Abstract
In addition to highlighting recent progress, however, the review also points to several important limitations of recent studies—and to gaps in our knowledge. Taking stock of not only progress, but also of what is still to be learned, will be critical to advancing further the care of our patients. So, what have we learned to date, what are the remaining unresolved issues, and how do we proceed from here?
To date, we have learned that systemic therapies, principally vascular endothelial growth factor receptor (VEGF-R)–targeted kinase inhibitors, can induce dramatic and often durable disease regression in many patients (up to 50% per RECIST criteria) with progressive RAI-refractory metastatic DTC. This is an important starting point in advancing the care of such patients, but many important questions remain unresolved.
We are still unfortunately relatively naïve related to the impact of kinase inhibitors and other therapies on patient survival, quality of life—and upon personal and health-system economics. We are also uninformed as to which of many competing systemic therapeutic approaches might be overall superior/equivalent/inferior (comparative therapeutic efficacy) in varying clinical contexts. We are also uncertain as to how best to approach therapy in patients who have already experienced disease progression despite use of systemic therapy of various sorts (therapeutic sequencing)—and we are moreover beginning to struggle with the question of whether and/or how to adapt therapy based upon tumor histology and/or dominant tumor mutations (personalized/individualized therapy). Hence, albeit progress has been made, much more remains to be learned.
Are we positively impacting patient survival and quality of life through the use of novel therapeutics in DTC? Anecdotal evidence suggests that this is likely to be the case for at least some patients. For instance, patients with oxygen-dependence attributable to RAI-refractory DTC lung metastases can attain sufficiently robust disease regression in response to kinase inhibitor therapy in order, for a time, to gain oxygen independence and improved functional status; few would question attainment of improved survival and quality of life in such patients. However, such examples are relatively few, and statistical verification of improved survival and/or quality of life resulting from therapy in RAI-refractory DTC has not yet been attained. Such examples importantly also illustrate that the assessment of therapeutic benefit in DTC is quite challenging, with results highly dependent upon the patient populations being treated/studied. For instance, asymptomatic RAI-refractory DTC patients with modest disease burden and indolent disease will alternatively stand to incur worsening quality of life from therapy—and may furthermore not enjoy improved survival. These examples point to critical importance of judicious patient selection when applying and studying systemic therapies. Future trials must be designed to attempt to resolve these important survival and quality-of-life questions, ideally within specific and constrained clinical contexts.
What about the economic impact of systemic therapy in DTC? As the present review highlights (1), there are no studies specifically addressing economic burden effects as a function of therapeutic approach in RAI-refractory thyroid cancer. This said, thyroid cancer has been reported to represent the second most common cause of cancer-related medical bankruptcy (after lung cancer) in the United States—with 4.8% of thyroid cancer patients filing for medical bankruptcy compared to 2.1% among the cohort of all cancer patients combined (2). This suggests that thyroid cancer may impact personal, and even societal, economics to a greater extent than would be expected related to its overall favorable prognosis compared to most other cancers. Kinase inhibitor therapy is furthermore extremely expensive, with annual costs of off-study drugs alone exceeding $40,000 per patient. As DTC is not presently an FDA-approved indication for these agents, insurance may also not cover these costs. Clearly, there is strong motivation to assess more rigorously the economic impacts of DTC therapies at the patient as well as at the systemic/societal level.
We also require more data in order to clarify (i) which of many competing systemic therapeutic approaches might be overall superior/equivalent/inferior in various clinical contexts; (ii) how to best approach therapy in patients who have experienced disease progression despite prior use of various systemic therapies; and (iii) whether and/or how to adapt therapy based upon tumor histology and/or dominant tumor mutations. To approach any of these issues meaningfully, we will need to develop randomized prospective multicohort comparative studies—yet all but one of the published DTC trials to date are instead single cohort studies (1). Encouragingly, more randomized trials are being developed, as evidenced by a review of ongoing trials (1). To make additional substantive therapeutic progress and to answer the questions posed above and others, clinical investigators will need to implement an evolving research paradigm that relies much more heavily upon randomized multicohort and multidimensional assessment of differing therapeutic approaches.
Hence, albeit that there has been dramatic recent progress in caring for patients with progressive metastatic RAI-refractory DTC, a great deal remains to be learned. We look forward to even more dramatic progress in the future.