Doxorubicin Hydrochloride (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxorubicin treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. Doxorubicin was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.

Doxorubicin decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area)

A single intravenous dose of 0.1 mg/kg doxorubicin (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

14 CLINICAL STUDIES

The clinical efficacy of doxorubicin containing regimens for the post-operative, adjuvant treatment of surgically resected breast cancer was evaluated in a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin containing regimens with CMF as an active control (6 trials including 3510 patients). Data from the meta-analysis of trials comparing CMF to no therapy were used to establish the historical treatment effect size for CMF regimens. The major efficacy outcome measures were disease-free survival (DFS) and overall survival (OS).

Of the 3510 women (2157 received doxorubicin containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. The analyses demonstrated that doxorubicin containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI, 0.8 to 1.01 ) and on OS with a HR of 0.91 (95% CI, 0.8 to 1.03 ). Results of these analyses for both DFS and OS are provided in Table 2 and Figures 1 and 2.

Table 2. Summary of Randomized Trials Comparing Doxorubicin Containing Regimens Versus CMF in Meta-Analysis

Study (starting year)	Regimens	No. of Cycles	No. of Patients	Doxorubicin Containing Regimens vs. CMF HR** (95% CI)
				DFS	OS
NSABP B-15 (1984)	AC CMF	4 6	1562* 776	0.93 (0.82 to 1.06)	0.97 (0.83 to 1.12)
SECSG 2 (1976)	FAC CMF	6 6	260 268	0.86 (0.66 to 1.13)	0.93 (0.69 to 1.26)
ONCOFRANCE (1978)	FACV CMF	12 12	138 113	0.71 (0.49 to 1.03)	0.65 (0.44 to 0.96)
SE Sweden BCG A (1980)	AC CMF	6 6	21 22	0.59 (0.22 to 1.61)	0.53 (0.21 to 1.37)
NSABC Israel Br0283 (1983)	AVbCMF† CMF	4 6 6	55 50	0.91 (0.53 to 1.57)	0.88 (0.47 to 1.63)
Austrian BCSG 3 (1984)	CMFVA CMF	6 8	121 124	1.07 (0.73 to 1.55)	0.93 (0.64 to 1.35)
Combined Studies	Doxorubicin Containing Regimens CMF		2157 1353	0.91 (0.82 to 1.01)	0.91 (0.81 to 1.03)

Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin, cyclophosphamide; AVbCMF = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin; FAC = 5-fluorouracil, doxorubicin, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval

* Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4
cycles followed by 3 cycles of CMF.
** a hazard ratio of less than 1 indicates that the treatment with doxorubicin containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF.

† Patients received alternating cycles of AVb and CMF.