Transcript: Eric J. Sherman, MD: Sorafenib has gone through a randomized phase III study against placebo in patients with RAI [radioactive-iodine]-refractory thyroid cancer. This was the DECISION study by Dr Brose. It was an international study and it was the first study that was completed that showed an improvement in progression-free survival. There was a crossover as part of the study. There was no benefit in overall survival, but no one was sure if there’s no benefit because of the crossover.

The one thing about this study that has us concerned is that the response rate was not that high. It was only around 12% to 13%. The progression-free survival benefit compared with placebo was only around 5 months. So we didn’t see this gigantic benefit by using sorafenib in this setting, but we did see some benefit.

The other thing we need to consider is toxicity. At the dosage that sorafenib is used—400 mg twice a day—65% to 70% of people needed a dosage reduction. It was very common that patients couldn’t stay at that top dosage because of adverse effects.

Hypertension is very common with this whole class of medications—VEGF [tyrosine kinase inhibitors] (TKIs) like sorafenib. Sorafenib does not cause as much hypertension as some of the other drugs, but it’s still a concern. What we typically do, at least at Memorial Sloan Kettering Cancer Center, is have patients check their blood pressure on a daily basis for at least the first 4 to 6 weeks that they’re on treatment. We give them a criterion of 140/90 [mm Hg]. I want them to call us if the pressure starts going up. We don’t always make adjustments with blood pressure medications just for that, but we want to know if that’s happening. We sometimes will have them recheck it 30 minutes to an hour later. But over the telephone, we’ll start making adjustments with blood pressure medications very early.

If you try to catch up, it’s nearly impossible. You really want to make these adjustments quickly and get the person on a good blood pressure regimen that ends up working for them. It’s not unusual that a patient may need 2 or 3 blood pressure medications. This is not something that you should ignore. You really have to watch this carefully.

Gastrointestinal side effects are not as much of a big deal. People may have some diarrhea from the drug. It’s not so common that it’s very worrisome, but it does happen. If it does, make sure patients know to take Imodium. You don’t want patients getting dehydrated. There are times when people will feel a bit gassy. Simethicone can also be used to manage these patients.

The bigger problem is hand-foot syndrome. That’s probably one of the leading reasons why people go down on the dosage of sorafenib. It’s important to prophylax patients with sorafenib. About 60% of patients are going to get hand-foot syndrome. It’s important that they use creams ahead of time and know what to avoid.

The worst cases of hand-foot syndrome I’ve seen were in a person who was a tennis player and another person who was a carpenter and swung a hammer. I gave advanced notice to the person who swung the hammer. I told this patient that he was going to run into trouble, and he did. The same thing happened with the tennis player. She went out to play tennis, and by the time she was done, her hand was completely swollen and completely red, and it bothered her quite a bit for a while.

The good thing is that it’s easy to take care of. You can hold the drug. It usually goes away after a few days, but it can last for up to a week. If you really need to do something, you can just go to a lower dosage. Patients on the lower dosage tend to tolerate it very well. It is important to make sure that they’re using cream and are wearing appropriate footwear. I often tell people to use Dr Scholl’s gel inserts. Wearing flip flops is not the best thing in the world. Walking around barefoot is probably not the best thing in the world. It’s important to try to wear some type of cushion.

Marcia S. Brose, MD, PhD: When I’m using sorafenib, a lot of people ask me, “Where do I start?” “What [dosage] do I use?” “What dosage do I change to?” I have a lot of experience with this drug because I did the phase II and phase III work. Based on my experience, also as a purist, and based on the DECISION study, if you want to get the same results as the study, you really need to dose it in the same way.

Instead of starting at the 800-mg-per-day dose, which is what was used in the DECISION study and is obviously what’s on the label for the prescribing information, if you start to play with lower dosages, I don’t think you’re going to get as good of a response. That said, you do have to adjust dosages occasionally for side effects.

In our practice we start everybody at 800 mg no matter what. And then, if they develop issues like hand-foot syndrome or whatever, if needed, we do go down in dosage. I do everything in my power to keep them either at a full dosage or at three-quarters of a full dosage. In my experience, I don’t think the results are as good in anybody who goes below that. A few times, for various reasons, patients went down to a half dosage. Initially, their tumors started to grow again. Then we had to come back up to three-quarters of a dose.

I also think it’s important for the community physician, who may not give this drug often, to not be overly ambitious or sort of lenient with dropping the dosage. It’s very important that you take managing the dosages much more seriously. If you do decrease a dosage, I’m very confident that you won’t see as superior a result. So there’s a balance there to be met. You want to maintain some benefit in the patient and don’t want them to have a terrible quality of life.

So you have to take intervening in these issues very strongly with over-the-counter medications or even non- over-the-counter interventions. You really need to interact with them about their side effects and try to control them as much as possible without decreasing the dosage. If you do that, patients will have a better outcome. They’ll have better shrinkage. In the long run, they’ll last longer on the medication.

It takes a physician who is very committed to the patient. You have to really listen. You have to ask about the side effects. But if you want to be successful, managing the adverse effects is absolutely paramount to getting a good result. Dosage intensity should be maintained as much as possible.

The optimal duration for treating patients with sorafenib is for as long as they have clinical benefit. When patients have their initial treatment, they often see some shrinkage. Maybe not a lot, but they’ll usually have some shrinkage. And then, after 4 to 6 months, they’ll sort of get into a phase where it doesn’t shrink any more, but it doesn’t grow.

The goal is to try to maintain that for as long as possible. I would argue to be very good about managing side effects and try to maintain that dosage for as long as you can. The optimal period is for as long as there is clinical benefit. In the DECISION study, at the time of progression, if the progression was a solitary nodule that could be treated by surgery or external beam radiation or cryoablation, or some local therapy, patients were unrandomized. This was assuming that they were on the therapeutic arm.

If they had solitary progression, they had the choice of getting that treated and then continuing on the drug. We found that over a 10-month period, on average—or an 11-month period prior to that event—if they got treated, they often had a similar duration of benefit.

So I would argue that as long as most of the nodules are responding, you should try to keep them on the systemic therapy for as long as possible and treat a solitary local recurrence, as needed, along the way. We’re finding that the clinical benefit far exceeds the actual progression-free survival interval. Sometimes we can manage these solitary nodules and have them continue on and get another 10 or 11 months of benefit.

Transcript Edited for Clarity