Bekelman and colleagues are to be congratulated on the publication of an important paper—reviewed in this issue of The ASCO Post—alerting us all to the underutilization of hypofractionated whole-breast irradiation in the treatment of early-stage breast cancer.1
As background, recent randomized radiation trials have proven what preclinical radiation biology studies and biologic models previously predicted. Specifically, these trials demonstrated that delivering fewer large daily radiation doses (hypofractionation) to a moderate total dose over approximately 4 weeks resulted in clinical outcomes comparable to those with conventional fractionation, which uses smaller daily fractions to higher total doses over 5 to 6 weeks.2-4
Preclinical laboratory studies in conjunction with linear-quadratic modeling suggested that short-course hypofractionation would result in high rates of tumor control while minimizing normal-tissue toxicity.5,6 This was indeed demonstrated in four recent randomized trials. These results were unexpected, since early studies using hypofractionation to high total doses resulted in increased rates of late normal-tissue toxicity and morbidity. This, in turn, led to the abandonment of using large daily doses and the adoption of smaller fractions as standard practice in most radiation centers. However, an important difference between the earlier hypofractionation schedules and the more recent hypofractionation trials was the reduction in the total dose in the recent trials, which, as predicted by biologic models, resulted in low rates of normal-tissue toxicity.
ASTRO Task Force
In 2009, the American Society for Radiation Oncology (ASTRO) convened a task force to review the data from the randomized hypofractionation trials and generate an evidence-based guideline for treatment recommendations for early-stage breast cancer.7 There was clear consensus among task force members that the data demonstrated no significant difference in the rates of tumor control in the breast, cosmesis, or complications between hypofractionated radiation and conventional fractionation in women 50 years and older with pathologic T1,2 N0 cancers who did not receive systemic chemotherapy and in whom dose homogeneity was within 7% of the prescribed dose. These patients represented the majority of the patients entered in the randomized trials. A consensus was not reached for other patient subgroups underrepresented in the trials. This guideline was published in 2011.
A Closer Look at the Bekelman Study
Bekelman et al now report the rates of usage of hypofractionated radiotherapy using claims data from 14 commercial health-care plans in the United States in patients treated with breast-conserving surgery and radiotherapy from 2008 to 2013.1 They show usage in 34.5% of the hypofractionation-“endorsed” cohort and 21.2% in those women for whom a consensus by the ASTRO task force was not reached (ie, the hypofractionation-“permitted” cohort). These rates of hypofractionated whole-breast irradiation were low despite equivalent results demonstrated in the clinical trials and the reduction in the adjusted mean total health-care expenditures associated with the shorter course.
The methodology in their study was rigorous, but the data were retrospective and based on claims thus subject to misclassification bias. The authors were unable to ascertain many of the clinical and pathologic factors (such as tumor size, nodal status, and dose homogeneity) important in the selection of patients in some of the randomized trials and important in the development of the ASTRO guideline. As the authors noted, misclassification would have biased the estimates of the use of hypofractionated radiotherapy downward.
The MROQC Initiative
The utilization of hypofractionated whole-breast irradiation in early-stage breast cancer patients treated with breast conservation was also recently reported by Jagsi et al using data prospectively collected in the state of Michigan from radiation oncology practices participating in the Michigan Radiation Oncology Quality Consortium (MROQC).8 This is a quality initiative funded by Blue Cross Blue Shield of Michigan.
Of MROQC participants registered between October 2011 and December 2013 with T1-2 N0 cancers, 31% were identified as having received hypofractionated whole-breast irradiation. When patients were further selected using factors consistent with the ASTRO-endorsed cohort (ie, age 50 years and older, no receipt of chemotherapy, and breast separation < 25 cm [a metric used to assess dose homogeneity]), the rate of hypofractionation use was increased to 43%. Although this rate was higher than that in the unselected cohort, these results demonstrated a lower rate of hypofractionated radiotherapy utilization than expected in patients who were excellent candidates for this fractionation schedule.
The reasons behind the low utilization rate of hypofractionated whole-breast irradiation are unclear. The financial differential for radiation oncology practices has been suggested as a contributing factor. Providers could also have been hesitant to use large fractions because of persistent concerns over placing patients at risk for the long-term toxicities observed in the hypofractionation studies of the past. Even in the ASTRO evidence-based guideline (published before the publication of the 10-year results of the START trials), task force members had “lingering uncertainty regarding late effects of hypofractionated whole-breast irradiation on cardiac function.”7 Thus, the relative “newness” of the hypofractionation schedules in the randomized trials may have tempered enthusiasm. Perhaps the low uptake was due in part to patient decisions not to choose the more-recent fractionation schemes with 10-year follow-up, when 20+ years of outcomes data were available for conventional whole-breast fractionated therapy.
Increasing Awareness
At present, we don’t understand the reason(s) leading to the underutilization of the short-course hypofractionated regimens: this must be carefully studied. However, if the increased trajectory for use observed among the hypofractionation-endorsed group in the last year of the Bekelman et al study is sustained, it suggests that large-fraction radiotherapy is being integrated into routine American practice. Continued education regarding the effectiveness of the shorter 4-week course, which offers greater patient convenience and health-care savings, will hopefully result in the increased use of this fractionation schedule.
ASTRO’s Choosing Wisely campaign encourages discussion of whole-breast hypofractionation in women 50 years and older diagnosed with early-stage disease.9 An update of the ASTRO guidelines is also anticipated in the coming months, and this will increase awareness of the clinical utility and practicality of the shorter course. Finally, prospective analyses from clinical trials and observational studies such as MROQC, as well as retrospective analyses from studies such as that by Bekelman et al, will also help to educate health-care providers and the patients we serve. ■
Disclosure: Dr. Pierce reported no potential conflicts of interest.
References
1. Bekelman JE, Sylwestrzak G, Barron J, et al: Uptake and costs of hypofractionated vs conventional whole breast irradiation after breast conserving surgery in the United States, 2008-2013. JAMA 312:2542-2550, 2014.
2. Whelan TJ, Pignol JP, Levine MN, et al: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362:513-520, 2010.
3. Owen JR, Ashton A, Bliss JM, et al: Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumor excision: Long-term results of a randomised trial. Lancet Oncol 7:467-471, 2006.
4. Haviland JS, Owen JR, Dewar JA, et al: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14:1086-1094, 2013.
5. Fowler JF: The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 62:679-694, 1989.
6. Whelan TJ, Kim DH, Sussman J: Clinical experience using hypofractionated radiation schedules in breast cancer. Semin Radiat Oncol 18:257-264, 2008.
7. Smith BD, Bentzen SM, Correa CR, et al: Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 81:59-68, 2011.
8. Jagsi R, Griffith KA, Heimburger D, et al: Choosing wisely? Patterns and correlates of the use of hypofractionated whole-breast radiation therapy in the state of Michigan. Int J Radiat Oncol Biol Phys 90:1010-1016, 2014.
9. American Society for Radiation Oncology: Five things physicians and patients should question. Available at: http://www.choosing wisely.org/doctor-patient-lists/american-society-for-radiation-oncology. Accessed January 29, 2015.
