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Hypofractionated Radiation Therapy in Breast Cancer: A Revolutionary Breakthrough or a Long Way to Go?

Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India

To the Editor:

A revolutionary breakthrough might be on the horizon in breast carcinoma treatment. This disease is the leading cancer in women,¹ and radiation therapy is an integral part of management in all breast conservation surgeries (BCSs) and for a large percentage of postmastectomy patients. Throughout the world, radiation therapy centers are struggling to keep pace with the ever-growing need for radiation therapy in patients with breast carcinomas.

A typical course of radiation therapy lasts for 6 weeks in post-BCS patients and nearly 5 weeks for postmastectomy patients. Conventionally, a dose per fraction per day of 1.8 to 2 Gy has been used in treatment of breast cancer, stemming from concern that fraction sizes of larger than 2 Gy might increase the likelihood of the late effects on healthy tissue toxicity and impairing cosmesis in BCS patients.² A number of reports of cosmetic assessment with schedules using 1.8 to 2.0 Gy per fraction have been published with 60% to 90% of patients reporting good to excellent cosmetic outcome.³

Therefore, a technique which reduces the treatment time by half (3 weeks instead of the present 6 weeks) while maintaining cosmetic and control rates needs to be viewed with great interest. In this context, recent studies examining examine 13 to 16 fractions of hypofractionated radiation therapy (using larger dose per fraction) compared with the present 25 fractions are providing crucial supportive evidence.^4-6

Two important randomized trials have evaluated the issue of hypofractionation in breast cancer. The first randomized trial by Whelan et al⁴ studied 1,234 patients with early-stage, lymph node-negative breast cancer treated with BCS in which they compared two fractionation schedules (42.5 Gy in 16 fractions and 50 Gy in 25 fractions) with doses per fraction of 2.6 Gy and 2 Gy, respectively. Baseline cosmesis at start of radiation therapy (83.8% in short-term arm and 82.6% in long-term arm) was comparable with the post-radiation therapy cosmesis. Their study supported the use of a shorter course of radiation therapy for patients with the most favorable infiltrating ductal carcinomas.

For the past few years, Yarnold et al from United Kingdom have been studying hypofractionated radiation therapy regimens to determine the optimal schedule for radiation therapy in BCS.⁶ In their recently reported trial, they analyzed 1,410 women with T1 to T3 N0 to N1M0 invasive breast cancer who were randomly assigned into one of three radiation therapy regimens: 50 Gy radiation therapy given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions. The primary end point was late change in breast appearance compared with postsurgical appearance, scored from annual photographs blinded to treatment allocation. They determined an /β value of 3 Gy for late normal tissue adverse effects changes in the breast by demonstrating an equivalence in the effects produced by a regime of 42.5 Gy in 13 fractions (3.2 Gy per fraction) and 50 Gy in 25 fractions (2 Gy per fraction) over 5 weeks.

Besides equivalence in cosmesis and palpable induration, hypofractionation should also prove itself in terms of an equivalent or superior local control rate and survival. Since the /β of breast cancer cells itself is being figured to be around 4 (which means that the tumor cells will be killed more by high dose per fraction compared with conventional 2 Gy per fraction), hypofractionated regimens should perhaps be more effective for local control of breast cancer. This may be difficult to prove because the local control rates with radiation therapy are already high, especially in early breast cancer. It is also known that although there is a 50% relative increase in local control rate for each 15 Gy over 50 Gy, in absolute terms the difference would be only 2% to 3%.⁷ The United Kingdom group has recently updated the local control rates with the hypofractionated regimens.⁸ The risk of ipsilateral tumor relapse after 10 years was 12.1% in the 50 Gy group, 14.8% in the 39 Gy group, and 9.6% in the 42.9 Gy group. There was no statistical difference in control rates between the control group and the two experimental arms. Earlier, Whelan et al⁴ also reported a 5-year local relapse-free survival of 96.8% after 50 Gy/25 fractions and 97.2% after 42.5 Gy/16 fractions (no statistical difference).

These successes of hypofractionated radiation therapy may sound like music to oncologists, planners of oncology resources, and patients with breast cancer, but cautionary notes should be sounded.¹⁰ These studies have not been without flaws. The United Kingdom group⁹ used conventional fractionation (14 Gy in seven fractions) for the local boost, which defies basic radiation therapy logic. This also appears contrary to the very hypothesis proposed in the article, which is that use of higher dose per fraction is better than, or at least equivalent to, conventional fractionation.⁹

In the Whelan et al⁴ study, more than one third patients were excluded because of presence of invasive or intraductal carcinoma at the inked margin of excision or the presence of large breast size. Thus, the results may not apply to women with large breasts. Also a very favorable subset of patients was taken into the study, limiting the generalization of the findings.

Further, it is an elementary principle of radiobiology that the late effects are strongly dependent on dose per fraction, so that the higher the dose per fraction (as is the case with hypofractionated regimens), the greater the susceptibility of healthy tissues to radiation therapy. Data on late lung and cardiac morbidity and survival rates has yet to emerge for the current hypofractionation schedules. Even with conventional fractionation, the Early Breast Cancer Trialists' Collaborative Group reported that radiation therapy reduced the annual mortality from breast cancer by 13%, but increased the annual mortality rate from other causes by 21%, and that this increase was due primarily to an excess number of deaths from cardiovascular causes.¹¹ Hypofractionation has the potential of making these figures worse. Furthermore, the cardiac adverse effects may not emerge until 15 years after treatment, and persist well beyond this period. Besides the cardiovascular effects, the final benchmark of success of the hypofractionation approach—overall survival—has not yet been reported for patients treated with hypofractionated regimens.

For reliable estimates of the fractionation sensitivity of breast cancer, results of the United Kingdom Standardization of Radiotherapy (UK START) trial A of 2,236 patients (International Standard Randomized Controlled Trial No. 59368779) are eagerly awaited, which includes randomized comparisons of 41.6 Gy in 13 fractions of 3.2 Gy and 39.0 Gy in 13 fractions of 3.0 Gy over 5 weeks with a control schedule of 50 Gy in 25 fractions of 2.0 Gy. The results of the UK START Trial B, which randomly assigned 2,215 women to 40 Gy in 15 fractions over 3 weeks or to 50 Gy in 25 fractions over 5 weeks, will attempt to confirm the findings of the Toronto trial. The other current endeavors include the randomized United Kingdom FAST trial, which compares two doses (5.7 Gy and 6.0 Gy) in 5 fractions over 5 weeks with a control dose of 50 Gy in 25 fractions.¹²

To summarize, hypofractionation in breast cancer is an issue that can have widespread implications in breast cancer throughout the world. If found to have equivalent cosmesis, locoregional control, and survival to standard doses and schedules, it would be a revolutionary breakthrough for the future for breast cancer. Unfortunately, the demonstration of all of these would need follow-up data nearing 15 years. For now, the general acceptance of hypofractionation in breast cancer hangs in the balance.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

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9. Touboul E, Belkacemi Y, Lefranc JP, et al: Early breast cancer: Influence of type of boost (electrons vs iridium-192) on local control and cosmesis after conservative surgery and radiation therapy. Radiother Oncol 34:105-113, 1995[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Munshi, A. Articles by Budrukkar, A. Search for Related Content PubMed Articles by Munshi, A. Articles by Budrukkar, A. Social Bookmarking                            What's this?