Aktuelle Therapie des Kolonkarzinoms

Colorectal cancer is one of the most common cancers worldwide, with 63,000 new cases diagnosed each year in Germany alone. About 30,000 of these patients die of colorectal cancer every year. In up to 20% of cases, distant metastases are already present at diagnosis. However, new data demonstrate that the presence of metastases per se does not constitute a palliative setting in colorectal cancer. In the case of complete resection of isolated liver or lung metastases, cure is possible for these patients. The choice of systemic treatment increasingly depends not only on the stage of the disease but also on the individual patient situation. The introduction of tumor-specific targeted therapies has considerably increased the therapeutic options. With the use of all available agents, a median overall survival of more than 30 months is achievable in the palliative setting. The multitude of targeted therapies that will be available for treating colorectal cancer in due course opens the door for personalized treatment of colorectal cancer, given that predictive biomarkers also exist to help guide the treatment.     

Selecting the best targeted agent in first-line treatment of unresectable liver metastases from colorectal cancer: does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.     

KRAS und weitere Signalmoleküle für die Therapieentscheidung beim metastasierten Kolonkarzinom

In recent years targeted therapy has made an impact in all aspects of oncology but in particular in the treatment of colorectal cancer. This development is the result of increasing knowledge on signal cascades in tumors in vitro and in vivo which play an essential role in the regulation of cell survival, tumor growth and metastasis. This has led to the development of strategies to interrupt signal cascades relevant for tumors and ideally with targeted medications to affect only the tumor and not other organs or cell systems. In the field of colorectal cancer the implementation of targeted therapies has if nothing else brought a clear improvement in tumor response, progression-free survival and total survival; however, not for all patients treated with these medications. There is therefore an increasing demand for predictive markers for therapy with these, even cost-intensive, therapeutics which allow a prediction whether a patient will profit from a certain targeted therapy. In this article the current state of the art and value of predictive markers for targeted therapy strategies against epidermal growth factor receptor for metastasized colorectal cancer will be presented.     

Targeting PI3K signaling as a therapeutic approach for colorectal cancer

Survival times of patients with colorectal cancer (CRC) have increased over the past decade, primarily as a result of treatment with combinations of conventional cytotoxic agents. Because CRC is commonly associated with mutations in genes that control growth factor signaling, therapies are being developed to target the products of these genes; individualized treatment might also be guided by specific mutations in tumors and by new biomarkers. Currently, targeted therapies confer limited clinical benefit; better drugs are therefore needed. Genomic studies indicate that phosphoinositide 3-kinase (PI3K) signaling is one of the most frequently deregulated pathways in several human cancers, including CRC. PI3K signaling has an important role in cancer cell proliferation, survival, motility, and metabolism and therefore could be an attractive therapeutic target. We review PI3K signaling in CRC and discuss current therapeutic approaches.     

Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape

BACKGROUND & AIMS: Normal and neoplastic cells release microvesicles, whose effects on the immune system still need to be elucidated. Because human colorectal cancer cells are hypothesized to escape immune recognition by expressing proapoptotic molecules, we investigated whether microvesicles bearing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand and inducing apoptosis of activated T cells are secreted by colorectal cancer cells both in vitro and in affected patients. METHODS: Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand expression were analyzed in colorectal cancer cells and purified microvesicles by flow cytometry, Western blotting, and immunoelectron microscopy. Microvesicle tumor origin was assessed through simultaneous detection of lysosomal (CD63) and adenocarcinoma (carcinoembryonic antigen) markers. Proapoptotic activity of microvesicles was evaluated by annexin V/propidium iodide staining and caspase activation in T cells, including CD8+ T lymphocytes from colorectal cancer patients. RESULTS: Colorectal cancer cells showed a granular pattern of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand expression, suggesting a secretory behavior. These proapoptotic molecules were detected on isolated microvesicles, together with class I HLA, CD63, and carcinoembryonic antigen. Microvesicles induced Fas ligand-mediated and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of activated CD8+ T cells generated from colorectal cancer patients. Microvesicles with comparable phenotypes and functions were found in plasma from patients with advanced disease, whereas vesicular structures expressing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand were also detected in colorectal cancer specimens. CONCLUSIONS: These data show that colorectal cancer induces T-cell apoptosis through the release of Fas ligand-bearing and tumor necrosis factor-related apoptosis-inducing ligand-bearing microvesicles both in vitro and in vivo. This mechanism of immune escape has potential implications as a prognostic factor and could be targeted for the development of new antitumor therapies in colorectal cancer patients.     

Controversies in the pathological assessment of colorectal cancer

Pathologic assessment of colorectal cancer specimens plays an essential role in patient management,informing prognosis and contributing to therapeutic decision making.The tumor-node-metastasis(TNM)staging system is a key component of the colorectal cancer pathology report and provides important prognostic information.However there is significant variation in outcome of patients within the same tumor stage.Many other histological features such as tumor budding,vascular invasion,perineural invasion,tumor grade and rectal tumor regression grade that may be of prognostic value are not part of TNM staging.Assessment of extramural tumor deposits and peritoneal involvement contributes to TNM staging but there are some difficulties with the definition of both of these features.Controversies in colorectal cancer pathology reporting include the subjective nature of some of the elements assessed,poor reporting rates and reproducibility and the need for standardized examination protocols and reporting.Molecular pathology is becoming increasingly important in prognostication and prediction of response to targeted therapies but accurate morphology still has a key role to play in colorectal cancer pathology reporting.     

Systemic treatment for metastatic colorectal cancer

Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and wholeexome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilit...     

Genomic diversity of colorectal cancer: Changing landscape and emerging targets

Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers(CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multiinstitutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual's tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC.     

Mechanisms f resistance o anti-EEGFR monoclonal antibody treatment in metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates.Novel targeted therapies (bevacizumab, and cetuximab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions.In addition, everal studies have proved that the CRC mutation profiles should influence patient selection or stratification in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted herapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of antiepidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies.Overall the accumulating vidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more ational options for treating this illness.     

The importance of molecular markers for diagnosis and selection of targeted treatments in patients with cancer

The past 30 years have seen the introduction of a number of cancer therapies with the aim of restricting the growth and spread of primary and metastatic tumours. A shared commonality among these therapies is their targeting of various aspects of the cancer hallmarks, that is traits that are essential to successful tumour propagation and dissemination. The evolution of molecular‐scale technology has been central to the identification of new cancer targets, and it is not a coincidence that improved therapies have emerged at the same time as gene expression arrays and DNA sequencing have enhanced our understanding of cancer genetics. Modern tumour pathology is now viewed at the molecular level ranging from IHC biomarkers, to gene signature classifiers and gene mutations, all of which provide crucial information about which patients will respond to targeted therapy regimens. In this review, we briefly discuss the general types of targeted therapies used in a clinical setting and provide a short background on immunohistochemical, gene expression and DNA sequencing technologies, before focusing on three tumour types: breast, lung and colorectal cancers. For each of these cancer types, we provide a background to the disease along with an overview of the current standard therapies and then focus on the relevant targeted therapies and the pathways they inhibit. Finally, we highlight several strategies that are pivotal to the successful development of targeted anti‐cancer drugs.     

Targeted therapeutic agents for colorectal cancer

The treatment of colorectal cancer (CRC) has evolved substantially during the past decade with the advent of molecular targeted therapies. Inhibitors to the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) pathways have been shown to enhance the efficacy of cytotoxic chemotherapy in patients with advanced CRC, and anti-EGFR antibodies demonstrate modest activity as monotherapeutic agents. These biologic agents have improved patient outcomes and survival and have been incorporated into routine clinical practice establishing a new standard of care. Molecular markers have recently been adopted into clinical practice with the finding that the KRAS oncogene is a predictive biomarker for anti-EGFR therapy, whereby the therapeutic benefit of anti-EGFR treatment is restricted to tumors with wild-type KRAS. The use of molecular targeted agents has fewer yet more specific toxicities compared with conventional cytotoxic drugs and enables a more personalized approach to cancer therapy. In contrast to the results for advanced CRC, targeted therapies have not shown a benefit in the adjuvant setting for patients with resected colon cancer. The goal of this review is to provide an update on the medical management of CRC, with a focus on the use of targeted therapy.     

One hundred and fifty years of the Journal of Internal Medicine (JIM)

Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.     

Proteomic and metabolic prediction of response to therapy in gastric cancer

Several new treatment options for gastric cancer have been introduced but the prognosis of patients diagnosed with gastric cancer is still poor. Disease prognosis could be improved for high-risk individuals by implementing earlier screenings. Because many patients are asymptomatic during the early stages of gastric cancer, the diagnosis is often delayed and patients present with unresectable locally advanced or metastatic disease. Cytotoxic treatment has been shown to prolong survival in general, but not all patients are responders. The application of targeted therapies and multimodal treatment has improved prognosis for those with advanced disease. However, these new therapeutic strategies do not uniformly benefit all patients. Predicting whether patients will respond to specific therapies would be of particular value and would allow for stratifying patients for personalized treatment strategies. Metabolic imaging by positron emission tomography was the first technique with the potential to predict the response of esophago-gastric cancer to neoadjuvant therapy. Exploring and validating tissue-based biomarkers are ongoing processes. In this review, we discuss the status of several targeted therapies for gastric cancer, as well as proteomic and metabolic methods for investigating biomarkers for therapy response prediction in gastric cancer.     

Treatment of metastatic cervical cancer: Future directions involving targeted agents

Cervical cancer is the third most common cause of female cancer mortality, and it remains a major health problem in populations with limited economic resources. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation have a poor prognosis, and are treated with palliative platinum-based chemotherapy. There are few effective therapeutic options for patients who progressed after first-line chemotherapy. Future advances in the treatment of metastatic or recurrent disease may rely on more effective and better-tolerated therapies, and molecularly driven targeted agents could represent an attractive option. Inhibition of tumor angiogenesis and epidermal growth factor receptor directed therapies have focused the most recent clinical research efforts. A thorough molecular characterization of cervical cancer remains crucial for a rationale implementation of targeted agents and companion biomarkers. Alternative clinical trial designs may also be necessary to optimize the clinical development of new drugs for metastatic cervical cancer.     

Is precision medicine for colorectal liver metastases still a utopia? New perspectives by modern biomarkers,radiomics, and artificial intelligence

The management of patients with liver metastases from colorectal cancer is still debated. Several therapeutic options and treatment strategies are available for an extremely heterogeneous clinical scenario. Adequate prediction of patients’ outcomes and of the effectiveness of chemotherapy and loco-regional treatments are crucial to reach a precision medicine approach. This has been an unmet need for a long time, but recent studies have opened new perspectives. New morphological biomarkers have been identified. The dynamic evaluation of the metastases across a time interval, with or without chemotherapy, provided a reliable assessment of the tumor biology. Genetics have been explored and, thanks to their strong association with prognosis, have the potential to drive treatment planning. The liver-tumor interface has been identified as one of the main determinants of tumor progression, and its components, in particular the immune infiltrate, are the focus of major research. Image mining and analyses provided new insights on tumor biology and are expected to have a relevant impact on clinical practice. Artificial intelligence is a further step forward. The present paper depicts the evolution of clinical decision-making for patients affected by colorectal liver metastases, facing modern biomarkers and innovative opportunities that will characterize the evolution of clinical research and practice in the next few years.     

Novel translational strategies in colorectal cancer research

Defining translational research is still a complex task. In oncology, translational research implies using our basic knowledge learnt from in vitro and in vivo experiments to directly improve diagnostic tools and therapeutic approaches in cancer patients. Moreover, the better understanding of human cancer and its use to design more reliable tumor models and more accurate experimental systems also has to be considered a good example of translational research. The identification and characterization of new molecular markers and the discovery of novel targeted therapies are two main goals in colorectal cancer translational research. However, the straightforward translation of basic research findings, specifically into colorectal cancer treatment and vice versa is still underway. In the present paper, a summarized view of some of the new available approaches on colorectal cancer translational research is provided. Pros and cons are discussed for every approach exposed.     

Challenges in the multidisciplinary management of stage IV colon and rectal cancer

Colorectal metastases still represent a challenge to all oncologists despite progresses achieved by improved resectability, systemic chemotherapy and targeted therapies. In particular in patients with oligo-metastases, the role of surgical resections has been redefined. Resection is the most effective treatment method for liver metastases performed with curative intent; however, primary rate of resectability is low. Several methods to increase resectability have been developed: conversion chemotherapy, portal vein embolization, two-stage resections, vascular reconstruction of the liver veins, combination of resection and intraoperative ablation. Liver resections can be performed at present with low mortality. Patients with isolated peritoneal metastases, no extra-abdominal disease, low volume tumor and complete surgical cytoreduction do benefit from surgery and hyperthermic intraperitoneal chemotherapy. Several national guidelines recommend multimodality treatment for highly selected patients. The management of stage IV colorectal cancer includes several disciplines with focus on resection. A multidisciplinary evaluation of all patients is of crucial importance to define the treatment sequence and individual strategies for each patient.     

Radiotherapie und Radiochemotherapie des Rektumkarzinoms

With optimized local treatment—achieved through preoperative short-course radiotherapy or preoperative radiochemotherapy and quality-controlled surgery with total mesorectal excision—distant metastases are by far the predominant sites of tumor failure in rectal cancer today. Capecitabine, oxaliplatin, and irinotecan as well as targeted therapies have improved results for colorectal cancer patients when treated in metastatic and adjuvant situations. These agents have now been incorporated into phase I and II studies for rectal cancer. The challenge is to define the best sequence of combinations. Phase III trials are needed to determine whether these novel combination regimens offer an advantage compared with 5-FU-based combined modalities.     

Colorectal cancer molecular biology moves into clinical practice

The promise of personalised medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the recent advances in testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers) and the prediction of treatment responses (predictive markers) are examined.