Shorter radiation course at higher doses may be beneficial

A shorter course of radiation therapy at higher doses per fraction than the standard regimen could reduce side effects and improve quality of life for some patients with breast cancer.

For patients with early-stage breast cancer who undergo breast-conserving therapy, the standard treatment regimen includes 6 weeks of whole-breast irradiation (WBI). However, the results of a recent clinical trial suggest that hypofractionated WBI, which involves fewer radiation fractions at higher doses per fraction but a lower total dose, causes fewer short-term side effects and lower rates of fatigue.

Hypofractionated WBI

The efficacy of hypofractionated WBI is well established. In the early 2000s, four large randomized controlled trials in Canada and the United Kingdom compared 3–4-week courses of hypofractionated WBI with 5–6-week courses of conventionally fractionated WBI and showed that the outcomes were similar with regard to tumor control, patient survival, and side effect profiles. At 10 years’ follow-up, the outcomes were still comparable.

Because the protocols of some of the trials did not include a radiation boost, which is standard in the United States, there were concerns about the applicability of the results to U.S. patients. Thus, hypofractionated WBI has not been widely adopted, and only 20% of eligible patients in the United States currently receive hypofractionated WBI instead of the longer course of conventionally fractionated WBI.

The slow adoption of hypofractionated WBI continues despite the 2011 publication of guidelines for the use of hypofractionated WBI. The guidelines, developed by a task force from the American Society for Radiation Oncology (ASTRO), were based on prior clinical studies showing that hypofractionated WBI was equivalent to conventionally fractionated WBI for patients 50 years or older who had pathologic stage T1–2 N0 breast cancer and had not received systemic chemotherapy.

The authors of the ASTRO guidelines noted that more research was needed to determine the role of hypofractionated WBI for patients with other characteristics and whether toxic effects differ between conventional and hypofractionated WBI delivered in conjunction with chemotherapy or a radiation boost.

Clinical trial

To clarify the appropriate use of hypofractionated WBI, researchers at MD Anderson established a clinical trial comparing long-term cosmetic outcomes and short-term toxic effects between hypofractionated and conventionally fractionated WBI.

The study population was more diverse than those of previous studies from Canada and the United Kingdom and included patients who were undergoing chemotherapy with anthracyclines or taxanes, had received neoadjuvant chemotherapy, or had ductal carcinoma in situ.

Eligible patients were women 40 years and older with ductal carcinoma in situ or early invasive breast cancer that was defined pathologically as Tis, T1, or T2 and N0, N1mi, or N1a. All patients had undergone breast-conserving surgery with negative surgical margins. Patients with more than three involved axillary lymph nodes were ineligible, as were those for whom regional lymph node irradiation was planned via the addition of a third field.

A total of 287 patients were enrolled from 2011 to early 2014 and randomly assigned to receive conventionally fractionated WBI (50 Gy in 25 fractions followed by a tumor bed boost of 10–14 Gy in 5–7 fractions) or hypofractionated WBI (42.56 Gy in 16 fractions followed by a tumor bed boost of 10.0–12.5 Gy in 4–5 fractions).

“Dogma suggests that low daily doses that accumulate to a high total dose give the best result, but what we’ve proposed is a higher dose per treatment for a lower total dose,” said Benjamin Smith, M.D., an associate professor of Radiation Oncology and the trial’s principal investigator. Co-investigators on the trial were Simona Shaitelman, M.D., an assistant professor of Radiation Oncology, and Thomas Buchholz, M.D., MD Anderson’s Executive Vice President and Physician-in-Chief, who is also a professor of Radiation Oncology.

Overall, the rates of acute toxic effects of grade 2 or higher were significantly lower among patients who received hypofractionated WBI than in patients who received conventionally fractionated WBI. Specifically, patients who received hypofractionated WBI had significantly lower rates of grade 2 or higher dermatitis, pruritus, breast pain, hyperpigmentation, and fatigue.

At baseline, patients in both arms had similar physical well-being and self-reported fatigue as assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. However, 6 months after completing radiation therapy, the patients who received hypofractionated WBI had better physical well-being and self-reported fatigue scores on the FACT-B than did those who received conventionally fractionated WBI. Oncologic outcomes, to date, are similar in the two arms.

“These were the first real data that the 4-week regimen was not just equivalent to the longer regimen in terms of oncologic outcomes but better in terms of side effects — especially fatigue,” Smith said. “In addition to the benefits of reduced side effects and improved overall quality of life, the treatment plan is decreased by 2 weeks, which the average patient prefers.”

The results of the study were presented by Shaitelman in September at ASTRO’s annual meeting in San Francisco and will be submitted for publication later this year.

Moving forward

Even as patients in the trial continue to be monitored for long-term cosmetic outcomes, Smith and his colleagues hope to build on the results of this study to open a randomized clinical trial to assess hypofractionated WBI in patients who do not meet the current ASTRO guidelines for such treatment.

This article originally appeared in the January 2015 issue of OncoLog.