Hypofractionation is a proven safe and effective modality for postoperative whole‐breast radiotherapy for early breast cancer patients

Arguing against the Proposition is Alan Rodger, MB, ChB. Dr. Rodger held the post of Professor and Medical Director of the Beatson West of Scotland Cancer Centre in Glasgow from 2003 until he retired in 2009. An Edinburgh graduate, he trained in surgery and clinical oncology, completing training at the M. D. Anderson Cancer Center. He specialized in breast cancer in the Edinburgh Breast Unit and then, in 1992, he took up the foundation posts of Director of Radiation Oncology at the Alfred Hospital and Professor of Radiation Oncology at Monash University, Melbourne, Australia, returning to Scotland in 2003. He is a member of the Cochrane Breast Cancer Editorial Group, Radiotherapy Specialty Editor for The Breast, and an International Advisor to the National Breast and Ovary Cancer Centre of Australia. His writing focuses on evidence-based clinical oncology. Hypofractionation applied to the whole breast in the modern era is safe and effective because of advances in technology that build on clinical experiences.1 Recent randomized radiotherapy trials in Canada and the UK with a decade or longer follow-up demonstrate that hypofractionation, higher than standard radiation doses delivered over fewer than standard number of fractions, postoperatively to whole breast gives at least comparable tumor control and late irradiation morbidity as does conventional fractionation for patients with early breast cancer.2,3 The supposed benefits of a classical multiple 1.8 or 2 Gy fractionation schedule are predicated on (1) the possibility of “reoxygenating” hypoxic tumor regions, and/or (2) exploiting differences in radiation repair capacities of adjacent late responding normal tissues and tumor, typically characterized as having ratios of 3 and 10 Gy, respectively; apparently neither factor limits the efficacy of hypofractionation radiotherapy. Regarding reoxygenation, radiotherapy-induced changes in the oxygen distribution resulting from the particular hypofractionation schedules employed are either similar to the conventional schedule or, alternatively, hypoxia may not be a limiting issue as has been argued to explain the unexpectedly high responses of tumors of the brain and lung following single fraction radiation.4 The recent breast cancer hypofractionation studies provide measures of tissue fractionation sensitivities, ratios, for soft tissue and breast cancer that were found to be similar and small, in the range of 3–4 Gy, suggesting that the radiation response of both breast cancer and normal breast are characterized by a relatively large proportion of repairable radiation lesions (small ratio).5 The benefit of a reduced number of fractions in addition to patient convenience is improved efficiency of delivery and less cost. From a radiobiological perspective, the intensification of treatment has benefits beyond the reduced time available for tumor growth during treatment. First and foremost, tumors respond better than theoretically expected with hypofractionation as evidenced for a variety of tumors including breast cancer. It has been hypothesized that a “new biology” governs tumor response to high dose radiation, especially focal radiation.4,6 Experimental evidence indicates that tumor response is affected by adjacent irradiated tumor through autocrine and paracrine factors via a bystander effect and/or by the response of nontumor cells, especially normal tissue stroma.4 It has been hypothesized that tumor response is influenced by the volume of normal tissue exposed, heterogeneity of radiation dose,4 and the unexpected radiation sensitivities of vasculature and/or cancer stem cells.6 Of particular current interest are the benefits of hypofractionation schedules combined with strategies to sensitize tumor and/or mitigate normal tissue injury. New preclinical evidence suggests that the effectiveness of both radiosensitization and radiation mitigation strategies improve under hypofractionation conditions; early clinical results show both approaches are safe.7,8 Consequently, although hypofractionation is a proven safe and effective modality for postoperative whole-breast radiotherapy for early breast cancer patients, the therapeutic advantage of this strategy is expected to improve even further. In conclusion, hypofractionation radiotherapy is safe and efficacious in contrast to what is expected from radiobiology theory and what is predicted from the results of historical clinical experience. This Proposition fails on two grounds: “Hypofractionation” is neither defined nor specific enough to permit its general recommendation; and the data on clinical effect are immature. The START Trialists’ Group9 defined hypofractionation as an “alternative schedule (of radiotherapy) based on a lower total dose delivered in fewer, larger fractions.” They allude to the use of such schedules over decades. Yet many of the earlier schedules did not reduce total dose.10 Hypofractionation embraces a plethora of schedules, doses, and fractionations: Daily and less than daily, shortened or “standard” overall treatment time, and fraction doses from just over 2 Gy to several times that, with doses selected empirically,11 clinically,10 or radiobiologically.3,13 The standard is 50 Gy in 25 daily fractions over 5 weeks, yet there is no randomized trial evidence justifying its elevated position. Hypofractionation is, therefore, any schedule of dose, fractionation, and duration delivered in less than 25 daily fractions. It cannot then be that hypofractionation is proven safe and effective. Second, “proven” demands proof. The minimal level of proof is evidence from a well-conducted randomized controlled trial (RCT) of superiority, or no inferiority, for all acute and late toxicity and for clinical effect. For whole-breast radiotherapy, the normal tissues are skin and subcutaneous fat, muscle, ribs, neural tissue, upper limb, and vascular tissue such as coronary arteries and great vessels. Clinical effectiveness is measured against the end points of overall survival, cause-specific survival, and local (and/or regional) recurrence. Only three RCTs qualify for consideration: The START A and B9,12 and Canadian13 trials. Between them they compared four different dose/fractionations against the standard in 5685 women. Median follow-ups were 61,12 69,13 and 729 months. Overall survival and cause-specific survival were not reported in detail in the START trials9,12 but overall survival was documented in the Canadian trial.13 While there is, as yet, no significant survival difference, the follow-up is too short to be categorical. Local recurrence was the same, but again at relatively short follow-up. My concerns with these trials are short follow-up and lack of prospective assessment of late toxicity. While the trials assiduously measured cosmesis, late toxicity is affected by both surgical and radiotherapy factors. Only the latter was assessed in these trials. Acute and late skin and subcutaneous effects were expertly assessed. For lung and rib damage, the trials recorded only symptomatic patients: No prospective radiological assessment was employed. Yet it was shown that radiological assessment detected a higher incidence of radiation-induced osteonecrosis than expected.11 Of more significance is late cardiotoxicity, the lag period for which is 10 years.14 Lastly, the Canadian study13 excluded nearly 2500 patients before randomization some because their breasts were considered too large. Many advocate hypofractionation use only when volume is taken into account and dose-compensating schemes are implemented.15 This Proposition fails because hypofractionation is too nonspecific a term and because the proof of effectiveness is immature and inadequate regarding prospectively measured late toxicity. Benefits of hypofractionation for postoperative whole-breast radiotherapy for early breast cancer patients that are not in dispute are improved patient convenience, less treatment costs, potentially less acute toxicity and, when assessed at five years, its effectiveness compared to standard schedules. At odds are the definition of hypofractionation and its long-term safety. Unfortunately on both counts, my esteemed colleague's arguments are flawed because he confuses proof of concept with optimization. Contrary to Dr. Rodger's view, hypofractionation is unambiguous. It is defined as “radiation therapy that gives larger doses (fractions) of radiation in fewer treatment sessions and over a shorter period of time than standard radiation therapy.”16 My assertion is that many hypofractionation schedules may be efficacious and safe; only one long-term study is needed for the proof of concept. The results of the Canadian study that my colleague uses to support his case compares 42.5 Gy, 16 fractions, 22 days to the standard, 50 Gy, 25 fractions, 35 days.2 The median follow-up at 144 months presented late last year demonstrates that hypofractionated whole-breast irradiation provides excellent long-term local control and limited late morbidity, similar to that seen with conventional fractionation for whole-breast irradiation.17 Future optimization will likely demonstrate further safety and improved efficacy as alternate fractionation schedules are tested that maximize tumor and minimize normal tissue responses. In addition, tumor radiosensitizers, such as the gene therapy approach developed at Henry Ford Hospital in Detroit,18 and normal tissue radioprotectors that function on intrinsic cellular radiation sensitivities (i.e., not the cell's repair capacity), examples of which are being developed under the NIH-sponsored Centers for Medical Counter Measures Against Radiation Injury,19 appear to be more effective under hypofractionated than standard schedules. In summary, the current studies employing hypofractionation for the treatment of breast cancer are of sufficient duration to declare that hypofractionation is both safe and effective; future optimizations are possible building on clinical experiences and radiobiological advances. My eminent opponent fails to persuade me. His claims that recent randomized trials have decades of follow-up are wrong, as I showed in my initial statement. Long-term toxicity data are not yet available. His radiobiological arguments are dubious and confused. While hypoxia may be an issue in inoperable breast cancer, it is unlikely to be relevant in a breast from which an early cancer has been fully excised. I accept that the UK START Trials provide radiobiological evidence that the ratio for breast soft tissue and breast cancer cells may be similar, but my opponent makes the mistake of then extrapolating data from fractionated schedules to single fraction treatments. There is, as yet, no randomized trial evidence to justify recommending single fraction radiotherapy to the breast. The randomized trials of intraoperative radiotherapy and of brachytherapy techniques are incomplete. That they may be common practice in some centers is no justification. While preclinical evidence of the possible effectiveness of radiosensitizers or radiation mitigation strategies in conjunction with hypofractionated schedules is undoubtedly interesting and, while early clinical results suggest safety, for these there are no long-term data on effectiveness and safety from randomized trials. This is an argument for further research, not a wholesale change in practice. The last supporting argument for the motion is based on convenience and reduced cost. It would be ground breaking indeed if those reimbursed on a fee-for-service basis were to embrace hypofractionation. Perhaps this explains why the trials of fractionated hypofractionation were pursued in Britain and Canada. Less treatment over fewer days is always worthwhile—provided it is safe and it works. Those objectives can only be proven by well-conducted randomized trials with sufficient follow-up. We have excellent trials and some continue, but we need more time. It is too early to say that “hypofractionation is a proven safe and effective modality…for early breast cancer.”

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