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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2405-2406 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.8451
Bowel Perforation After Radiotherapy in a Patient Receiving SorafenibDepartment of Experimental Oncology, Academic Medical Center, Amsterdam, the Netherlands
Department of Radiation Oncology, Academic Medical Center, Amsterdam, the Netherlands
A 61-year-old woman was diagnosed with renal cell carcinoma (RCC, clear-cell type) and cutaneous metastases. As a firstline treatment she received sorafenib (BAY-43-9006, Nexavar; Bayer, West Haven, CT, and Onyx, Richmond, CA), 400 mg twice a day. A rapid regression of the cutaneous metastases was observed, but an magnetic resonance imaging (MRI) scan after four weeks of treatment revealed no change in the tumor in the right kidney. Grade 1 and 2 (National Cancer Institute Common Toxicity Criteria) toxicity was documented, in addition to hand-foot syndrome and mouth pain. Five weeks after the start of sorafenib treatment, the patient developed severe low back pain. MRI of the lumbar spine showed a lytic bone metastasis of the lumbar vertebra (L) 4, which was treated with palliative radiotherapy on L3-L5 (8 Gy, one fraction).1,2 Sorafenib was stopped 2 days before radiotherapy to prevent radiosensitizing of the normal tissue. Sorafenib treatment was started again 3 days later. One week after radiotherapy the patient was admitted to our hospital suffering from of abdominal pain, diarrhea, and dehydration. On physical examination she had no fever, her blood pressure was RR 90/60 mmHg, and her pulse rate was 120 beats per minute. Abdominal examination revealed signs of peritonitis. Laboratory tests showed leukocytosis (24.7 x 109/L) and renal failure (creatinin, 324 mol/L; urea, 37 mmol/L). She was therefore treated with intravenous fluids and antibiotics. Her clinical condition worsened rapidly and she died the next day. The autopsy revealed multiple perforations of the transverse and sigmoid colon with fecal peritonitis (Fig 1; arrows point to perforations). Biopsy specimens of the colon showed ischemic enteritis with radiation-effects and vascular changes with thrombus formation, but no evidence of tumor metastases. The primary kidney tumor demonstrated a clear-cell RCC with extensive sarcomatoid changes. The outcome for patients with metastatic RCC has been shown to improve considerably with the administration of sorafenib and sunitinib, both small molecules with angiogenesis inhibiting activity which act by blocking the signaling through vascular endothelial growth factors (VEGFs) receptor and the platelet-derived growth factor receptor.3,4 In 75% of sporadic clear-cell RCC mutations are found in the von Hippel-Lindau gene. These mutations result in upregulation of hypoxia inducible factor 1-
The normal bowel tolerance dose of radiation is in the order of 50 Gy in 25 fractions.7 A single fraction of 8 Gy is biologically well below the tolerance dose. The incidence of sigmoid perforation caused by high-dose radiotherapy for cervical cancer is 0.6% with a range of between 3 and 98 months post-treatment.8 No gut toxicity resulting from single-dose 8 Gy radiotherapy has been reported. Irradiation causes hypoxia and upregulation of VEGF, a growth factor involved in radio-resistance.9 By inhibiting the activity of VEGF by receptor blockade, sorafenib can potentially act as a radiosensitizer. Several in vitro and in vivo studies have shown that combined treatment with such VEGF- or VEGF receptor–inhibitors with irradiation induces synergistic antitumor activity.10,11 A radiosensitizing effect of VEGF pathway inhibition on cancer cells has also been described in several preclinical studies, though clinical data on sorafenib is limited.12-14 In light of these reports, the high level bowel toxicity in our patient is surprising. Possibly the 2 day gap between the end of sorafenib treatment and the start of radiotherapy was too short. Since sorafenib has an approximate half-life of 24 to 48 hours, there may have been residual sorafenib present during radiation treatment and thus normal tissue was still radiosensitized via sorafenib. This report describes a patient receiving sorafenib that developed a lumbar metastasis that required irradiation. She died of complications in the bowel—the area directly targeted by irradiation. In conclusion, this case provides evidence for potential oversensitization of normal tissue by sorafenib. Further studies combining antiangiogenic therapy with radiotherapy are warranted in order to further determine the efficacy and toxicity of combination therapy of sorafenib with radiation. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest
REFERENCES
1. Rades D, Veninga T, Stalpers LJ, et al: Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol 25:50-56, 2007 2. van der Linden YM, Lok JJ, Steenland E, et al: Single fraction radiotherapy is efficacious: A further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 59:528-537, 2004[CrossRef][Medline] 3. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006 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, Bukowski RM: Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 24:5601-5608, 2006 6. Stadler WM, Huo D, George C, et al: Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol 170:1141-1145, 2003[CrossRef][Medline] 7. Willett CG, Goldberg S, Shellito PC, et al: Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 5:242-247, 1999[Medline] 8. Ramirez PT, Levenback C, Burke TW, et al: Sigmoid perforation following radiation therapy in patients with cervical cancer. Gynecol Oncol 82:150-155, 2001[CrossRef][Medline] 9. Wachsberger P, Burd R, Dicker AP: Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: Exploring mechanisms of interaction. Clin Cancer Res 9:1957-1971, 2003 10. Ma BB, Bristow RG, Kim J, et al: Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. J Clin Oncol 21:2760-2776, 2003 11. Duda DG, Jain RK, Willett CG: Antiangiogenics: The potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol 25:4033-4042, 2007 12. Lee CG, Heijn M, di Tomaso E, et al: Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565-5570, 2000 13. Zips D, Eicheler W, Geyer P, et al: Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition. Cancer Res 65:5374-5379, 2005 14. Plastaras JP, Kim SH, Liu YY, et al: Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res 67:9443-9454, 2007
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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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, which binds to a variety of transcriptional cofactors that activate transcription of hypoxia-inducible genes, including VEGF.
