Digital ischaemia and necrosis from oxaliplatin

Abstract

Oxaliplatin is a chemotherapeutic agent used in a variety of malignancies such as colorectal cancer and pancreatic cancer. It is a platinum derivative that results in direct cell cytotoxicity with resultant cell death. The most common side effects often noted are neurotoxicity, nausea, vomiting, diarrhoea, hepatotoxicity and myelosuppression. Oxaliplatin induced digital ischaemia and necrosis is a rare side effect that was observed in our patient. In general, digital ischaemia is a rare vascular disorder that is often associated with autoimmune disease. A patient with digital ischaemia due to oxaliplatin will be described in this case report.

Case presentation

A 49-year-old morbidly obese man with hypertension and type 2 diabetes mellitus was presented to a urology clinic with haematuria. Initially presumed to be prostatitis or urinary tract infection, he was treated with a fortnight of appropriate antibiotics without resolution. Imaging was done which revealed a mass in the anterior bladder and multiple enlarged retroperitoneal and right pelvic lymph nodes. He had a cystoscopy done, which was normal, so the patient was taken into the operating room for a partial cystectomy. A review of the pathology report shows an invasive mucinous adenocarcinoma of the urachus with rare signet ring forms. The tumour was 6.5 cm in the largest dimension and extends into the perivesical adipose tissue and muscularis propria. Lymphatic invasion was noted and one perivesical lymph node was positive for metastatic adenocarcinoma. The PET scan obtained post surgically showed expected postsurgical changes as well as hypermetabolic right iliac chain and infrarenal retroperitoneal lymph nodes that are suspicious for metastasis.

Urachal adenocarcinoma is a rare malignancy so there are no standardised treatment protocols or clinical trials that have been tested on large groups of patients. Most patients are treated with surgery and some are treated with chemotherapy. Two chemotherapy regimens that have been used are cisplatin based therapies and 5-fluorouracil based therapies. For our patient, due to nodal involvement with adenocarcinoma, he was initiated on a popular colorectal chemotherapy regimen called FOLFOX. This regimen consists of folinic acid, 5-fluorouracil and oxaliplatin and is the recommend regimen for treatment of node positive urachal adenocarcinoma according to the National Comprehensive Cancer Network guidelines.¹

The patient went on to receive seven cycles of FOLFOX chemotherapy. He presented with complaints of blackened fingertips during his chemotherapy clearance office visit prior to cycle 8 of planned FOLFOX. On the physical exam, painful necrosis was noted on the middle fingers on bilateral hands and early ischaemic change on the ring finger of the right hand (figure 1). There was no smell, swelling, erythema or drainage. All nails were intact and the rest of his hands were pink and warm. Bilateral radial and ulnar pulses were strong and palpable. There was pain at the acrocyanotic digits but no motor or sensory deficits noted elsewhere. Although the patient is diabetic, he did not have any neuropathy in his hands or feet and he was fully ambulatory. He has also lost about 100 lbs since his diagnosis which had led to improved control of his diabetes. After a telephone discussion with a vascular surgeon, the decision was made to delay chemotherapy and start the patient on aspirin, 81 mg daily and rivaroxaban, 10 mg daily. The patient was also referred to see the vascular surgeon urgently. He was found to have good circulation and pulses in bilateral hands and confirmed via Doppler and instructed to continue with antiplatelet and anticoagulation to prevent further necrosis.

Figure 1.

Digital ischaemia can be seen on the tips of the middle fingers on bilateral hands.

Because of the development of digital necrosis, FOLFOX regimen was stopped and he was started on another regimen called FOLFIRI, which is similar to FOLFOX with the exception that irinotecan is used in place of oxaliplatin. He went on to receive two cycles of FOLFIRI with improvement in pain in the involved digits. There was no further progression of his digital ischaemia and necrosis. Unfortunately, he passed away later on from cardiac arrest.

Discussion

Digital necrosis is a rare vascular complication that is usually associated with connective tissue disorders. Many other aetiologies have been linked which include arterial embolism, vasospasm, atherosclerotic plaque, hypercoagulable states, coronavirus disease 2019 and more.^2–5 It is important to identify this early on as it can progress to threaten the entire limb which can result in devastating amputations to save one’s life.

Colorectal cancer is the third leading cause of cancer related deaths in men and women in the United States with an estimated 149 500 new cases and 52 980 estimated deaths in 2020.⁶ Oxaliplatin is a commonly used chemotherapy drug in numerous solid malignancies including adenocarcinoma of the urachus and colorectal cancer. It is a third generation platinum compound that binds to DNA to produce crosslinks that results in inhibition of DNA synthesis culminating in cell death. The main side effects of oxaliplatin are peripheral neuropathy with paresthesias of the hands and feet, nausea, vomiting, diarrhoea, thrombocytopenia, anaemia and hepatotoxicity. Oxaliplatin induced digital necrosis is an uncommon side effect and only discussed in case reports.

The exact pathophysiology behind digital ischaemia and subsequent necrosis from oxaliplatin is unclear. One thought is vasospasm of a blood vessel with resultant end organ damage.⁷ There is a case report describing a patient with acute ST segment elevation myocardial infarction due to oxaliplatin induced transient coronary vasospasm.⁸ There are several other case reports that depict acute tubular necrosis of the kidneys from oxaliplatin⁹ which could be due to renal artery vasospasm resulting in decreased perfusion of the kidneys or direct toxicity. Other possible aetiologies are arteritis and hypercoagulability in which there are increased aggregation and activation of platelets with resultant clot formation.

Gemcitabine is another established chemotherapy agent that is frequently used to treat pancreatic adenocarcinoma and urothelial carcinoma. There have also been case reports showing that gemcitabine can also cause digital ischaemic events.^{10 11}

Our patient was treated with antiplatelet and anticoagulation agents and discontinuation of the offending agent. He had improvement of his ischaemia. Review of literature showed some patients were also treated with a prostacyclin analogue called iloprost with success as well.¹²

Learning points.

• Oxaliplatin is a platinum based chemotherapy drug used in a variety of solid organ malignancies.

• Oxaliplatin can cause ischaemia leading to end organ damage. It is important to recognise this to prevent morbidity and mortality.

• Discontinuation of oxaliplatin and antiplatelet, anticoagulant and prostacyclin analogues have been used to treat oxaliplatin induced ischaemia with success in various case reports. There are no standardised guidelines. Multidisciplinary care with a vascular surgeon is crucial.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.