CHHip: Conventional versus hypofractionated high-dose intensity modulated radiotherapy for localised prostate cancer
Prof David Dearnaley - Institute of Cancer Research, London, UK
What we’re doing at this meeting is to update the large randomised controlled trial, CHHip. CHHip is a study which compares the conventional radiotherapy treatment given over 7½ to 8 weeks with a shorter schedule given over 4 weeks. We can do this by increasing the dose per day so instead of giving 2Gy fractions of radiotherapy each day we give 3Gy fractions. It’s probably the largest study that has ever been performed in localised prostate cancer as a treatment trial; we randomised over 3,200 patients. Over 71 centres participated so it was a huge, huge team effort.
This effort was funded by Cancer Research UK and the Department of Health and sponsored by the Institute of Cancer Research and run by the Clinical Trials and Statistics Unit at the institute.
The eight year results have shown that we can confirm what we reported three years ago with the five year results that the 60Gy 4 week schedule is what we call non-inferior to 74Gy which was the standard dose given over 7½ weeks. The non-inferiority is certainly confirmed, in fact the 60Gy is marginally better, it’s about 3% better in control rate, about 84% now compared to 81%.
The study had three groups, it had two experimental groups and there was a 60Gy group and also a 57Gy group which was treated in 19 treatments. Now, that group is interesting, it performed a little bit less well than the 60Gy because it was a lower dose and that would be expected. But actually we showed that in patients over 75 years of age that it actually was a little bit better, it seemed, than the 74Gy. Now, that’s important because that schedule, the 57Gy schedule, has less side effects because it gives a lower dose. So we think that is particularly suitable and an option for patients over the age of 75 years who actually have more problems with side effects.
It’s all very well having a very effective and convenient shorter treatment but actually if it caused more side effects then actually this wouldn’t be a good deal at all. But, happily, using the advanced radiotherapy techniques that we’ve developed as part of the trial, what we call intensity modulated radiotherapy, the side effect profile is very low. In fact, if you go out to five years and use what we call clinician reported outcomes the side effects affecting either bowel or bladder are at a level of 2% or less for modest or greater side effects. This is actually about half the rate of side effects that we saw in our previous national trial so we regard that as a great success. When you turn to the important patient reported outcomes we find that for bowel this runs at about 6% and for bladder at about 8%. But for those outcomes it’s clear that the 57Gy schedule just has a little bit of an advantage over the 60Gy.
So we’ve concluded that we’ve confirmed that the 60Gy schedule is effective and safe and it is now the recommended standard of care by NHS England in the UK where it’s mandated that centres should use the 4 week schedule. But NHS England have also taken on board the favourable results in the more elderly population with the 57Gy and say that this should be considered as an option. That was one of the messages I wanted to get out internationally, that actually this was a good and a safe option. It’s important, particularly with elderly patients, that we don’t cause unnecessary distress.
Looking at disease control is one thing, that doesn’t necessarily affect how a patient feels. The things that really matter to a patient longer term are do they develop metastases. Now that’s a good news story because so far in the study out of, now, it’s nine year average follow-up, only 5% of patients have developed metastatic disease. Highly satisfactory and it’s the same between the three groups. How many patients have died? Well, it’s 13% that have died. Now, you obviously just noticed that 13% is higher than 5% and that’s because, in fact, the considerable majority of patients who die don’t die of prostate cancer at all. I’m estimating that probably the ratio between a cancer death and a non-prostate cancer death is probably about one in six or one in eight. So that’s again why I stress that it’s very important that we minimise side effects as far as possible.
Although we’ve followed this group of patients up for a long time, we must carry on doing it. We must also continue to do the various parts of translational research that we’ve embedded into the trial. This is important because we’ve looked at the biophysics of the doses we’ve given and we’ve defined new ways of actually describing how we should give the dose to make it safer. These new dose constraints have recently been published and we hope that those are going to have an international impact as well, making treatment even safer.
Most particularly we’ve defined some dose constraints which may, really for the first time, show how we can improve erectile dysfunction. We’ve been quite good at reducing bowel side effects but erectile dysfunction we haven’t really concentrated on before. For the first time I think we may be getting some mileage there, particularly if we use the more precise image guided radiotherapy which we’ve also studied as part of the trial.
We’ve also done a lot of biomarker work and we’re continuing with that to see if we can stratify patients according to an expected outcome, looking to see in the radiogenomics consortium that we work with whether we can identify patients who are going to be particularly sensitive to radiation or not. We’ve also combined these various aspects in a big data project, trying to bring it all together in one go. So although we’ve followed these patients for a very long time, and although actually we’re very pleased with the outcomes we’ve seen and we’ve changed both national and international standards of care, we’ve still got a lot of work to do.
