Consensus document
Spanish consensus for the management of patients with advanced radioactive iodine refractory differentiated thyroid cancerConsenso español sobre el tratamiento de los pacientes con cáncer de tiroides diferenciado avanzado resistente al yodo radiactivo

https://doi.org/10.1016/j.endonu.2015.08.007Get rights and content

Abstract

Background

Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients.

Methods

On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC.

Results

Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease.

Conclusions

In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care.

Resumen

Antecedentes

Alrededor de un tercio de los pacientes con cáncer diferenciado de tiroides (CDT) que desarrollan enfermedad metastásica estructural son refractarios al yodo radiactivo. Desafortunadamente, la mayoría de las muertes debidas al cáncer de tiroides ocurren en pacientes con CDT avanzado refractario al yodo radiactivo. El principal objetivo de este consenso es abordar los aspectos más controvertidos del manejo de estos pacientes.

Métodos

En nombre de la Sociedad Española de Endocrinología y Nutrición (SEEN) y del Grupo Español de Tumores Raros e Infrecuentes (GETHI), el grupo de trabajo para el Cáncer de Tiroides, compuesto por endocrinólogos y oncólogos, revisó la literatura más destacada y desarrolló una serie de preguntas clínicamente relevantes concernientes al manejo de los pacientes con CDT refractario.

Resultados

Diez preguntas clínicamente relevantes fueron identificadas por el grupo de trabajo. En las respuestas el grupo incluyó recomendaciones sobre la mejor definición de la refractariedad, las mejores opciones terapéuticas, entre las cuales se incluyen la actitud expectante, las terapias locales y la terapia sistémica (por ejemplo inhibidores de tirosín-cinasa), cuándo esperar la recaptación de yodo radiactivo mediada por NIS y cómo los recientes avances en genética molecular han ayudado a comprender mejor la enfermedad.

Conclusión

En respuesta a nuestro compromiso como grupo de trabajo de la SEEN y GETHI hemos creado un consenso para asistir al manejo clínico de los pacientes con CDT avanzado refractario al yodo radiactivo. Pensamos que este consenso proporcionará unas recomendaciones útiles y actualizadas que ayuden a los pacientes con esta enfermedad a tener un cuidado óptimo.

Introduction

Thyroid cancer is the most prevalent type of endocrine malignancy and its incidence has been steadily increasing over the last three decades.1 Due to this rise in its incidence, thyroid cancer is currently the fifth most common new cancer diagnosis in women and the eighth most common new cancer diagnosis overall in the United States of America (USA).2 It is now more frequently diagnosed than all leukaemias combined, as well as ovarian, uterine, pancreatic, or oesophageal cancers. For the majority of patients with thyroid cancer, treatment with surgery, radioactive iodine (RAI) ablation and TSH suppressive therapy allows an overall survival (OS) rate of 97.7% at five years.3 Nevertheless, locoregional recurrence occurs in up to 20% of patients, and distant metastases in approximately 10% at 10 years. Some of these patients with locorregional recurrences and/or distant metastases lose the ability for iodine uptake leading to RAI-refractory metastatic disease. Patients with RAI-refractory metastatic disease have an overall survival rate of less than 50% at three years and account for more deaths in the USA at present than Hodgkin's lymphoma, osteosarcoma, or testicular cancer.

Differentiated thyroid cancer (DTC) derive from thyroid follicular cells and accounts for more than 90% of all thyroid cancers. The dominant histotypes are papillary and follicular cancers, while Hürthle cell thyroid cancer (a follicular thyroid cancer subtype) and poorly differentiated thyroid cancer are less common variants. Undifferentiated or anaplastic thyroid carcinomas, always RAI-refractory, are not reviewed in this consensus. Around one third of DTC patients with structurally-evident locorregional and/or metastatic disease becomes RAI-refractory, with inadequate radiation doses to malignant cells and failure to eradicate metastasis. Thus, RAI-refractory DTC is defined more by behavior than specific histopathology. Notably, although anaplastic thyroid cancers have higher mortality rates than DTC, most of the estimated deaths from thyroid cancer will be in patients with RAI-refractory DTC.2

Over the last decade, there have been substantial advances in the management of RAI-refractory DCT. Because controversy exists in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI) have created together a national task force in order to establish a consensus addressing the most challenging aspects regarding the management of these patients. To address these aspects, we developed a series of clinically relevant questions which were as follows:

  • (1)

    Do we really know the incidence and prevalence of RAI-refractory DTC in Spain?

  • (2)

    Which is the best definition of RAI-refractory DTC?

  • (3)

    Which patients with RAI-refractory metastatic DTC can be followed without additional therapy (watchful waiting)?

  • (4)

    Which patients with RAI-refractory DTC are candidate for local therapies?

  • (5)

    Which patients should be considered for kinase inhibitor therapy in RAI-refractory DTC patients? What kinase inhibitors do we use?

  • (6)

    Is sodium iodide symporter (NIS) restoration and subsequent RAI reinduction a feasible strategy in RAI-refractory DTC patients?

  • (7)

    How can we use the advances in molecular biology knowledge of DTC for the treatment of RAI-refractory disease?

  • (8)

    What is the role of chemotherapy and radiotherapy in RAI-refractory DTC?

  • (9)

    Is thyroglobulin a useful biomarker in RAI-refractory DTC?

  • (10)

    Is TSH suppression still necessary in RAI-refractory setting?

Section snippets

(1) Do we really know the incidence and prevalence of radioactive iodine-resistant differentiated thyroid cancer in Spain?

The lack of national registries for thyroid cancer patients in Spain makes difficult an estimation of the new cases per year and the percentage of patients that become refractory to RAI therapy. As a Western Europe country, Spain is expected to have an age-standardized rate of around 6 per 100,000 females.4 Available data of estimated incidence in Spain shows an incidence rate of 2.12 per 100,000 males and 6 per 100,000 females in 2004.5 If we apply the European incidence rates of new

(2) Which is the best definition of radioactive iodine-refractory differentiated thyroid cancer?

Various terms such as “refractory,” “resistant,” “nonresponsive,” or “non-avid” have been used to characterize DTC patients with locoregional and/or distant metastases for whom RAI therapy provides no further clinical benefit. The first three terms all imply that RAI therapy has not yield a clinical benefit despite cells may be avid for RAI. The last term “non-avid” describes tumors not absorbing any amount of RAI on a diagnostic or post-therapy scintigraphy. Therefore, tumors may retain their

(3) Which patients with radioactive iodine-refractory metastatic differentiated thyroid cancer can be followed without additional therapy (watchful waiting)?

RAI-refractory metastatic DTC can be asymptomatically stable for long periods of time and in such patients the benefits of novel therapies might be largely outweighed by drug toxicities. Therefore, there is a great risk of overtreatment if we do not discriminate appropriately these patients and anticipate the natural course of the disease. Patients with an indolent clinical course with no apparent tumor progression documented by radiological techniques, no symptoms and no adverse impact from

(4) Which patients with radioactive iodine-refractory differentiated thyroid cancer are candidate for local therapies?

The indication of local therapies for RAI-refractory DTC will be conditioned by the location and number of metastasis, tumor burden and technically feasible approaches. Locorregional recurrences are the most frequent sites of tumor relapse in DTC patients, followed by lung, extracervical lymph nodes, bones and brain. Local therapies include salvage locoregional or distant metastatic surgery, external beam radiation or radiosurgery, radiofrequency or ethanol ablation, and chemoembolization, in

(5) Which patients should be considered for multikinase inhibitor therapy in radioactive iodine-refractory differentiated thyroid cancer patients? What kinase inhibitor should we use?

Currently, there is general agreement that multikinase inhibitors (MKI) therapy should be considered only in RAI-refractory DTC patients with progressive and/or symptomatic metastatic disease not otherwise amenable to local therapies. The reasons for such limitations arise from clinical trials. Since the first multicenter therapeutic trial of a MKI was performed in progressive DTC, evidence favored the clinical use of MKIs but also revealed limitations concerning drug toxicity and patient

(6) Is sodium iodide symporter (NIS) restoration and subsequent radioactive iodine reinduction a feasible strategy in radioactive iodine-refractory differentiated thyroid cancer patients?

Advanced RAI-refractory DTC shows negligible 131I uptake due to loss of functional sodium iodide symporter SLC5A5 expression. As long as a few NIS molecules are functionally expressed in thyroid cancer cells, thyroid cancer can be successfully treated with RAI administration. RAI selectively targets and destroys any remnant or metastatic NIS-expressing thyroid cancer cells. Decreased expression of NIS and/or impaired targeting of NIS to the membrane of thyroid cancer cells (which is required

(7) How can we use the advances in molecular biology knowledge of differentiated thyroid cancer for the treatment of radioactive iodine-refractory disease?

The deeper knowledge of the main molecular steps that lead to the transformation of the normal follicular cell into an invasive thyroid carcinoma has developed several translational and clinical studies that have opened a more optimistic point of view in the treatment of these patients. Thyroid carcinogenesis has become one of the most fascinating models and a particularly promising paradigm for targeted therapy. A multistep model involving the main genetic changes that carry out the tumor

(8) What is the role of chemotherapy and radiotherapy in radioactive iodine-refractory differentiated thyroid cancer?

Classical chemotherapeutic agents have shown limited activity in DTC. There are several trials that have evaluated the activity of different agents in patients with DTC with disappointing results, between 0 and 20% of response rates, of short duration, without complete remissions and no impact in overall survival. The most developed drug has been doxorubicin alone and in combination with other cytotoxics, mainly cisplatin, with no increasing in response rates but higher adverse events.

(9) Is thyroglobulin a useful biomarker in radioactive iodine-refractory differentiated thyroid cancer?

Thyroglobulin serum levels have been one of the most important tools to follow up patients with persistent or recurrent disease. Usually, significant increasing in thyroglobulin levels, particularly a thyroglobulin doubling time less than one year, suggests disease progression. In this situation, successive sessions of RAI therapy until the tumor is cured or becomes resistant to RAI therapy are recommended. When refractoriness appears, thyroglobulin levels could lose accuracy in correlation

(10) Is TSH suppression still necessary in radioactive iodine-refractory setting?

Overall TSH suppression is suggested in patients with DTC after surgery to reduce the risk of recurrence.21 Initial suppression below 0.1 mU/L is recommended in high and intermediate risk thyroid cancer patients, while maintenance below lower normal limit (0.5 mU/L) is appropriate for low risk patients. However, no clear recommendation is available TSH suppression in RAI-refractory DTC. The progressive undifferentiating process that DTC cells suffer during the disease period time produces a

Concluding remarks. Future directions and research

Multidisciplinary management of thyroid cancer should be mandatory and focused in referral centers to maximize patients’ chances for being cured. Future research will be focused in the search of prognostic biomarkers and better patients’ molecular characterization, redifferentiation process of follicular thyroid cancer cells leading to NIS restoration and RAI reinduction, optimization and innovation in nuclear medicine targeted therapy and novel molecular targeted agents and combinations that

Conflict of interests

Garcilaso Riesco-Eizaguirre has received honoraria for advisory boards or lectures from Genzyme, Merck and Bayer.

Juan Carlos Galofré has been a consultant for AstraZeneca, Bayer, and Genzyme, and has received speaker honoraria from Genzyme and Merck.

Enrique Grande: advisory/speaker role of Bayer y Eisai.

Jaume Capdevila: advisory/speaker role of Bayer and Eisai, and has received research funding from Bayer.

Elena Navarro González: advisory/speaker role of Bayer.

Javier Santamaría Sandi has

References (21)

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