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Data support accelerated radiotherapy as standard of care for breast cancer

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January 8, 2019

Benjamin Smith
Benjamin D. Smith

When followed by a tumor bed boost, hypofractionated and conventionally fractionated whole-breast irradiation appeared to yield comparable 3-year outcomes among patients with breast cancer, according to a randomized noninferiority phase 3 study published in Journal of Clinical Oncology.

Thus, hypofractionated whole-breast irradiation (HF-WBI) should be the standard of care regardless of tumor bed boost, chemotherapy and larger breast size.

“Our study adds to the existing literature additional evidence relevant to recent patients treated in the United States, confirming prior trials that demonstrate HF-WBI is similar to conventionally fractionated [CF]-WBI with regard to tumor control and side effect profile,” Benjamin D. Smith, MD, associate professor in the radiation oncology department at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “We specifically showed that HF-WBI was similar, if not better than, CF-WBI among patients with large breasts, specifically D cup or larger. Previously, there was controversy as to whether or not HF-WBI would still be safe in patients with large breasts.”

ASTRO guidelines recommend HF-WBI for patients with breast cancer of all ages, tumor stages and chemotherapy exposures. Still, there has been a reluctance among U.S. clinicians to adopt HF-WBI, partially due to cosmetic outcomes of this procedure, especially when used with a tumor bed boost or for women with larger breast sizes who undergo chemotherapy.

Smith and colleagues evaluated 287 women with stage 0 to stage 2 breast cancer who were enrolled at MD Anderson Cancer Center and four nearby centers between February 2011 and February 2014. Eligible participants were aged 40 years or older, had stage Tis-T2N0-N1M0 breast cancer, and were treated with margin-negative segmental mastectomy.

Researchers randomly assigned women to undergo CF-WBI (n = 149) — 50 Gy in 25 fractions — or HF-BWI (n = 138), 42.56 Gy in 16 fractions. Randomization was stratified by baseline physician-evaluated cosmesis, bra cup size, chemotherapy receipt, margin status and location of treatment.

The percentage of patients with an adverse cosmetic outcome 3 years after treatment — according to a score of 2.5 or higher on the Breast Cancer Treatment Outcomes Scale — served as the study’s primary endpoint.

Median follow-up was 4.1 years.

Overall, 286 patients received the protocol-specified radiation dose, 30% underwent chemotherapy and 36.9% were classified as having large breast size.

Researchers found that at 3 years, adverse cosmetic outcomes were 5.4% lower with HF-WBI (P for noninferiority = .002); absolute risks were 8.2% (n = 8) with HF-WBI and 13.6% (n = 15) with CF-WBI.

Patients treated with chemotherapy and HF-WBI had a 4.1% higher rate of adverse cosmetic outcomes (90% upper confidence limit, 15%), leading to inconclusive noninferiority results for this subgroup.

Among patients with large breast size, adverse cosmetic outcomes were 18.6% lower (90% upper confidence limit, –8%) with HF-WBI vs. CF-WBI.

Researchers observed no difference in 3-year poor or fair photographically evaluated cosmesis (28.8% vs. 35.4%) and 3-year local RFS (99% for both) between the CF-WBI and HF-WBI groups.

“Our study has helped to change our practice at MD Anderson,” Smith told HemOnc Today. “We now treat over 90% of our patients with HF-WBI. We believe our study findings, which strongly support the new ASTRO guideline on whole-breast irradiation, should lend additional evidence to support widespread adoption of the ASTRO guideline recommendations.” – by Jennifer Byrne

For more information:

Benjamin Smith , MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, Building 318, 1515 Holcombe Blvd., Houston, TX 12345; email: bsmith3@mdanderson.org.

Disclosures : The study was supported by a Career Development Award from ASCO’s Conquer Cancer Foundation funded by the Breast Cancer Research Foundation. Smith reports research funding from Varian Medical Systems He also reports having an equity interest in Oncora Medical as part of a partnership agreement. Please see the study for a list of all other authors’ relevant financial disclosures.

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Gary Freedman, MD
Perspective

In 2011, ASTRO published a cautious consensus statement that supported hypofractionation only in a population of women who made up a majority of those enrolled on four randomized trials from Canada and the U.K. — women aged 50 years or older with T1 to T2 and N0 disease, no systemic chemotherapy, radiation to the breast only and no tumor bed boost.

For perspective, imagine if we had spent the decade of the 1990s to 2000s recommending mastectomy for women who had sentinel node biopsy, doxorubicin or taxane-based chemotherapy, lobular or tubular cancers, or who were aged younger than 50 years or older than 70 years, because they were underrepresented on the randomized breast conservation vs. mastectomy trials!

So, the trial reported by Shaitelman and colleagues represents a very timely effort in the 2011 to 2014 period to address these concerns about hypofractionation in selected underrepresented subgroups. The researchers chose cosmesis as the main endpoint of their phase 3 trial — correctly, in retrospect, because the main concern about hypofractionation is based on possible differences in toxicity rather than tumor control. 

The trial has provided very important data supporting use of hypofractionation in many subgroups that were not endorsed by the 2011 ASTRO consensus statement, such as tumor bed boost, large breast size and ductal carcinoma in situ. The use of a boost in this trial was mandated in both arms of the study.

The overall study finding showed the number of patients with an adverse cosmetic outcome was low at 3 years, and lower with hypofractionation, concordant with the results of U.K. START trials (now out to 10 years).

Only 8% and 14% had adverse cosmetic outcomes in the two arms, which appeared much lower than their expected 35% to 40% before the trial started. This is very supportive that the routine use of a boost with hypofractionation has no additional toxicity compared with when used with conventional fractionation.

Large breast size had historically been associated with increased skin and soft tissue toxicity and worse cosmetic outcomes with conventional standard tangential radiation. For this reason, the Canadian trial specifically excluded women with breast separation larger than 25 cm. However, since then, there have been significant advances in tangential radiation positioning and treatment planning that have been able to improve dose homogeneity and reduce skin and tissue complications. For example, the current trial allowed prone positioning and used field-in-field forward planning to keep the hot spot at 108% or less. By enrolling over one-third of women with large breast size, and showing that adverse cosmesis was actually 19% lower with hypofractionation,  the current trial adds important prospective data to the existing randomized trials and further dismantles a perceived size barrier to hypofractionation.

Also, women with pure DCIS were included in both arms of this trial — but not the earlier hypofractionation trials — and there were no significant differences in this subgroup, either.

The current study also adds to the existing phase 3 data for hypofractionation with chemotherapy, or for those age younger than 50 years, but less conclusively. In this trial, 30% received neoadjuvant or adjuvant chemotherapy — none concurrent with radiation — and all had more modern anthracycline- or taxane-based regimens than earlier trials. Researchers reported a modest 4% increase in adverse cosmetic outcomes with hypofractionation vs. conventional hypofractionation, but the upper confidence limit exceeded 10%, so Shaitelman and colleagues could not conclude noninferiority.

These inconclusive data may not settle those with remaining concerns about hypofractionation after chemotherapy, but, even if a real effect (given the overall very low 8% incidence of adverse outcomes in the hypofractionation arm), I think it is likely to be small and not of clinical significance. The concern for hypofractionation in young women may be due to physician or patient concern about a long life expectancy so that 15- or 20-year data are needed, or that women aged younger than 40 years are more likely to remain concerned about cosmesis for 20 years compared with a woman getting radiation in her 60s. Only 11% on this trial were aged younger than 50 years, and none were younger than 40 years, which is actually less representation than the earlier randomized trials. More data in both of these subgroups would be useful to further expand use of hypofractionation.

In summary, whole-breast hypofractionation is now standard practice in the United States and supported by large prospective data for the majority of women treated by lumpectomy.  Although adoption in the 2010 to 2018 period has been slow in the U.S., it should continue to increase as more data like this from Shaitelman and colleagues study is published. Their study supports use of hypofractionation in women treated with tumor bed boost, DCIS, large breast size and nonconcurrent chemotherapy — groups that are now also fully endorsed by the updated ASTRO consensus statement of 2018. In my practice, the utilization of hypofractionation after lumpectomy is now greater than 90%.

Gary M. Freedman, MD

Perelman School of Medicine at University of Pennsylvania

Disclosure: Freedman reports no relevant financial disclosures.