, São Paulo, SP, Brazil c Department of Statistics, Bioscience Institute of Botucatu, São Paulo State University, São Paulo, SP, Brazil Received 15 September 1998; accepted 27 April 2002

Abstract The frequency of dental abnormalities, such as delayed dental development, microdontia, hypoplasia, agenesis, V-shaped root and shortened root was evaluated in 76 acute lymphoblastic leukemia (ALL) pediatric patients who had been off chemotherapy for 6 months. These children had been subjected to one of the three Brazilian Protocols or the BFM86 Protocol. The patients were divided into three groups: Group I (GI; high risk) treated with one of the three Brazilian Protocols who received high-dose chemotherapy, intensive maintenance and cranial radiotherapy; Group II (GII; low risk) who were also treated with one of the three Brazilian Protocols using low-intensive chemotherapy with no radiotherapy; and Group III (GIII) based on the BFM86 Protocol. Of 76 children, 13 showed no dental abnormalities (8 were at the age of tooth formation). The remaining 63 children (82.9%) showed at least one dental anomaly. The abnormalities were probably caused by the type, intensity, frequency of the treatment and age of the patients at ALL diagnosis and this might have important consequences for the children’s dental development. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Odontogenesis drugs effects; Antineoplastic agents adverse effects; Chemotherapy dental abnormalities; Late effects of ALL treatment

1. Introduction Acute lymphoblastic leukemia (ALL) is a hematological malignancy that predominantly affects children up to the age of 14 years. In this period, odontogenesis occurs beginning in the fourth week of uterine life and finishing around the age of 21 years. Chemotherapy and cranial radiotherapy are the treatment modality that has been widely used for ALL. However, since chemotherapy and radiotherapy are administered during the age of tooth formation, they might affect stages of odontogenesis. The radiosensitivity of developing teeth has been demonstrated in animal models. Mature ameloblasts are permanently damaged by 10 Gy of radiation halting tooth development from the time the teeth are irradiated. Radiation damage occurs simultaneously in the bone, periodontal ligament and pulp. Radiation effects on teeth are limited to the irradiated area [1]. The nature and severity of the potential side effects of radiation on developing teeth vary with the child’s age at diagnosis, the stage of tooth development, ∗

Corresponding author. Tel.: +55-14-8220982; fax: +55-14-8220982. E-mail address: [email protected] (E.M. Minicucci).

the doses and schedules of treatment and the anatomic region treated. The principal dental abnormalities caused by radiation include destruction of the tooth germ with failure of tooth development, stunted growth of the whole tooth or root, incomplete calcification, tapering roots, etc. [1–11]. Chemotherapy attempts to destroy tumor cells with minimal toxicity on normal cells. Chemotherapy is selectively toxic to actively proliferating cells by interfering with DNA synthesis and replication, RNA transcription and cytoplasmic transport mechanisms [4]. Although chemotherapy is a systemic treatment for malignant diseases, it may have effects on the oral cavity regardless of the local and type of neoplasia. The most common effects observed are: mucositis [12–14], temporary xerostomia [14], infection [14], gingival hemorrhage [13] and dental abnormalities [4]. Chemotherapy interferes with the cell cycle and with intracellular metabolism and in the teeth may thereby cause retarded dental development, microdontia, enlarged pulp chamber and root stunting [4]. These dental abnormalities are more frequent in patients with leukemia, solid tumors and other malignant diseases treated with chemotherapy only or chemotherapy and radiotherapy [4,13,15–21]. The

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E.M. Minicucci et al. / Leukemia Research 27 (2003) 45–50

nature and extent of dental sequelae vary with the type of drugs used, their doses and the frequency of treatment cycles [1], as well as the age of the patient at diagnosis [4].The abnormal maxillary (hypo-development of the jaws) and dental development (hypodontia) may be caused either by the direct effect of chemotherapeutic drugs or by an indirect effect induced by the growth hormone deficiency [22,23]. Cyclophosphamide is a cytostatic agent used in cancer therapy that acts as an alkylating agent that cross-links the guanine bases in double stranded DNA, thus inhibiting cell division or causing mutations. Such an effect on the sensitive odontogenic mesenchymal cells apparently interferes with dentine formation and, if the lesion is sufficiently severe, with enamel formation [4,24–28]. The study of the rat incisors using the colchicine technique and tritiated thymidine showed that the cells in the internal enamel epithelium were not always homogeneous regarding epithelium cell proliferative activity. In addition, this study showed that a higher number of mitoses occurred in the apical extremity of the pulp and that the highest concentration of mitoses occurred adjacent to the terminal odontogenic epithelium [29,30]. Karim and co-worker also observed osteodentin formation in the rat incisors after adriamycin administration [31,32]. The aim of this study is to determine the frequency of the different types of dental abnormalities in pediatric patients diagnosed with ALL who were treated with chemotherapy and with or without cranial radiotherapy. 2. Materials and methods 2.1. Patients Two hundred and eighty children with were admitted to the Department of Pediatrics of the Cancer Hospital in

São Paulo, Brazil, from January 1980 to December 1990. One hundred and twenty-four of them who had been off chemotherapy for at least 6 months were contacted to participate in this study. Of these 76 responded and were available. 2.2. Clinical and radiographic evaluations Clinical evaluation—dental conditions, such as caries, restorations, absent teeth and extracted teeth were evaluated. The dental abnormalities, such as hypoplasia, microdontia and other clinically detected odontological abnormalities were evaluated. For the radiographic evaluation, roentgenograms (incisors, premolars and molars) and a panoramic radiograph were carried out. Delayed dental development was established by comparing chronological and dental age using the chronology table of dental eruption (Schroeder and Massler) [38]. The frequency of the different types of dental abnormalities were based on dental and radiographic exams carried out 2–13 years (mean age 5.4 years) after diagnosis of ALL. The age after treatment was completed and the first dental exam was 0.6–9.0 years (mean age 2.9 years). 2.3. Protocols of treatment From January 1980 to December 1990, four protocols were used for the treatment of ALL children in the Department of Pediatrics at the Cancer Hospital using the three Brazilian Cooperative Protocols (ALL 1980, 1982 and 1985) [33] or the BFM86 Protocol [34]. Details of the protocols can be seen in Table 1. The patients seen between January 1980 and December 1987 were treated using one of the three Brazilian Cooperative Protocols, assessing risk factors based on laboratory and clinical data. In this study, the patients were divided into three groups: Group I (GI; high

Table 1 ALL Cooperative Protocols—Cancer Hospital, São Paulo, Brazil and BFM Protocol Protocol

Induction

CNS-profilaxis

ALL-80 Low risk High risk

P, V, D P, V, D, CTX

Rxt 18 or 24 Gy Rxt 24 Gy

ALL-82 Low risk High risk

P, V, D P, V, D, CTX

Rxt 18 Gy + MADITb Rxt 24 Gy + MADITb

l-ASP + ARA C l-ASP + ARA C

6-MP + MTX, VM26 + ARA C, CTX + DOXO 6-MP + MTX, VM26 + ARA C, CTX + DOXO

ALL-85 Low risk High risk

P, V, D P, V, D

Rxt 18 Gy or MADITa Rxt 24 Gy + MADITb

l-ASP + ARA C l-ASP + ARA C

6-MP+ MTX, DEXA + VCR, VM26 + ARA C Rotating 6-MP + MTX, VM26 + ARA C, DEXA + VP16 + VCR

P, V, D, l-ASP

High dose MTX, no Rxt

6-MP+ MTX

P, V, D, l-ASP

High dose MTX, Rxt 12 Gy

P, V, D, l-ASP

High dose MTX, Rxt 18 Gy

CTX + ARA C+ 6-MP + MADIT CTX + ARA C + 6-MP + MADITa CTX + ARA C + 6-MP + Rxt 18 Gy

BFM-86 Standard risk group Risk group Experimental group a b

Consolidation

Maintenance 6-MP + MTX, CTX + DOXO 6-MP + MTX, CTX + DOXO

MADIT (intrathecal MTX + ARA C + DEXA)—included during maintenance. MADIT until the end of the Rxt.

6-MP + MTX 6-MP + MTX, Protocol S ((IFO + ARA C + P + VM26 + VELBAN) for 4 weeks) + 6-MP + MTX

E.M. Minicucci et al. / Leukemia Research 27 (2003) 45–50

risk), Group II (GII; low risk) and Group III (GIII; based on the BMF86 Protocol). The children in GI were subjected to high-dose chemotherapy during the maintenance with the administration of VM26 + ARA C, MTX + 6-methyl mercaptopurine (MP), VP16 + DEXA + VCR, and then to three other pairs of drugs rotated every 4 weeks for 2 years. These patients were also subjected to cranial radiotherapy. The children in GII (low risk) received low-intensive chemotherapy with no cranial radiotherapy. The treatment of children in GIII was based on the BMF86 Protocol with the administration of high doses of methotrexate (MTX) as CNS prophylaxis with no radiotherapy during induction and re-induction, while during maintenance they received MTX + GMP for 18 months. The cranial radiotherapy that was carried out on the risk group (12 Gy—dose as 18 Gy if CNS positive) and on the experimental group (18 Gy—dose as 24 Gy if CNS positive); patients less than 1 year of age did not receive Rxt even with overt CNS disease; children aged between 1 and 2 years received 12 or 18 Gy if CNS positive. 2.4. Statistical analysis The Goodman Test [35] was used to compare the frequency of dental abnormalities between the three chemotherapy groups with significance of 5%.

3. Results The 76 children treated (43 male and 33 female), were 1–12 years old (mean age 5.1 years) in the beginning of ALL treatment. The mean age of these patients in the period of study was 10.7 years. Thirteen patients (17.1%) showed no dental abnormalities, of which eight were at the age of dental formation. The remaining 63 children (82.9%) had at least one dental abnormality. The frequency of the abnormalities was highest in GII and less in GIII and GI, respectively (Table 2). The relationship between the frequency of dental abnormalities and the total number of children in each group was in GII 87.5%, in GIII 85.7% and in GI 78.1% (Table 2). GII showed a higher number of dental abnormalities. The age of the children in this group was lower. GIII received

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Fig. 1. Hypoplasia.

high-dose chemotherapy for the first 6 months. GII and GIII received MTX and 6-methyl mercaptopurine (6-MP) for 72 and 96 weeks, respectively. GI showed fewer dental abnormalities (78.1%) in comparison to GII and GIII, and in this group 50% of the children were between 1 and 6 years of age at ALL diagnosis (Table 2). In GI, the children received cranial radiotherapy and pairs of drugs over the period of 120 weeks without the constant administration of MTX and 6-MP during maintenance. When comparing the total number of children and the number of affected teeth, the most common dental abnormalities detected were delayed dental development, hypoplasia and microdontia (Figs. 1–3). Comparing children with dental abnormalities (A) against those without abnormalities (B) reveals statistical significance for late development in GII (A) 83% and (B) 17%, and in GIII (A) 82% and (B) 18%; for microdontia in GII (A) 75% and (B) 25%, and in GIII (A) 73% and (B) 27%, respectively. The proportion of children with dental abnormalities was higher than that without abnormalities (Table 3).

Table 2 The distribution of patients with and without dental abnormalities by age at ALL diagnosis and chemotherapy groups Chemotherapy groups

1–6 years

7–12 years

With alteration

Without alteration

With alteration

GI GII GIII

16 (50.0) 11 (68.7) 16 (57.1)

5 (15.6) 2 (12.5) 4 (14.3)

9 (28.1) 3 (18.7) 8 (28.6)

2 (6.3) – –

Total

43 (56.6)

11 (14.5)

20 (26.3)

2 (2.6)

Percentage values are given in parentheses.

Without alteration

Fig. 2. Pulp chamber (1), shortened and tapered root (2) and delayed dental development. Chronological age: 9 years; dental age: 7 years.

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E.M. Minicucci et al. / Leukemia Research 27 (2003) 45–50

Fig. 3. Microdontia and delayed dental development. Chronological age: 8 years; dental age: 6 years.

When making comparisons between the groups for the number of teeth with abnormalities, statistical significance can be seen for late development comparing GI (16%) with GII (26%), and GI (16%) with GIII (27%); for microdontia comparing GII (18%) with GIII (10%); and for hypoplasia comparing GII (16%) with GIII (28%) (Table 3). The first and the second upper and lower premolars showed a higher incidence of abnormalities. Concerning the number of caries, 44 children showed more than four. However, we cannot confirm that chemotherapy was responsible for caries, since economic factors and oral hygiene may also have been contributory factors.

4. Discussion Dental development may be affected by illness, trauma, chemotherapy [17,18,23,24,36] or radiation therapy [12,16,23,24,36] at any time before complete maturation. Dental abnormalities were detected in survivors of ALL who had received multi-agent chemotherapy with and without cranial radiation. Kaste et al. evaluated 423 children treated for ALL with and without cranial radiation. These authors observed that 50% of the patients in the “radiation” group had dental ab-

normalities, whereas only 25% of the “non-radiation” group showed dental abnormalities. These abnormalities included root stunting, microdontia, hypodontia, enlarged pulp chamber and over-retention of primary teeth. The frequency of these factors was determined in relation to the age at the beginning of treatment, the addition of cranial irradiation and the chemotherapeutic protocol used [36]. In this study, the higher frequency of dental abnormalities was observed in GII where the children were only subjected to chemotherapy. Most of them (68.7%) were between 1 and 6 years of age at ALL diagnosis (Table 2). Between these ages, dental development is very active; therefore, in this group the chemotherapy might have directly affected dental development. With regard to the type of dental abnormalities, microdontia and delayed dental development, which are more frequently caused by chemotherapy alone, a higher incidence was seen in GII and GIII. The results shown in Table 2 suggest that the causative factor of dental abnormalities in GI was the frequency with which chemotherapeutic drugs were administered during 120 weeks of treatment period. However, radiation therapy cannot be excluded, although the teeth were outside the field of irradiation. Kaste et al. reported that of the 423 patients evaluated only 39% had dental abnormalities [36]. In our study, 82.9% of the patients had at least one dental abnormality. With regard to the groups treated with chemotherapy alone, Kaste et al. reported that only 25% of the patients showed dental abnormalities, while our results demonstrated that GII (87.5%) had the highest incidence. In this study, the dental abnormalities were different depending on the protocols used. Hypoplasia (Fig. 1), shortened root (Fig. 2), were more common in GI. Microdontia and delayed dental development (Figs. 2 and 3) showed higher incidence in GII and GIII. Hypoplasia is caused by a disturbance of ameloblasts during tooth formation expressed by alterations of ameloblastic reproduction, secretory function, membrane permeability and calcium exchange across the cell membrane, being manifested clinically by enamel opacities [4]. These alteration are significantly more common in children surviving cancer than in their siblings. Children who had been treated for ALL seemed to be more severely affected and this may be reflected in the longer duration of therapy leading to a greater risk of affecting developing ameloblasts [16,19,37].

Table 3 The frequency of the principal dental abnormalities compared with the chemotherapy groups and the number of children with abnormalities (A) and without abnormalities (B), and number of teeth with abnormalities (C) and normal teeth (D) Group

GI GII GIII

Number of patients

Number of teeth

Late development

Microdontia

Hypoplasia

A

B

A

B

A

11 (61) 10 (83) 18 (82)

7 (39) 2 (17) 4 (18)

11 (61) 6 (75) 11 (73)

7 (39) 2 (25) 4 (27)

13 (65) 5 (71) 7 (64)

Percentage values are given in parentheses.

Late development

Microdontia

Hypoplasia

B

C

D

C

D

C

D

7 (35) 2 (29) 4 (36)

36 (16) 45 (26) 117 (27)

186 (84) 131 (74) 322 (73)

21 (12) 19 (18) 12 (10)

157 (89) 85 (82) 202 (90)

47 (20) 12 (16) 31 (28)

182 (80) 62 (84) 80 (72)

E.M. Minicucci et al. / Leukemia Research 27 (2003) 45–50

Histological studies showed changes in dental morphology induced by a high-dose chemotherapy and total irradiation in patients. These studies also showed that chemotherapy mainly induces qualitative disturbances in dentine and enamel, whereas total body irradiation induced both qualitative and quantitative changes [16]. Enlarged pulp chambers represent a delay in the development and proper positioning of Hertwig’s root sheath after formation of the tooth crown resulting in the apical displacement of the pulpal floor and bifurcation area. This abnormality most frequently affects molars but has been reported in premolars. The clinical importance of enlarged pulp chamber lies in the thinned and shortened root structure of the affected teeth. Early-age chemotherapy may retard the development of Hertwig’s root sheath by interfering with epithelio-mesenchymatose induction during the odontogenesis process [36]. Altered odontoblastic activity, a consequence of the abnormal secretory function of microtubules and of complex changes in inter- and intra-cellular relationships, can produce shortened, thinned and blunted roots [4]. Repetitive high doses of some chemotherapeutic agents may result in root agenesis. Intensive, repetitive chemotherapy at the time of initial hard tissue formation may cause tooth agenesis [4]. Studies in rats have established that chemotherapeutic agents used to treated patients with ALL delay or disrupt odontogenesis, as shown by the increased number of incremental lines and deranged pronunciation of dentinal matrix after the administration of these drugs [28]. We observed that dental age was delayed in relation to chronological age. Of the 13 children without dental abnormalities, 11 were between 1 and 6 years of age at ALL diagnosis (Table 2) and 8 were at the age of tooth formation, and thus they may develop dental abnormalities in the future. The teeth with higher incidence of abnormalities were the first and second upper and lower premolars, maybe because their development begins when children are 2 years old. In our study, the children were between 1 and 6 years of age at the time of ALL diagnosis and the beginning of chemotherapy. From the results obtained, it can be suggested that dental abnormalities are related to the stage of dental development. These dental abnormalities may be directly related to the children’s age at the beginning of chemotherapy, as well as to the type, intensity and frequency of the drugs administered. Dental abnormalities are common in pediatric patients treated for ALL, who then require dental follow-up. Some dental abnormalities may have important consequences for these children, such as aesthetic, functional and occlusal disturbances. Nowadays, modern therapeutic procedures enable better detection of dental abnormalities. Dentists should understand about these dental abnormalities, as well as learn how to handle them to help provide their patients with a better quality of life.

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Acknowledgements We wish to thank Dr. Daisy Maria Fávero Salvadori for critical reading of the manuscript, Dr. Luis Marcelo Sˆeneda, Miss Yara Pinto Chaves, Mrs. Helo´ısa Maria Pardini Toledo, Miss Ana Em´ılia Costa da Fonseca, and Dr. José Carlos Neiva C. Silva for technical assistance. E.M. Minicucci and L.F. Lopes contributed equally to the concept, design, assembly of data, analysis of data, drafting and revising the manuscript and giving final approval. A.J. Crocci provided the statistical expertise and assisted with data analysis and interpretation. References [1] Kaste SC, Hopkins KP, Jenkins JJ. Abnormal odontogenesis in children treated with radiation and chemotherapy, imaging findings. Am J Roentgenol 1994;162:1407. [2] Engelmeier RL, King GE. Complications of head and neck radiation therapy and their management. J Prosthet Dent 1983;49:514. [3] Fromm M, Littman P, Raney RB, Nelson L, Handler S, Diamond G, et al. Late effects after treatment of 20 children with soft tissue sarcomas of the head and neck. Cancer 1986;57:2070. [4] Goho C. Chemoradiationtherapy: effect on dental development. Pediatr Dent 1993;15:6. [5] Goodman ED, Iuks AB. The effects of anti-leukemia therapy on the developing dentition: case report. Pediatr Dent 1985;7:318. [6] Gorlin RJ, Meskin LH. Severe irradiation during odontogenesis: report of a case. Oral Surg Oral Med Oral Pathol 1963;16:35. [7] Hazra TA, Shipman B. Dental problems in pediatric patients with head and neck tumors undergoing multiple modality therapy. Med Pediatr Oncol 1982;10:91. [8] Karim AC, Eddy EL. A light and electron microscopic study of osteodentin formation in the rat incisor after adriamycin administration. Am J Anat 1984;169:207. [9] Maxymiw WG, Wood RE. The role of dentistry in head and neck radiation therapy. J Can Dent Assoc 1989;55:193. [10] Petrokovski J, Menezel J. Tooth dwarfism and root underdevelopment following irradiation. Oral Surg Oral Med Oral Pathol 1966;22:95. [11] Weyman J. The effect of irradiation on developing teeth. Oral Surg Oral Med Oral Pathol 1968;25:263. [12] Rosemberg SW. Oral complications of cancer chemotherapy—a review of 398 patients. J Oral Med 1986;41:93. [13] Rosemberg SW, Kolodney H, Wong GY, Murphy ML. Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. Cancer 1987;59:1640. [14] Williams MC, Martin MV. A longitudinal study of the effects on the oral mucosa of treatment for acute childhood leukemia. Int J Pediatr Dent 1992;2:73. [15] Dahllof G, Nasman M, Borgstrom A, Modeer T, Forsberg CM, Heimdahl A, et al. Effect of chemotherapy on dental maturity in children with hematological malignancies. Pediatr Dent 1989;11:303. [16] Dahllof G, Rozell B, Forsberg CM, Borgstrom B. Histologic changes in dental morphology induced by high-dose chemotherapy and total body irradiation. Oral Surg Oral Med Oral Pathol 1994;77:56. [17] Jaffe N, Toth BB, Hoar RE, Ried HL, Sullivan MP, McNeese MD. Dental and maxillofacial abnormalities in long-term survivors of childhood cancer. Effects of treatment with chemotherapy and radiation to the head and neck. Pediatrics 1984;73:816. [18] Macleod RI, Welbury RR, Soames JV. Effects of cytotoxic chemotherapy on dental development. J R Soc Med 1987;80:207. [19] Maguire A, Craft AW, Evans RGB, Aminiddine H, Kernahan J, Macleod RI, et al. The long-term effects of treatment on the

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