NEW YORK The safer and better-tolerated "stealth" form of doxorubicin(Drug information on doxorubicin) has a potential for the treatment of metastatic breast cancer that has not yet been realized due to overly toxic dosing schedules, Charles L. Vogel, MD, of Cancer Research Network, Inc., Plantation, Florida, said at the Chemotherapy Foundation Symposium XIX (abstract 45).
Compared with standard doxorubicin, the toxicity profile of pegylated liposomal doxorubicin (Doxil) includes less alopecia, nausea/vomiting, and neutropenia, and possibly less cardiac dysfunction. However, the high rates of plantar-palmar erythrodysesthesia (PPE) and stomatitis have been a problem, and trials to date have used doses that some investigators think are too high to achieve maximal tolerability.
"Doxil, with a proper development plan, could eventually replace doxorubicin if it is proved to be equivalent, or better," Dr. Vogel said. "And it probably could do that, because of its long half-life, but not with the dose-dense strategies that have been used in past studies."
Pegylated liposomal doxorubicin has a half-life approximately 100 times that of doxorubicin. Its polyethylene glycol (PEG) coating evades the immune system (hence its "stealth" moniker) and remains encapsulated until reaching the tumor, thus increasing drug concentration at the tumor site, as documented in studies of Kaposi’s sarcoma and breast cancer.
Unfortunately, there is very little clinical data on use of Doxil as a single agent in breast cancer. The first major trial in metastatic breast cancer, published in 1997, evaluated a variety of doses in 71 mostly untreated patients. While response rates of 29% to 50% were seen, rates of PPE ranged from 34% to 85%.
"I maintain that these doses (60 mg/m² every 3 weeks, 45 mg/m² every 3 or 4 weeks) were probably too high," Dr. Vogel said. "In fact, there haven’t been studies at doses I think are more tolerable." Subsequently, Israeli investigators reported that higher, protracted doses (every 5 weeks or every 6 weeks) were associated with an increased incidence of stomatitis.
However, the lack of cardiac dysfunction has been encouraging. In studies of liposomal doxorubicin in patients with prior chemotherapy, there was no cardio-toxicity noted at total doses up to 1,260 mg/m², "far higher" than with nonliposomal doxorubicin, Dr. Vogel noted.