Treatment of differentiated thyroid cancer has been slow to advance. Three decades lapsed between the description of the first differentiated thyroid cancer patient being cured by radioactive iodine in the 1940s1 and the report of the study that led to the approval of doxorubicin in the 1970s.2 The approval of doxorubicin was based on scanty evidence of efficacy, and this agent was eventually deemed ineffective and abandoned as a treatment option in this setting. For several decades, the standard of care for these patients was thyroid-stimulating hormone (TSH)-suppressive therapy and observation or referral to clinical trials, which were few and far between.
It was not until 2004 that the first trials with targeted multikinase inhibitors were started in differentiated thyroid cancer, bringing new hope for thyroid cancer patients with advanced radioactive iodine–refractory disease. Thanks to the efforts of several thyroid cancer experts, the U.S. Food and Drug Administration (FDA) has permitted phase III thyroid cancer trials to randomly assign patients to the standard of care, observation (ie, placebo), instead of to the more toxic option, doxorubicin. The culmination of these efforts came in 2013, when the FDA approved sorafenib (Nexavar) for differentiated thyroid cancer on the basis of the landmark DECISION trial.3
DECISION Trial
This trial, recently reported by Brose et al in The Lancet and reviewed in this issue of The ASCO Post, enrolled patients with chemotherapy-naive disease that had progressed within the past 14 months and randomly assigned them to sorafenib or placebo. The trial allowed for crossover from placebo to sorafenib in case of disease progression, and the primary endpoint of the study was progression-free survival, as opposed to overall survival.
The investigators found an absolute difference in progression-free survival of 5 months (10.8 in the treatment arm vs 5.8 in the placebo arm, hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.45–0.76, P < .0001), satisfying the trial’s primary endpoint. Responses in the treatment arm were surprisingly low, and overall survival benefit was not seen; however, at the time of the primary analysis, the median overall survival had not been reached in either arm.
Furthermore, the trial allowed for crossover, rendering overall survival difficult to assess. Even if crossover had not been permitted, patients might have sought out a commercial supply of sorafenib or another clinical trial, which also could have affected overall survival assessment. An update on overall survival presented at the 2014 ASCO Annual Meeting adjusted for crossover,4 but the results were inconclusive.
Quality-of-Life Considerations
The DECISION results are groundbreaking, given that few advances have been made in thyroid cancer for the past several decades. Brose et al should be commended for their accomplishment in carrying out and completing the first targeted multikinase inhibitor phase III trial in differentiated thyroid cancer.
That being said, it is still not clear whether the progression-free survival advantage without clear-cut evidence of overall survival advantage is truly beneficial to differentiated thyroid cancer patients, given that sorafenib was shown to decrease quality of life when compared to placebo.5 The discontinuation, drug hold, and dose-reduction rates reported—19%, 64%, and 66%, respectively—were surprisingly higher than those in phase III sorafenib trials in other solid tumors. For example, in renal cell carcinoma, the discontinuation, drug hold, and dose-reduction rates were 10%, 21%, and 13%, respectively, and in hepatocellular carcinoma, they were 11%, 44%, and 26%.
These results seem to suggest that sorafenib is more toxic in thyroid cancer patients, a finding that is explained by the recent study presented at the 2014 ASCO Annual Meeting6 showing increased sorafenib exposure (area under the concentration-time curve) in differentiated thyroid cancer patients as compared to those with renal cell carcinoma and hepatocellular carcinoma. Given that these drugs are chronic, continuous therapies that are toxic and in some cases can lead to death, sorafenib and other similar targeted agents should be reserved for patients with clinically significant, progressive, radioactive iodine–refractory differentiated thyroid cancer. In the absence of convincing evidence of an overall survival advantage, cautious use of sorafenib is recommended.
SELECT Trial
The search for more effective treatments for advanced thyroid cancer has not ended with the DECISION trial. Results of the SELECT trial, presented at the 2014 ASCO Annual Meeting by Schlumberger et al,7 represent the most exciting results in a thyroid cancer phase III trial to date. This trial of lenvatinib (E7080), a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT, was also a randomized, placebo-controlled trial that allowed crossover.
The treatment population was quite similar; however, in contrast to the DECISION trial, SELECT allowed for one previous line of chemotherapy, and this group accounted for 25% of the patients on the lenvatinib arm. The progression-free survival results were exciting—a median of 18.3 months in lenvatinib group vs 3.6 months in placebo patients (HR = 0.21, 99% CI = 0.14–0.31, P < .0001). A subgroup analysis showed that previously treated patients had a substantial progression-free survival benefit of approximately 1 year. Response rates were very high (65%), and responses were durable.
As with the DECISION trial, SELECT revealed no overall survival advantage, although the median overall survival has not been reached. The discontinuation, drug hold, and dose-reduction rates in the lenvatinib arm were 14%, 82%, and 68%, respectively; these are comparable to the sorafenib results and, like the sorafenib results, quite high.
Adverse events were similar to those with sorafenib, but lenvatinib-treated patients had a higher frequency of hypertension and a lower frequency of hand-foot skin reaction. A higher incidence of serious adverse events was reported for lenvatinib (51% in the SELECT lenvatinib-treatment arm and 37% in the DECISION sorafenib-treatment arm). Although head-to-head trial evidence is lacking, these results suggest that lenvatinib may be superior in efficacy to sorafenib, possibly at the cost of more toxicity.
Conclusions
Sorafenib and lenvatinib are effective in radioactive iodine–refractory differentiated thyroid cancer; however, observation and TSH-suppressive therapy continue to be the standard treatment for most of these patients. Again, patients should only be treated with these targeted drugs if they have clinically significant, radioactive iodine–refractory, progressive disease. This point cannot be stressed enough, given the drugs’ toxicity, the fact that responses are temporary and not maintained after drug discontinuation, and the lack of a clear overall survival benefit.
Certainly, significant strides in differentiated thyroid cancer treatment have been made over the past 70 years and, without a doubt, will continue to be made. The next challenges are to identify effective treatments for patients in whom first-line therapy fails, to find less toxic alternatives, to improve quality of life in patients on these systemic therapies, and, ultimately, to find a cure for advanced, radioactive iodine–refractory differentiated thyroid cancer. ■
Dr. Cabanillas is Associate Professor and Faculty Director of Clinical Research, Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston.
Disclosure: Dr. Cabanillas has received research funding and is on the advisory board (uncompensated) for Eisai.
References
1. Seidlin SM, Marinelli LD, Oshry E: Radioactive iodine therapy: Effect on functioning metastases of adenocarcinoma of the thyroid. JAMA 132:838-847, 1946.
2. Gottlieb JA, Hill CS Jr, Ibanez ML, et al: Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients. Cancer 30:848-853, 1972.
4. Brose MS, Jarzab B, Elisei R, et al: Updated overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid caner (RAI-rDTC) treated with sorafenib in the phase 3 DECISION trial. ASCO Annual Meeting. Abstract 6060. Presented May 31, 2014.
5. Schlumberger M, Jarzab B, Elisei R, et al: Phase III randomized, double-blinded, placebo-controlled trial of sorafenib in locally advanced or metastatic patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC): Exploratory analyses of patient-reported outcomes. American Thyroid Association Annual Meeting, Abstract 100. Presented October 18, 2013.
6. Bastholt L, Brose MS, Jarzab B, et al: Population PK modeling and exposure-response analyses of sorafenib in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) in the phase III DECISION trial. ASCO Annual Meeting. Abstract 6061. Presented May 31, 2014.
7. Schlumberger M, Tahara M, Wirth LJ, et al: A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). ASCO Annual Meeting. Abstract LBA6008. Presented June 2, 2014.
