Doxorubicin is a chemotherapy agent that doctors use alone or in combination with other treatments such as Velcade (bortezomib), Revlimid (lenalidomide), Thalomid (thalidomide), and/or dexamethasone to treat patients with newly diagnosed and relapsed myeloma. It is administered through infusion or injection into the bloodstream.
A reformulated version of doxorubicin, which is a liposomal-coated form also available under the brand name Doxil. This formulation stays longer in the bloodstream, enabling it to access cancer cells over a longer period of time.
How does doxorubicin work?
Doxorubicin belongs to the anthracycline class of chemotherapy agents. It was first isolated as an antibiotic from Streptomyces bacteria. The anticancer mechanisms of doxorubicin include:
- Binding to genomic DNA and preventing the progression of topoisomerase 2. (Topoisomerase 2 is an enzyme necessary for DNA repair, DNA synthesis, and transcription.)
- Generating toxic reactive oxygen species (ROS), which damage cellular DNA, proteins, and membranes, which induces cell death.
Through these mechanisms, doxorubicin significantly affects the growth and survival of cancer cells, which require robust DNA and protein synthesis in order to multiply.
Doxil in clinical trials
A Phase 1/2 clinical trial (NCT00724568) evaluated the combination of Revlimid, Velcade, Doxil, and dexamethasone (RVDD) in newly diagnosed myeloma patients. A total of 72 patients received four dose levels of treatment in a 21-day cycle for four or eight cycles. This included maximum tolerated dose (MTD) of 25 mg Revlimid, 1.3 mg/m2 Velcade, 30 mg/m2 Doxil, and 20/10 mg dexamethasone. The primary objective was to define an MTD of the combination therapy and evaluate treatment responses.
The results of the study were published in the journal Blood. The most common adverse events (side effects) were fatigue, constipation, peripheral neuropathy, and infection. The partial or better response rates after four and eight cycles were 96% and 95%, respectively; the complete response rates were 29% and 35%, respectively. The estimated 18-month progression-free survival and overall survival rates were 80.8% and 98.6%, respectively. Patients tolerated the combination treatment well.
A Phase 3 randomized clinical trial (NCT00103506) studied the safety and efficacy (effectiveness) of a combination of Doxil and Velcade versus Velcade alone in relapsed myeloma patients. The study randomly assigned 646 patients to receive 1.3 mg/m2 injection into the bloodstream of Velcade on days 1, 4, 8, and 11 of a 21-day cycle for eight cycles either alone or in combination with 30 mg/m2 injection into the bloodstream of Doxil on day 4 of the 21-day cycle for eight weeks. The primary outcome measures included time to disease progression. The secondary outcome measure included overall survival and the number of patients who had treatment-related adverse events.
The results of that study were published in the Journal of Clinical Oncology. The median time to disease progression in patients receiving Doxil plus Velcade was 9.3 months compared to 6.5 months for those receiving Velcade alone. The 15-month survival rate for Doxil plus Velcade was 76% compared to 65% for Velcade alone. The complete plus partial response rates for both treatments were comparable (44% for the combination vs. 41% for Velcade alone). The median duration of response increased from seven months for Velcade alone to 10 months for Doxil plus Velcade. Grade 3 or 4 adverse events were more common in the combination group compared to the Velcade-only group (80% vs. 64%). The combination group showed an increased incidence of grade 3/4 neutropenia (low neutrophil counts), thrombocytopenia (low platelet counts), asthenia (physical weakness), fatigue, diarrhea, and hand-foot syndrome.
Several other clinical trials have demonstrated the safety and efficacy of different combinations of Doxil with other chemotherapy agents in newly diagnosed and relapsed myeloma patients.
The common side effects of doxorubicin are a feeling of weakness, tiredness, fever, nausea, stomatitis (painful redness or sores in the mouth), vomiting, diarrhea, constipation, loss of appetite, hand-foot syndrome, rash, low white blood cell count, thrombocytopenia, and anemia.
Nearly 40% of myeloma patients receiving doxorubicin report peripheral neuropathy.
Doxorubicin also may cause heart-related problems such as congestive heart failure, and infusion reactions during administration.
Last updated: March 17, 2020
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