European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Radiotherapy between or during chemo cycles for breast cancer

Dr Indrajit Fernando – Queen Elizabeth Hospital, Birmingham, UK

 

This trial, the SECRAB trial, was a trial that was designed to see if we could manipulate the sequencing of chemotherapy and radiotherapy in order to reduce the risk of local recurrence in early stage breast cancer. Now you might ask, is this important? Is reducing local recurrence in breast cancer of any importance? Well the first thing to say is that if any of you are actually in a clinic with breast cancer patients who develop local recurrence, it’s absolutely devastating. It’s as devastating as developing a recurrence anywhere. What we didn’t know when we actually set up this study was that in addition to the terrible shock and morbidity of developing a recurrence, we can also potentially have an impact on survival. We know from the overview of 2005 that for every four recurrent local recurrences we can prevent, we can also potentially save the life of one of our patients. Now, for a cancer like breast cancer which is very common, this has very, very important implications and it means that even small improvements in local control will have a long-term continuous benefit.

So how can sequencing affect local recurrence? Well, the first study that was done looking at that was a study from the United States, from Dr Reich and colleagues. The initial results from that certainly suggested that if you change the normal sequence, which is to give chemotherapy followed by radiotherapy, to radiotherapy first, there was potentially a detriment in long-term outcome and survival, survival was worse. So it suggested that we really mustn’t delay the onset of chemotherapy.

An alternative way of trying to manipulate sequencing is to actually take your radiotherapy and not give it at the end, which is what most people in the world would actually do at the moment, but to bring the radiotherapy and bring it much earlier and try and what we call either sandwich or give it in a synchronous manner. And this, of course, means that you avoid the delay of the radiotherapy; it means that potentially you shorten the patient’s treatment time and also giving it together in this manner, there might actually be a synchronous effect, an effect of the two treatments that might make local control better than giving chemotherapy followed by radiotherapy, which is the standard treatment.

Now throughout the world there are different fractionations, but what I meant by fractionations is different courses of radiotherapy that are used. In the United Kingdom and Canada people tend to use a three week course of radiotherapy; in the United States and Europe they tend to use a longer course. And we would look at those two different ways of doing it because there’s a three week gap between chemotherapy courses and we can either sandwich the radiotherapy like this, or give it over a slightly more prolonged manner, what we call the concomitant manner.

So this was the aim of the study: could local control be improved by the synchronous delivery of chemotherapy and radiotherapy. And you might say to me, well why don’t we just do that anyway? The reason we can’t do that anyway is that what we don’t know is is giving the two treatments together likely to worsen the side effects of treatment and the long-term toxicity. So both of these needed to be assessed.

This the trial design, a very simple trial design, patients with early stage breast cancer suitable for either wide local excision or mastectomy, fixed for treatment, and they had to have a complete macroscopic removal of the tumour and patients could be given either a CMF type chemotherapy or an anthracycline followed by CMF chemotherapy. We had to use CMF because CMF was the chemotherapy regime that we could actually combine with radiation treatment. Then the patients were randomised to either synchronous or sequential therapy and followed up for ten years. We aimed to achieve a 2,000 patient trial, the largest trial in the world looking at sequencing of chemotherapy and radiotherapy in early stage disease.

These are the important results that we are showing at ESMO, which are the five year local recurrence rates, and what we see is a significant reduction in local breast cancer recurrence in patients having the synchronous treatment. 2.3% reduction, that was statistically significant; this is equivalent to a 35% reduction in the risk of local recurrence, so a very large benefit, very similar to the benefit seen with chemoradiation in other sites.

What’s the price to pay for that? The price to pay for it is we do certainly see an increased acute skin reaction, and you can see here that we combine moderate and severe skin reactions. It’s 24% in the synchronous arm, 15% in the sequential arm, but I think it’s important to note that the percentage of severe reactions was very, very small, it was only 4%. In the vast majority of these patients, 96% of the patients, the acute skin reaction had completely settled within 4-6 weeks of completing treatment so it was really a modest increase in acute skin toxicity. We should also note that, of course, this trial ran between 1998 and 2004 and since then we are using far more modern ways of delivering radiotherapy which significantly reduce acute skin reaction, compared to the methods used when this study was running.

Have we impacted on survival? By giving the synchronous treatment, have we made the chemotherapy less active? The answer is no, the survival rates are exactly the same; we’re not compromising the patient’s survival in any way by giving these treatments concurrently. And what about quality of life, have we made their life miserable by giving the synchronous treatment compared to sequential? The answer again is no, there is no difference in quality of life between synchronous treatment and sequential treatment.

So how does SECRAB impact? We have to use a CMF type regime and you can use an anthracycline and potentially there’s no reason why you can’t use a taxane as well, but you have to use a CMF type regime. The trial has shown that giving synchronous treatment you get a 35% reduction in the risk of developing a local recurrence either in the breast or in the chest wall. The effect was seen both for patients being treated with a three week regime and those being treated with a regime longer than that. The biggest benefit as far as the patients were concerned, and why the trial was so popular and why it recruited beyond its target number, patients liked the fact that when they finished their last chemotherapy they’d finished all their treatment. They didn’t have to wait another four weeks to start their radiotherapy, it’s a long haul for patients having adjuvant chemotherapy and radiotherapy. They liked the fact that they finished their chemotherapy, they can book their holiday, they can get back to work, there are lots of benefits in that way too. And with careful patient selection and with modern radiotherapy techniques, I think the acute… we’re talking very slight increase in acute skin toxicity, can also be dealt with.

Thank you very much.