The paper by Higgins et al published in this issue highlights the important advances that have been made in the treatment of advanced thyroid cancer over the past few years. Patients with iodine-refractory metastatic thyroid cancer have suffered badly due to the reputation of thyroid cancer as being a “good” cancer to have.
The paper by Higgins et al published in this issue highlights the important advances that have been made in the treatment of advanced thyroid cancer over the past few years. Patients with iodine-refractory metastatic thyroid cancer have suffered badly due to the reputation of thyroid cancer as being a “good” cancer to have. The success of treatment for patients with stage I and II disease has led to the misconception that there is no need for research into treatment for this disease. However, the numbers are misleading. While most patients can be successfully managed with surgery, radioiodine (131I), and thyroid-stimulating hormone (TSH) suppression, several groups of patients are more likely to have difficulty.
These patients include those with disease subtypes that carry a poor prognosis at diagnosis, such as tall cell and insular papillary thyroid carcinoma, Hrthle cell carcinoma, and tumors that are multicentric or have capsular invasion. Male patients also do more poorly, and as a result, although thyroid cancer is diagnosed in women more often than in men (approximately 3:1), men make up 50% of patients accruing to trials for advanced, 131I-refractory disease.[1-4]
Historically, without an effective treatment, these patients are managed expectantly and are forced to undergo multiple rounds of surgery, 131I, external-beam radiotherapy, cryosurgery, and interventional bronchoscopy. These additional invasive medical approaches account for greater numbers of procedures than the rarity of the tumor and the good overall prognosis would suggest, and significantly diminish the patient’s quality of life. Yet, convincing both the National Institutes of Health and the pharmaceutical industry that this is a population of patients worth the time and expense for the development of new therapies has been a challenge.
A further misconception about radioiodine-refractory thyroid cancer patients is that they are stable for a long time, and therefore, if they are not symptomatic at the time they are seen by the oncologist, they may not need treatment. However there are studies indicating that this is not the case and that the survival of these patients is on average 2 to 3 years.[5,6] Thus, although patients may not have symptoms currently, if they have distant metastases that are iodine-nonavid or positron-emission tomography (PET)-positive, it is time to intervene, as their disease will be fatal if not controlled.
The phase II studies to date have required progressing measurable disease by response evaluation criteria in solid tumors (RECIST), and this is likely a good place to begin treatment. First, it identifies a group of patients that may not be symptomatic, and thus presents the opportunity to prevent some of the morbidity of the disease and the associated treatments that are likely to come. Furthermore, if a patient does not respond to one treatment, or at least stabilize, there is time to try a second-line therapeutic approach. Patients with bone-only disease (a small minority will not also have measurable disease) is a small group of patients who will warrant treatment despite the fact that they have not been eligible for the trials completed to date.
Over the past 5 years, the field of thyroid cancer has changed dramatically. Patients with radioiodine-refractory disease are now being treated with success using agents that target molecular pathways that are frequently altered in this disease. It is clear that agents that target the vascular endothelial growth factor receptor (such as sorafenib [Nexavar], sunitinib [Sutent], and axitinib) are active in this disease and this is likely primarily due to the antiangiogeneic effects of these agents. The role of other potential targets of kinase inhibitors-such as BRAF (eg, sorafenib), RET (eg, sorafenib, motesanib), and platelet-derived growth factor receptor (eg, sorafenib, sunitinib, axitinib)-in either the response of these patients or progression-free survival has yet to be determined, but may result in differences between these agents in the long run. Higgins et al do not discuss the potential importance of altered signaling through the AKT/PI3K pathway recently documented in thyroid cancer (as reviewed in reference 7) to the development of a new group of tractable therapeutic targets.
Management of toxicities will play an increasing role in treatment choice and success for these patients. While both sorafenib and sunitinib can present with toxicities in the initial phase of treatment, side effects can be well controlled with over-the-counter remedies and brief dose holidays or adjustments. Interestingly, following a short holiday from these agents due to intolerable toxicity, many patients are able to resume the same dose with less difficulty, allowing them to be managed at the starting dose. Importantly, many of the toxicities associated with the start of therapy for these agents are significantly improved after the initial 3 to 6 months without dose adjustment, and thus can be tolerated with good quality of life. This property distinguishes these agents from non–kinase inhibitors that tend to become less well tolerated as treatment continues.
Historically, few patients with refractory thyroid cancer were treated by the oncologist due to the lack of response and high toxicity of traditional cytotoxic therapy. While Higgins et al point out that older studies[8,9] report responses ranging from 10% to 37% with doxorubicin, these studies are currently discounted as producing overestimates of doxorubicin activity because they predated the use of computed tomography (CT) scans, RECIST criteria, and the dose limit of 600 mg/m2. Using current standards, the response rate of doxorubicin is estimated at 5%.[10,11]
With the evolution of effective therapies for thyroid cancer patients, oncologists will need to be trained in the disease and treatment course of thyroid cancer patients. They will need to understand how to monitor TSH levels to maintain adequate suppression and to interpret biomarker levels (thyroglobulin and calcitonin), which can be affected by therapy and therefore may no longer predict progression.
Due to the rarity of the tumor, patients for clinical trials in this setting are limited. With a large number of agents already shown to have activity in thyroid cancer, additional phase II trials should be pursued only when enrollment to a phase III trial is not available, if any of these agents are to make it to the general population. This will take a concerted effort by the oncology and endocrine communities to enroll patients, so that the agents already shown to have significant activity can be studied in trials that are sufficiently large for definitive results to be obtained.
Financial Disclosure: Dr. Brose has received speaker honoraria from Bayer HealthCare.
1. Cohen EE, Needles BM, Cullen KJ, et al: Phase 2 study of sunitinib in refractory thyroid cancer (abstract 6025). J Clin Oncol 26:322s, 2008.
2. Gupta-Abramson V, Troxel AB, Nellore A, et al: Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26:4714-4719, 2008.
3. Kloos RT, Ringel MD, Knopp MV, et al: Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 27:1675-1684, 2009.
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5. Durante C, Haddy N, Baudin E, et al: Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy (see comment). J Clin Endocrinol Metab 91:2892-2899, 2006.
6. Robbins RJ, Wan Q, Grewal RK, et al: Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 91:498-505, 2006.
7. Shinohara M, Chung YJ, Saji M, et al: AKT in thyroid tumorigenesis and progression. Endocrinology 148:942-947, 2007.
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10. Matuszczyk A, Petersenn S, Bockisch A, et al: Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res 40:210-213, 2008.
11. Pfister DG, Fagin JA: Refractory thyroid cancer: A paradigm shift in treatment is not far off. J Clin Oncol 26:4701-4704, 2008.