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Metronomic Oral Topotecan Prolongs Survival and Reduces Liver

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Metronomic Oral Topotecan Prolongs Survival and Reduces Liver Gut Online First, published on April 28, 2012 as 10.1136/gutjnl-2011-301585 Colon cancer ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2011-301585 on 28 April 2012. Downloaded from Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models Christina Hackl, Shan Man, Giulio Francia, Chloe Milsom, Ping Xu, Robert S Kerbel < Additional figures are ABSTRACT published online only. To view Objective Advanced and recurrent diseases are the Significance of this study these files please visit the major causes of death in colon cancer. No standard journal online (http://gut.bmj. com/content/early/recent). preclinical model addresses advanced disease and What is already known on this subject? spontaneous metastasis after orthotopic tumour growth. Department of Medical < Local recurrence and metastatic disease remain In this study, the authors report the establishment of Biophysics, Molecular and the leading causes of death in colon cancer. This such standardised orthotopic mouse models of colon Cellular Biology Research, is likely to be a major factor in the disparity of Sunnybrook Research Institute, cancer and their use in evaluating metronomic topotecan therapy results that are so frequently obtained University of Toronto, Toronto, alone or in combination with standard chemotherapy. using localised, ectopically implanted tumour Ontario, Canada Design Human colon cancer cell lines, transfected with models with those observed in clinical investi- human chorionic gonadotropin and luciferase, were Correspondence to gations, clearly highlighting the need for injected orthotopically into the caecal wall of severe Dr Christina Hackl, Molecular & improved preclinical models. Cellular Biology Research, combined immunodeficient mice, intrasplenically or < Metronomic cyclophosphamide plus uracil/ Sunnybrook Research Institute, subcutaneously. For adjuvant therapy, caecal resections tegafur was shown to be remarkably effective S-Wing, Room 217, 2075 were performed 3e5 weeks after tumour cell injection. Bayview Avenue, Toronto, in prolonging the survival of mice with advanced Chemotherapy drugs tested included uracil/tegafur, Ontario M4N 3M5, Canada; metastatic human breast cancer (Munoz et al. [email protected] folinic acid, oxaliplatin, topotecan, pazopanib and various Cancer Res 2006;66:3386e91). A similar combinations. regimen with bevacizumab is now undergoing Revised 24 February 2012 Results Subcutaneous tumours showed exaggerated Accepted 25 February 2012 randomised phase III clinical trial evaluation sensitivity to treatment by delayed tumour growth because of its efficacy and because of its (p¼0.002) and increased survival (p¼0.0064), but no minimal toxicity as reported in a prior phase II metastatic spread. Intrasplenic cell injection resulted in http://gut.bmj.com/ clinical trial (Dellapasua et al. J Clin Oncol rapid and extensive but artefactual metastasis without 2008;26:4899e905 and http://www.clinical- treatment effect. Intracaecal cell injection with tumour trials.gov, NCT01131195. take rates of 87.5e100% showed spontaneous < With respect to colon cancer, the concept of metastases at clinically relevant rates. Metronomic metronomic therapy appears to be highly topotecan significantly polonged survival and reduced promising and two randomised phase III trials metastasis. In the adjuvant setting, metronomic (CAIRO3 und ACT2, http://www.clinicaltrials. maintenance therapy (after FOLFOX-like induction) on September 30, 2021 by guest. Protected copyright. gov; NCT 00442637 and NCT 01229813) are prolonged survival compared with vehicle controls currently under way to evaluate metronomic (p¼0.0003), control followed by topotecan (p¼0.0161) maintenance therapy with the oral 5-fluorouracil or FOLFOX-like therapy (p¼0.0003). prodrug capecitabine, combined with molecular Conclusion The refined orthotopic implantation targeted therapy (bevacizumab and erlotinib), technique proved to be a clinically relevant model for following upfront standard maximum tolerated metastasis and therapy studies. Furthermore, dose induction therapy. metronomic therapy with oral topotecan may be < Uncovering further potentially useful drugs or promising to consider for clinical trials of metastatic drug combinations for metronomic therapy of colon cancer and long-term adjuvant maintenance colorectal adenocarcinoma is therefore an therapy of colon cancer. important area of translational cancer research. Sixty per cent of metastases in CRC patients occur INTRODUCTION in the liver, and up to 35% have metastases exclu- Colorectal adenocarcinoma (CRC) is the second sively in this organ.3 While surgical management of most common cancer worldwide.1 Although the colorectal liver metastases has undergone enormous majority (85%) of CRC patients in developed improvements during the past years,4 non-surgical countries can undergo initially curative local resec- approaches are still being developed. For example, This paper is freely available tion,2 leading causes of death are local recurrence standard neoadjuvant, or conversion therapy online under the BMJ Journals unlocked scheme, see http:// and metastatic disease. Therefore, adjuvant therapy regimen before hepatic resection, needs to be gut.bmj.com/site/about/ and treatment of advanced metastatic disease are established, as do adjuvant therapy after hepatic unlocked.xhtml two critically important fields of research in CRC. resection and optimal liver-specific chemotherapy. CopyrightHackl C, Man Article S, Francia author G, et al. Gut (or(2012). their doi:10.1136/gutjnl-2011-301585 employer) 2012. Produced by BMJ Publishing Group Ltd (& BSG) under licence.1of13 Colon cancer that oral topotecan may be an ideal candidate for metronomic Significance of this study therapy in CRC. Gut: first published as 10.1136/gutjnl-2011-301585 on 28 April 2012. Downloaded from Preclinical CRC therapy studies in mice are mostly performed using localised, ectopically implanted (subcutaneous) primary What are the new findings? 12e14 < This study presents an improved, reproducible, orthotopic and tumours. To study metastatic disease, investigators often spontaneously metastatic preclinical xenograft model of colon use so-called experimental metastasis models by injecting CRC cells intraveneously, intrasplenically or directly into secondary cancer. Transfection of tumour cells with the genes for 15e17 luciferase and b-human chorionic gonadotropin enables non- sites (eg, liver, peritoneum). Major discrepancies are invasive in vivo monitoring of primary growth and metastasis frequently observed between encouraging preclinical therapy at regular intervals. Caecal resections, combined with results and subsequent, much less impressive or negative clinical trial results.18 Only very few investigators use orthotopic imaging, enable adjuvant therapy studies to be undertaken. 19e24 < Comparing the new orthotopic model with existing preclinical injection of tumour cells into the caecal wall. It is likely colon cancer models, it is shown that subcutaneous tumours that one reason for the failure of most other investigators to showed exaggerated sensitivity to treatment, but no routinely use intracaecal tumour cell injections is that many metastatic spread. Intrasplenic cell injection resulted in rapid technical obstacles can compromise the successful establishment and extensive but artefactual metastasis without treatment of an orthotopic model. There is an urgent need to develop an improved, reliable method to increase the routine use of these effect. Intracaecal cell injection showed spontaneous metas- 18 25 tases at clinically relevant rates. models in preclinical research. < In the orthotopic model, metronomic topotecan significantly In this study, we present a detailed description of the tech- prolonged survival and reduced metastatic spread in primary nical establishment of orthotopic intracaecal injection of CRC fi and adjuvant treatment protocols. cells along with, for the rst time, a thorough cross-comparison < It is shown, for the first time, that metronomic therapy with with three existing human xenograft models of CRC. We then fi oral topotecan may be promising to consider for clinical trials use the orthotopic model to evaluate the ef cacy of metronomic of advanced metastatic colon cancer, and for long-term UFT, topotecan, and, since targeted therapies (eg, using the adjuvant maintenance therapy after FOLFOX induction. monoclonal antibodies bevacizumab or cetuximab) are part of the standard therapy for metastatic CRC,26 an oral anti-angio- How might it impact on clinical practice in the foreseeable genic targeting agent, pazopanib. Pazopanib targets vascular future? endothelial growth factor (VEGF) receptors, platelet-derived < Using modified orthotopic intracaecal cell implantation models growth factor receptors (PDGFR) and c-kit.27 28 The combina- can improve and facilitate translating preclinical therapy tion of UFT, oral topotecan and pazopanib enabled us to eval- results into appropriate clinical trial designs and, hence, more uate a metronomic multidrug regimendcomposed entirely of successful outcomes. orally bio-available drugs. To our knowledge, this is the first time < Several possible phase II clinical trials testing metronomic oral that such a study has been conducted preclinically in orthotopic topotecan in colon cancer are suggested. and adjuvant settings. We show that metronomic topotecan http://gut.bmj.com/ significantly prolongs survival
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