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.

Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials.

BACKGROUND: Breast cancer patients with prior response to endocrine therapy achieve subsequent benefit from additional endocrine therapies. The efficacy and safety of an aromatase inhibitor, fadrozole HCL, were compared with megestrol acetate in post menopausal patients who had disease progression after receiving antiestrogen therapy either for metastatic disease or as adjuvant therapy. METHODS: In 2 multiinstitutional prospective trials, 683 postmenopausal patients were randomized to receive either fadrozole HCL, 1 mg twice daily, or megestrol acetate, 40 mg 4 times daily, in a double blind fashion after progression on first-line hormonal therapy. Objective response rates, time to progression, survival and safety of the two regimens were compared. RESULTS: Results of intent-to-treat analyses are presented in this study. No significant differences were detected between the two treatment groups in time to progression, objective response rates, duration of response, and survival in either trial. There were no clinically meaningful differences between the treatment groups in the incidence and severity of adverse experiences, except that weight gain, fluid retention, and dyspnea were observed in more patients in the megestrol acetate group compared with those receiving fadrozole HCL, whereas nausea and vomiting were observed in more patients in the fadrozole HCL group compared with those receiving megestrol acetate. CONCLUSIONS: Fadrozole HCL was as efficacious as megestrol acetate in postmenopausal patients with metastatic breast carcinoma after one hormonal therapy. Adverse experiences were mild with both therapies, but megestrol acetate was associated wiht a higher frequency of weight gain, fluid retention and dyspnea, whereas fadrozole HCL was associated with a higher frequency of nausea and vomiting.

The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer.

Fadrozole hydrochloride at a dose of 2 mg b.i.d. has been shown to be an effective aromatase inhibitor in advanced stage breast cancer patients as determined by its ability to significantly suppress endogenous estrogen biosynthesis over a 12-week period. Continued suppression of circulating estrogen levels over a prolonged period has not yet been examined in published reports. In this study, we report the extended use of fadrozole hydrochloride at a maintenance dose of 2 mg b.i.d. in a cohort of 11 patients extending to 973 days of therapy. Results show that the degree of suppression of plasma and urinary estrogens was maintained in all patients throughout the extended period of drug use. Continued estradiol suppression of over 50% or greater from baseline was observed, as was continued suppression of estrone to over 80% from baseline. Cortisol determinations after 9 months of treatment showed no suppression from baseline. The aldosterone values and responses to cortrosyn stimulation continued to be suppressed as first noted following the initial 3 months of the core clinical trial. Objective tumor response noted in the core clinical trial did not change until disease progression. These findings suggest that fadrozole hydrochloride maintains its ability to suppress the aromatase enzyme during long term use. No observable escape from suppression of plasma and urinary estrogens occurred during prolonged treatment.

Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor.

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.

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.