Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group.

BACKGROUND: An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications. METHODS: A panel of experts, convened to design an objective, simple, and reproducible assessment tool to evaluate mucositis with specific application to multicenter clinical trials, developed a scale that measured objective and subjective indicators of mucositis. Nine centers participated in the study's validation. Paired investigators at each center evaluated patients receiving chemotherapy or head and neck radiation. Objective measures of mucositis evaluated ulceration/pseudomembrane formation and erythema. Subjective outcomes of mouth pain, ability to swallow, and function were measured. Analgesia use for mouth sensitivity was recorded. RESULTS: One hundred eight chemotherapy and 56 radiation therapy patients were evaluated. Seventy-eight percent of chemotherapy patients and 64% of radiation therapy patients had clinically significant mucositis. Cumulative daily mucositis scores demonstrated a high correlation among observers. Using area under the curve analysis, it was found that for chemotherapy patients, the highest correlations (correlation coefficient > 0.92) occurred for the scores that selected the three highest daily values over the course of mucositis assessment. High interobserver correlations were noted for patients receiving radiation therapy. Objective mucositis scores demonstrated strong correlation with symptoms. CONCLUSIONS: The scoring system evaluated was easily used, showed high interobserver reproducibility, was responsive over time, and measured those elements deemed to be associated with mucositis. The use of concomitant symptomatic measurements appeared to be unnecessary.

Fadrozole hydrochloride in postmenopausal patients with metastatic breast carcinoma.

BACKGROUND: Fadrozole hydrochloride (CGS-16949A) belongs to the class of aromatase inhibitors that lowers circulating estrogen levels by inhibiting the conversion of androgens to estrogens, thereby causing tumor regression in patients with breast carcinoma. METHODS: This was a prospective, randomized, Phase II study of fadrozole hydrochloride in postmenopausal patients with metastatic breast carcinoma. The three treatment groups received, respectively, fadrozole hydrochloride 0.6 mg three times daily, 1 mg twice daily, and 2 mg twice daily orally. RESULTS: Fifty-six patients were entered on protocol and 54 were eligible (2 patients were perimenopausal). Eight patients had received no prior therapy, 15 patients had received prior hormonal therapy, 5 patients had received prior chemotherapy, and 28 patients had received both. After 12 weeks of treatment, 2 complete and 3 partial responses were observed. Forty patients continued treatment beyond 12 weeks, and 3 additional responses were achieved. Thus, 8 of 56 patients responded (14% overall response rate). Responses did not appear to be dose-related. The median duration of response was 36 months (range, 8-45 months). Subjective toxicity was mild to moderate and appeared more frequent on the 2 mg twice daily dosing schedule. No objective toxicity in laboratory parameters was observed. No patient had severe or life-threatening toxicity. Fadrozole hydrochloride plasma concentrations (obtained every 2 weeks for 12 weeks) appeared to be dose-dependent and noncumulative. CONCLUSIONS: This study confirms modest activity of fadrozole hydrochloride in a heterogeneous group of patients with breast carcinoma treated at three different dose levels.

The pharmacodynamic inhibition of estrogen synthesis by fadrozole, an aromatase inhibitor, and its pharmacokinetic disposition.

In this dose-ranging phase I study, the relationship between in vivo androgen to estrogen conversion kinetics and plasma concentrations of fadrozole was investigated in postmenopausal women receiving therapy with this aromatase inhibitor. Patients received ascending doses, ranging from 0.3-8 mg fadrozole twice daily, each for a period of 2 weeks. Drug kinetics and endocrine effects were evaluated specifically for the 2- and 8-mg twice daily treatment regimens. The in vivo activity of the drug was demonstrated by the suppression of estrone and estradiol biosynthesis from testosterone and androstenedione, respectively. The drug inhibitory constant, KI, for the estrone synthetic pathway, was 3.0 ng/mL (13.4 nmol/L) and was of similar magnitude as that determined under in vitro conditions. The KI for the estradiol synthetic pathway was 5.3 ng/mL (23.7 nmol/L). The disparity between KI values may indicate that the two pathways are not equivalent in terms of their inhibition by fadrozole. Pharmacokinetic data demonstrated tha the drug was rapidly absorbed after oral dosing, with peak plasma concentrations achieved in median times of 1 and 2 h, respectively, for the 2- and 8-mg twice daily treatment regimens. The average half-life and oral clearance values were 10.5 h and 621 mL/min, respectively. Oral clearance was independent of dose.

A phase I trial of CGS 16949A. A new aromatase inhibitor.

CGS 16949A is a new, nonsteroidal competitive inhibitor of the aromatase enzyme. In this Phase I trial, 16 heavily pretreated postmenopausal patients with metastatic breast cancer were treated with escalating doses of CGS 16949A from 0.6 to 16 mg total daily oral dose. No hematologic, biochemical, or significant clinical toxicity was encountered. Endocrinologic and pharmacologic data were available from 12 of these patients. Maximum inhibition of estrogen biosynthesis was observed at a dose of 2 mg CGS 16949A daily. At this dose, the inhibition of estrogen biosynthesis was equivalent to 1000 mg aminoglutethimide (AG). The fall in plasma and urinary estrogens without a concomitant drop in androgens confirmed the specific blockade of aromatase activity. At doses of 4 to 16 mg daily, CGS 16949A appeared to inhibit the C21-hydroxylase enzyme as well. The t1/2 of CGS 16949A in the circulation was 10.5 hours. Of 16 evaluable patients there were two partial responses and seven patients with stable disease.