Contribution of the Biological Dosimetry for Treatment Decisions in Patients with Differentiated Thyroid Carcinoma (DTC) under Radioiodine-131 Therapy

Transcription

1 Contribution of the Biological Dosimetry for Treatment Decisions in Patients with Differentiated Thyroid Carcinoma (DTC) under Radioiodine-131 Therapy Fadel, A.; Chebel, G.; Di Giorgio, M.; Radl, A.; Taja, M.R.; Bubniak, R.; Deminge, M. and Oneto, A. Presentado en: 13 th International Congress on the International Radiation Protection Association. Glasgow, Escocia, 13 al 18 de mayo de 2012

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3 Contribution of the Biological Dosimetry for Treatment Decisions in Patients with Differentiated Thyroid Carcinoma (DTC) under Radioiodine-131 Therapy 1 Fadel, A.; 1 Chebel, G.; 2 Di Giorgio, M.; 2 Radl A.; 2 Taja, M. R.; 2 Bubniak, R.; 2 Deminge, M.; 3 Oneto, A. (1) Endocrinology Division, General de Agudos Dr. Carlos Durand Hospital- Buenos Aires, Argentina (2) Biological Dosimetry Laboratory, Nuclear Regulatory Authority- Buenos Aires, Argentina (3) TCba, Salguero Laboratory- Buenos Aires, Argentina Abstract Radioiodine-131 therapy is applied in patients with DTC, within the therapeutic scheme following thyroidectomy, for the ablation of thyroid remnants and treatment of metastatic disease. Several approaches for the selection of a therapeutic dose were used. The objective of this work is to estimate the absorbed dose to the whole body and bone marrow, due to the therapeutic administration of 131 I in patients with DTC, by applying cytogenetic techniques, which include the evaluation of dose distribution in the body, for treatment decisions. Thirty three DTC patients (Pt) treated with total thyroidectomy, followed by 131 I therapy, with cumulative activities from medium to high (exceeding 37.0 GBq) and persistent/recurrent disease, were assessed. A prospective clinical follow-up was conducted, and was correlated with cytogenetic, hematological and endocrinology data. For the cytogenetic studies, blood samples were obtained before each patient treatment and on day 8 after the administration of 131 I. Cytogenetic methods were applied to quantify chromosome aberrations for dose assessment. The results of this work show that the biological dosimetry have contributed to optimize the 131 I therapeutic administration in 5 out of the 33 patients evaluated with cumulative activities higher than 1000 mci, and to decide the application of a complementary surgery in one case. For the remainder, the routine treatment protocol was applied as the biodosimetry confirmed that this further 131 I administration would result in a low risk of reaching the myelotoxicity threshold (2Gy). The assessment of dose distribution in the body was conducted to evaluate consistency with the clinical status. Patients with inhomogeneous distribution correlated with the presence of metastasis. From a clinical point of view, the biodosimetry conducted on samples from Pt with previous treatments, before a new therapeutic administration, could allow the cytogenetic status assessment (radiation damage and repair capacity) to become a warning signal for reducing potential hematological complications. Key words: differentiated thyroid carcinoma, biological dosimetry, hematological complications, serum thyroglobulin 1- Introduction Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. Radioiodine-131 therapy is applied in patients with DTC, within the therapeutic scheme following thyroidectomy, for the ablation of thyroid remnants and treatment of metastatic disease [1]. Several approaches for the selection of a therapeutic dose were applied. The aim of this therapy is to achieve a lethal dose in the tumor tissue, without exceeding the dose of tolerance in healthy tissues (doses greater than 2 Gy in bone marrow could lead to myelotoxicity). In this work, the treatment protocol used incorporates the assessment by biological dosimetry (BD) for estimating doses to whole body and bone marrow, to tailor patient s treatment. The objective of the present work is to estimate the absorbed dose to the whole body and bone marrow, due to the therapeutic administration of 131 I in patients with DTC, by applying cytogenetic techniques, which include the evaluation of dose distribution in the body, for treatment decisions.

4 2. Materials and Methods Patients Thirty three patients with differentiated thyroid cancer from Carlos Durand Hospital, treated with total thyroidectomy, followed by 131 I and levothyroxine therapy, were included in the present study. The study was approved by the Research and Ethics Committee of the Hospital. Signed informed consents (Helsinki II declaration) were included in the study protocol of each treated patient. The criteria for the inclusion of patients involve: 1. cumulative activities: range 1.85 GBq (50 mci) to 85.1 GBq (2300 mci), 2. persistent/recurrent disease that would require the administration of new therapeutic doses 3. hematological complications. Patients with partial thyroidectomy and with recent chemotherapy treatments were excluded. A prospective clinical follow-up was conducted, and was correlated with cytogenetic, hematological and endocrinology (serum thyroglobulin) data. Sample Collection A total of 3ml of blood was collected into lithium heparin venous blood collection tubes (Vacutainer, BD), transported with refrigerant gels and maintained at about 4 C, until processed within 24 h. Medical Treatment: Thyroidectomy is usually followed by radioiodine treatment to remove any remnant of normal thyroid tissue and microscopic residues of malignant tissue. Prior to radioiodine remnant ablation, serum thyroid stimulating hormone (TSH) elevation is necessary to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH is achieved by withholding of synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary TSH. After remnant ablation, patients are placed on synthetic thyroid hormone supplements to replace endogenous hormone and to suppress serum levels of TSH in order to avoid TSH-stimulated tumor growth [2,3]. Thereafter, patients are followed for the presence of remnants, or of residual or recurrent cancer, by thyroglobulin (Tg) testing, usually with radioiodine imaging. This follow-up testing is most effective when conducted under TSH stimulation, achieved by thyroid hormone withdrawal. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH [1,3]. Endocrinology data: All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/ml. As Tg antibodies may confound the Tg assay and render Tg levels uninterpretable, patients were further evaluated for Tg antibodies. Biological Dosimetry: a prospective study on the decline of unstable chromosome aberrations was conducted, considering the damage induced by each therapeutic administrated activity and its respective recovery before a new required administration. For the cytogenetic studies, a blood sample was obtained before each patient treatment and another was obtained on day 8 after the administration of 131 I. Cytogenetic methods (dicentrics) were applied to quantify chromosome aberrations [4,5,6], which were referred to a dose-response curve for dose assessment. 3. Results Data on Table 1. and their correlation with clinical follow-up indicate: Thyroglobulin values showed correlation with recurrent or persistent disease. The cytogenetic method applied resulted sensitive and specific for the identification of radiation treatment, as it is shown in patient 30 that did not present cytogenetic damage (zero dose) previously to 131 I internal radiotherapy and exhibited cytogenetic damage (whole body dose of Gy) after the therapeutic administrated activity. The risk of recurrent/persistent disease and the need for the administration of reiterative doses, generate the requirement of bone marrow status knowledge. The results of this work show that BD assessment contributed to optimize the 131 I therapeutic administration in 5 out of the 33 patients evaluated with cumulative dose higher than 1000 mci, and to decide the application of a complementary surgery in one case. For the remainder, the routine treatment protocol was applied as the doses estimated by BD confirmed that this further 131 I administration would result in a low risk of reaching the myelotoxicity threshold (2Gy).

5 13th International Congress of the International Radiation Protection Association (IRPA) May 2012, Glasgow- Scotland Table 1. Therapeutic administration, Tg blood levels, mean dose for the last administrated treatment and clinical status. 1absorbed dose to the whole body and bone marrow, due to the last therapeutic administration; 2cumulative absorbed dose assessed before the last therapeutic administration Figure 1. shows the distribution of cumulative activities among the evaluated patients. 93

6 Hypothesis: An increase in cytogenetic toxicity (DNA damage) is expected with the increase in 131 I cumulative activities. Figure 2. represents the relationship between cumulative activities with the mean dose due to the last treatment. Figure 3. indicates the relationship between last treatment activity with the cytogenetic status, previous to the last administrated activity. It is observed an increase in mean dose (due to the last treatment) with last 131 I administrated treatment activity. It can be inferred that cumulative activities are modified by the elapsed time between 131 I treatments and consequently, by the patient DNA repair capacity.

7 Figure 4. shows the relationship between cumulative activities and the cytogenetic status. Cumulative activities between 300 mci and 1300 mci induced whole body doses in the range of 0.4 Gy 1.0 Gy, at different elapsed times between previous and last treatment. 4. Discussion Cytogenetic damage and recovery showed dependency with the 131 I activity administrated in each treatment, the cumulative activity, the elapsed time between previous and last treatment and with the individual DNA repair capacity. From a clinical point of view, the BD conducted on samples from patients with previous treatments, before a new therapeutic administration, could allow the cytogenetic status assessment (radiation damage and repair capacity) to become a warning signal for reducing potential hematological complications. In cases with cumulative doses higher than 1000 mci, it could be useful to indicate the need to consider therapeutic schemes alternative to the administration of 131 I, such as surgery, chemotherapy or radiotherapy, reducing morbidity. Additionally, data from in vivo models could be used to estimate the risk due to accidental intake of 131 I and would contribute to the design of therapeutic strategies Further studies correlating biological dosimetry data and endocrinology data with morphological analysis and patient details, including evidence on tumour aggressiveness and recurrence, will increase our understanding of the link between radiation exposure and cancer development, and provide evidence which will inform decisions on radiation protection and on clinical management of patients with radiation associated cancers. 5- References 1. Van Nostrand, D. and Wartofsky, L. Radioiodine in the Treatment of Thyroid Cancer. Endocrinol Metab. Clin. N. Am (2007). 2. Society of Nuclear Medicine. Society of nuclear medicine procedure guideline for therapy of thyroid disease with iodine-131 (sodium iodide). Procedure manual, version 1.0;. p (2002). 3. Meier DA, Brill DR, Becker DV, et al. Procedure guideline for therapy of thyroid disease with I-131. J. Nuc. Med.,43: (2002). 4. International Atomic Energy Agency. Cytogenetic Analysis for Radiation Dose Assessment. A Manual. Tech. Rept Series 405, IAEA,Vienna, Austria (2001). 5. Lloyd, D.C.; Purrott, R.J.; Dolphin, G.W. A comparison of physical and citogenetic estimates of radiation dose in patients treated with iodine-131 for thyroid carcinoma, Int. J. Radiat. Biol., 30 N 5, (1976). 6. Livinsgton, G.K.; Foster, A.E.; Elson, H.R. Effect of in vivo exposure to iodine-131 on the frequency and persistence of micronuclei in human lymphocytes, Journal of Toxicology and Environmental Health, 40, p (1993).