NCRI Cancer Conference 2010, 7 November 2010, Liverpool

Interview with Professor Nick James (Queen Elizabeth Hospital & University of Birmingham, UK)

Chemoradiotherapy for bladder cancer

I’m talking about the results of our recent chemoradiotherapy study in bladder cancer. So the background is that, broadly speaking, there are two ways of treating bladder cancer – you can either do surgery to take the bladder out or you can do radiotherapy with the aim of preserving the bladder. Now part of the problem with radiotherapy is that the recurrence rate is quite high if you just use radiotherapy as sole treatment, so from our own experience round about one in three patients end up losing their bladders. So that’s the worst possible outcome because they’ve had all the side effects of radiotherapy and still had to go through the surgery and the surgery is more complicated because they’ve had previous radiotherapy. But for the other two-thirds that get to keep their bladders, then they’ve had a good result because they’ve had an outpatient treatment, they’ve avoided the need for quite high risk surgery that takes months and months to recover from.

So what we wanted to try and explore was ways of improving the results of radiotherapy that would be applicable to the sorts of patients I see in the clinic. Now the way the patients divide up between surgery and radiotherapy varies across the world, so in the UK about 50% of patients get radiotherapy, about 50% get surgery. Broadly, younger, fitter patients get surgery, older, less fit patients get radiotherapy but there is considerable overlap in the middle.

Elsewhere in the world the balance is much more pro-surgery and in North America radiotherapy is hardly offered at all so patients are more likely to be offered palliative care than radiotherapy if they’re not fit for surgery. So how these results relate to people in general currently depends on where you live in the first place.

Now from the point of view of how you might get radiotherapy to work better, one of the things we’re very interested in is how you combined it with drugs. Previous trials carried out in the 1980s and 1990s showed that you got modest improvements in survival rates by adding quite toxic platinum-based combination treatments upstream of radiotherapy, but the order of magnitude, again, is quite small - maybe one patient in twenty gains, the rest are either going to be cured anyway or are going to relapse anyway.

So we were looking around to see if we could do better than that. And in general, and there’s an emerging literature, if you give chemotherapy at the same time as radiotherapy the gains seem to be potentially much bigger. And there was a trial published in the 1990s using Cisplatinum again as a radiosensitizer from Canada, this showed around a 50% reduction in the recurrence rate compared with radiotherapy alone but with platinum doses we simply couldn’t give to our patients - platinum is too nephrotoxic, too toxic to the kidneys for at least half of our patients and is also quite an unpleasant drug in terms of nausea, vomiting, general side effects.

So what we did is we had a look through the literature to see what other drugs might radiosensitize that we could give at the same time as bladder radiotherapy and essentially there is quite a big literature on using chemosensitizing drugs in anal cancer. Now the thing about the drugs used for anal cancer is that they were benign drugs used at lower doses but chronically through the treatment so it seemed a much more deliverable thing. And the second thing was that the drugs used aren’t particularly critically affected by kidney function, which is often impaired in bladder cancer patients because the kidneys get blocked by the bladder tumour, kidney drainage.

So we picked a particular combination that had been extensively used in anal cancer, which was 5FU and Mitomycin C. Now we first of all had to do a phase I trial to just optimise the combination so we started with a combination based on the anal cancer regimens but they didn’t entirely fit for various reasons. So we had to optimise that so we did a phase I trial to find what seemed to be the maximum tolerated dose; did a phase II trial which confirmed that this was deliverable, was safe and appeared to have a very high response rate in terms of number of patients clear of tumour at check cystoscopy, number of patients clear of tumour at a year and so on. So on that basis we got funding from CRC, as it then was, it took a long time to do the trial, to do the phase III trial. In fact we bundled two phase III trials into one; it’s been very difficult to recruit to bladder trials in general because it’s a relatively rare disease, a lot of the patients coming through the oncology clinic are quite old, quite frail. So we combined two questions into the trial, the first was radiotherapy with or without chemo which is, if you like, my trial. The second was building on work done from the Marsden by Robert Huddart, and what they were interested in doing was reducing the dose given to uninvolved bladder to try and reduce the toxicity to patients. So obviously for that part of the trial we were trying to measure the toxicity decreasing whilst at the same time showing that we weren’t doing that at a penalty in control rates.

So we had two separate questions and we ran the trial in such a way that patients could go into one or other of the randomisations or go into both. In the event, only about half the patients went into both the randomisations so, in effect, we’ve got two overlapping trials. Now the results of the radiotherapy canning trial, Robert Huddart’s trial, were in the end a little bit disappointing in that we were unable to show an improvement in side effects from reducing the radiotherapy volume. I think probably we weren’t actually brave enough in terms of the amount of reduction we put in. But on the positive side from that trial we did show that there was no impact on tumour control rates from reducing the dose to uninvolved bladder by a modest amount.

We were able to show a possible benefit in terms of changes in bladder volumes, although this wasn’t enough that the patients could perceive, we potentially could demonstrate it. We were also able to show that the long-term reduction in bladder volume across the whole trial was only about 15ml out of a typical bladder volume of 500ml, so a really very modest change. Because one of the issues with the surgeons is they have this sort of caricature that sure you can preserve a bladder with radiotherapy but you end up with a small shrunken, useless bladder. Well we were able to show definitively that’s not true.

For the chemotherapy part of the study, which is the main thrust of the data today, we were very pleased with the results. So the primary endpoint of the trial was the local regional recurrence rate, so the recurrence either in the bladder or adjacent nodes. This reduced by around 33% with radiotherapy plus chemotherapy compared with radiotherapy alone. When we drilled down into that a bit further and broke the recurrences down into superficial recurrences which the surgeons can just scrape out from the inside which means you get to keep your bladder, and invasive recurrences which are the ones that are potentially lethal and require a salvage cystectomy, it turned out that pretty much all of the reduction in the recurrences was down to the invasive recurrences and not the superficial ones so we prevented the most serious recurrences with very little effect on the superficial ones, which in truth are probably just new tumours growing in an unstable bladder lining rather than true recurrences. So we were pleased with that.

And then the second thing we obviously wanted to check was that we hadn’t reduced the recurrence rate at a huge price in side effects. So we had two sets of side effect measurements plus quality of life assessments as well. So for the acute side effects during radiotherapy we actually were hard pushed to detect a difference between radiotherapy and radiotherapy plus chemo, and the difference that was there was mostly in grade 1 – 2 toxicity on a scale that goes up to 4 with no statistically significant difference between radio and chemoradiotherapy for grade 3, 4 toxicity, presumably because we were giving the chemo a little bit at a time and if you just stopped giving the chemo patients started getting side effects. Obviously our dose modification schedule worked in that the clinicians were just backing off the chemo before you ran into serious problems.

And then for late side effects, which arguably are at least as important, we were very keen to demonstrate that we didn’t have an increase in severely dysfunctional bladders as the price to pay for keeping your bladder. And we were again very pleased with this because the surgical caricature is that they have this awful toxic unstable bladder. We tested them from three months out, every three months, and if they got a recurrence that data was then censored from three months before the recurrence so we were looking at bladder function once the acute side effects had settled. Essentially 75% of patients reported no side effects at all attributable to the radiotherapy. Of the 25% who did, the majority of those again were only grade 1 or 2. Only a very small percentage, under 5%, reported grade 3 or 4 toxicity. So it looked very good and there was no penalty from adding the chemo, it was the same with both arms.

And then the other thing that we did was we allowed patients to go into the trial having had prior neo-adjuvant chemotherapy, as it’s called. We wanted to check that the benefit that accrued to having synchronous chemotherapy wasn’t just another way of getting the same benefit from prior chemotherapy. Essentially, whether or not you have prior chemotherapy, you still got the same reduction in your local recurrence from the synchronous chemo so it suggests that synchronous chemotherapy and prior neo-adjuvant chemotherapy are working in different ways, which again was an important result, we think.

What key messages can clinicians take from these results?

Well the message would be that adding small amounts of chemotherapy, 5FU Mitomycin in this case, on top of radiotherapy had minimal impact on the side effects and a big impact on the invasive recurrences. So we would strongly encourage people to factor this into their treatment planning for patients with bladder cancer.

Around 15% of the patients in this trial were aged over 80, so this result is applicable well into quite extreme old age. Basically, if they’re fit for radiotherapy, they’re fit to have those treatments added in on top.

How does this therapy benefit patients?

I think there are two reasons. One is if you’re a patient destined to have radiotherapy then you definitely should be asking to have some sort of radiosensitizing treatment on top of it. Because, apart from our trial, there are two other trials of different radiosensitizing regimens and they all have more or less the same result, which is a reduction in recurrence but without a significant long-term side effect penalty. So for patients really getting radiotherapy on its own, unless they’re very old and frail, I think it’s not really justifiable any more.

But the second group of patients who may be interested, patients who are either borderline fit for surgery or even just desperately don’t want surgery, this is a much more viable alternative than just radiotherapy on its own. Our invasive recurrence rate was only 18% at two years, which on historical grounds against other series, let alone against our own control arm, is a very low rate of recurrence. Only 11% of the patients on the chemoradiotherapy arm ended up needing a cystectomy because the treatment didn’t work in a way that couldn’t be salvaged some other way.