Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial

Abstract

The combination therapy of doxorubicin and trastuzumab has been proven to be highly effective for metastatic breast cancer (MBC) patients with Her2/neu over-expressing tumors. However, this regimen is characterized by frequent cardiac toxicity, occurring in 27% of all treated patients and aggravating when the two substances are given concurrently. Pegylated liposomal doxorubicin (PLD) as a single agent reduces significantly cardiac toxicity and maintains efficacy compared to conventional doxorubicin. This prospective open labeled, multicenter phase II study assessed the potential cardiotoxicity and efficacy of PLD and trastuzumab as first and second line combination therapy in Her2/neu over-expressing MBC patients. Patients with Her2 over-expressing, measurable MBC with a baseline left ventricular ejection fraction (LVEF) C50% were treated with PLD 40 mg/m 2 every 4 weeks for 6 up to 9 cycles and weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg). Cardiotoxicity was defined as the appearance of clinical signs or symptoms of congestive heart failure in combination with a decrease in LVEF B44% or C10 units below the normal value of 50% in the obligatory, subsequently performed transthoracic echocardiography. Due to conflicting interests, the planned accrual goal of 30 patients was not reached. Finally 16 patients were enrolled. Ten patients presented with more than one metastatic site and six of them were in second-line therapy. The median LVEF in the study cohort was 66.1 ± 8.68% at baseline, 62.7 ± 5.11% after 6 cycles of therapy, 64.4 ± 7.61% at the first follow up and did not change significantly (61.0 ± 5.56% even at the 5th followup). Six out of 12 assessable patients (50.0%) demonstrated a clinical benefit and after a median follow-up of 15.4 months a median progression free survival of 9.67 and a median overall survival of 16.23 months. Non-cardiac side effects were mild with only 3 CTC grade 3 events of 247 treatment cycles (1.2%) and no grade 4 toxicities. The combination of PLD and trastuzumab in patients with Her2/neu over-expressing metastatic breast cancer is a safe, feasible and effective therapy. However, cardiac function should be monitored at close intervals. Due to the promising clinical response rates and mild toxicity profile in this prognostically unfavorable group, this combination therapy should be evaluated in larger studies.

Never use anthracyclines with trastuzumab: it is time to reconsider the taboo

“…On statistical and clinical grounds both aspects of the conduct of the trial substantially limit the wider applicability of the safety and efficacy findings of the report to the population of patients with HER2-positive breast cancer. However, as pointed out by the Authors [7], the study goes in the same direction of many other reports that are reconsidering the combination of anthracyclines and trastuzumab as a relevant treatment option for women with HER2 positive breast cancer. These studies were recently reviewed and all together challenge the tenet that combining anthracyclines and trastuzumab should be avoided [8].…”

“…In this issue of the Journal E. Stickeler et al [7] publish a small but provocative study showing that the combination of pegylated lipomosal doxorubicin (PLD) and trastuzumab is feasible without excessive cardiac events and associated with promising antitumor activity. The study accrued only 16 of the 30 patients originally planned.…”

“…The study accrued only 16 of the 30 patients originally planned. In addition it was designed to enroll patients with prior exposure to a maximum of 400 mg/m 2 of doxorubicin or 600 mg/m 2 of the less cardiotoxic epirubicin, but only three of the women who participated in the trial had previously received anthracyclines [7]. On statistical and clinical grounds both aspects of the conduct of the trial substantially limit the wider applicability of the safety and efficacy findings of the report to the population of patients with HER2-positive breast cancer.…”

Cardiovascular Complications Caused by Chemotherapy and Targeted Agents

“…Ответом на этот вопрос могут быть результаты пяти исследований, в которых в каче-стве партнера для трастузумаба был избран пегилиро-ванный липосомальный доксорубицин [21][22][23][24][25].…”

“…Таким образом, один из важнейших выводов, сделанных авторами исследования, демон-стрировал равную противоопухолевую эффективность обеих лекарственных форм. Возвращаясь к возможности безопасной комби-нации ПЛД с трастузумабом, обратимся к двум упомя-нутым ранее исследованиям II фазы: E. Stickeler [24] и C. Christodolou [25] с соавторами. В первом из них, небольшом, объединившем 16 больных мРМЖ, которые получали комбинацию еженедельного трастузумаба с ПЛД 40 мг/м 2 1 раз в 4 недели, оценивалась эффектив-ность и кардиотоксичность использованного режима.…”