Guidelines for radioiodine therapy of differentiated thyroid cancer

Abstract

Introduction

The purpose of the present guidelines on the radioiodine therapy (RAIT) of differentiated thyroid cancer (DTC) formulated by the European Association of Nuclear Medicine (EANM) Therapy Committee is to provide advice to nuclear medicine clinicians and other members of the DTC-treating community on how to ablate thyroid remnant or treat inoperable advanced DTC or both employing large 131-iodine (¹³¹I) activities.

Discussion

For this purpose, recommendations have been formulated based on recent literature and expert opinion regarding the rationale, indications and contraindications for these procedures, as well as the radioiodine activities and the administration and patient preparation techniques to be used. Recommendations also are provided on pre-RAIT history and examinations, patient counselling and precautions that should be associated with ¹³¹I iodine ablation and treatment. Furthermore, potential side effects of radioiodine therapy and alternate or additional treatments to this modality are reviewed. Appendices furnish information on dosimetry and post-therapy scintigraphy.

Appendices

Chart 1. Indications and contraindications radioiodine treatment of DTC

A. Definite indications

• 1. Unresectable iodine-avid lymph node metastases where one or more of the following is true:

  • morphological imaging does not reveal location

  • surgery is high-risk or contraindicated

  • distant involvement is present that would indicate RAIT anyways

• 2. Iodine-avid pulmonary micrometastases, especially before they become visible on CT

• 3. Non-resectable or partially resectable iodine-avid pulmonary macrometastases

• 4. Non-resectable or partially resectable iodine-avid soft tissue metastases

B. Optional indications

• 1. Recurrent iodine-avid lymph node or distant metastases, as an adjuvant to surgery

• 2. Unresectable iodine-avid lymph node metastases where one or more of the following is true:

  • size is small

  • involvement includes numerous nodes or is widespread

• 3. Non-resectable or partially resectable iodine-avid bone metastases, especially when symptomatic or threatening vital structures

• 4. Known or suspected metastatic DTC where iodine avidity is not yet known, especially if Tg is detectable or increasing^a

• 5. Anaplastic or poorly differentiated thyroid carcinomas that have (relevant) well-differentiated areas or express Tg, especially if symptomatic or progressive^b

C. Non-indications

• 1. Iodine non-avid lymph node metastases

• 2. Iodine non-avid lung macrometastases

• 3. Iodine non-avid bone metastases

D. Contraindications

• 1. Pregnancy

• 2. Breastfeeding

• 3. Clinically relevant bone marrow depression when high-activity RAIT is planned (relative contraindication)

• 4. Clinically relevant pulmonary function restriction together with expected important accumulation in lung metastases (relative contraindication)

• 5. Clinically relevant salivary gland restriction, especially if ¹³¹I accumulation in known lesions is questionable (relative contraindication)

Legend:

CT, computed tomography; DTC, differentiated thyroid carcinoma; ¹³¹I, 131-iodine; RAIT, radioiodine therapy; Tg, thyroglobulin

Notes:

^aThese patients should receive an initial course of RAIT, and if the rxWBS is negative, RAIT should be discontinued.

^bIn these patients, the indication for XRT and the urgency of RAIT should be considered in the decision on whether to give RAIT.

Appendix 1. Pre-therapeutic dosimetry concepts for radioiodine therapy

Pre-therapeutic dosimetry for RAIT may take either or both of two forms: (1) remnant- and lesion-based dosimetry and (2) bone marrow (blood) dosimetry.

A. Remnant- and lesion-based dosimetry

• 1. Objective

  The objective of remnant or lesion dosimetry, sometimes referred to as the “Maxon approach” in honour of one of its key developers, is to determine the individualised radioiodine activity that delivers the recommended doses of radiation to ablate thyroid remnant or to treat metastatic disease whilst minimising the risk to the patient. These absorbed doses are traditionally considered to be ≥300 Gy to ablate thyroid remnant and ≥80 Gy to successfully treat metastatic disease [115]. Individualising the RAIT activity may help avoid over- or under-treating the remnant, tumour or both, which is presumed to have efficacy or safety benefits, or both.

• 2. Procedures

  To perform these calculations, it is necessary to measure the uptake and clearance of the ¹³¹I from identifiable thyroid remnants, DTC metastases or both. To determine the ¹³¹I concentration, one needs to know how much activity is contained in the lesion. One way to determine this is through an analysis of selected ROIs on conjugate view gamma camera images or on SPECT images [116].

  These images are obtained at several time points following the administration of a tracer activity. Typically, these images would be acquired up to 96 h after tracer administration, but later time samples might be necessary if the uptake and clearance are delayed. In addition, transmission images, scatter images or both might be necessary to correct for attenuation or scatter or in the region of the lesion. Images of a standard for calibration purposes might also be needed [116]. A curve-fitting procedure then is used to determine the assumed single-exponential half-life value and to extrapolate the curve to time zero to determine the initial activity in the lesion.

  Pre-therapeutic dosimetric assessments of the activity required to achieve a certain prescribed absorbed dose to a remnant or lesion are often based on adaptations of the generic MIRD equation for absorbed dose [117]:

  $$\overline D = \frac{{\tilde A \times S \times m_{\text{r}} }}{{m_{\text{t}} }}$$

  where $\overline D$ denotes the mean absorbed dose to the remnant/lesion, $\tilde A$, the cumulative activity (the integral of the activity–time curve), m _r, the reference mass of the thyroid (20.7 g), and m _t is the remnant/lesion mass. S is the MIRD-defined S value for thyroid self-irradiation (5.652 × 10⁻³ Gy MBq⁻¹ h⁻¹, see MIRD Pamphlet 11 [117] or, for example, the guidelines of the German Society of Nuclear Medicine [118]).

• 3. Mass determination

  The lesion mass is another variable needed in order to calculate the activity concentration delivering the required absorbed dose. For ablation therapies, remnant volumetry methods such as US or CT are unreliable, as it is impossible to differentiate thyroid tissue from haematoma on these modalities. Thus no thoroughly validated method yet exists to exactly determine the mass of thyroid remnants after surgery [73]. For this reason, one must be careful when reporting absorbed doses to the target tissue. For lesion dosimetry, higher spatial resolution images, such as those obtained with CT or US, can be used for attenuation correction and to determine the mass.

  If the lesions are small, the nodule module of the OLINDA/EXM software might be useful to generate a spherical model of the remnant, tumour or both [119]. Furthermore, if the dimensions of the lesions are smaller than approximately 5 mm—assuming that this could be accurately determined—then the range of the beta particles can no longer be neglected in the dose calculation [120].

• 4. PET-based lesion dosimetry

  The use of ¹²⁴I was proposed for quantifying in vivo tumour radioiodine concentration and biodistribution in DTC patients [78, 79, 121, 122]. Due to the complex decay process of ¹²⁴I, the quantification process cannot be performed in the same way as for the pure positron emitter FDG. Pentlow et al. [78] measured resolution, linearity and the ability to quantify the activity contents of imaged spheres of different sizes and activities in different background activities. It was shown that the ¹²⁴I quantification could reproduce the activities administered. ¹²⁴I PET was also successfully applied to the measurement of thyroid volume [121, 122]. Today’s state-of-the-art ¹²⁴I PET-based DTC dosimetry protocol has been described in recent publications by Sgouros et al. [79]. Using the PET results as input to a fully three-dimensional dose planning programme, those investigators calculated spatial distributions of absorbed doses, isodose contours, dose–volume histograms and mean absorbed dose estimates for a total of 56 tumours. The mean tumour absorbed dose for each patient ranged widely, from 1.2 to 540 Gy. The absorbed dose distribution for individual tumour voxels was even more widely distributed, ranging from 0.3 to 4,000 Gy.

  Findings similar to those of the Sgorous and coworkers study, of median per-patient tumour radiation absorbed doses between 1.3 and 368 Gy, were recently reported by de Keizer et al. [71] who performed tumour dosimetry after rhTSH-stimulated ¹³¹I treatment. Dosimetric calculations were performed using tumour radioiodine uptake measurements from post-treatment ¹³¹I scintigrams and tumour volume estimations were generated from radiological images.

• 5. Limitations

  The main disadvantages of a lesion-based approach to RAIT dosimetry in DTC are:

  • Absorbed lesion doses range widely even within a single patient.

  • Contrary to assumptions inherent in dosimetry protocols, absorbed dose distributions vary within lesions, which could result in incomplete tumour destruction.

  • A mono-exponential model may not accurately reflect lesional radioiodine kinetics.

  • Unclearly defined correction factors must be applied for the initial phase of increasing uptake (up to approximately 24 h post-radioiodine administration).

  • An accurate estimate of the lesion mass is not always possible, e.g. with disseminated iodine-avid lung metastases or irregularly shaped lesions.

  • Low uptake in lesions and, therefore, low count rates may cause statistical errors in the measurements.

  • The biological effectiveness of dosimetry-guided RAIT is not proven yet.

  • Doses may be systematically underestimated for lesions <5 mm in diameter if no corrections are applied.

In addition, currently, when ¹³¹I is used, relatively high diagnostic activities, i.e. at least 37 MBq, are necessary for quantitative imaging of the target thyroid tissue for dosimetry; these activities have the potential to induce “stunning” (see the “Precautions” section above), which is a particularly critical consideration in radioiodine treatment of metastatic disease [123].

B. Bone marrow (blood) dosimetry

• 1. Overview

  The method originally reported by Benua et al. [42] and Leeper [124] allows the estimation of the radiation dose that will be delivered to the haematopoietic system from each GBq administered to any patient. The method involves measurement of radiation counts of serial blood samples and serial calibrated probe measurements of the patient’s whole-body activity over the course of 4 or more days after ¹³¹I tracer administration. The original Benua et al. study [42] determined that the subgroup of patients who received ≤2 Gy to the blood avoided serious myelosuppression; this dose has become the principal traditionally accepted safety threshold for RAIT. In addition, the whole-body retention at 48 h after radioiodine administration should not exceed 4.44 GBq (120 mCi) in the absence of iodine-avid diffuse lung metastases or 2.96 GBq (80 mCi) in the presence of such lesions [39].

• 2. More recent developments

  In the classic Benua approach, the blood is considered the critical organ that is irradiated either by the particles emitted from activity in the blood itself or by the emissions originating from activity dispersed throughout the remainder of the body. Recently, in the framework of international multi-centre studies of radioiodine biokinetics after rhTSH administration [125], the absorbed dose to the blood was calculated with a modified method derived from a procedure originally described by Thomas et al. [126]. Refinements to this model have been introduced to account for:

  • the contribution to the blood dose of penetrating radiation from activity in distant blood,

  • the mass dependency of the S value representing the radiation from the total body to the blood,

  • a mean value, $S_{{\text{blood}} \leftarrow {\text{blood}}}$, representing an average for blood circulating in vessels of varying diameters and s values [44].

The recent studies show that the results of pre-therapeutic blood-based dosimetry agree well with measured post-therapeutic absorbed doses. Therefore, the pre-therapeutic data can reliably project therapeutic absorbed doses to blood.

For blood-based dosimetry, only two compartments need be monitored for radioactivity: the blood and the gamma ray absorbed doses to the whole body. The activity in the blood is determined by measuring periodic heparinised blood samples. The activity in the whole body, i.e. remaining in the patient, can be monitored redundantly using independent techniques: 24-h urine collections, whole-body counting with a probe using a fixed geometry and, if applicable, conjugate views of a WBS obtained with a dual-headed gamma camera.

Details regarding the sampling times, measurements and calculations can be found in the EANM Dosimetry Committee Series on Standard Operational Procedures for Pre-Therapeutic Dosimetry (I. Blood and Bone Marrow Dosimetry in Differentiated Thyroid Cancer Therapy) [44].

The recommended equation for the absorbed dose to the blood per unit of administered activity [44] is:

$$\frac{{D_{{\text{blood}}} }}{{A_0 }}\left[ {\frac{{{\text{Gy}}}}{{{\text{GBq}}}}} \right] = 108 \times \tau _{{\text{ml}}\;{\text{of}}\,{\text{blood}}} \left[ {\text{h}} \right] + \frac{{0.0188}}{{\left( {{\text{wt}}\left[ {{\text{kg}}} \right]} \right)^{{2 \mathord{\left/ {\vphantom {2 3}} \right. \kern-\nulldelimiterspace} 3}} }} \times \tau _{{\text{total}}\;{\text{body}}} \left[ {\text{h}} \right]$$

τ _{total body} [h] and τ _{ml of blood} [h] stand for the residence time in a source organ, representing the integral of the time–activity curve in that organ (cumulative activity) divided by the administered activity A ₀; wt represents the patient’s weight. In addition, the EANM Dosimetry Committee guidelines give a formula for the assessment of the absorbed dose to the bone marrow [44].

The tracer activity necessary for a reliable assessment of the whole-body residence time depends on the equipment used (see Section 3.3 in [44]). The potential risk of the diagnostic absorbed dose dramatically changing the iodine kinetics in target tissue limits the administered activity to amounts much lower than 74 MBq ¹³¹I [123]. Under all circumstances, one should avoid administering activities which lead to total absorbed doses to iodine-avid tissue of >5 Gy [127].

An activity of 10–15 MBq of ¹³¹I should suffice for a pre-therapeutic blood-based dosimetry assessment. Based on experience to date, this range of activities will provide sufficient count statistics whilst most probably not causing any changes between pre- and post-therapeutic biokinetics of ¹³¹I.

• 3. Strengths and limitations

  The strengths of the blood-based approach are:

  • determination of the maximal safe activity of radioiodine for each RAIT in each individual,

  • identification of patients for whom empiric fixed activities are not safe [128],

  • the potential to administer higher activities once instead of lower activities multiple times in a “fractionated” therapy to avoid changes in lesion biokinetics after multiple therapies that have been observed, e.g. by Samuel et al. [129],

  • a long history of use in several institutions,

  • an expected increase in the probability of curing patients in advanced stage of the disease with fewer courses of therapy.

  Limitations that need to be mentioned are:

  • a benefit of the strategy is plausible, but no valid clinical data yet exist on improved response or outcome rates;

  • the absorbed dose to the tumour is not known: higher activities might be administered without achieving a better therapeutic effect when using this methodology;

  • the current debate regarding the issue of “stunning” argues that diagnostic administrations of ¹³¹I could alter lesion biokinetics and, consequently, the absorbed dose in a subsequent RAIT;

  • increased cost and inconvenience, although this may be outweighed by rendering further treatments unnecessary.

Patient-specific blood-based dosimetry is easy to perform both pre-therapeutically and peri-therapeutically and allows the RAIT activity for selected patients to be increased without risk of severe side effects. In addition, simplified protocols have not been tested yet.

Appendix 2. Additional considerations in rxWBS

A. Purpose of rxWBS

Detection and localisation or exclusion of one or more of functioning thyroid remnants, persistent or recurrent local disease or metastases in patients with DTC.

B. Image acquisition

¹³¹I rxWBS should employ a gamma camera with a large field of view and a high-energy collimator. Preferably, a camera with a thick, e.g. 2.5 cm, sodium iodide crystal should be used to increase the sensitivity of the scan.

The patient should lie supine on an imaging table with moderate head reclination. Anterior and posterior images should show the whole body. Spot images should be obtained for at least 5–10 min per view. If images are obtained with a whole-body scanner, the scan speed should be adjusted so that whole-body imaging takes at least 20–30 min per view. Longer imaging times may be helpful for images obtained more than 3 days after radioiodine administration.

C. Interpretation and quantification

rxWBS images should be interpreted visually for location of functional tissue. The quantification of radioiodine uptake in functioning tissue by a ROI technique and by comparison with a calibrated ¹³¹I activity can be helpful for post-therapeutic dosimetry and for follow-up data.

D. Reporting and documentation

The report should include the location, size and intensity of any areas of uptake that correspond to any functioning tissue. Description of comparisons with prior images is useful. The results of Tg assays and TSH are helpful for the interpretation of the scintigraphic findings.

Documentation (radiographic films or paper prints or computer files) should include:

• patient’s name for identification,

• radiopharmaceutical administered,

• activity administered in MBq,

• timing of the images in relation to radiopharmaceutical administration,

• acquisition time in minutes and counts acquired,

• in the case of functioning tissue, imaging of ROIs of the hot spot, of background activity and of calibrated activity (for dosimetry purposes).

E. Quality control

Many national nuclear medicine societies have written guidelines to promote the cost-effective use of high-quality nuclear medicine procedures. Relevant parameters of quality control for gamma cameras are, e.g. background activity, energy window, homogeneity, spatial resolution and linearity.

F. Error: potential sources and avoidance

Potential sources of error in rxWBS interpretation include:

• local contamination (clothing, skin, hair, collimator, crystal),

• oesophageal activity,

• asymmetrical salivary gland uptake,

• non-specific uptake, e.g. in pulmonary infections, oedema, the breast, kidney cysts and the thymus.

To avoid artefacts caused by cutaneous contamination with radioiodine, the patient should shower and change underwear before rxWBS.