Medical Management of an Infusion Site Extravasation Injury After Peripheral Intravenous Infusion of Ado-Trastuzumab Emtansine in a 38-Year-Old Woman with Breast Cancer: A Case Report

Introduction

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate indicated for the treatment of early-stage and adjuvant human epidermal growth receptor 2 (HER-2)-positive breast cancer (BC) [1]. Mechanistically, T-DM1 works by using an antibody, trastuzumab, to target malignant cells with over-expression of HER-2 [1]. Once bound to those cells, the molecule is internalized and degraded, releasing its toxic payload, emtansine (DM1) [1]. DM1 binds to tubulin and disrupts microtubules in the cell, causing cell cycle arrest and apoptotic cell death [1]. As a strong microtubule inhibitor, DM1 carries the same risk of peripheral neuropathy and pancytopenia as other drugs in this class [1]. These risks are mitigated by the targeted nature of the drug [1]. T-DM1 is administered as an intravenous (i.v.) infusion only, not as an i.v. push or bolus [1].

An infusion site extravasation injury occurs when medication is unintentionally administered or leaked into unintended tissues as opposed to the vasculature or lymphatic systems [2]. Not only is this uncomfortable, but it can also cause tissue damage, including blistering, swelling, and necrosis [2]. Clinical studies for T-DM1 observed reactions secondary to extravasation, and the package insert includes extravasation as a known adverse event [1]. Reported reactions are usually mild and consist of erythema, tenderness, skin irritation, pain, or swelling at the infusion site; specific treatment is unknown [1].

To our knowledge, there are 3 other case reports published discussing extravasation and management of T-DM1. Two of the 3 patients were treated with conservative measures including close monitoring, arm elevation, and pain management [3,4]. In the third case study, the patient initially elevated the affected arm, resulting in increased pain and erythema. After further consultation, watchful waiting was employed. The patient eventually underwent blister removal and treatment with topical silver sulfadiazine to prevent infection [5]. These case reports demonstrated wound healing times of up to 6 weeks. We present the case of a 38-year-old woman with breast cancer who was treated with T-DM1 and experienced an infusion site extravasation injury that led to skin necrosis. We discuss the medical measures with which she was treated and discuss the timeline of healing.

Case Report

A 38-year-old woman with no relevant medical history was diagnosed with de novo stage IV BC. Her primary tumor was in the left breast. The tumor was estrogen-receptor (ER) 90%, progesterone-receptor (PR) 70%, and HER-2 immunohistochemistry (IHC) 3+. The patient had 1 small pelvic lesion on imaging and was therefore treated with curative intent. She received neoadjuvant systemic therapy (docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles) followed by a left breast mastectomy. She had residual cancer burden of 2 (moderate residual disease) and was started on adjuvant T-DM1. Access was repeatedly discussed with the patient, who continued to decline port placement. Medication was administered via peripheral i.v. Eighty minutes into her first T-DM1 infusion, the i.v. medication was found to have infiltrated. The medication was stopped, with no critical issues documented. The patient was observed for 90 minutes and given educational information for extravasation care at home, including compresses, avoiding friction, and monitoring for spread.

One week later, she reported the area of extravasation was extremely painful and blistering. It had extended beyond the boundaries of the original marking, despite daily cleaning and application of non-medicated petroleum jelly. She was sent to the Same-Day Dermatology Clinic, where the direct toxic effect from infiltrated chemotherapy was confirmed. She was given oral antibiotics (cefadroxil 500 mg twice daily for 7 days), a topical steroid (clobetasol 0.05% applied twice daily), and gabapentin for pain control. High-dose vitamin D (ergocalciferol 50 000 units once weekly for 3 weeks) was also prescribed, as there are data to suggest that vitamin D is a critical factor in the epidermal response to wounds [6], although the patient was told that this benefit would likely be minimal. She was also educated on cold compression and appropriate wound care and scheduled for close follow-up with wound assessment and documentation. No biopsies were done, and the patient was monitored with physical evaluation. After about 3 weeks, she saw her dermatologist and reported having considerable itching. The provider wanted to be steroid-sparing and prescribed a calcineurin inhibitor (tacrolimus 0.1% ointment applied twice daily). Tacrolimus and other calcineurin inhibitors have known benefits for itching, likely due to inhibition of inflammatory cytokine expression [7,8]. Approximately 4 weeks after the extravasation, the wound was almost entirely healed and pain-free, with some residual hyperpigmentation. The patient consented to port placement and received the remaining doses of T-DM1 via the port during wound healing (Figures 1–6).

Discussion

This patient’s experience with extravasation and skin necrosis highlights the importance of port placement with T-DM1 infusions. Further, it shows the benefits of using various treatment modalities to expedite healing and prevent infection, discomfort, and prolonged wounding. To our knowledge, this case of T-DM1 extravasation was treated differently than others in the literature with various medical measures provided upfront. Three case reports describing the management of T-DM1 extravasation have been published. Two of them describe treatment with conservative measures such as arm elevation and pain management [3,4]. In a third case report, elevation and watchful waiting were employed, but the patient did require blister removal and topical infection prophylaxis [5]. Our patient received more interventions than the patients described in other case reports, including antibiotics (cefadroxil), a topical steroid (clobetasol) and calcineurin inhibitor (tacrolimus) to aid in itching, high-dose ergocalciferol for its potential benefit in wound healing, and pain management (gabapentin). As this case report is based on a single-patient experience, there is certainly a limitation to the generalizability of this treatment. Further studies would need to be performed to ensure this management will be helpful to various patients. Our patient achieved almost complete resolution of the wound in less than 4 weeks. Other case reports have shown resolution of extravasation wounds taking up to 6 weeks, suggesting the benefit of treatment with multiple agents.

Conclusions

We recommend the use of port access when administering T-DM1, although it is not currently required by the manufacturer. In the unfortunate event of extravasation, we recommend comprehensive medical management to help prevent infection, control pain and itching, and encourage wound healing.