ASCO GU 2013

Chemo-radiotherapy for bladder cancer

Professor Nick James – University of Birmingham, UK

In the UK there is a long history of treating bladder cancer with radiotherapy with salvage cystectomy whereas in most parts of the world the standard practice is cystectomy with a very small print role for radiotherapy. So under 10% of patients get radiotherapy for bladder cancer in the USA, for example, whereas it’s over 50% in the UK get primary radiotherapy. Now the study we carried out, we were looking at patients receiving radiotherapy as their main treatment and we randomised patients to either radiotherapy alone or radiotherapy plus synchronous chemotherapy with 5FU and mitomycin C. The reason we picked these drugs is that they’re well tolerated in patients with renal impairment, they’re generally low toxicity and there’s a long track record of using them as radiosensitizers. And the primary endpoint of the study was locoregional control in the pelvis and bladder. We found around about a 40% reduction in pelvic recurrences, particularly in bladder recurrences, driven in the main by a 50%, a near 50%, reduction in invasive bladder recurrences. So at two years we had a bladder recurrence rate, invasive bladder recurrence rate, of only 18% which was roughly half the radiotherapy only bladder recurrence rate. Part of the trial, a big part of the trial, was demonstrating that we didn’t, by intensifying the treatment with the synchronous chemoradiotherapy, cause a lot of side effects. And so we collected a lot of late toxicity data, bladder volume data, things like this. The average change in bladder volume was 10-20ml at one year and two years; around 80% of the patients reported no bladder dysfunction whatsoever after the acute side effects had settled so it was well tolerated.

How does treatment vary in other parts of the world?

What tends to happen in most other countries is that patients have managed, if at all possible, with cystectomy and the remaining patients who are too old, too unfit or whatever, mostly just get palliative care in a lot of countries. So there’s very good data, very recently published data in the United States, for example, showing that older patients, less fit patients, mostly get no attempt at curative treatment whereas our data shows that you can very safely treat patients well into their eighties with radical chemoradiotherapy.

With a surgical approach are you removing all of the disease?

Yes and no; yes conceptually you’ve got rid of it and it’s in a bucket in the path lab but it’s a pretty morbid operation, you end up with a urostomy or some sort of complicated diversion, patients take a long time to recover from it. You have to bear in mind this is a smoking-related tumour, the average age at diagnosis is in the mid-70s, these are mostly not the fittest patients so a lot of them struggle with coping with stomas and so on or struggle with just recovering from the operation. So there’s a lot of attraction, I find with my patients, in a treatment that is a day case, outpatient treatment; they don’t have to come into the hospital, the treatment takes four weeks and they have to have check cystoscopies but essentially there’s no in-patient stay whatsoever.

What’s the long-term viability of this approach?

Long term, the long-term side effects are really very little so there’s an acute… with radiotherapy, with or without chemo, you get an acute sunburn in the inside of the bladder so you get frequency dysuria and rectal urgency and so on. Those side effects largely settle completely. Only around 10% of patients have grade 3 or 4 side effects post treatment, once the acute side effects had settled. So from three months on from the end of treatment most patients had no side effects.

Is there a movement more towards surgical approaches?

I think for younger patients, particularly if they’ve got a lot of carcinoma in situ or have had a lot of prior intravesical procedures performed, they will often have relatively poorly functioning bladders so there’s not a lot of point in preserving a poorly functioning bladder. I think there is some concern, particularly amongst urologists, that you may be delaying the recurrence of the bladder cancer. I’m not sure there’s evidence to support that but I think for older patients the risks of cystectomy are high and we had no treatment related deaths in 450 patients in this trial whereas even the best cystectomy series will have mortality rates at 30 days in the several per cent range, rising to 10-20% once you get up into the over-80s which comprise quite a big proportion of our trial.

How would you advise doctors to proceed?

I think patients have to be offered and counselled that there are alternatives to cystectomy because I think that’s one of the things that simply doesn’t happen in many places. I think that’s partly just a lack of awareness, that radical chemoradiotherapy is a viable treatment alternative. So one of the things I was very pleased about with this meeting was to be given the opportunity to talk about it in an invited session, to talk about the role of it. So clearly there is an increasing awareness of this as a treatment amongst American oncologists in general of all sorts – surgical, medical, radiation, and a realisation that, for older, less fit patients in particular, they still should be offered the option of radical therapy but just not surgery.

So there are two radiotherapy oncology group studies incorporating our chemoradiotherapy regime into the core of the study design. We were naturally very pleased about that, to have it cemented into practice in that way.