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I-131 In the Management of Differentiated thyroid Cancer – an Update on Current Recommendations and Practices
Review Article
Review Article
I-131 IN THE MANAGEMENT OF DIFFERENTIATED THYROID CANCER – AN UPDATE ON CURRENT RECOMMENDATIONS AND PRACTICES Uma Ravishankar, Surbhi Pande and N Savita Department of Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Uma Ravishankar, Senior Consultant, Department of Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. I-131 is an established diagnostic and therapeutic modality for patients with functioning residual disease after surgery, and is widely used for remnant ablation and treating recurrence or metastatic disease. Over the years, evidence has grown demonstrating the benefits of combining surgery with radioactive iodine therapy, which has resulted in higher cure rates, lower recurrence, improved quality of life and longer survival. Management of well differentiated thyroid cancer in the current era is a multidisciplinary approach, comprising surgery, endocrinology and nuclear medicine, and the managemnt strategy include thyroidectomy, replacement with thyroid hormone and post-surgical radioactive iodine (RAI) ablation where indicated. This article briefly reviews the currently reccomended clinical practice guidelines on management of thyroid cancer, and our experiences at Indraprastha Apollo Hospital in the diagnosis and treatment of well differentiated thyroid cancer. Key words: I-131, Well differentiated thyroid cancer, Remnant ablation.
INTRODUCTION Thyroid cancer accounts for approximately 1% of all carcinomas and is the most common endocrine malignancy, occurring in any age group, although it is most common after age 30. Peak onset ages reported to be 30-50 years. Females are more likely to have thyroid cancer in a ratio of three to one. Prior external irradiation in childhood and a family history of thyroid cancer are predisposing factors thyroid malignancy and preexisting benign thyroid diseases like nodules in individuals younger than 20 years or older than 60 years, are additional risk factors. Types of thyroid cancer • • • •
Papillary Follicular and/or Hürthle cell. Medullary Others (Anaplastic/ Primary thyroid lymphoma)
Papillary tumors (including mixed papillary-follicular cancer) are the most common of all thyroid cancers (>70%) [1]. This subtype has a high cure rate with ten year survival rates for all patients estimated at around 80-90%. Diagnosis is established by presence of follicular differerentiation and distinctive nuclear features. Variants of this subtype include follicular variant, diffuse scelerosing, tall and columnar cell variants. Papillary Ca is frequently multifocal and can be bilateral in 20-80% cases. It commonly metastasizes to cervical 347
lymph node, and nodal metastases results in higher recurrence rate but not a higher mortality rate. Distant metastasis is uncommon, and lung and bone are the most common sites.Malignant epithelial tumor with evidence of follicular cell differentiation but lacking diagnostic features of papillary carcinoma are labelled as follicular cancers. These account for about 10% of cases of all thyroid cancers. Hürtle cell cancer is a tumor composed of more 75% oncocytic cells and is usually classified with follicular tumors. It has been classified as oxyphillic variant of follicular thyroid carcinoma by WHO. Medullary cancer of the thyroid is significantly less common, but with worse prognosis. These cancers tend to spread to large numbers of lymph nodes very early on, and hence require a much more aggressive approach than the more localized papillary and follicular cancers. Approximately 25% of MTCs are familial, usually occurring as a part of syndrome complex of MEN IIa or IIb or familial (non-MEN). Undifferentiated (anaplastic) thyroid cancer is the least common and most aggressive form of thyroid cancer, being rapidly fatal within months of the diagnosis. Histological verification of this subtype is essential as cancers such as lymphomas, and MTCs, which require different therapeutic approaches are occasionally confused with undifferentiated cancers. The term differentiated thyroid cancer is defined as carcinoma derived from follicular epithelium and retaining basic biological characteristics of normal thyroid tissue, and Apollo Medicine, Vol. 6, No. 4, December 2009
Review Article
includes both papillary cancer and follicular cancer. Separating patients with differentiated cancers into those with good to excellent prognoses from those with poorer prognoses is important for optimizing treatment plans. Prognostic factors include patient characteristics (older age, male gender and family history at higher risk), histological subtype ( tall cell and columnar variants of papillary, widely invasive follicular and anaplastic Ca have poorer prognoses), tumor burden, with larger tumors and those extending beyond capsule, bilateral cervical nodal or mediastinal involvement and distant metastases are reported to have an overall poorer prognosis [2]. Initial treatment is also an important prognostic factor, and longer time of treatment interval from diagnosis, incomplete resection and non administration I-131 where indicated leading to higher recurrence rates and mortality [3]. DIAGNOSTIC EVALUATION Most well differentiated thyroid cancers present as an asymptomatic nodule, although larger ones may produce symptoms like hoarseness of voice and dysphagia. Laboratory tests such as serum TSH are not useful in differentiating benign from malignant nodules and are generally performed to exclude thyroid dysfunction in cases with thyroid nodules. Fine-needle Aspiration Cytology (FNAC) remains the cornerstone for evaluation of solitary thyroid nodules or dominant nodules within multinodular goiters, with a false negative rate of less than 5% and a falsepositive rate of 1% [4]. The 4 types of interpretations include (a) benign, (b) malignant, (c) suspicious for a follicular/Hürthle cell tumor, and (d) insufficient for a diagnosis repeat FNAC is considered in the event of insufficient diagnosis in the first instance. Approximately 10% of FNA findings remain non diagnostic/ indeterminate. For solitary nodules that are repeatedly non diagnostic on biopsy, the risk of malignancy is not established, but is reported to be to 5-10%. Although many molecular markers like antigalectin 3, telomerase etc have been evaluated to improve diagnostic accuracy for these nodules, none are currently recommended in routine practice. A finding of follicular or Hürthle cell tumor warrants further evaluation and management, since these two entities can only be differentiated by the presence or absence of capsular or vascular invasion on histological examination of surgical specimens. Radionuclide scan with I-123 or 99m pertechnetate is useful in mapping functional activity in known nodules. High resolution thyroid ultrasonography defines the size and number of nodules, and is also useful in discovering sub clinical nodules and in guiding FNA in non palpable nodules. Ultrasound identifies suspicious cervical lymhadenopathy in 20-31% of cases and a preoperative neck ultrasound for the contralateral lobe and cervical (central and bilateral) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic Apollo Medicine, Vol. 6, No. 4, December 2009
findings on biopsy. Other imaging modalities like computed tomography or magnetic resonance although not routinely indicated, may be helpful in morphological assessment of tissue mass extent and involvement of surrounding structures and in determining the extent of a retrosternal goiter or the presence or degree of tracheal compression. MANAGEMENT OF DIFFERENTIATED THYROID CANCER Goals of initial therapy of differentiated thyroid cancer include (a) removal of primary tumor, the thyroid capsule, and involved cervical lymph node as completeness of surgical resection determines long term outcome (b) facilitate postoperative treatment with radioactive iodine appropriate (c) to permit accurate long-term surveillance for disease recurrence and (d) to minimize the risk of disease recurrence and metastatic spread. Surgery Although surgery is undoubtedly the established choice so far as primary treatment is concerned. Considerable debate exists as regards the extent of optimal surgery in well differentiated thyroid carcinomas [5], with some experts being of the opinion that simply removing the lobe of the thyroid which harbors the tumor and the isthmus will provide as good a chance of cure as removing the entire thyroid in case of small tumors not invading other tissues. These proponents of conservative surgical therapy cite increased risk of hyperparathyroidism and recurrent laryngeal nerve injury in patients undergoing total thyroidectomy and relate the low rate of clinical tumor recurrence (5-20%) despite the fact that small amounts of tumor cells can be found in up to 88% in the contralateral lobe. In contrast, some advocate the more aggressive approach of total thyroidectomy. In experienced hands,the incidence of recurrent nerve injury and permanent hyperparathyroidism are quite low (about 2%). More importantly, studies have established that patients with total thyroidectomy followed by radioiodine therapy and thyroid suppression have a significantly lower recurrence rate and lower mortality when tumors are greater than 1.5cm. Based on these studies and the natural history and epidemiology of papillary carcinoma, current recommendations propose near-total or total thyroidectomy in most case with thyroid lobectomy alone is deemed sufficient treatment for small, low-risk, isolated, intrathyroidal papillary carcinomas in the absence of cervical nodal metastases [5,6]. ROLE OF RADIOACTIVE IODINE IN THE POST SURGICAL SETTING Radiobiology of I-131
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Radioactive iodine treatment (RAIT) is defined as the
Review Article
selective irradiation of thyroid tissue by systemic administration of I-131. The use of radioiodine for thyroid cancers is based on radiation-induced cell damage caused by the emitted high-energy E-radiation . I-131 is produced by neutron irradiation of tellurium or as a by product of Uranium fission. It is a E-emitting radionuclide with a maximum energy of 606 keV and an average energy of 191 keV. Average range of Eparticles in tissue is 0.8 mm and has a principal J-ray of 364 keV. The magnitude of cell functional damage is proportional to the absorbed dose. Only well-differentiated thyroid cancer cells concentrate radioiodine to a significant degree. These include papillary, follicular, and mixed papillary-follicular cancers. Anaplastic thyroid cancers do not concentrate radioiodine. ROLE OF PRE THERAPY RADIOIODINE SCAN Radioiodine WBS detects presence of iodine-avid thyroid tissue, including the presence of residual disease in the postoperative setting [7]. In cases with large thyroid remnant, the scan is dominated by uptake within the remnant and this can potentially mask extrathyroidal disease, resulting in decreased sensitivity of lesion detection. Some proponents propose avoiding pre therapy radioiodine scans altogether because of possibility of a pretreatment diagnostic dose 131 I-induced stunning of thyrocytes. Stunning has been shown to occur with higher doses of I-131 (5-10 mCi), increased duration between the diagnostic dose and therapy, and is not appreciated at lower doses (1-3 mCi) [8]. In recent years, there has been an increasing trend to avoid pre therapy scan altogether. Most guidelines recommend pre therapy scans with measurement of thyroid bed uptake in situations where the extent of the thyroid remnant cannot be accurately ascertained from neck ultrasonography, or when the results would potentially alter the amount of activity of radioiodine to be administered [9]. Pretherapy scans where performed should use low-dose in the range of 1-3 mCi [6,9].
surgical thyroid remnant, seeking to destroy residual thyroid tissue to decrease the risk for recurrent locoregional disease. Although a large numbers of retrospective studies have demonstrated significant reduction in the rates of disease recurrence and cause-specific mortality [11,12], others have failed to show any significant benefits, and due to the generally overall favorable prognosis of DTC, the role of radio-iodine treatment remains debatable in patients with the lowest risk for mortality and is most advantageous in patients with larger tumors (>1.5 cm), or with residual disease after surgery. Most guidelines recommend radioiodine ablation for patients with stages III and IV disease (AJCC sixth edition), all patients with stage II disease younger than age 45 years and most patients with stage II disease 45 years or older, and selected patients with stage I disease, particulary those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and with aggressive histological subtype [6]. Successful remnant ablation is defined as an absence of visible radioiodine uptake on a subsequent diagnostic radioiodine scan. Doses ranging between 30 and 100 mCi of 131 have shown of successful remnant ablation, with larger activities showing higher rates success rates [13,14]. For low risk patients, the minimum possible activity (30-100 mCi) is necessary to achieve successful remnant is recommended. Larger doses (100-200 mCi) are considered appropriate, if residual microscopic disease is suspected or with aggressive tumor histology [6]. In our centre, successful ablation has been achieved in doses ranging from 30 -75 mCi in most cases of the former category (Fig 1). PATIENT PREPARATION To maximize the radioiodine uptake by residual thyroid tissue or thyroid metastases, pretreatment imaging and treatment are preferred when the TSH level in serum is >30 IU/dL. A waiting period of 6 wk is recommended after
RADIOACTIVE IODINE THERAPY Radioactive iodine is used in the following settings: (a) Ablation- healthy thyroid remnant / microscopic DTC (Ablation). (b) Irradiation of non resectable or incompletely resectable DTC. The former procedure(ablation) is a post surgical adjuvant modality, the purpose being complete elimination of thyroid remnants to facilitate treatment of microscopic tumor deposits and increase the sensitivity and specificity of subsequent long-term surveillance with whole-body iodine scans and stimulated thyroglobulin [10]. Postoperative radioiodine remnant ablation is used to eliminate the post-
(a)
(b)
Fig. 1. Remnant ablation d following I-131 therapy. Significant residual thyroid noted in pre therapy scan (a) subsequent follow up scan (b) six months after I-131 therapy shows complete ablation.
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near-total thyroidectomy, before patient can be taken up for therapy. If the patient is thyroxine replacement therapy, the thyroid hormone should be discontinued for 4-6 wk to allow for adequate rise in the TSH level. Some centers also propose a low-iodine diet for 2 wk before diagnostic scanning or 131I therapy to help increase the iodine uptake by functioning thyroid tissue or metastases. Iodine containing medication and medications that can alter iodine uptake and utilization should be avoided before treatment for an appropriate duration of weeks or months depending on their effect on iodine metabolism. COMPLICATIONS OF RADIOIODINE THERAPY Radioiodine is considered to be a reasonably safe therapy. However, it is associated with a cumulative doserelated risk of complications such as acute and chronic salivary gland damage, nasolacrimal duct obstruction, and late complications including gonadal dysfunction and secondary malignancies. Although there exists no definite dose of radioactive iodine that is completely safe nor are there any maximum cumulative established dose limits, with higher individual and cumulative doses there are increased risks of these side effects. Long-term follow-up studies have demonstrated a risk of secondary malignancies like bone and soft tissue malignancies, Leukemia in longterm survivors. This risk of secondary malignancies is doserelated. Other complications include bone marrow toxicity, which vary from minimal transient effects in white blood cell (WBC) and platelet counts, hence administered activities are selected to remain below 200cGy to the bone marrow. Temporary amenorrhea or oligomenorrhea lasting up to 10 months has been reported in 20-25% of women after 131I therapy for thyroid cancer. No definitive evidence of long-term infertility or fetal malformation has been established in women after radioiodine therapy. However, it is recommended that pregnancy should be postponed for 1 year. I-131 is secreted in milk and radioactive therapy should be deferred until a time when lactating women have stopped breast-feeding for at least 6-8 weeks. In men, radioiodine therapy may be associated with oligospermia and elevated serum follicle-stimulating hormone (FSH) levels, which is usually transient, but may become definitive with cumulative dosage. Sperm banking may be considered in men who may receive cumulative radioiodine doses over 400 mCi. Measures like adequate hydration, frequent voiding help to limit Gonadal radiation. LONG-TERM FOLLOW UP Following total or near-total thyroidectomy and thyroid remnant ablation, disease free status is declared when there is no clinical evidence of tumor, no imaging evidence of tumor( no uptake outside the thyroid bed on the post treatment whole body scan, or neck ultrasound, and Apollo Medicine, Vol. 6, No. 4, December 2009
undetectable Tg levels. Subsequently, suppression of thyrotropin with periodic follow up is considered appropriate management in these cases. The degree of suppression needs to be individualized to avoid complications of subclinical hyperthyroidism. The goal of follow up is prevention of recurrence and early detection of metastatic disease. Long term follow-up protocols in most centers include basal and TSH-stimulated serum thyroglobulin (Tg) measurement, iodine-131 whole body scan (WBS) and neck ultrasound. Serum Tg measurement is the most sensitive and specific marker of differentiated thyroid cancer [15]. Undetectable serum Tg levels are found in the large majority of disease-free patients, while elevated concentrations of serum Tg are associated with the presence of residual or metastatic thyroid tissue. As the release of Tg from thyroid cells is , thyrotropin-dependent, a low Tg value while patients are receiving thyrotropin suppressive therapy may be misleading. Tg assays are therefore recommended under TSH stimulation. Screening for the presence of interfering antithyroglobulin antibodies that may give falsely negative Tg results is also recommended. In cases with elevated thyroglobulin levels, WBS under TSH stimulation (either after withdrawal of L-thyroxine therapy or after recombinant human TSH stimulation) and neck ultrasound are the most informative tests for the detection of distant or local metastases. Using this strategy, definitive cure and with a normal quality of life is achievable. TREATMENT OF METATASTATIC DISEASE Distant metastases can occur in upto 10% of differentiated thyroid cancers. Individual prognosis depends upon factors including sites of metastasis (e.g., brain, bone, lung), tumor burden [16]. Improved survival rates have been demonstrated with radioiodine therapy and even in the absence of demonstrable survival benefit, RAIT is useful in significant palliation, reduction of morbidity and improving quality of life. Compared with the initial remnant ablation, the metastases/recurrences detected during follow-up examinations require larger amounts of I-131. Administered amounts generally range from 150 to 250 mCi. In spite of demonstrated benefits, the importance of therapeutic intervention is significantly limited by potential toxicity and determination of appropriate dose is important to limit complications. Among the various methods for determination of therapy dose, “fixed-dose” regimen is the most widely used, with 150 mCi for cervical and pulmonary metastases, and higher doses in the range of 200-250 mCi for skeletal metastases. Another method is to use the largest amount of I-131 that delivers no more than 200 rads to the blood ( assuming this dose reflects bone marrow dose). Lesion dosimetry, quantifies activity in the tumor and is useful with larger tumors that would accumulate sufficient amounts of I-131 to allow for accurate uptake measure-
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ments. Response to therapy is assessed objectively by demonstrating decrease in the size of the lesions and decreasing thyroglobulin levels. Durante, et al [17] reported an overall survival of 92% at 10 yr after initiation of 131I treatment in patients with bone metastases who achieved a negative whole body scan, compared with 19% in those who could not achieve a negative whole body scan. Although complete remission is not frequent in skeletal and pulmonary metastases, partial response or symptomatic improvement in most cases is well documented in our centre, patients with bone metastases have received cumulative doses upto 800 Ci , with achievement of partial to near complete response, as assessed by objectively by whole body scanning (Fig 2), Tg levels estimation and symptom palliation. MANAGEMENT IN PATIENTS WITH A NEGATIVE WHOLE-BODY SCAN AND THE ROLE OF 18FFDG-PET For localizing disease focus in patients without detectable disease by I-131 scan and rising thyroglobulin levels , FDG-PET scanning should be considered, as benefit might be achieved in some by empirical therapy. FDG - PET imaging takes advantage of the increased utilization of FDG in rapidly multiplying cancer cells [18]. However, PET is not useful in patients with well-differentiated thyroid cancer that retain good iodine ability, and the term “flip-flop” pattern, describes the alternating uptake pattern of I-131 and FDG by the papillary or follicular thyroid carcinomas depending on tumor differentiation (Fig. 3) . Various studies have reported sensitivities in the range of 60-94% and specificity of 25-90% for FDG PET in the detection of recurrent or metastatic cancer in patients who have negative radioiodine scans [19]. Management strategies in this
subgroup are varied. Thyroglobulin positive, WBSnegative patients with disease focus not identified on FDGPET scan can be managed with thyroid hormone suppression therapy and monitoring without any additional therapy. Other options include, external beam radiotherapy, chemotherapy, radiofrequency ablation, chemoembolization. RECENT DEVELOPMENTS CT-SPECT in therapy planning in differentiated thyroid cancer SPECT and co registration of CT with SPECT have been recent additions to the nuclear medicine armamentarium which until recently had to rely on planar scintigraphy. Precise anatomic localization, which is critical in therapy planning, was challenging with these techniques. Hybrid single photon emission computed tomography/ computed tomography (SPECT/CT) allows for more precise diagnosis and anatomic localization of disease foci (Fig. 4) , which is particularly useful in differentiating actual disease foci from physiological uptake. Recombinant TSH(rhTSH) in long term follow up Adequate TSH stimulation is required for I-131 imaging and subsequent therapy. Until recently, this was achieved by endogenous TSH stimulation by withdrawal of thyroid hormone. However, the resultant hypothyroidism caused diminished quality of life, more so prolonged hypothyroid state was intolerable in patients with serious coexisting medical conditions. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and hence help overcome the associated morbidity. The use of rhTSH is based on its
Fig. 2. Sequential imaging during treatment of lung metastases demonstrating reduction in volume and number of lung lesions
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(a)
(b)
Fig. 3. FDG-PET scan showing hot spots in the neck, upper mediastinum, the sternum and 12th thoracic vertebra in a patient with negative whole body scan and evidence of regional lymph node metastases cervical ultrasound [20]
ability to stimulate the uptake of radioiodine into thyroid remnants and metastases of thyroid cancer, as well as its ability to stimulate normal or neoplastic thyroid cells to produce thyroglobulin. Currently, approval for rhTSH is limited only for diagnostic purpose i.e., for the detection of recurrent/persistent disease with stimulated thyroglobulin measurement and scintigraphy. Notwithstanding the fact that stimulation of thyroid tissue after RTSH administration is not as intense as after withdrawal, numerous studies worldwide have reported comparable results with rhTSH stimulation compared with conventional thyroxine withdrawl [21,22], two consecutive daily injections of 0.9 mg are recommended for adequate stimulation of TSH [23]. Complications are rare, however, serious side effects like central nervous system deficits, bone pain, and respiratory difficulty related to rapid swelling of thyroid tissue have been infrequently reported. In the coming years, rh TSH appears is likely to play an important role in, role in thyroid cancer monitoring [24]. Dedifferentiation therapy Dedifferentiation has been documented in up to 30% of thyroid cancers resulting in tumors refractory to conventional treatment. In recent years, novel approaches for the treatment of dedifferentiated thyroid carcinomas therapy has been evaluated in vitro and in vivo studies. Apollo Medicine, Vol. 6, No. 4, December 2009
Redifferentiation therapy by either redifferentiating agents like retinoic acid or gene transfer of differentiation-related genes may retard tumor growth and render tumors responsive to conventional therapies. Cell culture experiments in thyroid carcinoma lines show that RA treatment affects thyroid specific functions (type I 52'-deiodinase, sodium/iodide-symporter), and differentiation markers (alkaline phosphatase, CD97), growth, and tumorigenicity. In various clinical studies, about 20-40% of the patients have been reported to respond to RA application [25], as demonstrated by an increased radioiodide uptake. These studies encourage possibility of therapeutic benefit in patients unresponsive to other treatments. FUTURE DIRECTIONS Future therapeutic strategies that hold promise particularly for RAI-non-avid tumor include characterization and cloning of NIS protein and evaluating agents that affect the rate of thyroid-specific gene transcription, i.e., retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, these have shown their potential for induction of redifferentiation, growth inhibition, promotion of apoptosis and cell cycle regulation in various pre clinical studies [20,26,27] but whether these are translated into actual therapeutic strategies remains to be seen.
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Fig. 4. Usefulness of CT-SPECT imaging in localization and defining extent of lesion in a case of follicular Ca with skelelatal metastases.
CONCLUSION For the treatment of differentiated thyroid cancer, surgery, radioiodide therapy, and thyrotropin-suppressive thyroxin application represent established therapeutic measures of proven efficiency, affording a good prognosis for this disease. However, with the more widespread use of radioactive iodine in the management of thyroid cancers,
more understanding of the long term-risks of radioiodine use is required. REFRENCES
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1. Sherman SI. Thyroid carcinoma. Lancet 2003; 361: 501511. 2. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid Apollo Medicine, Vol. 6, No. 4, December 2009
Review Article carcinoma.J Clin Endocrinol Metab 1990; 71:414-423
1995; 80: 2041-2045.
3. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97:418-428. 4. Garib H, Goelner JR. Fine-needle aspiration biopsy of thyroid-an appraisal. Annals of internal medicine. 1993;118:282-289. 5. Friedman M, Pacella BL Jr. Total versus subtotal thyroidectomy. Arguments, approaches, and recommendations. Otolaryngol Clin North Am 1990 ; 23: 413-427. 6. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. The American Thyroid Association Guidelines Taskforce. Thyroid 2006; 16(2): 1-33. 7. Carril JM, Quirce R, Serrano J, Banzo I, Jimenez-Bonilla JF, Tabuenca O, Barquin RG. Total body scintigraphy with thallium-201 and iodine-131 in the follow-up of differentiated thyroid cancer. J Nucl Med 1997; 38: 686692. 8. Hilditch TE, Dempsey MF, Bolster AA, McMenemin RM, Reed NS. Self-stunning in thyroid ablation: Evidence from comparative studies of diagnostic 131I and 123I. Eur JNucl Med Mol Imaging 2002 ; 29:783-788. 9. Park HM, Park YH, Zhou XH. Detection of thyroid remnant/ metastasis without stunning: An ongoing dilemma. Thyroid 1997; 7: 277-280. 10. Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997 ; 7: 265-271. 11. Samaan NA, Schultz PN, Hickey RC, Goepfert H, HaynieTP, Johnson DA, Ordonez NG. The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75: 714-720. 12. Simpson WJ, Panzarella T, Caruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys. 1988;14:1063-1075. 13. Rosario PW, Reis JS, Barroso AL, Rezende LL, Padrao EL, Fagundes TA. Efficacy of low and high 131I doses for thyroid remnant ablation in patients with differentiated thyroid carcinoma based on post-operative cervical uptake.Nucl Med Commun 2004; 25: 1077-1081. 14. Bal C, Padhy AK, Jana S, Pant GS, Basu AK. Prospective and randomized clinical trial to evaluate the optimal dose of 131 I for remnant ablation in patients with differented thyroid carcinoma. Cancer 1996; 77: 2574-2580. 15. Ozata M, Suzuki S, Miyamoto T, Liu TR, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the follow up of patients with treated differentiated thyroid cancer. J Clin Endocrinol Metab. 1994; 79:98-105. 16. Dinneen SF, Valimaki MJ, Bergstralh EJ, Goellner JR, Gorman CA, Hay ID. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab
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17. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli J P, Caillou B, Ricard M, Lumbroso J D, De Vathaire F, Schlumberger M. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91(8): 2892-2899. 18. Joensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma with fluorine-18 fluorodeoxyglucose. J Nucl Med 1987; 28: 910-914. 19. Grunwald F, Schomburg A, Bender H, et al. Fluorine-18fluorodeoxyglucose positron emission tomography in the follow-up of differentiated thyroid cancer. Eur J Nucl Med 1996; 23: 312-319. 20. Khan N, Oriuchi N, Higuchi T, Zhang H, Endo K. PET in the follow-up of differentiated thyroid cancer. British Journal of Radiology 2003; 76: 690-695. 21. Haugen BR, Pacini F, Reiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab.1999; 84: 3877-3885. 22. Luster M, Lippi F, Jarzab B, Perros P, Lassmann M, Reiners C, Pacini F. rhTSH-aided rrther widespread use adioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review.Endocrine Related Cancer 2005;12(1): 49-64. 23. Robbins RJ. Coming of age: Recombinant human thyroidstimulating hormone as a preparation for 131I therapy in thyroid cancer. J Nucl Med.2003; 44:1069-1071. 24. Hoffman T, Ioffe V, Tuttle M, et al. Near-lethal respiratory failure after recombinant human thyroid-stimulating hormone use in a patient with metastatic thyroid carcinoma. Thyroid 2003; 13: 827-830. 25. Cornelia Schmutzler, Josef Köhrle. Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid. 2000, 10(5): 393-406. 26. Jin-Woo Park, Rasa Zarnegar, Hajime Kanauchi, Mariwil G. Wong, William C. Hyun, David G. Ginzinger, Margaret Lobo, Philip Cotter, Quan-Yang Duh, Orlo H. Clark. Troglitazone, the Peroxisome proliferator-activated receptor-J agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid 2005; 15, 3: 222-231. 27. Neziha Cengic, Claire H. Baker, Martin Schütz, Burkhard Göke, John C. Morris’ Christine Spitzweg. A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression. J Clin Endocrino Metab 2005; 90(8): 4457-4464. 28. Sarlis NJ. Metastatic Thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research. Current Drug Targets, Immune Endocrine and Metabolic Disorders 2001; 1(2): 103-115.
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I-131 IN THE MANAGEMENT OF DIFFERENTIATED THYROID CANCER – AN UPDATE ON CURRENT RECOMMENDATIONS AND PRACTICES Uma Ravishankar, Surbhi Pande and N Savita Department of Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Uma Ravishankar, Senior Consultant, Department of Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. I-131 is an established diagnostic and therapeutic modality for patients with functioning residual disease after surgery, and is widely used for remnant ablation and treating recurrence or metastatic disease. Over the years, evidence has grown demonstrating the benefits of combining surgery with radioactive iodine therapy, which has resulted in higher cure rates, lower recurrence, improved quality of life and longer survival. Management of well differentiated thyroid cancer in the current era is a multidisciplinary approach, comprising surgery, endocrinology and nuclear medicine, and the managemnt strategy include thyroidectomy, replacement with thyroid hormone and post-surgical radioactive iodine (RAI) ablation where indicated. This article briefly reviews the currently reccomended clinical practice guidelines on management of thyroid cancer, and our experiences at Indraprastha Apollo Hospital in the diagnosis and treatment of well differentiated thyroid cancer. Key words: I-131, Well differentiated thyroid cancer, Remnant ablation.
INTRODUCTION Thyroid cancer accounts for approximately 1% of all carcinomas and is the most common endocrine malignancy, occurring in any age group, although it is most common after age 30. Peak onset ages reported to be 30-50 years. Females are more likely to have thyroid cancer in a ratio of three to one. Prior external irradiation in childhood and a family history of thyroid cancer are predisposing factors thyroid malignancy and preexisting benign thyroid diseases like nodules in individuals younger than 20 years or older than 60 years, are additional risk factors. Types of thyroid cancer • • • •
Papillary Follicular and/or Hürthle cell. Medullary Others (Anaplastic/ Primary thyroid lymphoma)
Papillary tumors (including mixed papillary-follicular cancer) are the most common of all thyroid cancers (>70%) [1]. This subtype has a high cure rate with ten year survival rates for all patients estimated at around 80-90%. Diagnosis is established by presence of follicular differerentiation and distinctive nuclear features. Variants of this subtype include follicular variant, diffuse scelerosing, tall and columnar cell variants. Papillary Ca is frequently multifocal and can be bilateral in 20-80% cases. It commonly metastasizes to cervical 347
lymph node, and nodal metastases results in higher recurrence rate but not a higher mortality rate. Distant metastasis is uncommon, and lung and bone are the most common sites.Malignant epithelial tumor with evidence of follicular cell differentiation but lacking diagnostic features of papillary carcinoma are labelled as follicular cancers. These account for about 10% of cases of all thyroid cancers. Hürtle cell cancer is a tumor composed of more 75% oncocytic cells and is usually classified with follicular tumors. It has been classified as oxyphillic variant of follicular thyroid carcinoma by WHO. Medullary cancer of the thyroid is significantly less common, but with worse prognosis. These cancers tend to spread to large numbers of lymph nodes very early on, and hence require a much more aggressive approach than the more localized papillary and follicular cancers. Approximately 25% of MTCs are familial, usually occurring as a part of syndrome complex of MEN IIa or IIb or familial (non-MEN). Undifferentiated (anaplastic) thyroid cancer is the least common and most aggressive form of thyroid cancer, being rapidly fatal within months of the diagnosis. Histological verification of this subtype is essential as cancers such as lymphomas, and MTCs, which require different therapeutic approaches are occasionally confused with undifferentiated cancers. The term differentiated thyroid cancer is defined as carcinoma derived from follicular epithelium and retaining basic biological characteristics of normal thyroid tissue, and Apollo Medicine, Vol. 6, No. 4, December 2009
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includes both papillary cancer and follicular cancer. Separating patients with differentiated cancers into those with good to excellent prognoses from those with poorer prognoses is important for optimizing treatment plans. Prognostic factors include patient characteristics (older age, male gender and family history at higher risk), histological subtype ( tall cell and columnar variants of papillary, widely invasive follicular and anaplastic Ca have poorer prognoses), tumor burden, with larger tumors and those extending beyond capsule, bilateral cervical nodal or mediastinal involvement and distant metastases are reported to have an overall poorer prognosis [2]. Initial treatment is also an important prognostic factor, and longer time of treatment interval from diagnosis, incomplete resection and non administration I-131 where indicated leading to higher recurrence rates and mortality [3]. DIAGNOSTIC EVALUATION Most well differentiated thyroid cancers present as an asymptomatic nodule, although larger ones may produce symptoms like hoarseness of voice and dysphagia. Laboratory tests such as serum TSH are not useful in differentiating benign from malignant nodules and are generally performed to exclude thyroid dysfunction in cases with thyroid nodules. Fine-needle Aspiration Cytology (FNAC) remains the cornerstone for evaluation of solitary thyroid nodules or dominant nodules within multinodular goiters, with a false negative rate of less than 5% and a falsepositive rate of 1% [4]. The 4 types of interpretations include (a) benign, (b) malignant, (c) suspicious for a follicular/Hürthle cell tumor, and (d) insufficient for a diagnosis repeat FNAC is considered in the event of insufficient diagnosis in the first instance. Approximately 10% of FNA findings remain non diagnostic/ indeterminate. For solitary nodules that are repeatedly non diagnostic on biopsy, the risk of malignancy is not established, but is reported to be to 5-10%. Although many molecular markers like antigalectin 3, telomerase etc have been evaluated to improve diagnostic accuracy for these nodules, none are currently recommended in routine practice. A finding of follicular or Hürthle cell tumor warrants further evaluation and management, since these two entities can only be differentiated by the presence or absence of capsular or vascular invasion on histological examination of surgical specimens. Radionuclide scan with I-123 or 99m pertechnetate is useful in mapping functional activity in known nodules. High resolution thyroid ultrasonography defines the size and number of nodules, and is also useful in discovering sub clinical nodules and in guiding FNA in non palpable nodules. Ultrasound identifies suspicious cervical lymhadenopathy in 20-31% of cases and a preoperative neck ultrasound for the contralateral lobe and cervical (central and bilateral) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic Apollo Medicine, Vol. 6, No. 4, December 2009
findings on biopsy. Other imaging modalities like computed tomography or magnetic resonance although not routinely indicated, may be helpful in morphological assessment of tissue mass extent and involvement of surrounding structures and in determining the extent of a retrosternal goiter or the presence or degree of tracheal compression. MANAGEMENT OF DIFFERENTIATED THYROID CANCER Goals of initial therapy of differentiated thyroid cancer include (a) removal of primary tumor, the thyroid capsule, and involved cervical lymph node as completeness of surgical resection determines long term outcome (b) facilitate postoperative treatment with radioactive iodine appropriate (c) to permit accurate long-term surveillance for disease recurrence and (d) to minimize the risk of disease recurrence and metastatic spread. Surgery Although surgery is undoubtedly the established choice so far as primary treatment is concerned. Considerable debate exists as regards the extent of optimal surgery in well differentiated thyroid carcinomas [5], with some experts being of the opinion that simply removing the lobe of the thyroid which harbors the tumor and the isthmus will provide as good a chance of cure as removing the entire thyroid in case of small tumors not invading other tissues. These proponents of conservative surgical therapy cite increased risk of hyperparathyroidism and recurrent laryngeal nerve injury in patients undergoing total thyroidectomy and relate the low rate of clinical tumor recurrence (5-20%) despite the fact that small amounts of tumor cells can be found in up to 88% in the contralateral lobe. In contrast, some advocate the more aggressive approach of total thyroidectomy. In experienced hands,the incidence of recurrent nerve injury and permanent hyperparathyroidism are quite low (about 2%). More importantly, studies have established that patients with total thyroidectomy followed by radioiodine therapy and thyroid suppression have a significantly lower recurrence rate and lower mortality when tumors are greater than 1.5cm. Based on these studies and the natural history and epidemiology of papillary carcinoma, current recommendations propose near-total or total thyroidectomy in most case with thyroid lobectomy alone is deemed sufficient treatment for small, low-risk, isolated, intrathyroidal papillary carcinomas in the absence of cervical nodal metastases [5,6]. ROLE OF RADIOACTIVE IODINE IN THE POST SURGICAL SETTING Radiobiology of I-131
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Radioactive iodine treatment (RAIT) is defined as the
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selective irradiation of thyroid tissue by systemic administration of I-131. The use of radioiodine for thyroid cancers is based on radiation-induced cell damage caused by the emitted high-energy E-radiation . I-131 is produced by neutron irradiation of tellurium or as a by product of Uranium fission. It is a E-emitting radionuclide with a maximum energy of 606 keV and an average energy of 191 keV. Average range of Eparticles in tissue is 0.8 mm and has a principal J-ray of 364 keV. The magnitude of cell functional damage is proportional to the absorbed dose. Only well-differentiated thyroid cancer cells concentrate radioiodine to a significant degree. These include papillary, follicular, and mixed papillary-follicular cancers. Anaplastic thyroid cancers do not concentrate radioiodine. ROLE OF PRE THERAPY RADIOIODINE SCAN Radioiodine WBS detects presence of iodine-avid thyroid tissue, including the presence of residual disease in the postoperative setting [7]. In cases with large thyroid remnant, the scan is dominated by uptake within the remnant and this can potentially mask extrathyroidal disease, resulting in decreased sensitivity of lesion detection. Some proponents propose avoiding pre therapy radioiodine scans altogether because of possibility of a pretreatment diagnostic dose 131 I-induced stunning of thyrocytes. Stunning has been shown to occur with higher doses of I-131 (5-10 mCi), increased duration between the diagnostic dose and therapy, and is not appreciated at lower doses (1-3 mCi) [8]. In recent years, there has been an increasing trend to avoid pre therapy scan altogether. Most guidelines recommend pre therapy scans with measurement of thyroid bed uptake in situations where the extent of the thyroid remnant cannot be accurately ascertained from neck ultrasonography, or when the results would potentially alter the amount of activity of radioiodine to be administered [9]. Pretherapy scans where performed should use low-dose in the range of 1-3 mCi [6,9].
surgical thyroid remnant, seeking to destroy residual thyroid tissue to decrease the risk for recurrent locoregional disease. Although a large numbers of retrospective studies have demonstrated significant reduction in the rates of disease recurrence and cause-specific mortality [11,12], others have failed to show any significant benefits, and due to the generally overall favorable prognosis of DTC, the role of radio-iodine treatment remains debatable in patients with the lowest risk for mortality and is most advantageous in patients with larger tumors (>1.5 cm), or with residual disease after surgery. Most guidelines recommend radioiodine ablation for patients with stages III and IV disease (AJCC sixth edition), all patients with stage II disease younger than age 45 years and most patients with stage II disease 45 years or older, and selected patients with stage I disease, particulary those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and with aggressive histological subtype [6]. Successful remnant ablation is defined as an absence of visible radioiodine uptake on a subsequent diagnostic radioiodine scan. Doses ranging between 30 and 100 mCi of 131 have shown of successful remnant ablation, with larger activities showing higher rates success rates [13,14]. For low risk patients, the minimum possible activity (30-100 mCi) is necessary to achieve successful remnant is recommended. Larger doses (100-200 mCi) are considered appropriate, if residual microscopic disease is suspected or with aggressive tumor histology [6]. In our centre, successful ablation has been achieved in doses ranging from 30 -75 mCi in most cases of the former category (Fig 1). PATIENT PREPARATION To maximize the radioiodine uptake by residual thyroid tissue or thyroid metastases, pretreatment imaging and treatment are preferred when the TSH level in serum is >30 IU/dL. A waiting period of 6 wk is recommended after
RADIOACTIVE IODINE THERAPY Radioactive iodine is used in the following settings: (a) Ablation- healthy thyroid remnant / microscopic DTC (Ablation). (b) Irradiation of non resectable or incompletely resectable DTC. The former procedure(ablation) is a post surgical adjuvant modality, the purpose being complete elimination of thyroid remnants to facilitate treatment of microscopic tumor deposits and increase the sensitivity and specificity of subsequent long-term surveillance with whole-body iodine scans and stimulated thyroglobulin [10]. Postoperative radioiodine remnant ablation is used to eliminate the post-
(a)
(b)
Fig. 1. Remnant ablation d following I-131 therapy. Significant residual thyroid noted in pre therapy scan (a) subsequent follow up scan (b) six months after I-131 therapy shows complete ablation.
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near-total thyroidectomy, before patient can be taken up for therapy. If the patient is thyroxine replacement therapy, the thyroid hormone should be discontinued for 4-6 wk to allow for adequate rise in the TSH level. Some centers also propose a low-iodine diet for 2 wk before diagnostic scanning or 131I therapy to help increase the iodine uptake by functioning thyroid tissue or metastases. Iodine containing medication and medications that can alter iodine uptake and utilization should be avoided before treatment for an appropriate duration of weeks or months depending on their effect on iodine metabolism. COMPLICATIONS OF RADIOIODINE THERAPY Radioiodine is considered to be a reasonably safe therapy. However, it is associated with a cumulative doserelated risk of complications such as acute and chronic salivary gland damage, nasolacrimal duct obstruction, and late complications including gonadal dysfunction and secondary malignancies. Although there exists no definite dose of radioactive iodine that is completely safe nor are there any maximum cumulative established dose limits, with higher individual and cumulative doses there are increased risks of these side effects. Long-term follow-up studies have demonstrated a risk of secondary malignancies like bone and soft tissue malignancies, Leukemia in longterm survivors. This risk of secondary malignancies is doserelated. Other complications include bone marrow toxicity, which vary from minimal transient effects in white blood cell (WBC) and platelet counts, hence administered activities are selected to remain below 200cGy to the bone marrow. Temporary amenorrhea or oligomenorrhea lasting up to 10 months has been reported in 20-25% of women after 131I therapy for thyroid cancer. No definitive evidence of long-term infertility or fetal malformation has been established in women after radioiodine therapy. However, it is recommended that pregnancy should be postponed for 1 year. I-131 is secreted in milk and radioactive therapy should be deferred until a time when lactating women have stopped breast-feeding for at least 6-8 weeks. In men, radioiodine therapy may be associated with oligospermia and elevated serum follicle-stimulating hormone (FSH) levels, which is usually transient, but may become definitive with cumulative dosage. Sperm banking may be considered in men who may receive cumulative radioiodine doses over 400 mCi. Measures like adequate hydration, frequent voiding help to limit Gonadal radiation. LONG-TERM FOLLOW UP Following total or near-total thyroidectomy and thyroid remnant ablation, disease free status is declared when there is no clinical evidence of tumor, no imaging evidence of tumor( no uptake outside the thyroid bed on the post treatment whole body scan, or neck ultrasound, and Apollo Medicine, Vol. 6, No. 4, December 2009
undetectable Tg levels. Subsequently, suppression of thyrotropin with periodic follow up is considered appropriate management in these cases. The degree of suppression needs to be individualized to avoid complications of subclinical hyperthyroidism. The goal of follow up is prevention of recurrence and early detection of metastatic disease. Long term follow-up protocols in most centers include basal and TSH-stimulated serum thyroglobulin (Tg) measurement, iodine-131 whole body scan (WBS) and neck ultrasound. Serum Tg measurement is the most sensitive and specific marker of differentiated thyroid cancer [15]. Undetectable serum Tg levels are found in the large majority of disease-free patients, while elevated concentrations of serum Tg are associated with the presence of residual or metastatic thyroid tissue. As the release of Tg from thyroid cells is , thyrotropin-dependent, a low Tg value while patients are receiving thyrotropin suppressive therapy may be misleading. Tg assays are therefore recommended under TSH stimulation. Screening for the presence of interfering antithyroglobulin antibodies that may give falsely negative Tg results is also recommended. In cases with elevated thyroglobulin levels, WBS under TSH stimulation (either after withdrawal of L-thyroxine therapy or after recombinant human TSH stimulation) and neck ultrasound are the most informative tests for the detection of distant or local metastases. Using this strategy, definitive cure and with a normal quality of life is achievable. TREATMENT OF METATASTATIC DISEASE Distant metastases can occur in upto 10% of differentiated thyroid cancers. Individual prognosis depends upon factors including sites of metastasis (e.g., brain, bone, lung), tumor burden [16]. Improved survival rates have been demonstrated with radioiodine therapy and even in the absence of demonstrable survival benefit, RAIT is useful in significant palliation, reduction of morbidity and improving quality of life. Compared with the initial remnant ablation, the metastases/recurrences detected during follow-up examinations require larger amounts of I-131. Administered amounts generally range from 150 to 250 mCi. In spite of demonstrated benefits, the importance of therapeutic intervention is significantly limited by potential toxicity and determination of appropriate dose is important to limit complications. Among the various methods for determination of therapy dose, “fixed-dose” regimen is the most widely used, with 150 mCi for cervical and pulmonary metastases, and higher doses in the range of 200-250 mCi for skeletal metastases. Another method is to use the largest amount of I-131 that delivers no more than 200 rads to the blood ( assuming this dose reflects bone marrow dose). Lesion dosimetry, quantifies activity in the tumor and is useful with larger tumors that would accumulate sufficient amounts of I-131 to allow for accurate uptake measure-
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ments. Response to therapy is assessed objectively by demonstrating decrease in the size of the lesions and decreasing thyroglobulin levels. Durante, et al [17] reported an overall survival of 92% at 10 yr after initiation of 131I treatment in patients with bone metastases who achieved a negative whole body scan, compared with 19% in those who could not achieve a negative whole body scan. Although complete remission is not frequent in skeletal and pulmonary metastases, partial response or symptomatic improvement in most cases is well documented in our centre, patients with bone metastases have received cumulative doses upto 800 Ci , with achievement of partial to near complete response, as assessed by objectively by whole body scanning (Fig 2), Tg levels estimation and symptom palliation. MANAGEMENT IN PATIENTS WITH A NEGATIVE WHOLE-BODY SCAN AND THE ROLE OF 18FFDG-PET For localizing disease focus in patients without detectable disease by I-131 scan and rising thyroglobulin levels , FDG-PET scanning should be considered, as benefit might be achieved in some by empirical therapy. FDG - PET imaging takes advantage of the increased utilization of FDG in rapidly multiplying cancer cells [18]. However, PET is not useful in patients with well-differentiated thyroid cancer that retain good iodine ability, and the term “flip-flop” pattern, describes the alternating uptake pattern of I-131 and FDG by the papillary or follicular thyroid carcinomas depending on tumor differentiation (Fig. 3) . Various studies have reported sensitivities in the range of 60-94% and specificity of 25-90% for FDG PET in the detection of recurrent or metastatic cancer in patients who have negative radioiodine scans [19]. Management strategies in this
subgroup are varied. Thyroglobulin positive, WBSnegative patients with disease focus not identified on FDGPET scan can be managed with thyroid hormone suppression therapy and monitoring without any additional therapy. Other options include, external beam radiotherapy, chemotherapy, radiofrequency ablation, chemoembolization. RECENT DEVELOPMENTS CT-SPECT in therapy planning in differentiated thyroid cancer SPECT and co registration of CT with SPECT have been recent additions to the nuclear medicine armamentarium which until recently had to rely on planar scintigraphy. Precise anatomic localization, which is critical in therapy planning, was challenging with these techniques. Hybrid single photon emission computed tomography/ computed tomography (SPECT/CT) allows for more precise diagnosis and anatomic localization of disease foci (Fig. 4) , which is particularly useful in differentiating actual disease foci from physiological uptake. Recombinant TSH(rhTSH) in long term follow up Adequate TSH stimulation is required for I-131 imaging and subsequent therapy. Until recently, this was achieved by endogenous TSH stimulation by withdrawal of thyroid hormone. However, the resultant hypothyroidism caused diminished quality of life, more so prolonged hypothyroid state was intolerable in patients with serious coexisting medical conditions. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and hence help overcome the associated morbidity. The use of rhTSH is based on its
Fig. 2. Sequential imaging during treatment of lung metastases demonstrating reduction in volume and number of lung lesions
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(a)
(b)
Fig. 3. FDG-PET scan showing hot spots in the neck, upper mediastinum, the sternum and 12th thoracic vertebra in a patient with negative whole body scan and evidence of regional lymph node metastases cervical ultrasound [20]
ability to stimulate the uptake of radioiodine into thyroid remnants and metastases of thyroid cancer, as well as its ability to stimulate normal or neoplastic thyroid cells to produce thyroglobulin. Currently, approval for rhTSH is limited only for diagnostic purpose i.e., for the detection of recurrent/persistent disease with stimulated thyroglobulin measurement and scintigraphy. Notwithstanding the fact that stimulation of thyroid tissue after RTSH administration is not as intense as after withdrawal, numerous studies worldwide have reported comparable results with rhTSH stimulation compared with conventional thyroxine withdrawl [21,22], two consecutive daily injections of 0.9 mg are recommended for adequate stimulation of TSH [23]. Complications are rare, however, serious side effects like central nervous system deficits, bone pain, and respiratory difficulty related to rapid swelling of thyroid tissue have been infrequently reported. In the coming years, rh TSH appears is likely to play an important role in, role in thyroid cancer monitoring [24]. Dedifferentiation therapy Dedifferentiation has been documented in up to 30% of thyroid cancers resulting in tumors refractory to conventional treatment. In recent years, novel approaches for the treatment of dedifferentiated thyroid carcinomas therapy has been evaluated in vitro and in vivo studies. Apollo Medicine, Vol. 6, No. 4, December 2009
Redifferentiation therapy by either redifferentiating agents like retinoic acid or gene transfer of differentiation-related genes may retard tumor growth and render tumors responsive to conventional therapies. Cell culture experiments in thyroid carcinoma lines show that RA treatment affects thyroid specific functions (type I 52'-deiodinase, sodium/iodide-symporter), and differentiation markers (alkaline phosphatase, CD97), growth, and tumorigenicity. In various clinical studies, about 20-40% of the patients have been reported to respond to RA application [25], as demonstrated by an increased radioiodide uptake. These studies encourage possibility of therapeutic benefit in patients unresponsive to other treatments. FUTURE DIRECTIONS Future therapeutic strategies that hold promise particularly for RAI-non-avid tumor include characterization and cloning of NIS protein and evaluating agents that affect the rate of thyroid-specific gene transcription, i.e., retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, these have shown their potential for induction of redifferentiation, growth inhibition, promotion of apoptosis and cell cycle regulation in various pre clinical studies [20,26,27] but whether these are translated into actual therapeutic strategies remains to be seen.
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Fig. 4. Usefulness of CT-SPECT imaging in localization and defining extent of lesion in a case of follicular Ca with skelelatal metastases.
CONCLUSION For the treatment of differentiated thyroid cancer, surgery, radioiodide therapy, and thyrotropin-suppressive thyroxin application represent established therapeutic measures of proven efficiency, affording a good prognosis for this disease. However, with the more widespread use of radioactive iodine in the management of thyroid cancers,
more understanding of the long term-risks of radioiodine use is required. REFRENCES
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1. Sherman SI. Thyroid carcinoma. Lancet 2003; 361: 501511. 2. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid Apollo Medicine, Vol. 6, No. 4, December 2009
Review Article carcinoma.J Clin Endocrinol Metab 1990; 71:414-423
1995; 80: 2041-2045.
3. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97:418-428. 4. Garib H, Goelner JR. Fine-needle aspiration biopsy of thyroid-an appraisal. Annals of internal medicine. 1993;118:282-289. 5. Friedman M, Pacella BL Jr. Total versus subtotal thyroidectomy. Arguments, approaches, and recommendations. Otolaryngol Clin North Am 1990 ; 23: 413-427. 6. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. The American Thyroid Association Guidelines Taskforce. Thyroid 2006; 16(2): 1-33. 7. Carril JM, Quirce R, Serrano J, Banzo I, Jimenez-Bonilla JF, Tabuenca O, Barquin RG. Total body scintigraphy with thallium-201 and iodine-131 in the follow-up of differentiated thyroid cancer. J Nucl Med 1997; 38: 686692. 8. Hilditch TE, Dempsey MF, Bolster AA, McMenemin RM, Reed NS. Self-stunning in thyroid ablation: Evidence from comparative studies of diagnostic 131I and 123I. Eur JNucl Med Mol Imaging 2002 ; 29:783-788. 9. Park HM, Park YH, Zhou XH. Detection of thyroid remnant/ metastasis without stunning: An ongoing dilemma. Thyroid 1997; 7: 277-280. 10. Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997 ; 7: 265-271. 11. Samaan NA, Schultz PN, Hickey RC, Goepfert H, HaynieTP, Johnson DA, Ordonez NG. The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75: 714-720. 12. Simpson WJ, Panzarella T, Caruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys. 1988;14:1063-1075. 13. Rosario PW, Reis JS, Barroso AL, Rezende LL, Padrao EL, Fagundes TA. Efficacy of low and high 131I doses for thyroid remnant ablation in patients with differentiated thyroid carcinoma based on post-operative cervical uptake.Nucl Med Commun 2004; 25: 1077-1081. 14. Bal C, Padhy AK, Jana S, Pant GS, Basu AK. Prospective and randomized clinical trial to evaluate the optimal dose of 131 I for remnant ablation in patients with differented thyroid carcinoma. Cancer 1996; 77: 2574-2580. 15. Ozata M, Suzuki S, Miyamoto T, Liu TR, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the follow up of patients with treated differentiated thyroid cancer. J Clin Endocrinol Metab. 1994; 79:98-105. 16. Dinneen SF, Valimaki MJ, Bergstralh EJ, Goellner JR, Gorman CA, Hay ID. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab
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17. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli J P, Caillou B, Ricard M, Lumbroso J D, De Vathaire F, Schlumberger M. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91(8): 2892-2899. 18. Joensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma with fluorine-18 fluorodeoxyglucose. J Nucl Med 1987; 28: 910-914. 19. Grunwald F, Schomburg A, Bender H, et al. Fluorine-18fluorodeoxyglucose positron emission tomography in the follow-up of differentiated thyroid cancer. Eur J Nucl Med 1996; 23: 312-319. 20. Khan N, Oriuchi N, Higuchi T, Zhang H, Endo K. PET in the follow-up of differentiated thyroid cancer. British Journal of Radiology 2003; 76: 690-695. 21. Haugen BR, Pacini F, Reiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab.1999; 84: 3877-3885. 22. Luster M, Lippi F, Jarzab B, Perros P, Lassmann M, Reiners C, Pacini F. rhTSH-aided rrther widespread use adioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review.Endocrine Related Cancer 2005;12(1): 49-64. 23. Robbins RJ. Coming of age: Recombinant human thyroidstimulating hormone as a preparation for 131I therapy in thyroid cancer. J Nucl Med.2003; 44:1069-1071. 24. Hoffman T, Ioffe V, Tuttle M, et al. Near-lethal respiratory failure after recombinant human thyroid-stimulating hormone use in a patient with metastatic thyroid carcinoma. Thyroid 2003; 13: 827-830. 25. Cornelia Schmutzler, Josef Köhrle. Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid. 2000, 10(5): 393-406. 26. Jin-Woo Park, Rasa Zarnegar, Hajime Kanauchi, Mariwil G. Wong, William C. Hyun, David G. Ginzinger, Margaret Lobo, Philip Cotter, Quan-Yang Duh, Orlo H. Clark. Troglitazone, the Peroxisome proliferator-activated receptor-J agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid 2005; 15, 3: 222-231. 27. Neziha Cengic, Claire H. Baker, Martin Schütz, Burkhard Göke, John C. Morris’ Christine Spitzweg. A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression. J Clin Endocrino Metab 2005; 90(8): 4457-4464. 28. Sarlis NJ. Metastatic Thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research. Current Drug Targets, Immune Endocrine and Metabolic Disorders 2001; 1(2): 103-115.
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