Shorter High-Dose Radiotherapy Effective for Breast Cancer

Two large 10-year follow-up randomized trials in the United Kingdom show that less frequent but higher-dose radiotherapy regimens are as safe and effective as the standard regimen of more frequent lower doses for women with early breast cancer post-surgery. The newer 3-week regimen equates to a lower cumulative radiotherapy exposure compared with a standard 5-week regimen.

Breast shrinkage, telangiectasia, and breast edema were less common in the 3-week regimen compared with the 5-week schedule.

The survival benefit shown with a 40 Gy dosage schedule at a 5-year analysis was confirmed at the 10-year follow-up.

The results of the two UK Standardisation of Breast Radiotherapy (START) trials are published in Lancet Oncology.

The results “reassure us that 3 weeks of radiotherapy is as good as the 5 weeks still used in many countries, with less damage to nearby healthy tissue,” said lead study author John Yarnold, MD, of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in Sutton, United Kingdom, in a statement. The newer regimen is also more convenient for patients, with fewer hospital visits and less costly for health service providers, said Yarnold.

“The result is not unexpected, but confirms that the relationships between the [newer and standard] schedules did not change between 5 and 10 years [of follow-up],” Yarnold told Cancer Network.

Efficacy and safety results were similar, despite differences in age, tumor grade, chemotherapy, and breast cancer stage.

The trials were based on prior evidence that breast cancer may be more sensitive to changes in dose of radiotherapy for each dose fraction. Radiotherapy doses are generationally spread over time (fractioned), which allows normal cells, but not cancer cells, to recover from the damage.

According to the study authors, these results suggest that a small 2 Gy fraction allows cancer tissue, as well as healthy tissue, to recover, “bringing no benefit to patients.”

The START-A trial compared a 50 Gy dose in 25 fractions over 5 weeks with a 41.6 Gy or 39 Gy dose in 13 fractions over 5 weeks. The START-B trial compared a 5-week 50 Gy dose regimen with a hypofractionated regimen: 40 Gy in 15 fractions over 3 weeks. Patients were enrolled between 1999 and 2002 in the United Kingdom after complete excision of their primary invasive breast tumors.

A total of 2,236 women took part in the START-A trial, and 2,215 women took part in the START-B trial.

Both the START-A and START-B results show that few women had breast cancer relapse irrespective of the dose regimen.

START-A Trial

At 10 years, the distant relapse, distant disease-free survival, and overall survival rates were not significantly different among the three START-A trial arms. According to the study authors, neither the hypofractionated regimens nor the standard regimen were particularly detrimental.

Women had similar rates of local recurrence and distant recurrence in both the hypofractionated and standard radiotherapy arms.

At a median follow-up of 9.3 years, a total of 140 women had local-regional relapse in the START-A trial: 7.4% of women receiving 50 Gy, 6.3% of women receiving 41.6 Gy, and 8.8% of women receiving 39 Gy of radiotherapy. The differences were not statistically significant. A total of 331 patients had distant relapse during the follow-up. The differences in rates of distant relapse by radiotherapy dosage also were not statistically significant.

Physicians did not observe great differences in the effects of normal tissue to the radiotherapy treatment. Normal tissue effects were similar for the 50 Gy– and the 41.6 Gy–treated groups, while moderate or marked breast induration, telangiectasia, and breast edema were significantly less common in patients treated with the 39 Gy regimen compared with those treated with the 50 Gy regimen.

START-B Trial

In the START-B trial, 5.5% of women after a 50 Gy regimen and 4.3% after a 40 Gy regimen had local-regional relapse (hazard ratio [HR] = 0.77; P = .21). Two hundred and seventy-nine patients had distant relapse, 16% in the 50 Gy arm compared and 12.3% in the 40 Gy arm. The difference was not statistically significant.

The 3-week 40 Gy regimen had significantly better outcomes for healthy tissue compared with the 5-week regimen.

In general, fewer patients in the START-B trial relapsed. The authors attributed this to the slightly better prognosis of patients recruited to the START-B study compared with those in the START-A study.

Patients treated with the 3-week 40 Gy regimen had a lower all-cause mortality compared with patients treated with the 5-week 50 Gy regimen (HR = 0.8; P = .042).

Conclusions

The authors concluded that the “START pilot trial, Ontario trial, and START-A and START-B trials, considered together, present robust evidence that hypofractionation is a safe and effective approach to breast cancer radiotherapy.”

The 5-year results in 2009 changed practice across the United Kingdom, and Canada has adopted a 16-fraction dose following results of their own randomized trial, said Yarnold. Other European and Asian countries have also changed their practices to the 3-week schedule.

Other large hypofractionation trials of whole breast radiography are ongoing, including a 2,000-plus patient trial by the Radiation Therapy Oncology Group, aimed to validate these findings. The FAST-Forward trial in the United Kingdom is currently enrolling 4,000 patients to compare a 1-week schedule of two dose levels to a 3-week schedule.

According to Yarnold, many US centers still use a 5-week 25-fraction schedule, although the American Society for Radiation Oncology (ASTRO) does allow a 15-fraction regimen in older patients with low-risk tumor.