ISTANBUL, Turkey—Dexrazoxane is an effective antidote for anthracycline extravasation, researchers reported here at the European Society for Medical Oncology Congress last month.
“There are a lot of methods that have been empirically tested to limit skin and tissue damage due to anthracycline extravasation, but these were more abracadabra methods, than really good methods,” said Giuseppe Giaccone, MD, PhD, Professor and Head of the Department of Medical Oncology from VU Medical Center in Amsterdam, the Netherlands, who presented the new work.
Such approaches have included cooling, flushing, dimethylsulfoxide, or treatment with granulocyte-macrophage colony-stimulating factor. Despite these attempts, though, previously published patient series indicate that up to 50% of patients require surgery to remove necrotic tissue or limit damage.
In the two studies presented at the ESMO Congress, just 2% of the 54 patients treated with dexrazoxane required surgery. Based on these data, dexrazoxane was approved by the European Agency for the Evaluation of Medicinal Products (EMEA) in July for the treatment of anthracycline extravasation. Dexrazoxane has orphan drug status in the United States and is expected to gain full approval from the Food and Drug Administration as soon as the company can “clarify specific manufacturing issues,” according to a spokesperson for TopoTarget, the company that makes the drug.
“This is quite a dramatic result, and I don't think we need a randomized study to conclude that this is effective,” said Dr. Giaccone, noting that such studies would be difficult to do because anthracycline extravasation is a rare event, occurring in just 0.1 to one percent of treatments. The largest patient series, from the University of Texas M. D. Anderson Cancer Center, identified 44 cases out of probably 60,000 treatments and 10 of those required surgical intervention.
No Control Arm
But not everyone is quite so convinced of dexrazoxane's effectiveness as yet. Howard N. Langstein, Chief of the Division of Plastic Surgery at the University of Rochester (NY), who was the first author of that M. D. Anderson study, said he thinks the new data look promising but also expressed frustration at the lack of a control arm.
“The data are interesting and certainly deserving of further study, but it is very difficult to compare these to historical controls because the amount of extravasation has a lot to do with what happens,” he said.
“For scientific rigor it would have been nice if they had randomized every other patient to dexrazoxane—then you could follow the ones who did get the therapy and the ones who didn't. If their results are so dramatic they wouldn't have needed very many patients.”
Without a control arm it is harder to know what to do with the data, continued Dr. Langstein, who has recently finished a book chapter on the subject of extravasation treatments.
“If I get called tomorrow about a patient who has a doxorubicin extravasation, I am not going to be calling pharmacy and finding out if we can get some dexrazoxane on a special order quickly so I can give it to the patient. I know that three-quarters of the patients aren't going to require [surgical] intervention anyway.”
On the other hand, if they can drop the rate of patients who do require intervention from 25% to 2%, he said, “I'm listening.”
The first trial reported at the meeting involved 23 patients from 17 centers in Denmark. All patients had to have biopsy-confirmed anthracycline extravasation before treatment. (Since anthracyclines are fluorescent, extravasation can be confirmed by looking at punch biopsies on a fluorescence microscope.)
Of these, 18 patients were evaluable for efficacy and safety. Four patients were excluded from the study because there was no evidence of extravasation based on central review of biopsies. One patient was excluded because the suspected extravasation occurred from a central catheter and could not be confirmed by biopsy.
The clinical trial protocol specified that dexrazoxane therapy had to start within six hours of the initial incident because preclinical studies in mice showed that the timing of the therapy was important.
Additionally, those same studies indicated that better responses occurred when the animals received several infusions of the drug over time. Thus, patients were given a series of three infusions, with the first dose of 1,000 mg/m2 delivered over one to two hours.
At 24 hours, the patients received a second dose, and at 48 hours they received a half-sized dose of 500 mg/m2. Efficacy and safety were evaluated starting weekly for the first month and then at three months.
Of the 18 evaluable patients, 16 had swelling at baseline, 14 had redness, seven had pain, and two had blisters. The median area of the lesion was 23.6 cm2, with a range of 1 cm2 to 75 cm2.
None of the patients required surgical treatment after dexrazoxane therapy. One patient did show evidence of necrosis, but the researchers concluded that it was due to biopsy rather than to the extravasation event itself.
Six patients (33%) had chemotherapy treatments delayed or cancelled as a result of the extravasation, and nine (50%) had to be hospitalized as a result of the incident.
At three months, 16 patients (89%) showed no remaining sequelae from the extravasation. Two patients (11%) reported sensory disturbances at that time, one (6%) had skin atrophy, and one (6%) was still experiencing pain.
Dr. Giaccone noted that because dexrazoxane is weakly cytotoxic and causes myelosuppression, the researchers were unable to know which side effects occurred as a result of the dexrazoxane and which were due to the anthracycline treatments themselves.
However, injection site reactions, which occurred in 61% of the patients and were severe in some, were clearly due to dexrazoxane. Similarly, dexrazoxane infusions caused mild phlebitis in 26% of patients.
The second study included 57 patients enrolled at 34 European centers. Confirmation of the extravasation by biopsy was not required for enrollment in the trial, but was required for inclusion in the subsequent analysis of the drug's efficacy.
Twenty-one patients were excluded from that analysis, primarily due to negative biopsies, lack of biopsies, or the failure to initiate dexrazoxane within six hours of the extravasation as required by the protocol.
Because of the high rate of injection site reactions and phlebitis in the first trial, the investigators diluted the drug in a buffer prior to infusion in this study. The overall dose of the drug remained the same.
At baseline, the mean area of the lesion for the patients included in the efficacy analysis was 39.0 cm2, with a range of one to 253 cm2. Of these 36 patients, 81% had swelling at baseline, 78% had redness, and 44% had pain at baseline.
Following anthracycline extravasation and dexrazoxane treatment, one patient required resection.
Additionally, three patients (8%) had tissue necrosis due to the biopsy. Physicians had to delay chemotherapy for 10 (28%) of the patients, and 13 (36%) required hospitalization as a result of the extravasation.
Twenty-three patients (64%) had no evidence of long-term sequelae at three months. Seven (19%) had sensory disturbances, four (11%) had skin atrophy, and nine (25%) still had pain at that time. Additionally, one (3%) patient was disfigured after the extravasation event, despite dexrazoxane therapy, and three (8%) had some limitation of movement.
The toxicity profile was improved in the second trial, relative to the first, with only 14% of patients having injection site reactions and none having phlebitis.
Mechanism of Action
Like anthracyclines, dexrazoxane binds to topoisomerase II, but the effect of the two agents is very different. The topoisomerase enzyme is critical for breaking, unwinding, and resealing the DNA during DNA replication.
Anthracyclines bind to topoisomerase II in such a way that the enzyme can cut DNA but cannot reseal the breaks. By contrast, dexrazoxane stabilizes the enzyme at a different point in the catalytic cycle at a point when DNA breaks are not made.
Thus, when dexrazoxane competes with the anthracyclines for binding to topoisomerase, it protects the cell from DNA damage and cell death.
Dexrazoxane is marketed under the brand name Savene in Europe and will be sold under the name Totect in the United States if it gains final approval.