Thyroid cancer has long been a tumor that was within the purview of surgeons and endocrinologists, with the role of medical oncologists limited at best. Since most patients with differentiated thyroid cancer (DTC) were destined to do well with their disease, referral to oncology was infrequent and usually confined to patients with radioiodine-refractory advanced, and progressive disease. The oncologist was often relegated to the role of providing supportive care for patients and support for caregivers. Options for treatment were limited as standard chemotherapy agents failed to offer meaningful activity in the form of tumor response and improved survival.
Although not specifically studied, clinical experience would indicate that chemotherapy also fails to provide substantial clinical benefit in the form of symptom control and functional improvement. For many years, the best option for such patients was participation in clinical trials.
The past decade has seen a dramatic shift in treatment of this complex group of cancers, with oncologists now being called upon to participate actively in the management of patients. Unfortunately, most oncologists in a general practice setting have had little training in the diagnosis and management of thyroid malignancies. Oncologists are thus challenged to:
1. Understand the evolving treatment strategies for thyroid cancer;
2. Recognize the importance of a multimodality team approach that includes endocrinologists, radiation oncologists, endocrine surgeons, and radiologists; and
3. Gain adequate knowledge about the appropriate use of therapeutic agents in the treatment of thyroid malignancies
While there has always been institutional variability in the management of DTC, for many decades management was largely unchanged and somewhat standardized. A majority of patients received total thyroidectomy followed by I-131 therapy and were then followed lifelong with measurement of thyroglobulin levels and periodic withdrawal from thyroid hormone for diagnostic whole body radioiodine (RAI) scans. Rising thyroglobulin was often treated with more liberal use of RAI, and locoregional recurrences were treated with surgery, often followed by further RAI therapy.
The past 15 years have seen a marked change in management across the disease trajectory. The evolving treatment strategies for DTC are reflected in the American Thyroid Association (ATA) guidelines. In the short time between 2006 and 2009, the guidelines expanded greatly, particularly as relates to initial management. For example, the 2006 guidelines (Thyroid 2006;16:109-142) give a brief recommendation to use the AJCC/UICC staging “to improve prognostication and to plan follow-up” (Recommendation 31).
By 2009, this same section includes a novel three-tiered risk stratification (low-, intermediate-, and high-risk) to guide practical decision-making (Thyroid 2009;19:1167-1214). Similarly, the guidelines related to decisions regarding postoperative RAI ablation are greatly expanding—reiterating high-risk features that clearly justify RAI therapy, but also clarifying patient populations where therapy is not indicated and greatly expanding discussion of patient categories where therapy is more controversial.
The most dramatic change in management of thyroid cancer was the incorporation of recombinant human TSH (rhTSH) into diagnostic and treatment strategies. Initially approved in the U.S. in 1998 for diagnostic scans, and subsequently in 2007 for initial ablation with RAI, rhTSH improved quality of life by alleviating the need for thyroid hormone withdrawal.
Beyond the ATA guidelines, risk stratification has permeated the field. No longer is TSH suppression the goal for all patients, but the target TSH is now adjusted based on risk (from normal in low-risk patients, to mildly low in intermediate-risk, to fully suppressed in patients with persistent disease or a high risk of recurrence).
Likewise, surveillance is now much more customized; many low-risk patients receive surveillance simply with unstimulated thyroglobulin and cervical ultrasound, without the need for cumbersome diagnostic radioiodine scans. FDG-PET imaging has become more common and earlier in the evaluation, again not simply for diagnostic purposes but to assess risk, noting increased mortality in FDG-avid malignancies. Strategies to reassess risk categories based on the response to initial therapy are published.
Regarding systemic therapy, clinicians are familiar with agents such as sorafenib, because they are commonly used from the treatment of other malignancies. It should be noted however, that both well-differentiated thyroid cancer and medullary thyroid cancers behave in a distinct manner in comparison to the rapid growth seen in tumors such as renal cell carcinoma.
Although individual patients may have aggressive and rapidly growing tumors, in general well-differentiated papillary and medullary thyroid cancers are indolent in nature, and patients may have asymptomatic disease that progresses slowly over years.
New agents may be effective in improving outcomes; however, they are associated with substantial toxicity and cost. One of the major issues facing the clinician is to decide when to incorporate these agents into the treatment for individual patients.
In general, published studies have required that patients have radioiodine-resistant cancers that are either visibly progressive or that manifest tumor-related symptoms. Furthermore, simply defining “radioiodine-refractory” can be challenging, with care needed to ensure that radioiodine testing is performed under appropriate circumstances (e.g., a recent patient at our institution previously deemed to have iodine-negative disease based on radioiodine imaging performed one day after receiving iodinated contrast).
Moreover, previous concepts of iodine-refractoriness will need reconsideration given recent demonstration of improved RAI uptake in previously non-avid lesions after a short course of the MEK inhibitor selumetinib (NEJM 2013; 368:623-632).
Thus, clinicians are challenged with initiating therapy before the patient's disease progresses to the point where therapy is either not feasible or unlikely to be of benefit while conversely ensuring that treatment is not instituted too early, thereby exposing the patient to undue and unneeded toxicity. The multimodality clinic or tumor board is indispensable to bring together the expertise of medical oncologists, endocrinologists, surgeons, nuclear medicine physicians, and radiation oncologists.
Available data such as FDG avidity, thyroglobulin doubling-times, and progression on anatomic imaging in size or number of lesions can all be used to consider if any therapy is indicated, given long-term stability in many patients. It should be noted that the role of these agents in the adjuvant setting or in patients with asymptomatic slowly progressive disease is unknown.
The question as to whether earlier rather than later therapy for patients with high-risk disease is worthy of investigation, but in the meantime, oncologists must resist the temptation to use expensive and potentially toxic agents for the treatment of patients with low-risk and asymptomatic disease.