PET Evaluation of Recurrent Differentiated Thyroid Cancer (THYROPET)

Differentiated thyroid cancer (DTC) is the most frequent endocrine tumor, with an annual incidence per 100.000 individuals of 1 - 3 in men and 2 - 4 in women. In general DTC has a good prognosis, and only 6% of patients will die of their disease, but the prognosis is less favourable when the disease recurs after primary treatment.

Measurement of the tumor marker Thyroglobulin (Tg) in serum plays a pivotal role in the follow-up of differentiated thyroid cancer. Serum Tg should be undetectable in DTC patients following thyroid remnant ablation with radioactive iodine-131 (131I), and any detectable level signals the persistence of (neoplastic) thyroid tissue. A serum Tg cut-off level of ≥ 2 ng/ml following rhTSH is highly sensitive for identifying patients in whom persistent tumor may be found.

Historically the follow-up of patients with DTC included diagnostic planar scintigraphy with a low dose of 131I, but nowadays this is no longer recommended because of poor sensitivity. Instead, whole body scintigraphy after blind administration of high dose, 'therapeutic', 131I is recommended, both to diagnose and stage the potential recurrence, and to initiate its treatment. This strategy can be effective, but an estimated 38% - 50% of patients will have a negative post-therapeutic whole body scan and/or no objective therapy effect. These patients will have received a total body irradiation of 450 mSv and potentially will have suffered from side effects such as nausea, sialoadenitis, loss of taste, or reduced spermatogenesis. Also, the prolonged thyroid hormone withdrawal and subsequent hypothyroidism necessary for 131I therapy has major impact on quality of life with a majority of patients suffering from significant changes in physical, psychological, and social well-being. The high frequency of high dose 131I therapies from which patients do not derive any benefit but are exposed to its toxicity and potential adverse oncological effects, has led to a search for new diagnostic tools to improve the selection of patients before such treatment.

Historically, ultrasound of the neck is applied to detect local recurrence or regional lymph node metastases, and it allows direct biopsy to confirm the diagnosis. But ultrasound is limited to the neck only, and when it is negative in the presence of detectable Tg, a form of whole body evaluation is required.

Recently Iodine-124 (124I) became available as a novel radionuclide for whole body PET imaging in the follow-up of DTC, with a promising diagnostic accuracy and a considerably lower radiation exposure as compared to planar whole body scintigraphy after high dose 131I. Furthermore, recent experience has shown that 124I-PET images may be representative for the biodistribution and radiation dosimetry of subsequent treatment with high dose 131I. Thus, with the availability of 124I-PET, it might become possible to more accurately re-stage patients in a whole body procedure, perform dosimetry for subsequent 131I therapy and predict the outcome of the treatment.

At the same time, some recurrent DTC lesions do not accumulate iodine, which is correlated with tumor dedifferentiation and poor prognosis. Patients suspected of non-iodine accumulating DTC, so far only evident after futile blind 131I therapy, require restaging before local or systemic therapy may be installed. Metabolic PET imaging with the glucose analogon 18F-fluorodeoxyglucose (FDG), stimulated with rhTSH, has a high sensitivity for recurrent DTC in patients with detectable Tg and negative iodine scintigraphy, may correlate with a more aggressive tumor behaviour and poor prognosis, and is able to select patients for additional surgery or external beam radiotherapy. This technique is currently applied only when prior treatment and imaging with high dose 131I has proven to be ineffective. The value of FDG-PET before 131I treatment has not been tested.

The uptake of 124iodine and FDG are related to histopathological characteristics of tumor tissue, such as the resected primary tumor or metastases. 124I uptake is related to expression of the sodium iodine symporter (NIS), while FDG uptake is related to hexokinase-I (HKI) activity. The power of combined 124I-PET and FDG-PET for detection and characterization of DTC lesions has been suggested in proof of concept studies. The relation of these imaging findings and histopathological parameters (such as thyroglobulin, TTF1, Ki-67 and Cytokeratine-19 staining) and response to 131I treatment has not been elucidated in sufficiently large series.

Based on the characteristics of 124I-PET and FDG-PET, it is reasonable to assume that a combined strategy of imaging and histopathological evaluation at the time of suspected recurrence will yield adequate information on the disease stage prior to treatment with 131I, regardless of tumor dedifferentiation, with a potential impact on clinical decision making. This hypothesis needs proper testing, to increase fundamental knowledge about DTC and further improve treatment.

The multi-center design of this study requires a standard acquisition of the 124I-PET scans. Previously this was done for FDG-PET in the Netherlands, the so-called NEDPAS protocol. In order to compare the scans between the centers calibration and standardization of the 124I-PET scans prior to the start of the study will be done.

Additional to this objective the study aims to answer whether thyroid hormone withdrawal and rhTSH preparation for the 124I-PET results in different scan results.

In summary, high dose 131I treatment for recurrent DTC is effective in many cases, but the current blind approach also leads to overtreatment, delay, and unnecessary decrease in quality of life in a significant number of cases. As we have shown, a combination of diagnostic tests has a potential to allow earlier and better restaging and selection for treatment. The proposed trial aims to test the value and optimal implementation of these new tests, standalone and in combination, to derive parameters for a new personalised strategy for diagnosis and treatment of patients with (suspected) recurrent DTC.