Critical acral ischaemia leading to multiple finger amputation: side-effect of long-term (>30 cycles) pemetrexed maintenance treatment in a patient

Pemetrexed is a new-generation antifolate agent, which was approved in the last decade for treatment of nonsquamous nonsmall cell lung cancer and malignant pleural mesothelioma [1]. In July 2009, the US Food and Drug Administration approved the use of single-agent pemetrexed in maintenance therapy of nonsquamous nonsmall cell lung cancer after successful first-line treatment [1]. We report the first case of maintenance pemetrexed that caused digital ischaemic gangrene requiring amputation. A 65-year-old African-American female was diagnosed with stage 4 lung adenocarcinoma with distant pulmonary metastases. Her only comorbidities were hypercholesterolaemia and hypertension, both controlled with the use of a statin and angiotensin-converting enzyme inhibitor, respectively. She completed four cycles of carboplatin and pemetrexed, resulting in partial tumour response. Following this, she was started on maintenance pemetrexed at 500 mg m−2 every 3 weeks, and her disease remained stable. The patient presented to the emergency room after the 32nd cycle of maintenance pemetrexed, complaining of episodes of intense pain in the digits of her left hand for 1 week. The pain started 1 day after the 32nd pemetrexed cycle, was initially intermittent, and lasted from a few minutes to a few hours. Pain was most severe in the left fourth digit. She also complained of episodic numbness, swelling and blanching of all digits. She denied any systemic symptoms or smoking history. Examination showed mild blanching of all left-hand fingers, and worsening of pain/blanching on exposure to cold water. Blood parameters, including a complete blood count, metabolic panel, sedimentation rate, C-reactive protein and antinuclear antibodies, were normal. Imaging studies showed stability of lung cancer. Arterial Doppler ultrasound revealed normal upper extremity macrocirculation. Her symptoms were thought to be related to Raynaud's phenomenon induced by chemotherapy. She was advised to avoid cold and was prescribed a calcium channel blocker. The patient had two subsequent emergency room visits for the same complaints, when further tests, including cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, cryoglobulins, C3- and C4-complement and two-dimensional echocardiography were performed. None of these tests showed any abnormality. Meanwhile, the patient went on to receive the 33rd scheduled chemotherapy cycle, following which she experienced significant worsening of pain and developed swelling and cyanosis of the fingers of the left hand. On re-evaluation, black eschar formation was seen on the tip of left fourth digit. An emergent angiogram of the left upper extremity showed patent ulnar and radial vessels but poor perfusion in the distal digital arteries, most severe in the fourth digit. There was no evidence of thrombus, embolus or any focal area of stenosis. The plasma level of D-dimer was within the normal range, similar to the baseline level prior to the initiation of chemotherapy. Given the extent of occlusion and gangrene formation, her fourth digit was amputated. Pemetrexed infusions were stopped owing to known chemotherapy-induced endothelial dysfunction. Two months later, she also needed amputation of the left third digit due to ischaemia/gangrene. No further episodes of digital ischaemia or gangrene have occurred to date, over a follow-up period of 21 months. Off pemetrexed, the patient's lung cancer progressed after 10 months and she was started on daily erlotinib treatment. Her disease has since been stable, and no recurrent ischaemic symptoms have been experienced thus far. The onset of ischaemic symptoms in this patient was seen in association with prolonged pemetrexed infusion in the absence of other disorders. There was rapid progression from the initial pain symptoms to a gangrenous finger, and symptoms resolved after discontinuation of pemetrexed. Paraneoplastic syndrome is unlikely to be responsible for the patient's symptoms because the cancer was stable at the time of presentation. All these findings suggest that the patient's ischaemic symptoms were an adverse consequence of long-term pemetrexed treatment (and not Raynaud's phenomenon or paraneoplastic syndrome). We hereby draw the following conclusions: (i) pemetrexed-induced non-embolic occlusive arterial disease can mimic Raynaud's phenomenon in the initial stages; (ii) patients on maintenance pemetrexed chemotherapy who report persistent digital pain require special attention and thorough investigation; (iii) the time window from the beginning of pain to the development of a nonsalvageable gangrenous digit may be short; (iv) cumulative toxicity from multiple pemetrexed infusions may lead to severe endothelial dysfunction and limb-threatening gangrene; (v) this potential risk of long-term pemetrexed use should be discussed with patients who have a high predisposition for an impaired micro- or macrocirculation; and (vi) postmarketing surveillance of long-term pemetrexed (>30 cycles) use should be studied to determine a definitive causal relationship between prolonged pemetrexed use and peripheral arterial ischaemic disorders.