Correlation of Doxil Toxicity with Pharmacokinetics in Metastatic Breast Carcinoma
ABSTRACT & COMMENTARY
Synopsis: Pegylated liposomal Doxorubicin (Doxil) has antitumor activity in patients previously treated with anthracyclines and has a pharmacokinetic and toxicity profile that differs from that of non-pegylated Doxorubicin. Palmar-plantar erythrodysesthesia (PPE), mucositis, and, to a lesser extent, myelosuppression, are typical dose-limiting toxicities. PPE has been particularly problematic with Doxil administration, especially on an every-three-weeks schedule. Significant clinical activity occurs in patients with ovarian cancer, Kaposi sarcoma, and breast cancer. A previous study in Kaposi sarcoma suggested that response was correlated with maximal drug concentration (Cmax). Lyass and colleagues reported a correlation between the plasma half-life (T½) of Doxil and the occurrence of PPE while mucositis and leukocyte nadir correlated with the Cmax. Most of the objective antitumor responses in this small study occurred when Doxil was given at higher doses less frequently. This study demonstrated the ability to give higher doses of Doxil with longer cycling times and apparently maintain the therapeutic efficacy. When given in higher doses less frequently, the toxicity pattern of Doxil changes with stomatitis becoming the more predominant dose-limiting toxicity. Patients who develop PPE may better tolerate the same Doxil dose intensity if given higher doses less frequently.
Source: Lyass O, et al. Cancer 2000;89:1037-1047.
This study treated 45 women with metastatic breast cancer (32 of whom had previously received Doxorubicin or Mitoxantrone in an adjuvant or metastatic setting) with Doxil using six different dosing regimens of approximately equal dose intensity. Doses ranged between 35 and 70 mg/m2 and were given every 3-6 weeks, depending on the dose. The dose intensity of all regimens was between 12 and 15 mg/m2 per week. Doxil pharmacokinetics were obtained in 24 patients at four different dose levels. The development of PPE was correlated with the T½ of Doxil while myelosuppression and stomatitis correlated with the Cmax. Grade 2-3 PPE occurred in eight out of 11 patients receiving 35 mg/m2 every three weeks while in only one out of five patients receiving similar dose intensity of 50 mg/m2 every four weeks. Conversely, grade 2-3 stomatitis occurred in four out of 11 patients and four out of five patients on these two schedules, respectively. The frequency and severity of mucositis increased progressively when higher doses of Doxil were given at intervals of five or six weeks while the incidence of PPE remained relatively low. The median Cmax for all patients receiving Doxil was 24.6 mg/L and the median T½ was 79.4 hours. Eight of nine patients with a Cmax greater than the median developed a grade 2-4 stomatitis and seven of nine patients with a T½ greater than the median developed PPE. Comparatively, of the patients with grade 0-1 stomatitis or PPE, only four of 15 and three of 12, respectively, had Cmax and T½ values greater than the median. Dose and Cmax, but not T½, correlated significantly with the leukocyte nadir count and the stomatitis grade. Conversely T½, but not dose or Cmax, correlated with PPE grade. The volume of distribution for Doxil approximated that of the plasma. Nine out of 45 patients exhibited objective tumor regressions and an additional six patients had improvement of their disease for 4-25 months but did not meet the criteria for partial response. Six out of 21 (29%) patients who received doses between 35 and 50 mg/m2 had evidence of antitumor effect compared to nine out of 24 (38%) patients who received between 60 and 70 mg/m2. At the ends of spectrum of schedules tested, two of 11 patients receiving 35 mg/m2 every three weeks had an objective antitumor response compared to four out of 12 patients receiving 70 mg/m2 every six weeks.
COMMENT BY MICHAEL J. HAWKINS, MD
Pegylated Liposomal Doxorubicin has a prolonged T½ that alters its toxicity profile and apparently results in greater accumulation in tissues when compared to free Doxorubicin.
The toxicity profile is relatively mild and the drug is generally well tolerated by patients. The most disturbing toxicity is PPE, which frequently requires prolongation of the treatment cycle beyond three weeks. These researchers explored a number of Doxil treatment regimens with dose intensities between 12-15 mg/m2/wk. Higher doses with longer cycle times were associated with more stomatitis and myelosuppression while more frequent administration, especially every three weeks, was associated with a high incidence of PPE. There has been speculation that the every three-week-dosing cycle may be particularly problematic because of the increased tissue distribution seen with liposomal preparations. Since PPE typically does not occur before the second or third cycle, it is possible that Doxil is being distributed in sensitive tissues during a period of subclinical inflammation. Although the number of patients was small, there was no apparent loss of anti-tumor activity when the dose and treatment interval were increased. Prevention of recurrence of PPE was best achieved by prolongation of dosing intervals from three weeks to four or five weeks. Higher doses less frequently may be better tolerated in some patients, especially those who clear Doxil more slowly. To date, there are no data to suggest that these regimens would be associated with a loss of antitumor activity as long as a dose intensity of 12 mg/m2/wk is maintained.
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