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Clinical Trial
. 2021 Jul 15;27(14):3861-3866.
doi: 10.1158/1078-0432.CCR-20-4592. Epub 2021 Feb 25.

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial

Robin L Jones  1   2 , Andrew J Wagner  3   4 , Akira Kawai  5 , Kazuo Tamura  6 , Ashwin Shahir  7 , Brian A Van Tine  8 , Javier Martín-Broto  9 , Patrick M Peterson  10 , Jennifer Wright  10 , William D Tap  11
Affiliations
Clinical Trial

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial

Robin L Jones et al. Clin Cancer Res. .

Abstract

Purpose: Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943).

Patients and methods: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m2. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%.

Results: A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m2 (range, 72.3-634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450-<600 mg/m2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m2, 82 of 159 patients (51.6%) who received 450-<600 mg/m2, and 50 of 89 patients (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m2, 3% at 450-<600 mg/m2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs was low across all dose ranges.

Conclusions: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration.See related commentary by Benjamin and Minotti, p. 3809.

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Conflict of interest statement

Conflicts of interest:

Dr R.L. Jones reports receiving personal fees for consulting apart from the submitted work from Eli Lilly and Company, Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Merck, and PharmaMar.

Dr A.J. Wagner reports receiving personal fees for consulting from Eli Lilly and Company, Daiichi-Sankyo, Five Prime Therapeutics, Novartis, Deciphera, and NanoCarrier; and grants to his institution from Eli Lilly and Company, Daiichi-Sankyo, Karyopharm, Aadi Biosciences, and Plexxikon.

Dr A. Kawai reports receiving personal fees for travel to meetings and participation in review activities from Eli Lilly and Company for this trial. Apart from the submitted work, Dr A. Kawai reports receiving personal fees from Novartis, Eisai, Takara Bio, Taiho, and Daiichi Sankyo.

Dr K. Tamura reports receiving personal fees for consulting apart from the submitted work from Eli Lilly and Company, Eisai, SymBio and AC Medical.

Dr B.A. Van Tine reports receiving Basic Science Grant Funding from Pfizer, Tracon, and Merck; consulting fees from Epizyme, Lilly, CytRX, Janssen, Immune Design, Daiichi Sankyo, Plexxicon and Adaptimmune; speaking fees from Caris, Janseen and Lilly; and is on the scientific advisory board of Polaris Inc.

Dr J Martin-Broto reports grants to his institution and personal fees for preclinical and clinical trials from Eli Lilly and Company and PharmaMar; grants to his institution from Eisai, Novartis, GSK, and Lixte; and non-financial support for clinical trials from Karyopharm, Celgene, Pfizer, Bristol Myers Squibb, Blueprint, Deciphera, Nektar, Forma, Amgen, and Daiichi-Sanchyo.

Drs P. Peterson, A. Shahir, and J. Wright are employees and stockholders of Eli Lilly and Company.

Dr W.D. Tap reports receiving a standard budget from Eli Lilly and Company for site participation for the original trial. Apart from the submitted work, Dr. W.D. Tap reports receiving personal fees from Eli Lilly and Company, EMD Serono, Novartis, Eisai, Janssen, Immune Design, Deciphera, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, Agios Pharmaceuticals, and NanoCarrier. In addition, Dr W.D. Tap reports having a patent pending to MSKCC/SKI for Companion Diagnostic for CDK4 inhibitors 14/854,329; Advisory Board participation for and stock ownership of both Certis Oncology Solutions and Atropos Therapeutics; and consulting for Daiichi Sankyo FDA Oncologic Drugs Advisory Committee meeting on pexidartinib.

Comment in

References

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