Adoption of Hypofractionated Radiotherapy in Early-Stage Breast Cancer

Aaron Falchook, MD

Whole-breast radiotherapy has been proven to reduce local recurrence and improve overall survival when used as part of a breast-conserving treatment paradigm for women with early-stage breast cancer. Historically, a “conventional” radiotherapy fractionation scheme was used-typically 50 Gy given in 25 fractions of 2 Gy per fraction. This fractionation scheme was used in many of the randomized trials that demonstrated the benefit of post-lumpectomy radiotherapy. When the tumor bed “boost” is also considered, a typical conventional course of radiotherapy takes between 6 to 7 weeks to complete.

Since 2002, there have been four large randomized controlled trials that demonstrated the efficacy and safety of a shorter “hypofractionated” course of radiotherapy. These hypofractionated courses use larger daily doses of radiotherapy for fewer fractions, and therefore a lower total dose. These shorter courses often can be completed in 4 to 5 weeks, even when a tumor bed boost is used. The largest of these randomized trials were the START A and START B trials, which studied over 4,500 women from the United Kingdom. Initial results were published in 2008, with long-term follow-up results published in 2013.

The topic of hypofractionated radiotherapy adoption has been in the news lately, due to the recent publication of several studies that examined this topic. Bekelman et al published a retrospective study using the HealthCore administrative claims database, which included over 9.2 million women. Among the women for whom guidelines endorsed the use of radiotherapy (age ≥ 50, no lymph node involvement, no chemotherapy used, and favorable anatomy to allow for optimal radiation dose distribution), the authors found that use of hypofractionation increased from 11% in 2008 to 35% in 2013. It is worth noting that the T-stage and N-stage could not be directly measured in this study, and had to be inferred based on billing claims data for procedures performed. Similarly, measure of radiation “dose heterogeneity” could not be directly measured but was evaluated through the use of obesity as a surrogate (obese patients typically have larger breasts and therefore increased dose heterogeneity). Two other studies, published by Jagsi et al and Wang et al, evaluated the Surveillance, Epidemiology, and End Results-Medicare claims database and the National Cancer Data Base to evaluate the same question. These studies found similar low rates of hypofractionation use that increased modestly since publication of randomized trials.

It is true that adoption of hypofractionation has been relatively slow since the publication of large randomized trials, but it is important to put these results in context. The use of conventional fractionated radiotherapy has been established by no fewer than 14 randomized trials performed in the 1980s and 1990s. With the first long-term follow-up results published by Whelan et al in 2010, and the START A/B long-term follow-up results not published until 2013, perhaps it is not surprising that hypofractionation rates prior to 2013 remained low. This is especially true as we consider the long follow-up times needed to detect differences in survival for women with early-stage breast cancer treated with breast-conserving therapy (as seen in the earlier trials that evaluated lumpectomy with or without radiotherapy). Reassuringly, the long-term follow-up data of hypofractionated radiotherapy not only continue to demonstrate efficacy, but breast cosmesis with hypofractionation remained favorable as well.

There are a significant proportion of patients for whom hypofractionated radiotherapy is not appropriate. Obesity rates in the United States are higher than many other countries, and these patients may be inappropriate candidates for hypofractionated radiotherapy due to anatomic limitations that would create excessive “hot spots,” or areas of dose in excess of the prescription, within the breast. I think it is likely that we will continue to see hypofractionated radiotherapy use rise, but we need to also keep in mind that patients we see in clinic are not identical to patients who participate in randomized clinical trials. While national guidelines and consensus statements are useful tools that help inform medical decision making, individual patient factors cannot be ignored as we seek to provide the best care for our patients.