SABCS 2012

Breast cancer hypo-fractionated radiotherapy offers long-term tumour control

Professor John Yarnold – Institute of Cancer Research and Royal Marsden Hospital, UK

The question we addressed back in the nineties was the standard practice over decades of treating women with radiotherapy using multiple small doses over a five week period, giving a high total dose but giving it in small daily doses which were traditionally assumed to be gentle on the healthy tissues, and good reasons, but harmful on the cancer. Retrospective data that had been collected many years previously shows that breast cancer probably reacts differently to radiotherapy than many other cancers, say other cancers of the head and neck region, the cervix or the uterus and the lung, for example, where radiotherapy was first tested many decades ago. So the trial was using as a randomised trial comparing as the control arm, the control group, the standard regimen that’s used internationally, that is 25 treatments over five weeks to a total dose of 50Gy, against a lower total dose in fewer, larger fractions. In one of the two trials that we ran it was fifteen fractions every three weeks, so it was comparing a five week schedule to a three week schedule over 2,000 women. The mature data at ten years show that the dose reduction from 50Gy to 40Gy in fifteen fractions is gentler on the healthy tissues and there are about eight women for every hundred treated that get significant fewer side effects. So that’s more than a 20% reduction in the risk of a chronic side effect, but without losing any effectiveness in terms of preventing tumour recurrence.

Now tumour recurrence is low in all patients today which is obviously excellent but it’s important to prevent tumour recurrence because for every four recurrences prevented by radiation one prevents one death from breast cancer. So that trial, 40Gy in fifteen fractions in three weeks, that regimen has become the standard in the UK since 2009. So all women with early breast cancer are referred for radiotherapy either after breast conservation surgery or after mastectomy, whether or not they need radiotherapy to the armpit or the area above the collarbone, are now treated with that schedule. It’s made a big difference to them and also, of course, to the health services because radiotherapy for early breast cancer represents a substantial use of radiotherapy resource usage.

Could you explain why breast tumours react differently to radiotherapy?

This is a generalisation but the starting point is that normal tissues vary in sensitivity to fraction size and that has been known for a hundred years. That variation is closely associated with what we call the proliferative status of those tissues. So, for example, the superficial covering of the skin, the sunburn reactions, the sunburn-like reactions, that one gets with radiotherapy or the lining of the mouth, the lining of the intestines, those tissues, those membranes are replacing themselves continuously. So the cells are dividing frequently and we call those tissues highly proliferating. We know that those tissues are not sensitive to fraction size. Cancers that are also relatively highly proliferating like squamous cell carcinomas of the head and neck, lung and cervix are also insensitive to fraction size. It’s in that situation where small doses are best and that’s why they’ve been used. On the other hand, cancers which are relatively slow, have slow proliferative indices, certainly we know breast cancer  now as a result of this trial but also prostate cancer, they behave more like what we call the late onset normal tissues, the ones that develop radiotherapy side effects many years later. For example, a woman after breast radiotherapy may notice that her breast shrinks slightly in size, it may become firmer to the touch due to fibrosis, it may become tender, the muscles may become slightly stiff, those are what we call chronic effects, those tissues are very sensitive to fraction size. So that is why we turn to these trials to see whether breast cancer was actually behaving like what we call a late reacting normal tissue.

Could this reduction also be applied to prostate cancer?

Yes, that’s correct and clinical trials are underway testing that. In the UK in our Breast Radiotherapy Triallists groups we’ve gone on from that since 2003 to test a five fraction regimen for women who need radiotherapy to the breast only after breast conservation surgery. The first trial was giving one fraction a week so the overall treatment time remained as five weeks, but those early data which were published two years ago look very favourable and we’re now running a large trial of 4,000 women which is testing a five fraction schedule delivered in one week. So we would envisage that within ten years, obviously depending on the outcome of that trial, that a one week schedule of curative radiotherapy will be identified which is certainly as safe and as gentle on the normal tissues as the current three week standard is and equally effective.

What does this mean for the quality of life for the patient?

We had a very large quality of life programme associated with the START trial using the European Quality of Life questionnaires, all standard validated questionnaires. Those data were published two years ago and they show that there’s a high level of concordance between the women when one examines them at the population level and the clinical assessments so that we can reproduce the same results if we plot the patients’ self-report outcomes as we do when we report the clinician outcomes or the outcomes of the photographic assessment.