The response rates to conventional chemotherapy are low in patients with WDTC requiring palliation of symptoms.2,3
In addition, many patients have asymptomatic progressive disease and it is important that palliative treatments do not worsen a patient’s quality of life. Recently, multi-targeted tyrosine kinase inhibitors have shown significant activity in patients with iodine-refractory WDTC and MTC.15,17,18,19,20
The activity of these agents has been consistently superior to conventional chemotherapy and associated with a favorable side effect profile. summarizes efficacy results from these trials. The studies have shown long intervals of progression free survival that suggest a change in the natural history of the disease. Because many patients with these tumors can have an indolent course that does not require therapy, most trials have attempted to select patients with more aggressive disease. Some trials have required documentation of disease progression by RECIST over 6 or 12 months prior to enrollment.
or the presence of symptomatic disease.15,17,20
However, the definition of progressive disease in studies requiring disease progression for entry was either unclear or evaluated individually by each investigator in a multi-center trial.15,17
The typically slow progression of even refractory thyroid cancer can make documentation of disease progression challenging. The current trial used a simple objective criterion for entry, namely, the presence of at least one FDG-PET avid lesion with uptake clearly above blood pool background. Although the entry criteria for this study may not be directly comparable to prior studies of other TKIs in thyroid cancer, the presence of FDG-avid tumors is strongly predictive of a more aggressive course of the disease, and associated with 5-year overall survival of less than 50%.4
Tumors were highly metabolically active by FDG PET, with median lesion SUV of 7.9, indicating an aggressive phenotype.
As in some prior published studies, we included both patients with iodine-refractory WDTC and MTC, both diseases for which there are few, if any, accepted systemic therapy choices. Although we reported results from both cancers combined, the RECIST response rates were similar (WDTC = 28%; MTC = 50%), and sunitinib clearly had activity in both tumor types.
Although it is not possible to directly compare results from the current trial with those previously published, therapy with continuous sunitinib was associated with a high rate of disease control. Seventy seven percent of patients had no evidence of disease progression 3 months after trial initiation. The median time to disease progression was 12.8 months and the median survival has not been reached. These results seem to compare favorably with what would be expected in this population with FGD-PET avid tumors.4
Furthermore, 78% of patients had some degree of tumor reduction. This is very important as patients with stable disease per RECIST criteria represent a heterogeneous group, which includes patients with a 29% reduction and a 19% increase in tumor size. Radiological response and disease control were seen both in WDTC and MTC. In addition, in those patients with measurable serum tumor markers, 58% of patients with WDTC and 50% with MTC had a significant decrease from baseline levels.
We attempted to correlate the results of a FDG-PET scan one week after therapy initiation with subsequent response to therapy, based upon data showing that a decline in FDG uptake could be an early indicator of response in other diseases treated by sunitinib.21,22
This could provide a very useful method to predict treatment benefit, particularly when using an expensive therapy in a clinical situation where stable radiologic disease is of unclear significance. We observed a significant association of average SUV percent change and RECIST response. Patients with partial/complete response and stable disease had a significant decline in average SUVs compared to patients with progressive disease. This is also true of mean percent change in the SUV of the most PET avid lesion. This is somewhat similar to, but of somewhat lower magnitude compared to results for sunitinib treatment in GIST, upon which the exploratory analysis was based and where early changes in FDG uptake have been shown to predict response.21
The early repeat FDG PET was an exploratory analysis; however, results suggest that, as in the use of sunitinib in GIST, FDG PET may provide an early indication of response, and importantly a lack of response. Thus early FDG PET might help identify patients unlikely to respond to sunitinib, sparing them the expense and toxicity of treatment. This would need to be studies more formally in future trials, but early results appear somewhat promising. It is possible, and perhaps likely, that a FDG-PET done later than one week from treatment initiation would have been a better predictor of benefit and may merit further investigation. This trial also showed that tumor markers were unreliable predictors of treatment benefit compared to objective response measures (RECIST). This result has also been shown in other trials using multi-targeted tyrosine kinase inhibitors.19
Dose reductions from 37.5 mg of continuous sunitinib were common, however a majority of patients requiring dose reduction, for non-hematologic toxicity, had documented disease control on 37.5 mg. Only four toxicities grades 3 and 4 were seen in more than 10% of patients: fatigue, diarrhea, hand/foot syndrome and leukopenia/neutropenia. The most serious complication was bleeding, with one treatment related death. Although the use of anticoagulation is not a contraindication for the use of sunitinib, our experience suggests that continuous administration of sunitinib in patients with well differentiated thyroid carcinoma may be associated with significant risk of serious bleeding episodes, particularly in the setting of full-dose anticoagulation. This trial also had two patients with grade 2 hemoptysis and subsequently we excluded patients with prior history of hemoptysis. We also observed more neutropenia than previously reported with sunitinib. This may be a consequence of our schedule of continuous administration. It is also possible that prior marrow radiation during radioactive iodine therapy may have contributed to this toxicity. Despite the frequent neutropenia, no patient in the trial developed fever in the setting of neutropenia. Data from this trial support the cut-off of 0.75 × 109cells/ L neutrophil count used to allow for treatment continuation.
In conclusion, continuous oral administration of sunitinib was effective in patients with iodine-refractory well-differentiated thyroid carcinoma and medullary carcinoma of the thyroid. Gastrointestinal bleeding and hemoptysis were the most serious complications of therapy and may be associated with the use of anticoagulation. Multi-targeted tyrosine kinase inhibitors have changed the therapy of WDTC and MTC. Although phase III clinical trials are necessary to define their precise clinical benefit, phase II trials conducted to date show a toxicity profile favorable to that of cytotoxic chemotherapy, with more consistent response rates and response duration.
Statement of Translational Relevance
Until recently, the treatment of advanced thyroid cancer has been limited by the poor efficacy of available chemotherapy agents. The introduction of tyrosine kinase inhibitors (TKIs), is leading to a paradigm shift in how this disease is treated. Our work focuses on two important aspects of TKI therapy to improve the future use of these agents in thyroid cancer. The first is the use of continuous dosing of sunitinib to improve response and better understand the toxicity in this unique patient population. The second is the investigation of FDG-PET imaging early in the treatment course to assess response. The use of functional imaging to assess treatment response and aid in clinical decision-making is a powerful tool that has the potential to be broadly applicable in the future practice of oncology.