'Mounting Evidence' for Hypofractionation in Breast Cancer

Alexander M. Castellino, PhD

August 06, 2015

Radiation oncologists treating women following surgery for early-stage breast cancer have a choice between hypofractionation (HF) (shorter courses of radiation given in larger daily fraction sizes) and conventional fractionation (CF) radiotherapy.

Although the American Society for Radiation Oncology (ASTRO) has urged the use of HF–whole breast irradiation (HF-WBI) for women aged 50 years and older on the basis of category 1 evidence, its adoption has been slow.

Now, two complementary articles published in JAMA Oncology on August 6 provide further evidence that HF is associated with less toxicity and provides women with a better quality of life compared with CF.

"The mounting evidence supporting hypofractionation can no longer be ignored," say experts in an accompanying editorial.

"With comparable tumor control, lower costs, and reduced morbidity, hypofractionation should be strongly considered for the majority of patients with early-stage disease," write Shyam K. Tanguturi, MD, the Harvard Radiation Oncology Program, Boston, and Jennifer R. Bellon, MD, of the Dana-Farber Cancer Institute, Boston.

Randomized Study Details

The randomized trial was from the MD Anderson Cancer Center, in Houston, Texas, and showed that women receiving HF-WBI may experience lower toxic effects, feel less tired, and have less trouble meeting family responsibilities.

Benjamin D. Smith, MD, and his colleagues from the Department of Radiation write: "[Our] findings should be communicated to patients as part of shared decision making regarding election of radiotherapy regimen."

The study was conducted in 287 women aged 40 years and older with early-stage breast cancer (stage 0-2), who were randomly assigned to receive either HF-WBI (42.56 Gy in 16 fractions of WBI; n = 138) or CF-WBI (50.00 Gy in 25 fractions of WBI; n = 149).

The rate of physician-assessed toxicity of grade 2 or higher was significantly lower for women receiving HF-WBI (47% vs 78%; P < .001), as were acute toxic effects of grade 3 of higher (0% vs 5%; P = .01). In particular, rates for physician-assessed fatigue, pruritus, breast pain, and dermatitis were significantly lower for women receiving HF.

Although patient-reported quality of life, as reported from the Functional Assessment of Cancer Therapy for Patients with Breast Cancer, was similar for women receiving HF and CF, items associated with lack of energy and trouble meeting family needs favored women receiving HF.

"No measured adverse effects or QOL parameters were worse with HF-WBI compared with CF-WBI," Dr Smith and colleagues write.

Real-World Study Details

The real-world, community based study was based on data from the Michigan Radiation Oncology Quality Consortium (MROQC).

The authors, led by Reshma Jagsi, MD, DPhil, from the Department of Radiation Oncology at the University of Michigan Medical School, Ann Arbor, conclude that HF not only improves convenience but is also associated with less acute pain, fatigue, and dermatitis.

Dr Jagsi and colleagues prospectively analyzed data from a cohort of women with breast cancer registered by MROQC — a radiation-specific statewide patient registry used as a model for generating high-quality, generalizable data from the community setting.

Of 2605 patients who received radiation therapy following lumpectomy, the analysis included 2309 patients for whom a physician toxicity evaluation (done within 1 week of radiation) was available: of these, 578 women received HF, and 1731 received CF.

The analysis showed that fewer women who received HF experienced grade ≥2 breast pain (5.9% vs 20.0%; P = .003), dermatitis (27.4% vs 62.6%; P < .001), skin induration (13.7% vs 21.1%; P = .01), and chest pain (6.8% vs 18.5%; P < .001).

"Overall, patients receiving conventional fractionation were much more likely to experience at least 1 grade 2 or greater toxic effect during treatment than those treated with hypofractionation,” Dr Jagsi and colleagues write.

Patients receiving HF were also less likely to experience moderate to severe breast pain, moist or dry desquamation, bother from skin stinging or burning, bother from hurting in the treated breast, and fatigue.

"[Our data suggest] that selection of radiation fractionation schedule may affect incidence of acute, treatment-related toxic effects of adjuvant whole-breast radiotherapy, which may compromise patients' quality of life during this challenging period," Dr Jagsi and colleagues write.

"This study provides information about the frequency and nature of acute toxic effects during whole-breast hypofractionated radiotherapy, highly relevant to women considering this treatment and absent from the literature to date," the authors write.

"Given the importance of patient-reported outcomes and generalizable evidence of comparative effectiveness from patients treated outside the context of clinical trials, it provides a complement to the findings of randomized trials and encourages enthusiasm for this innovative approach," they conclude.

Hypofractionation Can No Longer Be Ignored

In their commentary, Dr Tanguturi and Dr Bellon write: "In the last 5 years, mature follow-up analyses of randomized trials have been published offering fundamental insight into questions of dose and fractionation in breast cancer radiotherapy."

Two landmark studies — one in the United Kingdom and one in Canada — have shown that HF given during a 3- to 4-week period resulted in comparable disease control rates and overall survival at 10 years compared with CF.

One of ASTRO's five recommendations for the Choosing Wisely campaign recommends "not to initiate whole breast radiation therapy as a part of breast conservation therapy in women age ≥50 with early-stage invasive breast cancer without considering shorter treatment schedules."

Only 1 in 3 women receive HF as adjuvant therapy for early-stage breast cancer, as indicated from the study of Dr Jagsi and colleagues and from another observational cohort study.

When asked why HF is not provided to women as guidelines suggest, Dr Bellon said: "I think this is likely multifactorial. Some likely want additional mature data showing equivalency to conventional fractionation. Some physicians may be concerned that the side effects are greater with hypofractionation. Both of these studies will hopefully help allay these doubts."

"Finally, there is the possibility that some [physicians] might be swayed by the financial incentives of longer courses of treatment," she added.

Dr Bellon indicated that the oncology community must be alerted to the advantages of HF from a number of sources. Additional data from large randomized efficacy trials, quality-of-life studies, such as these now published in JAMA Oncology, as well as ongoing lectures at scientific meetings and incorporation into national guidelines will provide further support, she said.

"Ultimately, the demand will also come from patients when they hear more about shorter treatments on the Internet and in the lay press," Dr Bellon added.

Medscape Medical News also asked Dr Bellon to comment on whether breast size would preclude women from receiving HF radiation. "Breast size is still a concern," she said.

"However, the MD Anderson study is reassuring, as it did not exclude patients on the basis of body habitus," Dr Bellon said.

"Even with modern radiation treatment planning, it can be difficult to achieve an even distribution of the radiation dose in women with a high body mass index and/or large breast size. The concern is that hypofractionation coupled with large 'hot spots' can potentially lead to chronic breast or chest wall pain and a poorer cosmetic result," Dr Bellon told Medscape Medical News.

The MD Anderson study also addresses the concern that large women may not be receiving HF radiation. The authors write: "Limited adoption of HF-WBI in the United States has been attributed in part to concerns regarding the applicability of the available evidence to practice patterns in the United States, where use of a tumor bed boost is much more common and where higher prevalence of obesity may result in fewer patients meeting the dose homogeneity or central axis separation criteria applied in the randomized trial literature."

"Within this context, results from our trial provide strong reassurance that HF-WBI with a sequential tumor bed can be safely administered with regard to acute and short-term toxic effects in a patient population where three-quarters of patients were overweight or obese," they add.

A concern expressed by Dr Bellon was that the follow-up was not uniform, in that all patients were not followed at the same time after finishing treatment.

"It's possible that the acute toxicity was more prominent after radiation finished for patients receiving hypofractionation, but a time point not captured by the investigators," she told Medscape Medical News.

"In contrast, patients with conventional fractionation may have had more toxicity during treatment, when they would be more closely followed," she added.

However, Dr Tanguturi and Dr Bellon were complimentary about the quality-of-life measures captured in the studies. "We applaud these authors for incorporating prospectively collected quality-of-life measures as their primary end points in a field that has traditionally underemphasized and undervalued patient experience and patient-reported outcomes," they write.

Several investigators at the MD Anderson Cancer Center receive grant funding and honoria from industry. Dr Jagsi and colleagues report no relevant fal relationships.

JAMA Oncol. Published online August 6, 2015.

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