Endoperspectives, Volume 5, Issue 2

Department of Endocrine Neoplasia and Hormonal Disorders NEWSLETTER Volume 5, Issue 2, 2012 Metastatic Differentiated Thyroid Cancer: When is Systemic Therapy Beyond RAI Warranted? ® Maria E. Cabanillas, MD Assistant Professor Department of Endocrine Neoplasia and Hormonal Disorders Introduction consideration of local therapy or systemic treatment Patients with widely meta- with the newer tyrosine kinase inhibitors or cytotoxic static differentiated thyroid chemotherapy is appropriate once significant progres- cancer (DTC; includes papil- sion is documented. Figure 1 shows the algorithm for lary, follicular, and Hurthle cell treatment of patients who present with metastatic dis- carcinoma) can pose a chal- ease and those who later develop metastatic disease lenge to physicians, especially after first line therapy. those who see few cases of Definition of RAI-refractory this relatively rare presenta- A patient is considered RAI-refractory when radioio- tion. While the 10 year median survival after the dis- dine is no longer effective either because the disease covery of metastatic disease is 42%, the prognosis can does not take up iodine (usually determined on a pre- or be vastly different among patients and depends on the post-treatment, diagnostic whole body scan) at known age of patient, histology, location and size of the dis- sites of metastatic disease or because the disease con- tant disease, as well as whether the disease takes up tinues to grow despite previous treatment. Radioiodine and responds to radioactive iodine (RAI)1. For example, can continue to have efficacy over 9-12 months (some- younger patients (<40 years) with micronodular (<1cm) times longer) and therefore the patient is considered lung disease have an excellent overall survival of 95% at RAI-refractory only when the distant disease grows over 10 years, while older patients with macronodular lung a 1 year period after RAI. Because a cumulative dose of metastases or multiple bone metastases have a 14% RAI beyond 600 mCi has been shown to have little ef- overall survival at 10 years1. ficacy1, patients who have received this amount of RAI Metastatic DTC tends to be indolent in the majority can also be considered RAI-refractory, especially for the PERSPECTIVES of patients whereas a minority of others have meta- purpose of clinical trial entry criteria. In addition, some static disease that grows rapidly from the outset. Also, patients should not be considered for additional RAI if patients who initially had indolent disease may later they have had adverse events associated with high dos- demonstrate a more aggressive course. An understand- es of RAI. One example is bone marrow damage result- ing of the natural history and appropriate management ing in cytopenias. of this disease is important so that patients are not When are local therapies considered? under or over treated. Because metastatic DTC is often Searching for bone metastases in patients with mus- slow growing and asymptomatic, a more restrained ap- culoskeletal pain and elevated (Continued on Page 2) proach, compared with other solid tumors, is needed. In some cases, patient with rapidly progressive and/or Table of Contents symptomatic disease or disease in areas that are life- threatening or have the potential to become life-threatening require a more aggressive approach. • Metastatic Differentiated Thyroid Cancer Page 1 Management of metastatic DTC • Clinical Trials Insert Patients who present with newly diagnosed DTC • Case File: ACTH-Independent Mac- with distant metastases should be treated with first ronodular Adrenal Hyperplasia Page 4 line, standard therapy, which consists of surgery and • The Emergence of Oncologic Endocri- ENDO subsequent RAI. The thyroid and any regional disease are removed prior to RAI in order to remove a source nology as a Clinical and Research Field Page 5 of large iodine uptake. Once the thyroid and involved • New Oncologic Endocrinology Fellowship cervical lymph nodes are removed, RAI can be highly Training Program Page 6 effective to target distant metastatic disease. However, • Department Programs Page 7 if the distant disease is RAI-refractory (defined below), (Cabanillas, continued) RAI-refractory patients with progression within 6 thyroglobulin should be considered. Local therapy months, particularly those with symptomatic or life- with external beam radiation is often considered in threatening disease, should be considered for sys- Upcoming Events two scenarios: to palliate painful metastases and to temic therapy. Most clinical trials in thyroid cancer provide local control of disease when RAI is no longer require progression within 1 year in order to qualify American Society of effective or rapid disease control is imperative such for enrollment in a trial5 and therefore this is the Clinical Oncologists as treating bony metastatic disease in the vertebral standard that we use for initiating systemic therapy (ASCO) 2011 Annual spine. Embolization of a site of bony metastatic dis- in asymptomatic patients. Symptomatic patients or Meeting June 1-5, 2012. ease is useful in some cases and can lead to tumor patients with bulky disease that compromises organ Chicago, IL. (http://chi- shrinkage and palliation of pain. Metastatectomy is function and who cannot be managed with local cago2012.asco.org) sometimes performed if there is only one site of dis- therapies should initiate systemic therapy. High FDG ease. Zolendronic acid administered intravenously uptake on PET scan has been considered as a criteria Amerian Diabetes Associa- can also be used for pain and may be helpful for dis- for initiating systemic therapy because these patients tion (ADA) 72nd Scientific Sessions. June 8-12, 2012, ease control in patients with bony metastastic dis- exhibit a more aggressive course and are usually RAI- 6,7 Philadelphia, PA. (www.sci- ease, although little data exists to support the latter. refractory . However, it is important to prove RAI-re- entificsessions.diabetes.org) It is not uncommon for brain metastases to be as- fractoriness prior to recommending systemic therapy. ymptomatic. Therefore, imaging of the brain should Systemic therapies: ENDO: The Endocrine be considered prior to proceeding with any systemic Choices for systemic therapy include the newer Society Annual Meet- therapy. Treatment of unifocal brain metastases in- targeted agents (tyrosine kinase inhibitors, TKIs) or ing 2012. June 23-26, cludes surgery or stereotactic radiation. Whole brain cytotoxic chemotherapy. TKIs should be considered 2012. Houston, Texas. irradiation is considered in patients with extensive first because these have been shown to be efficacious (www.endo-society.org) multifocal metastatic disease. in DTC whereas cytotoxic chemotherapy has limited When to ‘watch and wait’ in patients who are RAI efficacy. While there are no TKIs approved by the FDA 13th International 8 9 Workshop on Multiple refractory for DTC, the ATA and NCCN guidelines recommend Endocrine Neoplasia. Dormancy of the metastatic disease is common in “off-label” use of TKIs (such as sorafenib, sunitinib, and Sept 5-8, 2012. Liege, DTC. The events which lead to progression likely are pazopanib) or treatment on a clinical trial (clinicaltri- Belgium. (www.iwmen. due to genetic and epigenetic events in the tumor als.gov). Table 1 shows the list of drugs that have been org/event/Liege2012/) which cause the disease to become more aggres- studied in DTC and their targets. Entry into phase 2 sive2. The rationale for the ‘watch and wait’ approach and 3 clinical trials is usually limited to patients with American Thyroid Asso- is based mainly on the fact that most patients with RAI-refractory, progressive disease. Phase 1 trials can ciation (ATA) 82nd An- widely metastatic, RAI-refractory DTC enjoy a long in- be considered for patients who do not meet entry nual Meeting. Sept 19-23, dolent phase where the tumor is stable or slowly pro- criteria. For example, a patient with very rapidly pro- 2012. Quebec City, PQ, gressive and asymptomatic. These patients can enjoy gressive disease who has an unresectable primary tu- Canada. (www.thyroid.org) a good quality of life for many years before requiring mor in the thyroid would likely not benefit from RAI. American Society for systemic therapy. Because systemic therapies have Rather than administer a treatment known to be inef- Bone and Mineral Re- many side effects, some of which can be fatal, delay- fective, this patient could be offered a phase 1 trial. search (ASBMR) 2012 ing therapy until the disease accelerates is prudent. Sorafenib, sunitinib, and pazopanib are oral antian- Annual Meeting. Oct TKIs are considered chronic therapies, as stopping giogenics approved for other indications. These drugs 12-15, 2012. Minneapolis, these drugs usually results in progression of disease. have been used in phase 2 trials and are promising MN. (www.asbmr.org) Furthermore, the TKIs have not cured any patient thus agents for patients with progressive, RAI-refractory far and it is not clear whether they will prolong overall disease. Common side effects include hypertension, ThyCa Conference 2012. survival. skin toxicity (rash and hand-foot syndrome), diarrhea, Oct 19-21, 2012. Chicago, Patients should have full staging exams to deter- weight loss and fatigue. Less common but potentially Ill. (www.thyca.org) mine extent of disease and pace of progression. Dis- fatal adverse events include congestive heart failure, 12th International tant disease limited to the mediastinum and lung slow

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