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Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further.

Combined modality treatment can be used to improve control of the local disease at the expense of increased toxicity. Several randomized trials have demonstrated that this combined modality therapy is better than radiotherapy alone or chemotherapy alone in the treatment of locally advanced diseases. Several new targets as well as potential new radio-sensitizers have been identified. To speed-up the process of developing new combined modality treatments, good preclinical models for optimization of the ratio between efficacy and toxicity and a well established methodology within a network of advanced high-tech laboratories and clinical departments devoted to early phase trials, are mandatory. The Synergy of Targeted Agents and Radiation Therapy (STAR) platform of the European Organisation for Research and Treatment of Cancer (EORTC) is gathering these tools.

Background: To the authors' knowledge, only limited data are available regarding the quality of end-of-life care for patients with hematologic malignancies. In this retrospective cohort study, the quality of end-of-life care was compared between patients with hematologic malignancies and those with solid tumors., Methods: All adult patients who died of advanced cancer between September 1, 2009 and February 28, 2010 while under the care of the study institution were included. The authors collected baseline demographics and end-of-life care indicators, including emergency room visits, hospitalization, intensive care unit admissions, and systemic cancer therapy use within the last 30 days of life., Results: Of a total of 816 decedents, 113 (14%) had hematologic malignancies. In the last 30 days of life, patients with hematologic malignancies were more likely to have emergency room visits (54% vs 43%; P = .03), hospital admissions (81% vs 47%; P < .001), ≥ 2 hospital admissions (23% vs 10%; P < .001), > 14 days of hospitalization (38% vs 8%; P < .001), intensive care unit admissions (39% vs 8%; P < .001) and death (33% vs 4%; P < .001), chemotherapy use (43% vs 14%; P < .001), and targeted therapy use (34% vs 11%; P < .001) compared with patients with solid tumors. Patients with hematologic malignancies were also less likely to have palliative care unit admissions (8% vs 17%; P = .02). The composite score for aggressiveness of care (with 0 indicating the best and 6 indicating the worst) was significantly higher among patients with hematologic malignancies compared with those with solid tumors (median, 2 vs 0; P < .001). On multivariate analysis, hematologic malignancy was found to be a significant factor associated with aggressive end-of-life care (odds ratio, 6.6; 95% confidence interval, 4.1-10.7 [P < .001])., Conclusions: The results of the current study indicate that patients with hematologic malignancies received more aggressive care at the end of life., (© 2014 American Cancer Society.)

Radical radiotherapy remains the cornerstone of treatment for patients with unresectable locally advanced non small cell lung cancer (NSCLC) either as single modality treatment for poor performance status patients or with sequential or concomitant chemotherapy for good performance status patients. Advances in understanding of tumour molecular biology, targeted drug development and experiences of novel agents in the advanced disease setting have brought targeted agents into the NSCLC clinic. In parallel experience using modified accelerated fractionation schedules in locally advanced disease have demonstrated improved outcomes compared to conventional fractionation in the single modality and sequential chemo-radiotherapy settings. Early studies of targeted agents combined with (chemo-) radiotherapy in locally advanced disease in different clinical settings are discussed below and important areas for future studies are high-lighted.

Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of "central dogma" of simplified reductionist transcription and single gene-phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.

Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways.

Objective: The advances achieved in the surgical management of vulvar squamous cell carcinoma (SCC) have not been mirrored in systemic therapy options. The objective of this paper is to summarize current evidence regarding systemic therapy in vulvar cancer, review the latest research on the biology of this disease, and identify future strategies to improve patient management., Methods: MEDLINE and EMBASE were searched for all relevant English-language articles from inception to December 10, 2012. Existing evidence regarding systemic therapy in vulvar SCC was synthesized descriptively, with an emphasis on prospective studies when available. Single-patient case-reports were excluded., Results: We identified 12 studies of neoadjuvant chemoradiation, 8 studies of neoadjuvant chemotherapy alone, 18 studies of chemoradiation as primary therapy, 4 studies of chemotherapy in the adjuvant setting, and 8 studies of chemotherapy for recurrent or metastatic disease. Review of the biology of vulvar cancer was performed, and promising targets for the future were identified based on the two biologic pathways of disease development. New therapeutic strategies such as immune-therapy and targeted agents hold promise for the future., Conclusions: Advances in systemic therapy for vulvar SCC are urgently needed, especially in the setting of recurrent and metastatic disease. A focus on the investigation of new targeted agents is encouraged and consideration of quality of life and sexual health issues is essential. International cooperation and adaptive trial designs are required to improve outcomes for this group of traditionally under-served women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin-containing regimens are critically presented and discussed in this review.

Neurologic complications of conventional cytototxic agents as well as those from monoclonal antibodies and targeted therapies are increasingly observed in patients with cancer. The major categories are represented by alkylating agents (platinum compounds, ifosfamide, procarbazine, thiotepa), mitotic spindle inhibitors (vinca alkaloids, taxanes, etoposide, teniposide), proteasome inhibitors (bortezomib), antibiotics, antimetabolites, thalidomide, lenalidomide, topoisomerase inhibitors, interferon-α, hormones, bevacizumab, trastuzumab, and small tyrosine kinase inhibitors. Peripheral neuropathy is a common adverse effect of a number of chemotherapeutic drugs and often represents a critical factor limiting an adequate dose-intensity of chemotherapy. Regarding the central nervous system (CNS), it is vulnerable to many forms of toxicity from chemotherapeutic agents, including encephalopathy syndromes and confusional states, seizures, headache, cerebrovascular complications, visual loss, cerebellar syndromes, and myelopathy. For a given drug, the occurrence of CNS toxicity depends on several factors, including the total dose, route of administration, presence of structural brain lesions, exposure to prior or concurrent irradiation, and interactions with other drugs. However, many of the neurotoxic reactions are rare and idiosyncratic, and remain unpredictable. Several forms of neuroprotection and rehabilitation are being investigated. Last, the so-called "chemobrain" is an emerging issue, as it is a model of a subtle of and long-lasting damage to neuronal structures from some antineoplastic agents., (© 2014 Elsevier B.V. All rights reserved.)

Mantle cell lymphoma has been recognized as a distinct entity from the other non-Hodgkin lymphomas in middle 1990's. It carries a worst prognosis among all mature B-cell malignancies. Cyclin D1 and recently SOX11 are the hallmarks for this disease. Even if it is highly responsive to induction treatment, it remains incurable, since it inevitably relapses. Highly aggressive approaches with stem cell transplantation can shift the survival curve for a bit, but even so the overall survival is not significantly improved in most of the cases. Small portion of patients with this heterogeneous disease have an indolent course with long-term survival. Conventional immunochemotherapy has reached its maximal possibilities, so novel target agents are absolutely warranted. The large number of ongoing early phase trials demonstrated promising results, especially emphasizing agents that target B-cell receptor. They are mostly investigated in relapsed/refractory disease, while front-line approaches with those agents need to be explored in future times.

Purpose: With the increasing use of novel targeted agents and the development of high imaging techniques, response evaluation criteria in solid tumour (RECIST) 1.1 developed primarily for cytotoxic agents and anatomic imaging, has demonstrated limitations. A survey was conducted of RECIST users to identify concerns and their suggestions for future RECIST criteria., Methods: 140 key partners of the RECIST collaboration were asked to complete a questionnaire. The 49 questions concerned (a) satisfaction and concerns with RECIST 1.1; (b) use of modified RECIST criteria and (c) suggestions for the next RECIST Version., Results: Sixty-five replies were received. 52.3% responders were satisfied with RECIST 1.1, while 10.8% indicated dissatisfaction. Areas of potential weakness included: (a) lack of incorporation of potential early indicators of response such as functional imaging, (b) lack of validation in rarer tumour types and (c) lack of validation for novel (targeted) agents. Suggestions were multiple, with highest numbers on two points: developing sub-criteria for certain disease types and including advanced imaging techniques for the evaluation., Conclusions: Constructive suggestions were received for optimising the next version. Ongoing data collection will make it possible to investigate the possible utilisation of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in tumour assessment, to verify whether RECIST is/can still be applicable in novel targeted therapy and to consider the need for criteria for specific disease types., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC.

The development of targeted therapies in lung cancer (mainly non-small cell lung cancer) has led to improvement in clinical outcomes and a more personalized approach to the management of these patients. This article discusses the main categories of novel targeted agents and the evidence behind their use., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen receptor, progesterone receptor, and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. There are several biologically distinct subtypes within TNBC. Although the incidence of BRCA mutations across all subsets of breast cancer is low, BRCA mutations are more common among those with TNBC and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early-stage TNBC and non-TNBC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: In phase II trials of cytotoxic agents, a multinomial phase II design incorporating early progression and response end points was shown to perform more efficiently than designs based only on response. We undertook a study to evaluate the performance of these designs in trials of targeted agents using the actual phase II data., Patients and Methods: Using best response data from sequentially enrolled patients in 15 NCIC Clinical Trials Group and 7 European Organization for Research and Treatment of Cancer trials of targeted agents, we determined that trials would have been stopped at the end of stage I of accrual by applying rules generated by the multinomial and Fleming designs. Two variants of the multinomial design were studied: to stop accrual after stage I of enrolment, Variant A required either response or progression criteria to be met, whereas Variant B required that both response and progression criteria to be met., Results: Using early progression, null/alternate hypotheses of 60% and 40% (60/40), the multinomial A variant recommended early stopping more often than the Fleming design. In most of the cases, this recommendation was correct given the final trial outcome. In contrast, the multinomial B variant never led to recommendations for early stopping and changing progression hypotheses did not improve the performance of this design., Conclusions: The multinomial A design using 60/40 hypotheses carried out better than the Fleming design in appropriately stopping trials of inactive targeted agents early. The multinomial B design was not useful for early stopping decisions. The multinomial A design may be favored over response-based designs in phase II trials of targeted agents.

Context: The use of targeted therapy at the end of life has not been well characterized., Objectives: To determine the frequency and predictors of targeted therapy use in the last days of life., Methods: All adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents., Results: Eight hundred sixteen patients were included: average age 62 years (range 21-97), female 48% and white 61%. The median interval between the last treatment and death was 47 (interquartile range [IQR] 21-97) days for targeted agents and 57 (IQR 26-118) days for chemotherapeutic agents. Within the last 30 days of life, 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy. Regimens given in the last 30 days of life included a median of one (IQR 1-2) chemotherapeutic or targeted agent and 43 (5%) patients receiving targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib (n = 25), bevacizumab (n = 20), rituximab (n = 11), gemtuzumab (n = 8), and temsirolimus (n = 8). On multivariate analysis, younger age (odds ratio [OR] 0.98 per year, P = 0.01), hematologic malignancy (OR = 6.1, P < 0.001), and lung malignancy (OR = 2.6, P = 0.05) were associated with increased targeted agent use in the last 30 days of life., Conclusion: Targeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed., (Copyright © 2013 American Cancer Society, Inc.)

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced hepatocellular carcinoma (HCC) remains poor. Fortunately, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC during the past few years. While there is early evidence of antitumor activity of several agents in phase I/II studies, phase III efforts with a few targeted agents have failed, highlighting the challenges of new drug development in HCC. This review summarizes the current status of other molecularly targeted agents under development in advanced HCC.

Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy significantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.

Lung cancer is the leading cause of cancer-related death in the United States. Though incremental advances have been made in the treatment of this devastating disease during the past decade, new therapies are urgently needed. Traditional cytotoxic agents have been combined with other modalities with improved survival for early-stage patients. Newer cytotoxic agents targeting the same or different mechanisms have been developed at different stages. Optimization of various chemotherapy regimens in different settings is one of the aims of current clinical trials. Some predictive biomarkers (eg, excision repair cross-complementing 1, ERCC1) and histotypes (eg, adenocarcinoma) are found to be associated with resistance/response to some cytotoxic drugs. Another notable advance is the addition of targeted therapy to lung cancer treatment. Targeted agents such as erlotinib and bevacizumab have demonstrated clinical benefits and gained Food and Drug Administration approval for lung cancer. More agents targeting various signaling pathways critical to lung cancer are at different stages of development. Along with the effort of new targeted drug discovery, biomarkers such as epidermal growth factor receptor and anaplastic lymphoma kinase mutations have proven useful for patient selection, and more predictive biomarkers have been actively evaluated in non-small cell lung cancer. The paradigm of lung cancer treatment has shifted towards biomarker-based personalized medicine.

Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14%-39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer.

With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC). Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents.

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the choice of optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration, with a median survival of approximately 7-11 mo and survival at 2 years rarely more than 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, several molecular targeting agents are now under evaluation in international randomized studies, and trastuzumab, an anti-HER2 monoclonal antibody, has shown antitumor activity against HER-2 positive AGC. However, this benefit is limited to only about 20% of patients with AGC (patients with HER-2 positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of predictive and prognostic molecular markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

The treatment options currently available in the medical therapy of advanced colorectal cancer (CRC) appear to be an abundance of riches. The integration of oxaliplatin and irinotecan as conventional cytotoxic agents as well as bevacizumab and the epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, as novel targeted agents into standard medical therapy have improved median overall survival in metastatic CRC beyond 2 years. It cannot be overemphasized that these significant improvements in outcome of patients with CRC are closely linked to the number of active drugs available to treat this disease. The abundance of treatment options, however, comes with specific challenges for the practical management of palliative medical therapy in advanced CRC, in particular with regard to the utilization of targeted agents. In this context, bevacizumab has established itself as the standard component of first-line chemotherapy. It is of interest for clinical practice that so far no predictive marker for the activity of bevacizumab in metastatic CRC has been identified. The key questions surrounding the use of bevacizumab in the palliative setting are whether its continuation beyond tumor progression provides clinical benefit, and which patient group is at higher risk for bevacizumab-related toxicities. Cetuximab and panitumumab have demonstrated efficacy both in combination with chemotherapy or - in contrast to bevacizumab - as single agent. In unselected patients, the effect of both EGFR antibodies on time-related parameters, progression free survival and overall survival, is moderate at best with emphasis more on the induction of tumor responses in a select group of patients. Therefore, until recently, EGFR antibodies were mainly regarded as salvage therapy options, in particular, since there did not appear to be a loss of activity when used in later lines of therapy. The finding that CRC harboring KRAS (and BRAF) mutations are resistant to EGFR antibodies, has allowed us to enrich the patient population with CRC that have a chance to benefit from cetuximab or panitumumab therapy. Biomarker-based treatment decisions are therefore now an integral part of clinical practice and trial design in CRC. In conclusion, targeted agents have become an integral part of medical therapy for advanced CRC. The challenge for current oncologic practice is to develop a rationale and biomarker-based treatment algorithm utilizing all potentially active agents as individualized therapy.

Fulfillment of the promise of the genomic revolution for personalizing cancer therapy will depend on the ability to identify specific alterations in tumor cells that are critical to their growth, and the development of drugs that can target these alterations and inhibit their growth. In this report, examples of where this has been successful are discussed, and the challenges faced in other cases are described. The identification of the patients most likely to benefit from targeted agents requires significant investment in the development and validation of predictive assays. The Program for the Assessment of Clinical Cancer Tests (PACCT) has proposed an approach that should speed the development of the diagnostic tools required and their acceptance into clinical practice. This approach is dependent on determining the most pressing clinical questions confronting clinicians today and the availability of adequate specimens to validate the assays.