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

• 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
• In several clinical trials, low-risk patients have been identified in whom the effect of postoperative whole-breast irradiation is modest:
  • 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 tumors 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:
    • 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 tumor recurrence falls with increasing age or no effect is seen:
    • 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 without adjuvant radiotherapy reduces the risk of tumor recurrence:
      • The investigators of the PRIME II trial designed a randomized 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
• Methods:
  • Participants:
    • They performed a phase 3 randomized controlled trial at 76 specialist cancer centres and district or regional hospitals in four countries (the UK, Greece, Australia, and Serbia)
    • They 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 to T2 (up to 3 cm, longest dimension); N0; M0; hormone receptor-positive (estrogen receptor, progesterone receptor, or both); clear excision margins (≥ 1 mm); no axillary involvement on histological examination (pN0); and receiving adjuvant hormone treatment (we permitted neoadjuvant hormonal treatment)
    • Staging investigations included full blood count, liver function tests, and chest radiography
    • They required re-excision margins to be 1 mm or greater, but we did not request the actual final measurement because this value can be difficult for the pathologist to estimate
    • All patients had to be fit for treatment and follow-up (as assessed by the participating centre) and able and willing to give informed consent
    • They did not request details of specific performance status nor formal documentation of comorbidities
    • Patients’ tumors could have grade 3 histological features or lymphovascular invasion, but not both
    • They excluded patients if they were younger than 65 years at the time pathological results were issued or if they had a history of previous in-situ or invasive breast cancer of either breast
    • We also excluded women with current or previous malignant disease within the past 5 years, other than non-melanomatous skin cancer or carcinoma in situ of the cervix
    • We did not record HER2 status in these patients because this marker was not routinely assessed at the start of the trial
    • The PRIME II study protocol received UK national ethics (MREC) approval on Sept 24, 2001
    • All patients gave written informed consent before randomization
    • Follow-up is ongoing and will end at the 10-year anniversary of the last randomized patient
  • Randomization and masking:
    • We randomly allocated patients to either whole-breast radiotherapy or no radiotherapy in a 1:1 ratio using a computerized randomization service
    • Randomization was by block permutation, stratified by center, with a block size of four
    • Once a patient had provided informed consent, a research nurse familiar with the trial contacted the central independent randomization service (Information Services Division Scotland, Edinburgh, UK) by telephone; a trial identifier was generated and treatment was assigned
    • The assignment was confirmed by a fax sent to both the registering center and the trial manager
    • They could not mask participants to the treatment being given
    • However, no evidence was present in the trial identifier to indicate to which treatment the patient had been allocated; therefore, during follow-up and data analysis, researchers were unaware of patients’ allocation unless they specifically looked for it
  • Procedures:
    • The total radiotherapy dose, number of fractions, and overall treatment time was administered according to local practice in every center:
      • However, we provided a guideline for dose fractionation of 40 to 50 Gy(2.66–2.00 Gy per fraction in 15 to 25 fractions) over 3 to 5 weeks at megavoltage irradiation to the breast
    • They permitted a breast boost with electrons of 10 to 15 Gy at appropriate energy or an iridium implant (eg, 20 Gy to 85% reference isodose)
    • Guidelines on radiotherapy included some form of immobilization, a planned target volume of the whole breast (margin of 1 cm), and all patients being simulated to establish the volume of lung irradiated (maximum lung thickness no greater than 3 cm)
    • They specified that the peripheral lymphatic system was not to be irradiated
    • They stated that a minimum of one transverse outline, taken at the central axis of the tangential fields, was to be taken
    • All fields were to be treated with megavoltage irradiation, with wedged fields so that dose homogeneity did not vary by more than 10%
    • They indicated that doses were to be prescribed to the reference point at or close to the center of the target volume (ICRU-50)
    • For the boost volume, they specified the tumor bed with lateral margins of 2 cm and a deep margin extending down to the underlying muscle
  • They indicated tamoxifen (20 mg daily for 5 years) as the standard adjuvant endocrine treatment, but we allowed other forms of adjuvant and neoadjuvant endocrine treatment
  • Follow-up was for 10 years and consisted of annual clinic visits, examination and mammography for at least 5 years, and, beyond this time, either a clinic visit or a phone call to the patients’ primary health care doctor to ascertain their health status, in addition to follow-up mammography
  • Outcomes:
    • The primary endpoint was ipsilateral breast tumor recurrence
    • Secondary endpoints were:
      • Regional recurrence, contralateral breast cancer, distant metastases, disease-free survival, and overall survival
    • They defined ipsilateral breast tumor recurrence as any cancer in the scar, the adjacent area in the same breast, or in a different quadrant of the same breast
    • They defined regional recurrence as disease in the ipsilateral axillary or supra- clavicular lymph nodes
    • The endpoints were not centrally assessed but based on local investigator review
• 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)
  • Of these, 39 did not receive radiotherapy after randomization and five received radiotherapy when they had been randomly allocated to the no radiotherapy group
  • Another three patients did not begin endocrine treatment after randomization or stopped taking it shortly after starting
  • 1263 patients were recruited from the UK, 22 were from Greece, 16 were from Australia, and 25 were from Serbia
  • Patients’ median age was 70 years (IQR 67–74)
  • Fewer than 10% of patients had tumors with poor estrogen receptor status
  • 91 (16%) of 584 patients for whom radiotherapy treatment data were available received a tumor bed boost after whole-breast radiotherapy
  • At median follow-up of 5 years (IQR 3·84–6·05):
    • Actuarial ipsilateral breast tumor recurrence was 1.3% (95% C1 0·2–2·3) in women allocated whole-breast radiotherapy and 4.1% (2.4–5.7) in those assigned no radiotherapy (log-rank p=0·0002)
    • The hazard ratio for ipsilateral breast tumor recurrence in patients allocated to no radiotherapy was 5.19 (95% CI 1·99–13·52; p=0·0007; full data, not truncated at 5 years)
    • The absolute risk reduction in ipsilateral breast tumor recurrence at 5 years was 2.9% (95% CI 1·1–4·8)
    • The number needed to treat was calculated to be 31.8 (95% CI 27·4–55·0), which equates to an adjusted absolute risk reduction of 3.1% (95% CI 1·8–3·6) by the Altman and Andersen methodology
    • 26 (4%) patients assigned to no radiotherapy and five (1%) women allocated to whole-breast radiotherapy had local recurrences
    • Of the 26 local recurrences in the no radiotherapy group:
      • 18 women had a local recurrence only
      • Six had both local and regional recurrence
      • Two had a local recurrence with distant spread
    • In the radiotherapy group:
      • Four patients had local recurrence only
      • One had local and regional recurrence
    • They did a multivariate Cox proportional hazards analysis of local recurrence according to known risk factors for local recurrence, including:
      • Pathological tumor size, margin status, tumor grade, age, presence of lymphovascular invasion, estrogen receptor status, and use of radiotherapy
    • Progesterone receptor status was excluded from analyses because roughly 30% of data were missing in each treatment group
    • The only factor that predicted local recurrence was:
      • Omission of radiotherapy (hazard ratio 4·87, 95% CI 1·86–12·74; p=0·0013), although poor estrogen receptor status and grade 3 tumors were of borderline significance (p=0·06):
        • However, very few women had either of these factors (36 [3%] patients had grade 3 tumors and 120 [9%] had poor estrogen receptor status)
    • Overall survival at 5 years was identical in the two treatment groups (93.9%, 95% CI 91.8–96·0; p=0·34)
    • At 5 years, no differences between treatment groups were noted:
      • In regional recurrences, distant metastases, contralateral breast cancers, or new cancers
    • Breast cancer-free survival at 5 years was 94.5% (95% CI 92·5–96·5) in women allocated to no radiotherapy and 97.6% (96·2–99·0) in those assigned to whole-breast radiotherapy:
      • The difference was attributable mainly to ipsilateral breast tumor recurrence
    • Only 12 (13%) of 89 deaths recorded by the time of analysis were due to breast cancer, eight (16%) of 49 women assigned to no radiotherapy and four (10%) of 40 allocated to whole-breast radiotherapy
    • In a hypothesis-generating unplanned subgroup analysis of local recurrence by estrogen receptor score:
      • Local recurrence at 5 years for women in the rich estrogen receptor subgroup was lower than in the whole population:
        • For patients assigned no radiotherapy, 20 (3%) of 593 patients had a local recurrence compared with five (<1%) of 601 women allocated whole-breast radiotherapy:
          • 5-year ipsilateral breast tumor recurrence was 3.3% [95% CI 1·7–4·8] and 1.2% [0·1–2·2], respectively; p=0·002
        • In women with poor estrogen receptor status, six (9%) of 65 women allocated no radiotherapy had local recurrence compared with none of 55 women allocated to whole-breast radiotherapy (ipsilateral breast tumor recurrence at 5 years was 10.3% [95% CI 2·5–18·2] and 0%, respectively; p=0·026); however, the number of patients in this analysis is small
• Conclusion
  • Postoperative whole-breast radiotherapy achieved a significant but relatively small reduction in local breast recurrence at 5 years in a population of low-risk older patients with early breast cancer after breast-conserving surgery and adjuvant endocrine treatment
  • The only other trial in which omission of radiotherapy was investigated in a low-risk population was the CALGB 9343 trial,17,18 in which a similar 3% reduction in local recurrence at 5 years was noted with addition of radiotherapy
  • Our findings add to existing evidence of the safety of omitting radiotherapy after breast-conserving surgery in older patients, in whom the benefits of adjuvant radiotherapy have been controversial, and they might encourage clinicians to consider omission of radiotherapy in all or selected older women with low-risk breast cancer after breast-conserving surgery depending on the weight they and the patient give to local recurrence

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