A five-year multi-centre randomised control trial shows similar recurrence rates of breast cancer in patients treated by accelerated partial breast irradiation (APBI) over the course one week compared to whole breast radiation delivered over three to five weeks.
Accelerated partial breast irradiation (APBI) sees larger doses of radiation delivered to parts of the breast affected by cancer. This treatment takes place in one week or less, further reducing length of treatment from the standard treatment of three to five weeks. T
“We wanted to do a study to see if we could shorten treatment as three to five weeks is not ideal for patients,” said first author Timothy Whelan, professor of oncology at McMaster University and a radiation oncologist of Hamilton Health Sciences. He holds a Canada research chair in breast cancer research.
The randomised controlled trial, called RAPID, occurred between 2006 and 2011 in 33 cancer centres across Canada, Australia and New Zealand. The 2,135 patients were women aged 40 or older with ductal carcinoma or node-negative breast cancer which had been treated by breast conserving surgery.
Approximately half of the patients were randomly assigned whole breast radiation, delivered once per day over three to five weeks. The other half received external beam APBI, considered to be the least invasive approach to partial breast irradiation, which was given twice a day over five to eight days.
The study was long-term, with a median follow-up of 8.6 years. At eight years, the risk of cancer recurrence in the breast was very low and similar for the two groups. For patients treated with APBI the risk was three per cent and for patients treated with whole breast radiation the risk was 2.8 per cent.
“The results after more than eight years are exciting because they showed, with long follow-up, that the risk of cancer coming back in the breast was reduced with APBI to the same degree as whole breast radiation,” Whelan said.
However, his research team was surprised to find that although less early toxicity within three months of treatment was observed with APBI, the twice-daily regimen was likely associated with higher late toxic effects and worse cosmetic outcomes. This included increased small blood vessels visible on the skin, and thickening of breast tissue related to radiation.
“About 13% of patients who had whole breast radiation had moderate toxicity, compared to 32% for those who had APBI,” said Whelan. “As well, about 16% more women treated with accelerated partial breast treatment didn’t feel their breast looked as good. “Based on this, it is difficult to recommend the twice per day regimen at this time.”
Whelan and his team are now conducting a clinical trial to examine whether once per day APBI with more time between treatments will have better outcomes. “We’re looking at external beam accelerated partial breast irradiation with five treatments, but only once per day rather than twice,” he said. “The early results are very promising because we’re not seeing that toxicity and our goal is to examine that further.”
The study was funded by the Canadian Institutes of Health Research and the Canadian Breast Cancer Research Alliance. The trial was conducted by the Ontario Clinical Oncology Group of McMaster and Hamilton Health Sciences.
Background: Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation.
Methods: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035.
Findings: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5–15·0), 5 years (16·5%, 12·5–20·4), and 7 years (17·7%, 12·9–22·3).
Interpretation: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied.
Funding: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.
Timothy J Whelan, Jim A Julian, Tanya S Berrang, Do-Hoon Kim, Isabelle Germain, Alan M Nichol, Mohamed Akra, Sophie Lavertu, Francois Germain, Anthony Fyles, Theresa Trotter, Francisco E Perera, Susan Balkwill, Susan Chafe, Thomas McGowan, Thierry Muanza, Wayne A Beckham, Boon H Chua, Chu Shu Gu, Mark N Levine, Ivo A Olivotto