Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases☆
Introduction
Bevacizumab (Avastin®), a monoclonal humanized antibody directed against vascular endothelial growth factor (VEGF), is being increasingly used in the treatment of mCRC. In a large randomized phase III clinical trial bevacizumab given in combination with conventional chemotherapy significantly improved survival of patients with mCRC1 and has been approved by the FDA and EMEA as a first-line therapy for colorectal cancer. Bevacizumab is considered to be only effective in conjunction with cytotoxic drugs and may be given in combination with 5-fluorouracil- based chemotherapy plus oxaliplatin (5-FU/oxaliplatin).2
5-FU/oxaliplatin is being administered prior to liver resection in mCRC patients and prolongs recurrence-free survival.3 The use of chemotherapy prior to liver surgery offers the possibility to convert a patient from unresectable disease to resectable disease and to treat undetected micrometastases.4, 5 Furthermore, as reported recently in a prospective non-randomized trial in our institution, tumor response to 5-FU/oxaliplatin is qualified to predict benefit from liver resection for colorectal liver metastases with respect to recurrence-free survival.6 Disadvantages of neoadjuvant chemotherapy are an increased, albeit still low postoperative morbidity rate.3 However, postoperative morbidity after liver resection is associated with the number of chemotherapy cycles administered before surgery, independently of the scheme applied.7 Therefore, one of the rationales of combining chemotherapy and bevacizumab is to shorten the length of chemotherapy while offering the same (or even better) quantity of response to the patient. We showed recently in a prospective non-randomized trial that bevacizumab can be administered before liver resection safely and with a low postoperative complication rate.8
The neoadjuvant use of oxaliplatin is associated with the occurrence of a distinctive type of hepatic injury, namely the sinusoidal obstruction syndrome.9, 10 For 5-fluorouracil and irinotecan, an association with hepatic steatosis has been shown.11 For this type of hepatic steatosis, which belongs to the family of non-alcoholic fatty liver disease (NAFLD), the term CASH (chemotherapy-associated steatohepatitis) has been introduced.12 Cytotoxic chemotherapy primarily affects the tumor itself with tumor necrosis and tumor fibrosis as regression correlates.13
Bevacizumab neutralizes free VEGF and thus inhibits VEGF-mediated endothelial cell proliferation, survival and migration in vitro.14 On the other hand, bevacizumab induces apoptosis in hypoxia susceptible tumor cell lines.15 Bevacizumab is able to normalize tumor vasculature, thereby decreasing intratumoral fluid pressure and increasing delivery of chemotherapy to the tumor cells.16 Thus, it is a priori not predictable how bevacizumab affects the tumor and the non-tumor bearing parenchyma when combined with chemotherapy. In this retrospective exploratory analysis of two non-randomized prospective trials of our institution,6, 8 we compared non-tumor bearing liver histology and tumor response between patients treated with 5-FU/oxaliplatin and patients treated with 5-FU/oxaliplatin plus bevacizumab. We addressed the following questions: (1) which effect, if any, does bevacizumab have on chemotherapy induced hepatic injury, and furthermore, (2) does bevacizumab have an impact on the radiologic response, according to RECIST?
Section snippets
Patients and chemotherapy
Two phase II trials of our institution including patients with resectable colorectal cancer liver metastases were analyzed retrospectively for pathohistology of the non-tumor bearing liver and tumor response. 56 patients treated neoadjuvantly with capecitabine, oxaliplatin and bevacizumab were entered into one trial. The primary objective of this study was to assess the feasibility of bevacizumab therapy before surgery.8 The second trial analyzed 50 patients treated with 5-fluorouracil based
Patient data
The patient demographics did not differ among the non-bevacizumab and the bevacizumab group, as outlined in Table 1. The median age of patients at the time of liver resection was 62.4 (95% confidence interval [CI] 59.2–64.5) and 63.0 (95% CI 58.9–64.4) for the non-bevacizumab and the bevacizumab group, respectively (p = 0.96). Sex of patients was equally distributed in both groups (p = 0.25). Body mass indices (BMI) were calculated as BMI = weight [kg]/(height [m])2. The mean values were 24.4 ± 3.9 and
Discussion
Liver surgeons are familiar with the observation of friable liver parenchyma or “blue liver” in patients who have received a chemotherapeutic schema containing oxaliplatin. The oxaliplatin associated sinusoidal obstruction syndrome most likely produces this bluish discoloration and spongiform consistency of the liver. In its severe form, it is associated with increased transfusion requirements20 and a higher complication rate after major hepatectomy.21 Chemotherapy-associated liver injury is
Conflict of interest
Authors who have financial or other interest that is relevant to the subject matter under consideration in this article: Employment or Leadership Position: None. Consultant or Advisory Role: None. Stock Ownership: None. Honoraria: Thomas Gruenberger, F. Hoffmann-LaRoche Ltd. Research. Funding: Thomas Gruenberger, F. Hoffmann-LaRoche Ltd. Expert Testimony: None. Other Remuneration: None.
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This paper was presented at the 14th International Congress of the European Society of Surgical Oncology held from 10th to 12th September 2008. The abstract was one of the highest scoring papers as judged by the Scientific Committee.