SIOG 2015

Multicycle efficacy and safety of oral fixed combinations

Prof Matti Aapro - Clinique de Genolier, Vaud, Switzerland

Looking at antiemetics generally, for the older patient tolerating chemotherapy and tolerating treatment is a big issue. Where do we stand with antiemetics in older patients with cancer?

Before I answer directly your question about the older patients, I think we should realise that in the past year there have been major advances in antiemetics. There are two drugs that have been recognised by the FDA and EMA in the setting of antiemetics, they represent what we call the NK-1 receptor antagonists. One of them is called rolapitant, this drug is given separately from the other drugs, is very efficacious as aprepitant was and continues to be. It has a potential advantage of having no drug-drug interaction in the sense that it does not affect what we call the CYP3A4 pathway of metabolism. This is important for elderly patients because they have often two, three, four, five, even more drugs to take and anything that could potentially influence the metabolism of any other drugs is something that we might want to avoid. Now, we know that this is very theoretical because there have not been any reports of major issues with aprepitant so this advantage could be considered somewhat theoretical.

The other drug that has been developed is netupitant which was actually developed along with palonosetron in a capsule that I called abbreviated nepa, netupitant plus palonosetron. In one single capsule you have an NK-1 receptor antagonist and a 5-HT3 receptor antagonist so you have the combination of the two key drugs which, along with corticosteroids, improve the response rate of patients that have chemotherapy to very high levels meaning that vomiting today is extremely rare, nausea is still not fully controlled.

What is the issue about QTc interval and how big an issue is that?

Thank you for asking the question about QTc interval. This is indeed very important for our elderly patients; they often have cardiac issues. There is a warning that has been put forward by the FDA and EMA about the setrons, the 5-HT3 receptor antagonists, except for palonosetron, it’s the only one that does not have this warning. For the others there is a potential prolongation of QTc which can lead to cardiac arrhythmia so if we can avoid that it’s much better for the patients.

All the drugs have toxicities though so how big an issue has that warning been practically?

In practice it’s a rare event, fortunately, a very rare event, so authorities have had to collect quite a few observations before they came out with this warning but now the warning is clearly there. So, again, there’s also some data to show, and all guidelines concur, that if you are using a 5-HT3 receptor antagonist just by itself because there is no indication for an NK-1 receptor antagonist together, then palonosetron is the preferred drug because it is somewhat more efficacious than the standard setrons.

But you have done a very interesting study with nepa, this is a combination approach, tell me about that please.

There have been several studies that have led to registration of this combination, netupitant and palonosetron, and I’m presenting here at the Geriatric Oncology Conference a paper showing that it’s not only first cycle, the second, third, fourth, fifth cycle patients have a benefit and this is true in the elderly patients and the younger patients without any excessive toxicity in the older patients.

So the combination is turning out to be recommendable, in your view?

The combination is now accepted in guidelines for the highly emetogenic and carboplatin and AC-like chemotherapies.

It seems, then, for the cancer doctor in every day practice there is quite a range of possibilities for antiemesis. How would guide the doctor, to sum up then, in how she or he should approach antiemetics now for the cancer patient, especially the older cancer patient?

I believe that the way to go is to follow the guidelines. They all come to the same recommendations and to use a triple combination the patient is at high risk of nausea and vomiting, i.e. cisplatin, carboplatin and AC-like chemotherapy in female patients.

And the place of the new combination therapy, where might that be in those guidelines?

The combination of netupitant and palonosetron being a single capsule, that makes it easier for the patient to have to have one more tablet to take. Rolapitant, as I said, is given separately but has the potential advantage of having no drug-drug interaction with the CYP3A4 pathway but, as I said, it might be only theoretical.

In a nutshell, how much have things improved?

Things have improved a lot but we still have to work on nausea. Nausea is still something that patients complain about but we don’t really know what nausea really represents.

What about dosing issues, to moderate that too? Obviously you want to give full dose but can you back off the dose?

No, the antiemetics should be given as prescribed on the label but there is one question which is the dosing issue in the sense that we used to give higher doses of some of these 5-HT3 receptor antagonists in the past. These have been related a little bit more to QTc intervals so the authorities have now stated that for some of these drugs we have to use a reduced dose.

And in older patients chemotherapy dose is an issue because doses might well be different from a younger patient. Is that something that affects all of this?

This is a very, very important field you are asking me to discuss, the relationship between the dose and efficacy. For cytotoxics when the patient has a tumour which is clearly sensitive to cytotoxic agents we have, I believe, enough evidence to say that it’s important to maintain dose intensity. I had the opportunity to present at this meeting data on the use of G-CSF according to the guidelines of EORTC which are very similar to the ASCO guidelines, actually they were developed in parallel. There is sufficient evidence to say that the elderly patients are at higher risk of febrile neutropenia and in order to maintain dose intensity where there is curative treatment with chemotherapy we should absolutely use G-CSF, we should not dose reduce.

So the brief take home message, it’s a bit complicated now we’re talking about dose of chemotherapy but also antiemetics. What should doctors be taking home from this in just a few words?antiemetics. What should doctors be taking home from this in just a few words?

In just a few words, unless there’s compelling evidence that the patient might not tolerate the treatment we should be aiming to give the patient the treatment as for a  younger patient with appropriate support, i.e. G-CSF if needed, erythropoietin, appropriate antiemetics in order to give the full dose. If it’s palliative treatment then we have to think of the quality of life first and not about the quantity of life and then the discussion becomes very much patient centred on what is the patient’s ultimate goal.