John Yarnold, MBBS
Historically, standard radiotherapy following surgery in early breast cancer has consisted of a 50 Gy regimen administered over 5 weeks in 25 daily 2 Gy doses, or fractions (Fr). However, randomized studies, including the START trials, have demonstrated that hypofractionated radiotherapy—a lower total dose administered in fewer, larger fractions—matches the efficacy and safety of the standard regimen. At the 35th Annual San Antonio Breast Cancer Symposium (SABCS), researchers presented 10-year follow-up data from the START trials further supporting the use of hypofractionated radiotherapy in early-stage breast cancer.
“What our trials have shown is that you can be gentler on the normal tissue and produce fewer adverse effects if you give a slightly lower total dose [of radiation] in fewer, slightly larger fractions without losing the ability to eradicate the cancer,” said John Yarnold, MBBS, professor of Clinical Oncology at the Institute of Cancer Research in London and honorary consultant at the Royal Marsden NHS Foundation Trust, who presented the data in a press session at SABCS.
The START trials randomized 4451 women with invasive breast cancer (T1-3, N0-1, M0) to various radiotherapy schedules following primary surgery. Yarnold said that START A was exploratory and START B was a pragmatic trial designed to determine a schedule that would work in clinical practice.
In START A, 2236 patients were randomized 1:1:1 to 50 Gy in 25 Fr (2.0 Gy) over 5 weeks, or 41.6 Gy or 39 Gy in 13 Fr (3.2 Gy and 3.0 Gy, respectively) over 5 weeks. In START B, 2215 patients were randomized 1:1 to 50 Gy in 25 Fr (2.0 Gy) over 5 weeks or 40 Gy in 15 Fr (2.67 Gy) over 3 weeks. Yarnold said that virtually all patients were treated with external-beam radiation therapy. The primary endpoint for both trials was local-regional (LR) relapse, with a secondary endpoint of normal tissue effects assessed by both physicians and patients.
Long-term follow-up results showed that the hypofractionated regimens were as effective as the 50-Gy standard. In START A, at a median follow-up of 9.3 years, LR relapse rates were 7.4%, 6.3%, and 8.8%, after 50 Gy, 41.6 Gy, and 39 Gy, respectively. In START B, at a median follow-up of 9.9 years, LR relapse rates were 5.5% after 50 Gy, and 4.3% after 40 Gy.
In both trials, the safety profiles were similar between the hypofractionated and standard arms. In START A, long-term rates of moderate/marked late normal tissue effects were 43.9%, 49.5%, and 50.4% after 39 Gy, 41.6 Gy and 50 Gy, respectively. In START B, the rates were 37.9% after 40 Gy and 45.3% after 50 Gy.
Yarnold said that the 3-week 40 Gy 15 Fr regimen established in the START B trial is the current treatment standard in the United Kingdom, but other countries, including the United States, still use the traditional standard. “Since 2009, when the START trial reported its 5-year data, the whole country [has used] the 3-week measurement. Whereas in the US and in other countries, for example, Japan and elsewhere, they still give 50 Gy in 25 fractions to the majority of their patients.”
Going forward, researchers will examine the potential to individualize treatment based on a greater understanding of the molecular mechanisms driving fraction size sensitivity. In the meantime, the FAST-Forward trial is examining the new 3-week standard with a 1-week schedule of whole breast radiotherapy.
Haviland JS, Agrawal R, Aird E, et al. The UK START (Standardisation of Breast Radiotherapy) Trials: 10-year follow-up results. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. S4-1
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