Duration of AI therapy

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS.

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS.

At a median follow-up of 6.3 years, DFS was significantly improved in patients randomly assigned to receive letrozole (HR, 0.66; 95% CI, 0.48–0.91; P = .01). The 5-year DFS rate was improved from 91% to 95%.[81][Level of evidence B1]

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS.

OS rates showed no difference (HR, 0.97; 95% CI, 0.73–1.28; P = .83). More patients who received letrozole had fractures (14%) than did patients who received placebo (9%) (P = .001).

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS.

QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS. › QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.

No between-group differences were found on the four MENQOL subscales or on the SF-36 summary score.

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[81] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI. The primary study end point was DFS. › QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.

SF-36 role-emotional and bodily pain scores were statistically significantly worse (P = .03) among patients receiving letrozole, but the differences observed were fewer than the minimum clinically important differences for the SF-36 instrument.

A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[Level of evidence B1] [82]

A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[Level of evidence B1] [82]

DFS events were similar in both groups (HR, 0.92; 95% CI, 0.74–1.16). The distant metastasis-free interval was also similar (HR, 1.06; 95% CI, 0.78–1.45).

A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[Level of evidence B1] [82]

A subgroup analysis did not identify patients who benefited from 5-year extended therapy.

A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[Level of evidence B1] [82]

This study did not show that 10 years of AI therapy was superior to 7.5 years of AI therapy.

A phase III trial (NSABP-B42 [NCT00382070]) randomly assigned, in a double-blind fashion, 3,966 women who received 5 years of initial adjuvant therapy with an AI or received tamoxifen for 2 to 3 years followed by an AI to receive 5 mg of letrozole or placebo for 5 additional years.[83][Level of evidence B1] The planned analysis of DFS was carried out after a median follow-up of 6.9 years.

A phase III trial (NSABP-B42 [NCT00382070]) randomly assigned, in a double-blind fashion, 3,966 women who received 5 years of initial adjuvant therapy with an AI or received tamoxifen for 2 to 3 years followed by an AI to receive 5 mg of letrozole or placebo for 5 additional years.[83][Level of evidence B1] The planned analysis of DFS was carried out after a median follow-up of 6.9 years.

The 7-year DFS rate was 81.3% in the placebo group and 84.7% in the letrozole group (HR, 0.85; 95% CI, 0.73–0.999; P = .048). The observed difference was not statistically significant when interim analyses were accounted for.

A phase III trial (NSABP-B42 [NCT00382070]) randomly assigned, in a double-blind fashion, 3,966 women who received 5 years of initial adjuvant therapy with an AI or received tamoxifen for 2 to 3 years followed by an AI to receive 5 mg of letrozole or placebo for 5 additional years.[83][Level of evidence B1] The planned analysis of DFS was carried out after a median follow-up of 6.9 years.

There were no statistically significant differences in adverse events between the arms.

A phase III trial conducted by the IBCSG (SOLE [NCT00553410]) included 4,851 receptor-positive postmenopausal women who had completed 5 years of adjuvant therapy with an AI, a selective estrogen receptor (ER) modulator, or both. Patients were randomly assigned to receive 2.5 mg of letrozole daily for 5 years or to an intermittent schedule in which there was a 3-month break at the end of each of the first 4 years, but not in the final year.[84]

A phase III trial conducted by the IBCSG (SOLE [NCT00553410]) included 4,851 receptor-positive postmenopausal women who had completed 5 years of adjuvant therapy with an AI, a selective estrogen receptor (ER) modulator, or both. Patients were randomly assigned to receive 2.5 mg of letrozole daily for 5 years or to an intermittent schedule in which there was a 3-month break at the end of each of the first 4 years, but not in the final year.[84]

There was no observed advantage to the intermittent schedule with respect to DFS (HR, 1.08; 95% CI, 0.93–1.26; P = .31) or in the frequency of adverse events.[84][Level of evidence B1]

A phase III trial conducted by the Dutch Breast Cancer Study Group (DATA [NCT00301457]) randomly assigned 1,860 eligible receptor-positive postmenopausal women who had received 2 to 3 years of tamoxifen to receive either 3 or 6 years of anastrozole (1 mg daily).[85]

A phase III trial conducted by the Dutch Breast Cancer Study Group (DATA [NCT00301457]) randomly assigned 1,860 eligible receptor-positive postmenopausal women who had received 2 to 3 years of tamoxifen to receive either 3 or 6 years of anastrozole (1 mg daily).[85]

At 3 years, 1,660 of these women were free of disease: among them, DFS was observed to be improved, but not statistically significantly so, on the extended-therapy arm (HR, 0.79; 95% CI, 0.62–1.02).[85][Level of evidence B1] Myalgia and osteoporosis/osteopenia were more frequent on the extended-therapy arm.

A phase III, open-label, Italian trial (NCT01064635) included 2,056 hormone receptor–positive postmenopausal women who had received 2 to 3 years of tamoxifen treatment. Patients were randomly assigned to receive letrozole for either 2 to 3 years (control) or 5 years (extended therapy). The primary end point was IDFS.[86]

A phase III, open-label, Italian trial (NCT01064635) included 2,056 hormone receptor–positive postmenopausal women who had received 2 to 3 years of tamoxifen treatment. Patients were randomly assigned to receive letrozole for either 2 to 3 years (control) or 5 years (extended therapy). The primary end point was IDFS.[86]

After 11.7 years of follow-up, the 12-year DFS rate was 62% in the control group and 67% in the extended-therapy group (HR, 0.78; 95% CI, 0.65–0.93; P = .0064). These results were confirmed in a landmark analysis that excluded patients who experienced a DFS event or who were lost to follow-up before treatment divergence (2–3 years after randomization).

A phase III, open-label, Italian trial (NCT01064635) included 2,056 hormone receptor–positive postmenopausal women who had received 2 to 3 years of tamoxifen treatment. Patients were randomly assigned to receive letrozole for either 2 to 3 years (control) or 5 years (extended therapy). The primary end point was IDFS.[86]

The 12-year OS rate was 84% in the control group and 88% in the extended-therapy group (HR, 0.77; 95% CI, 0.60–0.98; P = .036).[86][Level of evidence A1]

A phase III, open-label, Italian trial (NCT01064635) included 2,056 hormone receptor–positive postmenopausal women who had received 2 to 3 years of tamoxifen treatment. Patients were randomly assigned to receive letrozole for either 2 to 3 years (control) or 5 years (extended therapy). The primary end point was IDFS.[86]

Grade 3 or greater arthralgia and myalgia were slightly more frequent in the extended-therapy group than in the control group (3.0% vs. 2.2% and 0.9% vs. 0.7%, respectively).

The phase III ABCSG-16 study enrolled 3,484 postmenopausal women with hormone receptor–positive breast cancer who had completed 5 years of endocrine therapy with tamoxifen and/or an AI to either 2 or 5 years of extended therapy with anastrozole. The primary end point was DFS in the 3,208 patients who remained in the study after 2 years. Secondary end points included OS, time to contralateral breast cancer, time to second primary cancer, fractures, and toxicity.[87]

The phase III ABCSG-16 study enrolled 3,484 postmenopausal women with hormone receptor–positive breast cancer who had completed 5 years of endocrine therapy with tamoxifen and/or an AI to either 2 or 5 years of extended therapy with anastrozole. The primary end point was DFS in the 3,208 patients who remained in the study after 2 years. Secondary end points included OS, time to contralateral breast cancer, time to second primary cancer, fractures, and toxicity.[87]

After 10 years of follow-up, there was no difference in DFS between the two arms (73.6% for the 2-year course vs. 73.9% for the 5-year course [HR, 0.99; 95% CI, 0.85–1.15; P = .90]). In addition, there was no difference in OS, time to second primary cancer, and time to contralateral breast cancer between the arms.[87][Level of evidence B1]

The phase III ABCSG-16 study enrolled 3,484 postmenopausal women with hormone receptor–positive breast cancer who had completed 5 years of endocrine therapy with tamoxifen and/or an AI to either 2 or 5 years of extended therapy with anastrozole. The primary end point was DFS in the 3,208 patients who remained in the study after 2 years. Secondary end points included OS, time to contralateral breast cancer, time to second primary cancer, fractures, and toxicity.[87]

There was a trend toward more fractures in the 5-year arm (4.7% vs. 6.3%; HR, 1.35; 95% CI, 1.00–1.84).

An open-label trial in Japan included 1,697 patients who had received either (1) 5 years of anastrozole or (2) 2 to 3 years of tamoxifen, followed by 2 to 3 years of anastrozole. Patients were randomly assigned to either discontinue anastrozole or continue it for 5 years. The primary end point was DFS.[88]

An open-label trial in Japan included 1,697 patients who had received either (1) 5 years of anastrozole or (2) 2 to 3 years of tamoxifen, followed by 2 to 3 years of anastrozole. Patients were randomly assigned to either discontinue anastrozole or continue it for 5 years. The primary end point was DFS.[88]

In an analysis done after all patients had completed protocol therapy, DFS was improved in the continued-therapy group (5-year DFS rate, 91% vs. 86%; HR, 0.62; 95% CI, 0.46–0.83; P < .0010).[88][Level of evidence B1]

An open-label trial in Japan included 1,697 patients who had received either (1) 5 years of anastrozole or (2) 2 to 3 years of tamoxifen, followed by 2 to 3 years of anastrozole. Patients were randomly assigned to either discontinue anastrozole or continue it for 5 years. The primary end point was DFS.[88]

There was no difference in distant DFS or OS.