Doxorubicin hydrochloride is given by intravenous injection of a solution in sodium chloride 0.9% into a fast-running infusion of sodium chloride 0.9% or glucose 5% over 3 minutes or more. When used as a single agent, the dose is 60 to 75 mg/m2, or 1.2 to 2.4 mg/kg, once every 3 weeks. Alternatively, doses of 20 to 25 mg/m2 have been given daily for 3 days every 3 weeks, although dividing the dose in this way may increase the incidence of mucositis. A regimen of 20 mg/m2 as a single weekly dose may be used, and is reported to be associated with a lower incidence of cardiotoxicity.
Doses may need to be reduced if doxorubicin is given with other antineoplastics: a dose of 30 to 40 mg/m2 every 3 weeks has been suggested. Doses should also be reduced in patients with liver dysfunction.
The maximum total dose should not exceed 450 to 550 mg/m2; in patients who have received radiotherapy to the chest, or other cardiotoxic drugs, it may be advisable to further limit the total dose.
In the management of AIDS-related Kaposi’s sarcoma pegylated liposomal doxorubicin hydrochloride is given in a dose of 20 mg/m2 infused over 30 minutes once every 2 to 3 weeks. For the treatment of breast and ovarian cancers, the suggested dose of this liposomal formulation is 50 mg/m2 infused over 1 hour once every 4 weeks. In these three conditions, treatment should be continued for as long as the patient responds satisfactorily and tolerates treatment. The pegylated liposomal formulation should be diluted only with glucose 5%.
A non-pegylated liposomal formulation is also available and contains a doxorubicin citrate complex prepared with the aid of doxorubicin hydrochloride. It is given in the treatment of metastatic breast cancer in doses equivalent to doxorubicin hydrochloride 60 to 75 mg/m2 every 3 weeks, with cyclophosphamide. Doses are given by intravenous infusion over 1 hour, diluted in sodium chloride 0.9% or glucose 5% to a final concentration of 0.4 to 1.2 mg/mL doxorubicin.
Blood counts should be made routinely during treatment with doxorubicin (see also Bone-marrow Depression, ) and cardiac function should be monitored at regular intervals for early signs of cardiotoxicity.
Doxorubicin hydrochloride has also been instilled into the bladder in the local treatment of malignant neoplasms. For this purpose 50 mL of a 1 mg/mL solution may be instilled into the bladder for one hour once a month. Doxorubicin has been given intra-arterially.
Various novel formulations of doxorubicin have been investigated. Doxorubicin with carbon/iron carrier particles (MTC-DOX) is a magnetically targeted treatment, using an external magnet to keep the drug at the tumour site, that has been investigated for hepatocellular carcinoma. A polymer of doxorubicin and polyisohexylcyanoacrylate in nanoparticle form is under investigation, given via the hepatic intra-arterial route, for hepatocellular carcinoma.
Although sensitive to light at low concentrations, doxorubicin is not subject to significant photodegradation at clinical concentrations and special precautions to protect solutions from light during administration do not appear to be necessary.1,2 Solutions in sodium chloride solution 0.9% were reported to be stable for 24 days when stored in PVC minibags at 25 degrees and for even longer if stored in minibags or polypropylene syringes at 4 degrees. Stability in solution seems to be partly related to pH, with doxorubicin becoming more stable3-5 at acid pH. A fall in pH of the solution also significantly decreases the loss of doxorubicin by adsorption and precipitation onto the surface of a positively-charged in-line filter.6
Some liposomal doxorubicin formulations should be diluted only with glucose 5%. If not used immediately, they may be stored for 24 hours at 2 degrees to 8 degrees.
Adverse Effects and Treatment
Doxorubicin and other anthracyclines cause pronounced bone-marrow depression, which may be dose-limiting. White cell count reaches a nadir 10 to 15 days after a dose and usually recovers by about 21 days.
The anthracyclines may produce cardiac toxicity, both as an acute, usually transient disturbance of cardiac function marked by ECG abnormalities and, sometimes, arrhythmias; and as a delayed, sometimes fatal, irreversible congestive heart failure, which may occur suddenly. Severe cardiotoxicity is more likely in adults receiving total cumulative doses of doxorubicin greater than 450 to 550 mg/m2, and may occur months or even years after use.
Gastrointestinal disturbances include moderate or sometimes severe nausea and vomiting; stomatitis and oesophagitis may progress to ulceration. More rarely, facial flushing, conjunctivitis, and lachrymation may occur. Alopecia occurs in the majority of patients. The urine may be coloured red. Occasional hypersensitivity reactions may occur. Hyperuricaemia may occur due to tumour lysis syndrome.
Doxorubicin and other anthracyclines are very irritant and thrombophlebitis and streaking of the skin over the vein used for injection has been reported; extravasation is serious and may produce extensive local necrosis and ulceration. Intravesical instillation can cause bladder and urethral irritation, haematuria, and haemorrhagic cystitis.
Combination therapy including doxorubicin has rarely been associated with secondary acute myeloid leukaemia
Formulations of liposomal doxorubicin may be associated with a reduced potential for local tissue necrosis, and possibly a reduced incidence of cardiotoxicity, although current clinical experience is limited, and such toxicity remains a possibility. Conversely, palmar-plantar erythrodysesthesia appears to be more common, and may be dose-limiting. In addition, an acute pseudo-allergic reaction may be seen on initial infusion, but generally resolves on slowing or temporarily stopping the infusion.