HCC: Considerations in First-Line Use of Sorafenib

Transcript:Arndt Vogel, MD: The optimal patients to start sorafenib with are patients who have been included in the clinical trials that have looked at the efficacy of sorafenib, which means the patient should be similar, should fulfill the inclusion criteria of the STORM study, for example. These are, in general, patients who are not candidates for local therapies because they have more advanced disease. They should have good liver function. In general, they have vascular invasion, and they might also have extrahepatic metastases. So, these are probably the patients that benefit the most from systemic therapy with sorafenib.

Richard Finn, MD: Hepatocellular carcinoma is a very diverse disease molecularly. We know from the clinical aspect that it is very hypervascular. We see that on imaging. We talked about how chemoembolization, essentially an antivascular therapy, plays a very important role, and we know that elevated levels of the vascular endothelial growth factor can be correlated with poor outcomes in liver cancer. Many of the systemic drugs that have been looked at in liver cancer have had some component of antiangiogenic effect, such as targeting the VEGF receptor, VEGF itself, or even the fibroblast growth factor receptor.

Sorafenib is a multikinase inhibitor that has activity against the VEGF receptor, PDGFR (platelet-derived growth factor receptor), and RAF kinase. I think many of us feel that the most important component of this mix is probably its effect on the VEGF receptor, although we don’t exactly know for sure. It is a multikinase inhibitor. It does have vascular endothelial growth factor—associated toxicities, toxicities we see when we block VEGF, such as hypertension. It’s generally fairly mild in the liver cancer population, but easily managed with antihypertensives if needed. Probably the two most common side effects we see are GI toxicities, such as diarrhea and hand-foot skin reaction. Diarrhea can generally be managed with Imodium, dose reductions, and dose holds as indicated, and having patients keep well hydrated. The hand-foot skin syndrome, again, can be very mild—just some redness on the palms of the hands or on the soles of the feet—or it can be significant with blisters and thick callus. Often, the prophylactic use of urea-based creams can minimize this. Telling patients to wear thick-soled socks and comfortable shoes can limit the irritation on the feet. Often, patients may need a break or a dose reduction at times.

There are data to suggest that getting the optimal benefit from a drug like sorafenib means keeping patients on a prescribed dose for some period of time. And, obviously, what will dictate that is how well the patient is tolerating it. The prescribed starting dose with sorafenib is 400 mg twice a day. I think educating a patient up front to keep in touch with the office should they have any early side effects is important. They should know to have Imodium at home should they have GI problems. It also involves giving them, prophylactically, urea-based cream, or having them call the office should they start having skin problems.

It is an oral drug, but it is an anti-cancer drug, and it has well-known side effects. So, typically, I think seeing patients within 2 weeks of starting the drug is important to mitigate any toxicities early. Should a patient need a dose reduction, that reduction would be from 400 mg twice a day to 400 mg each day, and then the next reduction would be 400 mg every other day before you stop the drug completely. Sometimes it takes patients a while to get used to the side effects. There is some cooling down of the side effects over time. So, if a patient does experience a dose reduction, it is not unreasonable to re-escalate once things are stable and under control. In general, I think the toxicities are manageable if we’re proactive about them. If we give a patient a prescription and say, “Come back in 6 weeks,” those are patients who will get into trouble. So, I do think you need to see patients regularly.

Arndt Vogel, MD: Response to therapy with sorafenib is completely different from measuring response to therapy with TACE. Again, as we have discussed before, in TACE, we are looking for partial response, complete response, and we are not satisfied with stable disease. This is a little bit different with the systemic therapies we have available at the moment. Because we know we can’t really achieve partial response in most patients, the main aim we have is to have stable disease, have good liver function, and have stable performance status in our patients. How do we measure response in daily clinical practice? It’s most often that we do CT scans every 2 to 3 months. And when we do the evaluation, we most often use RECIST. In clinical trials, we would also use mRECIST to have a better idea of whether we get a partial response or not. But, I think for daily use, RECIST would be okay. And as long as you have stable disease, we would continue with the systemic therapy.

Transcript Edited for Clarity