Sorafenib Side Effects Not Inconsequential in Thyroid Cancer

Nancy A. Melville

October 23, 2013

SAN JUAN, Puerto Rico — A new quality-of-life assessment of sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) from a phase 3 trial in radioactive iodine (RAI)–refractory differentiated thyroid-cancer patients shows that side effects stand out as the main bone of contention.

The findings, reported at the 2013 Annual Meeting of the American Thyroid Association, come from the phase 3 DECISION trial, a randomized, double-blinded, placebo-controlled study, reported in June, which showed that sorafenib doubled the rate of progression-free survival in RAI differentiated thyroid-cancer patients.

Sorafenib, a multikinase inhibitor, currently has approval from the US FDA for use in patients with inoperable hepatocellular carcinoma and renal-cell carcinoma and has priority review status for the treatment of RAI-refractory differentiated thyroid cancer. Only about 5% to 15% of thyroid-cancer patients become refractory to RAI, but with no other standard treatments available and median survival estimated to be 2.5 to 3.5 years, the need for better treatment options is pressing, said Martin Schlumberger, MD, a professor of oncology at the University Paris-Sud, France, who presented the new findings.

Overall, the health-related quality-of-life assessment "showed a small but statistically significant difference in favor of placebo," he said. "The [scores] decreased at the first assessment for the sorafenib group…due to the drug's side effects, but it did not decrease thereafter."

Joshua Klopper, MD, from the division of endocrinology, metabolism, and diabetes at the University of Colorado, Aurora, who moderated the session, said: "These types of studies are important to reinforce for physicians that these medications have a relevant side-effect profile and that patients should be aware of these side effects prior to starting therapy. Patients then need to make a personal choice as to whether the 'benefits' of the medication are worth the 'costs.' "

Dr. Klopper said the study's observations are consistent with his experience in treating RAI-refractory differentiated thyroid-cancer patients with sorafenib — some patients have discontinued the drug due to intolerable side effects, particularly hand-foot syndrome, involving a painful rash and sensitivity, he noted.

But he pointed out that adjustments in dosing may represent one approach for addressing such adverse effects. "One issue that was appropriately not addressed in the presentation but is relevant is the potential to dose-reduce patients, [which] may improve side effects while retaining clinical efficacy. We have had that experience, as have others," he noted.

Differences in Quality of Life Due to Side Effects

Most differentiated thyroid-cancer patients have traditionally been treated by endocrinologists, with surgery and radioactive iodine being the mainstay of therapy. Although this type of thyroid cancer has the reputation of being a "good cancer" because it can be easily cured, a minority of patients (around 10%) resistant to RAI treatment will have an overall survival of only around 2 to 3 years.

Sorafenib is being used off label for these patients by some medical oncologists; DECISION is a pivotal trial in around 400 patients aimed at gaining approval of the drug for this indication. The primary results showed that median progression-free survival was 10.8 months in the sorafenib group compared with 5.8 months in the placebo arm. Safety results were consistent with the drug's known side effects, which include hand-foot skin reaction, diarrhea, alopecia, rash, fatigue, and hypertension.

The new analysis evaluated patients' quality of life using scores on the Functional Assessment of Cancer Therapy-General (FACT-G), a validated tool that tracks well-being in 4 domains: physical, social/family, emotional, and functional. In addition, patients were assessed with the EuroQoL-5 Dimensions (EQ-5D) Index and the EQ-5D visual analog scale (EQ-5D VAS), which measures general health status.

The measures, assessed at baseline and day 1 of every 28-day cycle of treatment, showed a dip in the score in the sorafenib group at the first assessment, representing cycle 2, with the FACT-G score for the sorafenib group being 3.45 points lower than placebo (P = .0006).

A closer evaluation of patient responses showed similarities between the treatment and placebo groups, with the exception of physical domain and questions relating to side effects.

"We found the physical well-being domain was responsible for the vast majority of the cycle 2 decrease in the sorafenib group," Dr. Schlumberger said. "The other domains were not significantly different, and within the physical domain, the main difference was seen in the question relating to side effects."

Can Dose Reduction Help With Side Effects?

Speaking with Medscape Medical News regarding the practice of reducing the dose of sorafenib in order to limit side effects, Leonard Wartofsky, MD, MACP, chair of the department of medicine at the Washington Hospital Center in Washington, DC, said he was familiar with this approach.

"There's one patient whom we are following who was started on 800-mg sorafenib and developed the so-called hand-foot disease, so the dose was dropped by half to 400 mg a day to allow for healing, and the idea is to slowly increase it up to 600 mg, and, if tolerated, back up to 800 mg," he said.

"It doesn't seem to compromise efficacy, but one can presume the efficacy is better with the higher dose," he noted.

Dr. Wartofsky cautioned, however, that, in addition to the known side effects, concerns have been raised about sorafenib in an Italian study of the drug in RAI-refractory differentiated thyroid cancer that reported that 3 patients out of 17 died from severe bleeding events and 2 died from cardiac arrest. (Clinical Endocrinol. 2013;78: 760-767).

"Drugs in this family are known to potentially affect the QT interval," he said. "They didn't see that effect [in the phase 3 study], but in seeing these couple of deaths in the Italian study, one wonders if that might be related."

But Sorafenib Not a Cure for Thyroid Cancer

And while the Italian study also showed a median progression-free survival of 9 months with sorafenib, Dr. Wartofsky cautioned that these types of findings should not be unduly hyped.

"Every time a new cancer drug comes out, everyone gets excited, but there is a risk for unreasonable expectations. This is not a cure for thyroid or any other cancer," he said.

"What it achieves is some improvement in progression-free survival, but it does not increase overall survival, and there are not data showing that patients who take this actually live longer."

Furthermore, he noted that in the DECISION trial, some patients in the placebo group were switched to sorafenib when their tumors started progressing.

"Therefore, there wasn't that clean separation between the treatment and placebo groups to actually get to the bottom line of survival because the groups became mixed up."

Keeping in mind these caveats, Dr. Wartofsky nevertheless expressed optimism on the prospects of research on the multikinase inhibitors for RAI-refractory differentiated thyroid cancer.

"My take is it's a step in the right direction that we're developing these new drugs," he said.

"There are probably a dozen or so drugs like sorafenib that are in development in phase 1 through 3 trials, and sooner or later there will be a good one that will come along."

The DECISION trial was sponsored by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Klopper has reported no relevant financial relationships. Dr. Schlumberger's disclosures included relationships with AstraZeneca, Bayer, Eisai, Exelixis, Genzyme, and Roche Pharmaceuticals. Dr. Wartofsky disclosed that he participated in a session organized by Bayer Healthcare Pharmaceuticals designed to obtain clinician feedback on sorafenib, but he is not a consultant for the company or on its payroll.

2013 Annual Meeting of the American Thyroid Association. Abstract 100, presented October 18, 2013.

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