Lancet Oncol. 2015-03-01
Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
Abstract
Background
For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years.
Methods
Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1-T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumour histology or lymphovascular invasion, but not both, were permitted), who had had breast-conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomised controlled trial at 76 centres in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40-50 Gy in 15-25 fractions) or no radiotherapy by computer-generated permuted block randomisation, stratified by centre, with a block size of four. The primary endpoint was ipsilateral breast tumour recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomised patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329.
Findings
658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84-6·05), ipsilateral breast tumour recurrence was 1·3% (95% CI 0·2-2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4-5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumour recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99-13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8-96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer.
Interpretation
Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients.
Funding
Chief Scientist Office (Scottish Government), Breast Cancer Institute (Western General Hospital, Edinburgh).
Related Questions
How would you manage a patient with a negative axillary ultrasound but no sentinel lymph node evaluation at the time of lumpectomy for early-stage breast cancer?
If the patient meets PRIME criteria, one can do either APBI or FAST-Forward, based on the preference of the patient. If doesn’t meet PRIME criteria, favor a whole breast like the SOUND study.
How does the recently published SOUND Trial affect your approach to breast RT?
This is a great question. Some radiation details were given in the SOUND trial. We know that ~98% of women in both arms got radiation. The vast majority of patients got whole breast radiation (84% in the SLNB group and 81% in the no axillary surgery group) and a smaller group got PBI with IOERT (~11...
Would you consider omission of radiotherapy in patients 70 years and older with invasive ductal carcinoma who had initially positive lumpectomy margins, but had no residual disease upon re-excision?
The only data I know of on this specific subject comes from the subgroup analysis of the PRIME II trial, which randomly assigned patients to endocrine therapy alone or with radiation therapy. Its eligibility criteria included age 65 or older, tumor size 3 cm or smaller, grade 1 or 2, either grade 3 ...
How do you approach the decision to boost patients diagnosed with DCIS?
Based on prospective and also retrospective data Chua, AACR Volume 81, Issue 4 Supplement, pp. GS2-04. We would recommend for high grade, < 50 years and close margin and in the era of genomic testing to patients with high genomic score.
What early stage breast cancer patients would you give IOeRT?
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Would a finding of isolated tumor cells on SNB impact your decision to offer omission of radiation in a patient with breast cancer who is otherwise a candidate?
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Do you offer ultra-hypofractionated 5-fraction RT regimens for DCIS s/p lumpectomy?
The premise of this question attempts to "split" DCIS from early-stage invasive disease. When we live in an eternal present-tense, we naturally repeat the mistakes of the past. Again, as for modest hypofractionation, we are not going to see a "separate" clinical trial for pure DCIS in this space. In...
Are there any special radiotherapy considerations for women who have double lumpectomy?
Z11102 looked at multiple ipsilateral breast cancers and lumpectomies. For these cases, I would be fine with hypofractionated WBI. Boost would be based on features of each cancer so if it was otherwise low risk for both, I would omit boost vs. if both were higher risk (< 50, ER-), I would boost both...
Does the presence of DCIS in conjunction with invasive breast cancer require consideration of adjuvant RT where invasive disease alone may allow for omission?
I'm not sure there is a lot of data in the PRIME II/CALGB 9343 subset of patients looking at impact of associated DCIS in conjunction with invasive disease and its impact on recurrence with and without radiation therapy. I have not considered this an additional risk factor and have offered omission ...
Do you consider omitting adjuvant radiation therapy in an older patient with node positive TNBC who achieve pCR to neoadjuvant chemotherapy?
It depends on what surgery the patient has received. If lumpectomy plus SLNB, I would not omit unless there is absolute contraindications, intolerance to radiation therapy. PRIME II, CALGB 9343, and this meta-analysis provided evidence that post lumpectomy radiation therapy can be omitted in women >...
Are there situations in which you would definitely recommend radiation in an elderly patient with ER+, early stage breast cancer?
I always have a little trepidation in answering questions whereby I would “definitely†recommend any therapeutic path as clinical decision making needs to be a bit more nuanced. Every situation requires a careful weighing of multiple inputs including clinical trial data and patient-specific fact...
Would you recommend observation in an elderly patient with an ER positive, early stage breast cancer who has a high risk Oncotype Dx score?
I would not favor observation in high oncotype Dx as is it is a risk factor for high local relapse (based on NSABP where it showed higher risk relapse even after lumpectomy and RT, although risk was higher in younger vs. older).Even in PRIME 2 high grade was associated with higher risk of relapse wi...
For an early stage, estrogen receptor positive breast cancer in an elderly patient, would you recommend: hormonal therapy alone, radiation alone or both?
Based on the CALGB (and PRIME II, shorter follow up) data hormonal therapy without RT is a reasonable choice for many older patients given that there is no survival advantage to the addition of RT. Some patients who are in excellent health and want the maximum risk reduction, may be candidates for a...
Would you recommend post lumpectomy RT in an elderly woman with a T1N0M0 stage breast cancer ER/PR/HER2 positive?
As your question states, neither CALGB 9343 nor the PRIME II study assessed HER2 status of its patients as both of these trials commenced prior to the routine testing of HER2 status. So we cannot glean any information from these randomized trials of the omission of radiation in the ER+ HER2+ patient...
Would you consider adjuvant RT in an elderly patient with a T1N0 ER+ breast cancer who initially proceeds with endocrine therapy alone and is unable to tolerate it?
Given the low-risk nature of T1N0 luminal lesions among older patients (per the CALGB 9343 and Prime II trials), the conundrum of whether to pursue adjuvant endocrine therapy, radiotherapy (RT), or both after lumpectomy arises with some frequency. Patients who decline RT yet ultimately cannot tolera...
What is the best management of early stage breast cancer in patients with a minimal life expectancy (<10yrs)?
I believe in individualized, whole patient care. Life expectancy is incredibly difficult to estimate, but if we are somehow certain a patient will live less than 10 years, then quality (rather than quantity) of life likely becomes the primary concern of a patient with early stage breast cancer. We d...
What is the age cut-off to omit radiation therapy after breast conserving surgery for early stage breast cancer?
I agree with the above answers and would like to expand a bit. What is so special about being over 70 (or over 65 for that matter) when your breast cancer is diagnosed? Not much. Age is a rough surrogate for life expentancy and perhaps also for biologic subtype. But we have SEVERAL trials across bro...