Scientists have found that radiation therapy, often a follow-up after breast cancer surgery and which has unpleasant side-effects, may not be needed by older patients, whose overall survival, they said, won’t be harmed without the treatment.
The therapy did, however, reduce the risk of cancer returning in the same breast by 10-fold, reports STAT News. That was even higher for patients who had tumours that didn’t strongly express oestrogen receptors.
That means the phase three trial raises key questions around the decision to omit radiation, experts said, and which patients can truly do so safely.
Radiation can reduce the risk of the cancer’s recurrence, but it is accompanied by unpleasant potential side-effects including pain, a slight risk of organ damage and a very small risk of secondary cancer.
“The issue has been controversial for years,” said Ian Kunkler, a clinical oncologist at the University of Edinburgh and lead author on the study, published in the New England Journal of Medicine.
“There was particular interest as to whether it might be omitted in older patients. Most patients encounter a non-specific fatigue during radiotherapy and sometimes for several weeks afterwards, which can be particularly burdensome to older patients, especially if they have other comorbidities.”
Part of the debate is that most trials studying radiation didn’t include patients over 65, who represent more than half of the patients Kunkler sees in the breast clinic. So he and his colleagues designed a randomised clinical trial to test if radiation truly made a difference to some of those patients, specifically those with smaller tumours that were less likely to be aggressive.
The results of this study, along with an earlier trial called CALGB 9343 that tested omitting radiation for breast cancer patients 70 or older, provided further evidence that radiation may not impact the overall survival of older patients with small, low-risk tumours.
For the study, Kunkler and colleagues recruited 1 326 women 65 or older, all of whom had a tumour 3cm wide or less, and hormone-receptor positive. They had all had surgery to remove the tumours: half received radiation, while the other half didn’t. Afterwards, most of the patients received endocrine therapy for five years that reduces the risk of recurrence.
“Overall survival was 80% in both groups. That’s an important finding – no compromise in overall survival,” Kunkler said. “Most patients were not dying of breast cancer. It was other causes – nearly 10% of cardiac causes and more than 20% from other cancers.”
There was also no difference in distant spread, or recurrence in areas other than the breast, between both groups, but radiation mattered when it came to recurrence in the same breast. Overall, those who received the radiation had a 0.9% risk of local recurrence: those who didn’t get irradiated had a 9.5% risk of the cancer returning in the same
But there were two key caveats. When patients had tumours with weaker oestrogen receptor expression – or when the oestrogen receptor was not as present on cancer cells – forgoing radiation had a bigger impact. Of those patients, 19.1% saw their cancers return in the same breast after 10 years.
“The other interesting analysis was in women who were in the radiation arm and did not adhere to five years of endocrine therapy,” wrote Naamit Gerber, a radiation oncologist at NYU Langone Perlmutter Cancer Centre who did not work on the trial. “Local recurrence was more than four times higher in these women.”
Endocrine or hormonal therapy, like the drug tamoxifen, reduces the likelihood that breast cancer will return for patients who have hormone-positive tumours. The downside is it can be difficult to tolerate the side effects, which include menopause-like symptoms, nausea, weight gain, and more. “Thus, caution must be exercised in omitting radiation for these patients,” Gerber wrote.
“How you make that decision has changed. There are nuances we didn’t ask, the patient didn’t ask, in the past, like the degree of oestrogen receptor positivity and what types of regimens your radiation oncologist offers,” said Alice Ho, co-director of the breast clinical research unit at Duke University Medical Centre who wrote an accompanying editorial in NEJM but did not work on the trial.
“I think this trial will change much. It demonstrated details not available before.”
Radiation, she added, has also got far easier and safer in recent years as well. The risk of damage to nearby organs like the lungs or heart has reduced, and patients can complete modern radiotherapy in as few as five days, whereas in the past it may have taken several weeks.
"Even if radiation does not change survival for an older woman, many may say, ‘If it reduces my risk of local recurrence, and I can do it in five days without burdening my life, ok,’” Ho said.
That means patients must weigh carefully the decision to skip radiation and decide which course of action seems the most acceptable.
“Where do they see themselves in five to 10 years from diagnosis, and what’s the most important goal for them? If they are worried about cancer returning, which most of them are, then what is the percent recurrence rate that is important to them? It’s about tailoring the treatment and customising it to the patient’s disease and preferences.”
Study details
Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer
Ian Kunkler, Linda Williams, Wilma Jack, David Cameron, and Michael Dixon.
Published in New England Journal of Medicine on 16 February 2023
Abstract
Background
Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor–positive early breast cancer receiving adjuvant endocrine therapy.
Methods
We performed a phase 3 randomised trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor–positive, node-negative, T1 or T2 primary breast cancer (with tumours ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and overall survival were also assessed.
Results
A total of 1 326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.
Conclusions
Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor–positive early breast cancer.
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