Treating relapsed brain tumours with anti-angiogenic metronomic therapy

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Published: 8 Feb 2016
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Dr Irene Slavc - Medical University of Vienna, Vienna, Austria

Dr Slavc talks to ecancertv at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.

In the interview she discusses the use of metronomic anti-angiogenic therapy in patients with relapsed brain tumours.

Together with colleagues in Boston and several other European centres, Dr Slav is conducting a trial in children and young adolescents who have relapsed medulloblastoma.

These patients have a very poor prognosis even when treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of all these approaches.

The novel treatment regimen being tested in the trial consists of biweekly intravenous bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and alternating cycles of daily low-dose oral etoposide and cyclophosphamide).

This is augmented with alternating courses of intrathecal etoposide and liposomal cytarabine.

I think this is a really novel approach to treat recurrent embryonal tumours. We have used this approach in many different tumours, about 60 patients in total, and we have seen that it works the best in medulloblastomas and in atypical teratoid rhabdoid tumours. We have so far treated 17 patients with medulloblastomas with this approach and also 8 patients with atypical teratoid rhabdoid tumours and we have started an international trial for metronomic antiangiogenic therapy including Boston and several European countries at the moment for recurrent medulloblastomas. At the moment the trial is open in Austria, in the Czech Republic, in Sweden and in Denmark and in Boston. We have 8 patients on this trial; these are not included in the 17 patients I have mentioned before but of these 17 patients we have treated since 2006 10 patients are in remission, 8 in complete remission, and 6 off treatment for 3 months to 5½ years. This really seems to be a promising approach for these devastating situations of recurrent medulloblastomas.

What exactly does the treatment consist of?

The drugs we are using are three drugs which are not chemotherapeutic drugs in the classical sense, it’s fenofibrate, which is a lipid lowering drug, it’s celecoxib, which is an anti-inflammatory drug, and it’s thalidomide which is a clearly antiangiogenic drug. These three drugs are given daily, daily fenofibrate, twice daily celecoxib and daily thalidomide, and then this combination of three oral drugs are combined with oral etoposide at very low doses alternating with oral cyclophosphamide, both dosed in antiangiogenic dosing and not in chemotherapeutic dosing. On top of that we give bevacizumab, 10mg/kg every two weeks, augmented with intraventricular therapy consisting of liposomal cytarabine alternating every two weeks with intrathecal etoposide, 0.5mg on five consecutive days. This complete treatment is given for a total of one year and for the second year we discontinue the oral etoposide and oral cyclophosphamide and extend the intervals of the intrathecal therapy but continue on with the oral fenofibrate, celecoxib and fenofibrate and the bevacizumab. The whole treatment is stopped after two years if tolerated.

Why was that treatment regimen selected?

Actually this five drug combination is a protocol that was started in Boston in 2006 based on a four drug protocol that did not include the fenofibrate and had been published in 2005. We inherited a patient from the United States who had a third recurrence of a medulloblastoma with leptomeningeal disease and, interestingly enough, after he had had tandem high dose chemotherapy and re-irradiation of his metastases he had received for his second relapse this five drug protocol and he had an almost complete resolution of his leptomeningeal tumours. Unfortunately his bone marrow tolerance was so poor that he could not continue on with this combination and three months after stopping the treatment he recurred again. So when he transferred to Europe for personal reasons he asked whether he could be treated at our hospital and we were thinking what we could do. We saw that he would not tolerate etoposide and cyclophosphamide any more so we reduced the dose to 10-15% of the planned dose and added on the bevacizumab and added on the intrathecal therapy because he had leptomeningeal disease. This patient survived for five years and three months after his third recurrence and he himself claimed that he had a good quality of life for four or five years of this time. 

So starting with these patients we then treated all consecutive patients with recurrent brain tumours with this approach and saw that it is most effective in medulloblastomas and atypical teratoid rhabdoid tumours.

Where are you going with this research?

At the moment we are extending this official phase II study we have initiated in 2014, which started in 2014, initiated a long time ago but started in 2014. We hope that we will recruit enough patients in a short period of time so that we can prove this treatment and then from when we have this data from the phase II study we can go ahead and design randomised trials for the consecutive trials, taking out and in some of the drugs or exchanging some of the drugs. Because for antiangiogenic therapy it is very important to have a combination of different drugs because most of the time a single drug will only last and show efficacy for a short period of time.

What’s your take home message?

I think it’s very important that we collaborate, as we start doing here for the intrathecal therapy as well, because brain tumours even though they constitute 25% of neoplasms in children are still rare and there is still very little interest by the pharmaceutical companies to invest in brain tumours, particularly leptomeningeal disease of brain tumours. It’s very important to design and develop brain sparing therapies for brain tumours because so far we have used a lot of craniospinal radiation which in the long run has very deleterious late effects for the patients. Leukaemia has shown that it’s possible to substitute some of the cranial irradiation with intrathecal therapy and our goal should be to get to this point also in paediatric brain tumours.

So hopefully this will be the start for a better international collaboration that then eventually will also attract pharmaceutical companies to help us to develop slow release formulations and different delivery techniques for suitable drugs to be delivered to the CSF.