|Ahead of print
5-Fluorouracil induced extravasation injury
Sangana Sunitha Reddy1, Shalaka Somayaji1, Mamatha Krishna Murthy1, Vinayak V Maka2
1 Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangaluru, Karnataka, India
2 Department of Medical Oncology, M.S. Ramaiah Medical College and Hospitals, Bengaluru, Karnataka, India
|Date of Submission||04-Apr-2019|
|Date of Decision||21-May-2019|
|Date of Acceptance||25-May-2019|
|Date of Web Publication||22-Jul-2020|
Mamatha Krishna Murthy,
Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Antineoplastic drugs based on their ability to cause local damage are classified as irritants, vesicants, and non-vesicants. Previous literature has reported higher rate of vesicants induced extravasation (EV) compared to irritants. We report the first case of irritant, 5-fluorouracil causing grade III EV in 55-year-old woman. The patient was diagnosed with esophageal squamous cell carcinoma. Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) chemotherapy regimen was planned and administered through peripheral venous access. Patient experienced grade 3 extravasation in her 3rd cycle following 5-fluorouracil (5-FU) administration. The suspected drug was withdrawn immediately and discontinued from the 4th cycle of the regimen. The patient completely recovered from the symptoms of pain and erythema in the next cycle and care was taken not to infuse drug in the same site again. Since there is no appropriate antidote available to manage this condition, measures need to be taken to identify the predisposing factors for EV and prevent them.
Keywords: 5-fluorouracil, carcinoma, chemotherapy, extravasation
| » Introduction|| |
Extravasation is a known complication of intra-venous administration of chemotherapeutic agents. Severity of extravasation injury was graded using CTCAE v4.3 grading scale, symptoms range from pain, erythema, mottling of skin to tissue necrosis., Antineoplastic drugs based on their ability to cause local tissue damage are classified as irritants, vesicants, and non-vesicants. Docetaxel, Cisplatin, 5-Fluorouracil (DCF), a standard combination regimen finds its use in squamous cell carcinoma of anal canal and esophagus with a response rate of 35–40%. According to European Society for Medical Oncology - European Oncology Nursing Society (ESMO-EONS), docetaxel is a vesicant while cisplatin and 5-fluorouracil (5-FU) are categorized as irritants. There are reports on docetaxel and cisplatin induced extravasation injuries, but reports on 5-fluorouracil causing grade III extravasation are minimal.
As indicated by previous literature, [5,6] an irritant does not cause any permanent damage, however we report a case of 55-year-old woman diagnosed with esophageal carcinoma experienced severe extravasation following 5-FU with the symptoms of pain, erythema, and blackening of veins. The patient was managed by immediate discontinuation of drug and the line was not repeated for further cycles.
| » Case Report|| |
A 55-year-old woman presented with difficulty in swallowing since 6 months and was a known case of type 2 diabetes mellitus. Investigations like computed tomography (CT) scan and endoscopy revealed tumor growth from lower end of esophagus extending to gastroesophageal junction. Histopathology was consistent with HER-2/neu negative, moderately differentiated adenocarcinoma of esophagus.
On further evaluation, PET-CT showed cancer of gastroesophageal junction extending to distal esophagus and gastric lesser curvature with metastasis to lower periesophageal gastrohepatic and right supraclavicular lymphadenopathy. The metastasis was further confirmed by fine needle aspiration cytology (FNAC) from the right supraclavicular node (SCN), which was found to be positive for malignancy. The patient was diagnosed with carcinoma of esophagus stage IV.
DCF regimen of 6 cycles once in 3 weeks was planned and port was connected through peripheral venous access to the dorsum area of the hand. In first and second cycle, patient was admitted for 5 days in which docetaxel and cisplatin were given in the first 2 days over 2 hours with 5-FU on-flow on all the days. Patient was readmitted after 15 days for 3rd cycle, where docetaxel and cisplatin were administered on the first day along with on flow 5-FU for 5 days in the following way: Docetaxel 140 mg over 90 minutes, Cisplatin 70 mg over 2 hours and 5-FU 1400 mg over 24 hours. Severe extravasation [Figure 1] injury was detected by end of the cycle and patient experienced grade 3-extravasation categorized according to CTCAE v4.3, presented with mottling of skin, pigmentation along with pain and erythema. The suspected drug 5-fluorouracil was discontinued in the 4th cycle; while docetaxel and cisplatin were continued. The patient completely recovered from pain and erythema without any worsening of the injury. However, pigmentation of the veins persisted around the area of extravasation (EV). The patient's recovery after discontinuation served as a confirmation that 5-FU was responsible for the injury. 5-fluorouracil was again readministered in the next consequent cycles, further care was taken not to infuse drug in the same site again. No antidote was used in the management of above condition in the patient. A written informed consent was obtained from the patient.
| » Discussion|| |
Antineoplastic drugs can cause toxic local tissue reactions due to extravasation, which is an unsuitable or accidental infiltration of cytotoxic drugs into subdermal tissues that surround the IV-line site. The drugs absorbed by adjacent cells in the tissue bind to DNA and microtubules causing cell death. After this cytolysis process, the surrounding cells may be affected by the drug released from the dead cells; this repetitive process impairs healing and results in chronic tissue injury. These injuries are variable and range from less remarkable erythematous reactions to skin necrosis. [2,8] The damage caused can progress into surrounding nerves, tendons, and joints. Surgical debridement, skin grafting, and amputation are a few unfortunate consequences, if the damage is ignored or left untreated.
As per literature, the incidence rate of extravasation is 0.6–1%, but this rate is doubted due to under reporting. Limited number of studies is also responsible for inadequate understanding of predictive and preventive factors of extravasation. The incidence rates of extravasation are known to vary greatly depending on drugs, efficiency of staff, and the patient themselves.
5-Fluorouracil is an antimetabolite fluoropyrimidine analog of the nucleoside pyrimidine with antineoplastic activity, used in different types of cancers such as colon, rectal, breast, and gastrointestinal cancers like anal, esophageal, pancreas, and gastric cancers. In vivo, 5-fluoruracil is converted to active metabolites that incorporate into both RNA and DNA and results in major effects on RNA processing and functioning there by inhibiting cell growth. Along with their therapeutic effects on tumor cells, it also has the potential to cause the destruction of healthy and normal cells surrounding the cannulation site.
According to ESMO-EONS classification of cytotoxic drugs, 5-fluorouracil was classified under irritants based on its ability to cause tissue damage. Irritants generally do not cause permanent damage, until it is given as continuous infusion for long duration, but may cause pain and inflammation at the catheter site and vein. Previous experiences in other studies have advocated measures or steps such as peripheral vein must only be opted for chemotherapy that requires short duration infusions, preferably dorsum and wrist areas of hand needs to be avoided. However, in our hospital setting, peripheral line was opted more while central line was preserved for patients with inaccessible peripheral sites. Those chemotherapy drugs that have shown higher tendency of severe tissue damage, necessitates the use of central over peripheral line as a preventive measure.,
Availability of fewer antidotes for the management of extravasation compels the health care team to choose one based on the desired outcome to either disperse and dilute or localize and neutralize the cytotoxic drugs. Primary management should be to stop and discontinue the infusion immediately after extravasation and as much as possible the offending drug should be removed by aspiration, followed by hot or cold compresses if required.
| » Conclusion|| |
Chemotherapy drugs are known to cause an arena of adverse effects. EV, being one of the most painful events, is preventable in many instances. Suitable measures to ascertain the extent of extravasation injury, possible predictors before administration and patient education through a multidisciplinary approach can contribute to an appropriate preventive strategy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Authors thankfully acknowledge the principal Dr. V. Madhavan, Professor and Head, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences and all the staff of the Department of Pharmacy Practice for their continuous guidance and support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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