| Background and Objection:Thyroid gland is the major endocrine gland regulating metabolism. Radiotherapy of head and neck cancers can affect thyroid gland and induce thyroid disorders including thyroiditis, hypothyroidism, Graves'disease and thyroid nodules. Among these radiation-induced complications, primary hypothyroidism is the most common, affecting 20-30% of patients after radical radiotherapy to the neck. Radiation damages thyroid cells and small vessels in the gland capsule, the former responsible for acute effects and the latter for the late injury.For external beam radiotherapy of nasopharyngeal carcinoma (NPC), neck lymphatics are routinely included in the target volume because over 75% of patients present with clinically positive or occult cervical lymphadenopathy. A variable portion of the thyroid gland is included in the irradiation field. The total dose delivered to the thyroid gland depends on the N-stages of the disease and the radiotherapy techniques. The prognosis of NPC patients has been improving as a result of advancements in radiotherapy techniques. Therefore it is likely that the risk of thyroid dysfunction after radiotherapy for NPC has also increased. The literature indicates that hypothyroidism after external radiation in the head and neck region usually occurs within 2 years. High doses of over 40 Gy to the thyroid gland further shorten the latency period and several authors observed early onset of hypothyroidism within 3 months after radiotherapy. Since it is estimated that the thyroid gland receives over 50 Gy during radiotherapy for NPC, the onset time of thyroid gland dysfunction could well be within the first 12 months after irradiation. There is little information regarding this, however. Therefore, we carried out a longitudinal study to evaluate radiation associated changes in the thyroid gland in NPC patients.Methods and materialsThis was a prospective longitudinal study of patients with NPC who were treated by external beam radiotherapy between December 2007 and August 2008. There were no patients with history of thyroid abnormalities or recurrent or residual NPC as they had been excluded from the study. The patients had received neck irradiation by techniques ranging from single anterior cervical beam to multiple intensity modulated radiotherapy (IMRT) beams to the cervical nodal regions. The single anterior cervical treatment covered the lower mandible down to the supra-sternal notch with a median block to spare the larynx and spinal cord, whereas the IMRT technique used 7-9 beams to irradiate the neck node in continuation with the primary nasopharyngeal tumor. For the IMRT planning, there was no specification of dose constraints to the thyroid gland during the plan optimization process of the inverse planning procedure. Because of the difference in beam arrangements, the volume of thyroid gland irradiated by high dose varied among the patients. This resulted in a spectrum of mean thyroid doses received by the subjects, which facilitated the evaluation of dose-complication relationship in this study. Six-MV photon was used for all techniques and the prescribed dose to the neck ranged from 50-70 Gy depending on the N-stage of the patients. The study procedure was explained to all subjects who signed a written consent before the start of treatment. The study was approved by the Research Committees of Cancer Hospital, Shantou University Medical College and Hong Kong Polytechnic University.A baseline CT examination, a routine for radiotherapy planning, and thyroid function tests were performed for each subject prior to the commencement of radiotherapy. The CT image provided the volume information and the first set of CT scans was a pre-requisite for the generation of a treatment plan. Thyroid function tests were obtained at 3,6,12 and 18 months after completion of treatment. Follow up CT scans were performed at 6,12 and 18 months post-treatment as part of routine post-radiotherapy follow up procedures for NPC patients. During CT, the subjects were supine with the head and neck in a straight position. Contrast media was administered prior to the scan to highlight the thyroid in the CT images. The scan included the vertex down to the level of first thorax spine (T1) with 3 mm thick slices. Images generated from the scanner were transferred to the radiotherapy treatment planning system (TPS) for treatment planning. The volume of the thyroid gland was automatically calculated by the software of the TPS after delineating the thyroid gland in the corresponding CT slices.Thyroid function tests included serum TSH, the free T3 (FT3), free T4 (FT4), Anti-TPO and Anti-TG, and were performed by the electrochemiluminescence (ECL) method using the Elecsys 2010 analyzer (Roche, USA). The reproducibility of the three thyroid hormones tests were acceptable with their coefficient variations (CV) varied between 1.3% and 1.5%. The estimation of dose received by the thyroid gland was conducted by the radiotherapy TPS using dose volume histogram which gave the values of the maximum (hottest spot) and mean doses (average dose within the entire volume of the organ) of the thyroid gland. SPSS Statistics 17.0 was used to carry out the statistical analysis. Repeated-measures ANOVA and LSD were used to compare variables of thyroid gland before and after radiotherapy. Pearson or Spearman correlation test were used to evaluate the relationships between variables of the thyroid gland. T-test was used wherever required. The significant level was set to a =0.05.Results:This was a prospective longitudinal study of 45 patients with NPC who were treated by external beam radiotherapy between December 2007 and August 2008. The patients'age range was 24 to 65 (mean 46.7±8.7). There were 36 men and 9 women. Their nodal (N) stage ranged from NO to N3.Thyroid gland volumeThere was a trend for the thyroid volume to decrease in the 18 months after radiotherapy. The mean volume was significantly reduced from 17.27±7.82cm3 before radiotherapy to 14.14±5.65 cm3 six months after radiotherapy (LSD, P<0.05), a reduction of 16.4%. The decrease in mean volume was less after 6 months, becoming almost more stable between 12 and 18 months. The mean volumes at 12 and 18 months were 13.22±5.42 cm3 and 12.65±5.06 cm3. The relative percentage volume reduction, which was defined as the volume change at.specific time after radiotherapy divided by the volume before radiotherapy×100%, between 6 and 18 month after radiotherapy was within 8.7% which was not significant. The mean doses received by the thyroid gland among all the abnormal subjects ranged from 18.3Gy to 61.4Gy. There were significant correlations between the estimated mean thyroid dose and the percentage decrease in thyroid volume at 6,12 and 18 months after radiotherapy (correlation coefficients -0.427,-0.617 and -0.552 respectively). However, this correlation did not show between the maximum thyroid dose and the percentage decrease in thyroid volume. (correlation coefficients -0.245,0.118,-0.275 respectively).Thyroid hormonesThe mean values of serum FT3 showed little change (2.28%) in the first six months after radiotherapy, going from 5.17 to 4.98 pmol/L. During the 6 to 12 month period after radiotherapy there was a greater decrease (12.09%) in the serum FT3 (P=0.007). However, the mean serum FT3 between 12 and 18 months increased for 8.14%, closed to the 6 months level with statistical significance (P=0.019).Similarly the mean values of serum FT4 also showed little change (2.5%) in the first six months after radiotherapy, going from 14.16 to 16.73 pmol/L. During the 6 to 12 months period after radiotherapy there was a greater decrease (8.78%) in the serum FT4 (P=0.016). There was a mild increase (1.72%) in the mean serum FT4 between 12 and 18 months after radiotherapy.The mean values of serum TSH showed little change (11.99%) in the first three months after radiotherapy, going from 1.79 to 1.82 mlU/L. During the 3 to 6 month period after radiotherapy there was a greater increase (55.07%) in the serum TSH. There were greater increases in the mean serum TSH at 12 months for 228.49% with P=0.011. At 18 months after radiotherapy, the mean serum TSH increased for 218.25%, less than at 12 months with P=0.016.Before radiotherapy, all study patients had with normal serum FT3, FT4 and TSH concentrations. The normal ranges for the three hormones in the local Chinese population are 3.1-6.8 pmol/1,12.0-22.0 pmol/L and 0.27-4.20 mIU/L respectively. Three to 6 months after radiotherapy 8 patients presented with abnormal hormone levels but 2 of them returned to normal after 12 months. At 12 months after radiotherapy, twelve patients (including the previous six patients) showed an elevated serum TSH which was a characteristic of primary hypothyroidism. There was no patient with thyrotoxic condition (characterised by low serum TSH and normal or high FT3 and FT4) and central thyroid dysfunction (normal serum TSH with abnormal FT3 or FT4). There was a significant difference in the mean thyroid dose between 12 patients with hypothyroidism (46.04±9.43Gy) and 33 cases with normal thyroid function (38.57±10.39Gy, P=0.014). Eighteen months after radiotherapy, there were 17 patients appeared with clinical hypothyroidism or sub-clinical hypothyroidism. The mean thyroid doses between these 2 groups of patients (46.94±7.79Gy VS 37.37±10.43Gy) also showed a significant statistical difference.Significant negative correlations were found between the mean thyroid dose and the change of serum FT4 level at 12 and 18 months after radiotherapy (r=-0.229 and -0.318 respectively). The change of hormone level was defined as the difference between the baseline level (before radiotherapy) and the level at the specified time interval. Significant positive correlations were present between the mean thyroid dose and the change of serum TSH level at 12 and 18 months after radiotherapy (r= 0.415 and 0.420 respectively). However there was no dose correlation in the serum FT3 level in all time intervals.There were significant correlations between the percentage volume shrinkage at 18 months after radiotherapy and the reduction of serum FT3 and FT4 levels (r=0.391 and 0.392 respectively), but the correlation with that of the serum TSH level was not significant (r=-0.110).Thyroid auto-immune antibodies The Anti-TPO autoantibody titres at pre-treatment,3,6,12,18 months after treatment were 57.24±136.78IU/mL,52.72±118.88IU/mL,82.00±147.65IU/mL, 107.86±165.32IU/mL and 100.01±159.75IU/mL, respectively. Mauchly test showed significant differences among various intervals before and after treatment.The Anti-TG autoantibody titres at pre-treatment,3,6,12,18 months after treatment were 37.42±89.78IU/mL,63.28±196.01IU/mL,190.98±455.53IU/mL, 254.34±301.44IU/mL and 317.66±496.93IU/mL, respectively. Mauchly test showed significant differences among various intervals before and after treatment.Both Anti-TPO and Anti-TG percentage showed no correlationship to mean thyroid dose and percentage of thyroid volume. There was no significant correlationship between thyroid auto-immune antibodies and FT3. For FT4, Anti-TG showed strong negative correlation with FT4 at 3,6,12 months (r=0.748, P=0.000; r=-0.409, P=0.022; r=-0.386,P=0.032). TSH was correlated with Anti-TPO at 3 and 12 months after treatment (r=0.376, P=0.037; r=0.513, P=0.003). At 12 and 18 months after treatment, Anti-TG was positively correlated with TSH (r=0.550, P=0.001; r=0.486, P=0.006).Spearman correlation analysis showed either Anti-TPO or Anti-TG positive was correlated to hypothyroidism at 3 months (r=0.445, P=0.012; r=0.411, P=0.022). At months, only Anti-TPO positive was correlated with hypothyroidism (r=0.411, P=0.022).Conclusion1 After radiotherapy reduction of thyroid gland volume was observed in this study. The shrinkage of the gland was more remarkable in the first 6 months after radiotherapy then became more stable towards the 12 months interval. Volume reduction of the thyroid was correlated to the mean dose received by the thyroid gland with statistical significance but not the maximum dose.2 The changes of the serum FT3 and FT4 levels in the first 6 months after radiotherapy were relatively small. But both of these two hormones demonstrated a greater decreasing trend at 12 months, and then slowed down afterwords. Contrary to the serum FT3 and FT4, the serum TSH level demonstrated an overall rising trend after completion of radiotherapy. However, it started going up at 6 months and became more significant from 12 months onward, and then this rising trend slowed down.3 The levels of thyroid hormones changes were correlated to the mean radiation dose received by the thyroid gland and thyroid volume change.4 Hypothyroidism emerged soonly in 3 months after radiotherapy, patient number of hypothyroidism increased rapidly to 12 months after radiotherapy. Thyroid hormone levels restored in part of these patients in 18 months after radiotherapy. The mean thyroid dose received by patient with hypothyroidism was higher then that of patient with nomal thyroid hormone level.5 Thyroid auto-immue antibodies rose after radiotherapy. Anti-TPO rose more obviously at 6 months after radiotherapy, to the peak at 12 months, and then began slightly reduce at 18 months. Anti-TG kept rising up until 18 months.6 Thyroid auto-immue antibodies did not show correlationship with percentage change of thyroid volume, however, they were highly related to the thyroid hormone changes. Analysis also proved that thyroid auto-immue antibodies were correlated to the incidence of hypothyroidism. All of these evidences indicated that thyroid anti-immue response is one of the major causes of radiation induced thyroid damage.
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