In this multicentered, controlled trial, administration of ZOLADEX (3.6 mg depot) and flutamide capsules (250 mg t.i.d.) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P =0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P < 0.001).

Endometriosis: In controlled clinical studies using the 3.6 mg formulation every 28 days for 6 months, ZOLADEX was shown to be as effective as danazol therapy in relieving clinical symptoms (dysmenorrhea, dyspareunia, and pelvic pain) and signs (pelvic tenderness, pelvic induration) of endometriosis and decreasing the size of endometrial lesions as determined by laparoscopy. In one study comparing ZOLADEX with danazol (800 mg/day), 63% of ZOLADEX-treated patients and 42% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. In the second study comparing ZOLADEX with danazol (600 mg/day), 62% of ZOLADEX-treated and 51% of danazol-treated patients had a greater than or equal to 50% reduction in the extent of endometrial lesions. The clinical significance of a decrease in endometriotic lesions is not known at this time; and in addition, laparoscopic staging of endometriosis does not necessarily correlate with severity of symptoms.

In these two studies, ZOLADEX led to amenorrhea in 92% and 80%, respectively, of all treated women within 8 weeks after initial administration. Menses usually resumed within 8 weeks following completion of therapy.

Within 4 weeks following initial administration, clinical symptoms were significantly reduced, and at the end of treatment were, on average, reduced by approximately 84%.

During the first two months of ZOLADEX use, some women experience vaginal bleeding of variable duration and intensity. In all likelihood, this bleeding represents estrogen withdrawal bleeding, and is expected to stop spontaneously.

There is insufficient evidence to determine whether pregnancy rates are enhanced or adversely affected by the use of ZOLADEX.

Breast Cancer: The Southwest Oncology Group conducted a prospective, randomized clinical trial (SWOG-8692 [INT-0075]) in premenopausal women with advanced estrogen receptor positive or progesterone receptor positive breast cancer which compared ZOLADEX with oophorectomy. On the basis of interim data from 124 women, the best objective response (CR+PR) for the ZOLADEX group is 22% versus 12% for the oophorectomy group. The median time to treatment failure is 6.7 months for patients treated with ZOLADEX and 5.5 months for patients treated with oophorectomy. The median survival time for the ZOLADEX arm is 33.2 months and for the oophorectomy arm is 33.6 months.

Subjective responses based on measures of pain control and performance status were observed with both treatments; 48% of the women in the ZOLADEX treatment group and 50% in the oophorectomy group had subjective responses. In the clinical trial (SWOG 8692 [INT 0075]), the mean post treatment estradiol level was reported as 17.8 pg/mL. (The mean estradiol level in post-menopausal women as reported in the literature is 13 pg/mL). During the conduct of the clinical trial, women whose estradiol levels were not reduced to the postmenopausal range, received two ZOLADEX depots, thus, increasing the dose of ZOLADEX from 3.6 mg to 7.2 mg.

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