Delayed presentation of vincristine extravasation

Introduction

Vincristine, a vinca alkaloid, is an anti-neoplastic drug that is used as intravenous (IV) for the treatment of many solid tumors and hematologic malignancies. The most common side effects of vincristine include gastrointestinal toxicity, respiratory toxicity, and neurotoxicity.^1–4

IV use of chemotherapy drugs is one of the main ways of drug delivery in malignant disorders and cancers ⁵ but this route of administration of chemotherapeutic drugs may be associated with severe side effects such as extravasation. Extravasation is defined as the leakage of a drug from a vessel to the extravascular tissue at the injection site.^6,7 The actual incidence of extravasation of vesicants is unknown, but one previous study estimated an incidence of 0.1%–6% from peripheral IV infusions and 0.3%–4.7% from implanted IV access port infusions ⁸ and according to a retro-prospective study the time interval between the IV use of chemotherapeutic drugs and initiating symptoms was approximately 2 h in 80% of the patients. ⁹ Extravasation symptoms, including burning, erythema, and swelling, usually begin immediately and worsen over several days. Symptoms in small extravasation volumes usually resolve within a few weeks. However, in some cases, the onset of symptoms may be delayed by a few days.^9–13 The rate of extravasation with vincristine is reported 1%–2%. ¹⁴ The diagnosis of delayed symptoms of extravasation after vincristine may be complicated. If proper treatment is not started for the patient, it may lead to tissue necrosis, tendon and nerve damage, and joint movement problems. According to mentioned above, its management can be very challenging.^11,15 We aimed to report a case of a 29-year-old woman with ALL-B cell who had no extravasation symptoms during infusion but the symptoms such as irritation and burning at the injection site has appeared after 48 h.

Case report

A 29-year-old woman with diagnosis of ALL-B cell (Acute lymphoblastic leukemia) was on maintenance POMP regimen including methotrexate 50 mg weekly for 2 doses, mercaptopurine 75 mg once daily, and vincristine monthly. She received IV vincristine and felt pain and burning at the injection site (cubital area) 48 h after injection, then in the next days the extravasation site became brownish and larger with tenderness and the patient had severe limitation of limb movement. Two days after the onset of symptoms, the extravasated area became infected and purulent discharge was present. Seven days after the onset of symptoms, the patient was admitted to Tabriz Shahid Ghazi Hospital with a 4  ×  6 cm lesion.

Management & outcome

After hospitalization, an arterial-venous Doppler ultrasound of the left upper limb showed normal blood flow in the vessels of the target organ without evidence of thrombosis. Levofloxacin 750 mg daily was started. Given that the application of warm compresses is recommended 24 to 48 h following vincristine extravasation, ¹⁶ it can be inferred that this approach may not be effective in cases of delayed extravasation. Furthermore, the administration of hyaluronidase as an antidote in an infected area is not advised due to the risk of spreading the infection. ¹⁷ Betamethasone topical cream every 6 h and dimethyl sulfoxide (DMSO) every 6 h was started on the second day of hospitalization. The use of DMSO was separated by at least three hours from the topical betamethasone cream. In addition, DMSO solution should be administered on dry skin and left on the desired area for 3 h. Two days after the initiation of topical therapies, relative improvement in local symptoms such as pain, swelling, and erythema was observed and the movements of the involved limb returned to normal. The patient was discharged from the hospital on the fifth day with cephalexin 500 every 6 h, clindamycin 600 every 8 h, and the continuation of local treatments. As shown in Figure 1, after 10 days of starting the topical treatment, her lesions had completely healed, leaving a pale hyperpigmented area. Pictures 1 and 2 were recorded before hospitalization at home. Photos 3 to 5 were recorded during hospitalization and photos 6 to 10 were recorded after discharge.

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Figure 1.

The skin lesion before (pictures 1 and 2), and after (pictures 3–10) the initiation of topical therapies.

Discussion

Extravasation is one of the rare but severe side effects of antineoplastic drugs which is defined as the leakage of vesicant drugs such as vincristine from the veins into the interstitial tissues. It can cause skin and tissue damage and its clinical manifestations can range from skin irritation to necrosis and shedding of the skin.^5,16 All patients who take chemotherapy are in danger of this complication and the main action is to avoid it if possible. We can prevent extravasation by selecting large and healthy veins for peripheral infusion, medical staff and patient education, avoiding injection into sites with sclerosis, thrombosis, or scarring, and appropriate dilution in isotonic saline or 5% dextrose. Early diagnosis of this side effect is very important to initiate effective treatment for the prevention of serious problems and decrease the time to recovery. Our case experienced delayed extravasation without acute signs. At this time, there was no firm recommendation on the management of delayed extravasation ¹⁷ and the emergency use of standard antidote such as hyaluronidase will not have any positive effect. ²

Given that there is no evidence of an inflammatory process in extravasation, the use of intradermal or systemic glucocorticoids is not recommended and can worsen tissue destruction and increase the need for surgical interventions, especially in the case of vinca alkaloids and epipodophyllotoxins. ¹⁸ However, the use of the topical form can be effective in reducing irritation in the area and reducing erythema.^19–21

Another drug used in extravasation is DMSO topical solution, which can penetrate through the skin tissue and its anti-inflammatory effects have been proven. The mechanism of action of this drug is not fully known, but DMSO can stimulate the release of histamine, causing vasodilation, increasing tissue blood supply and ultimately reducing ischemia. ²² Based on the hypothesis, the damage caused to the tissue after the extravasation of cytotoxic drugs is due to the production of hydroxyl radicals, and DMSO with its free radical scavenging properties can play an important role in this process. In addition to the mentioned effects, the positive effects of DMSO on revitalizing the skin and healing injuries have been reported.^17,20,23 According to studies DMSO has been effective in off-label treatment of anthracyclines and mitomycin extravasation.^18,24,25 In a case report, extravasation occurred during the infusion of doxorubicin and vincristine, which was immediately treated with chondroitin sulfate subcutaneously, and DMSO solution was used topically for 2 weeks, which finally resolved all inflammatory effects. ²⁶ However, there are no guideline recommendations or reported cases of using this solution in extravasation that occurs with vinca alkaloids alone, particularly late extravasation. According to the described conditions, we used successfully DMSO solution and betamethasone cream for the management of delayed extravasation every 6 h and the desired lesion on the cubital area was completely resolved after 10 days (Table 1).

Conclusion

In most cases, extravasation occurs during the injection, but it may occur several days after the infusion. Due to lack of effective treatment for the delayed extravasation following vincristine, proper management and treatment in these cases can prevent the deterioration of the lesion and its progress towards necrosis. Due to the beneficial effect of our clinical approach, it could consider for the management of similar cases with delayed extravasation following vincristine administration.

Naranjo score

Naranjo Score → 7

Adverse Drug Reaction → PROBABLE

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Table 1.

Naranjo Adverse Drug Reaction Probability Scale.

Question	Yes	No	Do Not Know	Score
1. Are there previous conclusive reports on this reaction?	+ 1	0	0	+ 1
2. Did the adverse event appear after the suspected drug was administered?	+ 2	−1	0	+ 2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+ 1	0	0	+ 1
4. Did the adverse event reappear when the drug was re-administered?	+ 2	−1	_0	0
5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?	−1	+ 2	0	+ 2
6. Did the reaction reappear when a placebo was given?	−1	+ 1	_0	0
7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+ 1	0	_0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+ 1	0	_0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+ 1	0	_0	0
10. Was the adverse event confirmed by any objective evidence?	+ 1	0	0	+ 1
TOTAL SCORE:				7

Modified from: Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–245.