Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities

Dentofacial Development in Long-Term Survivors of Acute Lymphoblastic Leukemia A Comparison of Three Treatment Modalities Andrew L. Sonis, DMD,**tNancy Tarbell, MD,*$ Richard W. Valachovic, DMD,*st Richard Gelber, PhD,§ Molly Schwenn, MD, 11 and Stephen Sallan, MD*f§ Ninety-seven children who were diagnosed with acute lymphoblastic leukemia before 10 years of age and treated with chemotherapy alone, chemotherapy plus 1800-cGy cranial irradiation (RT), or chemotherapy plus 2400-cGy RT were evaluated for effects of therapy on dentofacial development. All patients were seen at least 5 years postdiagnosis. Dental abnormalities were determined from panoramic radiographs, and craniofacial evaluations were made from lateral cephalometric radiographs. Ninety-one (94%) of all patients and 41 (100%) of patients younger than 5 years of age at diagnosis had abnormal dental development. The severity of these abnormalities was greater in children who received treatment before 5 years of age and in those who received RT. Observed dental abnormalities included tooth agenesis, arrested root development, microdontia, and enamel dysplasias. Craniofacial abnormalities occurred in 18 of 20 (90%) of those patients who received chemotherapy plus 2400-cGy RT before 5 years of age. Mean cephalometric values of this group showed significant deficient mandibular development. The results of this study suggest that the severity of dentofacialdevelopmental abnormalities secondary to antileukemia therapy are related to the age of the patient at the initiation of treatment and the use of cranial RT. Cancer 662645-2652,1990.

As

THE PROGNOSIS for childhood acute lymphoblastic leukemia (ALL) has improved, more attention has been focused on .the effects of therapy on the developing child. We previously reported on the high incidence of acute oral complications in this age group.' The lack of specificity of both chemotherapeutic agents and radiation therapy (RT) in terms of differentiating neoplastic cells from metabolically active normal cells might result in abnormalities of dental and facial development.2-6In addition to the direct effects of therapy on growing cells, an indirect effect might also occur due to

altered hypothalmic-pituitary function resulting in diminished growth hormone produ~tion.~-" This in turn may also adversely effect odontogenesis and craniofacial development. Currently, several different therapeutic regimens are used in the treatment of ALL: chemotherapy with and without varying doses of RT. We compared retrospectively the effects of three treatment approaches on dental and craniofacial development. Materials and Methods

Patients From the *Children's Hospital, tHarvard School of Dental Medicine, $Joint Center for Radiation Therapy, §Dana Farber Cancer Institute, and IJNewEngland Medical Center Floating Hospital, Boston, Massachusetts. Address for reprints: Andrew L. Sonis, DMD, The Children's Hospital, 300 Longwood Avenue, Boston, MA 02 1 15. Accepted for publication July 2, 1990.

Ninety-seven children who were diagnosed with ALL between 1973 and 1983, were younger than 10 years of age when therapy began, and remained in continuous remission were studied. All patients were evaluated at least 5 years after diagnosis.

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Antileukemia Treatment All patients received various combinations of chemotherapeutic agents given by previously described protocols.I2-l4 Central nervous system treatment consisted of either: (1) intrathecal methotrexate (IT MTX) alone (n = 19), (2) IT MTX plus 1800-cGy cranial RT (n = 27), or (3) IT MTX plus 2400-cGy cranial RT (n = 51). All radiation therapy was given on 4 to 8-MV linear accelerators, primarily in 200-cGy fractions with opposed lateral fields using a clinically placed lens block. The inferior border of the field was positioned along a line from the inferior orbital ridge to the middle of the second cervical vertebra (Fig. 1). All patients were treated isocentrically.

I I1 111 IV V VI VII VIII IX

Vol. 66 Dental Disturbance Classification and Seventy Rating Scale Classification

Severity rating

Normal root development Arrested root development with shortened tapered V-shaped roots (greater than 50% normal root length) Arrested root development with shortened blunted roots (less than 50% normal root length) Anomalies in root number Arrested root development (total) Normal crown development Enamel hypoplasia diagnosed as notches on proximal surfaces Microdontia Agenesis

0 1

3 1

5 0 2 4 6

Dental Evaluation Panoramic radiographs were obtained on all patients and examined for dental abnormalities. Disturbances in development were classified using a modification of the system developed by Dahllof and c o - ~ o r k e r s(Table '~ I). A dental-disturbance severity scale was developed to permit a comparison between groups using stratified Wilcoxon rank-sum tests of significance. Abnormalities in maxillary lateral incisors, third molar development and agenesis of second premolars were excluded from the study because these occur with a relatively high frequency in a normal population.

FIG. 1. Typical cranial field for CNS prophylaxis. The field includes the entire cranial meninges. The inferior border of the fields are positioned along a line extending from the inferior orbital ridge to approximately I cm below the mastoid tip to the middle ofthe second cervical vertebra.

Crmiofacial Analysis Standardized lateral cephalometric radiographs were obtained on all patients. Each film was digitized,and linear and angular variables were computed and compared with established normal values. Cephalometricreference points included sella (S), nasion (N), porion (Po), orbitale (Or), subspinale (A), supramentale (B), D point (D), gnathion (Gn), gonion (Go), and condylion (Co) (Fig. 2). Cephalometric reference planes, angulations, and linear measure-

-

/

FIG.2. Reference landmarks for cephalometric analysis. 1: Sella (S), center of sella tursica; 2: Nasion (N), intersection of the frontal bone with the nasofrontal suture in the midsagittal plane; 3: Porion (Po), highest point on the upper margin of external auditory meatus: 4: Orbital (Or), deepest point on the infraorbital margin; 5: Subspinale (A), most posterior point on the concavity between the anterior nasal spine and prosthion; 6 : Supramentale (B),most posterior point on the concavity between pogonion and infradentale; 7: D point (D), center of mandibular symphosis in midsagittal plane. 8: Gnathion (Gn), lowest and most fonvard point on hard tissue chin; 9: Gonion (Go), lowest most posterior point on mandible with teeth in occlusion; 10: Condylion (Co), highest point on outline of mandibular condyle.

LONG-TERMSURVIVORS OF ALL

No. 12 TABLE 2.

Treatment and age at diagnosis Group 1: no irradiation 5 yr of age (1 1 patients) Group 3: 1800 cGy t 5 yrofage(13 patients) Group 4: 1800 cGy >5 yr of age (14 patients) Group 5: 2400 cGy t 5 yr of age (20 patients) Group 6: 2400 cGy >5 yrofage(31 patients) Total

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Type and Distribution of Dental Disturbances According to Treatment and Age at Diagnosis Type 111: blunted roots

Type IV: altered root

8 (100%)

1 (12%)

4 (36%)

Type 11: V-shaped

Mean disturbance severity rating

Type V: total root

Type VII: enamel hypoplasia

Type VIII: microdontia

Type IX: agenesis

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

1.38

1(9%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0.64

13 (100%)

9 (69%)

7 (54%)

0 (0%)

5 (38%)

3 (23%)

0 (0%)

5.31

9 (64%)

5 (36%)

8 (57%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

2.29

20 ( 100%)

20 ( 100%)

17 (85'70)

20 ( 100%)

19 (95%)

15 (75%)

5 (25%)

16.25

3 1 (100%)

24 (77%)

14 (45%)

3 (9.7%)

3 (9.7%)

3 (9.7%)

0 (0%)

4.85

85 (88%)

60 (62%)

46 (47%)

3 (24%)

27 (28%)

21 (22%)

5 (5%)

5.12

roots

ments defined by the above points included SNA, SNB, ANB, SND, Pog:NBmm, GoGn to SN, GoGn(mm), GoGn minus GoCo(mm), and GoGn to Co. Results

Group 1 (Patients Younger Than 5 Years ofAge at Diagnosis M 'ho Received No Radiation Therapjd This group consisted of five girls and three boys with a mean age at the time of examination of 13 years 2 months (range, 9 years 2 months to 15 years). All eight patients had dental-developmental disturbances which included abnormal root form of the maxillary and/or mandibular premolars and canines (V-shaped); one patient had blunting of the maxillary and mandibular second premolar roots (Table 2). The mean disturbance severity rating for this group was 1.38. There was no statistically significant difference in mean cephalometric values for this group compared with normal values.

Group 2 (Patients 5 Years of Age or Older at Diagnosis Who Received No Radiation Therapy) This group consisted of seven girls and four boys with a mean age at the time of examination of 14 years 1 month (range, 8 years 11 months to 14 years 1 1 months). Five of 1 1 (45%) of these patients had dental-developmental disturbances which consisted of V-shaped roots (36%)and blunted roots (9%)(Table 2). These involved the maxillary and mandibular canines, premolars, and second molars. This group had the lowest mean disturbance severity rating (0.64). There was no statistically significant difference

in cephalometric values for this group compared with normal values.

Group 3 (Patients Younger Than 5 Years ofAge at Diagnosis Who Received 1800-cGy Cranial Radiation Therapy) This group consisted of eight girls and five boys who had a mean age at the time of examination of 11 years 9 months (range, 8 years 2 months to 13 years 9 months). All 13 patients had dental disturbances. All had V-shaped roots of several permanent teeth, nine (69%)had blunting of the roots of the maxillary and/or mandibular premolars or molars, and seven (54%) had altered root number, most commonly of the permanent mandibular second molar. Additionally, five (38%)had enamel hypoplasia, and three (23%) had microdontia (Table 2). The mean cephalometric values for this group were all within one standard deviation of normal values.

Group 4 (Patients 5 Years of Age or Older at Diagnosis Who Received 1800-cGy Cranial Radiation Therapy) This group consisted of eight girls and six boys who had a mean age at the time of examination of 1 1 years 1 1 months (range, 8 years 2 months to 14 years 1 month). All 14 of these patients had dental-developmental disturbances. Root anomalies were most commonly observed as being V-shaped, blunted, or altered in number (Table 2). Teeth most often affected were the maxillary and mandibular canines, premolars, and second molars. The mean cephalometric values for this group were all within one standard deviation of normal values.

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FIG.3. Representative panoramic radiograph of patient younger than 5 years of age at diagnosis who received chemotherapy only (no RT). Notice V-shaped roots of mandibular canine and premolar teeth.

Group 5 (Patients Younger Than 5 Years of Age at Diagnosis W'ho Received 2400-cGy Cranial Rudiuiion Them& This group consisted of 14 girls and six boys who had a mean age at the time of examination of 9 years 2 months (range, 8 years 1 month to 10 years 3 months). This group had the most severe dental-developmental disturbances. All 20 patients had total root arrest, five (25%) had agenesis, and 15 (75%) had microdontia (Table 2). The teeth most often affected were the maxillary and mandibular canines, premolars, and first and second molars. All cephalometric values were within one standard deviation of normal values, except those involving mandibular measurements (Table 3). Eighteen patients had significantly altered measurements indicative of an underdeveloped mandible including SNB (74.2) (normal, SO), ANB (7.9) (normal, 2), SND (71) (normal, 76), GoGn (mm) (62) (normal, 70 to 86), and GoGn minus GoCo (mm) (13.1) (normal, 21).

Group 6 (Patients 5 Years of Age or Older at Diagnosis Who Received ,7400-cGy Radiation Therap)? This group consisted of 19 girls and 12 boys who had a mean age at the time of examination of 15 years I month (range, of 12 years 4 months to 16 years 2 months). All 3 1 patients had dental-developmental disturbances, most commonly resulting in V-shaped or blunted roots. Three patients had total root arrest and microdontia (Table 2). The teeth most commonly affected were the max-

illary and mandibular canines, premolars, and first and second molars. All cephalometric values were within one standard deviation of normal values. These six patient groups were compared with respect to the severity of the dental-disturbance scores using twosided, stratified Wilcoxon rank-sum tests of significance. Patients who were younger than 5 years of age at diagnosis and initial treatment had statistically significantly higher scores than older patients (mean score, 9.9 versus 3.4; P < 0.000 1, stratified by RT group). Patients who received 1800-cGy cranial R T had higher scores than those who received no radiation (mean score, 3.7 versus 0.9; P = 0.0008, stratified by age). The dental-disturbance scores were higher for the 2400-cGy group (mean score, 9.3) compared with the 1800-cGy group ( P < 0.000 1) and the no RT group ( P < 0.0001). Discussion Our results indicate that current therapies for childhood ALL often result in developmental disturbances of the permanent dentition and craniofacial skeleton. The degree and severity of these defects depend on the child's age at diagnosis, type of central nervous system treatment, and the dose of cranial RT. Children treated before 5 years of age had the most severe dental defects, suggesting that immature teeth were at greater risk for developmental disturbances than mature teeth. Many case reports and animal studies confirm this hypothesis'6-22and suggest that dental defects may be re-

No. 12

LONG-TERM SURVIVORS OF ALL

Sonis et a/.

2649

FIG. 4. Representative panoramic radiograph of patient younger than 5 years of age at diagnosis who received 1800 cGy cranial RT. Notice abnormalities of root morphology, enamel hypoplasia, and microdontia of premolars and second molars. Patient is currently undergoing orthodontic therapy.

lated to chemotherapy, RT, or both. This is consistent with reports of increased toxicity to the other developing tissues and organs including the brain and heart in younger patients with ALL.23324 Chemotherapy without central nervous system RT resulted in the least severe dental disturbances. Abnormalities were limited to atypical root morphology that most commonly involved the maxillary and mandibular premolars in children younger than 5 years of age, and the maxillary and mandibular canines, premolars, and molars in children older than 5 years of age at time of diagnosis. These findings are similar to those reported by Rosenberg and co-authors2' who reviewed 17 pediatric ALL patients treated with chemotherapy alone. Animal studies also show deleterious effects of various chemotherapeutic

agents, including vincristine, cyclophosphamide, and others on dental d e v e l ~ p m e n t . ' ~ - ~ ~ The effects of RT on developing dentition have been well documented.'6-22Doses of 2000 to 4000 cGy in both animals and humans have shown tooth and root dwarfism, root foreshortening, hypoplasia, microdontia, and atypical root morphology. Before morphodifferentiation and calcification, RT may result in arrest of the developing tooth bud. At later stages of development, dental malformations or arrested development have been observed. In a study by Dahllof and c o - ~ o r k e r s ,patients '~ who received total body RT (1000 cGy) and children younger than 6 years of age at the time of treatment had the most severe dental aberrations, including impaired root development, enamel hypoplasia, and microdontia.

FIG.5 . Representative panoramic radiograph of patient younger than 5 years of age at diagnosis who received 2400 cCy cranial RT. Notice agenesis of maxillary second molars, abnormalities of root morphology, and microdontia.

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FIG.6. Representative cephalometric radiograph of patient younger than 5 years of age at diagnosis who received 2400 cGy of cranial RT. Notice retrognathic mandible with normal positioned maxilla.

In our study, the use of RT for central nervous system treatment resulted in an increased incidence of disturbances of dental development in all patients. However, children younger than 5 years of age were affected more severely than older patients, and patients who received 2400 cGy were more severely affected than those who received the 1800 cGy. This was probably due to the relatively high position of the maxillary permanent posterior teeth in young children, which would place those teeth in the direct field of irradiation. Consequently, the teeth TABLE 3. Mean Cephalometric Values for Group V (patient 4 yr; 2400 cGy) Norm

Group V

SNA: 82 SNB: 80 ANB: 2 S N D 76 GoGn to SN: 32 GoGn (mm): 76 GoGn minus GoCo (mm): 2 I GoCn to Co: 123

82.1 74.2* 7.9* 71* 33.1* 62* 13.1* 124

* Significant P < 0.0 1.

most severely involved were the maxillary canine, premolar, and molar teeth. The mandibular permanent posterior teeth, although not in the direct field of irradiation, undoubtedly were exposed to some scattered doses of radiation. It is estimated that teeth located along the edge of the field were exposed to approximately 45% of the administered dose, and teeth which were, at a maximum, 1 cm away from the edge of this field could have received 1% of this dose.34Consequently, the mandibular posterior teeth, which were closer to the field, were more severely affected than mandibular anterior teeth. These data would also suggest that direct radiation doses as low as 18 to 24 cGy, in combination with chemotherapy, adversely affected dental development. Craniofacial effects of therapy were observed in only those children who received 2400 cGy before 5 years of age. Ninety percent of children in this group had diminished mandibular growth as determined by cephalometric analysis. Several other studies examined the effects of RT on the developing craniofacial skeleton. Guyuron and coa u t h o r ~examined ~~ 4 1 patients who received irradiation to the head and face during growth. Thirty-eight of them had soft tissue or bony deformities. An analysis of those

No. 12

LONG-TERM SURVIVORS OF ALL

changes relative to the radiation dose delivered indicated that the harmful dose for soft tissue was as low as 400 cGy and for hard tissue, 3000 cGy. However, because orthovoltage was used in 12 of the patients, doses given were not “dose to bone” which could actually have been two to three times greater. Moreover, because these patients had various head and neck tumors, ages ranging from 1 to 17 years, and treatment consisting of either orthovoltage or megavoltage RT, a comparison of their results with ours was difficult. Studies by Engstrom and c o - ~ o r k e r showed s ~ ~ that RT doses of 2000 to 8000 cGy to the cranial vault of growing rats resulted in significant alterations of craniofacial growth, especially at sites in the irradiated field. The field of irradiation in our patients included a portion of the ascending ramus and the entire condyle of the mandibles. In the growing child, this might adversely affect mandibular development. It would seem, however, that some threshold existed above the dose of 1800 cGy for this phenomenon to occur; it was only observed in patients younger than 5 years of age who received 2400 cGy of cranial RT. Another mechanism might explain the development of altered craniofacial growth. Several authors reported growth failure or growth hormone deficiency in children It is possible that who received cranial RT for altered pituitary function adversely affected craniofacial development. A recent study by Sarnat and co-authors3’ found reduced jaw size in patients with large Laron-type dwarfism, suggesting a role for human growth hormone in normal jaw development. This effect was observed mainly in the mandible, although not to the extent observed in the patients with ALL. Interestingly,an increased prevalence of hypodontia was also observed in these growth hormone-deficient patients. The prognosis for correcting the described craniofacial abnormalities through orthodontic therapy is, at best, guarded. The many dental abnormalities, such as rootless and malformed teeth, often preclude conventionaltherapy and necessitate alternatives from an ideal treatment plan. Moreover, mandibular growth remains retarded, leaving patients with a skeletal disharmony between the two jaws. Conventional orthodontic correction of these problems often relies upon mandibular growth, although an attempt is made to retard maxillary growth therapeutically, allowing the mandible to “catch up” to the maxilla. Because the mandibles of our patients lacked intrinsic growth potential, correction may only be achieved with orthognathic surgery. Our results showed that dental and craniofacial abnormalities were sequellae of successfultherapy for childhood ALL. These abnormalities were presumed to result from the interference of normal orofacial development by various treatment modalities including chemotherapy, RT,

*

Sonis et al.

265 1

and possibly altered pituitary function. The dentofacial disturbances we described and other late side effects of treatment must be balanced against the demonstrated antileukemic efficacy of current therapeutic regimens. REFERENCES 1. Sonis A, Sonis ST. Oral complications of cancer therapy in pediatric patients. J Pedo 1979; 3:122. 2. Brodsky I, Kahn SB, eds. Cancer Chemotherapy 11, ed. 2. New York: Grune and Stratton, 1972. 3. Cline MJ, Haskell CM. Cancer Chemotherapy. New York: Raven, 1975. 4. Lampkin BC, McWilliams NB, Mauer AM. Cell kinetics and chemotherapy in acute leukemia. Semin Hematol 1972; 9:211. 5. Henderson ES. The treatment of acute leukemia. Scmin Hematol 1969; 6271. 6. Holland JF, Glidewill 0. Chemotherapy of acute lyniphocytic leukemia of childhood. Cancer 1972; 30:1480. 7. Blatt J, Bercu BB, Gillin JC, Mendelson WB, Poplack DG. Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia. J Pediatr 1984; 104: 182. 8. Shalet SM, Price DA, Beardwell CG, Moms-Jones PH, Pearson D. Normal growth despite abnormalities of growth hormone secretion in children treated for acute leukemia. J Pediatr 1979; 94:719. 9. Samaan NA, Vieto R, Schultz PN et al. Hypothalmic, pituitary and thyroid dysfunction after radiotherapy to the head and neck. Int J Radiat Oncol Biol Phys 1982; 8:1857. 10. Herber SM, Kay R, May R, Milner RDG. Growth of long-term survivors of childhood malignancy. Acta Paediatr Scand 1985; 74:438. 11. Shalet SM, Gibson B, Swindell R, Pearson D. Effect of spinal irradiation on growth. Arch Dis Child 1987; 621461. 12. lnati A, Sallan SE, Cassady JR ef al. Efficacy and morbidity of central nervous system “prophylaxis” in childhood acute lymphoblastic leukemia: Eight years’ experience with cranial irradiation and intrathecal methotrexate. Blood 1983; 6 1:297-303. 13. Green DM, Freeman AI, Sather HN et a/. Comparison of three methods of central nervous system prophylaxis in childhood acute lymphoblastic leukemia. Lancet 1980; 1:1398-1402. 14. Freeman AI, Weinberg V, Brecher ML et al. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med 1983; 308:477-484. 15. Dahllof G, Barr M, Bolme P et al. Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg 1988; 65:41. 16. Gorlin RJ, Meskin LN. Severe irradiation during odontogenesis: Report of a case. Oral Surg 1963; 46:35. 17. Pietrokouski J, Menezel J. Tooth dwarfism and root underdevelopment following irradiation. Oral Surg 1966; 22:95. 18. Weyman J. The effect of irradiation in developing teeth. Oral Surg 1968; 25:623. 19. Hazra TA, Shipman B. Dental problems in pediatric patients with head and neck tumors undergoing multiple modality therapy. Med Pediatr Oncol 1982; 10:91. 20. Adhns KF. The effect of 1200R on x-irradiation of dentinogenesis in the mandibular teeth of rats. Arch Oral Bid 1967; 12: 1569. 21. Jaffe N, Toth BB. Hoar RE, Reid 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. 22. Donohue WB, Perrault JG. The effect of x-ray irradiation on the growth of the teeth and jaw in kittens. Arch Oral Biol 1964; 9:739. 23. Peylan-Ramu N, Poplack DG, Pizzo PA et a/. Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. N Engl J Med 1978; 298% 15-819.

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