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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 30e-31 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5318
Non–Islet-Cell Tumor Induced Hypoglycemia in Patients With Advanced Gastrointestinal Stromal Tumor Possibly Worsened By ImatinibDepartment of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands
Department of Clinical Chemistry, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands
Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands
Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands
Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands To the Editor: Numerous causes for hypoglycemia exist including hepatic, renal, or adrenal dysfunction, toxins such as alcohol and drugs, congestive heart failure, sepsis, malnutrition, prolonged exercise, hypopituitarism, autoimmune disorders, and increased insulin production by islet-cell tumors or small-cell carcinomas. Next to these causes, hypoglycemic episodes in cancer patients can be caused by non–islet-cell tumor induced hypoglycemia (NICTH). NICTH results from overproduction of incompletely processed forms of proinsulin-like growth factor-II (pro-IGF-II), which may lead to an excessive stimulation of the insulin receptors at various target tissues. NICTH is predominantly encountered in patients with large mesenchymal tumors, including gastrointestinal stromal tumors (GISTs),1-4 but epithelial tumors have also been reported to be associated with NICTH.5,6 We describe two GIST patients with hypoglycemia related to a raised concentration of pro-IGF-II; in one case imatinib (Gleevec; Novartis Pharma, Basel, Switzerland) is likely to have contributed to the severity of the hypoglycemia. A 57-year-old male GIST patient with liver metastases had previously been treated with imatinib and subsequently with SU 11248 (sunitinib) because of progressive disease. Later he participated in a phase I study with a nuclear factor-kappa B inhibitor, but showed further disease progression shortly after treatment initiation. Two weeks after his last treatment, he was admitted because of hypoglycemic coma (glucose, < 1.0 mmol/L; reference value fasting glucose, 4.0 mmol/L to 6.4 mmol/L). Additional laboratory investigation showed no abnormalities except pre-existing, slightly increased liver enzyme concentrations while bilirubin was normal. He did not use medication and repeatedly measured glucose concentrations before admission were normal. After intravenous glucose administration all symptoms disappeared. Additional evaluation revealed reduced serum concentrations of IGF-I, and IGF-binding protein (IGFBP)-3, a slightly increased serum concentration of total IGF-II, and considerably elevated concentrations of pro-IGF-II and IGFBP-2 (Table 1) —characteristic of NICTH. Concentrations of other mediators known to affect glucose concentrations were normal. After a few days he did not need any glucose infusions to retain a normal glucose concentration and no more hypoglycemic episodes were detected despite extensive monitoring. The concentration of pro-IGF-II decreased spontaneously but remained elevated at 13.7 nmol/L (reference value, 3.8 nmol/L to 10.7 nmol/L).
The second patient was a 52-year-old woman diagnosed with intra-abdominal metastases of GIST without liver involvement. She was treated with 400 mg of imatinib once daily. She had no other medical history. Seven weeks after initiation of imatinib, she was admitted to the hospital because of abdominal pain, which was considered to be due to the abdominal metastases. During admission repeated nonsymptomatic hypoglycemic episodes occurred almost daily, with blood glucose concentrations as low as 1.2 mmol/L, which could only be resolved with glucose 20% infusions. Glucose concentrations measured before admission were normal. Additional laboratory investigation did not show hepatic or (ad)renal dysfunction. Analysis to elucidate the underlying mechanism of the hypoglycemia revealed reduced serum concentrations of IGF-I and IGFBP-3, a markedly elevated concentration of pro-IGF-II, while the concentrations of both total IGF-II and IGFBP-2 were within the normal range (Table 1). Computed tomography scanning showed disease progression but still without liver involvement. Imatinib was continued since it has been suggested that discontinuation could lead to acceleration of tumor growth.7 The diagnosis of NICTH was based on the low serum concentrations of IGF-I and IGFBP-3 in combination with the elevated concentration of pro-IGF-II. However, an effect of imatinib treatment on glucose homeostasis could not be ruled out. Preliminary data suggest that imatinib affects glucose handling, as discussed in greater detail later. Serum samples were analyzed for imatinib, and glucose concentrations and an inverse relation between imatinib and glucose concentrations was found (Fig 1). To exclude a circadian phenomenon, the dosing time of imatinib was changed from an evening dose to a morning dose, but the inverse relation remained, although less distinct. Two months after admission, the patient died from progressive disease.
In five additional imatinib-treated GIST patients not known to suffer from hypoglycemic episodes, imatinib and glucose concentrations were measured for 24 hours after drug intake. In these patients, there was no relation between glucose and imatinib concentration. NICTH is an infrequent cause of hypoglycemia in patients with advanced cancer. Recently a few patients with advanced GIST and NICTH have been reported2-4 and also in our patients the diagnosis of NICTH could be established. In addition, in the second patient, imatinib is likely to have contributed to the severity of the hypoglycemia given the inverse relation between glucose and imatinib concentrations. Recently, there has been mounting evidence that imatinib can influence glucose handling. A 70-year-old woman with long standing type 2 diabetes mellitus was treated with imatinib because of chronic myeloid leukemia (CML). During imatinib treatment the insulin doses were discontinued, after titrating down. Her diet, physical activity, and weight remained unaltered during treatment. Oral glucose-tolerance testing confirmed regression of type 2 diabetes mellitus.8 Breccia et al9 reported seven diabetic CML patients who were treated with imatinib. Six patients had cytogenetic response and simultaneously improvement of fasting glucose (FG) concentrations allowing reduction of glucose lowering drugs. One patient had imatinib-resistant CML and did not obtain adequate control of blood glucose concentration. Of these seven patients, three patients had previously achieved CML remission during treatment with interferon-alpha without any improvement in FG.9 This suggests that FG improvement is more likely to be caused by imatinib treatment than by diminished insulin resistance associated with leukemic response. The hypothesis that imatinib alters glucose handling is also supported by several preclinical studies. Imatinib results in a lowered glucose uptake in BCR-ABL-positive leukemic cells. Concomitantly with inhibition of proliferation, a shift from glycolytic to mitochondrial oxidative metabolism occurred, resulting in a higher energy state.10 Furthermore, imatinib leads to a dramatic loss of hexose uptake activity due to relocation of glucose transporters from the cell membrane to the cell interior.11 A relationship between imatinib and glucose concentrations was lacking in imatinib-treated GIST patients without hypoglycemic episodes, which would suggest that imatinib-induced hypoglycemia only occurs in patients with a disturbed glucose metabolism, like NICTH. However, this hypothesis is based on a number of patients too small to draw firm conclusions. In conclusion, NICTH should be considered in patients with GIST and hypoglycemia. Worsening of hypoglycemia in patients with NICTH might be caused by imatinib treatment, but additional investigations on the precise effects of imatinib on glucose metabolism are warranted. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Sharyn D. Baker (Johns Hopkins, Baltimore, MD) for the analysis of the imatinib concentrations. REFERENCES 1. Carroll MF, Burge MR, Schade DS: Severe hypoglycemia in adults. Rev Endocr Metab Disord 4:149-157, 2003[CrossRef][Medline] 2. Rikhof B, Van Den Berg G, Van Der Graaf WT: Non-islet cell tumour hypoglycemia in a patient with a gastrointestinal stromal tumour. Acta Oncol 44:764-766, 2005[CrossRef][Medline] 3. Beckers MMJ, Slee PHThJ, van Doorn J: Hypoglycemia in a patient with a gastrointestinal stromal tumor. Clin Endocrin (Oxford) 59:402-404, 2003 4. Pink D, Schoeler D, Lindner T, et al: Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: A report of two cases. J Clin Oncol 23:6809-6811, 2005 5. Lloyd RV, Erickson LA, Nascimento AG, et al: Neoplasms causing nonhyperinsulinemic hypoglycemia. Endocr Pathol 10:291-297, 1999[Medline] 6. LeRoith: Tumor-induced hypoglycemia. N Engl J Med 341:757-758, 1999 7. Van Den Abbeele AD, Badawi RD, Manola J, et al: Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning. J Clin Oncol 22:198S, 2004 (abstr 3012) 8. Veneri D, Franchini M, Bonora E: Imatinib and regression of type 2 diabetes mellitus. N Engl J Med 352:1049-1050, 2005 9. Breccia M, Muscaritoli M, Aversa Z, et al: Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 22:4653-4655, 2004 10. Gottschalk S, Anderson N, Hainz C, et al: Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clin Cancer Res 10:6661-6668, 2004 11. Barnes K, McIntosh E, Whetton AD, et al: Chronic myeloid leukemia: An investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation. Oncogene 24:3257-3267, 2005[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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