Elsevier

The Lancet Oncology

Volume 16, Issue 3, March 2015, Pages 266-273
The Lancet Oncology

Articles
Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial

https://doi.org/10.1016/S1470-2045(14)71221-5Get rights and content

Summary

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).

Introduction

Breast cancer is a growing global health care issue in older women. The incidence of breast cancer has risen steadily in most European countries between 1990 and 2002 in women aged 70 years or older.1 In several clinical trials, low-risk patients have been identified in whom the effect of postoperative whole-breast irradiation is modest,2, 3, 4 although these studies have been done mainly in younger patient populations. However, in older patients, the biology of breast cancer might be less aggressive, in view of the increased proportion of hormone receptor-positive tumours in this age group.

Postoperative whole-breast radiotherapy remains the standard of care for most patients treated by breast-conserving surgery, irrespective of age and other risk factors.5 However, little evidence exists for the role of postoperative radiotherapy in older patients after breast-conserving surgery and adjuvant endocrine treatment because many trials, historically, excluded patients older than age 70 years. Extrapolation of the results of trials in younger patients to older patients might not be valid, particularly because of the competing risks of comorbidities in older patients. Data for the effect of age on local recurrence after breast-conserving surgery have been conflicting. In some trials, ipsilateral breast tumour recurrence falls with increasing age6 or no effect is seen.7, 8 However, patients older than 65 years (and particularly those older than 75 years) were not well represented in any of these trials. Since tamoxifen with or without9, 10 adjuvant radiotherapy reduces the risk of tumour recurrence, we designed a randomised controlled trial in a group of older, low-risk, node-negative women with invasive breast cancer after breast-conserving surgery and adjuvant endocrine treatment to assess the effect omission of whole-breast irradiation has on local control.

Section snippets

Participants

We did a phase 3 randomised controlled trial at 76 specialist cancer centres and district or regional hospitals in four countries (the UK, Greece, Australia, and Serbia; appendix pp 5–6). We recruited women aged 65 years or older with breast cancer who had undergone breast-conserving surgery and pathological axillary staging (ipsilateral four-node lower axillary node sample, sentinel node biopsy, or axillary node clearance). Eligibility criteria were: T1–T2 (up to 3 cm, longest dimension); N0;

Results

Between April 16, 2003, and Dec 22, 2009, 1326 patients were randomly allocated to either no radiotherapy (n=668) or whole-breast radiotherapy (n=658; figure 1). Of these, 39 did not receive radiotherapy after randomisation and five received radiotherapy when they had been randomly allocated to the no radiotherapy group. Another three patients did not begin endocrine treatment after randomisation or stopped taking it shortly after starting. 1263 patients were recruited from the UK, 22 were from

Discussion

The null hypothesis of the PRIME II study was that there was no difference between the radiotherapy and no radiotherapy groups in terms of local recurrence at 5 years, with an alternative hypothesis of a 3% difference between groups (2% with radiotherapy vs 5% with no radiotherapy). On the basis of the results of this trial, we can reject the null hypothesis (p=0·0002, log-rank test). At median follow-up of 5 years, the absolute risk reduction in ipsilateral breast tumour recurrence at 5 years

References (31)

  • Breast cancer quality standard: NICE quality standards (QS12)

  • U Veronesi et al.

    Radiotherapy after breast-conserving surgery in women with localized cancer of the breast

    N Engl J Med

    (1993)
  • B Fisher et al.

    Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer

    N Engl J Med

    (1995)
  • B Fisher et al.

    Conservative surgery for the management of invasive and noninvasive carcinoma of the breast: NSABP trials

    World J Surg

    (1994)
  • B Fisher et al.

    Tamoxifen, radiation therapy or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with breast cancers of one centimetre or less

    J Clin Oncol

    (2002)
  • Cited by (693)

    View all citing articles on Scopus
    View full text