Hypofractionation Emerges as Standard, but Not Yet for Every Patient

OncologyLive, June 2013, Volume 14, Issue 6

Recently published clinical trial results support new radiation therapy protocols for many breast cancer survivors⎯protocols that could greatly improve collective outcome.

Tim Whelan, MSc, FRCPC

Professor, Department of Medicine

Associate Member, Department of Clinical Epidemiology & Biostatistics

Director, Supportive Cancer Care Research Unit

Juravinski Cancer Centre McMaster University Hamilton, Ontario, Canada

Recently published clinical trial results support new radiation therapy protocols for many breast cancer survivors⎯protocols that could greatly improve collective outcomes despite working little better than existing standards of care, according to Tim Whelan, MSc, FRCPC.

Whelan analyzed the results of the Ontario Clinical Oncology Group (OCOG) trial he led and additional British studies of hypofractionation during the 30th Annual Miami Breast Cancer Conference, which Physicians’ Education Resource (PER)® hosted in Miami Beach, Florida, in March. Hypofractionation is used as a general term for radiation regimes that reduce therapy duration by packing moderately large doses of energy (2.1 Gy−3 Gy) into each day’s treatment.

The studies began more than a decade ago, when researchers started testing alternatives to the long radiation treatments that physicians have used after breast-conserving surgery for more than 30 years: 50 Gy of radiation divided in 25 “fractions” of 2 Gy, and delivered every weekday for five weeks.

“We now have a mountain of evidence, a full 10 years of data on thousands of patients, so we really can feel comfortable in concluding that hypofractionation should indeed become the standard of care for many groups of breast cancer survivors,” Whelan said in an interview. “It will save patients large amounts of time and money while delivering outcomes and side effect profiles that are at least as good as the current standard—and possibly somewhat better.”

The British studies, known as the START A and B trials, tested various hypofractionation programs in 4451 women who had been diagnosed with invasive breast cancer and undergone primary surgery.

In the OCOG trial, 1234 patients were randomized to receive either 50 Gy administered in 25 fractions over five weeks or 42.5 Gy delivered in 16 fractions over three weeks. After 12 years’ median follow-up, the probability of local recurrence was 6.7% for those who received the standard radiation therapy versus 6.2% for those who received the hypofractionated dose (hazard ratio [HR] = 0.95; CI, 0.63-1.46), Whelan said in his presentation.

Table. Radiation Regimen Trial Results


Radiation Treatment Arms

Patients (No)

Median Follow-up (years)

Recurrencea (%)


42.5 GY/16 Fr/3 wk

50 Gy/25 Fr/5 wk







39 Gy/13 Fr/5 wk

41.6 Gy/13 Fr/5 wk50 Gy/25 Fr /5 wk









40 Gy/15 Fr/3 wk

50 Gy/25 Fr/5 wk






aLocal recurrence in OCOG; locoregional for START trials

Fr indicates fractions; Gy, gray; OCOG, Ontario Clinical Oncology Group; START, Standardisation of Breast Radiotherapy.

Adapted from Whelan T. Should hypofractionation be the new standard after BCS? Presented at: 30th Annual Miami Breast Cancer Conference; March 7-10, 2013; Miami Beach, FL.

Moreover, the cosmetic outcome by time and treatment was nearly identical among the two groups, with 71% of 216 evaluable patients in the standard therapy group achieving an excellent or good outcome, compared with 70% or 235 evaluable patients with the same outcomes.

In START A, 2236 patients were randomized evenly among the longtime standard and two experimental regimes: 41.6 Gy delivered in 13 fractions over five weeks or 39 Gy, delivered in 13 slightly smaller fractions over the same five weeks. At a median follow-up of 9.3 years, local-regional relapse rates were 7.4%, 6.3%, and 8.8%, respectively, while long-term rates of moderate/marked late normal tissue effects were 43.9%, 49.5%, and 50.4%.

Putting Findings Into Practice

In START B, 2215 patients were randomized evenly between the standard (50 Gy in 25 fractions of 2.0 Gy, administered over five weeks) and 40 Gy in 15 fractions of 2.67 Gy, administered over just three weeks. At a median follow-up of 9.9 years, local-regional relapse rates were 5.5% and 4.3%, respectively, while rates of long-term tissue effects were 45.3% and 37.9%, respectively.Whelan drilled down into those results, along with more data from his Ontario trial, to explain which subgroups would likely benefit from hypofractionation and which subgroups should probably continue with the former standard, pending results from further study.

“If you just glance at the results, the figures look very compelling, but we’re not at the point where we should be giving three-week programs to everyone,” said Whelan. “For example, the data definitely support usage of hypofractionation for older patients. In some cases, as with younger patients with node-negative tumors, the evidence is there as well. In other cases, it isn’t. Not yet, at least.”

Such evidence may emerge from ongoing trials of hypofractionation, such as those that are currently examining the effect of radiation “boosts” targeted directly at the surgical cavity. These boosts, administered along with whole-breast irradiation, use recent advances in radiation technology in hopes of further reducing recurrence and further shortening treatment times.

While such studies continue, other nations are acting on the data that are already available. Indeed, the United Kingdom adopted a three-week hypofractionation program as its standard of care when five-year data from the START trials were released in 2009. Canada has since done likewise.

Whelan sees two significant reasons why other nations should, too.

First, the switch to hypofractionation will save time and money. Patients would miss less time at work and home, while payers would see savings at a time when healthcare costs are increasing dramatically. He estimated the cost of hypofractionated radiation at about $6100, compared with $8500 for whole-breast irradiation and $10,900 for whole-breast irradiation with boosts.

Second, the lower cost and shorter duration of hypofractionation regimes should reduce the number of women who fail to get any radiation therapy after surgery, a group that may be as large as 30% in some regions.

“There’s a very natural tendency to think that improving cancer outcomes is the real key to improving treatment quality and that making treatment easier on patients is a distinctly secondary consideration,” Whelan said. “But if, by making treatments easier without reducing efficacy, you can increase patient compliance rates and you can greatly improve outcomes on a population basis.

“Hypofractionation may not be much more effective than the existing standard, but it is certainly more effective than no treatment at all. If the switch leads to more women receiving the treatment they need, then it will prove to be a very significant improvement in breast cancer treatment,” Whelan said.