ESMO 2016

Risk of serious and fatal adverse events with sorafenib use in patients with solid cancers

Dr Bishal Gyawali - Nagoya University, Nagoya, Japan

We presented a meta-analysis of sorafenib induced serious adverse events and fatal adverse events in patients with solid cancers who were treated with sorafenib versus control. The control group could be either placebo alone or chemotherapy and the intervention group was either sorafenib alone or chemotherapy plus sorafenib. So we basically tried to see how excess number of patients suffer serious adverse events or fatal adverse events with the use of sorafenib. We found a total number of twelve phase III studies and from twelve phase III studies we found around 6,790 patients who piqued our eligibility criteria. Our finding was basically with respect to serious adverse events the risk increased significantly and the relative risk of getting serious adverse events with sorafenib was around 1.5, 1.49. So this is highly increased in the risk of serious adverse events. But although this is a significant increase in risk if we see it in terms of absolute number the absolute incidence of serious adverse events with sorafenib was around 27% and this should be compared with around 17% for the control group. So there is a significant increase in the risk of sorafenib, in the risk of serious and fatal adverse events with the use of sorafenib, but there is also some risk in the control group as well. So this helps us in making an informed risk-benefit ratio judgement for a patient when starting on sorafenib. We need to tell the patient clearly that, OK, this drug will give you around this much months of benefit in progression free survival or overall survival, depending on the cancer, but you will also have this much risk in getting a serious adverse event - out of 100 patients nearly 27 patients get serious adverse events. Serious adverse event is a very important factor in making treatment decisions because when we usually start our patients on any drug we talk about very common side effects, like in the case of sorafenib you will have hand foot syndrome and about hyperthyroidism. So we concentrate on those things while making an informed consent with the patient but we do not talk about what exactly is the incidence of serious adverse event and serious adverse event is important because it includes the risk of hospitalisation, the risk of being physically handicapped, such things that are of prime importance to the patient. But we frequently ignore this while consenting the patient so this data will be very important for the patient to make a decision of whether or not to accept the treatment.

You also looked into fatal adverse events?

Fatal adverse events we defined usually as the cases of treatment related mortality. Of course there are other causes of cancer death but we are interested in how many patients died due to the treatment and not due to the disease itself. So this is another data of utmost importance to our patients. We found in our meta-analysis that the risk increases very significantly and the relative risk ratio was 1.84 which is a very, very significant increase in the risk. But again this needs to be looked at in the context of the absolute increase in the incidence of the fatal adverse events. So in the control group they had 0.7% incidence of fatal adverse event but in the sorafenib group we found 1.4% so it’s nearly double. So even if you are not taking sorafenib there is still a chance of having a fatal adverse event of 0.7% incidence but if you are taking sorafenib the incidence goes to 1.4% and the risk increases by a factor of 1.8. This is another important data for a patient to understand that he could die from the drug itself. Of course we did a subgroup analysis and we did a test of heterogeneity to see if one particular cancer type of patient has this risk and another cancer type doesn’t have and it did not differ according to the cancer types. So overall this risk is increased in a cancer patient while undertaking treatment with sorafenib, he needs to understand these things and until now there was no clear data on exactly how many patients died because of the treatment. So I think this will form an important part in having a discussion with the patient.

We usually try to focus on the benefit of the drug rather than the side effect and even when we are talking about side effects we usually focus on the common side effects. That is very understandable because the common side effects are fatigue or hand foot reaction, allergies, those are important because they give a significant morbidity to the patient, it feels very bad to have fatigue every day when you wake up. But there is another part of side effects that is the SAE, serious adverse event, and the FAE, fatal adverse event, which are of grave importance because it is related to being hospitalised or dying. But during the treatment discussion with the patient we usually don’t talk about fatal adverse events because we tend to believe more on the efficacious side of the drug. But these things should be clearly told to the patient while having an informed consent.