Liver-directed therapies in colorectal cancer

The liver is the most common site of metastatic colorectal cancer (CRC) and the status of this organ is an important determinant of overall survival in patients with advanced disease. Complete resection of hepatic CRC metastases can provide a long-term cure for some patients, but the majority of liver metastases are not amenable to such surgery. Furthermore, most patients after curative resection ultimately suffer from recurrence, and the majority of such failures occur in the liver. Various ablative techniques can achieve local control of tumor after incomplete resection or for palliation. Tumor ablation currently has a secondary therapeutic role, as there is no evidence that it can achieve long-term survival comparable to surgical resection. Regional chemotherapy delivers tumoricidal agents in a selective fashion, minimizing systemic toxicity and damage to normal liver cells. Chemotherapy agents delivered through the hepatic artery can extend time to liver recurrence after curative resection and may prolong survival both in the adjuvant setting and when given to patients with unresectable disease. Molecular-based therapies, such as gene delivery and oncolytic viruses, provide promise for curative outcomes in patients with advanced disease.     

Liver-directed therapies in metastatic colorectal cancer

Colorectal cancer (CRC) is a major health concern in the United States (US) with over 140,000 new cases diagnosed in 2012. The most common site for CRC metastases is the liver. Hepatic resection is the treatment of choice for colorectal liver metastases (CLM), with a 5-year survival rate ranging from 35% to 58%. Unfortunately, only about 20% of patients are eligible for resection. There are a number of options for extending resection to more advanced patients including systemic chemotherapy, portal vein embolization (PVE), two stage hepatectomy, ablation and hepatic artery infusion (HAI). There are few phase III trials comparing these treatment modalities, and choosing the right treatment is patient dependent. Treating hepatic metastases requires a multidisciplinary approach and knowledge of all treatment options as there continues to be advances in management of CLM. If a patient can undergo a treatment modality in order to increase their potential for future resection this should be the primary goal. If the patient is still deemed unresectable then treatments that lengthen disease-free and overall-survival should be pursued. These include chemotherapy, ablation, HAI, chemoembolization, radioembolization (RE) and stereotactic radiotherapy.     

Liver-directed therapy in metastatic colorectal cancer

Introduction: Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions.

Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization.

Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence     

Liver-directed therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. This disease can be treated through several surgical and nonsurgical approaches. Although the only curative options for patients with HCC are surgical (resection or transplantation), most patients unfortunately present with advanced neoplastic disease or experience the effects of chronic liver disease, making surgical resection implausible. Several additional options are available for treating this population. Ablative therapies such as percutaneous ethanol injection, cryotherapy, radiofrequency ablation, laser ablation, and microwave hyperthermic ablation can be used with varying degrees of success. Transarterial chemoembolization can be used in patients with advanced disease or advanced chronic liver disease that cannot be treated with resection or ablation. This article explores the various liver-directed therapies, including surgical resection, and defines morbidity, mortality, and survival for each.     

Liver-directed therapies for metastatic neuroendocrine tumors

Neuroendocrine tumors, despite being indolent, frequently cause significant morbidity and mortality from hepatic metastatic lesions. It is possible to directly target these liver lesions with embolization/chemoembolization, radiofrequency ablation, or other therapies. The observational studies that exist seem to indicate a prolongation of survival. Liver-directed therapies are also able to decrease symptoms in most patients. The value of these therapeutic interventions therefore lies mainly in their palliative capabilities. Coupled with aggressive use of octreotide, local ablative techniques may frequently control symptoms of hormone excess and tumor bulk. Because of the possible adverse effects of these interventions, however, careful patient selection is essential to minimize the morbidity and mortality of the procedures.     

Liver-directed therapies for patients with primary liver cancer and hepatic metastases

Opinion statement Liver cancer, whether primary or metastatic, is a major cause of death throughout the world. The surgical management of these diseases varies according to the extent of disease and the overall health of the patient. Surgical resection of hepatic disease remains the only chance for cure. However, a large proportion of patients with liver cancer are unable to undergo a complete surgical resection. These patients are often treated with liver-directed therapies. Although not as effective as surgical resection, these approaches can help to improve the survival of patients. In patients with primary liver cancer, underlying liver disease often prohibits surgical intervention. However, survival advantages have been gained with the application of percutaneous alcohol injection and radiofrequency ablation (RFA). In patients with hepatic metastases, the number of metastases is often what prevents surgical resection. In these patients, RFA, cryoablation, and hepatic artery infusional therapy have all aided in prolonging survival. As chemotherapeutic agents improve and targeted therapies are developed, more patients will be able to undergo surgical management of their liver cancer, primary or metastatic.     

Liver-directed therapies in patients with advanced neuroendocrine tumors

Neuroendocrine tumors (NETs) are increasing in incidence. Incidental NETs that may have little clinical significance, such as gastric and rectal primaries, are often identified because of increased screening efforts and advanced imaging modalities. Although NETs are biologically indolent cancers, many patients present with incurable metastatic disease to the liver at initial diagnosis. Some literature suggests a delay averaging almost 5 years in making the correct diagnosis based on clinical symptoms. Although surgical resection offers the only potentially curative therapy, liver-directed therapies, such as embolization and ablation, offer effective alternatives to control symptoms and potentially impact overall survival. This article reviews the latest liver-directed approaches to the management of advanced NETs.     

Antibody-based therapies for colorectal cancer

The recent successful development of novel monoclonal antibodies that target key components of biologic pathways has expanded the armamentarium of treatment options for patients with colorectal cancer. Two targets in particular--the process of new blood vessel development, or angiogenesis, and the epidermal growth factor receptor and its signaling pathway--are exploited by the newest monoclonal antibodies that are available for use in colorectal cancer patients. This clinical review focuses on the defining role of the two most clinically advanced novel agents, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) and cetuximab (Erbitux; ImClone Systems, Inc., New York, http://www.imclone.com), in colorectal cancer.     

应用病毒治疗结直肠癌的研究进展*

基于病毒的抗肿瘤治疗是一种新兴的生物治疗方式,病毒载体感染肿瘤组织,引起溶瘤效应,制成疫苗激活体内抗肿瘤免疫,搭载基因行癌症的基因治疗。随着对病毒的不断改造,各类病毒治疗肿瘤更趋于安全和高效,同时,病毒载体与现有的抗肿瘤疗法合理联用,可提高治疗效果。因此,基于病毒的抗肿瘤治疗将作为极具潜力的方法而逐渐引起人们的重视。本文就近些年各种病毒在治疗结直肠癌中的研究进展做一综述。      

Integrating anti-EGFR therapies in metastatic colorectal cancer

Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study.EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.Key Words: Epidermal growth factor inhibitors (EGFR inhibitor), metastatic colorectal cancer (mCRC), cetuximab, panitumumab, KRAS, targeted therapy     

Current therapies for advanced colorectal cancer

Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years, namely due to the introduction of three novel cytotoxic agents-capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin)-and the recent approval of two biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux). During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. Recent clinical trial results suggest that the anti-VEGF antibody bevacizumab can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant settings. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.     

The role of epigenetic therapies in colorectal cancer

Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.     

Targeted therapies in colorectal cancer: surgical considerations

Colorectal cancer (CRC) is a leading worldwide health concern that is responsible for thousands of deaths each year. The primary source of mortality for patients with CRC is the development and subsequent progression of metastatic disease. The most common site for distant metastatic disease is the liver. Although patients with metastatic disease to the liver have several effective treatment options, the only one for cure remains surgical resection of the liver metastases. Historically, most patients with liver metastases have had unresectable disease, and only a small percentage of patients have undergone complete curative resection. However, improved systemic therapies have led to an evolution in strategies to treat metastatic CRC to the liver. Under most conditions the management of these patients remains complex; and as chemotherapy options and new targeted therapies continue to improve outcomes, it is clear that a multidisciplinary approach must be the foundation on which advanced surgical and medical techniques are employed. Here, in this review, we highlight the role of targeted therapies in the surgical management of patients with metastatic CRC to the liver.Key Words: Colorectal cancer (CRC), metastatic colorectal cancer (mCRC), liver, targeted therapies, chemotherapy, surgical management     

Liver-directed therapies in liver metastases from neuroendocrine tumors of the gastrointestinal tract

Presence of liver metastases in neuroendocrine tumors is a major factor altering both quality of life and prognosis. Surgery is recognized as the sole curative treatment. When it is not possible, radiological directed therapies are crucial, particularly in liver metastases from the small bowel. Thermal ablative therapies as radiofrequency ablation and microwave are alternative treatments alone or in combination with surgery. Hepatic artery embolization or chemoembolization, as radioembolization, has been shown to have good clinical, biochemical, and morphological responses when liver burden does not permit ablative therapies. However, technical issues are multiple and there is no randomized study to compare their efficacy. The choice of management depends on liver burden and metastases pattern, but also on origin of the primary tumor, tumor differentiation, and tumor proliferative activity. These patients should benefit of a multidisciplinary management to limit morbidity and mortality.     

Quality-of-life assessment in colorectal cancer patients: evaluation of cancer therapies

There is increasing recognition of the need to assess the impact of colorectal cancer and its treatment on patients' quality of life (QL). An overview is provided of generic and (colorectal) cancer-specific QL questionnaires that yield adequate levels of reliability and validity. These measures have been or could be used in clinical research settings among colorectal cancer patients. Additionally, QL-based studies in colorectal cancer aimed at identifying the most optimal (cost-) effective treatment, or the parameters that best predict objective outcome, are described and exemplified. As is illustrated, QL data complement clinical outcomes and are essential to further improve the treatment and care of colorectal cancer patients and to support decision-making.     

Targeted therapies in colorectal cancer: Complications and management

The promise of targeted therapeutics is tumor selectivity. The gold standard for this approach is monoclonal antibodies with exquisite target specificity. In the case of colorectal cancer, this promise has been partially fulfilled. The epidermal growth factor and vascular endothelial growth factor pathways were identified as putative therapeutic targets and inhibitory antibodies were developed with clinical activity. However, although these reagents are not associated with toxicities characteristic of traditional cytotoxics, they are not devoid of side effects. In fact, these side effects can generally be explained on the basis of expected biologic effects of the reagents, highlighting the notion that targets with true tumor specificity remain elusive. In this review, we will profile the unique toxicities associated with monoclonal antibody inhibitors of the epidermal growth factor receptor and vascular endothelial growth factor, and offer suggestions for management.     

Clinical results of EGFR-targeted therapies in advanced colorectal cancer

This paper is an updated review of the pre-clinical rationale and clinical results of new EGFR-targeted agents – cetuximab and panitumumab – employed in the management of advanced/ metastatic colorectal cancer. The addition of either biologic agent or last generation standard chemotherapy regimens – FOLFIRI and FOLFOX – has yielded better results as compared to those reported for chemotherapy alone. These results have been obtained without a significant increase in severe toxicity with the exception of skin side-effects.     

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer

Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.     

Continuum of care with anti-angiogenic therapies in metastatic colorectal cancer

Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients’ whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.Key Words: Colorectal cancer, metastatic, angiogenesis, bevacizumab, ziv-aflibercept, regorafenib