Extravascular leakage of dexrazoxane during treatment of diffuse large B-cell lymphoma: A case report

Extravascular leakage of dexrazoxane during treatment of diffuse large B-cell lymphoma: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Extravascular leakage of dexrazoxane during treatment of diffuse large B-cell lymphoma: A case report Nao Wakamiya, Masanori Suzuki, Tatsuya Isezaki, Ryohkan Funakoshi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5987269/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jun, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Abstract Background: Dexrazoxane is used to treat extravascular leakage of anthracycline antitumor agents, but its own extravascular leakage and management remain underreported. This case aimed to highlight both doxorubicin and dexrazoxane leakage during treatment for diffuse large B-cell lymphoma. Case presentation: A 55-year-old man with diffuse large B-cell lymphoma developed doxorubicin leakage during R-CHOP therapy, which was treated with dexrazoxane. Subsequently, dexrazoxane leakage occurred, causing erythema and swelling. Topical clobetasol propionate was applied, leading to symptom resolution without necrosis. The patient successfully completed chemotherapy and achieved long-term remission. Conclusions: This case report is one of the first to document the management of dexrazoxane extravascular leakage using topical steroids, effectively preventing severe outcomes. The findings suggest that topical steroids may be a desirable treatment approach for dexrazoxane leakage. Prompt intervention and interdisciplinary care contributed to the favorable outcome. This case highlights the need for further research and guideline refinement to optimize the management of inflammatory extravascular leakage. Dexrazoxane Extravasation Anthracycline antitumor agent Case report Figures Figure 1 Figure 2 Figure 3 Background The incidence rate of malignant lymphoma is increasing every year [ 1 ]. Furthermore, diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma in Japan [ 2 ], for which combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP) remains the first choice of treatment [ 3 ]; however, a serious complication associated with doxorubicin administration during R-CHOP is extravascular leakage. The frequency of extravascular leakage due to necrotizing antitumor agents ranges from 0.1–6.5% [ 4 ], and that through central venous catheters is 0.4–0.7% [ 5 ]. Extravascular leakage of antitumor agents occurs at relatively low frequency, but even small amounts of extravascular leakage can damage the skin and surrounding tissues, which is characterized by redness, swelling, blistering, necrosis, ulceration, and severe pain. Early conservative treatment may be unsuccessful, resulting in skin necrosis and refractory skin ulcers requiring surgical intervention. Extravascular leakage causes burden and distress to patients, such as reduced quality of life due to physical and psychological effects, increased risk of infection due to tissue damage, and a reduced number of vascular sites where antitumor agents can be administered due to vascular injury. The most invasive drugs regarding the degree of skin tissue necrotic damage during extravascular leakage are necrosis-induced antitumor agents. Doxorubicin is classified as a DNA-binding necrosis-inducing antitumor drug that remains in the intracellular space and causes repeated damage, which may lead to long-term tissue damage and progressive ulcer formation [ 6 – 8 ]. Treatment with corticosteroids, bicarbonate, dimethyl sulfoxide, hyaluronidase, and α-tocopherol has been tried for extravascular leakage of antitumor agents [ 9 – 10 ]. Dexrazoxane (Sabine® 500 mg for intravenous infusion) is a therapeutic agent used for extravascular leakage of anthracyclines such as doxorubicin [ 11 ]. Although it was initially developed as an antitumor agent [ 12 ], it is now considered to inhibit tissue damage caused by extravascular leakage. Dexrazoxane was approved in Japan in 2014 and is used in hospitals in Japan. It has been adopted in Kameda General Hospital since the same year and has been used in almost all cases of anthracycline leaks. With the increased use of doxorubicin, the potential for extravascular leakage of dexrazoxane has also increased. However, there are still no clear reports on the treatment of extravascular leakage of dexrazoxane. We, therefore, aimed to present a case wherein dexrazoxane was administered for extravascular leakage of doxorubicin, an anthracycline antitumor agent, and the patient subsequently experienced extravascular leakage of dexrazoxane. This case has been reported with the approval of the Clinical Research Review Committee of Kameda General Hospital (Permission No.: Case 23 − 015). Case presentation Patient: 55 years old, male. Diagnosis on admission: Primary tonsillar DLBCL. Stage: I. Current medical history: In October 2017, a continuous mass was discovered from the right palatine tonsil and diagnosed as DLBCL. The hematology/oncology department opted to implement chemotherapy (R-CHOP). Extravascular leakage of doxorubicin occurred on Day 2 of the second course of R-CHOP, and dexrazoxane was administered. Pain and swelling at the puncture site were observed on Day 2 of dexrazoxane administration, and a diagnosis of extravascular leakage of dexrazoxane was made. Medical history: None. History of side effects, allergies: None. Family history: No diabetes, heart disease, or cancer. Activities of daily living: Independent. On admission: length 167.8 cm, weight 63.5 kg, body surface area 1.72 m 2 , body mass index (BMI) 22.55 kg/m 2 . Clinical course of events A pharyngeal mass was found in the right palatine tonsil at another hospital; a diagnosis of DLBCL was made after biopsy of the same area, and the patient was referred to our hematology/oncology department. A five-drug combination of R-CHOP was initiated as chemotherapy. Because constipation occurred after the first course, from the second course, vincristine was administered at a 50% dose, while all other drugs were administered at a 100% dose. On Day 1 of the second course, a 22-G indwelling needle was inserted into the left median forearm vein, and rituximab infusion (700 mg dissolved in 630 mL of 0.9% saline) was administered intravenously. Drug administration was completed without any adverse reactions. On Day 2, after confirming the reversal of blood loss, cyclophosphamide (1,300 mg dissolved in 500 mL of 0.9% saline) was administered intravenously. After this, an infusion of doxorubicin hydrochloride (85 mg dissolved in 100 mL of 0.9% saline) was initiated. Twenty minutes after the start of dosing, an internal pressure of 100 mL of fresh food and a supplemental solution of doxorubicin hydrochloride were applied, and the titration was determined to be faulty. The air needle was then punctured, but the infusion solution continued to fail to drip; therefore, the pharmacist in charge was consulted, and the air needle was punctured into the infusion solution body, but the solution did not drip. At this point, we also suspected obstruction on the venous side and attempted to draw reverse blood, but were unable to do so. There was no pain or swelling at this point, but erythema in the 1.5 cm x 2.5 cm range was noted along the vein from the incisional site to the central side (Fig. 1 a). A new line was established on the right side opposite the leak site, the remaining doxorubicin was resumed, followed by the administration of vincristine (1 mg in 100 mL of 0.9% saline), and the swollen area on the left arm was marked. Based on these circumstances, the pharmacist suspected extravascular leakage of doxorubicin and reported this to the hematologist, who requested the administration of dexrazoxane and concurrent dermatological consultation. After examination, the physician suspected extravascular leakage of doxorubicin, and a 3-day infusion of dexrazoxane (1,700 mg dissolved in 100 mL distilled water followed by 500 mL lactated Ringer’s solution on days 1 and 2; 850 mg dissolved in 100 mL distilled water followed by 500 mL lactated Ringer’s solution) was initiated. In addition to dexrazoxane administration, cooling and topical steroid application (clobetasol propionate ointment) were initiated twice daily. Because of the poor stability of dexrazoxane, an infusion pump was used, and dosing was initiated at 500 mL/h. Thirty minutes after the initiation of treatment, the patient complained of vascular pain. The administration rate was changed to 400 mL/h, and a warm towel was applied to the puncture site; however, there was no change in pain. Therefore, the administration rate was changed to 300 mL/h and continued thereafter. The administration was completed within the period in which the stability of dexrazoxane was ensured. On Day 3 (Day 2 of dexrazoxane administration), 5 min after starting dexrazoxane administration at 500 mL/h, the patient complained of vascular pain. There was a 0.3 cm × 0.3 cm internal hemorrhage at the insertion site of the right forearm and pain. After replacement of the 22-G indwelling needle, administration was resumed at 300 mL/h of dexrazoxane using an infusion pump, after which the angialgia disappeared. There was no swelling or pain at the angialgia site. On Day 4, there was no pain, and dexrazoxane administration was terminated, although a cord-like induration was observed in the right forearm wrist joint, the site where vasculopathy appeared the previous day. There was no complaint of pain in the left arm, but a central induration remained in the area where the indwelling needle was removed; some erythema and heat were also observed, which had become slightly more pronounced since the previous day. On Day 7, the patient complained of swelling and redness at the dexrazoxane administration site on the right forearm, with a numeric rating scale score of 5. A slightly bulging swelling (10 cm × 7 cm) with erythema and tenderness without induration was observed along the central vein from the dexrazoxane extraction site (Fig. 2 a), and numeric rating scale level 3 pain persisted. Because phlebitis or inflammation associated with dexrazoxane leakage was suspected, the patient was referred to a hematologist. The patient was diagnosed with a dexrazoxane leak, and a dermatological follow-up was planned. Information was collected regarding the risk of extravascular leakage due to dexrazoxane and the appropriate intervention. Injection site reactions occur at the site of dexrazoxane [ 13 ], and dexrazoxane itself is an inflammatory drug [ 14 ]. A clobetasol propionate ointment was prescribed to treat the affected area in accordance with the response to an inflammatory drug leak, and the patient began application to the affected area twice daily. On Day 9, mild induration, swelling, and dark redness persisted on the right forearm, but the pain disappeared; however, the dermatologist examined the patient on Day 10, and the cord-like induration, which was palpable from the right forearm to the wrist on Day 8, was no longer detectable upon examination. Topical steroid application to the site of doxorubicin leak was discontinued, and topical dexrazoxane to the leak site was continued. On Day 11, erythema of the right forearm persisted, but the erythema and swelling tended to disappear, and the induration and pain disappeared. However, on Day 15, erythema tended to shrink, and pigmentation was observed, but there was no pain or ulceration. On Day 17, the induration around the doxorubicin leak had disappeared (Fig. 1 b), and no induration of the dexrazoxane leak was palpable (Fig. 2 b); therefore, the patient was judged to be doing well, and the dermatologist completed the concurrent consultation. After the third course of R-CHOP, the patient was discharged without extravascular leakage. The patient did not develop any ulceration or serious skin lesions at the leakage site and was able to complete the rest of the courses of R-CHOP as an outpatient without any change in the scheduled chemotherapy. The patient responded positively to the application of clobetasol propionate to the site of dexrazoxane leakage, saying that he no longer awoke at night with pain after applying the ointment and felt that it was working. Figure 3 shows the clinical course. Discussion and conclusions In this case, doxorubicin, an anthracycline antitumor agent, leaked, and the patient was treated with dexrazoxane under medical supervision; however, extravascular leakage of dexrazoxane was observed. Dexrazoxane was initially developed as an antitumor agent [ 12 ] and has topoisomerase II inhibitory activity [ 15 ], which poses a risk of extravascular leakage. At the time of the extravascular leak in 2017, there were no general recommendations for dexrazoxane leaks; however, we acted based on the literature, classifying it as an inflammatory agent. The European Society for Medical Oncology [ 16 ] and the National Cancer Control Programme have prepared guidelines for the management of extravascular leaks, with no specific recommendations on how to respond depending on the degree of skin tissue necrosis. Although no specific response recommendations have been made, the guidelines prepared by the East Midlands Cancer Alliance recommend the use of topical steroids (weak steroids) in response to leaks of inflammatory antitumor agents. Additionally, the 2023 edition of the Guidelines for the management of Chemotherapy Extravasation in Japan recommends the use of topical steroids [ 17 ]. We reviewed the literature for previous reports of extravascular leakage of dexrazoxane, like the present case, and summarized the reports that focused on the extravascular leakage of anthracyclines in Table 1 [ 18 – 25 ]. In most cases of anthracycline extravascular leakage since the launch of dexrazoxane, dexrazoxane has been administered. In about half of the cases, topical steroids were administered in combination with dexrazoxane. No necrotic tissue was observed in the dexrazoxane-treated cases. In cases where only dimethyl sulfoxide was administered, necrotic tissue was reported, and there were reports of procedures such as skin grafts and skin valves [ 18 ]. There are few reports on the outcome of the present disease, with the longest follow-up being up to 1 year and 6 months after treatment [ 23 ]. There have been no reports of extravascular dexrazoxane leakage in any patient. Case reports of common extravascular leaks have reported that the use of topical steroids prevents serious outcomes such as necrotic tissue; the strongest steroids were used in this case. In the latest edition of the Guidelines for the management of Chemotherapy Extravasation [ 17 ], the inflammatory classification of dexrazoxane prepared in 2023 is not listed. In addition to the application of the ointment, the administration rate slowed as soon as vascular pain appeared, which was completed within the time required to ensure stability [ 11 ] after dexrazoxane preparation. Furthermore, we believe that the smooth exchange of information between nurses and pharmacists when extravascular leakage of dexrazoxane was detected and the daily sharing of symptom progress enabled the establishment of a system to promptly report to a hematologist–oncologist and dermatologist and request medical consultation when symptoms worsened after 3 days, which contributed to patient outcomes. The importance of establishing an in-hospital system for the administration of dexrazoxane for extravascular leakage of anthracyclines has been reported [ 22 ]. Our hospital has established an administration response flow for dexrazoxane administration, which may have had a small influence on its effectiveness. As for the response to the extravascular leak, prompt action was taken after the discovery of the leak, including confirmation of reverse bleeding, removal of the line, and consultation with a dermatologist, and the doxorubicin hydrochloride extravascular leak reduced without necrosis 6 days later. In addition, for dexrazoxane extravascular leakage, we applied steroid ointment as a topical treatment for inflammatory extravascular leakage, and the symptoms showed a tendency to lighten after 7 days. Therefore, we believe that our initial response was sufficient. Various risk factors for extravascular leakage have been reported [ 16 ]; in this case, there were no clear factors, except that this was the second course of chemotherapy. One of the factors may have been the extravascular leakage of doxorubicin, which had been administered earlier, and the right forearm being secured at the radial cutaneous vein, which is on the opposite side, where it is a thin vessel susceptible to body movement. We believe that understanding the patient’s background with a focus on risk factors [ 16 ], establishing an initial response flow when an extravascular leak is detected, and improving the education system for hospital staff will impact patient outcomes. The site of extravascular leakage of doxorubicin hydrochloride improved after dexrazoxane administration. Local irritation, skin discoloration, and atrophy, which are recognized local side effects of topical steroids, did not occur [ 26 ]. The most important lesson learned from this experience is that in the event of a dexrazoxane leak, the application of topical steroids can prevent serious outcomes. Although there are reports that dexrazoxane falls under the category of inflammatory agents, there have also been reports of skin necrosis due to extravascular leakage of inflammatory antitumor agents [ 27 ], and since there is a possibility of serious outcomes, even in the case of leakage of inflammatory agents, topical application may be recommended as an inflammatory agent, as in the case of necrosis-inducing agents. A limitation of this case is that the R-CHOP regimen included systemic administration of high-dose prednisolone, and there are no cases of leakage of dexrazoxane alone in the absence of systemic administration of high-dose steroids. Based on the outcome of this case, it appears that localized steroid injection or prophylactic debridement is not necessary as an additional treatment; however, if painful inflammation develops, topical steroids or other agents may be considered. Our patient completed treatment and achieved remission without regimen modification or reduction in the antitumor agent dosage after doxorubicin and dexrazoxane extravascular leakage. Six years after the extravascular leak episode, the patient was alive without recurrence. Although this was a short-term case of extravascular leakage, it is significant because the decision to continue chemotherapy can affect the long-term outcomes of the patient. Abbreviations DLBCL Diffuse large B-cell lymphoma Declarations Ethics approval and consent to participate This case has been reported with the approval of the Clinical Research Review Committee of Kameda General Hospital (Permission No.: Case 23-015). This case was reported after written consent was obtained from the patient. Consent for publication Verbal and written informed consent was obtained from the patient to publish this case report. Availability of data and materials Data sharing is not applicable to this article as no new data were created or analyzed in this study. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Authors' contributions NW wrote a first draft of this manuscript,MS and IT advised interpretation of phenomenon in this case, RF supervised the writing of the manuscript. All authors read and approved the fnal manuscript. Acknowledgements We would like to acknowledge all the teams involved in his management. Authors' information (optional) References Wang SS. Epidemiology and etiology of diffuse large B-cell lymphoma. Semin Hematol. 2023;60:255-66. The world health organization classification of malignant lymphomas in Japan: Incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists. Lymphoma Study Group of Japanese Pathologists. Pathol Int. 2000;50:696-702. Ohmachi K. JSH practical guidelines for hematological malignancies, 2018: II. Lymphoma-5-diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Int J Hematol. 2019;110:131-46. Dorr RT. Antidotes to vesicant chemotherapy extravasations. Blood Rev. 1990;4:41-60. Cassagnol M, McBride A. Management of chemotherapy extravasations. US Pharm. 2009;34:3-11. Cox RF. Managing skin damage induced by doxorubicin hydrochloride and daunorubicin hydrochloride. Am J Hosp Pharm. 1984;41:2410-4. Luedke DW, Kennedy PS, Rietschel RL. Histopathogenesis of skin and subcutaneous injury induced by Adriamycin. Plast Reconstr Surg. 1979;63:463-5. Schulmeister L. Extravasation management. Semin Oncol Nurs. 2007;23:184-90. Tsavaris NB, Karagiaouris P, Tzannou I, Komitsopoulou P, Bacoyiannis C, Karabellis A, et al. Conservative approach to the treatment of chemotherapy-induced extravasation. J Dermatol Surg Oncol. 1990;16:519-22. Tsavaris NB, Komitsopoulou P, Karagiaouris P, Loukatou P, Tzannou I, Mylonakis N, et al. Prevention of tissue necrosis due to accidental extravasation of cytostatic drugs by a conservative approach. Cancer Chemother Pharmacol. 1992;30:330-3. Chiamaka Eneh, Manidhar Reddy Lekkala. Dexrazoxane. StatPearls Publishing; 2024 Jan. Duke DI. Prenatal Effects of the cancer Chemotherapeutic Drug ICRF 159 in Mice, Rats, and Rabbits. Teratology 1975;11:119-126. Seppo W, Langer. Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manag Res. 2014;6:357-63. Kreidieh FY, Moukadem HA, El Saghir NS. Overview, prevention and management of chemotherapy extravasation. World J Clin Oncol. 2016;10:87-97. RoCA JO, Ishida R, Berger JM, Andoh T, Wang JC. Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc Natl Acad Sci U S A 1994;91:1781-5. Fidalgo JP, Fabregat LG, Cervantes A, Margulies A, Vidall C, Roila F, ESMO Guidelines Working Group. ESMO Guideline Working Group. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012;23:vii167-73. Matsumoto K, Ryushima Y, Sato J, Aizawa Y, Aoyama T, Akaishi Y, et al. Extravasation associated with cancer drug therapy: multidisciplinary guideline of the Japanese Society of Cancer Nursing, Japanese Society of Medical Oncology, and Japanese Society of Pharmaceutical Oncology. ESMO Open. 2024;9:103932. Nedomansky J, Haslik W, Pluschnig U, Kornauth C, Deutschmann C, Hacker S, et al. Tissue distribution of epirubicin after severe extravasation in humans. Cancer Chemother Pharmacol. 2021;88:203-9. Takagi M, et al. Experience in treating forearm skin necrosis caused by extravascular leakage of epirubicin. Wound 2017;8:57-60. Nakagawa Y, et al. A case of extravascular leakage of an anticancer drug treated with dexrazoxane. Clin Dermatol. 2016;58:1462-3. Arroyo PA, Perez RU, Feijoo MA, Hernandez MA. Good clinical and cost outcomes using dexrazoxane to treat accidental epirubicin extravasation. J Cancer Res Ther. 2010;6:573-4. Tyson AM, Gay WE. Successful experience utilizing dexrazoxane treatment for an anthracycline extravasation. Ann Pharmacother. 2010;44:922-5. Kawamoto S, Shirahata T, Katori T, Izumo T, Kadono H, Fujita H, et al. Effectiveness of dexrazoxane for extravasation of anthracycline antitumor antibiotics - Reporting measures developed against extravasation in the hospital. Gan To Kagaku Ryoho 2016;43:2517-21. Takahata T. Four Cases who experienced extravasation of anthracyclines and had dexrazoxane therapy. Cancer Chemother. 2023;50:467-71. Howell G, Oliai C, Schiller G. Liposomal cytarabine-daunorubicin (CPX-351) extravasation: Case report and literature review. Anticancer Res. 2018;38:6927-30. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006;54:1-15. Okuda H, Masatsugu A, Sijimaya T, Arai R. Skin necrosis due to the extravasation of irritant anticancer agents. Intern Med. 2018;57:757-60. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Literaturereview.xlsx Cite Share Download PDF Status: Published Journal Publication published 12 Jun, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5987269","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":414499945,"identity":"139fc8fe-6a94-4b18-a1b2-ff1ef04fb0e7","order_by":0,"name":"Nao 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09:58:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":335860,"visible":true,"origin":"","legend":"\u003cp\u003eDexrazoxane leak sites and their outcomes. a) Dexrazoxane leakage, Day 1. b) Dexrazoxane leakage, Day 15.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5987269/v1/250f61173b340d5b27837ae7.png"},{"id":76193416,"identity":"de190f90-7a93-4da2-a773-bd6771eeaa04","added_by":"auto","created_at":"2025-02-13 09:58:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":125497,"visible":true,"origin":"","legend":"\u003cp\u003eProgress\u003c/p\u003e\n\u003cp\u003eThe course of the drugs administered, the events that occurred, and the blood laboratory values (white blood cells, C-reactive protein [CRP]) are represented in one figure.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5987269/v1/cf3014a99cabcd719489fad7.png"},{"id":84726432,"identity":"2f734b15-8a50-4d6f-ba51-d61d7adc5f5a","added_by":"auto","created_at":"2025-06-16 16:00:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1629866,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5987269/v1/0fc07fd4-7bd2-4125-a89a-f01df845b9e2.pdf"},{"id":76193415,"identity":"5c6f8f0d-1ea6-47f7-995c-73ab7a6a2e1d","added_by":"auto","created_at":"2025-02-13 09:58:17","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":13346,"visible":true,"origin":"","legend":"","description":"","filename":"Literaturereview.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5987269/v1/6e4f1f0c5cb21519e18143b5.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Extravascular leakage of dexrazoxane during treatment of diffuse large B-cell lymphoma: A case report","fulltext":[{"header":"Background","content":"\u003cp\u003eThe incidence rate of malignant lymphoma is increasing every year [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin\u0026rsquo;s lymphoma in Japan [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], for which combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP) remains the first choice of treatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]; however, a serious complication associated with doxorubicin administration during R-CHOP is extravascular leakage.\u003c/p\u003e \u003cp\u003eThe frequency of extravascular leakage due to necrotizing antitumor agents ranges from 0.1\u0026ndash;6.5% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and that through central venous catheters is 0.4\u0026ndash;0.7% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Extravascular leakage of antitumor agents occurs at relatively low frequency, but even small amounts of extravascular leakage can damage the skin and surrounding tissues, which is characterized by redness, swelling, blistering, necrosis, ulceration, and severe pain. Early conservative treatment may be unsuccessful, resulting in skin necrosis and refractory skin ulcers requiring surgical intervention. Extravascular leakage causes burden and distress to patients, such as reduced quality of life due to physical and psychological effects, increased risk of infection due to tissue damage, and a reduced number of vascular sites where antitumor agents can be administered due to vascular injury.\u003c/p\u003e \u003cp\u003eThe most invasive drugs regarding the degree of skin tissue necrotic damage during extravascular leakage are necrosis-induced antitumor agents. Doxorubicin is classified as a DNA-binding necrosis-inducing antitumor drug that remains in the intracellular space and causes repeated damage, which may lead to long-term tissue damage and progressive ulcer formation [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Treatment with corticosteroids, bicarbonate, dimethyl sulfoxide, hyaluronidase, and α-tocopherol has been tried for extravascular leakage of antitumor agents [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDexrazoxane (Sabine\u0026reg; 500 mg for intravenous infusion) is a therapeutic agent used for extravascular leakage of anthracyclines such as doxorubicin [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although it was initially developed as an antitumor agent [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], it is now considered to inhibit tissue damage caused by extravascular leakage. Dexrazoxane was approved in Japan in 2014 and is used in hospitals in Japan. It has been adopted in Kameda General Hospital since the same year and has been used in almost all cases of anthracycline leaks. With the increased use of doxorubicin, the potential for extravascular leakage of dexrazoxane has also increased. However, there are still no clear reports on the treatment of extravascular leakage of dexrazoxane.\u003c/p\u003e \u003cp\u003eWe, therefore, aimed to present a case wherein dexrazoxane was administered for extravascular leakage of doxorubicin, an anthracycline antitumor agent, and the patient subsequently experienced extravascular leakage of dexrazoxane. This case has been reported with the approval of the Clinical Research Review Committee of Kameda General Hospital (Permission No.: Case 23\u0026thinsp;\u0026minus;\u0026thinsp;015).\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003ePatient: 55 years old, male.\u003c/p\u003e \u003cp\u003eDiagnosis on admission: Primary tonsillar DLBCL.\u003c/p\u003e \u003cp\u003eStage: I.\u003c/p\u003e \u003cp\u003eCurrent medical history: In October 2017, a continuous mass was discovered from the right palatine tonsil and diagnosed as DLBCL. The hematology/oncology department opted to implement chemotherapy (R-CHOP). Extravascular leakage of doxorubicin occurred on Day 2 of the second course of R-CHOP, and dexrazoxane was administered. Pain and swelling at the puncture site were observed on Day 2 of dexrazoxane administration, and a diagnosis of extravascular leakage of dexrazoxane was made.\u003c/p\u003e \u003cp\u003eMedical history: None.\u003c/p\u003e \u003cp\u003eHistory of side effects, allergies: None.\u003c/p\u003e \u003cp\u003eFamily history: No diabetes, heart disease, or cancer.\u003c/p\u003e \u003cp\u003eActivities of daily living: Independent.\u003c/p\u003e \u003cp\u003eOn admission: length 167.8 cm, weight 63.5 kg, body surface area 1.72 m\u003csup\u003e2\u003c/sup\u003e, body mass index (BMI) 22.55 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical course of events\u003c/h2\u003e \u003cp\u003eA pharyngeal mass was found in the right palatine tonsil at another hospital; a diagnosis of DLBCL was made after biopsy of the same area, and the patient was referred to our hematology/oncology department. A five-drug combination of R-CHOP was initiated as chemotherapy. Because constipation occurred after the first course, from the second course, vincristine was administered at a 50% dose, while all other drugs were administered at a 100% dose.\u003c/p\u003e \u003cp\u003eOn Day 1 of the second course, a 22-G indwelling needle was inserted into the left median forearm vein, and rituximab infusion (700 mg dissolved in 630 mL of 0.9% saline) was administered intravenously. Drug administration was completed without any adverse reactions. On Day 2, after confirming the reversal of blood loss, cyclophosphamide (1,300 mg dissolved in 500 mL of 0.9% saline) was administered intravenously. After this, an infusion of doxorubicin hydrochloride (85 mg dissolved in 100 mL of 0.9% saline) was initiated. Twenty minutes after the start of dosing, an internal pressure of 100 mL of fresh food and a supplemental solution of doxorubicin hydrochloride were applied, and the titration was determined to be faulty. The air needle was then punctured, but the infusion solution continued to fail to drip; therefore, the pharmacist in charge was consulted, and the air needle was punctured into the infusion solution body, but the solution did not drip. At this point, we also suspected obstruction on the venous side and attempted to draw reverse blood, but were unable to do so. There was no pain or swelling at this point, but erythema in the 1.5 cm x 2.5 cm range was noted along the vein from the incisional site to the central side (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA new line was established on the right side opposite the leak site, the remaining doxorubicin was resumed, followed by the administration of vincristine (1 mg in 100 mL of 0.9% saline), and the swollen area on the left arm was marked. Based on these circumstances, the pharmacist suspected extravascular leakage of doxorubicin and reported this to the hematologist, who requested the administration of dexrazoxane and concurrent dermatological consultation.\u003c/p\u003e \u003cp\u003eAfter examination, the physician suspected extravascular leakage of doxorubicin, and a 3-day infusion of dexrazoxane (1,700 mg dissolved in 100 mL distilled water followed by 500 mL lactated Ringer\u0026rsquo;s solution on days 1 and 2; 850 mg dissolved in 100 mL distilled water followed by 500 mL lactated Ringer\u0026rsquo;s solution) was initiated. In addition to dexrazoxane administration, cooling and topical steroid application (clobetasol propionate ointment) were initiated twice daily. Because of the poor stability of dexrazoxane, an infusion pump was used, and dosing was initiated at 500 mL/h. Thirty minutes after the initiation of treatment, the patient complained of vascular pain. The administration rate was changed to 400 mL/h, and a warm towel was applied to the puncture site; however, there was no change in pain. Therefore, the administration rate was changed to 300 mL/h and continued thereafter.\u003c/p\u003e \u003cp\u003eThe administration was completed within the period in which the stability of dexrazoxane was ensured. On Day 3 (Day 2 of dexrazoxane administration), 5 min after starting dexrazoxane administration at 500 mL/h, the patient complained of vascular pain. There was a 0.3 cm \u0026times; 0.3 cm internal hemorrhage at the insertion site of the right forearm and pain. After replacement of the 22-G indwelling needle, administration was resumed at 300 mL/h of dexrazoxane using an infusion pump, after which the angialgia disappeared. There was no swelling or pain at the angialgia site.\u003c/p\u003e \u003cp\u003eOn Day 4, there was no pain, and dexrazoxane administration was terminated, although a cord-like induration was observed in the right forearm wrist joint, the site where vasculopathy appeared the previous day. There was no complaint of pain in the left arm, but a central induration remained in the area where the indwelling needle was removed; some erythema and heat were also observed, which had become slightly more pronounced since the previous day.\u003c/p\u003e \u003cp\u003eOn Day 7, the patient complained of swelling and redness at the dexrazoxane administration site on the right forearm, with a numeric rating scale score of 5. A slightly bulging swelling (10 cm \u0026times; 7 cm) with erythema and tenderness without induration was observed along the central vein from the dexrazoxane extraction site (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), and numeric rating scale level 3 pain persisted. Because phlebitis or inflammation associated with dexrazoxane leakage was suspected, the patient was referred to a hematologist. The patient was diagnosed with a dexrazoxane leak, and a dermatological follow-up was planned.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInformation was collected regarding the risk of extravascular leakage due to dexrazoxane and the appropriate intervention. Injection site reactions occur at the site of dexrazoxane [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and dexrazoxane itself is an inflammatory drug [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A clobetasol propionate ointment was prescribed to treat the affected area in accordance with the response to an inflammatory drug leak, and the patient began application to the affected area twice daily.\u003c/p\u003e \u003cp\u003eOn Day 9, mild induration, swelling, and dark redness persisted on the right forearm, but the pain disappeared; however, the dermatologist examined the patient on Day 10, and the cord-like induration, which was palpable from the right forearm to the wrist on Day 8, was no longer detectable upon examination. Topical steroid application to the site of doxorubicin leak was discontinued, and topical dexrazoxane to the leak site was continued. On Day 11, erythema of the right forearm persisted, but the erythema and swelling tended to disappear, and the induration and pain disappeared. However, on Day 15, erythema tended to shrink, and pigmentation was observed, but there was no pain or ulceration.\u003c/p\u003e \u003cp\u003eOn Day 17, the induration around the doxorubicin leak had disappeared (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), and no induration of the dexrazoxane leak was palpable (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb); therefore, the patient was judged to be doing well, and the dermatologist completed the concurrent consultation. After the third course of R-CHOP, the patient was discharged without extravascular leakage. The patient did not develop any ulceration or serious skin lesions at the leakage site and was able to complete the rest of the courses of R-CHOP as an outpatient without any change in the scheduled chemotherapy.\u003c/p\u003e \u003cp\u003eThe patient responded positively to the application of clobetasol propionate to the site of dexrazoxane leakage, saying that he no longer awoke at night with pain after applying the ointment and felt that it was working. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the clinical course.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003eIn this case, doxorubicin, an anthracycline antitumor agent, leaked, and the patient was treated with dexrazoxane under medical supervision; however, extravascular leakage of dexrazoxane was observed. Dexrazoxane was initially developed as an antitumor agent [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and has topoisomerase II inhibitory activity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which poses a risk of extravascular leakage. At the time of the extravascular leak in 2017, there were no general recommendations for dexrazoxane leaks; however, we acted based on the literature, classifying it as an inflammatory agent. The European Society for Medical Oncology [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and the National Cancer Control Programme have prepared guidelines for the management of extravascular leaks, with no specific recommendations on how to respond depending on the degree of skin tissue necrosis. Although no specific response recommendations have been made, the guidelines prepared by the East Midlands Cancer Alliance recommend the use of topical steroids (weak steroids) in response to leaks of inflammatory antitumor agents. Additionally, the 2023 edition of the Guidelines for the management of Chemotherapy Extravasation in Japan recommends the use of topical steroids [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe reviewed the literature for previous reports of extravascular leakage of dexrazoxane, like the present case, and summarized the reports that focused on the extravascular leakage of anthracyclines in Table\u0026nbsp;1 [\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In most cases of anthracycline extravascular leakage since the launch of dexrazoxane, dexrazoxane has been administered. In about half of the cases, topical steroids were administered in combination with dexrazoxane. No necrotic tissue was observed in the dexrazoxane-treated cases. In cases where only dimethyl sulfoxide was administered, necrotic tissue was reported, and there were reports of procedures such as skin grafts and skin valves [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. There are few reports on the outcome of the present disease, with the longest follow-up being up to 1 year and 6 months after treatment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. There have been no reports of extravascular dexrazoxane leakage in any patient. Case reports of common extravascular leaks have reported that the use of topical steroids prevents serious outcomes such as necrotic tissue; the strongest steroids were used in this case. In the latest edition of the Guidelines for the management of Chemotherapy Extravasation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the inflammatory classification of dexrazoxane prepared in 2023 is not listed.\u003c/p\u003e \u003cp\u003eIn addition to the application of the ointment, the administration rate slowed as soon as vascular pain appeared, which was completed within the time required to ensure stability [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] after dexrazoxane preparation. Furthermore, we believe that the smooth exchange of information between nurses and pharmacists when extravascular leakage of dexrazoxane was detected and the daily sharing of symptom progress enabled the establishment of a system to promptly report to a hematologist\u0026ndash;oncologist and dermatologist and request medical consultation when symptoms worsened after 3 days, which contributed to patient outcomes. The importance of establishing an in-hospital system for the administration of dexrazoxane for extravascular leakage of anthracyclines has been reported [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our hospital has established an administration response flow for dexrazoxane administration, which may have had a small influence on its effectiveness. As for the response to the extravascular leak, prompt action was taken after the discovery of the leak, including confirmation of reverse bleeding, removal of the line, and consultation with a dermatologist, and the doxorubicin hydrochloride extravascular leak reduced without necrosis 6 days later. In addition, for dexrazoxane extravascular leakage, we applied steroid ointment as a topical treatment for inflammatory extravascular leakage, and the symptoms showed a tendency to lighten after 7 days. Therefore, we believe that our initial response was sufficient.\u003c/p\u003e \u003cp\u003eVarious risk factors for extravascular leakage have been reported [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; in this case, there were no clear factors, except that this was the second course of chemotherapy. One of the factors may have been the extravascular leakage of doxorubicin, which had been administered earlier, and the right forearm being secured at the radial cutaneous vein, which is on the opposite side, where it is a thin vessel susceptible to body movement. We believe that understanding the patient\u0026rsquo;s background with a focus on risk factors [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], establishing an initial response flow when an extravascular leak is detected, and improving the education system for hospital staff will impact patient outcomes.\u003c/p\u003e \u003cp\u003eThe site of extravascular leakage of doxorubicin hydrochloride improved after dexrazoxane administration. Local irritation, skin discoloration, and atrophy, which are recognized local side effects of topical steroids, did not occur [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The most important lesson learned from this experience is that in the event of a dexrazoxane leak, the application of topical steroids can prevent serious outcomes. Although there are reports that dexrazoxane falls under the category of inflammatory agents, there have also been reports of skin necrosis due to extravascular leakage of inflammatory antitumor agents [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and since there is a possibility of serious outcomes, even in the case of leakage of inflammatory agents, topical application may be recommended as an inflammatory agent, as in the case of necrosis-inducing agents. A limitation of this case is that the R-CHOP regimen included systemic administration of high-dose prednisolone, and there are no cases of leakage of dexrazoxane alone in the absence of systemic administration of high-dose steroids. Based on the outcome of this case, it appears that localized steroid injection or prophylactic debridement is not necessary as an additional treatment; however, if painful inflammation develops, topical steroids or other agents may be considered.\u003c/p\u003e \u003cp\u003eOur patient completed treatment and achieved remission without regimen modification or reduction in the antitumor agent dosage after doxorubicin and dexrazoxane extravascular leakage. Six years after the extravascular leak episode, the patient was alive without recurrence. Although this was a short-term case of extravascular leakage, it is significant because the decision to continue chemotherapy can affect the long-term outcomes of the patient.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDLBCL\u003c/p\u003e\n\u003cp\u003eDiffuse large B-cell lymphoma\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case has been reported with the approval of the Clinical Research Review Committee of Kameda General Hospital (Permission No.: Case 23-015). This case was reported after written consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVerbal and written informed consent was obtained from the patient to publish this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no new data were created or analyzed in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNW wrote a first draft of this manuscript,MS and IT advised interpretation of phenomenon in this case, RF supervised the writing of the manuscript. All authors read and approved the fnal manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge all the teams involved in his management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information (optional)\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWang SS. Epidemiology and etiology of diffuse large B-cell lymphoma. Semin Hematol. 2023;60:255-66.\u003c/li\u003e\n\u003cli\u003eThe world health organization classification of malignant lymphomas in Japan: Incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists. Lymphoma Study Group of Japanese Pathologists. Pathol Int. 2000;50:696-702.\u003c/li\u003e\n\u003cli\u003eOhmachi K. JSH practical guidelines for hematological malignancies, 2018: II. Lymphoma-5-diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). 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Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc Natl Acad Sci U S A 1994;91:1781-5.\u003c/li\u003e\n\u003cli\u003eFidalgo JP, Fabregat LG, Cervantes A, Margulies A, Vidall C, Roila F, ESMO Guidelines Working Group. ESMO Guideline Working Group. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012;23:vii167-73.\u003c/li\u003e\n\u003cli\u003eMatsumoto K, Ryushima Y, Sato J, Aizawa Y, Aoyama T, Akaishi Y, et al. Extravasation associated with cancer drug therapy: multidisciplinary guideline of the Japanese Society of Cancer Nursing, Japanese Society of Medical Oncology, and Japanese Society of Pharmaceutical Oncology. ESMO Open. 2024;9:103932.\u003c/li\u003e\n\u003cli\u003eNedomansky J, Haslik W, Pluschnig U, Kornauth C, Deutschmann C, Hacker S, et al. Tissue distribution of epirubicin after severe extravasation in humans. Cancer Chemother Pharmacol. 2021;88:203-9.\u003c/li\u003e\n\u003cli\u003eTakagi M, et al. Experience in treating forearm skin necrosis caused by extravascular leakage of epirubicin. Wound 2017;8:57-60.\u003c/li\u003e\n\u003cli\u003eNakagawa Y, et al. A case of extravascular leakage of an anticancer drug treated with dexrazoxane. Clin Dermatol. 2016;58:1462-3.\u003c/li\u003e\n\u003cli\u003eArroyo PA, Perez RU, Feijoo MA, Hernandez MA. Good clinical and cost outcomes using dexrazoxane to treat accidental epirubicin extravasation. J Cancer Res Ther. 2010;6:573-4.\u003c/li\u003e\n\u003cli\u003eTyson AM, Gay WE. Successful experience utilizing dexrazoxane treatment for an anthracycline extravasation. Ann Pharmacother. 2010;44:922-5.\u003c/li\u003e\n\u003cli\u003eKawamoto S, Shirahata T, Katori T, Izumo T, Kadono H, Fujita H, et al. Effectiveness of dexrazoxane for extravasation of anthracycline antitumor antibiotics - Reporting measures developed against extravasation in the hospital. Gan To Kagaku Ryoho 2016;43:2517-21.\u003c/li\u003e\n\u003cli\u003eTakahata T. Four Cases who experienced extravasation of anthracyclines and had dexrazoxane therapy. Cancer Chemother. 2023;50:467-71.\u003c/li\u003e\n\u003cli\u003eHowell G, Oliai C, Schiller G. Liposomal cytarabine-daunorubicin (CPX-351) extravasation: Case report and literature review. Anticancer Res. 2018;38:6927-30.\u003c/li\u003e\n\u003cli\u003eHengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006;54:1-15.\u003c/li\u003e\n\u003cli\u003eOkuda H, Masatsugu A, Sijimaya T, Arai R. Skin necrosis due to the extravasation of irritant anticancer agents. Intern Med. 2018;57:757-60.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dexrazoxane, Extravasation, Anthracycline antitumor agent, Case report","lastPublishedDoi":"10.21203/rs.3.rs-5987269/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5987269/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eDexrazoxane is used to treat extravascular leakage of anthracycline antitumor agents, but its own extravascular leakage and management remain underreported. This case aimed to highlight both doxorubicin and dexrazoxane leakage during treatment for diffuse large B-cell lymphoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eA 55-year-old man with diffuse large B-cell lymphoma developed doxorubicin leakage during R-CHOP therapy, which was treated with dexrazoxane. Subsequently, dexrazoxane leakage occurred, causing erythema and swelling. Topical clobetasol propionate was applied, leading to symptom resolution without necrosis. The patient successfully completed chemotherapy and achieved long-term remission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis case report is one of the first to document the management of dexrazoxane extravascular leakage using topical steroids, effectively preventing severe outcomes. The findings suggest that topical steroids may be a desirable treatment approach for dexrazoxane leakage. Prompt intervention and interdisciplinary care contributed to the favorable outcome. This case highlights the need for further research and guideline refinement to optimize the management of inflammatory extravascular leakage.\u003c/p\u003e","manuscriptTitle":"Extravascular leakage of dexrazoxane during treatment of diffuse large B-cell lymphoma: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-13 09:58:13","doi":"10.21203/rs.3.rs-5987269/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8066158a-8519-423b-889e-0b7496ee9830","owner":[],"postedDate":"February 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-16T15:58:21+00:00","versionOfRecord":{"articleIdentity":"rs-5987269","link":"https://doi.org/10.1186/s40780-025-00446-1","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2025-06-12 15:56:53","publishedOnDateReadable":"June 12th, 2025"},"versionCreatedAt":"2025-02-13 09:58:13","video":"","vorDoi":"10.1186/s40780-025-00446-1","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00446-1","workflowStages":[]},"version":"v1","identity":"rs-5987269","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5987269","identity":"rs-5987269","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}