Gemcitabine-induced digital ischaemia in a patient with metastatic breast cancer

Background

Gemcitabine is a pyrimidine nucleoside antimetabolite that is used in treatment of various malignancies including metastatic breast cancer.1 The most common toxicities of gemcitabine include nausea, vomiting, diarrhoea, myelosuppression, hepatotoxicity, fever, dyspnoea, rash and peripheral oedema.1 2 However, gemcitabine is also associated with some rare adverse events including thrombotic microangiopathy, capillary leak syndrome, vasculitis and gangrene.3 4 The mechanism of gemcitabine-induced vascular toxicity is unclear and likely multifactorial.5

We describe a case of gemcitabine-induced digital ischaemia and dry gangrene in a patient with oestrogen/progesterone receptor negative and HER2/neu-positive, metastatic breast cancer treated with gemcitabine after multiple prior lines of therapy. While this rare toxicity has been described in the context of other malignancies such as lung, bladder and pancreatic cancer, this is the first case reported in a patient with breast cancer to the best of our literature review.

Case presentation

A woman in her 50s with HER2/neu-positive, oestrogen/progesterone receptor negative, metastatic invasive ductal carcinoma of breast, presented to the oncology clinic with acral cyanosis, severe throbbing pain and purplish discolouration of the fingers of both hands, and to a lesser degree of her toes of both feet. She also developed a black gangrenous area with loss of sensory perception over the distal fourth finger of the right hand (see figure 1).

The patient was initially diagnosed with metastatic HER2-positive breast cancer 5 years prior to this admission. Over the course of her disease, she had progressed on multiple lines of therapy, all of which included an anti-HER2/neu-targeted agent. Her prior treatments included paclitaxel, trastuzumab and pertuzumab; vinorelbine and trastuzumab; trastuzumab emtansine; capecitabine and lapatinib; fam-trastuzumab deruxtecan; and cyclophosphamide and trastuzumab-anns. One month prior to the said admission, she was started on margetuximab 15 mg/kg on day 1 with gemcitabine 1000 mg/m² on days 1 and 8 of a 21-day cycle. Margetuximab was discontinued due to an allergic reaction. The patient subsequently received cycle 2 day 1 of gemcitabine with trastuzumab-anns. She developed the afore-mentioned symptoms a few days after that.

The patient initially tried topical triamcinolone, oral acetaminophen, ibuprofen and gabapentin without improvement in the symptoms. She was admitted to the hospital for further management. She denied fever, arthralgias, rash, photosensitivity or oral ulcers. The patient had no history of smoking, diabetes, peripheral vascular disease, Raynaud phenomenon or autoimmune illness.

Investigations

• Complete blood count: white blood cell count 5.4 (normal range 3.5–10.6×10⁹/L), haemoglobin 101 (115–151 g/L), platelet count 223 (150–450×10⁹/L).

• C reactive protein 34.3 (<5 mg/L), erythrocyte sedimentation rate 70 (0–14 mm/hour).

• Elevated antinuclear antibody (ANA) titre at 1:640 with a homogenous pattern.

• Testing yielded normal results for antineutrophil cytoplasmic antibody, antidouble-stranded DNA, anti-Scl 70, anti-Smith, anti-Sjogren’s syndrome A and anti-Sjogren’s syndrome B, anti-RNA polymerase III, anti-Jo 1, anti-U1 ribonucleoprotein, anticyclic citrullinated peptide, rheumatoid factor and complement levels. Urine analysis was negative for proteinuria.

• Arterial doppler exam of the upper extremities was normal. On the right, the wrist/brachial index was 1.10 and digit/brachial index measured 1.06, with an absolute pressure of 137 mm Hg. On the left, the wrist/brachial index was 1.09 and digit/brachial index measured 1.18, with an absolute pressure of 152 mm Hg. On both sides, blood flow waveforms were triphasic. Photoplethysmogram tracings at the digits had normal upstroke and pulsatility with retention of the dicrotic notch.

Differential diagnosis

Given the timing of the development of symptoms and known vascular toxicity of gemcitabine, drug-induced vasculopathy and digital ischaemia was the most likely diagnosis. Autoimmune syndromes were considered; however, the patient did not have any supportive clinical or laboratory findings except for an isolated elevation of ANA. Rheumatology was consulted who felt that the elevated ANA was likely due to the patient’s malignancy and indicated that the suspicion for an autoimmune condition or other rheumatologic disease was low.

Treatment

Gemcitabine was discontinued permanently. The patient was started on aspirin 81 mg once daily and heparin 5000 units subcutaneously every 8 hours. Heparin was chosen over oral anticoagulants given the ease of reversal and clearance if the patient was to require urgent surgical intervention. Amlodipine 5 mg once daily and topical 2% nitroglycerin ointment thrice daily were used for vasodilatory action. For pain control, ibuprofen, acetaminophen–hydrocodone and hydromorphone were prescribed as needed.

Outcome and follow-up

The patient had significant pain for 3–4 days. She had gradual improvement in the level of pain and recovery of the cyanosis in both hands and feet over the following weeks, except for a small necrotic area over the right fourth digit which developed a black eschar. She did not require surgical revascularisation, amputation or debridement. This small, dry, necrotic area persisted and did not slough off or get replaced by normal skin on a follow-up 3 months after discharge. Her cancer treatment was subsequently changed to a weekly doxorubicin regimen. After progression on doxorubicin, she was started on carboplatin and trastuzumab. Subsequently, she was started on capecitabine and neratinib after progression.