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Tumor Lysis Syndrome After Treatment of a Gastrointestinal Stromal Tumor With the Oral Tyrosine Kinase Inhibitor Sunitinib

Department of Oncology, University of California, San Diego, CA

Tumor lysis syndrome is a well-known entity in the world of hematologic malignancies and has occasionally been observed in selected aggressive and chemotherapy-sensitive solid tumors (eg, small-cell lung cancer). It is the result of an overwhelming systemic release of cellular contents, usually at the onset of highly effective therapy for a patient with a substantial tumor burden. Laboratory features include hyperkalemia, hyperuricemia, renal dysfunction, hyperphosphatemia, and hypocalcemia if the serum phosphate is high enough to induce calcium phosphate precipitation.¹ Tumor lysis syndrome is best managed expectantly with the initiation of aggressive hydration and allopurinol before cytotoxic therapy. The current standard-of-care first- and second-line treatments for gastrointestinal stromal tumor (GIST) are the oral receptor tyrosine kinase inhibitors imatinib and sunitinib, agents which mechanistically are not expected to produce brisk cell lysis. The following case of mild tumor lysis syndrome argues for clinicians to have a higher index of suspicion for the syndrome in medically fragile patients who receive sunitinib therapy for GIST.

The patient was a 56-year-old man who presented with a bowel obstruction 4 years earlier. He underwent urgent surgical exploration and was found to have GIST metastatic to his mesentery, omentum, liver, and small bowel. His clinical course over the next several years was characterized by repeated and persistent responsiveness to imatinib coupled with self-initiated dose reductions and treatment holidays for as long as 6 months at a time. After almost 3 years of such a pattern, a computed tomography scan found evidence of progression despite a period of adherence to his prescribed dose of imatinib. He was then started on sunitinib, 50 mg daily, on a 4 weeks on and 2 weeks off schedule. After one cycle, a computed tomography scan revealed shrinkage of his serosal and liver metastases but swelling of his septated, fluid-filled 16 x 12 cm mesenteric mass (Fig 1). Given that he was experiencing substantial abdominal discomfort, the patient opted for surgical debulking of the largely necrotic mass. The surgical pathology was characteristic of GIST and showed more than 40 mitoses/50 high-powered fields (Fig 2A, low-power hematoxylin and eosin; Fig 2B, high-power hematoxylin and eosin; arrows denote mitoses); malignancy is defined as more than 5 mitoses/50 hpf. It was highly proliferative as more than 30% of the cells were positive by MIB-1 immunostaining for nuclear Ki-67² (Fig 3; see arrows for selected representative nuclei). The tumor cells were strongly positive for CD117 and positive for platelet derived growth factor receptor alpha (PDGFR-), both receptors which are characteristically overexpressed in GIST and are inhibited by sunitinib.

View larger version (37K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1.

View larger version (139K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2.

View larger version (91K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3.

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4.

One of the hallmarks of GIST is that up to 90% of the tumors feature the activation of KIT (ie, CD117 or stem cell factor receptor), a cell-surface transmembrane receptor with intracellular tyrosine kinase activity that mediates cellular proliferation and resistance to apoptosis. A gain of function mutation in PDGFR-, another tyrosine kinase, is present in 5% of cases. As GIST had historically been notoriously refractory to cytotoxic chemotherapy,³ it was a major advance when the small molecule kinase inhibitor imatinib was shown to produce objective responses in more than 50% of patients with advanced tumors, presumably through its ability to block the activation of KIT.⁴ Sunitinib is an oral receptor tyrosine kinase inhibitor like imatinib but inhibits a greater number of kinases, including PDGFR- and vascular endothelial growth factor receptors 1 through 3.³ Early phase trials established a 4 weeks on and 2 weeks off dosing cycle as longer periods of continuous therapy led to bone marrow and adrenal toxicity in animal models. As dose-limiting toxicities with this schedule were common at 75 mg or higher, 50 mg has since been the working dose.⁵ Notably, the minimum effective dose has not yet been established. Those early human trials revealed toxicities that included "reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula,"⁶—an apt description of this patient's chronic difficulties after initiation of sunitinib. Several factors predisposed this patient to tumor lysis syndrome while taking sunitinib. First, he had a particularly aggressive tumor with a high rate of mitoses (Fig 2). Second, his serum albumin was strikingly low due to his fistula output, making him particularly susceptible to the development of low effective circulating volume. Third, plasma protein binding of sunitinib is estimated to be approximately 95%,⁷ so his low albumin may have caused his effective dose to be much higher than anticipated. Fourth, his tumor seemed to be highly sunitinib sensitive as the enhancing tissue-density portion of the mass receded to only a thin peripheral rim after earlier cycles of treatment. Whether this response is attributable to a poorly understood cytotoxic mechanism or to further compromise of tumor blood supply with resultant tumor necrosis, it is clear that tumor cells were lysing briskly. This finding is particulary notable in an imatinib refractory tumor. Finally, he had undergone several recent blood transfusions and may have been experiencing a dangerous synergy between tumor cell lysis and high red cell turnover due to the fragility of transfused cells. Although this patient was clearly medically fragile, he had reached an impasse. His tumor burden had rapidly increased as sunitinib was held, yet the reinitiation of therapy carried a substantial risk of clinical deterioration. He tolerated the additional week of sunitinib poorly but his case is informative as it clearly demonstrates the risk of tumor lysis syndrome on oral therapy with sunitinib in patients with a large GIST tumor burden. Close laboratory monitoring and expectant management with aggressive fluids and even allopurinol must therefore be considered in such clinical scenarios.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

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3. Edmonson JH, Marks RS, Buckner JC, et al: Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest 20:605-612, 2002[CrossRef][Medline]

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