Radiotherapy for breast cancer patients can be delivered as a lower overall dose in fewer, larger doses, giving similar tumour control and fewer adverse side effects than current practices. These are the conclusions of the authors of the START[1] A and B trials, with START A published early Online and in the April edition of the Lancet Oncology, and START B published early Online and in an upcoming edition of The Lancet.

The international standard radiotherapy schedule for early breast cancer delivers 50 Gy[2] of radiation in 25 small doses (fractions) of 2.0 Gy over five weeks. However, cancer specialists in the UK have long believed that a lower total dose delivered in fewer, larger fractions can be at least as safe and effective as this standard schedule. Professor John Yarnold, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK, Professor Judith Bliss, Clinical Trials and Statistics Unit, Institute of Cancer Reseach, Sutton, UK, and colleagues from the START trials collaborative group, comprising researchers from 35 UK cancer centres, carried out both START trials to test this hypothesis. Their conclusions come after ten years of work on these trials. The studies were jointly funded by Cancer Research UK, the UK Medical Research Council, and the UK Department of Health.

In Start A, 2236 women with early breast cancer at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy (749 women) versus 41.6 Gy in 13 fractions of 3.2 Gy (750 women) or 39 Gy in 13 fractions of 3.0 Gy (737 women). All regimens were given over five weeks, and women were eligible if they were aged over 18, did not have immediate surgical reconstruction, and were available for follow-up. The endpoints of the trial were tumour relapse, defined as the reappearance of cancer at irradiated sites, the effect of the regimen on normal or 'cancer free' tissues, and quality of life for the patient.

The researchers found that after a median follow up of 5.1 years, the rate of tumour relapse at five years was 3.6 per cent after 50Gy, 3.5 per cent after 41.6 Gy, and 5.2 per cent after 39 Gy. Neither late adverse effects nor local tumour relapse after 41.6 Gy were different compared to 50 Gy - the absolute difference in local tumour relapse could be up to 1.3 per cent better and at most 2.6 per cent worse after 41.6 Gy. Both photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy. The authors conclude: "A lower total dose (41.6 Gy) in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50Gy in 25 fractions."

In Start B, 2215 women with early breast cancer at 23 centres in the UK were randomly assigned after primary surgery to receive 50Gy in 25 fractions of 2.0 Gy over five weeks (1105 women) and 40 Gy in 15 fractions of 2.67 Gy over three weeks (1110 women). The eligibility for the trial and its measured endpoints were the same as for Start A (see above).

The researchers found that after a median follow-up of 6.0 years, the rate of tumour relapse at five years was 2.2 per cent in the 40 Gy group and 3.3 per cent in the 50 Gy group, which translated into an absolute difference of between -1.7 and +0.9 per cent in the 40 Gy group - ie, the absolute difference in tumour relapse could be up to 1.7 per cent better and at most one per cent worse after 40 Gy than after 50 Gy. Again, both photographic and patient self-assessments suggested lower rates of late adverse effects after 40 Gy than with 50 Gy. The authors conclude: "After surgery for early breast cancer, a radiotherapy schedule delivering 40 Gy in 15 fractions over three weeks seems to offer local regional tumour control and rates of late normal tissue effects at least as good as the accepted international standard of 50 Gy in 25 fractions over five weeks."

In an accompanying Comment, Dr Harry Bartelink, Netherlands Cancer Institute, Amsterdam, Netherlands, and Dr Rodrigo Arriagada, Institut Gustave Roussy, Villejuif, France, say: "We realise that hypofractionation is convenient for patients, because it reduces the number of visits to radiotherapy departments and waiting lists in several cancer centres. Nevertheless we have to wait for data on longer follow-up before final conclusions can be drawn from the START trials."


[1] START = UK Standardisation of Breast Radiotherapy Trial
[2] Gy = Gray, a standard unit of absorbed radiation dose.

Source: Lancet