Temozolomide after radiotherapy improves glioma survival
Dr Martin Van Den Bent - Erasmus MC Cancer Center, Rotterdam, The Netherlands
Ladies and gentlemen, it’s my pleasure to report on behalf of the EORTC Brain Tumour Group the results of this trial that will be practice changing. It’s the CATNON trial and the trial set out to investigate the activity of temozolomide in 1p/19q non-co-deleted anaplastic glioma.
What are anaplastic astrocytoma? Anaplastic astrocytoma are a subgroup of the gliomas, it’s an orphan disease. There are approximately 15,000 new cases diagnosed each year in the United States. We set out for this trial because in previous studies we had made two observations. First of all, the EORTC identified temozolomide as a major component for better treatment of glioblastoma patients. We conducted a trial in the early 2000s that showed that if you combined radiation therapy with temozolomide and you followed that with another six cycles of adjuvant temozolomide survival is increased. Glioblastoma is a chemotherapy resistant disease.
At the same time we did a very similar study on adjuvant chemotherapy in another subset of anaplastic glioma, the so-called oligodendroglioma. We made in that trial the observation that adjuvant chemotherapy did not improve outcome whereas that disease is to be considered chemotherapy sensitive so that was strange. We also noted in that trial that there was a particular subgroup of patients with a particular worse outcome, the patients without the 1p/19q co-deletion. We already knew at that time that 1p/19q co-deleted patients were much more sensitive to chemotherapy than the patients without 1p/19q co-deletion. So we asked ourselves whether if we would give temozolomide to these patients without the 1p/19q co-deletion whether that would improve their outcome. And we set out a little bit complicated trial, especially if you consider that this is an orphan disease. So we asked ourselves basically two questions – will temozolomide given during radiation therapy improve outcome in these patients? The other questions we asked was whether temozolomide given after radiation therapy would improve outcome.
The primary endpoint of this study was overall survival. We required for inclusion in the study that the central laboratory confirmed the presence of an anaplastic glioma and of the absence of 1p/19q loss. So it was also from the logistical respect a complicated study. Samples had to be sent before patient inclusion. We randomised our patients into four arms: radiation therapy alone; radiation therapy plus concurrent temozolomide, temozolomide during radiation therapy; radiation therapy followed by twelve months of adjuvant temozolomide and then radiation therapy with both concurrent temozolomide and adjuvant temozolomide.
On Sunday morning at eight o’clock at the CNS symposium I will show the outcome of question number two. So we are comparing, basically, arm one and two in which no adjuvant chemotherapy was given to arm three and four in which adjuvant chemotherapy was given. Why are we doing this? It was a complicated trial, like I said, and this is an orphan disease so it took the collaboration of many co-operative groups to enrol the number of patients that were required for the study. We needed 750 patients, to get those 750 patients we screened no less than 1,400 patients in 180 institutions, twelve countries and three continents.
We had a planned interim analysis after 41% of events would have occurred and that was in the summer of 2015, just after the completion of enrolment. We did not anticipate anything to come out of this interim analysis as usually these trials take a long time to produce positive results. But we were completely taken by surprise when the IDMC that looked into the data recommended the release of the data of adjuvant temozolomide. We had at no point in time anticipated this outcome.
Why did they recommend this? Here you see a univariate analysis of the outcome of the study for adjuvant temozolomide treatment only. In red you see the patients that were not treated with adjuvant temozolomide, in blue you see the patients that were treated with adjuvant temozolomide. What does it come down to in figures? If you look at the five year survival, that increases from 44% without adjuvant temozolomide to 56% with adjuvant temozolomide. That corresponds to a hazard ratio of 0.67 and a highly statistically significant p-value.
What do we know now? We know now that temozolomide given after radiation therapy improves survival in this disease. By this, this trial has become a practice changing trial. We need further follow up for question number two as the IDMC made no recommendation about that part of the treatment. So some of the results of this trial are still unknown to us and it will take more years of follow up before we can make definitive statements about the contribution of that part of the treatment.
What is also for us quite important to emphasise is that this is a rare disease and it requires trials of many, many years duration so it’s a privilege to have been working with a number of groups that made this possible. We had EORTC and its partners in the UK, in Australia, in the United States of America and Canada to work with us to make this possible but you can imagine that it took quite an effort to make the results of this trial available in an orphan disease like this. Thank you for your attention.