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SJR usa un algoritmo similar al page rank de Google; es una medida cuantitativa y cualitativa al impacto de una publicación. 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. Ten clinically relevant questions were identified by the task Adelgazar 40 kilos. 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.
We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care. Diez preguntas clínicamente relevantes fueron identificadas por el grupo de trabajo.
Thyroid cancer is the most prevalent type of endocrine malignancy and its incidence has been steadily increasing over the last three decades. 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 The dominant histotypes are papillary and follicular cancers, while Hürthle Dtc weight loss center thyroid Dtc weight loss center 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. Notably, although anaplastic thyroid Dtc weight loss center have higher mortality rates than DTC, most of the estimated deaths from thyroid cancer will be in patients with RAI-refractory DTC.
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?. What kinase inhibitors do Dtc weight loss center use?.
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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 perfemales.
In routine clinical practice, patients with appropriate TSH stimulation and iodine preparation can be defined as RAI-refractory if they meet any of the following criteria Table 1 : Dtc weight loss center no uptake of RAI at the initial diagnosis of distant metastases or locoregional recurrence. Clinical criteria defining radioactive iodine-refractory differentiated thyroid cancer. Although general agreement can be found with the previous Dtc weight loss center, there are other situations and definitions less clear and a consensus within multidisciplinary teams are needed before considering RAI-refractory disease and potential candidates for systemic therapy Table 1 : a total cumulative doses of RAI over mCi; b significant uptake in 2-deoxyfluoro- d -glucose positron emission tomography 18 FDG-PET Dtc weight loss center with computed tomography CT.
RAI-refractory metastatic DTC can be asymptomatically stable for long periods de peso Ejercicios para bandas elasticas con bajar time and in such patients the benefits of novel therapies Dtc weight loss center be largely outweighed by drug toxicities. Therefore, there is a great risk of overtreatment Dtc weight loss center we do not discriminate appropriately these patients and anticipate the natural course of the disease.
Patients with an indolent clinical course with no apparent Dtc weight loss center progression documented by radiological techniques, no symptoms and no adverse impact from their disease burden despite having a structurally evident metastatic disease, watchful waiting should be considered Table Therapeutic options in radioactive iodine-refractory differentiated thyroid cancer.
One is the presence of asymptomatic small lower than 5—8 mm metastatic lymph nodes after RAI ablation, particularly after prior neck compartmental dissection. In these cases surgery or other local therapies have not proved any benefit in terms of improving gross clinical disease recurrences or disease-specific survival.
Secondly, for some patients with small pulmonary metastatic disease usually lower than 1 cmin which the disease is not progressing or is slowly progressing, patients can often be followed conservatively on TSH suppressive therapy.
The third clinical situation in which watchful waiting is recommended is the presence of bone metastases that are asymptomatic, stable lesions that do not threaten nearby critical structures.
However, despite the indolent course of these patients, careful and thoughtful surveillance must be performed in the setting of a multidisciplinary team. Apart from determining thyroglobulin levels and neck ultrasound, attention should be directed toward determining the extent of metastatic disease by functional and cross-sectional imaging FDG-PET, magnetic resonance MRICT and the rate of progression of radiological evident lesions Dtc weight loss center applying response evaluation criteria in solid tumors RECIST.
In this situation, disease progression status by RECIST is difficult to define, as no previous comparable images are usually available. In addition to imaging, assessing the Dtc weight loss center of current or potential symptoms and understanding the co-morbidities that might influence the choice of therapy may be really helpful to make important decisions during the follow up of these patients.
Overall, patients with refractory disease that are asymptomatic, low tumor burden, stable or minimally progressive, and not likely to Dtc weight loss center rapidly progressive disease, do not need any further treatment but TSH suppression and active surveillance. Clinically significant complications can be monitored with imaging every three to six months along with the assessment of the degree of current or potential symptoms.
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The indication of local therapies for RAI-refractory Dtc weight loss center 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 order to prevent complications in vital structures, such as central nervous system or central neck compartment.
A small fraction of patients may benefit from radiofrequency ablation, 7 ethanol ablation, 8 or embolization. In the case of locorregional disease, surgery is favored in the presence of bulky disease or disease amenable to surgery found on anatomic imaging such as ultrasonography, CT scanning, or MRI. In fact, surgery is the first option even if RAI uptake is present. On the other hand, it is not clear that treatment of locoregional disease is beneficial in the setting of untreatable distant metastases, except for Dtc weight loss center palliation of symptoms or prevention of airway or aerodigestive obstruction.
For tumors that invade the upper aerodigestive tract, surgery Dtc weight loss center with external beam radiation is generally advised. Techniques ranging from shaving tumor off the trachea or esophagus for superficial invasion, to more aggressive techniques when the trachea is more deeply invaded e.
For selected patients with pulmonary metastases, local La buena dieta need to be considered, such as metastasectomy, endobronchial laser ablation, or external beam radiation for palliation of symptomatic intrathoracic lesions e. Although some bone metastases are RAI avid, RAI therapy is rarely curative in the long term and patients will need further interventions.
Complete surgical resection of isolated symptomatic metastases has been associated with improved survival and should be considered, especially in patients younger than 45 years old with slowly progressive disease. For skeletal metastases, surgical palliation is recommended for symptomatic or asymptomatic tumors in weight-bearing extremities.
Intravenous bisphosphonate pamidronate or zoledronic acid therapy may be considered for symptomatic bone metastases, and embolization of metastases can also be considered. 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 eligibility.
Multiple kinase perdiendo peso and other targeted agents have prominently changed the management of patients with advanced RAI-refractory DTC Table 3. Of note, prolongation Dtc weight loss center progression free survival has been shown with sorafenib and lenvatinib compared with placebo in the two phase 3 trials published so far.
Based on published phase 2 trials, other orally available multikinase inhibitors such as sunitinib, axitinib, cabozantinib or pazopanib may produce some clinical benefit in this setting but only the results of the phase III study with vandetanib are expected in the near future.
Results of clinical trials of targeted therapies in radioactive iodine-refractory differentiated thyroid cancer. The most important one is patient's selection as no biological or genetic biomarker has been yet elucidated to predict tumor response or patient's outcome. The indolent course of the disease that can be observed in some cases with low tumor burden can jeopardize the efficacy of an early initiation of therapy and increase the risk of toxicity.
However, Dtc weight loss center for high tumor burden or for Dtc weight loss center onset of symptoms could compromise the survival of patients. The optimal management of these risks is clinically relevant, especially in view of the necessity of long-term application of these treatments in most cases.
Most common side effects observed with MKI include Dtc weight loss center, hand-foot syndrome, hypertension, diarrhea, skin rashes and erythema, weight loss, and various drug-specific toxicities that have been reported.
In summary, the use of MKI therapy should, therefore, be limited to patients with a progressive, metastatic and clinically relevant tumor burden disease that is not amenable to palliation with surgery or locoregional approaches. Patients with advanced progressive RAI-refractory DTC should additionally be referred to experienced centers that can offer interdisciplinary expertise in the individualization of treatment and participation in therapeutic clinical trials.
As long as a few NIS molecules are functionally expressed in thyroid cancer cells, thyroid cancer Dtc weight loss center be successfully treated with Dtc weight loss center administration. Cloning of the NIS gene and its characterization have allowed investigation of the molecular mechanisms leading to NIS loss of function, with potential Dtc weight loss center provide novel approaches for DTC therapy, intending to restore NIS-mediated iodide accumulation.
NIS is a key target for Dtc weight loss center thyroid cancer therapies. Although traditional therapies e. The MEK inhibitor selumetinib has been the first agent to reinduce iodide uptake in sufficient amount to exert a RAI-induced cytotoxic effect. Therapeutic efficacy seemed to be significantly prominent in RAS Dtc weight loss center tumors as all of five mutant tumors showed increased RAI uptake, with four demonstrating partial response and one stable disease.
Dabrafenib, a selective inhibitor of mutant BRAFhas been the second agent to show promising results. A potential advantage of this therapeutic strategy compared with long-term treatment with kinase inhibitors is Dietas rapidas a short course of kinase inhibitor therapy 45 days is required, which could limit side effects.
However, there are also some limitations with this approach, including the risk of hematological toxicity with accumulative doses of RAI therapy and the uncertainty in the relation of the reinduction of uptake of iodine and long-term responses.
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Dtc weight loss center international phase II and III studies are currently evaluating the efficacy of selumetinib in RAI sensitive metastatic patients and also in adjuvant setting. 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 Dtc weight loss center out the tumor initiating process of thyroid cancer of follicular cell origin has been suggested and also the so called oncogenic addiction to these particular mutations that make them particularly interesting for directed therapy.
The former pathway is also activated by inactivating mutations in the tumor suppression gene PTENor by activating mutations in the PI3KCA and AKT1which are common Dtc weight loss center follicular thyroid carcinoma, particularly in the most aggressive forms, and in poorly differentiated and anaplastic carcinomas.
Moreover, simultaneous activation of both pathways becomes more frequent in advanced RAI-refractory DTC with metastatic disease. Although the advances in molecular biology of thyroid cancer pathogenesis and the development of targeted therapies in this setting have been outstanding during the last years, nowadays no predictive biomarkers of clinical benefit for these targeted agents are available.
Classical chemotherapeutic agents have shown limited activity in DTC. The most developed drug has been doxorubicin alone and in combination with other cytotoxics, mainly cisplatin, with no increasing in response Dtc weight loss center but higher Dtc weight loss center events. Doxorrubicin is the only chemotherapeutic agent approved for refractory DTC and current recommendations limit its use, alone or in combination with taxane or platinum-based chemotherapy in anaplastic thyroid carcinoma.
External bean radiotherapy has been used to improve the locoregional disease control and to palliate some locations of distant metastases, such as central nervous system or bones. However, current recommendations Dtc weight loss center locoregional disease control are limited to macroscopic unresectable tumors in older patients and in combination with radiosensitizer drugs in anaplastic thyroid cancer.
Thyroglobulin serum levels have been one of the most important tools to follow up patients with persistent or recurrent disease.
Dtc weight loss center, 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 Dtc weight loss center appears, thyroglobulin levels could lose accuracy in correlation with tumor burden in parallel with the dedifferentiation process of DTC.
Additionally, no clear Adelgazar 15 kilos has been established with systemic therapies and thyroglobulin levels. For these reasons, no systemic therapies should be started based only in thyroglobulin levels, as well as no systemic therapies should be stopped based on thyroglobulin variations.
The progressive undifferentiating process that DTC cells suffer during the disease period time produces a TSH-independent growth that calls into questions TSH suppression in this setting. Additionally, most new targeted agents Dtc weight loss center some refractoriness to levothyroxine and TSH increase is commonly seen in thyroid cancer patients treated with MKIs being necessary an increase of levothyroxine doses to maintain TSH levels within normal range and to prevent a greater fatigue syndrome typically observed in these patients.
Garcilaso Riesco-Eizaguirre has received honoraria for advisory boards or lectures from Genzyme, Merck and Bayer. Javier Santamaría Sandi has received speaker honoraria from Genzyme.
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