Abstract
Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation.
Highlights
Colorectal cancer (CRC) is the second most common cancer and fourth most common cause of cancer-related death worldwide [1]
In patients not treated with bevacizumab, plasma levels of von Willebrand factor (VWF):Ag increased as the number of chemotherapy cycles increased (P
Serum AST levels increased with the number of chemotherapy cycles in patients not treated with bevacizumab doi:10.1371/journal.pone.0143136.g001 (P = 0.002 at 3 months, P = 0.013 at 5 months), but were unchanged in patients treated with bevacizumab (Fig 1D)
Summary
Colorectal cancer (CRC) is the second most common cancer and fourth most common cause of cancer-related death worldwide [1]. Oxaliplatin-based chemotherapy has benefited patients with CRC, chemotherapyassociated liver injury (CALI), including sinusoidal obstruction syndrome (SOS), has been observed after cytotoxic therapy. Bevacizumab was reported to have a protective effect in the liver of patients treated with oxaliplatin-based chemotherapy for CRC [11]. We investigated plasma VWF in patients with advanced CRC receiving oxaliplatin-based chemotherapy to determine the pathophysiology of CALI. Twenty-nine patients with CRC who received oxaliplatin-based chemotherapy between February 2011 and August 2013 at Nara Medical University Hospital were included in this study. Bevacizumab/panitumumab: 1) 5-FU and folinic acid plus oxaliplatin (FOLFOX6), 2) capecitabine plus oxaliplatin (CapeOX), or 3) S-1 plus oxaliplatin (SOX) These treatments comprised adjuvant chemotherapy after radical surgery in 14 patients, chemotherapy for unresectable metastatic CRC in 11 patients, and neoadjuvant chemotherapy to treat advanced CRC in 5 patients. Patient age sex primary lesion TNM stage purpose chemotherapy regimen response #
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