Liposomal Anthracycline Formulations Spare Heart

SAN ANTONIO—Cardiotoxicity is a constant concern with anthracycline chemotherapy, and one strategy for avoiding it is to use liposomal formulations of doxorubicin. Separate trials of the liposomal-doxorubicin formulations Doxil (or Caelix as it is called outside of the United States) and Myocet in advanced breast cancer were described at the San Antonio Breast Cancer Symposium. Doxil, a pegylated liposome, was tested as monotherapy for advanced breast cancer, while Myocet, a non-pegylated liposome, was combined with Herceptin for that disease. Pegylated and non-pegylated liposomal formulations have different safety profiles, but researchers from each trial reported low rates of toxicity in general and little or no cardiotoxicity in particular, as well as promising response rates. Non-Pegylated Liposome In the cardiac safety and efficacy trial of Myocet (TLC D-99) and Herceptin, reversible cardiotoxicity was seen in two of 37 patients, one of whom had pre-study Herceptin and both of whom had 240 mg/m2 of prior doxorubicin, reported Lauri Welles, MD, Senior Director of Clinical Research, Oncology for Myocet's manufacturer, Elan Pharmaceuticals, which conducted the trial. Cardiac safety has otherwise been documented by multigated (MUGA) imaging scan in the 28 patients who received four or more cycles of the combination regimen. The combination was also associated with less mucositis and less nausea and vomiting than would be expected with standard doxorubicin in this patient population, she said. Dr. Welles, whose coresearchers were from Memorial Sloan-Kettering Cancer Center, Dana-Farber Cancer Institute, and Jewish General Hospital of Montreal, presented data showing an overall response rate of 58 percent in the trial, including a 65% response rate in patients who had no prior Herceptin and 40% in those who had prior Herceptin. “The study showed that Myocet/ Herceptin might reasonably be given to patients with HER2-overexpressing breast cancer who are at increased risk of cardiotoxicity, such as the elderly or those previously treated with anthracyclines,” Dr. Welles said. “Myocet might also raise the anthracycline ceiling and permit higher cumulative anthracycline dosing for patients who are anthracycline-naïve.” Reduced cardiotoxicity represents a real therapeutic advantage for these liposomal anthracyclines, she said. “Conventional doxorubicin could not even be given with Herceptin, due to extremely high rates of clinically significant cardiotoxicity.” Myocet is also associated with significantly less mucositis than conventional doxorubicin, Dr. Welles noted. “Mucositis is one of the chemotherapy side effects that is difficult to control, and it often results in either the need for dose reduction or discontinuation of the drug that caused it.”Figure: Brigitte Mlineritsch, MDThere was also less nausea/vomiting with Myocet compared with conventional doxorubicin, she said, characterizing Myocet as a “kinder, gentler doxorubicin.” She said Elan will continue to study this combination, with the addition of other cytotoxic agents such as cyclophosphamide and the taxanes. Dr. Welles said there are also trials of Myocet in non-Hodgkin's lymphoma (NHL). Given that NHL regimens can be fairly toxic, typically involving three cytotoxic agents plus a corticosteroid, including Myocet in NHL regimens would “show that improved efficacy does not have to come at the cost of worsened toxicity,” she said. Pegylated Liposome In another presentation, Brigitte Mlineritsch, MD, an oncologist in the Outpatient Oncology Department of St. Johannes Hospital in Salzburg, Austria, reported that monotherapy with the liposomal doxorubicin Caelyx was well tolerated as second-line chemotherapy on an outpatient basis, and associated with a high rate of clinical benefit in pretreated patients with metastatic breast cancer. The partial-response rate among 30 patients was 31 percent, and no patient experienced cardiotoxicity. “Caelyx is safe enough to use for outpatient oncology treatment,” Dr. Mlineritsch said. She described her multicenter Phase II study of Caelyx in women who had one prior palliative chemotherapeutic regimen not including doxorubicin. Patients at study entry had adequate bone marrow, hepatic, and renal functions. Left ventricular ejection fraction had to be normal as determined by echocardiography, and the exam was repeated after six cycles of Caelyx. The patients' median age was 61 years (range 39 to 74), and 39 percent had a World Health Organization Performance status of 1. Approximately 18 percent of patients had predominantly visceral metastases. Before treatment with Caelyx, 26 percent of patients had pretreatment with a vinorelbine/gemcitabine combination, 43 percent received vinorelbine/fluorouracil/leucovorin, four percent had capecitabine pretreatment, and 27 percent received CMF (cyclophosphamide, methotrexate, fluorouracil). Patients were treated with Caelyx at 45 mg/m2 weekly for four weeks. The median number of cycles of Caelyx administered was five, with a range of one to eight. There were no complete responses, but 31 percent (9 of 30 patients) had partial responses, and disease stabilization was seen in another 55 percent, for a clinical benefit rate of 86 percent. The median time to progression was 28 weeks (range of 5 to 132), and the median duration of response was 28 weeks (range of 19 to 33). The median overall survival has not been reached, Dr. Mlineritsch said Toxicity was generally low, she reported, with the most common problem Grades 1 or 2 vomiting, seen in 47 percent of the women. Palmar-plantar-erythrodysthesia was experienced by 13 percent of patients, two patients had Grade 2 neutropenia, skin rash was seen in eight percent, alopecia in eight percent, and diarrhea in four percent. “Only one patient showed an acute infusion reaction,” she said, “and cardiotoxicity was not seen at all.” Dr. Mlineritsch said the next Caelyx trial will combine the drug with vinorelbine for elderly breast cancer patients, in whom a low risk of cardiotoxicity is especially important. Tobacco Industry Seeks Research Records In another chapter of the government's war against tobacco, lawyers for the industry have moved aggressively against researchers whose studies are being used as evidence by the Justice Department in a new lawsuit against cigarette makers. The Department sued in 1999, charging that the companies had long been aware of the dangers of their product and conspired to suppress that knowledge. The records were subpoenaed last year, but, with the exception of North Carolina State University, the scientists and the universities at which they work rejected the demand for appointment books, letters, daily schedule logs, and drafts of papers going back to the 1940s. The deadline for handing over the papers recently lapsed, and Harvard, NYU School of Medicine, and the Universities of California, Arizona, and Kentucky are gearing for a battle over what they call an infringement of academic freedom and confidentiality. What they object to is not the opposition's right to have them turn over some scientific records, but to the vast scope of the demands being made, which they characterize as a fishing expedition. Lawyers for cigarette makers have reponded that they need to go over years of research records in order to prove that the scientific community's knowledge about the dangers of smoking was as limited as that of their clients.

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