Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy
Jens Sperling
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David Brandhorst
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Thilo Schafer
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Christian Ziemann
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Anna Benz-Weier
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Claudia Scheuer
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Otto Kollmar
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Martin K. Schilling
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Michael D. Menger
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D. Brandhorst A. Benz-Weier C. Scheuer M. D. Menger Institute for Clinical and Experimental Surgery, University of Saarland
, Homburg/Saar,
Germany
1
Present Address: J. Sperling (&) Department of General and Visceral Surgery, University Medical Center, Georg August University Gottingen
, Robert-Koch-Strasse 40, 37075 Gottingen,
Germany
2
J. Sperling T. Schafer C. Ziemann O. Kollmar M. K. Schilling Department of General
, Visceral,
Vascular and Pediatric Surgery, Saarland University Hospital
, Homburg/Saar,
Germany
Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Salinetreated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.
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Colorectal carcinoma has a rising incidence and is the second
most cause of cancer related death worldwide [1, 2]. About
50 % of patients develop metastatic disease, whereby the
liver remains the most common site of metastasis. These
patients have a poor prognosis demonstrated by a 5-year
survival rate in the range of 58 %. The only potential cure is
complete resection of the hepatic tumor burden [3].
Unfortunately, a great number of patients suffer from unresectable
disease. In these patients the main goal is to induce tumor
response by systemic chemotherapy which can lead to
curative surgery of initially unresectable metastases.
During the last years, the development of new cytotoxic
drugs and regimens as well as biological targeted agents
like cetuximab (CE) or bevacizumab (BE) has improved
the survival outcome of patients with unresectable disease
[3]. Cetuximab is a monoclonal antibody directed against
the ligand binding domain of the epidermal growth factor
receptor (EGF-R). Bevacizumab is a monoclonal antibody
directed against the vascular endothelial growth factor
(VEGF). The use of these antibodies in modern sCHT
regimens has improved the 2-year survival rate, however, it
still does not exceed 40 %. Of interest, the analysis of the
5-year survival rate could not show a benefit of the survival
outcome [3, 4].
It is well known that liver-directed chemotherapy, which
is achieved by hepatic arterial infusion, yields reproducibly
higher response rates compared to sCHT both in preclinical
and clinical settings [2, 5]. However, the overall value of
HAI remains unclear [6]. Therefore, it has been suggested
to evaluate the effect of a HAI especially with the delivery
of novel cancer agents or drug combinations in further
studies [7]. Accordingly, we herein studied whether a HAI
of cetuximab plus bevacizumab (CE ? BE) alone or in
combination with oxaliplatin (OX) is more effective than
sCHT to inhibit tumor growth in a mCRC model of the rat
liver.
Materials and methods
For the experiments we used 48 male WAG/Rij rats with a
body weight of 248.3 5.5 g (mean standard error of
the mean (SEM)). Animals were kept in a temperature- and
humidity-controlled 12 h light/dark cycle environment
with free access to water and standard laboratory chow
(Altromin, Lage, Germany).
Experimental protocol
All experiments were approved by the local governmental
ethic committee. Animals were randomized to eight groups
(n = 6 each), whereby four groups of animals underwent
HAI and four groups underwent sCHT. 10 days after tumor
cell implantation relaparotomy was performed and animals
received either (CE ? BE), (OX) or all three drugs (CE ?
BE (...truncated)