droloxifene and Neoplasm-Metastasis

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Topics: Adult; Anastrozole; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Estrogen Antagonists; Female; Forecasting; Humans; Indoles; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Osteoporosis; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

Droloxifene, a new antiestrogen, has theoretical advantages over tamoxifen based on preclinical data. These include higher affinity to the estrogen receptor, higher antiestrogenic to estrogenic ratio, and more effective inhibition of cell growth and division in ER positive cell lines, as well as less toxicity, including reduced carcinogenicity in animal models. Droloxifene also exhibits more rapid pharmacokinetics, reaching peak concentrations and being eliminated much more rapidly than tamoxifen. A phase II study compared droloxifene in dosages of 20, 40, and 100 mg daily in postmenopausal women with metastatic, or inoperable recurrent, or primary locoregional breast cancer who had not received prior hormonal therapy. Of 369 patients randomized, 292 were eligible and 268 evaluable for response. Response rates (CR + PR) were 30% in the 20 mg group, 47% in the 40 mg group, and 44% in the 100 mg group (40 mg vs 20 mg, p = 0.02; 100 mg vs 20 mg, p = 0.04; pooled 40 + 100 mg vs 20 mg, p = 0.01). Median response duration also favoured the higher dosages (20 mg group = 12 months; 40 mg group = 15 months; 100 mg group = 18 months). When adjusted for prognostic factors, time to progression was significantly better for the 100 mg (p = 0.01) and the 40 mg (p = 0.02) group compared to the 20 mg group. Droloxifene increased SHBG and suppressed FSH at all dosages and suppressed LH at the 40 and 100 mg dosages. These hormonal effects increased with increasing dosage. Short-term toxicity was generally mild, and similar to that seen with other antiestrogens. Droloxifene appears active and tolerable. It may have a particular role in situations in which rapid pharmacokinetics, or an increased antiestrogenic to estrogenic ratio, are required.

Topics: Breast Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Postmenopause; Prognosis; Tamoxifen; Time Factors

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Resistance; Estrogen Antagonists; Female; Humans; Middle Aged; Neoplasm Metastasis; Tamoxifen; Treatment Outcome

To determine the optimal daily dose of a new antiestrogen, droloxifene, for the treatment of advanced breast cancer, we have conducted a multicenter, randomized, double blind trial. Postmenopausal women with advanced breast cancer, who could not benefit from loco regional therapy, with positive or unknown estrogen or progesterone receptors were entered in this study. Droloxifene was administered in a double blind randomized design, with daily dose of either 20 (group I), 40 (group II) or 100 mg (group III). None of the patients had received previous systemic antitumor therapy, with the exception of adjuvant chemotherapy terminated at least one year before the patient's recruitment. Patients with at least one measurable tumoral lesion were entered into the trial. Three hundred and sixty nine patients have been enrolled, 234 are fully evaluable for efficacy. Objective response rate (CR + PR) is 31.1, 44.6 and 41.9% for the groups I, II and III respectively (P = NS). Time to response has been short: in the three groups, 50% of the responses have been observed within the 2 first months of treatment. Time to disease progression is 6, 8.3 and 6 months respectively for the 20, 40 and 100 mg/day treatment group. Side effects have been moderate and not dose related. Hot flushes and gastro intestinal disorders have been observed most often. This promising new drug deserves further study and randomized comparison versus tamoxifen.

Topics: Aged; Breast Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Estrogen Antagonists; Female; Humans; Middle Aged; Neoplasm Metastasis; Postmenopause; Tamoxifen

To determine the optimal daily dose of the new antiestrogen droloxifene for the treatment of breast cancer, a multinational, multicenter, randomized, double-blind, phase II trial was initiated. Postmenopausal women with progressive advanced breast cancer (distant metastatic cancer, inoperable recurrent or primary tumor) with positive or unknown hormone receptor status (estrogen or progesterone) were entered in the study. Droloxifene was administered in a double-blind randomized design with daily doses of either 20, 40, or 100 mg once daily as first-line systemic therapy. None of the patients had received previous systemic antitumor therapy with the exception of adjuvant chemotherapy terminated at least one year before the patient's recruitment. Response was determined according to Union Internationale Contre le Cancer/World Health Organization criteria. Only patients with at least one measurable lesion were entered into the trial. The highest quality of data was achieved in two ways: source verification in the hospitals through monitors and peer review with subgroups of investigators determining the tumor response of each patient at adjudication meetings (evaluating parameters obtained from physical examination and reviewing X-rays and computer tomography scans). To date, 254 patients have been enrolled. Results from all these groups, without breaking the randomization code, based on 131 patients whose data have been verified are as follows: 10 complete responses (CR), 37 partial responses (PR), 47 no change, 29 progressive disease, 8 patients too early to evaluate. Thus, the overall response rate (CR + PR) was 38%. Droloxifene was well tolerated.

Topics: Antineoplastic Agents; Breast Neoplasms; Double-Blind Method; Drug Evaluation; Estrogen Antagonists; Female; Humans; Menopause; Middle Aged; Neoplasm Metastasis; Tamoxifen