Annals of Oncology Advance Access originally published online on December 21, 2006
Annals of Oncology 2007 18(3):546-550; doi:10.1093/annonc/mdl413
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© 2006 European Society for Medical Oncology
supportive care |
Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies
1 Department of Oncology, Copenhagen University Hospital, Denmark
2 Department of Medical Oncology, Free University, Amsterdam, The Netherlands
3 Department of Obstetrics and Gynaecology, University Hospital Kiel, Kiel, Germany
4 Department of Oncology and Haematology, Ravenna Public Hospital, Ravenna, Italy
5 Department of Oncology and Haematology, University Hospital of Hamburg, Germany
6 TopoTarget A/S, Symbion Science Park, Fruebjergvej, Copenhagen
7 Department of Plastic Surgery, Copenhagen University Hospital, Herlev, Denmark
* Correspondence to: Mrs L. Handskemager, TopoTarget A/S, Fruebjergvej 3, DK-2100 Copenhagen, Denmark. Tel: +45 39179495; Fax: +45 39178322; E-mail: leh{at}topotarget.com
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Abstract |
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Background: The purpose of this study was to assess the efficacy and tolerability of i.v. dexrazoxane [SaveneTM (EU), TotectTM (US)] as acute antidote in biopsy-verified anthracycline extravasation.
Patients and methods: Two prospective, open-label, single-arm, multicentre studies in patients with anthracycline extravasation were carried out. Patients with fluorescence-positive tissue biopsies were treated with a 3-day schedule of i.v. dexrazoxane (1000, 1000, and 500 mg/m2) starting no later than 6 h after the incident. Patients were assessed for efficacy (the possible need for surgical resection) and toxicity during the treatment period and regularly for the next 3 months.
Results: In 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis. One patient (1.8%) required surgical debridement. Thirty-eight patients (71%) were able to continue their scheduled chemotherapy without postponement. Twenty-two patients (41%) experienced hospitalisation due to the extravasation. Mild pain (10 patients; 19%) and mild sensory disturbances (nine patients; 17%) were the most frequent sequelae. Haematologic toxicity was common as expected from the fact that the extravasation occurred during a chemotherapy course. Other toxic effects were transient elevation of alanine aminotransferases, nausea, and local pain at the dexrazoxane injection site.
Conclusion: Dexrazoxane proved to be an effective and well-tolerated acute treatment with only one out of 54 assessable patients requiring surgical resection (1.8%).
Key words: anthracycline, antidote, dexrazoxane, extravasation, savene, totect
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Accidental extravasation may cause severe, progressive tissue damage that emerges within hours or days. The tissue damage may progress over days and weeks and cause pain, increased risk of infection, joint destruction, lesions of nerves, and permanent dysfunctional and cosmetic changes of the involved area. Surgical removal of damaged tissue with subsequent skin grafting is often necessary. In addition to local symptoms from the tissue destruction, the patient is subjected to the distress of major surgery, which in turn leads to delay of further cancer treatment [1].
There are no proven standard treatment principles for anthracycline extravasation. In some institutions a ‘wait-and-see’ approach is used, where surgery is carried out only for progressive symptoms or necrosis. Historically, a number of non-surgical local treatments have been used, e.g. topical dimethyl sulfoxide (DMSO), hyaluronidase, local cooling, and intralesional injection with corticosteroids. The sparse-published series, however, are characterised by lack of diagnostic verification and none of the previous trials have investigated the effect of an antidote in biopsy-verified anthracycline extravasation.
The two present studies were initiated on the basis of preclinical studies creating the hypothesis that the topoisomerase II inhibitor and iron chelator, dexrazoxane, could protect against the normal-tissue cytotoxicity of topoisomerase II poisons such as doxorubicin, epirubicin, and daunorubicin. Langer et al. demonstrated that systemic dexrazoxane treatment prevented anthracycline wound formation in a dose- and schedule-dependent matter when administered 3–6 h after extravasation in a mouse model [2–4]. Systemic administration was used since the local irritant effect of dexrazoxane prevented local treatment. The effect was found highly specific, as none of the control treatments (e.g. EDTA, DMSO, N-acetylcysteine, alfa-tocoferol, amifostine, hydrocortisone, or local cooling) were effective [2–4]. These findings were supported by a number of now published clinical case reports, which additionally indicated that dexrazoxane could halt progression of already established anthracycline necrosis [5–8].
Due to the accidental nature of extravasation, lack of proven methods of non-surgical treatment and because extravasation is a rare condition, both studies were conducted as multicentre, single-arm studies.
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patients and methods |
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study design
TT01 and TT02 were conducted in compliance with Good Clinical Practice (GCP), approved by regulatory authorities and ethical review boards. Informed consent was obtained after the anthracycline extravasation occurred and before any additional study-related procedures.
The overall purpose of the two trials was to investigate the efficacy of i.v. dexrazoxane in preventing tissue damage from accidentally extravasated anthracycline, and thus preventing patients from undergoing surgical debridement of the affected area as well as preventing development of sequelae. Secondary objectives were to prevent postponement of the scheduled cancer treatment and to evaluate the tolerability and toxicity of dexrazoxane.
TT01 was a Danish multicentre study recruiting patients from 17 oncology and haematology centres. TT02 was an international multicentre study recruiting patients from 36 oncology and haematology departments in Germany, The Netherlands, Italy, Poland and Denmark.
Both studies were open-label, single-arm, multicentre phase II–III studies of patients with anthracycline extravasation. The extravasation diagnosis had to be confirmed by positive fluorescence microscopy of at least one of the required biopsies. Further inclusion criteria were age >18 years and Eastern Cooperative Oncology Group performance status of two or more. Exclusion criteria were as follows: known allergy towards dexrazoxane, inadequate bone marrow reserve [
grade 2 Common Toxicity Criteria (CTC) haematologic levels], inadequate liver function (transaminases, alkaline phosphatase, bilirubin, or lactate dehydrogenase >3 times upper normal limit), inadequate contraception, pregnancy, or nursing. Patients were excluded if there was a reasonable suspicion of extravasation by vesicant compounds other than anthracyclines through the same i.v. access, e.g. the vinca alkaloids and mitomycin C.
Acute aspiration was recommended. Local cooling was permitted, however, not within 15 min of the dexrazoxane infusion. Local treatment with DMSO or steroids was not allowed.
treatment and end points
A 3-day schedule was based on the experience from animal studies [3, 4]. The dose dependency in this model led to the choice of a clinical dose close to the maximum tolerated dose of 1250 mg/m2/day, three to five times, defined in early clinical studies of the antitumour effect of dexrazoxane [9, 10]. This dose was lowered moderately due to the concomitant chemotherapy during which the extravasation took place. The patients therefore received i.v. infusion of dexrazoxane for 1–2 h once daily, three consecutive days at the following daily doses: 1000, 1000, and 500 mg/m2. The infusion was given in the opposite arm of that of the extravasation incident. The first dose was administered as soon as possible and no longer than 6 h after the extravasation, and the next two doses at 24 and 48 h. Patients were assessed for efficacy and safety at 24 and 48 h, weekly for the following month, and on day 90. Colour photographs at predetermined intervals documented the course. Possible progressive symptoms and need for surgery was evaluated by a team including a surgeon. Efficacy and safety data were evaluated by an independent review committee.
fluorescence biopsies
At least one positive of the obtained biopsies was required to confirm the anthracycline extravasation. Biopsies were not to contain any part of the vein, and had to be at least 6 mm wide and 6 mm long. Tissue was stored at –20°C to –80°C and in TT01 analysed at a local pathology department; in TT02, all samples were analysed centrally at the Department of Pathology, Copenhagen University Hospital, Denmark. Fluorescence microscopy was used. Biopsies were assessed as positive or negative.
statistical considerations
For the Danish study, dexrazoxane was regarded effective if operation could be avoided in 80% of patients, on the basis of the fact that in Denmark the pre-study operative frequency in biopsy-positive anthracycline extravasation was 100%. This trial aimed at including 25 assessable patients and specified an interim analysis if none of the first 17 assessable patients underwent surgery, i.e. the upper 95% confidence interval (CI) would be 19.5%, corresponding to an 80% response rate. The calculation of sample size for international study was slightly different and based on the literature, where 35%–50% of patients with suspected, not biopsy-verified, anthracycline extravasation required surgery. A sample size of 32 assessable patients was required to show a 70% or greater reduction in the incidence of surgery, i.e. from 35% to 10% or lower (one-sided binomial test, 
= 0.025, ß = 0.20). The failure rates are presented as the percentage requiring surgery and include 95% CIs.
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results |
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patient characteristics
In TT01, 23 patients were enrolled from 10 Danish sites. Four had negative biopsies; one patient's biopsy sample could not be obtained (central venous catheter). Thus, 18 patients were assessable for efficacy, and 23 for safety. In TT02, 57 patients were enrolled from 24 sites in Denmark (15), Germany (4), The Netherlands (3), and Italy (2). Thirteen patients did not have positive biopsies; two patients had concomitant treatment interfering with the protocol; two patients had their treatment several days too late; one patient had two extravasations within 8 days; one wished to be excluded on day 2; and one patient was excluded due to lack of clinical documentation. Thus, 36 patients were assessable for efficacy, 57 for safety.
Demographics and baseline characteristics in TT01 and TT02 are shown in Table 1. The patient populations in the two studies were similar with respect to sex, age, and underlying cancer. The majority of patients were female (mainly breast cancer patients). The mean age was 
55 years in both groups. The most commonly received anthracycline was epirubicin (45 patients), doxorubicin (33 patients), and daunorubicin (two patients). Other most frequently used drugs in the standard combinations were cyclophosphamide (23 patients), vinca alkaloids (25 patients), and 5-fluorouracil (10 patients). The majority of extravasation occurred during the first three cycles of anthracycline treatment, TT01 (50%), and TT02 (61%). All patients had at least one of the following baseline signs and symptoms: pain, swelling, blistering, redness, and/or dysaesthesia. Swelling and redness was noted in >3/4 of the patients, and pain in >40% of the patients (Table 1). The mean area of extravasation (swelling and redness) was larger in TT02, i.e. 39 cm2 compared with 23 cm2 in TT01.
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efficacy
surgery.
In TT01, the treatment proved 100% effective, i.e. none of the patients had surgery as a consequence of the extravasation. In TT02, the treatment prevented development of surgery-requiring necrosis in 35/36 patients (97.4%). Thus in the studies combined, only one patient out of 54 assessable patients had surgical resection. In the non-assessable population, one patient who had other treatment interfering with the protocol (intralesional steroid injections and continued cooling) was operated.
necrosis.
In TT01, one patient experienced infection (Staphylococcus aureus) in the biopsy area, a small necrosis was observed. It healed after antibiotic treatment. Surgical intervention was not required.
In TT02, there was one treatment failure in 36 patients (2.8%). The patient presented with initial symptoms of swelling and redness, covering an area of 253 cm2. On days 2–11, blistering occurred, and on day 11, necrosis was noted. Surgical resection of the necrosis was undertaken. Following surgery, skin atrophy remained. In two patients, the biopsies per se resulted in small necrotic areas, none of which required surgical intervention.
treatment delay.
In the efficacy population in TT01, six patients (33%) experienced delay in the planned cytotoxic treatment; the delay was 2–24 days (mean 8.7 days). In TT02, 10 patients (27.8%) experienced postponement of scheduled chemotherapy. The failure patient had no duration of postponement reported as no further chemotherapy was given because of surgery. The duration of delay was 7–15 days (mean 10 days) for the other nine patients.
Treatment delay was caused by reversible neutropenia in six patients.
hospitalisation.
In the efficacy population, nine patients in TT01 (50%) were hospitalised due to extravasation [duration from 1 to 6 days (mean 3.3 days)] and in TT02, 13 patients (36.1%) (duration 1–64 days, mean 13 days).
sequelae.
Sequelae (sensory disturbances 16.7% of patients, skin atrophy 9.3%, pain 18.5%, disfigurement 2.8%, and limitation of movement 5.6%) were mild except for those in the ‘failure’ patient in TT02, who experienced severe cosmetic changes, sensory disturbances, and limitation of movement, mainly due to surgery.
toxicity
Table 2 summarises the clinical adverse events and laboratory test-based CTC-graded toxicity. Toxic effects could causally be related both to the chemotherapy course and to the dexrazoxane treatment. The clinical safety pattern was dominated by CTC grade 1 local reactions at the dexrazoxane infusion site, and six patients (7.5%) experienced superficial phlebitis in TT01 versus none in TT02. In particular, injection site reactions were frequent in TT01 (14 of 23 patients, i.e. 60.8%) but it was markedly reduced to 14% (8 of 54 patients) after buffer changes of the solvent in TT02. Wound infections, nausea, and vomiting were the more frequent adverse events occurring in 10.0%, 18.8%, and 7.5%, respectively. The majority of events were observed in only one to two patients. There was no grade 4 toxicity, and there were no treatment-related deaths.
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Most of the laboratory test-based toxicity was directly related to suppression of bone marrow function. One-third of the patients had mild and reversible elevation of liver enzymes. Among patients with normal baseline values, four patients had reversible increase in bilirubin (duration 12–21 days) and 14 patients had transient increases in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (duration 7–21 days, median 8 days). Durations were not different in patients with already existing baseline abnormalities. There is no indication that the subsequent chemotherapy in such patients was more cytotoxic.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The natural course of significant anthracycline extravasation is well described. The morbidity of the surgical procedure and the often severe long-term effects of the extravasation (longstanding ulceration and infections, contractures, sympathetic dystrophy syndrome, compression syndromes, etc.) have stimulated interest for improved non-surgical methods, "the optimal treatment of anthracycline extravasation is still controversial" [1].
Only biopsy-verified (fluorescence microscopic) diagnosis should be used in clinical trials.
On the basis of the published literature, the progression rate to ulceration in anthracycline extravasations (non-biopsy proven) ranges from 25% to 50% [11–15]. Therefore, there is an urgent need for therapeutic intervention.
The study of dexrazoxane as an antidote was based on a series of experiments of the mechanism of action of anthracyclines and dexrazoxane [16]. The hypothesis created by the results prompted extensive trials with the murine extravasation model [2, 3]. Excellent results in pilot cases led to the two studies. Dose and schedule were based on published phase I and II studies of dexrazoxane as an antineoplastic agent (indicating expected toxic effects as reversible haematologic toxicity) and reversible elevation of the liver enzymes AST/ALT and upon preclinical experiments [2, 3, 9, 10, 17–22].
Results were quite uniform and the systemic treatment with dexrazoxane resulted in need for surgery in only one of 54 assessable patients (1.9%) with biopsy-confirmed anthracycline extravasations. The late effects of the extravasations in the two studies were very limited; the majority experienced no late effects after 3 months, the minority had mild pain, discrete sensory disturbances and/or atrophic skin changes. The majority of patients continued planned chemotherapy, hospitalisation was limited and of short duration. The two clinical studies confirm the high efficacy in preventing the acute and the late effects of anthracycline extravasation.
The 3-day schedule was well tolerated. As expected in the midst of chemotherapy series, haematologic toxicity was demonstrated. It is unclear how large the contribution of dexrazoxane was in this respect, but the toxicity was reversible and manageable.
Transient elevation of liver enzymes occurred in 25% and was generally mild; about 20% experienced nausea. Dexrazoxane infusion caused local symptoms such as mild pain in TT01, but it became rare after buffer changes of the solvent in TT02. Overall, the treatment was well tolerated.
In conclusion, these two prospective clinical studies of the efficacy of dexrazoxane in preventing the potentially devastating effects of biopsy-proven anthracycline extravasation demonstrated that dexrazoxane treatment is highly effective both on a short and a long term and moreover has manageable toxicity.
Received for publication September 22, 2006. Revision received October 6, 2006. Accepted for publication October 9, 2006.
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