Doxorubicin Extravasation Research Articles

PEGylated graphene oxide-mediated stimulation of vascular endothelial cells and responsive release of PD-1/PD-L1 inhibitor for efficient chemo-immunotherapy against cancer

Immune checkpoint blockade (ICB) has emerged as a promising immunotherapeutic modality against cancer in the clinic. However, only 10–30% of patients respond to ICB, primarily due to poor immunogenicity and insufficient T cell infiltration in solid tumors. Herein, we presented an approach for high-performance cancer treatment using the programmed cell death protein-1 and programmed cell death ligand-1 (PD-1/PD-L1) inhibitor (BMS-202)-loaded PEGylated graphene oxide (GPi). On the one hand, GPi dissociated tight junctions of vascular endothelial cells (VECs) in tumor, thus promoting the extravasation and intratumoral accumulation of liposomal doxorubicin (LipDox), which then effectively induced immunogenic cell death of tumor cells. On the other hand, GPi also stimulated VECs to upregulate the expression of cell-cell interaction molecules, such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, which facilitated the infiltration of T cells in tumor. Beyond acting as a stimulator of VECs, GPi could exert responsive release of BMS-202 under the acidic tumor microenvironment and blockade PD-1/PD-L1 axis in tumors. Finally, the alternating administration of GPi and LipDox effectively inhibited tumor growth in a 4T1 tumor model, providing a novel treatment mode for chemo-immunotherapy.

Effects of photobiomodulation (660 nm laser) on anthracycline extravasation: An experimental study.

Objective: to investigate the effect of using different agents (topical hyaluronidase, photobiomodulation, and the association of photobiomodulation with topical hyaluronidase) in preventing the formation of lesions caused by doxorubicin extravasation, as well as in the reduction of lesions formed by extravasation of this drug. Method: a quasi-experimental study conducted with 60 Wistar rats, randomized into four groups with 15 animals each. Group 1 (Control); Group 2 (Hyaluronidase); Group 3 (Photobiomodulation); and Group 4 (Hyaluronidase + Photobiomodulation). A wound was induced by applying 1 mg of doxorubicin to the subcutaneous tissue of the back of the animals. The concentration of topical hyaluronidase was 65 turbidity units/g and the energy employed was 1 joule of 100 mW red laser per square centimeter. With macroscopic evaluation every two days for 28 days, the following variables were observed: skin integrity, presence of blisters, hyperemia, exudate, bleeding, edema, crust, peeling and granulation tissue. Results: the animals from the groups subjected to photobiomodulation obtained better results in the assessment of the following variables: bleeding, hyperemia, exudate, intact skin and edema. Conclusion: it was evidenced that the association of photobiomodulation with topical hyaluronidase was effective in reducing the local effects and assisted in the wound healing process, and that PBM alone was able to prevent appearance of lesions.

Effects of photobiomodulation on wound contraction in rats undergoing doxorubicin extravasation: a histomorphometric analysis.

To analyze wound contraction and histomorphometric pattern of lesions in Wistar rats undergoing doxorubicin extravasation. Sixty adult female rats were used, divided into four groups of fifteen animals: Group 1 (Control, without antidote); Group 2 (Hyaluronidase); Group 3 (Photobiomodulation), and Group 4 (Hyaluronidase + Photobiomodulation). Doxorubicin 1mg (0.5 ml) was applied subcutaneously on the animals' back, inducing the wound. Macroscopic and morphometric evaluation of the lesions was performed every two days for 28 days. On the 30th day, euthanasia was performed and the material was collected for histological evaluation. The animals in the photobiomodulation and photobiomodulation + Hyaluronidase groups presented regeneration tissue with neovascularization and acute inflammation, with improvement in wound healing, which did not occur in the other groups. The contraction rates were better in those treated with photobiomodulation and photobiomodulation + Hyaluronidase, with healing percentages of 76.6% and 72.1%, respectively. The combination of photobiomodulation (660 nm-1 J) with topical hyaluronidase (65 UTR) proved to be effective in the process of wound healing due to extravasation of doxorubicin, and can be incorporated into the practice of clinical oncology.

The consequences of delayed treatment in doxorubicin extravasation

Doxorubicin (Adriamycin) is an anthracycline chemotherapy agent used for the treatment of several cancers including haematological malignancies. Extravasation is a well-recognized and possibly serious complication of administered intravenous therapies, especially in chemotherapeutic agents. Drug extravasation into the surrounding tissue has been estimated to occur in 0.1–6% of patients that receive chemotherapy. Signs of the injury can be subtle, and in case of delayed detection (> 6 h) and treatment, doxorubicin extravasation can result in substantial tissue damage with significant loss of function depending on the location of injury. Other consequences include pain, physical defect, psychological distress, cost of hospitalization and treatment and more extensive damage to skin and underlying tissue. In this article, we will discuss a case of delayed treatment of doxorubicin extravasation from a Venflon venous line at the dorsum of the hand with severe tissue necrosis as a result. Successful surgical reconstruction of the resulting substantial tissue damage using a SCIAP flap 25 days following the extravasation is described. Level of evidence: Level V, risk study.

Extravasation accidents with liposomal/liposomal pegylated anthracyclines treated with dexrazoxane: an overview and outcomes.

The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.

Ozone Ameliorates Doxorubicine-Induced Skin Necrosis - results from an animal model.

Doxorubicin (DXR) extravasation result with serious morbidity like skin ulceration and necrosis. The purpose of this study is to determine the protective effects of ozone, olive oil, dimethyl sulfoxide (DMSO), and coenzyme Q10 in the treatment of DXR-induced skin ulcers on rats. After an intradermal injection of DXR on a basis of an animal extravasation model, the materials were topically applied. The ulcer sizes were measured, and a punch biopsy was taken from the extravasation site in which the skin ulcers formed at the end of the experiment. The samples were analyzed for tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL1β), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzymes, and examined histopathologically. The ulcer sizes clearly decreased in the study groups, including DMSO, olive oil, ozone plus coenzyme Q10, and ozone plus olive oil groups in comparison with the control group with the exception of the coenzyme Q10 group. The malondialdehyde levels were lower in the DMSO, olive oil, ozone plus olive oil, and ozone plus coenzyme Q10 groups than they were in the control group, but they were not significantly different. The TNF-α level was lower in the DMSO, ozone plus olive oil, coenzyme Q10, and ozone plus coenzyme Q10 groups in comparison with the control group. There was no significant change in the SOD, GSH-Px, and IL1β levels in the study groups in comparison with the control and the sham groups. The ozone plus olive oil group could be considered to be an alternate therapy for skin ulcers due to DXR extravasation.

Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier

Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography–mass spectrometry (LC–MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2–3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.

Extravasation of doxorubicin – a dreaded complication of therapy

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Kopecký J, Slováček L, Priester P, Chovanec V, Petera J, Kopecký O. Case reportExtravasation of doxorubicin – a dreaded complication of therapy. Contemporary Oncology/Współczesna Onkologia. 2014. doi:10.5114/wo.2014.40593. APA Kopecký, J., Slováček, L., Priester, P., Chovanec, V., Petera, J., & Kopecký, O. (2014). Case reportExtravasation of doxorubicin – a dreaded complication of therapy. Contemporary Oncology/Współczesna Onkologia. https://doi.org/10.5114/wo.2014.40593 Chicago Kopecký, Jindřich, Ladislav Slováček, Peter Priester, Vendelin Chovanec, Jiří Petera, and Otakar Kopecký. 2014. "Case reportExtravasation of doxorubicin – a dreaded complication of therapy". Contemporary Oncology/Współczesna Onkologia. doi:10.5114/wo.2014.40593. Harvard Kopecký, J., Slováček, L., Priester, P., Chovanec, V., Petera, J., and Kopecký, O. (2014). Case reportExtravasation of doxorubicin – a dreaded complication of therapy. Contemporary Oncology/Współczesna Onkologia. https://doi.org/10.5114/wo.2014.40593 MLA Kopecký, Jindřich et al. "Case reportExtravasation of doxorubicin – a dreaded complication of therapy." Contemporary Oncology/Współczesna Onkologia, 2014. doi:10.5114/wo.2014.40593. Vancouver Kopecký J, Slováček L, Priester P, Chovanec V, Petera J, Kopecký O. Case reportExtravasation of doxorubicin – a dreaded complication of therapy. Contemporary Oncology/Współczesna Onkologia. 2014. doi:10.5114/wo.2014.40593.

ドキソルビシンの血管外漏出に対しデキスラゾキサンで治療した犬の1例

多中心型リンパ腫の犬の治療において静脈内に塩酸ドキソルビシンを点滴投与したところ、血管外漏出が発生した。漏出した塩酸ドキソルビシンの推定量は2-3㎎であった。塩酸ドキソルビシン漏出より10時間後、デキスラゾキサンを100㎎静脈内点滴投与し、さらにその12時間後、50㎎を同様に投与した。漏出から7日後、局所皮膚にはほとんど変化がみられなかったが、21日後には局所の色素沈着がみられた。皮膚の潰瘍化や壊死はみられなかった。塩酸ドキソルビシンの漏出に対するデキスラゾキサンの投与量や投与時期は明確になってはいないが、漏出量が少量であれば10時間後でも効果が期待できると考えられた。

Carnitine or dimethyl sulfoxide, or both, for the treatment of anthracycline extravasation in rats

This study aimed to compare the efficacy of topical dimethyl sulfoxide (DMSO), intralesional and systemic carnitine as monotherapy and in combination against ulceration in rats induced by intradermal doxorubicin extravasation. Sixty-nine 3-month-old male Wistar albino rats, weighing between 200–225 g, were used in this study. Rats were applied monotherapy or a combination of topical DMSO, intraperitoneal or intralesional carnitine. Control groups received saline or no drug. The necrotic area was measured and extravasated neutrophil leukocytes were counted in healthy tissue adjacent to necrotic areas. Monotherapy with topical and systemic carnitine did not significantly reduce the size of necrotic areas. However, topical DMSO had reduced necrotic areas and inflammatory cells significantly and the addition of systemic carnitine to topical DMSO had increased the efficacy. DMSO is an effective, safe, and easy-to-apply treatment for doxorubicin-induced extravasation. Further clinical studies are needed to evaluate the use of carnitine in combination with DMSO.

Dexrazoxane treatment of doxorubicin extravasation injury in four dogs

4 dogs were treated with dexrazoxane for known or suspected doxorubicin extravasation. Records were retrospectively reviewed. Doses and number of doses of dexrazoxane were variable. Dexrazoxane was administered within 2 hours after known extravasation in 3 dogs and 48 hours after suspected extravasation in 1 dog. Additional medical treatments included tissue cooling in all dogs, topically administered dimethyl sulfoxide ointment in 3, and orally administered piroxicam in 1. Mild erythema and edema at the extravasation site developed within 1 to 6 days after extravasation in the 3 dogs that received dexrazoxane within 2 hours after extravasation. Extensive tissue necrosis occurred in the dog treated 48 hours after suspected extravasation. Only the dog with severe tissue necrosis required surgical intervention. Lesions in the other 3 dogs resolved with medical management alone. All dogs survived the event. To date, use of dexrazoxane in the management of doxorubicin extravasation has not been reported in dogs. Treatment was successful in 3 of 4 patients. The most effective dosage and timing of administration are unknown; however, there is evidence to suggest that administration within 6 hours after the event is warranted. Further studies are needed to confirm efficacy and to optimize use of this drug in the prevention and treatment of anthracycline extravasation injury in veterinary patients.

Recovery of symptomatic extravasation of liposomal doxorubicin after dexrazoxane treatment

A patient with metastatic ovarian cancer was treated with liposomal doxorubicin and carboplatin. She had an extravasation during liposomal doxorubicin infusion. Initially, she was treated conservatively with cold compresses and topical treatment. However, because of worsening of symptoms, she received dexrazoxane once daily for 3 days after which complete recovery occurred. This is the first casereport on symptomatic extravasation of liposomal doxorubicin treated with dexrazoxane.

Erythropoietin Improves the Healing of Skin Necrosis Resulting From Doxorubicin Extravasation in a Rat Model

BackgroundDoxorubicin is an antineoplastic agent that causes skin necrosis when extravasated. Various agents have been tried to reduce tissue damage owing to extravasation. Erythropoietin (EPO) is an obligatory growth factor for red blood cells and has beneficial effects on wound healing. ObjectiveThe aim of this study was to test the hypothesis that local EPO injection can prevent and improve healing of necrosis at the doxorubicin injection site in rats. MethodsWe used 31 female Sprague-Dawley rats. The dorsal area of each rat was shaved, and 2 mg of doxorubicin in 0.5 mL saline was injected intradermally. The rats were then divided into 3 groups: control; control with intradermal injection of saline; and treatment, which received an intradermal injection of EPO. EPO in saline was injected into 4 quadrants of the same site where doxorubicin was injected 1 hour before. The rats were monitored and the area of each ulcer was measured. Skin biopsies were excised at the end of 4 weeks using anesthetic pentobarbital. Inflammation, edema, epithelization, neovascularization, necrosis, fibroblast proliferation, and collagen synthesis were evaluated and compared between groups. ResultsThe average areas of the lesions were significantly smaller in the EPO-injected rats (P = 0.03). The histopathologic evaluation revealed that the scores for epithelization, neovascularization, fibroblast proliferation, and collagen synthesis were higher (P < 0.001, P < 0.001, P = 0.002, and P = 0.04, respectively) and the score for necrosis was lower (P < 0.001) in the EPO-injected group than in both the saline-injected and control groups. ConclusionsIn this study using female Sprague-Dawley rats, EPO treatment improved the healing of skin necrosis caused by doxorubicin injection. This finding may lead to a new therapeutic approach for the management of skin necrosis caused by doxorubicin extravasation.

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin: Erratum

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin: Erratum

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin

Dexrazoxane is now authorized for the treatment of anthracycline extravasations. Several clinical cases of doxorubicin extravasation treated with dexrazoxane have been reported to date, but detailed cases have not been published. We report a case of a successful dexrazoxane treatment for a potentially severe extravasation of concentrated doxorubicin. We also describe objective outcome of this treatment, drug tolerance to dexrazoxane and long follow-up. A 29-year-old man diagnosed with Hodgkin's lymphoma was prescribed a regimen including 90 mg of doxorubicin in a 50 ml infusion using a reduced occlusion infusion pump. After this infusion, the patient complained of pain around the site of injection and presented a 10x6-cm swollen area with erythema and inflammation. A significant portion of doxorubicin was extravasated. Dexrazoxane was prescribed as an antidote. Side effects of dexrazoxane were restricted to reversible hematological toxicity, nausea, and vomiting. The next day, the inflammation of the extravasation area was reduced. On day 7, a painless mild induration in the extravasated area was the only remaining sign of the extravasation. On day 40, an arm nuclear magnetic resonance image showed no focal injuries. At 6-month follow-up, the patient has no sequelae. The two risk factors that could have increased the severity of the extravasation are the use of an infusion pump and the high drug concentration. Dexrazoxane proved to be effective and moderately well tolerated. A dexrazoxane stock in oncological facilities could help to promptly handle emergencies like this. Anthracyclines can be administered using reduced occlusion infusion pumps, but it seems preferable to always administer a free-running infusion to minimize accidents like this one.

Successful Experience Utilizing Dexrazoxane Treatment for an Anthracycline Extravasation

To describe a successful case of dexrazoxane treatment after an extravasation of doxorubicin and share a creative solution for formulary cost management. A 42-year-old female diagnosed with breast cancer was receiving doxorubicin as adjuvant treatment. The patient recently underwent a right mastectomy for a 3-centimeter grade 3 invasive ductal carcinoma. Three of 20 lymph nodes were positive, and the patient was stage 2B at presentation, with an estrogen receptor/progesterone receptor-positive and HER-2/neu-negative tumor. At an outside hospital, the patient was receiving doxorubicin through an infusion port when extravasation was noted after approximately 15 mL had been infused. She was transferred to Riverside Methodist Hospital and dexrazoxane treatment was initiated within 6 hours after extravasation. She received a full 3-day course of dexrazoxane treatment without complication and was discharged home. Significant delays in chemotherapy administration were avoided, and the patient successfully completed her planned chemotherapy course. Dexrazoxane has the potential to minimize tissue damage and treatment delays after an anthracycline extravasation. Although dexrazoxane is commercially marketed for 2 separate treatment indications, Totect is the Food and Drug Administration-approved product for anthracycline extravasations. Facilities administering anthracyclines should proactively resolve how to obtain, process, prepare, and administer this antidote to a patient within 6 hours of an extravasation event. Developing a preprinted chemotherapy extravasation order may facilitate the incorporation of the most recent Oncology Nursing Society guidelines to utilize dexrazoxane for an anthracycline extravasation. Cost sharing with other institutions may offer a creative solution to lessen the financial impact of stocking dexrazoxane therapy. Ensuring expedient treatment and accessibility to dexrazoxane therapy after an anthracycline extravasation is critical to the success of the treatment. All facilities utilizing anthracycline chemotherapy should purchase dexrazoxane or secure agreements with other facilities to guarantee the administration of this medication should extravasation occur.

Establishment of experimental model of doxorubicin extravasation injury in mice

Objective To establish animal models in order to provide an experimental study basis for both the pathogenesis study and taking effective prevention scheme for doxorubicin extravasation injury. Methods A total of 20 Kunming mice for experiments on doxorubicin extravasation injury were divided in-to four groups, I.e., high dose group(2 g/L), medium dose group(1 g/L), low dose group(0.5 g/L) and the control group (injection with water). Dosages were administered with subcutaneous injection on both sides of mice abdomen. The adverse reaction of body, damage areas of extravasation injury, recovery period were observed and histopathologic slides of animal models on both 4 days and 11 days after experiment were performed and compared. Results No significant adverse body reaction was observed after injection for all groups. The damage areas due to extravasation injury were dosage and concentration dependent. In addi-tion, significant differences in recovery period were observed for mice in different groups, that is, the higher injection concentration and dose led to the longer recovery period. Results from the histopathologic study in-dicated that the putrescence of damage area was developed in high dose group mice, and the ulcer occurred after 4 d of dosage in medium dose group mice, respectively. In contrast, no ulcer was observed in low dose group mice. Conclusions It would be feasible to establish a prevention model for mice on doxorubicin extravasation injury by subcutaneous injection at a dosage of 0.05ml(1 g/L). Key words: Doxorubicin; Extravasation injury; Animal model

Az extravazáció jelentősége az onkológiai ápolásban

The treatment of cancer may be associated with various chemotherapy-induced mucocutaneous reactions. One of the mucocutaneous adverse effects of antineoplastic drugs is the toxic local tissue reaction, the extravasation, which occurs in less than 1-2% of cytotoxic infusions. The standard management of vesicant extravasation includes: discontinuing all local infusions, aspiration of any residual drug, elevating the involved limb, local cooling or warm compresses, local anesthesia, antidotes (sodium thiosulfate for alkylating agents, dimethylsulfoxide (DMSO) for anthracyclines and mitomycin, and hyaluronidase for the vinca alkaloids), and finally surgical debridement with plastic surgery reconstruction. Because the anthracyclines are topoisomerase II poisons that are antagonized by topoisomerase II catalytic inhibitors such as dexrazoxane, it seems to be the treatment of choice immediately after extravasation of doxorubicin, epirubicin, daunorubicin, etc. One systemic dose of dexrazoxane after the accident may significantly reduce the toxic tissue lesions. Repeated intralesional injections of GM-CSF may accelerate the wound healing without the need of skin grafts.

Mediastinal extravasation of doxorubicin

A 48-year-old woman with a diagnosis of breast carcinoma was treated with adjuvant chemotherapy through a central venous catheter with subcutaneous reservoir (Port-A-Cath). While doxorubicin was administered, the patient presented thoracic pain and breathing distress due to superior vena cava perforation by the central catheter and subsequent extravasation of the drug into the mediastinum. The patient recovered without sequelae with conservative therapy. Cytostatic extravasation via central catheter is an uncommon complication in clinical practice. In this paper we present the first doxorubicin extravasation through a central catheter in adults and review the only ten cases found in the literature.

Treatment of Doxorubicin Extravasation with Intravenous Dexrazoxane in a Cat

Treatment of Doxorubicin Extravasation with Intravenous Dexrazoxane in a Cat