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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 152-154 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.5814
Brain Metastases in Patients With Renal Cell Cancer Receiving New Targeted TreatmentDepartment of Medical Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
Department of Medical Oncology, Free University Medical Center, Amsterdam, the Netherlands In December 2005, a 45-year-old man with progressive metastatic renal cell cancer (mRCC) started palliative treatment with sunitinib malate (Sutent; Pfizer, New York, NY) 50 mg daily oral dosing for 4 weeks followed by a 2-week rest period in cycles of 6 weeks. Right-sided nephrectomy had been performed for stage III clear cell carcinoma in March 2001. In October 2002, he was diagnosed with symptomatic mediastinal lymphadenopathy and lung metastases. He received fluorouracil, interleukin-2a, and interferon alfa, later followed by anti-interleukin-6, according to two different trial protocols. Both treatments resulted in a relatively long period of disease stabilization. At initiation of sunitinib, he was dyspneic on exertion and had a cough, but was otherwise in good general health. He was not using any medications. During the first five treatment cycles, he developed National Cancer Institute Common Terminology Criteria of Adverse Events (version 3.0) grade 2 skin rash, itch, fatigue, and stomatitis not requiring supportive medications or dose reduction. Response evaluation with thoracic and abdominal computed tomography scan after the first and fifth cycle showed stable disease according to Response Evaluation Criteria in Solid Tumors1 (Figs 1A: before treatment; and Figs 1B: after 6 months of sunitinib). During the 2-week rest period of the ninth cycle, he presented with right-sided headache and pain at the back of his right eye, accompanied by nausea and vomiting and sensory neuropathy in the left arm. All vital signs were normal. A magnetic resonance imaging scan of the brain showed three brain lesions with perilesional edema (Fig 2) suggestive of brain metastases. Neurologic symptoms disappeared promptly after initiation of dexamethasone, which was followed by whole-brain radiotherapy (five times; 4 Gy). Dexamethasone was tapered but not discontinued, despite possible drug interaction through cytochrome P450 isoenzyme 3A4 metabolism, because of relapsing headache.2 Disease evaluation confirmed previously documented stable disease (Fig 1C: after 12 months of sunitinib and at the time of brain metastases). Therefore, sunitinib treatment was reinitiated shortly after radiotherapy. Stable disease was maintained as demonstrated on a computed tomography scan 3 months after resuming sunitinib (Fig 1D). Unfortunately, 3 weeks later, he deteriorated with signs of brain herniation, which did not respond to corticosteroids, and died.
Sunitinib, a novel oral tyrosine kinase inhibitor (TKI) targeting multiple receptors involved in angiogenesis, is approved for the treatment of mRCC. It is not known whether sunitinib can prevent the occurrence of brain metastases. The incidence of brain metastases as the only metastatic site in mRCC is less than 1%3-5 and occurs as part of the first presentation of mRCC in approximately 3% of the patients.5,6 The cumulative incidence is approximately 10% in mRCC,4,6-8 and the median overall survival is 3 to 6 months,9 although a longer survival has been reported.10 We performed a retrospective analysis of 91 mRCC patients treated with sunitinib on a compassionate-use basis in our centers during the last 2 years and identified nine patients (10%; age 45 to 77 years) who developed symptomatic brain metastases. This incidence confirms previous results and suggests that sunitinib does not influence the incidence of brain metastases. Seven patients developed stable disease and two had partial response lasting 2 to 9 months until progression within the CNS. In all patients, CNS disease was the first sign of progression, but in six patients, including our patient described here, this was the only progressive metastatic site. After radiotherapy or surgery, the sunitinib was effectively continued in three patients. This suggests a difference in the pharmacokinetic behavior and less activity of sunitinib within the brain, compared with another registered TKI for mRCC, sorafenib, which has been suggested to reduce the incidence of brain metastases.11 No CSF measurements of sunitinib concentration have been performed in humans, but animal studies indicate that sunitinib penetrates the blood-brain barrier to some extent.12 Sunitinib could also be a substrate for P-glycoprotein–mediated efflux, similar to imatinib, which would limit its distribution within the brain.13 Of interest, six of nine patients developed CNS symptoms during the 2-week rest period of the treatment cycle. One explanation for this observation could be that sunitinib has antiedema activity, as observed for the multitargeted TKI,14 thereby masking pre-existent brain metastases. Our case series suggests that sunitinib is inadequate for control of brain metastases and may temporarily mask their existence. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Tsuchida Y, Therasse P: Response evaluation criteria in solid tumors (RECIST): New guidelines. Med Pediatr Oncol 37:1-3, 2001[CrossRef][Medline] 2. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006 3. Gay PC, Litchy WJ, Cascino TL: Brain metastasis in hypernephroma. J Neurooncol 5:51-56, 1987[CrossRef][Medline] 4. Hafez KS, Novick AC, Campbell SC: Patterns of tumor recurrence and guidelines for followup after nephron sparing surgery for sporadic renal cell carcinoma. J Urol 157:2067-2070, 1997[CrossRef][Medline] 5. Ljungberg B, Alamdari FI, Rasmuson T, et al: Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 84:405-411, 1999[CrossRef][Medline] 6. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al: Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865-2872, 2004 7. Gore ME, Porta C, Oudard S, et al: Sunitinib in metastatic renal cell carcinoma (mRCC): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis. J Clin Oncol 25:237s, 2007 (suppl; abstr 5010) 8. Schouten LJ, Rutten J, Huveneers HA, et al: Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94:2698-2705, 2002[CrossRef][Medline] 9. Wrónski M, Maor MH, Davis BJ, et al: External radiation of brain metastases from renal carcinoma: A retrospective study of 119 patients from the M.D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:753-759, 1997[CrossRef][Medline] 10. Sheehan JP, Sun MH, Kondziolka D, et al: Radiosurgery in patients with renal cell carcinoma metastasis to the brain: Long-term outcomes and prognostic factors influencing survival and local tumor control. J Neurosurg 98:342-349, 2003[Medline] 11. Massard C, Zonierek J, Laplanche A, et al: Incidence of brain metastasis in advanced renal cell carcinoma among patients randomized in a phase III trial of sorafenib, an oral multi-kinase inhibitor. Ann Oncol 17:ix146, 2006 (suppl 9; abstr 454P) 12. Patyna S, Peng G: Distribution of sunitinib and its active metabolite in brain and spinal cord tissue following oral or intravenous administration in rodents and monkeys. Eur J Cancer 4:21-22, 2006 (abstr 56) 13. Dai H, Marbach P, Lemaire M, et al: Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 304:1085-1092, 2003 14. Batchelor TT, Sorensen AG, di Tomaso E, et al: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83-95, 2007[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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