Elsevier

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 848-858
The Lancet Oncology

Articles
Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials

https://doi.org/10.1016/S1470-2045(15)00049-2Get rights and content

Summary

Background

The combined efficacy analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with tamoxifen plus OFS. We present patient-reported outcomes from these trials.

Methods

Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unmasked adjuvant treatment with 5 years of exemestane plus OFS or tamoxifen plus OFS. Gonadotropin-releasing hormone analogue triptorelin, bilateral oophorectomy, or bilateral ovarian irradiation were used to achieve OFS. Chemotherapy use was optional. Randomisation with permuted blocks was done with the International Breast Cancer Study Group's internet-based system and was stratified by chemotherapy use and status of lymph nodes. Patients completed a quality of life (QoL) form comprising several global and symptom indicators at baseline, every 6 months for 24 months, and then every year during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6 months, 24 months, and 60 months with mixed-models for repeated measures for each trial with and without chemotherapy and overall. The analysis was by intention to treat. At the time of analysis, the median follow-up was 5·7 years (IQR 3·7–6·9); treatment and follow-up of patients continue. The trials are registered with ClinicalTrials.gov, as NCT00066703 (TEXT) and NCT00066690 (SOFT).

Findings

Patients on tamoxifen plus OFS were more affected by hot flushes and sweats over 5 years than were those on exemestane plus OFS, although these symptoms improved. Patients on exemestane plus OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus OFS; these differences persisted over time. An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus OFS than patients on tamoxifen plus OFS. Changes in global QoL indicators from baseline were small and similar between treatments over the 5 years.

Interpretation

Overall, from a QoL perspective, there is no strong indication to favour either exemestane plus OFS or tamoxifen plus OFS. The distinct effects of the two treatments on the burden of endocrine symptoms need to be addressed with patients individually.

Funding

Pfizer, International Breast Cancer Study Group, and US National Cancer Institute.

Introduction

The combined analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with tamoxifen plus OFS in premenopausal women with hormone-receptor-positive breast cancer, providing a new treatment option for these patients who receive OFS as part of adjuvant endocrine therapy.1 In both trials, the decision to give chemotherapy was made by the physician and patient. In TEXT, chemotherapy was given concurrently with OFS after randomisation.2 In SOFT, patients who received chemotherapy were eligible for randomisation only if they remained premenopausal after completion.2

Tamoxifen has been compared extensively with aromatase inhibitors in postmenopausal patients. Patient-reported symptoms related to endocrine therapy were assessed in the ATAC trial3, 4 and the IES5 trial. The results of these trials showed no major differential effects of the endocrine agents on overall quality of life (QoL) or total symptom scores. Patients reported hot flushes as the most prevalent side-effect of treatment, but indicated no differences between tamoxifen and anastrozole3, 4 or exemestane.5 Self-reported gynaecological symptoms (ie, vaginal dryness, diminished libido, and pain with intercourse) were more frequent with anastrozole than with tamoxifen, whereas dizziness, cold sweats, and vaginal discharge were more frequent with tamoxifen.3, 4 Comparisons of exemestane and tamoxifen showed no differences for any of the endocrine symptoms except vaginal discharge, which was more common with tamoxifen for up to 24 months after 2–3 years of treatment.5 Patient-reported bone or joint pain was not assessed in these trials.

Research in context

Evidence before this study

We searched PubMed for clinical trials published in English between Jan 1, 1998, and Jan 1, 2003, and updated the search on Feb 26, 2015, in which patient-reported symptoms and quality of life (QoL) were assessed in premenopausal women with early breast cancer who were undergoing adjuvant endocrine treatment. We used the search terms “premenopausal”, “tamoxifen”, “aromatase inhibitors”, “QoL”, and “patient-reported outcome”. We manually reviewed the results and found no randomised phase 3 trials reporting patient-reported symptoms and QoL for the specific comparison of tamoxifen with an aromatase inhibitor in premenopausal women. Existing data were from postmenopausal women or placebo-controlled breast cancer prevention trials.

Added value of this study

In the TEXT and SOFT trials, patients assigned exemestane plus ovarian function suppression (OFS) reported greater bone or joint pain, vaginal dryness, loss of sexual interest, and difficulties becoming aroused, whereas patients assigned tamoxifen plus OFS were more affected by hot flushes and sweats. Global QoL domains were similar between the randomised treatment groups. The different effects on endocrine symptoms were only partly consistent with the findings of previous trials of an aromatase inhibitor compared with tamoxifen in postmenopausal patients (without OFS). In the IES trial, comparisons between patients receiving exemestane and tamoxifen showed no differences between treatments for any of the endocrine symptoms except vaginal discharge, which was greater with tamoxifen up to 24 months after 2–3 years of treatment. In the ATAC trial, self-reported gynaecological symptoms were more frequent with anastrozole than with tamoxifen, whereas dizziness, cold sweats, and vaginal discharge were more frequent with tamoxifen. Patient-reported bone or joint pain was not assessed in these trials.

Implication of all the available evidence

The combined analysis of the TEXT and SOFT trials showed a disease-free survival benefit for exemestane plus OFS compared with tamoxifen plus OFS in premenopausal patients with hormone-receptor-positive breast cancer, suggesting a new treatment option for premenopausal women who receive OFS as part of adjuvant endocrine therapy. From a QoL perspective, there is no strong indication to favour either exemestane plus OFS or tamoxifen plus OFS. The different effects of the two treatments on endocrine symptoms should be discussed with each patient individually.

The findings from placebo-controlled breast cancer prevention trials in postmenopausal women showed more vasomotor6, 7 and gynaecological symptoms, and sexual problems with tamoxifen,6 and worse menopausal-related QoL with exemestane.8 In the MAP.3 trial,9 exemestane had small negative effects on vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. No treatment differences were noted in general QoL domains.9

Little is known about the effect of chemotherapy on patients' perception of endocrine symptoms. In the ZIPP trial,10 the type of endocrine therapy given (goserelin, goserelin plus tamoxifen, or tamoxifen alone) had different effects on patient-reported symptoms only in patients who did not receive chemotherapy.10

The QoL analysis, a pre-planned secondary analysis, in the TEXT and SOFT trials was done in parallel with the efficacy analysis1 to elucidate differential effects of exemestane compared with tamoxifen on QoL in premenopausal patients who are treated with OFS during adjuvant endocrine therapy. Here, we present the combined patient-reported outcomes from the TEXT and SOFT trials.

Section snippets

Study design and participants

Details of the trials have been described elsewhere.1, 2 Eligibility for both trials included operable hormone-receptor-positive breast cancer and premenopausal status, defined by regular menses without exogenous hormones during the previous 6 months or oestradiol concentrations in the premenopausal range, or both. All patients in TEXT, and patients in SOFT who did not receive chemotherapy, were randomly assigned to treatment groups within 12 weeks of definitive surgery; patients in SOFT who

Results

Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. 621 patients were excluded from the QoL analysis: 27 were excluded from the intention-to-treat (ITT) efficacy analysis, 42 had a QoL eligibility exemption, 546 were at participating centres with poor compliance for submission of QoL forms (42 [8%] of 549 centres), and six had no QoL data submitted; the remaining 4096 patients were the ITT QoL population (figure 1

Discussion

In the SOFT and TEXT trials with OFS, exemestane and tamoxifen treatment showed distinct changes in QoL indicators. Patients assigned to receive exemestane plus OFS reported significantly greater bone or joint pain, vaginal dryness, loss of sexual interest, and difficulties becoming aroused, whereas patients assigned to tamoxifen plus OFS were significantly more affected by hot flushes and sweats. All patients reported substantial changes in key endocrine symptoms in the short, mid, and long

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