Hyaluronic Acid as a Marker of Sinusoidal Obstruction Syndrome after Oxaliplatin-based Chemotherapy for Colorectal Liver Metastases: Don’t Forget the Tumor

Abstract

A few decades ago, patients with colorectal cancer liver metastases were considered incurable, and treatment was mainly supportive. Treatment options for patients with metastatic colorectal cancer have changed greatly since then, as has the outcome of these patients. Although in the past survival of these patients was within the range of a few months, with no 5-year survivors, current studies report median survival rates of 20–25 months and 5-year survival rates of 30–60 %. What has happened? Numerous studies have taught us that in selected patients, surgical resection of metastases prolongs survival. As hepatic resection has evolved to a safe procedure even in patients requiring extended, complex, and/or two-stage resection for complete tumor clearance, its use has increased and has added to the improved long-term outcome. However, only approximately 15 % to 20 % of patients are initially amenable to potentially curative resection; therefore, further factors must have played a role in the marked improvement in survival. The development and increased use of effective chemotherapeutic regimens has contributed significantly to the treatment results we are currently documenting for metastatic colorectal cancer. Several phase III trials proved that the addition of oxaliplatin or irinotecan to the backbone of 5-fluorouracil (5-FU) and folinic acid is able to achieve objective response rates of 40–50 %. The antitumor activity of these combined chemotherapy regimens has clearly improved median survival rates compared to historic data of patients who received 5-FU monotherapy, which was the standard of care in the late 1980s. Moreover, these improved regimens rendered the disease of a higher proportion of patients resectable. Resectability rates in firstline chemotherapy trials with palliative intent range from 5 to 15 % and go up to 30 % in patients with more limited yet still unresectable disease receiving chemotherapy for the intent of downstaging. Furthermore, the addition of biological agents such as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), and cetuximab or panitumumab, monoclonal antibodies against the epidermal growth factor receptor, seem to further enhance response and resectability rates. Although the effectiveness of modern chemotherapy protocols in patients with metastatic colorectal cancer is undisputed, issues associated with these regimens, such as acquired resistance and increased toxicity, remain important future challenges for interdisciplinary management. In particular, liver toxicity related to the administration of irinotecanand oxaliplatin-containing regimens represents a significant concern; their development may interfere with the planned treatment concept. It has been demonstrated that preoperative chemotherapy correlates with significantly higher perioperative complications. Furthermore, the development of histological alterations in the liver parenchyma may impede the antitumor effects of systemic therapies. The pathological changes of the liver are specific to the administered agents. Irinotecan has been associated with chemotherapy-associated steatohepatitis. Oxaliplatin has been more frequently reported to cause hepatic injury, which typically manifests as sinusoidal obstruction syndrome (SOS) and occurs in up to 50 % of patients who receive an oxaliplatin-based regimen. SOS is considered to Society of Surgical Oncology 2013