Radioiodine therapy (RIT) is an integral component in the treatment of differentiated thyroid cancer (DTC). Patients usually undergo RIT as initial therapy or later in the case of recurrent or persistent disease. The most important requirement for a successful RIT is the ability of metastases and thyroid (remnant) tissue to accumulate radioiodine. In order to calculate the achievable absorbed radiation dose for a lesion, volume and iodine kinetics in the lesion need to be determined. Pretherapeutic imaging and dosimetry with 124I PET provide the methodology to answer these questions.
- 124I PET/CT
- thyroid cancer
Thyroid cancer is divided into differentiated thyroid cancer (DTC) and undifferentiated thyroid cancer. In contrast to the undifferentiated thyroid cancer, the vast majority of the DTC accumulates iodine in the tumour cells. Utilizing this characteristic, DTC patients can undergo radioiodine therapy (RIT). RIT of DTC patients provides a very effective therapy with only minimal side effects using standard activities, which is established for more than half a century. Patients are treated according to their tumour stage. Low-risk patients usually undergo a single RIT with activities up to 4 GBq 131I. High-risk patients undergo at least one or several RIT with higher activities [1, 2]. While performing RIT with high activities of 131I, the organs at risk need specific attention. These are the bone marrow and the lung, especially in case of multiple metastases. The amount of 131I activity and the number of RIT depend on the results of the first RIT: if metastases were detected in the posttherapeutic scan, further RIT may be necessary for an effective treatment of metastases. Therefore, a pretherapeutic diagnostic, which detects iodine avid metastases, is desirable. The same holds for the first RIT for patients with a high likelihood for metastases. The pretherapeutic risk stratification is one of the greatest challenges in treating DTC patients. Although the overall prognosis for the most DTC patients is excellent , unfortunately, some DTC patients suffer from recurrences or persistent disease. These patients have already undergone RIT. In cases of recurrent or persistent disease, the cancer cells often show less up to none radioiodine uptake. Patients with low or missing radioiodine uptake would not or would only slightly benefit from an additional RIT . Therefore, the knowledge of the localization and the radioiodine uptake level of lesions have great influence on therapy decision and the amount of therapeutic activity.
Pretherapeutic imaging of DTC patients can be performed with different radioiodine isotopes and the corresponding imaging modalities. 131I as diagnostic isotope is used since decades. Usually, activities up to 185 MBq 131I are administered . Another radioiodine isotope for pretherapeutic imaging is 123I, which is hardly used due to its lower imaging sensitivity and higher costs . Both isotopes can be visualized by planar scintigraphies with a gamma camera or as 3D imaging with a single photon emission tomography (SPECT) camera. Compared to positron emission tomography (PET), the spatial resolution of gamma cameras is lower. However, radioiodine diagnostics using 131I prior to intended RIT is not advisable mainly for two reasons. First, until today it is not possible to derive reliable lesion dosimetry data from 131I scans. Second, 131I imaging needs relative high activities resulting in high radiation doses. It is well known, that this leads to a so called stunning and, thus, reduces the response of subsequent RIT .
124I PET in combination with computed tomography (CT) overcomes both problems. It offers optimal imaging to detect radioiodine uptake in tumour cells before patients undergo RIT, while only low 124I activities are required compared to 131I imaging [7–11]. Stunning is unlikely and was not reported yet . In addition, pretherapeutic 124I diagnostic provides, in comparison with 131I and 123I, a higher quantitative capacity to perform a reliable lesion dosimetry. This enables a tailor-made RIT with optimized absorbed tumour doses and an 131I activity, which is considered to be safe for the patient, based on the blood dosimetry.
2. Patient preparation, 124I application and PET(/CT) imaging
There are two important requirements for a successful performance of 124I PET(/CT) diagnostics or RIT: First, all patients are put on a low iodine diet. This is important to increase the radioiodine uptake of the tumour cells. After performing a CT scan with contrast agents containing iodine, for example, the tumour cells are saturated with iodine and would show only a low radioiodine uptake. Therefore, any iodine contamination has to be avoided to ensure a good radioiodine uptake during diagnostic imaging or therapy. Second, the tumour cells have to be stimulated to achieve a high radioiodine uptake. The increase of the thyroid stimulating hormone (TSH) can be reached on two ways: endogenous or exogenous stimulation. The endogenous stimulation is usually chosen after initial thyroidectomy. Patients have to stay on hormone withdrawal for about 4 weeks, until the TSH serum concentration exceeds 30 mU/l [2, 5]. During this time, patients may experience hypothyroid symptoms such as fatigue, listlessness, depression and concentration disorders. The other way is an exogenous stimulation with recombinant human TSH (rhTSH). The rhTSH is administered via an intramuscular injection two and one day before diagnostic imaging or treatment. The exogenous stimulation spares patients having the hypothyroid symptoms. Moreover, a lower blood dose was reported in rhTSH stimulated patients [12, 13] compared to endogenous stimulation. However, the equivalence of therapeutic efficiency concerning tumour elimination under rhTSH stimulation is not proven.
124I is a positron emitting nuclide with a half-life of 4.2 days. Like many other positron emitting nuclides, 124I is produced in a cyclotron. Under endogenous or exogenous TSH stimulation, 124I can be administered in two different ways: orally or intravenously. The amount of administered 124I activities reported in the literature is between 25 MBq and 74 MBq [7, 14, 15].
In the time of combined PET/CT scanners, it is much easier to locate focal radioiodine uptake for example in the neck . The new scanner generation provides fast scans with an acquisition time of e.g. 15 min for a scan from thigh to head. Besides the scan parameters and the scanner properties, the time point of scan is very important. In the beginning of 124I PET(/CT) imaging, multiple scans were performed at 4, 24, 48, 72, and ≥96 h after 124I application. This time and resource consuming approach has been optimized and the necessary scans could be reduced to 2 time points: 24 and 96 h after 124I application . The first scan 24 h after 124I application enables the detection of focal pathological iodine uptake as correlate for metastases or local relapse. This scan is sufficient for diagnostic purpose. The first and second scans are mainly needed for lesion dosimetry to estimate the lesion absorbed (radiation) dose during RIT (details see below). However, occasionally, weakly radioiodine accumulating metastases only show uptake in the late scan.
3. 124I PET(/CT) in initial DTC staging
The RIT is crucial for an effective treatment of DTC [17, 18]. Patients with higher initial tumour stage or advanced disease with lymph node or distant metastases routinely undergo RIT with higher 131I activities or several RIT. The knowledge of metastases prior to first RIT would be beneficial for therapy planning. If no metastases are present, lower activities of 131I would be reasonable. Patients with many metastases, especially bone or pulmonary metastases, should be treated carefully because of bone marrow toxicity and the risk of radiation-related pneumonitis or lung fibrosis [19, 20].
Another advantage of pretherapeutic 124I PET is the re-staging and especially up-staging in patients with suspect findings in sonography. Shortly before RIT (about three weeks after thyroidectomy) patients should undergo sonography of the neck. If conspicuous lymph nodes are present, additional clarification is necessary to adapt therapy management. In this process, 124I PET offers the possibility to detect focal iodine uptake in case of lymph node metastases and therapy activity of 131I can be adapted. If no radioiodine uptake was found in conspicuous lymph nodes, it might be a reactive lymph node or a radioiodine negative lymph node metastasis; both will not be affected by the RIT.
During the first RIT, there is usually focal radioiodine uptake in the thyroid bed in accordance with thyroid remnant tissues. Other focal radioiodine uptake located beyond the thyroid bed is suspicious for malignancy, for example in the neck is typical for lymph node metastases.
4. 124I PET(/CT) in patients with persisting or recurrent thyroid cancer
In the clinical course of patients with DTC, some patients suffer from tumour persistence after initial RIT or experience a relapse of DTC at a later stage. These patients mostly present an elevated and/or increasing serum level of thyroglobulin. Sometimes new tissue in the thyroid bed or suspect lymph nodes can be detected in sonography of the neck as a correlate. The most preferable therapy option would be an additional RIT in these cases. Unfortunately, thyroid cancer cells can dedifferentiate and partially or completely lose the ability to accumulate iodine. These patients with the so-called radioiodine negative metastases do not or only slightly profit from additional RIT. Other therapies such as surgery or external beam radiotherapy would be the therapy of choice in radioiodine negative metastases. But not all patients are radioiodine negative in case of recurrent disease. Therefore, a selection must be performed prior to futile RIT.
After initial RIT and thyroid remnant ablation, no pathological focal iodine uptake should be visible. Therefore, every focal uptake, for example in the neck or lung, is highly suspect for metastases or local relapse (except physiological uptake, e.g. in the salivary glands).
5. 124I PET/MRI
Within the last years, simultaneous PET/MRI (PET/magnetic resonance imaging) has been successfully implemented into scientific and clinical imaging, demonstrating its excellent diagnostic potential, mainly in oncologic imaging. Based on its excellent soft tissue contrast, MRI is known to provide superior assessment of head and neck tumours and with the increasing implementation of integrated whole-body PET/MR devices, combining the strength of PET as well as morphological and functional MRI. In this assessment, it could be of great advantage in the localization of focal iodine uptake. The first publication about simultaneous 124I PET/MRI showed promising results .
6. 124I Dosimetry
The 124I dosimetry deals with the determination of tumour lesion dose per administered 131I activity (LDpA) and the estimation of the so-called maximum tolerable activity (MTA) of 131I. The LDpA can help in the decision process if an additional RIT is a promising approach. If a prescribed lesion dose seems to be reachable, the RIT is combined with a significant chance of cure [22–24]. Due to the heterogeneity of metastases of a patient, there may be a significant spread of LDpA in the different metastases. In consequence, RIT might be helpful in some metastases and the other metastases need to be treated by surgery or external beam radiotherapy.
The MTA derived from blood dosimetry is the 131I activity that results in 2 Gy blood dose, which is used as a surrogate for the bone marrow dose. Blood doses below 2 Gy are expected to be tolerable without relevant side effects . Furthermore, it is possible to evaluate the risk of radiation-related fibrosis in patients with or without disseminated lung metastases [19, 20]. The blood dosimetry is based on blood sample (BS) and whole-body counter (WC) measurements (see Figures 1-3).
The lesion and blood dosimetry consists of measurements at different time points after application of 124I to determine the iodine kinetics. The lesion dosimetry requires a minimum of two PET(/CT) scans at 24 and ≥96 h after 124I application. The blood dosimetry by the EANM dosimetry committee uses a comprehensive protocol with measurements over at least 4 days , which was optimized and shortened by Jentzen et al. . For the optimized blood dosimetry protocols, patients are divided into the groups prior to first RIT and after first RIT. Prior to initial RIT, more measurements are recommended due to the presence of thyroid tissue. After the first RIT, only three time points are sufficient. In Figure 4, the required measurements are visualized. Further details on the calculations of lesion and blood dosimetry can be found in Jentzen et al. [14, 26] (see examples in Figures 5 and 6).
Dietlein M, Dressler J, Eschner W, Grünwald F, Lassmann M, Leisner B, et al. Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 3). Nuklearmedizin. ISSN: 0029-5566. 2007;(46):213–219 2007;(5): (155-231) DOI: http://dx.doi.org/10.1160/nukmed-0286.
Haugen BR, Alexander EK, Bible KC, Doherty G, Mandel SJ, Nikiforov YE, et al. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid Off J Am Thyroid Assoc. 2016 Jan;26(1):1-133. doi: 10.1089/thy.2015.0020. 2015.
Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97(5):418–28.
Woodrum DT, Gauger PG. Role of 131I in the treatment of well differentiated thyroid cancer. J Surg Oncol. 2005;89(3):114–21.
Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, Oyen WJG, et al. Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2008;35(10):1941–59.
Morris LF, Waxman AD, Braunstein GD. Thyroid stunning. Thyroid. 2003;13(4):333–40.
Phan HTT, Jager PL, Paans AMJ, Plukker JTM, Sturkenboom MGG, Sluiter WJ, et al. The diagnostic value of 124I-PET in patients with differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2008;35(5):958–65.
Pettinato C, Spezi E, Nanni C, Grassetto G, Monari F, Allegri V, et al. Pretherapeutic dosimetry in patients affected by metastatic thyroid cancer using 124I PET/CT sequential scans for 131I treatment planning. Clin Nucl Med. 2014;39(8):e367–74.
Pettinato C, Monari F, Nanni C, Allegri V, Marcatili S, Civollani S, et al. Usefulness of 124I PET/CT imaging to predict absorbed doses in patients affected by metastatic thyroid cancer and treated with 131I. Q J Nucl Med Mol Imaging. 2012;56(6):509–14.
Beijst C, Kist JW, Elschot M, Viergever M, Hoekstra OS, de Keizer B, et al. Quantitative comparison of I-124 PET/CT and I-131 SPECT/CT detectability. J Nucl Med. J Nucl Med. 2016 Jan;57(1):103-8. doi: 10.2967/jnumed.115.162750. Epub 2015 Oct 22. 2015.
Ruhlmann M. High level of agreement between pretherapeutic 124I PET and intratherapeutic 131I Images in detecting iodine-positive thyroid cancer metastases. JNM. 2016.[pub ahead of print] J Nucl Med. 2016 May 5. pii: jnumed.115.169649. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/27151981?dopt=Abstract
Luster M, Lippi F, Jarzab B, Perros P, Lassmann M, Reiners C, et al. rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review. Endocr Relat Cancer. 2005;12(1):49–64.
Hänscheid H, Lassmann M, Luster M, Thomas SR, Pacini F, Ceccarelli C, et al. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med. 2006;47(4):648–54.
Jentzen W, Freudenberg L, Eising EG, Sonnenschein W, Knust J, Bockisch A. Optimized 124I PET dosimetry protocol for radioiodine therapy of differentiated thyroid cancer. J Nucl Med. 2008;49(6):1017–23.
Kist JW, de Keizer B, van der Vlies M, Brouwers AH, van der Zant FM, Hermsen R, et al. 124I PET/CT to predict the outcome of blind 131I treatment in patients with biochemical recurrence of differentiated thyroid cancer; results of a multicenter diagnostic cohort study (THYROPET). J Nucl Med Off Publ Soc Nucl Med. J Nucl Med. 2016 May;57(5):701-7. doi: 10.2967/jnumed.115.168138. Epub 2015 Nov 25 2015.
Freudenberg LS, Antoch G, Jentzen W, Pink R, Knust J, Görges R, et al. Value of 124I-PET/CT in staging of patients with differentiated thyroid cancer. Eur Radiol. 2004;14(11):2092–8.
Mazzaferri EL, Kloos RT. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab. 2001;86(4):1447–63.
Eustatia-Rutten CFA, Corssmit EPM, Biermasz NR, Pereira AM, Romijn JA, Smit JW. Survival and death causes in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;91(1):313–9.
Benua RS, Cicale NR, Sonenberg M, Rawson RW. The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. Am J Roentgenol Radium Ther Nucl Med. 1962;87:171–82.
Benua R, Leeper R. A method and rationale for treating metastatic thyroid carcinoma with the largest safe dose of 131I. In: Medeiros-Neta GE, Gaitan E, editors. Frontiers in Thyroidology. Plenum Medical; New York, NY: 1986. pp. 1317-1321.
Eur J Nucl Med Mol Imaging. 2016 Jun;43(6):1011-7. doi: 10.1007/s00259-015-3288-y. Epub 2015 Dec 19. Imaging with (124)I in differentiated thyroid carcinoma: is PET/MRI superior to PET/CT? Binse I1, Poeppel TD2, Ruhlmann M2, Gomez B2, Umutlu L3, Bockisch A2, Rosenbaum-Krumme SJ2.
Maxon HR, Thomas SR, Hertzberg VS, Kereiakes JG, Chen I-W, Sperling MI, et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med. 1983;309(16):937–41.
Maxon HR, Englaro EE, Thomas SR, Hertzberg VS, Hinnefeld JD, Chen LS, et al. Radioiodine-131 therapy for well-differentiated thyroid cancer—a quantitative radiation dosimetric approach: outcome and validation in 85 patients. J Nucl Med. 1992;33(6):1132–6.
Jentzen W, Hoppenbrouwers J, van Leeuwen P, van der Velden D, van de Kolk R, Poeppel TD, et al. Assessment of lesion response in the initial radioiodine treatment of differentiated thyroid cancer using 124I PET imaging. J Nucl Med. 2014;55(11):1759–65.
Lassmann M, Hänscheid H, Chiesa C, Hindorf C, Flux G, Luster M, et al. EANM dosimetry committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 2008;35(7):1405–12.
Jentzen W, Bockisch A, Ruhlmann M. Assessment of simplified blood dose protocols for the estimation of the maximum tolerable activity in thyroid cancer patients undergoing radioiodine therapy using 124I. J Nucl Med. 2015;56(6):832–8.