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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1569-1571 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.4989
Transient Sunitinib-Induced Coma in a Patient With Fibromyxoid SarcomaDepartment of Dermatology, Hôpital Saint Louis AP-HP, Paris, France
Department of Oncology, Saint Louis Hospital AP-HP, Paris, France
Department of Nuclear Medicine, Saint Louis Hospital AP-HP, Paris, France
Laboratory of Pathology, Saint Louis Hospital AP-HP, Paris, France
Pharmacie, Saint Louis Hospital AP-HP, Paris, France
Department of Dermatology, Hôpital Saint Louis AP-HP, Paris, France To the Editor: Soft-tissue sarcomas are rare cancers of mesenchymal origin. Their treatment is not yet standardized, but improved understanding of their molecular biology has led to the identification of novel therapeutic targets such as activated kinases. Promising new drugs specifically designed to inhibit these pathways have been developed. Sunitinib is an oral multitargeted tyrosine kinase inhibitor1,2 with antitumor activity in imatinib-resistant gastrointestinal stromal tumors3 and metastatic renal cell carcinoma.4-6 Common nonhematologic treatment-related adverse events in sunitinib trials were fatigue, diarrhea, hand-foot syndrome, and hypertension. Fatigue is the most common adverse event and has recently been linked to the onset of clinical and biologic hypothyroidism.7 We report here on the marked efficacy of sunitinib in a case of fibromyxoid sarcoma, as well as the first case of sunitinib-induced coma. A 64-year-old woman with multiple local recurrences of an abdominal fibromyxoid sarcoma operated on three times did not respond to two lines of chemotherapy (including anthracyclins, platinum compounds, and cyclophosphomid). In November 2006, she presented with a major abdominal mass and pulmonary and hepatic metastases documented by [18F]-fluorodeoxyglucose positron emission tomography (Fig 1, red cross). Molecular analysis did not reveal the FUS-CREB3L2 fusion gene resulting from the t(7;16) (q33;p11) translocation, normally found in more than 80% of these tumors. Given that she had unresectable tumors and previous chemotherapies had failed, treatment with sunitinib was initiated in November 2006 at a standard regimen (50 mg/d for 4 weeks every 6 weeks) after multidisciplinary review of the case.
The patient did well until December 2006, when she complained of asthenia and apathy. Thyroid function tests revealed mild hypothyroidism and thyroid hormone replacement was started. At this time, follow-up positron emission tomography scan showed a more than 25% reduction of the standard uptake value of the target lesions and disappearance of the standard uptake value of the hepatic metastasis (Fig 2, red cross). At the beginning of the second course of sunitinib, her general condition improved, and the tumor mass was markedly reduced when viewed by abdominal computed tomography scan. On the 12th day of the second course of sunitinib, she suddenly went into a coma (Glasgow Coma Scale = 8) and was transferred to the intensive care unit for further evaluation. Routine and metabolic blood tests were normal. Toxicologic blood screens were negative. Cranial spiral computed tomography scan, magnetic resonance imaging, EEG, and lumbar puncture did not reveal any abnormality. Sunitinib was immediately discontinued and the patient regained full consciousness during the next 24 hours. We decided to resume sunitinib at the same dose because the patient had partial remission, previous chemotherapy having failed, and there was no previous report of sunitinib-induced coma in the literature. Rechallenge resulted in the reappearance of similar symptoms at day 5. Sunitinib was discontinued, and the patient recovered without sequelae. The patient died of digestive tract hemorrhage attributed to vascular tumoral infiltration 2 months after sunitinib was discontinued.
This case and recent reports by Morgan et al8 and Sleijfer et al9 point to the potential value of sunitinib and other multitargeted tyrosine kinase inhibitors, such as sorafenib and pazopanib, for treating sarcomas. Larger scale prospective studies are now required to evaluate their efficacy. In our case, the onset of coma was clearly associated with sunitinib because there were no other identified causative factors, and there were positive dechallenge and rechallenge tests. To our knowledge, this is the first report of sunitinib-induced coma. The mechanism of this severe neurological side effect is as yet unknown, but the antiangiogenic properties of sunitinib may afford a clue through potential toxicity on cerebral vascular vessels. Furthermore, recent reports have indicated that reduced levels of vascular endothelial growth factor, which is essential to angiogenesis and has also been implicated in neuroprotection, predispose mice and humans to amyotrophic lateral sclerosis.10 Our report should be noted because of the increasing use of sunitinib in treating metastatic gastrointestinal stromal tumors and renal cell carcinoma. Physicians should be aware of possible severely adverse neurological events with this type of drug and must ensure a careful neurological follow-up, particularly in the long-term, for patients treated with multitargeted tyrosine kinase inhibitors. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Sun L, Liang C, Shirazian S, et al: Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46:1116-1119, 2003[CrossRef][Medline] 2. Mendel DB, Laird AD, Xin X, et al: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327-337, 2003 3. Demitri GD, van Oosterom AT, Blackstein M, et al: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST. J Clin Oncol 23, 2005 (suppl; abstr 4000) 4. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 5. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006 6. Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN- 7. Rini BI, Tamaskar I, Shaheen P, et al: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81-83, 2007 8. Morgan A, Le Cesne A, Chawla S et al: Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I). J Clin Oncol 25,2007 (abstr 10060) 9. Sleijfer S, Papai A, Le Cesne M, et al: Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043. J Clin Oncol 25,2007 (abstr 10031) 10. Lambrechts D, Storkebaum E, Morimoto M, et al: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34:383-394, 2003[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 24,LBA3 2006, (suppl; abstr LBA3)
