"Nov. 29, 2012 (Chicago) -- For cancer patients undergoing chemotherapy who have found their complaints of general mental fogginess and haziness dismissed by their doctors as not being a real medical condition, vindication has arrived.
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity.
Doxorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generates highly reactive species including the hydroxyl free radical OH•. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level.
Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.
Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy to testes in rats and dogs.
Pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. In four patients, doxorubicin has demonstrated dose-independent pharmacokinetics in the dose range of 30 to 70 mg/m2.
Distribution. The initial distribution half-life of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal half-life of 20 to 48 hours. Steady-state distribution volume ranges from 809 to 1214 L/m2 and is indicative of extensive drug uptake into tissues. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL.
Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approximately 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m2 of doxorubicin given as a 15-minute intravenous infusion and 100 mg/m2 of cisplatin as a 26-hour intravenous infusion. The peak concentration of doxorubicinol in milk at 24 hours was 0.11 µg/mL and AUC up to 24 hours was 9.0 µg.h/mL while the AUC for doxorubicin was 5.4 µg.h/mL.
Doxorubicin does not cross the blood brain barrier.
Metabolism.Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. Disposition of doxorubicinol (DOX-OL) in patients is formation rate limited, with the terminal half-life of DOX-OL being similar to doxorubicin. The relative exposure of DOX-OL, i.e., the ratio between the AUC of DOX-OL and the AUC of doxorubicin, compared to doxorubicin ranges between 0.4 and 0.6.
Excretion. Plasma clearance is in the range 324 to 809 mL/min/m2 and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as DOX-OL over 7 days.
Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.
Pharmacokinetics in Special Populations
Pediatric. Following administration of 10 to 75-mg/m2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m2 . Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older children and approached the range of clearance values determined in adults. Geriatric. While the pharmacokinetics of elderly subjects (=65 years of age) have been evaluated, no dosage adjustment is recommended based on age. (See PRECAUTIONS, Geriatric Use.) Gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hours).
Race.The influence of race on the pharmacokinetics of doxorubicin has not been evaluated.
Hepatic Impairment. The clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).
Renal Impairment. The influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.
The effectiveness of doxorubicin-containing regimens in the adjuvant therapy of early breast cancer has primarily been established based on data collected in a meta-analysis published in 1998 by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG obtains primary data on all relevant studies, both published and unpublished, for early stage breast cancer and regularly updates these analyses. The principal endpoints for the adjuvant chemotherapy trials were disease-free survival (DFS) and overall survival (OS). The meta-analyses allowed comparisons of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and comparisons of doxorubicin-containing regimens with CMF as an active control (6 trials including 3510 patients). The pooled estimates of DFS and OS from these trials were used to calculate the effect of CMF relative to no therapy. The hazard ratio for DFS for CMF compared to no chemotherapy was 0.76 (95% CI 0.71-0.82) and for OS was 0.86 (95% CI 0.80-0.93). Based on a conservative estimate of CMF effect (lower 2-sided 95% confidence limit of hazard ratio) and 75% retention of CMF effect on DFS, it was determined that the doxorubicin-containing regimens would be considered as non-inferior to CMF if the upper 2-sided 95% confidence limit of the hazard ratio was less than 1.06, i.e., not more than 6% worse than CMF. A similar calculation for OS would require a non-inferiority margin of 1.02.
Six randomized trials in the EBCTCG meta-analysis compared doxorubicin-containing regimens to CMF. A total of 3510 women with early breast cancer involving axillary lymph nodes were evaluated; approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS and are effective. The hazard ratio for DFS (dox:CMF) was 0.91 (95% CI 0.82-1.01) and for OS was 0.91 (95% CI 0.81-1.03). Results of these analyses for both DFS and OS are provided in Table 1 and Figures 1 and 2.
Table 1. Summary of Randomized Trials Comparing Doxorubicin-Containing
Regimens Versus CMF in EBCTCG Meta-Analysis
|Study (starting year)||Regimens||No. of Cycles||No. of Patients||Doxorubicin-Containing Regimens vs CMF HR (95%CI)|
|NSABP B-15 (1984)||AC||4||1562*||0.93 (0.82-1.06)||0.97 (0.83-1.12)|
|SECSG 2 (1976)||FAC||6||260||0.86 (0.66-1.13)||0.93 (0.69-1.26)|
|ONCOFRANCE (1978)||FACV||12||138||0.71 (0.49-1.03)||0.65 (0.44-0.96)|
|SE Sweden BCG A (1980)||AC||6||21||0.59 (0.22-1.61)||0.53 (0.21-1.37)|
|NSABC Israel Br0283 (1983)||AVb†||4||55||0.91 (0.53-1.57)||0.88 (0.47-1.63)|
|Austrian BCSG 3(1984)||CMFVA||6||121||1.07 (0.73-1.55)||0.93 (0.64-1.35)|
|Combined Studies||Doxorubicin-Containing Regimens||2157||0.91 (0.82-1.01)||0.91 (0.81-1.03)|
|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.
† Patients received alternating cycles of AVb and CMF.
Figure 1. Meta-analysis of Disease-Free Survival
Figure 2. Meta-analysis of Overall Survival
With respect to DFS, 2 of 6 studies (NSABP B-15 and ONCOFRANCE) met the non-inferiority standard individually and with respect to OS, 1 study met the non-inferiority margin individually (ONCOFRANCE). The largest of the 6 studies in the EBCTCG meta-analysis, a randomized, open-label, multicenter trial (NSABP B-15), was conducted in approximately 2300 women (80% premenopausal; 20% postmenopausal) with early breast cancer involving axillary lymph nodes. In this trial, 6 cycles of conventional CMF was compared to 4 cycles of doxorubicin and cyclophosphamide (AC) and 4 cycles of AC followed by 3 cycles of CMF. No statistically significant differences in terms of DFS or OS were observed. (See Table 1.)
Last reviewed on RxList: 9/11/2008
This monograph has been modified to include the generic and brand name in many instances.
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