The foregoing article by Burnison and Lim reviews recent progress in treating anaplastic thyroid cancer (ATC) patients, with a primary emphasis on the evolution of thinking related to locoregional radiotherapeutic approaches. Clearly, this is an important topic, as ATC poses a locoregional threat to the airway and esophagus that requires immediate attention; moreover, primary surgery is not always feasible. Burnison and Lim provide a brief discussion of systemic therapeutic approaches to ATC, but their emphasis is clearly on the attainment of locoregional control, primarily through the use of radiation therapy; furthermore, they do not review the topic of primary surgery for ATC. In this commentary, we highlight our view that an integrated and collaborative multimodality therapeutic approach is of critical importance in working towards our ultimate goals of improving ATC outcomes and survival.
Even before considering the administration of locoregional radiation therapy, we posit that surgery is a primary initial consideration, especially in nonmetastatic ATC. Many studies point to improved overall survival in ATC patients who receive more complete primary surgery,[1-7] with over 80% of the more than 20 published studies that examine this factor suggesting benefit from more complete (R0) resection. Clearly, the inference of improved outcomes from more aggressive primary surgery is based on analysis of retrospective data that are unavoidably biased by the presumption that patients with better prognoses will be more amenable to more complete initial surgery. Nonetheless, available data reveal only positive effects of aggressive initial surgery on ATC patient survival. Consequently, we believe that surgery should be the initial therapeutic maneuver in locoregionally confined ATC whenever technically feasible. A nihilistic approach that denies primary surgery to patients with locoregionally confined ATC is simply unjustified based on the available literature.
Issues related to the role(s)of systemic therapy in ATC are complex. However, the available data, albeit dominantly retrospective, nonetheless suggest that improved survival appears to result from the application of systemic therapy in ATC, particularly when initiated early on. Antimicrotubule agents (eg, taxanes, fosbretabulin) and anthracyclines (eg, doxorubicin(Drug information on doxorubicin)) have clinical activity in advanced ATC,[9-13] as well as radiosensitizing properties[14-17]; these agents therefore have potential not only to improve locoregional disease control when combined with radiation therapy—but also to treat occult or macroscopic systemic disease. Indeed, the integration of systemic therapy into ATC treatment regimens has been increasing—with feasibility demonstrated and with improved outcomes reported, including prolonged survival.[6,18-27]
An imminent threat in ATC is posed by both locoregional and metastatic disease; consequently, there is a need to attend to both threats as soon after diagnosis as possible. Even if locoregional disease control is attained, the vast majority of ATC patients historically succumb to metastatic disease—underscoring the fact that ATC should be considered a systemic process from the time of diagnosis even if apparently macroscopically locoregionally confined. Moreover, although systemic therapy has high response rates in metastatic ATC (see, for example, Ain KB et al. Thyroid. 2000), attained responses are uniformly brief—and metastatic ATC is incurable. These considerations have prompted what we believe is an emerging paradigm shift toward the earlier integration of systemic therapy into ATC management, on the theory that its earlier application may have a greater impact on survival. In our own Mayo experience, we were gratified and even surprised to find that median survival for stages IVA and IVB ATC seemingly changed from ~6 months historically to ~60 months upon initiation of the change in our practice pattern of combining intensity-modulated radiation therapy (IMRT) with docetaxel(Drug information on docetaxel)/doxorubicin radiosensitizing and adjuvant therapy—as well as with surgery whenever feasible. Whether our experience will be found generalizable remains to be seen, but our most recent experience suggests that it is reproducible.
Several critical questions remain with regard to optimization of ATC therapy, but these can only be answered through prospective randomized clinical trials. Two such questions are being approached by recent and ongoing trials. First, an ongoing Radiation Oncology Treatment Group (RTOG) trial is presently examining the issue of optimizing therapy combining IMRT with systemic agents (clinicaltrials.gov NCT01236547); this trial is designed to assess the benefits and risks of adding the vascular endothelial growth factor receptor (VEGFR)-directed, multitargeted kinase inhibitor pazopanib to IMRT plus weekly paclitaxel(Drug information on paclitaxel). Certainly, this prospective randomized multicenter trial is only approaching one part of the question—that of whether VEGFR inhibition can enhance outcomes beyond what can be attained with IMRT + paclitaxel. Additional critical and relevant questions remain to be examined (eg, is paclitaxel the best cytotoxic approach in this context?)—but this trial is an important start.
Another critical question involves defining the “best” approach to treating metastatic ATC. This was also the subject of a recent prospective randomized trial—this one comparing the effects of paclitaxel/carboplatin vs those of paclitaxel/carboplatin + fosbretabulin in advanced ATC (clinicaltrials.gov NCT00507429). Although patients enrolled in the fosbretabulin arm experienced improved survival, the trial closed after accrual of 80 of an intended 180 patients due to poor accrual—without meeting the primary prespecified statistical endpoint of overall survival, highlighting the challenges involved in studying ATC. Other trials addressing further questions related to the preliminary clinical activities of a variety of agents in advanced ATC are ongoing but are not randomized.
In the future, additional questions will arise, including those related to the role(s) of charged-particle (proton and carbon ion) therapy in treating locoregionally involved ATC; there is hope for diminished toxicities and improved locoregional tumor control using this approach, but effects on efficacy outcomes are not easily predictable. In terms of systemic disease, important questions are continuing to arise related to how to best translate emerging data defining the roles of a variety of molecular events into improved patient outcomes. Moreover, the extent to which surgery contributes incrementally to outcomes within the context of available and emerging radiotherapeutic approaches is also fertile ground for prospective study.
Like Burnison and Lim, we conclude conveying our sense of optimism that progress is being made—and that important clinical questions are being asked related to the care of patients afflicted with ATC. We believe, however, that in the final analysis, important progress will remain highly dependant upon collaborations conducted across specialties, across institutions, and across nations.
Acknowlegment: The kind administrative assistance of Ms. Candace Kostelec in conjunction with the preparation of this manuscript is much appreciated.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.