Beata Herberger

Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases

AIM In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited. METHODS Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone. CONCLUSIONS This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.

Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma

Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.

Dual inhibition of EGFR and mTOR pathways in small cell lung cancer

Background:In this report we investigated the combination of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathway inhibition as a possible new therapeutic strategy for small cell lung cancer (SCLC).Methods:EGFR, p-AKT, p-ERK, p-mTOR and p-p70s6K protein expressions were studied by immunohistochemistry in 107 small cell lung carcinomas and correlated with clinicopathological parameters. Cells of SCLC were treated with erlotinib±RAD001 and analysed for cell viability, proliferation, autophagy, and pathway regulation.Results:Epidermal growth factor receptor, p-AKT, p-ERK, p-mTOR, and p-p70s6K were expressed in 37, 24, 13, 55 and 91% of the tumour specimens of all SCLC patients, respectively, and were not associated with disease-free or overall survival. The expression of EGFR was lower in neoadjuvant-treated patients (P=0.038); mTOR pathway activation was higher in the early stages of disease (P=0.048). Coexpression of EGFR/p-mTOR/p-p70s6K was observed in 28% of all patients . EGFR immunoreactivity was associated with p-ERK and p-mTOR expression (P=0.02 and P=0.0001); p-mTOR immunoreactivity was associated with p-p70s6K expression (P=0.001). Tumour cells comprised a functional EGFR, no activating mutations in exons 18–21, and resistance to RAD001 monotherapy. We found synergistic effects of erlotinib and RAD001 combination therapy on the molecular level, cell viability, proliferation and autophagy.Conclusions:The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC.

Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study.

Objective:This study was conducted to analyze if the combination of Bevacizumab with standard chemotherapy increases postoperative morbidity and mortality after resection of colorectal liver metastases as compared with resection after chemotherapy alone. Parameters contributing to an increased morbidity were evaluated. Summary Background Data:Most patients referred for colorectal liver metastases are treated with neoadjuvant chemotherapy before hepatic surgery. Targeted agents like the vascular endothelial growth factor—antagonist Bevacizumab are increasingly added to standard therapy to prolong survival; however, little is known about the consequences of this policy in the perioperative period. Methods:One hundred-two patients treated between 2005 and 2009, who received neoadjuvant chemotherapy combined with Bevacizumab (CHT + B) were identified. A cohort of 112 patients treated without chemotherapy alone before resection served as the control group (CHT). Complications were graded within an established staging system and the therapeutic consequences were laid down. Uni- and multivariate analysis of factors contributing to postoperative complications in the CHT + B group was performed using a logistic regression model. Results:Postoperative complications occurred in 45 (44%, CHT + B) and 38 (34%, CHT) patients, respectively (P = 0.216). The incidence of severe complications requiring surgical or radiologic intervention or leading to organ failure was 10.8% in the CHT + B group and 7.1% in the CHT group (P = 0.350). Increased age, low serum albumin, resection of more than 3 liver segments and synchronous bowel procedures requiring an anastomosis were associated with an increased morbidity rate in the multivariate regression analysis. No patient died in either group. Conclusions:The addition of Bevacizumab to standard chemotherapy before resection of colorectal liver metastases does not seem to increase postoperative morbidity. Caution should be given to extended resections >3 liver segments and synchronous bowel anastomoses.

Complications after free flap surgery: do we need a standardized classification of surgical complications?

Our main objective was to apply a standard classification to surgical complications after free flap surgery for reconstructions of the head and neck. We used the modified Clavien-Dindo classification in a cohort of 79 patients who were having reconstructions with jejunal free flaps simultaneously with resections of oral and oropharyngeal cancer. The most common minor complication was the need for a blood transfusion, and the most common major complication of a respiratory nature. The medical complications, and those at the recipient site and the donor site were 53/79 (67%), 44/79 (56%), and 9/79 (11%), respectively. The Clavien-Dindo classification is suitable and can easily be used to evaluate postoperative complications after free tissue transfer.

Adequate preoperative staging rarely leads to a change of intraoperative strategy in patients undergoing surgery for colorectal cancer liver metastases

BACKGROUND Diagnostic tools used prior to hepatic surgery have significantly advanced during the last decade. We investigated the value of preoperative staging on detection of additional resectable hepatic lesions in metastatic colorectal cancer patients. METHODS One hundred ninety-four consecutive resections for colorectal liver metastases between January 2002 and December 2005 were prospectively analyzed. Data on imaging (multidetector computed tomography [MDCT] and magnetic resonance imaging [MRI]) were compared to intraoperative findings by intraoperative sonography and bimanual palpation together with histopathological examination. Univariate and multivariate analysis of factors influencing recurrence was performed. RESULTS In 16 (8.2%) resections, additional lesions were detected intraoperatively. In 11 cases (5.7%), these were small (<1 cm) and subcapsular. Detection of additional tumors was associated with shorter median recurrence free survival (5.4 vs. 13.4 months; P < .001) even though all lesions were resected and risk of recurrence was stratified by the Fong score. Patients treated with neoadjuvant chemotherapy did not generally have an increased risk of additional tumors; however, intraoperative detection of new lesions was associated with inferior outcome in this subgroup (median RFS 4.6 vs. 18.3 months in responders, P < .001). CONCLUSION Preoperative imaging with contrast-enhanced MDCT and MRI is efficient and very seldom leads to changes in intraoperative strategy. Patients exhibiting additional resectable hepatic lesions upon surgery have a high risk for early recurrence and should be monitored closely during follow-up.

Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells.

The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials. [Mol Cancer Ther 2009;8(6):1547–56]

Surgery after neoadjuvant chemotherapy for colorectal liver metastases is safe and feasible in elderly patients

Surgery for colorectal liver metastases is part of the endeavor to cure metastatic colorectal cancer (mCRC). Neoadjuvant chemotherapy increases progression free survival in resectable patients. The safety and feasibility of this concept has not been investigated in elderly patients.

Activity of bevacizumab at the time of surgery after 6 weeks of preoperative cessation.

455 Background: The use of bevacizumab (BV), a monoclonal antibody against VEGF, and combination chemotherapy (CTx) together with an increase in hepatic resection has improved the outcome of colorectal cancer (CRC) patients with liver metastasis. However, despite the frequent use of BV, its accurate timing prior to liver resection to avoid surgical complications and to allow for hepatic regeneration remains discussed controversially. In this context, it remains unclear to which extent VEGF is complexed by BV at the time of surgery. METHODS Fifty CRC patients with liver metastases, potentially curable by resection, were included. Patients received neoadjuvant CTx either with or without concomitant biweekly BV. The last cycle of therapy did not include BV, resulting in 5 weeks between the last administration of BV and surgery. Plasma and wound fluid subcutaneously and intra-abdominally were obtained perioperatively. Immunoprecipitation was applied to determine the proportion of BV-bound VEGF. RESULTS 42 patients underwent surgery. Median time of BV cessation was 5-6 weeks. No increased perioperative complications in this BV treated patients were observed (patients without complications: 59 % of BV + CTx patients versus 50 % in CTx patients). At the time of surgery, the majority of plasma VEGF was inactivated by BV. In wound fluid, the actual site of wound healing and hepatic regeneration, VEGF was remarkably low and also complexed by BV. This resulted in a highly significant reduction of unbound/biologically active VEGF levels in plasma and wound fluid of BV treated patients (both: P < 0.001). CONCLUSIONS These data documents that, after the clinical standard cessation time point of 5-6 weeks, BV is still fully active and binds to the majority of circulating and local (wound fluid) VEGF. Despite the potent VEGF inactivation, at the time of liver resection no substantial increase in perioperative morbidity after neoadjuvant BV therapy has been documented in our study and the current literature.