Fourteen children were conditioned with CY and TBI plantation on salivary function, changes in caries-associated. Patients and methods

Transcription

1 Bone Marrow Transplantation, (1997) 20, Stockton Press All rights reserved /97 $12.00 Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study G Dahllöf 1, M Bågesund 1 and O Ringdén 2 Departments of 1 Pediatric Dentistry, 2 Clinical Immunology and Transplantation Surgery, Karolinska Institutet, Stockholm, Sweden Summary: given carefully planned dental prophylaxis including fluorides and chlorhexidine, no increase in prevalence of caries Salivary function, dental caries and caries-associated could be found. 3,5 salivary microorganisms were investigated in children The aim of the present investigation was to study the undergoing BMT during a 4-year longitudinal study. effect of conditioning regimens used in bone marrow trans- Fourteen children were conditioned with CY and TBI plantation on salivary function, changes in caries-associated and 12 with CY with or without BU. Four years after microflora and development of dental caries in children, BMT the mean salivary secretion rate was 1.3 ± 0.7 during a 4-year longitudinal study. ml/min in the chemotherapy, compared to 0.7 ± 0.5 in the TBI/CY (P 0.05). The mean salivary secretion rate fell from 0.9 ± 0.5 ml/min before TBI to 0.2 ± 0.1 after 3 months (P 0.01), 0.3 ± 0.3 Patients and methods ml/min after 6 months (P 0.01) and 0.5 ± 0.6, 1 year after TBI (P 0.05). Mean reduction in stimulated salivary Patients flow 3 months after TBI was 78% in the TBI/CY The study included 26 recipients of allogeneic BMT, compared to 36% in the chemotherapy grafted between August 1983 and May Children over (P 0.05). Children conditioned with chemotherapy 4 years of age were considered able to cooperate to salivary showed an increased salivary flow compared to baseline; sampling during the follow-up. A total of 56 children, 4 to this was not found in TBI-treated children, suggesting 12 years of age were grafted during this period. Twentythree that damage to the salivary glands may be permanent. children died during the first year, three during the Four years after BMT, children conditioned with TBI second year and one child during the third year after BMT. had significantly higher counts of mutans streptococci Three children did not cooperate with the baseline salivary (P 0.05) and lactobacilli (P 0.01) compared to age- secretion test. The children were divided into two s matched controls. However, the prevalence of dental according to conditioning therapy: TBI/CY (n = 14) caries did not differ between children conditioned with and chemotherapy (n = 12). Baseline characteristics TBI, chemotherapy and healthy controls. of the children are presented in Table 1. Keywords: bone marrow transplantation; children; dental Patients with hematological malignancies were treated caries; mutans streptococci; total body irradiation with CY 60 mg/kg once daily i.v. on days 1 and 2 (total dose 120 mg/kg) combined with 10 Gy TBI, delivered by a linear accelerator at a mean dose rate of 0.04 Gy/min, with the lungs shielded to receive no more than 9 Gy, or Advances in treatment of malignancy in childhood have BU 4 mg/kg p.o. in divided doses daily for 4 days in combiresulted in an increasing number of long-term survivors. nation with CY (total dose 120 mg/kg). 6,7 Patients with Apart from acute toxicity, conditioning regimens used in SAA received CY (200 mg/kg) and since 1988 in combithe setting of BMT also induce long-term oral side-effects. 1 nation with antithymocyte globulin (ATG) (3 5 mg/kg/day) Regarding salivary function, Jones et al 2 found that sali- for 5 days. 6 Patients receiving marrow from unrelated vary flow rates and levels of mutans streptococci decreased donors were also given ATG. Patients were kept in reverse after pretransplant cytoreductive therapy and post- isolation until the number of neutrophils was above transplant prophylactic antibiotic therapy in adult patients /l on 2 consecutive days. In general patients were treated with BMT. Normal levels were found 2 years after conditioned according to the Seattle protocols. 6 8 MTX, BMT. Reduced salivary secretion was found 1 year after CYA or both, were used as prophylaxis against GVHD. 9 BMT in children conditioned with TBI/CY compared to GVHD was treated with steroids, cyclosporine and in a few those conditioned with chemotherapy only. 3,4 In children cases with ATG. The protocol was approved by the local Ethical Committee at Huddinge hospital. Oral health status 4 years after BMT was compared with Correspondence: Dr G Dahllöf, Department of Pediatric Dentistry, School of Dentistry, PO Box 4064, S Huddinge, Sweden a reference consisting of 52 children stratified for Received 24 February 1997; accepted 15 May 1997 age and sex. They were selected from children receiving

2 480 Table 1 Baseline characteristics of BMT recipients and reference All children were examined clinically and bite-wing radiographs were taken. Decayed (D) and filled (F) surfaces (S) were recorded clinically. Proximal caries was recorded Variable TBI Chemotherapy on bite-wing radiographs when a radioluscency reached into the dentine. A radioluscency limited to the enamel was (n = 14) (n = 12) defined as initial caries. Mean age ± s.d. (years) 8.0 ± ± 2.5 The method of saliva collection was similar for all chil- Age range (years) dren included in the study. Paraffin-stimulated whole saliva Male/female 9/5 7/5 was collected over 5 min and salivary secretion rate was Underlying disease determined. Buffer capacity was estimated using the Dento- ALL 3 1 buff (Orion Diagnostica, Espoo, Finland) method. 10 The AML 6 1 number of mutans streptococci per ml saliva was estimated SCID 1 according to Gold et al 11 and the number of lactobacilli per B cell lymphoma 1 Gaucher s disease 2 ml saliva was determined using Rogosa SL-agar 12 at the SAA/Fanconi anemia 4 Department of Oral Microbiology, Karolinska Institutet. Thalassemia major 2 The statistical analyses used were Mann Whitney U-test Myelodysplastic syndrome 1 for comparison between the three different s. Longi- CML 1 tudinal changes within the two treatment s were ana- FHL 3 lysed using the Wilcoxon signed ranks test. Donor matching Matched sibling 13 9 Mismatched 2 Matched unrelated donor 1 1 Results Conditioning regimen TBI + CY 14 Salivary secretion rate BU + CY 6 CY 2 Changes in stimulated salivary secretion rate during the 4 ATG + CY 1 years after BMT are presented in Figure 1. Four years after BU + CY + VP-16 3 BMT the mean salivary secretion rate was 1.3 ± 0.7 ml/min GVHD prophylaxis in the chemotherapy compared to 0.7 ± 0.5 in the CYA 4 1 TBI/CY (P 0.05). The mean salivary secretion rate MTX 3 1 fell from 0.9 ± 0.5 ml/min before TBI to 0.2 ± 0.1 after 3 CYA + MTX 6 10 months (P 0.001), 0.3 ± 0.3 ml/min after 6 months (P None ) and 0.5 ± 0.6 ml/min, 1 year after TBI/CY (P Reference 0.05). Two years after TBI/CY no significant difference No. of children was found compared to baseline values. In children con- Mean age ± s.d. (years) 12.0 ± ± 2.4 Age range (years) ditioned with chemotherapy only, saliva secretion rate fell Male/female 18/10 14/10 from 0.8 ± 0.4 ml/min before conditioning to 0.6 ± 0.6 their annual dental check-up at the Department of Pediatric Dentistry, Karolinska Institutet. 2 Salivary secretion rate (ml/min) Chemotherapy TBI/CY Time since BMT (years) Methods During the aplastic period, the children rinsed the oral cavity twice daily with a 0.1% chlorhexidine solution, nystatin IU/ml and % sodium fluoride solution. Follow-up examinations were performed at the department of Pediatric Dentistry, 3, 6 and 12 months after BMT, and thereafter on a yearly basis. The children and their parents received instructions in preventive dental care, individualised fluoride prophylaxis based on assessment of caries risk factors. The programme consisted of tooth brushing with fluoride tooth paste twice daily, fluoride tablets and fluoride varnish application every third month. Children with low salivary secretion rates were treated with sodium fluoride gel 0.1% combined with chlorhexidine gel 0.1% in customised trays. The preventive programme for the reference consisted of tooth brushing with fluor- ide tooth paste twice daily, and in seven patients, additional fluoride treatment with tablets and varnish application. Figure 1 Longitudinal changes in salivary secretion. Changes in salivary secretion rate during a 4-year period after BMT in children conditioned with chemotherapy (n = 12) and TBI/CY (n = 14). Mean values and standard deviation. Wilcoxon signed ranks test: P 0.05, P 0.01.

3 ml/min after 3 months (P 0.05) and 0.6 ± 0.5 ml/min after 6 months (P 0.01). One year after conditioning no difference was found compared to baseline, and from 3 years after BMT a significantly higher salivary secretion rate was found compared to baseline values (P 0.05). The mean reduction in stimulated salivary flow 3 months after BMT was 78% in the TBI/CY compared to 36% in the chemotherapy (P 0.05) (Figure 2). Four years after BMT the salivary secretion rate exceed the base- line value in the chemotherapy with 49%, while in the TBI/CY, the reduction was 18% compared to baseline. This difference between the two s was statistically significant (P 0.05). Four years after BMT one of the 12 children conditioned with chemotherapy had a salivary secretion rate 0.5 ml/min compared to six of 14 in the TBI/CY (P 0.05). Four years after BMT, children conditioned with chemotherapy had a similar salivary secretion rate 1.3 ± 0.7 ml/min as healthy controls, matched for sex and age, 1.3 ± 0.7 ml/min. Children conditioned with TBI/CY, on the other hand, had a significantly reduced secretion rate, 0.7 ± 0.5 compared to controls 1.6 ± 0.9 ml/min (P 0.01). There was a strong correlation between baseline salivary secretion rate and those 3 and 6 months after BMT (P 0.01) in both children conditioned with chemotherapy or TBI/CY. Significant correlations were also found in the two s, during the remaining follow-up period (P 0.05). Seven children were diagnosed with chronic GVHD, all in the conditioned with chemotherapy, at a mean period of 206 days after BMT. No reduction in salivary flow rate compared to children not diagnosed with chronic GVHD was found. As an example, salivary secretion rate after 1 year was 1.0 ± 0.6 ml/min in children diagnosed with cgvhd compared to 0.6 ± 0.6 ml/min in the other 19 children without cgvhd. Change in salivary secretion rate (%) Caries-associated micro-organisms in saliva In both s of children, high counts of salivary mutans streptococci and lactobacilli were found during the 4-year follow-up (Table 2). At baseline all children were colonised with mutans streptococci; a mean number of mutans streptococci per ml saliva were found in the TBI compared to /ml saliva in the chemotherapy. Four years after BMT, children conditioned with TBI exhibited significantly higher counts of mutans streptococci (P 0.05) and lactobacilli (P 0.01) compared to the reference. Dental caries The mean number of decayed and filled tooth surfaces (DFS) increased during the 4 year observation period in both s (Table 3). There was no statistically significant difference in caries prevalence between the TBI/CY and chemotherapy conditioned s. No significant corre- lation between caries prevalence and salivary secretion rate and counts of salivary caries associated microorganisms was found. Four years after BMT, the difference in DFS between the two treated s and their reference s was not statistically significant. Discussion The results of this study show that children conditioned with TBI/CY prior to BMT exhibit a reduced salivary secretion rate 4 years after BMT compared to children conditioned with chemotherapy only and healthy children of the same age. In 49 recipients of allogeneic BMT, we recently reported that TBI, female sex and pretransplant seropositivity to 3 4 herpes viruses were significant risk factors for salivary dysfunction 1 year after BMT. 13 Three months after BMT, children conditioned with TBI/CY exhibited a significantly greater decrease in salivary secretion rate 78%, compared to children conditioned 50 with chemotherapy, 36%. This is in contrast to Chaushu 40 TBI/CY et al 14 who reported that the immediated response to either 30 Chemotherapy irradiation or chemotherapy was similar in terms of parotid 20 flow rate. In agreement with two previous longitudinal studies, 10 salivary secretion rate was significantly reduced 4 0 months after BMT in children conditioned with TBI/CY 10 compared to patients conditioned with chemotherapy 20 only. 14,15 30 In children, salivary flow rate increases with age. 16 Children conditioned with chemotherapy showed an increased mean salivary flow rate compared to baseline 1 year after 60 BMT. Four years after BMT salivary secretion rate was 70 significantly higher than the baseline value and comparable 80 to that of healthy children of the same age. In children conditioned with TBI/CY, the salivary secretion rate did not Time since BMT (years) exceed the baseline value during the 4-year study period; after 3 years no improvement could be found, indicating Figure 2 Changes in salivary secretion compared to baseline. Percentage permanent salivary dysfunction. There was a strong correchange of baseline values in salivary secretion rate during a 4-year period lation between salivary secretion rate at baseline and after after BMT in children conditioned with chemotherapy (n = 12) and TBI/CY (n = 14). Mean values and standard deviations. Mann Whitney U-test: P and 6 months. These results are interesting because female sex has been shown to be a risk factor for salivary 481

4 482 Table 2 Groups BMT and salivary secretion in children Changes in salivary mutans streptococci and lactobacilli during the observation period: mean values and standard deviations Years after BMT Mutans streptococci 10 6 /ml saliva TBI 0.50 ± ± ± ± ± 2.86 Reference TBI 0.42 ± 0.60 Chemotherapy 2.19 ± ± ± ± ± 1.86 Reference chemotherapy 0.42 ± 0.71 Lactobacilli 10 5 /ml saliva TBI 3.41 ± ± ± ± ± 4.31 Reference TBI 0.77 ± 1.52 Chemotherapy 2.88 ± ± ± ± ± 1.20 Reference chemotherapy 1.83 ± 0.45 Mann Whitney U-test: P 0.05, P Table 3 Groups a Number of decayed and filled tooth surfaces in the permanent dentition during the follow-up period: mean values and standard deviations Years after BMT TBI 0.7 ± ± ± ± ± 2.9 Reference TBI 3.5 ± 3.9 Chemotherapy 0.3 ± ± ± ± ± 3.6 Reference chemotherapy 3.1 ± 3.1 a Mean age at baseline: 8.0 ± 2.9 years in the TBI and 8.2 ± 2.5 years in the chemotherapy. TBI/CY, but the difference did not reach statistical significance. A reference was included in this study to compare children 4 years after BMT to a of healthy children of similar age. No significant differences were found between the two BMT s and healthy children with regard to the caries prevalence. Conflicting results have previously been reported concerning the caries experience in children treated for malignant diseases. The results of this study are in agreement with Maguire et al 22 and Nunn et al 23 who compared children treated with chemo- therapy protocols with their siblings and found no differences in dental caries, gingivitis and oral hygiene. It is encouraging that caries prevalence is not increased after BMT compared to healthy individuals, despite the reduc- tion in salivary secretion and increase in caries-associated microorganisms. The reason for this may be the careful pre- ventive dental care these patients are given. There is no accepted, effective means of treating salivary gland dysfunction and accompanying xerostomia. Artificial substances are not successful from the standpoints of patient acceptance and physiologic saliva replacement. Gustatory or masticatory stimulation is short-lived, and long-term use may irritate the oral tissues. Recent studies using pilocarpine hydrochloride have relieved complaints of oral dryness in almost 90% of patients irradiated for head and neck cancers. The best effect was seen in patients who have remaining functional salivary tissue and an intact neural network. 24 dysfunction 1 year after BMT. 13 Girls exhibit significantly lower salivary secretion rates compared to boys during childhood and adolescence. 16 Studies of salivary function have shown that decreased secretion rates due to chronic GVHD cannot be differentiated from those due to irradiation during the first 4 9 months after BMT. 17,18 In agreement with the results from this study no reduction in salivary secretion rate has been found in patients when off immunosuppressive therapy and after resolution of chronic GVHD. 2 A shift in the microbial flora has been seen in patients who receive radiation therapy, with an increased number of mutans streptococci and lactobacilli in saliva. 2,19,20 The results of this study indicate that BMT children exhibit very high counts of mutans streptococci and lactobacilli during the whole 4-year period despite prophylactic efforts. In agreement with Dens et al 15 the shift towards higher counts was more pronounced in children conditioned with TBI. High counts of oral caries-associated microorgansisms after radiation can also be a result of a rapid recolonisation after preventive measures. Application of 1% chlorhexidine gel reduces the absolute bacterial counts of mutans streptococci and lactobacilli in patients treated for head and neck cancers, but 1 week after termination of therapy, the microbial counts already showed a rapid recovery in patients treated with irradiation. 21 The mean number of new decayed and filled surfaces was higher in the chemotherapy compared to the

5 In conclusion, the results of this study indicate that chilkemia? HLA-identical sibling bone marrow transplants for early leudren conditioned with TBI/CY before 12 years of age exhibit Blood 1993; 81: a reduced salivary secretion rate compared to those conbuffer capacity of saliva. Swed Dent J 1980; 4: Frostell G. A colourimetric screening test for evaluation of the ditioned with chemotherapy only and many of these 11 Gold OG, Jordan H, Van Houte J. A selective medium for children may require additional preventive measures during Streptococcus mutans. Archs Oral Biol 1973; 18: their whole life to maintain oral health. 12 Rogosa M, Mitchell JA, Wiseman RF. A selctive medium for the isolation and enumeration of oral lactobacilli. J Dent Res 1951; 30: Acknowledgements 13 Dahllöf G, Bågesund M, Remberger M, Ringdén O. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol 1997 (in press). This study was supported by grants from the TOBIAS-Foundation, the Swedish Patent Revenue Fund, the Children s Cancer 14 Chaushu G, Itzkovitz-Chauchu S, Yefenof E et al. A longi- Foundation, the Swedish Cancer Foundation, the Swedish Medical tudinal follow-up of salivary secretion in bone marrow trans- Research Council and FRF Foundation. plant patients. Oral Surg Oral Med Oral Pathol 1995; 79: Dens F, Boogaerts M, Boute P et al. Caries-related salivary References microorganisms and salivary flow rate in bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1996; 81: Crossner CG. Salivary flow rate in children and adolescents. 1 National Cancer Institute Monographs. Consensus development Swed Dent J 1984; 8: conference on oral complications of cancer therapies: 17 Izutsu KT, Truelove EL, Schubert M et al. Does graft-versus- diagnosis, prevention, and treatment. 9, host disease cause hyposalivation in bone marrow transplant 2 Jones LR, Toth BB, Keene HJ. Effects of total body recipients? J Dent Res 1982; 68: 264. irradiation on salivary gland function and caries-associated 18 Heimdahl A, Johnson G, Danielsson KH et al. Oral condition oral microflora in bone marrow transplant patients. Oral Surg of patients with leukemia and aplastic anemia. Oral Surg Oral Oral Med Oral Pathol 1992; 73: Med Oral Pathol 1985; 60: Dahllöf G, Heimdahl A, Bolme P et al. Oral condition in chil- 19 Keene HJ, Fleming TJ. Prevalence of caries-associated dren treated with bone marrow transplantation. Bone Marrow microflora after radiotherapy in patients with cancer of the Transplant 1988; 3: head and neck. Oral Surg Oral Med Oral Pathol 1987; 64: 4 Berkowitz RJ, Strandfjord S, Jones P et al. Stomatologic complications of bone marrow transplantation in a pediatric popu- 20 Llory H, Dammron A, Gioanni M, Frank RM. Some popu- lation. Pediatr Dent 1987; 9: lation changes in oral anaerobic microorganisms, streptococ- 5 Brown LR, Dreizen S, Handler S, Johnston DA. Effect of radi- cus mutans and yeasts following irradiation of the salivary ation-induced xerostomia on human oral microflora. J Dent glands. Caries Res 1972; 6: Res 1975; 54: Epstein JB, Loh R, Stevenson-Moore P et al. Chlorhexidine 6 Ringdén O, Remberger M, Persson U et al. Similar incidence rinse in prevention of dental caries in patients following radiof graft-versus-host disease using HLA-A, -B, and -DR ident- ation therapy. Oral Surg Oral Med Oral Pathol 1989; 68: ical unrelated bone marrow donors as with HLA identical siblings Bone Marrow Transplant 1995; 15: Maguire A, Craft AW, Evans RGB. The long-term effects of 7 Ringdén O, Ruutu T, Remberger M et al. A randomized trial treatment on the dental condition of children surviving maligcomparing busulphan with total body irradiation as condition- nant disease. Cancer 1987; 60: ing in allogeneic marrow transplants with leukemia. A report 23 Nunn J H, Welbury RR, Gordon PH et al. Dental caries and from the Nordic Bone Marrow Transplant Group. Blood 1994; dental anomalies in children treated by chemotherapy for 83: malignant disease: a study in the north of England. Int J Paed- 8 Thomas ED, Storb R, Clift RA et al. Bone marrow transplan- iatr Dent 1991; 1: tation. New Engl J Med 1975; 292: Fox PC, Atkinson JC, Macynski AA et al. Pilocarpine treat- 9 Ringdén O, Horowitz MM, Sondel P et al. Methotrexate, ment of salivary gland hypofunction and dry mouth cyclosporine or both to prevent graft-versus-host disease after (xerostomia). Arch Intern Med 1991; 151: