Osteoradionecrosis and Trismus Following Radiotherapy Is Genotype Dependent

Abstract

Statement of the ProblemRadiotherapy damage has been described as being almost synonymous with fibrosis. In the head and neck, according to the fibroatrophic theory, damage by fibrosis may present as osteoradionecrosis (ORN). Furthermore a similar fibrotic process may cause severe trismus. Fibrosis can be increased by the action of the transforming growth factor beta 1 (TGFβ1). A number of studies have shown that radiotherapy to the lungs increases both the levels of this growth factor and the degree of symptomatic fibrosis within the lungs particularly in individuals with a specific polymorphism in the TGFβ1 gene. A retrospective case control study was therefore undertaken to assess the influence of this polymorphism on the development of ORN, and trismus following radiotherapy.Materials and MethodsBlood was analyzed for the C-T polymorphism at -509 in the TGFβ1 gene, in patients who had either undergone primary radiotherapy or adjunctive radiotherapy following treatment for head and neck cancer. The development of ORN was assessed at 2 years after completion of radiotherapy and in a subgroup, the degree of trismus was assessed at a minimum of 6 months after completion of radiotherapy.Methods of Data AnalysisComparisons between 39 patients who developed ORN (ORN +ve and 101 who had not (ORN −ve) were made using the χ2 or Fisher exact test, as appropriate. The risk of ORN +ve associated with different genotypes was examined by calculating odds ratios (OR) and 95% confidence intervals (CI). The degree of trismus was analyzed in a subgroup of 47 patients who were both ORN +ve and −ve, across the 3 possible genotypes with a 1-way analysis of variance (ANOVA).Results of InvestigationThere were no significant differences in patient, cancer treatment, particularly radiation dose and tumor characteristics, between those who developed ORN and those who did not. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN the distribution was 56 (CC), 33 (CT) and 12 (TT). The difference in distribution was significant (P = .002). This gave an increased risk of ORN of 5.70 (95% CI: 1.69-19.21) for homozygote TT patients (P = .001) and 3.58 (95% CI CI:1.34-10.00) for heterozygotes (P = .004) when compared to patients with the CC genotype. Post-radiotherapy dentoalveolar surgery was most strongly associated with the development of ORN with those whose genotype was CC, compared to other genotypes, who were more likely to develop ORN without post radiotherapy surgery (P = .02). Of the group assessed for trismus 20 were homozygous (CC) for the TGFβ1(C-T) variant allele, 12 were heterozygous (CT) and 15 were homozygous (TT). These groups were similar in profile for age, sex, tumor stage, tumor site, type of resection and dose of radiotherapy. Mean measurements of mouth opening varied significantly between the genotypes (P = .003), with the largest measurements observed in those who were homozygous (CC) (mean 25.5), and the smallest in those homozygous (TT) for the TGFβ1(C-T) variant allele (mean=12.5).ConclusionIt is apparent that these 2 complications after radiotherapy can to a considerable extent be predicted by an analysis of their genotype. This may influence the decision to treat with radiotherapy, its dose and whether to carry out any post-radiotherapy surgery. Statement of the ProblemRadiotherapy damage has been described as being almost synonymous with fibrosis. In the head and neck, according to the fibroatrophic theory, damage by fibrosis may present as osteoradionecrosis (ORN). Furthermore a similar fibrotic process may cause severe trismus. Fibrosis can be increased by the action of the transforming growth factor beta 1 (TGFβ1). A number of studies have shown that radiotherapy to the lungs increases both the levels of this growth factor and the degree of symptomatic fibrosis within the lungs particularly in individuals with a specific polymorphism in the TGFβ1 gene. A retrospective case control study was therefore undertaken to assess the influence of this polymorphism on the development of ORN, and trismus following radiotherapy. Radiotherapy damage has been described as being almost synonymous with fibrosis. In the head and neck, according to the fibroatrophic theory, damage by fibrosis may present as osteoradionecrosis (ORN). Furthermore a similar fibrotic process may cause severe trismus. Fibrosis can be increased by the action of the transforming growth factor beta 1 (TGFβ1). A number of studies have shown that radiotherapy to the lungs increases both the levels of this growth factor and the degree of symptomatic fibrosis within the lungs particularly in individuals with a specific polymorphism in the TGFβ1 gene. A retrospective case control study was therefore undertaken to assess the influence of this polymorphism on the development of ORN, and trismus following radiotherapy. Materials and MethodsBlood was analyzed for the C-T polymorphism at -509 in the TGFβ1 gene, in patients who had either undergone primary radiotherapy or adjunctive radiotherapy following treatment for head and neck cancer. The development of ORN was assessed at 2 years after completion of radiotherapy and in a subgroup, the degree of trismus was assessed at a minimum of 6 months after completion of radiotherapy. Blood was analyzed for the C-T polymorphism at -509 in the TGFβ1 gene, in patients who had either undergone primary radiotherapy or adjunctive radiotherapy following treatment for head and neck cancer. The development of ORN was assessed at 2 years after completion of radiotherapy and in a subgroup, the degree of trismus was assessed at a minimum of 6 months after completion of radiotherapy. Methods of Data AnalysisComparisons between 39 patients who developed ORN (ORN +ve and 101 who had not (ORN −ve) were made using the χ2 or Fisher exact test, as appropriate. The risk of ORN +ve associated with different genotypes was examined by calculating odds ratios (OR) and 95% confidence intervals (CI). The degree of trismus was analyzed in a subgroup of 47 patients who were both ORN +ve and −ve, across the 3 possible genotypes with a 1-way analysis of variance (ANOVA). Comparisons between 39 patients who developed ORN (ORN +ve and 101 who had not (ORN −ve) were made using the χ2 or Fisher exact test, as appropriate. The risk of ORN +ve associated with different genotypes was examined by calculating odds ratios (OR) and 95% confidence intervals (CI). The degree of trismus was analyzed in a subgroup of 47 patients who were both ORN +ve and −ve, across the 3 possible genotypes with a 1-way analysis of variance (ANOVA). Results of InvestigationThere were no significant differences in patient, cancer treatment, particularly radiation dose and tumor characteristics, between those who developed ORN and those who did not. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN the distribution was 56 (CC), 33 (CT) and 12 (TT). The difference in distribution was significant (P = .002). This gave an increased risk of ORN of 5.70 (95% CI: 1.69-19.21) for homozygote TT patients (P = .001) and 3.58 (95% CI CI:1.34-10.00) for heterozygotes (P = .004) when compared to patients with the CC genotype. Post-radiotherapy dentoalveolar surgery was most strongly associated with the development of ORN with those whose genotype was CC, compared to other genotypes, who were more likely to develop ORN without post radiotherapy surgery (P = .02). Of the group assessed for trismus 20 were homozygous (CC) for the TGFβ1(C-T) variant allele, 12 were heterozygous (CT) and 15 were homozygous (TT). These groups were similar in profile for age, sex, tumor stage, tumor site, type of resection and dose of radiotherapy. Mean measurements of mouth opening varied significantly between the genotypes (P = .003), with the largest measurements observed in those who were homozygous (CC) (mean 25.5), and the smallest in those homozygous (TT) for the TGFβ1(C-T) variant allele (mean=12.5). There were no significant differences in patient, cancer treatment, particularly radiation dose and tumor characteristics, between those who developed ORN and those who did not. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN the distribution was 56 (CC), 33 (CT) and 12 (TT). The difference in distribution was significant (P = .002). This gave an increased risk of ORN of 5.70 (95% CI: 1.69-19.21) for homozygote TT patients (P = .001) and 3.58 (95% CI CI:1.34-10.00) for heterozygotes (P = .004) when compared to patients with the CC genotype. Post-radiotherapy dentoalveolar surgery was most strongly associated with the development of ORN with those whose genotype was CC, compared to other genotypes, who were more likely to develop ORN without post radiotherapy surgery (P = .02). Of the group assessed for trismus 20 were homozygous (CC) for the TGFβ1(C-T) variant allele, 12 were heterozygous (CT) and 15 were homozygous (TT). These groups were similar in profile for age, sex, tumor stage, tumor site, type of resection and dose of radiotherapy. Mean measurements of mouth opening varied significantly between the genotypes (P = .003), with the largest measurements observed in those who were homozygous (CC) (mean 25.5), and the smallest in those homozygous (TT) for the TGFβ1(C-T) variant allele (mean=12.5). ConclusionIt is apparent that these 2 complications after radiotherapy can to a considerable extent be predicted by an analysis of their genotype. This may influence the decision to treat with radiotherapy, its dose and whether to carry out any post-radiotherapy surgery. It is apparent that these 2 complications after radiotherapy can to a considerable extent be predicted by an analysis of their genotype. This may influence the decision to treat with radiotherapy, its dose and whether to carry out any post-radiotherapy surgery.