Hypofractionated Radiation in Breast Cancer Has Fewer Adverse Effects

By Charles Bankhead
SUTTON, England, March 20 -- In early-stage breast cancer, delivery of a lower total radiation dose in fewer but larger fractions reduces effects on normal tissue with no loss in tumor control, according to results of two large randomized trials. Five-year tumor control actually improved by as much as 1.7% with a total radiation dose of 40 Gy administered in 15 fractions versus the standard 50 Gy in 25 fractions, John Yarnold, M.D., of the Royal Marsden Hospital, and colleagues in the START trials, reported March 19 in The Lancet and Lancet Oncology. In the second study reported by the trialists, total radiation doses of 41.6 Gy and 39 Gy delivered in 13 fractions resulted in five-year tumor control rates that differed from the conventional regimen by less than 1%.
Photographic and patient self-assessments suggested the 40-Gy dose and the 39-Gy dose reduced late adverse effects compared with 50 Gy.
"The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to changes in radiotherapy fraction size," the authors concluded.
The most widely used schedule of adjuvant radiation therapy for localized breast cancer is 50 Gy administered in 25 fractions of 2.0 Gy over five weeks. That schedule evolved from the assumption that delivery of a high total dose of radiation in small fractions minimizes damage to normal tissue and maximizes tumor control, the researchers said.
Initial studies of hypofractionated radiation therapy supported the conventional approach, as rates of damage to normal tissue with fewer but larger fractions were unacceptable, the authors said. However, they noted, the total radiation dose was not reduced in those early trials.
Healthy breast tissue is sensitive to radiation fraction size, such that small changes in fraction size can lead to disproportionately larger changes in radiation effects on these tissues, the authors continued.
Some investigators have hypothesized that breast cancer is as sensitive as normal breast tissue to fraction size.
According to the hypothesis, small fraction sizes of 2.0 Gy or less offer no therapeutic advantage, and in fact, a more effective strategy would be to deliver fewer, larger fractions that result in a lower total radiation dose.
Dr. Yarnold and colleagues tested the hypothesis in two large randomized clinical trials, the Standardization of Breast Radiotherapy Trials (START). The first trial involved 2,236 women requiring adjuvant radiation therapy after breast-conserving surgery for early-stage breast cancer.
The patients were randomized to a 50-Gy total dose of radiation in 25 fractions over five weeks or to 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy, respectively, also administered over five weeks.
After a median follow-up of 5.1 years, the five-year rate of locoregional relapse was 3.6% with the conventional radiation regimen, 3.5% with the 41.6-Gy hypofractionated regimen, and 5.2% with 39 Gy in 13 fractions.
The estimated five-year absolute differences were 0.2% for 41.6 Gy and 0.9% for 39 Gy compared with 50 Gy.
The differences from the conventional regimen translated into hazard ratios of 1.05 for the 41.6-Gy total dose and 1.26 for the 39-Gy total dose, neither of which was statistically significant.
Similarly, all-cause mortality did not differ among the three groups, ranging from 11.2% with 50 Gy to 11.9% with 41.6 Gy.
In the second trial, investigators randomized 2,215 patients with early breast cancer to conventional radiation therapy or to a total dose of 40 Gy administered in 15 fractions.
After a median follow-up of six years, the five-year rate of locoregional relapse was 2.2% with the 40-Gy regimen versus 3.3% with the 50-Gy regimen.
The relapse rates translated into an absolute difference of 0.7% in favor of the 40-Gy regimen. The 95% confidence intervals suggested the advantage could be as much as 1.7% better than the conventional regimen or no more than 0.9% worse.
Longer follow-up is required to draw definitive conclusions about the trials' outcomes, Harry Bartelink, M.D., Ph.D., of the Netherlands Cancer Institute in Amsterdam, and Rodrigo Arriagada, M.D., of the Karolinska Institute in Stockholm, said in an accompanying commentary.
In a previous multinational European trial, a radiation booster dose led to a significantly lower risk of relapse at 10 years in younger and older women compared with five-year results, they noted.
They further expressed concern about the meaning of these studies. They wrote "to avoid highly speculative hypotheses, such as the assumption that a shorter treatment time, three weeks, would mainly benefit more aggressive local disease, we should accept that this result could be a false negative that might change with longer follow-up and more events."
Future studies should consider use of immunohistochemistry and extraction of mRNA samples from tissue blocks for microarray analysis to identify patients who might be most likely to benefit from hypofractionation, Drs. Bartelink and Arriagada added.
The trials were funded by Cancer Research UK, the UK Medical Research Council, and the Department of Health.
The researchers and the editorialists declared that they have no conflicts of interest.
Primary source: The LancetSource reference:The START Trialists' Group "The UK standardization of breast radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomized trial" Lancet. 2008; DOI: 10.1016/S1470-2045(08)70077-79. Additional source: The LancetSource reference: The START Trialists' Group "The UK Standardization of Breast Radiotherapy (START) Trial B of radiotherapy hypofraction for the treatment of early breast cancer: A randomized trial" Lancet. 2008; DOI: 10.1016/S0140-6736(08)60348-7.