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Recommendations for use of Endocrine therapy

Summary of trial or study results

Endocrine therapy in pre-menopausal women

A meta-analysis of four trials2 found that there was a significant overall survival benefit (p=0.02) and progression-free survival benefit (p=0.0003) for pre-menopausal women treated with combined tamoxifen and LH-RH agonist compared to pre-menopausal women treated with LH-RH agonist alone. One trial5 found that the incidence of hot flushes was significantly higher in women treated with combined tamoxifen and LH-RH agonist compared with women treated with tamoxifen alone (87% vs 40%; p=0.0001). There are currently insufficient data to guide the use of third generation aromatase inhibitors in combination with functional ovarian ablation/suppression or fulvestrant in pre-menopausal women. Further research is required to investigate the use of third generation aromatase inhibitors and fulvestrant in the pre-menopausal setting.

Overall survival

First-line therapy

A meta-analysis of two trials6,7 revealed third generation aromatase inhibitors confer no survival advantage over tamoxifen as first-line therapy for advanced breast cancer (p=0.98).

Second-line therapy

As second-line therapy a meta-analysis of four trials11-13,15 showed significant improvement in overall survival for women treated with third generation aromatase inhibitors compared with progestins (p=0.003). One trial showed a median survival benefit of 4.2 months.11

Endocrine therapy in post-menopausal women

Progression-free survival

First-line therapy

A meta-analysis of two trials6,9 revealed that women treated with third generation aromatase inhibitors show significant advantage in progression-free survival (p=0.0001) compared with women treated with tamoxifen (Bonneterre 2001:6 8.5 vs 7 months, Mouridsen 2001:9 9.4 vs 6 months).

Second-line therapy

A meta-analysis of four trials11-13,15 revealed a significant benefit in progression-free survival for women treated with third generation aromatase inhibitors compared to progestins (p=0.01). A meta-analysis of two trials16,17 revealed no significant difference in progression-free survival between women treated with a third generation aromatase inhibitor compared with women treated with fulvestrant (p=0.31).

Overall response rate

First-line therapy

As first-line therapy a meta-analysis of four trials6-9 showed that third generation aromatase inhibitors are statistically superior to tamoxifen with respect to tumour response (p=0.004).

Second-line therapy

All five trials11-15 in the meta-analysis found that overall response rate was higher in women treated with third generation aromatase inhibitors compared with women treated with progestins, although this difference was not significant. No trial has shown a statistically significant difference in overall response rate between women treated with third generation aromatase inhibitors compared with women treated with fulvestrant.

Comparing the efficacy of aromatase inhibitors

As first-line therapy, anastrozole and exemestane were not significantly different with respect to overall survival, progression-free survival, or overall response rate.

As second-line therapy, anastrozole and letrozole were equivalent in terms of overall survival and progression-free survival. Letrozole was statistically more effective than anastrozole in terms of overall response rate (19% vs 12%; p=0.014).19 This was not the case when women whose receptor status was unknown were excluded from the analysis.

Adverse events

First-line therapy

A meta-analysis6,7,9 of three trials showed no significant difference overall in adverse events between women treated with aromatase inhibitors compared with tamoxifen (p=0.25).

The largest trial in this meta-analysis (Bonneterre)6reported an overall incidence of adverse events with aromatase inhibitors of 83% compared with 85% for tamoxifen. However the incidence of vaginal bleeding was significantly lower in women treated with a third generation aromatase inhibitor compared with tamoxifen (p<0.001), as was the incidence of thromboembolic events (p=0.003).

Second-line therpay

There was no significant difference16,17 in overall incidence of adverse events between women treated with third generation aromatase inhibitors compared with women treated with fulvestrant (89% vs 89%; p=0.79). The incidence of specific adverse events (nausea, diarrhoea, rash, arthralgia, hot flashes, thromboembolic events and dyspnoea) was similar for both groups. The incidence of vaginal bleeding was not reported.

A meta-analysis of three trials12,13,15 showed no significant difference overall in adverse events for women treated with third generation aromatase inhibitors compared with progestins (p=0.31). There was however a significant increase of nausea (p=0.005), hot flushes (p<0.001),and diarrhoea (p<0.001) in women treated with a third generation aromatase inhibitor compared with women treated with a progestin. In contrast, the incidence of dyspnoea was significantly lower in women treated with aromatase inhibitors compared with progestins (p<0.0001).

Quality of life

Quality of life was poorly assessed and poorly reported across the trials and therefore no firm conclusions can be drawn. Most studies that did report on quality of life found that there was no significant difference between endocrine therapies. Further research is required to determine the short- and long-term effects of endocrine therapy on quality of life.

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