My study was the POUT trial which is looking at perioperative chemotherapy compared with surveillance in completely resected upper tract urothelial cancer. The reason to do this study is there's a real dearth of any evidence in this setting; this is the largest phase III randomised study ever in this patient group. The problem with this is that it's a niche group of patients: in the UK there are about 1,400 new cases of upper tract urothelial cancer every year diagnosed. The standard treatment is a nephroureterectomy but what happens after that is very uncertain, there's no international standard about whether you should have surveillance or chemotherapy. We know that this type of cancer tends to be chemosensitive in metastatic disease but there has never been any study done before and that was the rationale behind the study, to try and look at an international standard.
The study randomised patients within 90 days of their nephroureterectomy to either four cycles of chemotherapy, platinum based, or to surveillance. The chemotherapy, everybody got gemcitabine on day one and day eight and then patients got either cisplatin or carboplatin, based on their renal function, on their GFR, on day one. So the only reason to give carboplatin was based on renal function, if patients weren't fit enough for cisplatin otherwise then they weren't allowed to go into the study. The cut-off rates for that was using a GFR of greater than 50 for cisplatin and then 30-49 for carboplatin.
We had planned to get 361 patients into the study, however the study was shut prematurely because the data monitoring committee met and said we've met our primary endpoint which was disease free survival. At that point we had 261 patients from centres right across the UK, the UK really got together and delivered on this study with all the urologists and the oncologists across the UK in 71 different centres. The study is a positive study, it's a strongly positive study for the benefit of adjuvant chemotherapy. The results show that at two years 71% of patients who had had chemotherapy were free of cancer compared with 54% in the surveillance arm. That was strongly statistically significant with a hazard ratio of 0.49. The same results were true for metastasis free survival, so again in the chemotherapy arm very strong effect - 74% of patients were free of metastases at two years in the chemotherapy arm compared with 60% in the surveillance arm, so again a very statistically significant study.
We have got some very early data on overall survival but at the moment we can't apply any statistical constraints to that because it's still very early and we're collecting overall survival data. So this really sets an international standard from this UK-based, UK delivered study of changing practice internationally to look at giving up to a maximum of four cycles of platinum-based chemotherapy to these patients with T2 to T4, N0 to N3 completely resected urothelial upper tract CC.
Did the patients experience many adverse effects?
When we look at side effects, we collected side effect data until the end of cycle 4, so that was twelve weeks of treatment, and we looked at chemotherapy toxicity but we also collected at the same time points side effects in the surveillance arm. In those twelve weeks the chemotherapy toxicity for grade 3 was about 53%. Now it's a chemotherapy study so you're going to see side effects and they were nothing different to what we would expect. It was a neutropenic rate of about 25-35%, a neutropenic sepsis rate of between 5-7.8% but no neutropenic deaths, nausea and vomiting and low platelet count. The big thing to say is when we look at the age population of these patients, 80% of patients were over the age of 60; 40% were over the age of 70 and 5% were over 80. So for -an adjuvant chemotherapy study, giving chemotherapy to a maximum of four cycles with very manageable toxicity, nothing different to what we would expect, it shows that it's safe and well tolerated. In terms of the number of cycles we could get in, 71.8% of patients who had chemotherapy we got the full four cycles in so we showed that we can deliver it safely for something that's going to improve their survival.
Is there potential for international collaboration?
There are two things there. First of all when we started the study we did look for international collaboration and, for a variety of reasons, nothing to do with not trying very hard, it didn't happen. I think every country has its own different funding mechanisms and different issues. But what we're doing at the moment is looking for a successor study to POUT and we will definitely be looking for international collaboration with that. The biggest success of this is pulling together all of the urologists, all of the oncologists across the UK really got behind this study. I extensively promoted it from the time that we first had the first concept to the time when we recruited the first patient so it's really a triumph of something where it's a niche number of patients when you've really got to try and get potentially every eligible patient possible into the study. So it really is a triumph of everybody coming behind the study.