Fractionation in Breast Cancer Radiotherapy for Conservative Treatment: Are We Really Done Learning?

For the individual breast cancer patient post lumpectomy who is seen daily in radiation oncology departments across the country, the goal of breast radiotherapy is really twofold: (1) maximize local control so that her cancer outcome is at least as good as with mastectomy, had she elected to undergo this procedure; and (2) minimize the treatment effect on the breast so that cosmetically her treated breast resembles her untreated breast as closely as possible. It is in the context of these goals for the individual patient that we should consider the achievements of the randomized clinical trials evaluating hypofractionated breast radiotherapy, so nicely reviewed by Eblan et al in this issue of ONCOLOGY.[1]

Decades of data from randomized controlled trials, single institutions, and, more recently, large registries support the facts that for the individual patient, reassurance is warranted that whole-breast radiotherapy post lumpectomy results in cancer outcomes that are as least as good as those achieved with mastectomy. Furthermore, omission of whole-breast radiotherapy in her care can be associated with significantly higher rates of in-breast cancer recurrence and smaller but still significantly higher rates of distant metastases and breast cancer mortality.[2-3] In reality, the vast majority of historical data documenting the success of breast radiotherapy for breast conservation treatment was delivered with fraction sizes ≤ 2 Gy per day. Acknowledging this helps to underscore both the magnitude of the clinical experience with breast radiotherapy delivered with ≤2-Gy fractions and the achievement of the 4 randomized controlled trials[4-6] that have demonstrated statistically comparable local control outcomes at 10 years for breast radiotherapy delivered with the various hypofractionation regimens studied. However, in contrast to the discussion by Eblan et al, who seem to imply that hypofractionated whole-breast radiotherapy should be adopted for all breast-conservation patients in the name of healthcare savings, on closer inspection the more measured recommendations of the ASTRO Consensus Guidelines regarding fractionation for breast radiotherapy are still relevant.[7] For example, there are still relatively fewer long-term events for some patient subgroups-especially with respect to age and tumor grade. While it is recognized that 22.7% and 20.5% of breast cancer patients enrolled in START A and START B, respectively, were < 50 years of age, only 5% were < 40 years old.[6] As younger women tend to more frequently have higher-grade breast cancers, along with a consistently poorer prognosis, many clinicians may find it rational to rely on the abundance of existing data in this subset supporting the longer fractionation schemes. It is likely that with time, numerous publications on hypofractionated radiotherapy for younger women will emerge, as they did for breast radiotherapy with ≤ 2 Gy per fraction, to more fully inform our understanding of breast cancer outcomes beyond the 167 local recurrence events at 10 years that exist for those < 50 years of age in the meta-analysis of all 3 START trials.[6] The biology of breast cancer has evolved significantly since the initiation of the START trials, such that assessments of biomarkers now common in today’s practice (status of estrogen and progesterone receptors, presence of human epidermal growth factor receptor 2) were not part of routine trial data collection. Likewise, little is known about the interaction between the fractionation scheme and breast cancer intrinsic subtype. A recent analysis of the Ontario Clinical Oncology Group (OCOG) hypofractionation trial, which evaluated tumor factors based on examination of the tissue blocks available for roughly 82% of patients enrolled, revealed subtype to be a predictor of local recurrence but paradoxically did not find women with triple-negative breast cancer to have a higher rate of local recurrence.[8] The analysis also attempted to replicate the findings from the original OCOG analysis[5] that showed an interaction between hypofractionated breast radiotherapy and high tumor grade. Although the trend was in the same direction, the interaction term did not reach statistical significance (P = .11), and this was perhaps related to the smaller sample size. Finally, the START B trial findings of significantly higher rates of distant relapse and all-cause mortality in the group receiving a 50-Gy total dose at 2 Gy per fraction compared with the hypofractionated 40-Gy-total-dose group are inexplicable and deserve further scrutiny. It is inconsistent that the 3.3% absolute mortality, as well as the proportional improvement in all-cause mortality in the hypofractionated arm compared with the 2 Gy–per-fraction arm, in START B is similar to results seen in the Early Breast Cancer Trialists Collaborative Group meta-analysis comparing breast radiotherapy to no breast radiotherapy.[2] This finding is even more perplexing considering that in START B the experimental hypofractionated arm is not dose-equivalent to the 50 Gy total dose at 2 Gy per fraction standard arm, but estimates to roughly 10% less dose, 45 Gy in 2-Gy fractions. Collectively, these issues illustrate that clinical practice has not yet reached the end of its learning curve regarding hypofractionated breast radiotherapy and cancer outcomes, and additional investigation is warranted.

The appearance of the breast is an important outcome for women who elect to conserve their breasts. For hypofractionated breast radiotherapy, the incidence of late effects and its historical direct relationship with fraction size was one of the primary concerns about this approach. The START and OCOG trials have not detected worse physician- or nurse-assessed late toxicity or effects on breast appearance as a result of hypofractionation. The OCOG trial demonstrated that cosmetic outcome worsened over time, but no significant differences were observed between radiotherapy groups.[5] At 10 years, 71.3% of women in the 2 Gy–per-fraction group as compared with 69.8% of women in the hypofractionated-radiation group had an excellent or good nurse-assessed cosmetic outcome. In contrast, in START A the 39-Gy-in-3.2-Gy-hypofractionation group had a statistically significant 6% lower rate of physician-assessed breast induration and edema compared with the 41.6-Gy-in-3.3-Gy-hypofractionation group or the 50-Gy-in-2.0-Gy-per-fraction group. Similarly, in START B, physician-assessed outcomes revealed 5% and 4% lower rates of breast shrinkage and breast edema, respectively, in the 40-Gy-in 2.7-Gy-hypofractionated arm.[6] However, patient-reported outcomes by 5 years, in a subset of those enrolled in the START A and B trials that were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) general cancer scale (EORTC CLQ-C30) and breast cancer (EORTC BR23) questionnaires, revealed no difference in breast-related reported outcomes by treatment arms. The most frequently reported adverse effects from breast radiotherapy post lumpectomy were breast hardness and overall change in breast appearance (with estimated 5-year rates of 41% and 39%, respectively).[9] In all radiotherapy regimens, the EORTC breast symptom subscale score declined significantly from baseline to assessment at 60 months (P < .0001), but no significant differences between regimens were noted in START A (P = .5558) or START B (P = .8757) post lumpectomy. The role of technical and patient factors that contribute to late breast effects, such as boost volume, dose heterogeneity, and body mass index, have not been fully examined for interaction with hypofractionation. As appropriately highlighted by Eblan et al,[1] the technical delivery of breast radiotherapy has evolved from the two-dimensional (2D) central axis approach utilized in the randomized controlled trials of hypofractionation. The potential impact of the technical delivery is illustrated by the results of a clinical trial in which 50 Gy at 2 Gy per fraction breast radiotherapy was randomly assigned to be delivered with “simple IMRT” vs 2D methods, similar to the approach utilized in the OCOG and START trials.[10] At 5 years, women who received breast radiotherapy post lumpectomy with “simple IMRT” had 18% fewer physician-assessed changes in their breast appearance. In addition, it is now hypothesized that certain genotypes are associated with more toxicity from radiation, and this introduces numerous additional potential factors to study for interaction with fraction size. Lastly, the 30% rate of fair-to-poor cosmetic outcomes on the OCOG trial and the 40% rate of patient-reported moderate or marked breast changes from START A and START B indicate that there is a lot yet to learn in order to meaningfully reduce the deleterious effects on the breast from all fractionation schedules.

One of the achievements of the hypofractionation trials is that they represented a departure from the “one size fits all” approach of post lumpectomy whole-breast radiotherapy that was rooted in the ≤-2-Gy-per-fraction delivery model for nearly 2 decades. It is ironic then that Eblan et al[1] seem to now endorse a new “one size fits all” approach based on hypofractionation, particularly in an era that has continued to demonstrate that biologically breast cancer is a heterogeneous disease. So far, clinical trials have demonstrated that a hypofractionated regimen is a good option for many women who require whole-breast radiotherapy post lumpectomy; however, there is also a need to learn more about the effect of hypofractionation on an individual patient’s breast cancer outcomes and tissue toxicities, based on both biologic and technical variables, so that the treatment decision is not primarily a matter of dollars and cents.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Eblan M, Zeman E, VanderWalde N, Jones E. Hypofractionation for breast cancer: lessons learned from our neighbors to the North and across the pond. Oncology (Williston Park). 2014;28:538-46.

2. Agarwal S, Pappas L, Kokeny K, et al. Effect of breast conservation therapy vs mastectomy on disease-specific survival for early stage breast cancer. JAMA Surg. 2014 Jan 15. [Epub ahead of print]

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials. Lancet. 2011;378:1707-16.

4. Owen JR, Ashton AA, Bliss JM, et al. Effect of radiotherapy fraction size on tumor control in patients with early-stage breast cancer after local tumor excision: long-term results of a randomized trial. Lancet Oncol. 2006;7:467-71.

5. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-20.

6. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardization of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomized controlled trials. Lancet Oncol. 2013;14:1086-94.

7. Smith B, Bentzen S, Correa C, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;81:59-68.

8. Bane A, Whelan T, Pond R, et al. Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy. Ann Oncol. 2014;25:992-8.

9. Hopwood P, Haviland JS, Sumo G, et al. Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. Lancet Oncol. 2010;11:231-40.

10. Donovan E, Bleakly N, Evans P, et al. Randomized trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol. 2007;82:254-64.