Among patients with soft tissue sarcomas, those who received doxorubicin cumulative doses greater than 450 mg/m2, most of whom also received dexrazoxane, had a low rate of cardiotoxicity, according to the results of a study published in Clinical Cancer Research.

Investigators retrospectively analyzed cardiotoxicity safety data from the double-blind, randomized, phase 3 ANNOUNCE trial ( Identifier: NCT02451943) of doxorubicin plus olaratumab (monoclonal antibody to platelet-derived growth factor receptor α [Eli Lilly and Company]) in patients with advanced soft tissue sarcomas.

A total of 509 patients (median age, 57 [range, 29-82]; 58.2% women) were included in the study. Patients were naive to treatment with anthracycline, and their disease status at randomization was metastatic in 422 participants (82.9%) and locally advanced in 87 (17.1%). The participants’ median left ventricular ejection fraction (LVEF) at baseline was 65%.

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Patients could receive as many as 8 cycles of doxorubicin 75 mg/m2. The researchers had discretion to administer dexrazoxane before administration of doxorubicin and it was recommended in patients who received 5 or more cycles. Deterioration in LVEF was measured with echocardiogram or multigated acquisition scan and defined as a decrease to less than 50% or a decrease of greater than 10% from baseline value.

Of the 506 patients who had at least 1 study treatment, 504 (99.6%) received at least 1 cycle of doxorubicin, 347 (68.6%) received at least 4 cycles, 287 (56.7%) received at least 6 cycles, and 219 (43.3%) received 8 cycles. Two-thirds of patients (n=324, 64.0%) received at least 1 dose of dexrazoxane

Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450 to <600 mg/m2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. Median follow-up for cardiac adverse events was 6.4 months (range, 1.0-36.6 months), and the median follow-up of LVEF by echocardiogram/multigated acquisition was 11.4 months (range, 0.03-36.5 months).

LVEF decreases were observed in 62/153 patients (40.5%) who received a doxorubicin cumulative dose less than 450 mg/m2, 82/159 (51.6%) who received 450 to less than 600 mg/m2, and 50/89 (56.2%) who received at least 600 mg/m2. Most cases of reduced LVEF involved patients who had an absolute decrease from baseline >10%.

Grade ≥3 cardiac dysfunction occurred in 2% of patients who received a doxorubicin cumulative dose of less than 450 mg/m2, 3% at 450 to less than 600 mg/m2, and 1.1% who received at least 600 mg/m2. The incidence of treatment-related cardiac adverse events was low for all doxorubicin cumulative dose ranges.

The investigators noted that their findings are limited by the relatively short follow-up for cardiac events (median, 28 weeks), and the original trial was not designed to collect detailed cardiac safety data.

“Our study is important as it highlights the safety and feasibility of administering doxorubicin at a dose of 75 mg/m2 to 8 cycles (cumulative dose, 600 mg/m2) with dexrazoxane cardioprotection,” stated the researchers.

Disclosure: This study was funded by Eli Lilly and Company. Some of the authors reported affiliations with Eli Lilly and other pharmaceutical companies. Please see the original reference for a full list of disclosures.


Jones RL, Wagner AJ, Kawai A, et al. Prospective evaluation of doxorubicin cardiotoxicity in advanced soft tissue sarcoma patients treated in the ANNOUNCE phase 3 randomized trial. Clin Cancer Res. Published online February 25, 2021. doi: 10.1158/1078-0432.CCR-20-4592