Acute ischemia of the lower limb during chemotherapy for testicular cancer: A report of two cases

To the Editor

Arterial or venous thrombosis is a common complication in cancer patients, particularly during treatment. This is especially true with some antiangiogenic drugs (bevacuzimab, thalidomide) which are know to favor arterial thrombosis. Arterial complications are also described with chemotherapy regimens using cisplatin (CDDP) alone, particularly for testicular cancer. We report two cases of acute ischemia of the lower limb observed in patients given a CDDP based regimen for testicular cancer.

The first patient was a 36-year-old man with an uneventful personal and familial history, excepting active smoking evaluated at 20 package-years, who consulted for discomfort in the right testicle. Clinical work-up and computed tomography (CT) revealed a tumor of the right testis and lymph node enlargement of the mediastinal and aorta-cava chains. Tumor markers were negative. Right orchidectomy was performed via an inguinal approach and pathology examination of the surgical specimen disclosed exclusive seminoma, staged pT1N2M0 (no vascular emboli). A 4-cycle chemotherapy regimen (etoposide 100 mg/m²/d for 5 days + cisplatin 20 mg/m²/d for 5 days) was started.

Three days after the end of the first cycle, i.e. eight days after initiating the first cycle, the patient complained of pain in the left calf. Physical examination showed a pale left foot, a swollen calf, and sensorial deficit, leading to the diagnosis of arterial thrombosis. Emergency embolectomy with a Fogarty catheter was performed to clear the left femoro-popliteal-tibial arterial vasculature. Continuous heparin infusion was then given and followed by low-molecular-weight heparin (LMWH). Nine days later, the patient developed recurrent thrombosis of the same arterial territory, requiring a second embolectomy and aponeurotomy. The patient recovered well under anticoagulants. Pathology (both events) reported a fibrin clot with no sign of malignancy. Echocardiography was normal.

The three other chemotherapy cycles were delivered successfully with no vascular events. At the end of the treatment schedule, the patient had achieved complete remission.

The second patient was a 34-year-old smoker (10–15 package-years) with a history of urological surgery (cure for a right ectopic testis and bilateral orchidopexia for torsion of the right testicle) who consulted for increased volume and pain in the left testicle. Clinically, the patient presented a mass in the left testicle. Left orchidectomy was performed via the inguinal approach. Pathology reported a 7-cm mixed predominantly seminomatous germinal tumor with an embryonic carcinoma component. The cord was negative and there were no vascular emboli. Search for extension identified two enlarged left retroperitoneal lateral aortic nodes measuring 20 mm. Staging was pT1N1M0. A three-cycle chemotherapy protocol was planned: BEP (Etoposide 100 mg/m²/d for 5 days + Cisplatin 20 mg/m²/d for 5 days, Bleomycin 30 mg/d d1, d8 and d15). On day 15 counting from onset of the first cycle, the patient complained of sudden painful cramps in the left calf. Walking distance was limited to 150 m with no sensorial or motor deficit. The arterial pulses were palpated and free of bruit, excepting the posterior tibial. A duplex Doppler of the venous and arterial networks of the lower limb performed two days later disclosed thrombosis of the left middle popliteal artery with a recent obstructive thrombus and thrombosis of the peroneal artery which had only been reinjected in the lower third of the leg. A Fogarty catheter was used to clear the lower popliteal and tibial networks. Pathology reported fibrin clots with no sign of malignancy. Heparin was delivered intravenously in a continuous infusion then replaced with oral anticoagulants. Anticoagulation was difficult to control during chemotherapy. A control duplex-Doppler two weeks later revealed good patency of the lower limb arterial network. At last follow-up the patient has remained in complete remission.

Discussion

We report two similar cases of acute lower limb ischemia in two young male smokers with germ-cell tumors (seminoma in one patient and a mixed tumor in the other). The two patients were given similar chemotherapy regiments (4 EP, 3 BEP) and both developed arterial thrombosis during the first cycle.

Three pathogenic mechanisms could be put forward to explain the development of arterial thrombosis in these patients: drug toxicity, cancer of the testicle, smoking.

In both patients, the arterial thrombosis occurred early after initiation of the first chemotherapy cycle, a chronological argument in favor of drug toxicity in young patients with no radiological evidence of artherosclerosis [1]. Chemotherapy-related vascular phenomenon are well known, e.g. Raynaud's phenomenon, which some authors believe has a reduced incidence because of concomitant use of corticosteroids, and arterial thrombosis 2–4. Drug-induced thrombosis appears to be related to damage to the vascular endothelium, platelet activation, and alteration of the coagulation cascade. Bleomycin can cause venous obstruction, changes in the capillary and arteriole endothelium and in vitro stimulates production of collagen in fibroblast cultures. Cisplatin might also be incriminated 5–7 and in some instances the thrombosis could hit the aorta [8]. Several factors could be associated: smoking (both patients were active smokers), renal toxicity of cisplatin (not observed here), increased Willebrand factor, and severe hypomagnesemia leading to arterial vasospasm often reported in older studies [9] and due to cisplatin-induced tubulopathy (serum magnesium was not assayed in these patients).

A second hypothesis would be cancer-induced thrombosis. Thromboembolism is common in cancer patients, but arterial thrombosis is rarely described. However, in a recent meta-analysis comparing the risk of arterial thromboembolism in 1 745 patients with metastatic colorectal, breast or non-small-cell cancer given chemotherapy regimens with and without associated bevacizumab [10], the risk was 3.1 events per 100 patient-years among patients receiving chemotherapy alone and 5.5 for those receiving a combination with bevacizumab. In another cohort study [11] reviewing first-line treatment in 179 patients with testicular cancer between 1979 and 1997, from treatment onset to six weeks after treatment end, 15 patients experienced 18 thrombotic events, including three arterial events. There would thus be no reason to postulate a higher risk specifically among patients with testicular cancer, excepting the fact that the baseline risk would be expected to be very low in this younger population. This study found that risk factors for thrombosis were the presence of liver metastasis and high-dose corticosteroids (> 80 mg dexamethasone). Neither of our patients had liver metastases, but both received more than 420 mg prednisolone (the dose equivalent of 80 mg dexamethasone). Corticosteroids can induce thrombosis via a vasoconstrictor effect and a coagulation effect. At high doses, corticosteroids inhibit fibrinolytic activity while at low doses, they inhibit platelet aggregation, and consequently, affecting the risk of arterial thrombosis.

The third hypothesis of a smoking effect must also be considered, perhaps more as a co-factor than as a unique causal element.

Thus, cases of arterial thrombosis of the lower limb in patients given chemotherapy for testicular cancer are not exceptional, particularly when high-dose corticosteroids are given to counteract the emetic effect of chemotherapy regimens using cisplatin. While it would probably be hazardous to propose preventive anticoagulation systematically, clinicians must not overlook the possibility of arterial thrombosis, even in this young population. As for venous thrombosis, and particularly in the field of pancreatic cancers [12], the debate remains open concerning the continued use of LMWH for the curative treatment of arterial thrombosis in cancer patients [13].