Surgery versus primary endocrine therapy for elderly women with operable primary breast cancer

While younger women with early-stage, oestrogen-sensitive breast cancer are almost invariably treated with surgery plus endocrine therapy, (which deprives the cancer of the hormonal stimulus that induces its growth), women over the age of 70 years are frequently offered endocrine therapy alone. This is known as primary endocrine therapy.

Primary endocrine therapy using tamoxifen (a drug which blocks oestrogen receptors on the cancer cell, inhibiting its growth) was first suggested as a treatment for older women in the 1980s. Tamoxifen was given without surgery, radiotherapy or chemotherapy on the basis that older women are more likely to have cancers with oestrogen receptors and will therefore respond well to treatment. In addition they were thought less suitable for major surgery because of other existing health issues. However, a tumour will often only respond to this treatment for between 18 and 24 months, and those women who relapse will have to consider additional hormone treatment or opt for surgery or radiotherapy at a greater age. The long-term data suggest that, at 12 years of follow-up, more elderly women treated by primary tamoxifen alone will suffer a progression of their cancer than those who have had surgery.

We undertook this review to assess the evidence for the clinical effectiveness of surgery (with or without endocrine therapy) compared with primary endocrine therapy in the treatment of operable breast cancer in women aged 70 years and over. Based on seven trials and an estimated 1081 deaths in 1571 women, the results of this review showed no benefit in respect to survival for either surgery or primary endocrine therapy. However, women who had surgery were less likely to relapse than women on primary endocrine therapy.

The authors conclude that surgery controls breast cancer better than tamoxifen alone in older women but does not extend survival. Both interventions were associated with adverse events. Tamoxifen-related adverse effects included hot flushes, skin rash, vaginal discharge, indigestion, breast pain, sleepiness, headache, vertigo, itching, hair loss, cystitis, acute thrombophlebitis, nausea, and indigestion. Surgery-related adverse effects included tingling or numbness on the arm on the side of the surgery, and psychosocial problems. On this basis, primary endocrine therapy should only be offered to women with oestrogen receptor (ER)-positive tumours who are unfit for, or who refuse surgery. We need further trials to evaluate the clinical effectiveness of other agents such as aromatase inhibitors for use as primary endocrine therapy for an infirm older population with ER-positive tumours.

Authors' conclusions: 

Primary endocrine therapy should only be offered to women with oestrogen receptor (ER)-positive tumours who are unfit for surgery, at increased risk of serious surgical or anaesthetic complications if subjected to surgery, or who refuse surgery. In a cohort of women with significant co-morbid disease and ER-positive tumours it is possible that primary endocrine therapy may be a superior option to surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for an infirm older population with ER-positive tumours.

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Background: 

Several studies have evaluated the clinical effectiveness of endocrine therapy alone in women aged 70 years or over with operable breast cancer and who are fit for surgery.

Objectives: 

To systematically review the evidence for the clinical effectiveness of surgery (with or without adjuvant endocrine therapy) in comparison to primary endocrine therapy in the treatment of operable breast cancer in women aged 70 years and over, both in terms of local progression and mortality.

Search strategy: 

We conducted an updated search of the Cochrane Breast Cancer Group's Specialised Register (27th March 2013) and new searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 3), MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (apps.who.int/trialsearch/) and www.clinicaltrials.gov, using the search terms 'early breast cancer', 'endocrine therapy', 'psychosocial' or 'surgery'.

Selection criteria: 

Randomised trials comparing surgery, with or without adjuvant endocrine therapy, to primary endocrine therapy in the management of women aged 70 years or over with early breast cancer and who were fit for surgery.

Data collection and analysis: 

We assessed studies for eligibility and quality, and two review authors independently extracted data from published trials. We derived hazard ratios for time-to-event outcomes, where possible, and used a fixed-effect model for meta-analysis. We extracted toxicity and quality-of-life data, where present. Where outcome data were not available, we contacted trialists and requested unpublished data.

Main results: 

We identified seven eligible trials, of which six had published time-to-event data and one was published only in abstract form with no usable data. The quality of the allocation concealment was adequate in three studies and unclear in the remainder. In each case the endocrine therapy used was tamoxifen.

Data, based on an estimated 1081 deaths in 1571 women, did not show a statistically significant difference in favour of either surgery or primary endocrine therapy in respect of overall survival. However, there was a statistically significant difference in terms of progression-free survival, which favoured surgery with (474 participants) or without endocrine therapy (164 participants).

The hazard ratios (HRs) for overall survival were: HR 0.98 (95% confidence interval (CI) 0.81 to 1.20, P = 0.85; 3 trials, 495 participants) for surgery alone versus primary endocrine therapy; HR 0.86 (95% CI 0.73 to 1.00, P = 0.06; 3 trials, 1076 participants) for surgery plus endocrine therapy versus primary endocrine therapy. The HRs for progression-free survival were: HR 0.55 (95% CI 0.39 to 0.77, P = 0.0006) for surgery alone versus primary endocrine therapy; HR 0.65 (95% CI 0.53 to 0.81, P = 0.0001) for surgery plus endocrine therapy versus primary endocrine therapy (each comparison based on only one trial). Tamoxifen-related adverse effects included hot flushes, skin rash, vaginal discharge, indigestion, breast pain, sleepiness, headache, vertigo, itching, hair loss, cystitis, acute thrombophlebitis, nausea, and indigestion. Surgery-related adverse effects included paraesthesia on the ipsilateral arm and lateral thoracic wall in those who had axillary clearance. One study suggested that those undergoing surgery suffered more psychosocial morbidity at three months post-surgery, although this difference had disappeared by two years.

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