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Gefitinib-induced disseminated intravascular coagulation in a patient with non-small cell lung cancer

YUAN, Guang-jin; KE, Qin-hua; XU, Xi-ming; YANG, Ji-yuan; SU, Xiao-yan

Section Editor(s): WANG, Mou-yue; LIU, Huan

doi: 10.3760/cma.j.issn.0366-6999.2010.04.022
Case Report
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SDC

In February 2005, Gefitinib (Iressa), a small-molecular epidermal growth factor receptor and tyrosine kinase inhibitor, was approved in China as an anticancer agent for patients with advanced (local or metastatic) non-small cell lung cancer (NSCLC), who failed prior chemotherapy. The common adverse events of the drug include acne-like skin rash, paronychia, pruritus, diarrhea, nausea/vomiting, anorexia, hepatitis, and hyperbilirubinemia.1 However, these adverse events are generally mild in severity and reversible on cessation of the treatment. Therefore, gefitinib has been regarded as a relatively safe agent, and it has been used for the treatment of patients with an Eastern Cooperation Oncology Group (ECOG) performance status (PS) of 3-4. The present report describes a patient with NSCLC who developed disseminated intravascular coagulation (DIC) as a possible adverse drug effect resulting from gefitinib therapy.

Edited by

Cancer Center, 82nd Hospital of the Chinese People’s Liberation

Army, Huai’an, Jiangsu 223001, China (Yuan GJ)

Department of Oncology, First People’s Hospital of Jingzhou,

Jingzhou, Hubei 434000, China (Ke QH, Yang JY and Su XY)

Cancer Center, Renmin Hospital of Wuhan University, Wuhan,

Hubei 430060, China (Xu XM)

Correspondence to: Dr. SU Xiao-yan, Department of Oncology,

First People’s Hospital of Jingzhou, Jingzhou, Hubei 434000,

China (Tel: 86-716-8214001. Fax: 86-716-8216810. Email: jzsxy@hotmail.com)

(Received April 19, 2009)

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CASE REPORT

In May 2008, a 66-year-old woman presented with complaints of headache, dizziness and right thoracic backaches that lasted for over a month. She did not smoke or drink alcohol, and she had no prior history of bleeding diatheses or platelet abnormalities. A physical examination revealed an ECOG PS of 4 and an enlarged right supraclavicular lymph node measuring 3 cm in diameter. Computed tomography (CT) scans of the lung showed a right lower lobe mass combined with mediastinal lymph node metastases. Adenocarcinoma cells were detected in the enlarged supraclavicular lymph node through aspiration cytology. Magnetic resonance imaging showed multiple metastatic lesions in the bilateral cerebellar hemispheres, the cortex of the bilateral parieto-occipital lobes, and the right temporal lobe. She was finally diagnosed with advanced primary lung adenocarcinoma, clinical stage IV (T4N3M1). Laboratory investigations revealed that complete blood counts, liver function test results, renal function test results, and the electrolyte panel were within normal limits. Intravenous 20% mannitol, dexamethasone, and nutrition support were prescribed. A whole brain irradiation was performed for 30 Gy with 6 MV photons, and the prescribed dose was applied to the central point of the radiation field on mid axis with a daily fraction size of 3.0 Gy, 5 days per week. In view of her poor PS, we introduced gefitinib therapy rather than chemotherapy. On June 6, 2008, she began to take gefitinib at a daily dose of 250 mg.

On June 19, 2008, a physical examination demonstrated a significant regression of the enlarged supraclavicular lymph node, with a measurement of 0.5 centimeter in diameter. However, hip ecchymosis and venipuncture site bleeding occurred; Gefitinib was then stopped. A battery of laboratory tests were performed and revealed that white blood cell (WBC) count was 9.0×109/L (reference range: 4.0×109-10.0×109/L), red blood cell (RBC) count was 3.11×1012/L (reference range: 3.5×109-5.0×1012/L), hemoglobin was 87 g/L (reference range: 110.0-150.0 g/L), platelet count was 39×109/L (reference range: 100×109-300×109/L), and the liver and kidney function tests were within normal limits. Coagulation tests showed a prolonged prothrombin time (PT, >180 seconds, reference range: 10.10-14.60 seconds), an activated partial thromboplastin time (APTT, >240 seconds, reference range: 24.0-44.0 seconds), low fibrinogen level (1.71 g/L, reference range: 1.82-5.32 g/L), increased D-dimer level (2.6 mg/L, reference range: 0-0.3 mg/L), and plasma protamine paracoagulation (3P) test (+). There was no focus of infection, and the blood culture was negative. A diagnosis of DIC was made, and replacement therapies with platelet concentrates, fresh frozen plasma, cryoprecipitates, and low-molecular-weight heparin (low dose subcutaneous injection) were administered to the patient. Her hematologic and coagulation parameters improved gradually over the following 4 weeks.

On August 15, 2008, the patient’s family members reintroduced gefitinib to the patient by themselves, expecting to treat her lung cancer. On August 21, 2008, widespread petechiae, ecchymosis, and venipuncture site bleeding occurred once again. In light of a previous onset of DIC, fresh frozen plasma, cryoprecipitates, and low-molecular-weight heparin were administered promptly, and bleeding was controlled.

In October 2008, the patient developed repeated seizures, and died on October 20, 2008.

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DISCUSSION

DIC is a disorder characterized by the systemic intravascular activation of coagulation leading to bleeding (due to depletion of platelets and coagulation factors) and thrombosis (due to widespread deposition of fibrin in the circulation).2 A variety of clinical conditions may cause DIC. Bacterial infections, particularly septicemia, are the most common clinical conditions associated with DIC.3 Hemostatic abnormalities are frequently found in cancer patients, they are detectable in about 50% of patients with localized tumors and in more than 90% of patients with metastatic disease;4 DIC occurs in up to 6.8% of solid organ tumors, especially in older patients, male patients, and patients with advanced cancer, breast cancer, and necrotic tumors, and has a significant impact on survival probability.5 The management of cancer-associated DIC includes treatment of the underlying malignancy, replacement therapy (cryoprecipitate, fresh frozen plasma, platelet transfusion and red blood cell transfusion), low-molecular-weight heparin, and antithrombin concentrates. Among these treatments, control of the underlying malignancy plays a major role in successfully treating cancer-associated DIC. Chao et al6 have reported successful initial treatment of advanced gastric cancer associated with DIC with weekly intakes of etoposide, epirubicin, cisplatin, 5-fluorouracil, and leucovorin chemotherapy. In the present case, there was no focus or sign of infection, and the blood culture was negative. Therefore, infection-associated DIC may be excluded. In our case, although lung cancer might induce DIC complications, her DIC occurred after the ingestion of gefitinib, which rendered a significant regression of the enlarged supraclavicular lymph node from 3 centimeters to 0.5 centimeters in diameter. Thus, it is unlikely that her DIC was attributed to the lung cancer per se. The onset of DIC occurred after the administration of gefitinib, and reintroduction of the drug caused re-bleeding in the patient. Both of these facts support the assumption that her DIC may be associated with gefitinib.

The mechanism by which gefitinib induced DIC in the patient with lung cancer is unclear. A number of studies have shown that lung cancer patients have an increased propensity to clot and develope fibrinolytic system aberrations.7,8 In addition, prolonged PT, and abnormally elevated D-dimer, fibrinogen, and platelet counts are associated with a poor prognosis of lung cancer.9 Kanazawa et al10 have shown that gefitinib can affect the functions of the platelet by accelerating platelet aggregation via decreased prostaglandin (PG) I2/thromboxane (TX) A2 ratio. Furthermore, some adverse effects of gefitinib (i.e. skin rash and diarrhea) depend on platelet activation, which is reduced by the low-dose aspirin therapy.11 In the present case, advanced lung adenocarcinoma, clinical stage IV, (T4N3M1) was diagnosed. We infer that she might have an underlying hypercoagulable state, and gefitinib might have acted as a precipitant factor leading to the occurrence of her DIC.

In summary, we report a patient with NSCLC who developed DIC after treatment with gefitinib. DIC may be a possible adverse effect of gefitinib therapy for advanced lung cancer; this observation warrants the physician’s awareness and early recognition.

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REFERENCES

1. Park J, Park BB, Kim JY, Lee SH, Lee SI, Kim HY, et al. Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res 2004; 10: 4383-4388.
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6. Chao Y, Teng HC, Hung HC, King KL, Li CP, Chi KH, et al. Successful initial treatment with weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin chemotherapy in advanced gastric cancer patients with disseminated intravascular coagulation. Jpn J Clin Oncol 2000; 30: 122-125.
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11. Kanazawa S, Yamaguchi K, Kinoshita Y, Muramatsu M, Komiyama Y, Nomura S. Aspirin reduces adverse effects of gefitinib. Anticancer Drugs 2006; 17: 423-427.
Keywords:

gefitinib; non-small cell lung cancer; disseminated intravascular coagulation; adverse event

© 2010 Chinese Medical Association