Tamoxifen Citrate (Page 2 of 9)

Clinical Studies

Metastatic Breast Cancer:

Premenopausal Women (Tamoxifen Citrate vs. Ablation):

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared tamoxifen citrate to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (tamoxifen citrate/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving tamoxifen citrate, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen citrate therapy responded to subsequent ovarian ablation.

Male Breast Cancer:

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen citrate have shown that tamoxifen citrate is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen citrate which constitutes a 50% objective response rate.

Adjuvant Breast Cancer:

Overview:

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen citrate using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing tamoxifen citrate to no adjuvant therapy and 42% were entered into trials comparing tamoxifen citrate in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen citrate vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen citrate vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen citrate vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen citrate versus 64.3% for control (logrank 2p < 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen citrate, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of tamoxifen citrate on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

Anastrozole Adjuvant ATAC Trial — Study of Anastrozole compared to Tamoxifen Citrate for Adjuvant Treatment of Early Breast Cancer – An anastrozole adjuvant trial was conducted in 9366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, tamoxifen citrate 20 mg daily, or a combination of these two treatments for five years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen citrate did not demonstrate any efficacy benefit when compared with tamoxifen citrate therapy alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY-Special Populations-Drug-Drug Interactions, PRECAUTIONS-Laboratory Tests, PRECAUTIONS-Drug Interactions and ADVERSE REACTIONSsections for safety information from this trial. Please refer to the full prescribing information for ARIMIDEX^® (anastrozole) 1 mg Tablets for additional information on this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anastrozole arm compared to the tamoxifen citrate arm.

Node Positive — Individual Studies:

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when tamoxifen citrate was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen citrate was added to “low-dose” CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen citrate was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of tamoxifen citrate without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen citrate adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

Node Negative — Individual Studies:

NSABP B-14, a prospective, double-blind, randomized study, compared tamoxifen citrate to placebo in women with axillary node-negative, estrogen-receptor positive (≥10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving tamoxifen citrate. This benefit was apparent both in women under age 50 and in women at or beyond age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen citrate compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen citrate appeared to be independent of estrogen receptor status.

Duration of Therapy:

In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to tamoxifen citrate 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional 5 years of tamoxifen citrate or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of tamoxifen citrate were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of tamoxifen citrate (p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95% CI 0.87 to 1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant tamoxifen citrate 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.

Contralateral Breast Cancer:

The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving tamoxifen citrate compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with tamoxifen citrate of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving tamoxifen citrate were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen citrate reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen citrate 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p <0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen citrate 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

Ductal Carcinoma in Situ:

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of tamoxifen citrate or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen citrate therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.

In this trial 1,804 women were randomized to receive either tamoxifen citrate or placebo for 5 years: 902 women were randomized to tamoxifen citrate 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.

The tamoxifen citrate and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen citrate (44 cases — tamoxifen citrate, 74 cases — placebo; p=0.004; relative risk (RR)=0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen citrate groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen citrate and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen citrate therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of tamoxifen citrate therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

Table 1. Major Outcomes of the NSABP B-24 Trial

1 Updated follow-up data (median 8.1 years)
Type of Event	Lumpectomy,radiotherapy, and placebo		Lumpectomy,radiotherapy, and tamoxifen citrate		RR	95% CI Limits
	No. ofevents	Rate per 1000women per year	No. ofevents	Rate per 1000women per year
Invasive breast cancer (Primary endpoint)	74	16.73	44	9.60	0.57	0.39 to 0.84
-Ipsilateral	47	10.61	27	5.90	0.56	0.33 to 0.91
-Contralateral	25	5.64	17	3.71	0.66	0.33 to 1.27
-Sideundertermined	2	—	0	—	—
Secondary Endpoints
DCIS	56	12.66	41	8.95	0.71	0.46 to 1.08
-Ipsilateral	46	10.40	38	8.29	0.88	0.51 to 1.25
-Contralateral	10	2.26	3	0.65	0.29	0.05 to 1.13
All BreastCancer Events	129	29.16	84	18.34	0.63	0.47 to 0.83
-All ipsilateralevents	96	21.70	65	14.19	0.65	0.47 to 0.91
-All contralateralevents	37	8.36	20	4.37	0.52	0.29 to 0.92
Deaths	32		28
UterineMalignancies1	4		9
EndometrialAdenocarcinoma1	4	0.57	8	1.15
Uterine Sarcoma1	0	0.0	1	0.14
Second primarymalignancies(other thanendometrialand breast)	30		29
Stroke	2		7
Thromboembolicevents(DVT, PE)	5		15

Survival was similar in the placebo and tamoxifen citrate groups. At 5 years from study entry, survival was 97% for both groups.