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Purpose: The National Institutes of Health's policy for the inclusion of females in clinical research was a pivotal step towards the consideration of sex as a biological variable, which is of particular importance in oncology, given differential incidence and outcomes of cancer between the sexes, and known pharmacodynamic, pharmacokinetic, and immunological differences. Therefore, we aim to investigate if such biological sex-based differences translate to clinically meaningful outcome differences from recently approved systemic oncology therapies. Methods: A systematic review of randomized control trials (RCTs) cited in Food and Drug Administration, European Medicines Agency, and Health Canada approvals was conducted. Chemotherapy, targeted agents, and immunotherapy RCTs reporting sex-based sub-group analyses for overall/progression-free survival (OS/PFS) were considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized. Sensitivity analyses for survival endpoints, drug type, and cancer site were conducted. Results: Ninety-nine RCTs were included, representing 62,384 patients (23,574 (38%) female). Pooled OS HRs [95% CIs] were 0.77 [0.72–0.81] and 0.76 [0.72–0.79] for females and males, respectively (P = 0.73), and 0.51 [0.47–0.56] and 0.57 [0.53–0.61] (P = 0.08) for PFS. Sensitivity analyses yielded similar results. No RCTs reported sex-based toxicity or quality-of-life (QOL) data. Conclusion: Female and male patients appear to derive comparable benefits from recently approved systemic oncology therapies. Future RCTs are encouraged to report sex-based toxicity and QOL data. [ABSTRACT FROM AUTHOR]

Opinion statement: Extremity soft tissue sarcoma (ESTS) constitutes the majority of patients with soft tissue sarcoma (STS). Patients with localized high-grade ESTS > 5 cm in size carry a substantial risk of developing distant metastasis on follow-up. A neoadjuvant chemoradiotherapy approach can enhance local control by facilitating resection of the large and deep locally advanced tumors while trying to address distant spread by treating the micrometastasis for these high-risk ESTS. Preoperative chemoradiotherapy and adjuvant chemotherapy are often used for children with intermediate- or high-risk non-rhabdomyosarcoma soft tissue tumors in North America and Europe. In adults, the cumulative evidence supporting preoperative chemoradiotherapy or adjuvant chemotherapy remains controversial. However, some studies support a possible benefit of 10% in overall survival (OS) for high-risk localized ESTS, especially for those with a probability of 10-year OS < 60% using validated nomograms. Opponents of neoadjuvant chemotherapy argue that it delays curative surgery, compromises local control, and increases the rate of wound complications and treatment-related mortality; however, the published trials do not support these arguments. Most treatment-related side effects can be managed with adequate supportive care. A coordinated multidisciplinary approach involving sarcoma expertise in surgery, radiation, and chemotherapy is required to achieve better outcomes for ESTS. The next generation of clinical trials will shed light on how comprehensive molecular characterization, targeted agents and/or immunotherapy can be integrated into the upfront trimodality treatment to improve outcomes. To that end, every effort should be made to enroll these patients on clinical trials, when available. [ABSTRACT FROM AUTHOR]

Opinion Statement: Over the years, there have been significant advances in systemic treatments for metastatic pancreatic neuroendocrine tumors (panNETs). Despite these advancements, uncertainty remains regarding how to best sequence available therapies. For well-differentiated and metastatic panNETs that are somatostatin receptor (SSTR) avid on functional imaging, first-line therapy typically consists of somatostatin analogs (SSAs), given their favorable toxicity profile and overall low burden for patients. When progression of disease is observed on an SSA, multiple treatment options are available, including the targeted agents everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT), as well as chemotherapy, with the latter often preferred for those panNETs of heavy tumor burden, higher grade, and/or more aggressive behavior clinically and/or radiographically. Here, we review panNET classification, currently available systemic treatments, therapy sequencing, and areas of active investigation to further our treatments for the disease. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia-lymphoma (ATL), a rare and aggressive T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1), is associated with a poor prognosis. Evidence-based standard treatment options are lacking and outcomes are generally unsatisfactory, particularly for patients with relapsed or refractory disease. Continued research is contributing to changing treatment landscape as a number of existing and investigational agents are evaluated. We describe the epidemiology of HTLV-1 and ATL, discuss the biology behind the disease, review current treatment practices and guidelines, and provide an overview of emerging therapies in ATL, with a focus on those for relapsed or refractory disease. [ABSTRACT FROM AUTHOR]

Opinion Statement: The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed. The better understanding of thymic carcinogenesis may provide a rationale in this setting.Targeted agents approved for other solid tumors that have shown activity in thymic tumors include mTOR, KIT inhibitors, as well as somatostatin analogues. Anti-angiogenic agent sunitinib may be considered a standard in advanced lines of treatment. Ongoing studies are assessing the opportunity of targeting emerging targets, including PI3K, CDK, and immune checkpoint PD-1/PD-L1. [ABSTRACT FROM AUTHOR]

Opinion Statement: Two cycles of neoadjuvant cisplatin and fluoropyrimidine (CF) and 6 cycles of perioperative CF with or without epirubicin are an evidence-based approach in operable esophageal and esophagogastric junctional adenocarcinomas. Three-drug regimens with anthracycline or taxane are associated with significantly higher tumor regression rates, with an expected increase in toxicity. In order to achieve an R0 resection and consequently a survival advantage, in selected patients having a risk of a threatened margin or incomplete resection, chemotherapy might be continued beyond 2 cycles if a response has been demonstrated. In metastatic setting, multidrug combination regimens have demonstrated a significant survival benefit when compared to single-agent regimes. A three-drug regimen should be considered for fit patients and/or when a response is required for symptom control. The expected increase in toxicity needs to be carefully considered and discussed with patients. The choice to use a taxane in first-line setting may limit the options of second-line treatment to irinotecan-containing regimens and also precludes the use of anthracyclines in the first line. For this reason, we prefer to reserve taxane-based therapy for the second-line setting. [ABSTRACT FROM AUTHOR]

Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder-preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon. [ABSTRACT FROM AUTHOR]

Purpose: Hypoxia is commonly observed in regions of primary tumors and metastases, and is associated with resistance to treatment, more aggressive tumor phenotypes and poor prognosis. Reliable and validated imaging biomarkers of hypoxia are needed for pre-clinical studies and clinical use. Expression of cell-surface carbonic anhydrases IX and XII (CAIX and CAXII) in tumor cells has been associated with tumor hypoxia. CAIX and CAXII specific antibodies conjugated to fluorescent dye were evaluated for the non-invasive detection of hypoxia in vivo.Procedures: Human breast cancer cell lines (MCF10A, DCIS, MCF7, ZR-75.1 and MDA-mb231) were characterized for CAIX and CAXII expression by real-time RT-PCR and immunocytochemistry (ICC) under normoxic and hypoxic conditions. Immunohistochemical (IHC) staining of CAIX, CAXII and the commercially available exogenous hypoxia marker, pimonidazole, was performed using sections of ZR-75.1 and MDA-mb-231 orthotopic breast cancer xenograft tumors from nude mice. In vivo fluorescence imaging of ZR-75.1 tumors in animals housed at varied levels of oxygen was used to quantify the relative uptake of the CAIX and CAXII agents and a commercially available sulfonamide-based agent. Corresponding tumor sections were IHC stained for CAIX, CAXII and pimonidazole.Results: CAIX mRNA expression was significantly higher (p < 0.05) in hypoxia for all cell lines, which was in agreement with protein expression by ICC. CAXII expression was mixed, with a modest hypoxia-related increase in two cell lines (p < 0.05) and no change in others. Quantified IHC staining of ZR-75.1 and MDA-mb-231 tumor sections showed that CAIX and CAXII expression was elevated in regions with pimonidazole staining, but CAXII levels were lower than CAIX. Tumor uptake of the CAIX targeted agent, and IHC staining of CAIX and pimonidazole in corresponding tumor sections were correlated, and co-registered, and shown to be significantly elevated by level of oxygenation (p < 0.001): hypoxia > normoxia > hyperoxia. However, the CAXII and sulfonamide agents were not significantly correlated with hypoxia.Conclusion: These studies suggest that the fluorescently labeled CAIX-specific agent is a more robust indicator of hypoxia in vivo compared to the CAXII-specific agent or the agent specific to the CA active site. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a disease affecting mainly older people, a fact that is becoming more apparent with the global population aging. However, this patient group is more likely to be subjected to suboptimal treatment due to a number of factors, but most commonly as a result of the physician's weakness to recognize those fit for the full spectrum of cancer therapy. In this regard, clinical screening tests, such as the Comprehensive Geriatric Assessment, can be invaluable in guiding treatment decisions. Fluoropyrimidine-based adjuvant chemotherapy clearly confers a survival advantage in older individuals with node-positive disease; however, the benefit from the administration of oxaliplatin-based regimens is less clear. Palliative chemotherapy also has an important role in managing metastatic disease, and with the use of novel targeted agents it can potentially prolong survival and improve quality of life. The management of rectal cancer in this population can present a challenge, since it appears that the optimal treatment of chemoradiation followed by total mesorectal excision can be applied in select few. Indeed, the morbidity and mortality rates in older people treated with these combined modalities can be too high, guiding many physicians to opt for more conservative approaches, directed at providing palliation and local control, especially in those with limited life expectancy. In conclusion, in order to provide the best care in an older colorectal cancer patient, we need to individualize our approach, selecting the right patient for the right treatment. [ABSTRACT FROM AUTHOR]

Oncogenic transformation is believed to impact the vascular phenotype and microenvironment in cancer, at least in part, through mechanisms involving extracellular vesicles (EVs). We explored these questions in the context of acute promyelocytic leukemia cells (NB4) expressing oncogenic fusion protein, PML-RARa and exquisitely sensitive to its clinically used antagonist, the all- trans retinoic acid (ATRA). We report that NB4 cells produce considerable numbers of EVs, which are readily taken up by cultured endothelial cells triggering their increased survival. NB4 EVs contain PML-RARa transcript, but no detectable protein, which is also absent in endothelial cells upon the vesicle uptake, thereby precluding an active intercellular trafficking of this oncogene in this setting. ATRA treatment changes the emission profile of NB4-related EVs resulting in preponderance of smaller vesicles, an effect that occurs in parallel with the onset of cellular differentiation. ATRA also increases IL-8 mRNA and protein content in NB4 cells and their EVs, while decreasing the levels of VEGF and tissue factor (TF). Endothelial cell uptake of NB4-derived EVs renders these cells more TF-positive and procoagulant, and this effect is diminished by pre-treatment of EV donor cells with ATRA. Profiling angiogenesis-related transcripts in intact and ATRA-treated APL cells and their EVs reveals multiple differences attributable to cellular responses and EV molecular packaging. These observations point to the potential significance of changes in the angiogenic signature and activity associated with EVs released from tumor cells subjected to targeted therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second leading cause of cancer dead in Spain. About half the patients will eventually develop distant metastases. However, as treatment options are expanding, prognosis has steadily improved over the last decades. Management of advanced CRC should be discussed within an experienced multidisciplinary team to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures when indicated. Disease site and extent, resectability, tumor biology and gene mutations, clinical presentation, patient preferences, and comorbidities are key factors to design a customized treatment plan. The aim of these guidelines is to provide synthetic recommendations for managing advanced CRC patients. [ABSTRACT FROM AUTHOR]

Meningiomas are the most common intracranial tumors and the majority of cases is curable by surgical resection. Incompletely resected tumors and tumors with signs of increased malignancy (WHO grade II and III tumors) are prone to recur. In meningiomas relapsing after surgical resection and after exhaustion of radiotherapeutic options, drug therapy is to be considered. A variety of drugs has been studied in meningiomas, including hydroxyurea, temozolomide, irinotecan, interferon-alpha, mifepristone, octreotide analogues, megestrol acetate, bevacizumab, sunitinib, vatalinib, imatinib, erlotinib, and gefitinib. Unfortunately, most of these agents have shown no or very limited activity against meningiomas and cannot be recommended for clinical use. Compounds with antiangiogenic properties, i.e., bevacizumab, sunitinib, and vatalinib have shown potential efficacy in uncontrolled studies and should be investigated further, ideally in randomized clinical trials. Emerging clinical studies will evaluate novel medical treatment approaches including the tetra-hydroisoquinoline alkaloid trabectedin (European Organisation for Research and Treatment of Cancer (EORTC) phase II trial 1320) and SMO or AKT inhibitors in molecularly selected cases. [ABSTRACT FROM AUTHOR]

The potential for synergistic interactions between anticancer drugs has been used to justify combinations of agents in clinical trials. However, most combinations of targeted agents and chemotherapies have been tested in the clinic without previous systematic evaluation of their potential benefit. Preclinical studies may help in the identification of synergistic or antagonistic interactions. For antineoplastic therapies, these studies may reveal synergy or antagonism of the drug combinations. Synergy occurs when two agents given together produce higher antitumoral activity than the sum of each individual drug. This represents the ideal setting for the development of combinations of targeted agents and chemotherapies. On the other side, certain drug combinations have shown adverse results, indicative of an antagonistic effect. In this article, we review the preclinical molecular bases that justify approved combinations of targeted agents with chemotherapy including examples of synergistic and antagonistic combinations. We also discuss scenarios for rational associations of targeted agents based on biological data and propose strategies that may improve the success of combinations of anticancer agents. [ABSTRACT FROM AUTHOR]

Introduction: Renal cell carcinoma is counted among the most resistant tumors to chemotherapy and radiotherapy, respectively. However, therapeutic options expanded since the introduction of molecular agents, targeting specific pathways such as the vascular endothelial growth factor (VEGF)-α, the VEGF receptor (VEGFR), or the mammalian target of rapamycin (mTOR) pathway. These new agents almost doubled the time to tumor progression and in some trials even improved overall survival. Against this background, the role of local treatment strategies in metastasized or inoperable primary renal cell carcinoma has to be redefined. With the onset of new technical developments in radiotherapy and the possibility to precisely deliver higher doses per fraction, encouraging response and control rates have been reported for kidney cancer, supporting a possible role for irradiation in this setting. This overview summarizes the preclinical data and clinical experiences of modern radiotherapy with focus on possible synergies and toxicities when combined with molecular targeted agents. Methods: The available literature on preclinical and clinical data comprising prospective trials, retrospective analyses and case reports was reviewed. Conclusion: With the recent developments in stereotactic and image-guided radiotherapy, encouraging data concerning local control in the treatment for metastasized renal cell carcinoma have been generated and are therefore recommended whenever possible. It seems that with these high- precision irradiation schedules, the combination with targeted agents is feasible with no increase in severe adverse events. Nevertheless, the addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case. [ABSTRACT FROM AUTHOR]

Breast cancer has become curable for the majority of women in Western Europe and North America. Advances have been made in imaging diagnostics as well as the implementation of nationwide screening programmes. Nowadays, we talk about prevention as well as treatment. Pathology has moved from pure morphology (tumour type, grade and stage) to biological characterisation of the tumour. Treatment has changed considerably through a better understanding of the disease; from a local disease predominated by extensive and mutilating surgical techniques to a point where breast cancer has come into its own as a systemic disease with equal “rights” to local as well as systemic treatment. This paradigm shift has led to a multidisciplinary approach of the understanding and treatment of breast cancer. Molecular classification has changed the understanding of breast cancer and will be the basis for an even more individualised treatment. New (biological) agents will help to further tailor treatment to response or resistance. While systemic treatment has been increased in number and duration surgical/local strategies have been reduced to minimum. Evidence-based medicine has helped to improve and standardise treatment of breast cancer. This review summarises the 10th Biedenkopf meeting that was held to review the advances in breast cancer understanding and treatment. [ABSTRACT FROM AUTHOR]

The National Cancer Institute of the United States defines personalized medicine (PM) as 'a form of medicine that uses information about a person's genes, proteins and environment to prevent, diagnose and treat disease' (National Cancer Institute, Dictionary of Cancer Terms) []. Consequently, the ultimate dream is the generation of a 'molecular fingerprint' via a simple blood test or tumor sample that allows the physician to refine an individual patient's prognosis, select the best possible therapeutic option, and minimize the toxicity from therapies by identification of distinct genetic markers. The enormous gains to patients and ultimately health care systems are unmistakable. [ABSTRACT FROM AUTHOR]

Despite many recent advances in the treatment of metastatic colorectal cancer (mCRC) and corresponding improvements in patient survival, most of the pivotal trials have involved fit, young patients. Consequently, it is unclear whether efficacy and safety profiles from these large randomized trials are applicable to patients older than 70 years of age, who account for more than half of those with mCRC. Most of the conclusions regarding chemotherapy for elderly mCRC patients are derived from combined or subgroup analyses from large studies in which elderly patients are typically defined as those more than 65 or 70 years of age. In general, it was concluded that, as with young patients, systemic chemotherapy could be beneficial for these elderly patients also, with tolerable adverse events. Nonetheless, it was subsequently determined that serious adverse events occurred more frequently in elderly patients and that immediate intensive chemotherapy did not always result in better overall survival for this group. In patients scheduled for capecitabine, previous estimation of renal function and careful administration of the drug are necessary; however, contrary to expectations, the quality of life is not better than that achieved with 5-fluorouracil. Another therapeutic option is immediate doublet chemotherapy, but for elderly patients, a stop-and-go strategy or chemotherapy-free intervals should be considered. Targeted agents, including bevacizumab, cetuximab, and panitumumab, have resulted in outcomes no inferior for older than for younger patients, but they require further investigation to optimize their use. The variable findings obtained for elderly patients emphasize the need for a definition of 'elderly' that takes into account not only chronological age, but also physiological age, socioeconomic status, and the results of objective tools such as comprehensive geriatric assessment. [ABSTRACT FROM AUTHOR]

Despite a decrease in incidence and mortality, colorectal cancer (CRC) still represents the second leading cause of cancer worldwide. Recurrence following surgery and adjuvant treatment and the metastatic disease are still a major problem with a median overall survival of approximately 24 months. Nevertheless, there has been an improvement in outcome due to the introduction into clinical practice of new cytotoxic and targeted agents. The targeted agents that have improved the efficacy of the available chemotherapeutic regimens in CRC are the ones that target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). In particular, bevacizumab, a recombinant humanized monoclonal antibody against VEGF, cetuximab, and panitumumab, two monoclonal antibodies that target the EGFR, have been approved for the treatment of metastatic CRC (mCRC). While for anti-EGFR agents, predictive biomarkers have been found, no good biomarkers have been found yet for anti-VEGF agents. Aflibercept and regorafenib have recently also been approved in patients with mCRC. This article reviews in an extensive way the data of large randomized clinical trials for the use of anti-VEGF and anti-EGFR in CRC. Aim of this review is also to describe the current status of biomarkers discovery and highlight how to improve the therapeutic index of these targeted agents by selecting in advance the subgroup of patients who will benefit from these treatments. [ABSTRACT FROM AUTHOR]

Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) refers to a heterogeneous group of tumors that do not express the estrogen/progesterone-receptor (ER/PR), and human epidermal growth factor receptor-2 (HER2). TNBC is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapy regimens. There have been significant improvements in the outcome of other subtypes of breast cancer, including ER-positive/HER2 overexpressed tumors, attributed to the addition of targeted therapy, including hormonal agents and trastuzumab. However, no specific targeted agents are currently available for the treatment of TNBC. This review aims to collate and describe the most recent data on targeted therapies that have demonstrated efficacy in the management of metastatic TNBC. Targeted agents that have been investigated in the treatment of metastatic TNBC include inhibitors of poly(ADP-ribose) polymerase, angiogenesis, mammalian target of rapamycin, epidermal growth factor receptor, HDAC, Jak2, and Src. Several of these agents have shown considerable promise. [ABSTRACT FROM AUTHOR]

Despite contemporary innovations in systemic therapy and surgical treatment, renal cell carcinoma (RCC) remains the most lethal urologic malignancy. Still, around 20 % of patients with RCC present with metastases at diagnosis, and 40-50 % of those with localized advanced disease will ultimately progress to metastatic disease. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Searches were carried out in the PubMed database and the Cochrane Library of Controlled Clinical Trials. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy. In multivariate analysis, independent predictive factors included male gender, disease-free interval > 1 year, single metastatic site and complete metastasectomy. Other reports from selected patient materials show 29-31 % 5-year overall survival rates. In patients with recurrent disease after resection of a lung metastasis, 60 % were able to undergo a subsequent resection, compared with 25 % with recurrent bone metastasis. Also, metastasectomy after initial systemic therapy gave partial or complete response in a majority of patients. In these patients, the median survival was 4.7 years and 21 % remained free of disease at last follow-up. Patients with metastatic renal cell carcinoma should be considered for multimodal therapy, including surgery of metastatic lesions. A proportion of patients will achieve long-term survival with aggressive surgical resection. [ABSTRACT FROM AUTHOR]

For drugs such as anticancer agents every effort should be made to minimize inter-patient variability in drug exposure in order to maximize the benefit while maintaining an acceptable risk level of serious adverse effects. Anticancer drugs generally have a preferential route of elimination, either in urine or in bile and feces. In consequence, dose individualization to renal and liver function permits excessive toxicity to be avoided and expected therapeutic benefit to be achieved. However, less is known about the most appropriate starting doses of antineoplastic agents in these individuals. In this review, we discuss trials that have specifically assessed new targeted agents dosing strategies (mainly monoclonal antibodies and tyrosine kinase inhibitors) in the setting of overt biochemical renal and liver dysfunction and we proportionate recommendations and practical guidelines for dose individualization. [ABSTRACT FROM AUTHOR]

Neuroendocrine carcinomas are rare neoplasms although of increasing incidence and concern. While traditionally considered of indolent nature, once they progress beyond surgical resectability, the outcome is ultimately fatal for the majority of patients. Somatostatin analogs are useful to control symptoms in functioning tumors and may slow tumor progression in certain disease settings, but sensitivity to conventional cytotoxic chemotherapy is rather limited. In this context, results of the recently published randomized trials with sunitinib and everolimus have demonstrated for the first time that there are agents able to positively impact on the natural history of this complex disease. In this review, we will discuss available data on angiogenesis and mammalian target of rapamycin inhibitors for the treatment of advanced well-differentiated gastroenteropancreatic neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, and research advances over the past 20 years have allowed us to better understand the molecular mechanisms underlying both tumorigenesis and resistance to therapy. As a result, there are a wide range of novel agents currently under development that we anticipate will enter the clinical arena within the coming years. This review seeks to discuss a spectrum of key pathways and agents that may be particularly relevant to the treatment of CRC in the near future, as well as briefly discuss some of the challenges we face in this new era of drug discovery. [ABSTRACT FROM AUTHOR]

Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment. [ABSTRACT FROM AUTHOR]

This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged. [ABSTRACT FROM AUTHOR]

Patients with metastatic colorectal cancer (mCRC) who progress despite treatment with fluoropyrimidine and irinotecan or oxaliplatin have diminished survival, but they may derive clinically meaningful benefit from second-line or later chemotherapy. Literature from 2000 through mid-2008 on the treatment of patients with unresectable mCRC was reviewed to identify options for chemotherapy-resistant patients with mCRC. A recurring finding is that overall survival increases when patients are exposed to all available active agents throughout their course of care, independent of the line of treatment in which medication is delivered. Sequential administration of agents, including irinotecan, oxaliplatin, bevacizumab, and cetuximab, or, alternatively, deferred administration of various medications in combination, have shown promising efficacy that is at least equivalent to established combination regimens with the same agents. Palliative chemotherapy clearly improves survival in patients with unresectable mCRC, with overall survival recently reaching 28 months. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) caused over 500 000 deaths worldwide in 2002. Recent advances in the treatment of advanced disease include the incorporation of two new cytotoxic agents, irinotecan and oxaliplatin, into first-line regimens. The concept of planned sequential therapy involving three active agents during the course of a patient's treatment is evolving. Coupled with the integrated use of targeted monoclonal antibodies, we can now expect overall survival rates for advanced disease to exceed 20 months. This review considers current treatments and suggests where future progress may occur. [ABSTRACT FROM AUTHOR]

Upper gastrointestinal malignancies are major causes of morbidity and mortality worldwide. Despite the results of recent clinical trials with new chemotherapy strategies showing encouraging activity and efficacy, the prognosis of patients with advanced gastric, gastroesophageal junction and esophageal cancer remains poor. The demonstration in other tumor types of the effectiveness of anticancer drugs with a targeted mechanism of action, interfering with pathways involved in tumor growth and spread, has opened a new era in drug development. In patients with advanced colorectal cancer, the introduction of epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents has resulted in a significant increase in antitumor activity and survival. These targeted agents are currently being also evaluated in other tumor types including these upper gastrointestinal malignancies. These targeted agents include, among others, EGFR inhibitors, antiangiogenic agents, cell-cycle inhibitors, apoptosis promoters, and matrix metalloproteinase (MMP) inhibitors. The emerging data from the clinical development of these compounds provide novel opportunities in the treatment of these common malignancies that will probably translate into clinical benefit for patients with these diseases. This review describes the preclinical rationale and the current status of the clinical development of these compounds in patients with gastroesophageal neoplasms. [ABSTRACT FROM AUTHOR]

Opinion Statement: In the past, the standard of care for treatment of BM was whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and surgery. There has been a greater role for medical therapies in the last two decades due to the discovery of driver mutations and corresponding targeted therapies. These innovations have dramatically altered the approach to treating these patients. Some of the important mutations include epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in small cell lung cancer, human epidermal growth factor receptor (HER2) mutation in breast cancer, and BRAF mutation in melanoma. Disease-specific graded prognostic assessments have identified prognostic factors for each of the major tumor types associated with BM. These reflect the increased treatment sensitivity of these tumors to specific agents. Furthermore, there is a difference in the genetic makeup of BM compared to their primary tumor. Genomic studies of BM patients comparing somatic point mutations and copy number variations with their primary tumor have demonstrated that while both the primary tumor and BM share a number of common mutations, BM can often develop distinct mutations. Therefore, there is a need to individualize systemic therapies in BM. Several organizations including the Food and Drug Administration and the American Society of Clinical Oncology now emphasize the inclusion of BM patients in various phases of clinical drug development. [ABSTRACT FROM AUTHOR]

Cervical cancer constitutes a leading cause of morbidity and cancer deaths in women throughout the world. Approximately two thirds of the patients are diagnosed with locally advanced cervical cancer, showing disappointing survival rates despite correct multidisciplinary management. Metastatic disease implies a poor prognosis itself since diagnosis. Platinum-based chemotherapy has been the backbone treatment of metastatic cervical cancer for years with no major outstanding improvements on survival. The addition of new molecules, such as antiangiogenic agents, dramatically changed the treatment of this disease. Bevacizumab, an antiangiogenic agent that targets vascular endothelial growth factor 2 (VEGF-2), added to standard chemotherapy in cervical cancer showed significant improvement on survival; therefore, the combination of carboplatin, paclitaxel, and bevacizumab is currently the standard frontline treatment in cervical cancer. Other antiangiogenic agents have been tested in this disease with no further development nor approvals. New compounds are currently being under development with promising results in this disease as well as a number of new strategies that could potentially fulfill the unmet need of establishing effective therapeutic approaches in cervical cancer. [ABSTRACT FROM AUTHOR]