For women age 65 and older who are diagnosed with breast cancer, and who opt for breast-conserving surgery, adjuvant radiation therapy may not be necessary, according to results of the PRIME 2 study reported at the San Antonio Breast Cancer Symposium.
Overall in that study, the difference in disease-free survival between women who had radiation after surgery and those who did not was significantly in favor of radiation, In presenting the study, though, Ian Kunkler, MA, MB, BChir, FRCR, Professor of Clinical Oncology at the University of Edinburgh Cancer Research Center in Scotland, said the absolute difference of about three percent might actually mean that 95 percent of women in the study population were being overtreated.
“We have identified a subgroup of older patients at sufficiently low risk of recurrence for whom omission of postoperative radiotherapy after breast-conserving surgery and adjuvant endocrine therapy is a reasonable option,” he said. “In addition, we found that excluding radiation in this patient population did not compromise overall survival.”
After five years, 26 women who did not receive radiation lost local disease control—about 4.1 percent of the total—compared with six women in the radiation group (1.3%), he reported.
When the researchers scrutinized disease-free survival on the basis of the level of estrogen-receptor (ER) positivity, they observed that in women with low ER status, seven of 63 women who did not have radiation had a recurrence (11.1 percent). Among the 54 women with low ER status who did undergo whole breast irradiation, there were no recurrences.
“This would suggest that this is a group for whom radiotherapy should not be omitted,” Kunkler said. A multivariate analysis indicated that the only risk factors that proved to have an impact on outcome were radiation therapy and ER status.
Notwithstanding the significance in favor of radiation, though, he said the findings in the PRIME-2 trial should be considered in this manner: “Radiotherapy has been known to reduce the risk of breast cancer recurrence three- to four-fold. However, what our trial has shown is that although this is still the case, the proportion of women who will actually have a recurrence without radiotherapy is very small five years after treatment.
“For every 100 women treated with radiotherapy, one will have a recurrence anyway, four will have a recurrence prevented, but 95 will have had unnecessary treatment.”
And in overall survival, there is virtually no difference, the study showed. There were 49 deaths among the women who did not receive radiation—an overall survival rate of 93.8 percent, compared with 40 deaths or a five-year actuarial survival of 94.2 percent.
The PRIME 2 study evolved during the time in which any woman who was opting for breast-conserving surgery for early-stage breast cancer was counseled to undergo adjuvant whole breast irradiation irrespective of risk factors such as age, Kunkler explained.
Over the years, though, more and more women who have been diagnosed with breast cancer and who opt for breast-conserving surgery have been 65 or older. In fact, he said, more than half the women he sees in the clinic fit this category.
“They often have a relatively benign natural history, and radiotherapy may represent overtreatment. In addition there are competing risks of comorbidities in this age group. There is relatively sparse Level 1 evidence in this older age group of the effectiveness of postoperative radiation therapy following breast-conserving surgery.”
Hence, the PRIME 2 investigators enrolled 1,326 women into the study, assigning 658 to whole breast irradiation and 668 women to not receive radiation. The radiation dose used was 40-50 Gy in 15 to 25 fractions, with local policy determining the specific radiation dose and fractions.
“The aim of the trial was to assess the impact on local control of the omission of postoperative whole breast radiotherapy after breast-conserving surgery and adjuvant endocrine therapy in older patients considered to be at low risk,” Kunkler said.
Patients were eligible for the trial if they were at least 65 years old and were diagnosed with histologically confirmed unilateral invasive breast cancer. The tumors had to be less than three centimers in diameter, and the women had to opt for breast-conserving therapy. A negative margin of at least one millimeter was also required. The women also had to have ER or progesterone receptor positive cancer and were also treated with adjuvant endocrine therapy. No axillary node involvement on histological assessment was permitted.
Women were excluded if they were diagnosed with Grade 3 cancer or if they had previous in situ or invasive cancer of either breast, or had other cancers within the past five years.
The mean age of the patients was 71; about 85 percent of the women were diagnosed with tumors 20 mm in diameter or smaller and were considered T1. About 55 percent of the tumors were Grade N2; about 40 percent were Grade N1.
More than 90 percent of the women had undergone preoperative endocrine therapy, and the remaining women were given endocrine therapy once they were enrolled in the study.
98 Sites in Six Countries
The Phase III international, multicenter study was performed at 98 sites in six countries. The median follow-up was five years.
In further explaining the study's rationale, Kunkler said that although radiation may provide a slight improvement against the risk of recurrence, it can also affect later treatment options: “Once a patient has had radiotherapy, she is unable to have it again on the same breast. Had these women not had radiotherapy, they would have been able to have minor surgery and radiotherapy following a recurrence. Besides, radiotherapy carries its own health risks, particularly in the elderly, as well as the inconvenience of travel for daily treatment for three or four weeks.
“Allowing us to defer radiotherapy in this group of patients until a recurrence occurs will be of benefit to the patient and to the health service.”
He noted that the age cutoff of 65 was somewhat arbitrary, and that the median age in the study was a bit over 70. He said the exact age for the cutoff could be debated, although the result might also be due to the physical characteristics of the patients.
“Our results are likely to lead to the consideration of omission of postoperative radiotherapy in patients meeting the eligibility criteria for the trial. I think the implications of this trial will be generalizable to a large and growing number of women,” he said.
Comments from Kent Osborne
The symposium's Co-Director, C. Kent Osborne, MD, Director of the Dan L. Dunkin Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine and the moderator of a news conference that featured the study, explained that the older a woman is, the more likely she is to have a high ER status.
“When I was in my training 40 years ago we were in the era of ‘more is better’—Everyone thought that if you gave more treatment, more surgery, more radiation, more chemotherapy, high-dose chemotherapy, bone marrow transplantation, etc., then that would be better,” he said. “It is turning out, though, as we have evolved over the last three decades, that that is not the case. Now we are in a transition between a lot of things we have done in the past and a lot of things we are going to be doing in the future.”
Summing up, Kunkler said, “I think it is a matter for discussion between the patient and the physician whether that very modest benefit seen with radiation is worth the potential risks of the complications of radiotherapy and the burden of undergoing treatment.”
In a video interview on the iPad edition of this issue with OT reporter Dan Keller, Dr. Kunkler elaborates on the results, emphasizing that by avoiding routine radiotherapy, these women would still be eligible for minor surgery and radiotherapy if the cancer does recur.
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