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  • Report from Session VII of the Second International Colloquium on Cardio-oncology: Helping the cardio-oncologist: from real life to guidelines
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-20
    Saro H. Armenian, Wojciech Jurczak, Joseph R. Carver, Alessandra Gennari, Giorgio Minotti, Michael S. Ewer

    Guidelines for the diagnosis, management, and surveillance of cancer patients have evolved with the single goal of improving patient care based on available data when available, or in the absence of firm data, on the standard practices of those with broad experience in actual hands-on patient care. Two initiatives intended to disseminate information to cardio-oncologists, were discussed in this session: the first, from the American Society of Clinical Oncology was focused on available data and the confidence level of that data; the second, from The European Society of Cardiology was a position paper. Interestingly, notwithstanding the somewhat different focus, there is considerable agreement between these two initiatives. Nevertheless, guidelines my not be applicable to all afflicted patients, and may raise questions as to when deviations from published standards should be considered. Such deviations may result in allegations of failure to meet standards of care or legal liability.

    更新日期:2019-11-21
  • Report from Session IV of the Second International Colloquium on Cardio-oncology: Treatment specific toxicities: Hormones, antihormones, radiation therapy
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-19
    Chris Plummer, Richard M. Steingart, Wojcech Jurczak, Zaza Iakobishvili, Alex R. Lyon, John P. Plastaras, Giorgio Minotti

    Session IV of the Second International Colloquium on Cardio-Oncology held in Kraków, focused on the cardiovascular risks of using hormone replacement therapy in breast cancer and androgen deprivation therapy in prostate cancer and continued the theme from Session 3 with a discussion of risk reduction strategies. The discussion then moved to an overview of modern radiation therapy and evolving mechanisms of cardioprotection. The risks and late cardiotoxic effects that must be considered in patients treated prior to the “modern era” were enumerated stressing the importance of long term follow-up of this population.

    更新日期:2019-11-19
  • Report from Session III of the Second International Colloquium on Cardio-oncology: Cardio-oncological management of patients
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-19
    Daniela M. Cardinale, Ana Barac, Adam Torbicki, Bijoy K. Khandheria, Daniel Lenihan, Giorgio Minotti

    Session III of the Second International Colloquium on Cardio-Oncology focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs. With a large menu of biomarker and imaging modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. It has become increasingly clear that early diagnosis and intervention leads to less late cardiotoxicity and fewer cardiac-related events. This can be accomplished by taking a thorough history and performing a goal directed physical examination coupled with use of biomarkers and imaging studies. This session attempted to provide rationale for a current and integrated approach to these issues.

    更新日期:2019-11-19
  • Report from Session VI of the Second International Colloquium on Cardio-oncology: Cardiovascular events in cancer survivors
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-19
    Emily Howard, Richard M. Steingart, Gregory T. Armstrong, Alexander R. Lyon, Saro H. Armenian, Laura Cicconi, Francesco Lo Coco

    Malignant disease and its treatment carry huge burdens for patients. Some are immediate, in that the disease itself presents as a life threatening event, or the treatment may result in immediate and devastating toxicity. More often the treatment of cancer is associated with more subtle or late events, yet these may impact the quality of life for cancer survivors in a variety of ways. In addition to the physical sequelae of cancer or its treatment, cancer survivors often experience consequences in the form of social or mental incapacity. Session III of this Colloquium on Cardio-Oncology focuses on some of these concerns, both from the perspective of health care providers who strive to minimize the burdens, but also from the viewpoint of the patient him or herself who must deal with the price that must often be paid for increased survival or cure.

    更新日期:2019-11-19
  • Technological evolution of radiation treatment: Implications for clinical applications
    Semin. Oncol. (IF 3.606) Pub Date : 2019-07-30
    Roberto Pacelli, Mara Caroprese, Giuseppe Palma, Caterina Oliviero, Stefania Clemente, Laura Cella, Manuel Conson

    The contemporary approach to the management of a cancer patient requires an “ab initio” involvement of different medical domains in order to correctly design an individual patient's pathway toward cure. With new therapeutic tools in every medical field developing faster than ever before the patient care outcomes can be achieved if all surgical, drug, and radiation options are considered in the design of the appropriate therapeutic strategy for a given patient. Radiation therapy (RT) is a clinical discipline in which experts from different fields continuously interact in order to manage the multistep process of the radiation treatment. RT is found to be an appropriate intervention for diverse indications in about 50% of cancer patients during the course of their disease. Technologies are essential in dealing with the complexity of RT treatments and for driving the increasingly sophisticated RT approaches becoming available for the treatment of Cancer. High conformal techniques, namely intensity modulated or volumetric modulated arc techniques, ablative techniques (Stereotactic Radiotherapy and Stereotactic Radiosurgery), particle therapy (proton or carbon ion therapy) allow for success in treating irregularly shaped or critically located targets and for the sharpness of the dose fall-off outside the target. The advanced on-board imaging, including real-time position management systems, makes possible image-guided radiation treatment that results in substantial margin reduction and, in select cases, implementation of an adaptive approach. The therapeutic gains of modern RT are also due in part to the enhanced anticancer activity obtained by coadministering RT with chemotherapy, targeted molecules, and currently immune checkpoints inhibitors. These main clinically relevant steps forward in Radiation Oncology represent a change of gear in the field that may have a profound impact on the management of cancer patients.

    更新日期:2019-11-18
  • PET/CT in radiation oncology
    Semin. Oncol. (IF 3.606) Pub Date : 2019-07-26
    Rosa Fonti, Manuel Conson, Silvana Del Vecchio

    The progressive integration of positron emission tomography/computed tomography (PET/CT) imaging in radiation therapy has its rationale in the biological intertumoral and intratumoral heterogeneity of malignant lesions that require the individual adjustment of radiation dose to obtain an effective local tumor control in cancer patients. PET/CT provides information on the biological features of tumor lesions such as metabolism, hypoxia, and proliferation that can identify radioresistant regions and be exploited to optimize treatment plans. Here, we provide an overview of the basic principles of PET-based target volume selection and definition using 18F-fluorodeoxyglucose (18F-FDG) and then we focus on the emerging strategies of dose painting and adaptive radiotherapy using different tracers. Previous studies provided consistent evidence that integration of 18F-FDG PET/CT in radiotherapy planning improves delineation of target volumes and reduces the uncertainties and variabilities of anatomical delineation of tumor sites. PET-based dose painting and adaptive radiotherapy are feasible strategies although their clinical implementation is highly demanding and requires strong technical, computational, and logistic efforts. Further prospective clinical trials evaluating local tumor control, survival, and toxicity of these emerging strategies will promote the full integration of PET/CT in radiation oncology.

    更新日期:2019-11-18
  • Modern radiotherapy for head and neck cancer
    Semin. Oncol. (IF 3.606) Pub Date : 2019-07-26
    Daniela Alterio, Giulia Marvaso, Annamaria Ferrari, Stefania Volpe, Roberto Orecchia, Barbara Alicja Jereczek-Fossa

    Radiation therapy (RT) plays a key role in curative-intent treatments for head and neck cancers. Its use is indicated as a sole therapy in early stage tumors or in combination with surgery or concurrent chemotherapy in advanced stages. Recent technologic advances have resulted in both improved oncologic results and expansion of the indications for RT in clinical practice. Despite this, RT administered to the head and neck region is still burdened by a high rate of acute and late side effects. Moreover, about 50% of patients with high-risk disease experience loco-regional recurrence within 3 years of follow-up. Therefore, in recent decades, efforts have been dedicated to optimize the cost/benefit ratio of RT in this subset of patients. The aim of the present review was to highlight modern concepts of RT for head and neck cancers considering both the technological advances that have been achieved and recent knowledge that has informed the biological interaction between radiation and both tumor and healthy tissues.

    更新日期:2019-11-18
  • Ionizing radiation effects on the tumor microenvironment
    Semin. Oncol. (IF 3.606) Pub Date : 2019-07-30
    Luigi Portella, Stefania Scala

    The broad use of radiotherapy (RT) in the management of solid human tumors is based on its ability to damage cellular macromolecules, particularly the DNA, effectively inducing growth arrest and cell death locally in irradiated tumor cells. However, bystander effects, such as the transmission of lethal signals between cells via gap junctions or the production of diffusible cytotoxic mediators, can also contribute to the local antineoplastic action of RT. Traditionally, RT has been considered to exert immunosuppressive effects on the host. This idea largely stems from the radiosensitivity of quiescent lymphocytes and on the use of total body irradiation as part of myeloablative conditioning regimens preceding hematopoietic stem cell transplantation. Additionally, the occurrence of the so-called “abscopal effect,” where nonirradiated distant lesions display effects of RT response, suggests that RT may also induce tumor immunization. Several RT-induced effects on cancer, immune and stromal cells, contribute to the abscopal effect: (1) induction of “immunogenic cell death”, with release of tumor-associated antigens, (2) alterations of cancer cell immunophenotype, and (3) modulation of the tumor microenvironment. Damage and death of cancer cells leads to the surface exposure of immunogenic molecules as well as the release of damage associated molecular patterns such as adenosine triphosphate or High-Mobility-Group-Protein B1, and potentially tumor antigens that activate the innate and adaptive immune systems. Moreover, nuclear release and cytoplasmic sensing of altered nucleic acids via cyclic GMP-AMP Synthase/Stimulator of Interferon Genes is connected to the secretion of cytokines that support innate and adaptive antitumor immunity. As a result of the above, irradiated tumor cells may potentially act as an “in situ vaccine.”

    更新日期:2019-11-18
  • Healthcare professionals’ attitudes toward cancer precision medicine: A systematic review
    Semin. Oncol. (IF 3.606) Pub Date : 2019-06-10
    J. Vetsch, C.E. Wakefield, P. Techakesari, M. Warby, D.S. Ziegler, T.A. O'Brien, C. Drinkwater, N. Neeman, K. Tucker

    Use of precision medicine in oncology is burgeoning and can provide patients with new treatment options. However, it is not clear how precision medicine is impacting healthcare professionals (HCPs), particularly with regards to their concerns about this new approach. We therefore synthesized the existing literature on HCPs’ attitudes toward cancer precision medicine. We searched four databases for relevant articles. Two reviewers screened eligible articles and extracted data. We assessed the quality of each article using the QualSyst tool. We found 22 articles, representing 4,321 HCPs (63.7% cancer specialists). HCPs held largely positive attitudes toward cancer precision medicine, including their capacity to facilitate treatment decisions and provide prognostic information. However, they also had concerns regarding costs, insurance coverage, limited HCP knowledge about precision medicine, potential misuse, difficulties accessing the tests, and delays in receiving test results. Most HCPs felt that test-related decisions should be shared between families and HCPs. HCPs intended to disclose actionable results but were less inclined to disclose negative/secondary findings. HCPs had a strong preference for genetic counselor involvement when disclosing germline findings. Most HCPs intended to use somatic and germline tests in their future practice but the extent to which pharmacogenomic tests will be used is uncertain. HCPs indicated that additional evidence supporting test utility and increased availability of treatment guidelines could facilitate the use of testing. HCPs held generally positive attitudes toward cancer precision medicine, however there were some key concerns. Addressing concerns early, devising educational support for HCPs and developing guidelines may facilitate the successful implementation of precision medicine trials in the future.

    更新日期:2019-11-18
  • Report from Session V of the Second International Colloquium on Cardio-oncology: Cardio-oncology in clinical studies and real life
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-18
    Susan F. Dent, Thomas M. Suter, Teresa López-Fernández, Grzegorz Opolski, Pierantonio Menna, Giorgio Minotti

    Session V of the Colloquium was chaired by Professors Teresa López-Fernández of Spain and Grzegorz Opolski of Poland. The 3 speakers addressed cardio-oncology issues as they relate to both clinical studies and real life situations. Professor Susan Dent discussed cardio-oncology network for patients, emphasizing the importance of establishing a framework where the expertise of the cardiology consultant can supplement and reinforce the goals of optimal cancer therapy. Professor Thomas Suter moved the discussion further, sharing his insight into cardiac monitoring in clinical trials emphasizing the lack of uniform criteria and lack of consensus regarding reversibility of cardiac events and long-term implications of modest declines in systolic function frequently found in clinical trials for which long-term follow-up may not be a component of the trial. Professor Giorgio Minotti added important considerations to the discussion of clinical trials. He emphasized that the usual reporting of cardiac systolic function omits important diastolic dysfunction data generated but often ignored during the routine cardiac exams. The inclusion of cardiac biomarker changes would also help to broaden the perspective of cardiac effects and events seen in patients enrolled in clinical trials.

    更新日期:2019-11-18
  • A novel approach to assess real-world efficacy of cancer therapy in metastatic prostate cancer. Analysis of national data on Veterans treated with abiraterone and enzalutamide
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-16
    Harshraj Leuva, Keith Sigel, Mengxi Zhou, Julia Wilkerson, David H. Aggen, Yeun-Hee Anna Park, Christopher B. Anderson, Ta-Chueh Melody Hsu, Erik Langhoff, Glen McWilliams, Charles G. Drake, Richard Simon, Susan E. Bates, Tito Fojo

    Background: With 1.3 million new cases in 2018 worldwide, prostate cancer remains a challenge. Development of novel therapies targeting the androgen pathway followed recognition of the continued importance of androgens in castrate-resistant prostate cancer. To assess abiraterone and enzalutamide efficacy we analyzed data from US Veterans Administration Medical Centers (VAMCs). Methods: We used a novel method independent of assessment intervals and ideal for real-world analysis to estimate rates of tumor growth (g) and regression (d). Findings: Using the VA Informatics and Computing Infrastructure, we collected data from 5,116 Veterans with castrate-resistant prostate cancer prescribed abiraterone, enzalutamide or both. We estimated values for g and d and demonstrated a correlation of g with overall survival (P < .0001). Abiraterone and enzalutamide slowed growth rates across age groups and across the entire VAMC system, although less so in Veterans previously treated with a taxane and those with Gleason grade group 5 tumors. Abiraterone and enzalutamide efficacy in first-line were comparable although abiraterone in first-line slowed growth rates significantly more in African Americans than in Caucasians; enzalutamide was a better salvage therapy. When abiraterone was first-line and g was low, switching to enzalutamide was associated with a faster g in 67%. Interpretation: In the real-world g can be estimated using a novel analysis method indifferent to assessment intervals that correlates highly with OS. While we show excellent real-world outcomes with abiraterone and enzalutamide, 2 effective and tolerable therapies, our results in VAMCs suggest enzalutamide should follow abiraterone. Changing therapies may be detrimental and consideration should be given to continue monitoring of growth rates over time. Funding Support from the Prostate Cancer Foundation and the Blavatnik Family Foundation.

    更新日期:2019-11-18
  • Report from session I the Second International Colloquium on Cardio-oncology, Krakow, Poland: Mechanisms and clinical course of cardiovascular toxicity of cancer treatment
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-11
    Edward TH Yeh, Michael S. Ewer, Javid Moslehi, Monika Dlugosz-Danecka, Jose Banchs, Hui-Ming Chang, Giorgio Minotti

    The opening session of Second International Colloquium on Cardio-Oncology addressed two areas of vital interest. The first reviewed new thoughts related to established agents. While anthracycline cardiotoxicity has been studied and reviewed extensively, ongoing research attempting to understand why it appears the mechanism(s) of toxicity differs from that of oncologic efficacy continue to evoke comment and intriguing speculation. Better understanding of the role of β-topoisomerase II in toxicity has advanced our understanding of the cascade of events that lead to heart failure. Additionally, the cardioprotective role of dexrazoxane fits well with our new understanding of how β-topoisomerase II works. Beyond the anthracyclines, new insight is providing us insight to better understand the impact on cardiac function seen with other agents including those targeting HER2 and several tyrosine-kinase inhibitors. Unlike the anthracyclines, these agents affect cardiac function in ways that are less direct, and therefore have different characteristics and should be thought of in alternate ways. This new knowledge regarding established agents furthers our understanding of the spectrum of cardiotoxicity and cardiac dysfunction in the cancer patient. The session also addressed cardiovascular toxicities of newer and established agents beyond myocardial dysfunction including effects on the vasculature. These agents can temporary or permanent changes that range from subclinical to life-threatening. The session ended with a discussion of the cardiac effects of immune checkpoint inhibitors. These agents can cause rare but sometimes fatal cardiac inflammation, for which long-term follow up may be required.

    更新日期:2019-11-11
  • Mechanisms and clinical course of cardiovascular toxicity of cancer treatment II. Hematology☆
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-11
    Massimo Breccia, Joseph R. Carver, Sebastian Szmit, Wojciech Jurczak, Emanuela Salvatorelli, Giorgio Minotti

    Session II of the Second International Colloquium on Cardio-Oncology (Kraków, May 2–4 2018), chaired by Dr Breccia (Rome, Italy) and Dr Jurczak (Krakòw, Poland), focused on mechanisms and clinical course of cardiovascular toxicity of cancer treatment. Whereas the venerable anthracyclines keep challenging patients and clinicians with risk of left ventricular dysfunction and heart failure, other newer drugs cause substantially different clinical phenotypes of cardiovascular toxicity. In particular, Session II not only focused on arterial thrombosis and venous thromboembolism, but also hypertension or cardiomyopathy or atrial fibrillation induced by many otherwise life-saving drugs. Dr Breccia (Rome, Italy) reviewed incidence, mechanisms, risk factors, and principles for prevention of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest, such as those used to treat chronic myeloid leukemia. Dr Carver (Philadelphia) reviewed the incidence, predisposing factors, and principles for proactive management of cardiovascular events in patients treated by conventional chemotherapy or new drugs for treatment of multiple myeloma. Dr Szmit (Warsaw, Poland) discussed on how coagulation disorders should be classified according to patient- or drug-related factors and how they should be diagnosed and treated in patients with solid or hematologic tumors. Dr Minotti (Rome. Italy) illustrated some potential pitfalls of accelerated drug development and approval and their possible impact on clinical incidence of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest. Session II therefore offered a broad perspective of the risk-benefit ratio of new drugs that are plagued with concerns about cardiovascular events.

    更新日期:2019-11-11
  • A systematic review on the emerging association between the occurrence of immune-related adverse events and clinical outcomes with checkpoint inhibitors in advanced cancer patients
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-07
    Alessio Cortellini, Sebastiano Buti, Veronica Agostinelli, Melissa Bersanelli

    The correlation between clinical outcomes and treatment-related adverse events (AEs) has always been a debated topic in clinical oncology. Despite toxicities pharmacodynamics effects, the misunderstanding has always been around the corner: AEs themselves could lead to morbidity and mortality; on the other hand, the choice of the clinical outcomes to measure is not univocal. After the advent of immune checkpoint inhibitors (ICIs), such as anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, new class-specific AEs have emerged, called immune-related AEs (irAEs). With irAEs, the correlation between toxicity and clinical outcomes has suddenly been suggested, but it is still to be proven. We conducted a systematic literature review regarding this emerging association, pointing out all the available data and speculating on the possible underlying mechanisms. Thirty-six studies were included in the analysis, involving different malignancies (mostly melanoma and lung cancer), with different measured clinical outcomes. The most of them were retrospective. Despite the high heterogeneity, and the enormous biases of the revised studies, we can assume that irAEs occurrence is linked to the therapeutic activity of immune checkpoint inhibitors, with a (certain) direct proportionality, maybe subtending the likelihood of an immunogenic phenotype. This phenomenon seems to occur with both anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, and across different solid malignancies.

    更新日期:2019-11-07
  • Baseline tumor size and survival outcomes in lung cancer patients treated with immune checkpoint inhibitors
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-06
    Ashley M. Hopkins, Ganessan Kichenadasse, Ross A. McKinnon, Andrew Rowland, Michael J. Sorich

    Background Baseline tumor size (BTS) was recently indicated as prognostic of overall survival (OS) in patients advanced melanoma treated with pembrolizumab. We review the association between BTS and OS/progression-free survival (PFS) in patients with a diagnosis of advanced non–small-cell lung cancer (NSCLC) treated with atezolizumab. Methods Data from 1,461 patients with a diagnosis of advanced NSCLC enrolled in the OAK, POPLAR, BIRCH, and FIR trials and treated with atezolizumab were pooled and analyzed. Using Cox proportional hazards regression, we modeled the association between baseline SLD and survival outcomes. Multivariable analyses were adjusted for pretreatment ECOG PS, age, sex, race, smoking status, histology, count of prior treatments, PDL1 expression, serum LDH levels, and the presence of liver, lung, or brain lesions. Results On univariable and multivariable analysis, baseline sum of the longest diameters of target lesions (SLD) was identified as significantly associated with OS (hazard ratio [95% confidence interval] per decimeter: 1.64 [1.41–1.91], P < .001) and PFS (1.21 [1.07–1.38], P = .003). Median OS were 16 months versus 10 months for baseline SLD < median, versus baseline SLD ≥ median, respectively. Median PFS were 4 months versus 3 months, respectively. Conclusions Large BTS was identified as an independent prognostic factor of worse OS and PFS, raising the need to evaluate atezolizumab as an earlier NSCLC treatment in future trials.

    更新日期:2019-11-07
  • Coley's immunotherapy revived: Innate immunity as a link in priming cancer cells for an attack by adaptive immunity
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-06
    Ondrej Uher, Veronika Caisova, Per Hansen, Jan Kopecky, Jindrich Chmelar, Zhengping Zhuang, Jan Zenka, Karel Pacak

    There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.

    更新日期:2019-11-07
  • Significance of TIM3 expression in cancer: From biology to the clinic
    Semin. Oncol. (IF 3.606) Pub Date : 2019-11-06
    Cinzia Solinas, Pushpamali De Silva, Dominique Bron, Karen Willard-Gallo, Dario Sangiolo

    Targeting inhibitory immune checkpoint molecules has dramatically changed treatment paradigms in medical oncology. Understanding the best strategies to unleash a pre-existing immune response or to induce an efficient immune response against tumors has emerged as a research priority. In this work, we focus on a novel target for cancer immunotherapy, the inhibitory receptor T-cell immunoglobulin and mucin domain 3 (TIM3). This narrative review describes TIM3 biology in different (tumor-infiltrating) immune cells, particularly in the immunosuppressive regulatory T cells and dysfunctional/exhausted cytotoxic T lymphocytes, but also in cells that confer innate immunity – natural killer and dendritic cells. We discuss the functional role of TIM3, its expressions and its clinical significance in a variety of tumors, and confront the heterogeneous results emerging from different studies, including clinical trials of immunotherapy. Finally, this work summarizes the principal early-phase clinical trials exploring TIM3 blockade and discusses some future perspectives.

    更新日期:2019-11-07
  • External validation of a prognostic model for mortality among patients with non–small-cell lung cancer using the veterans precision oncology data commons
    Semin. Oncol. (IF 3.606) Pub Date : 2019-10-30
    David Cheng, Jaime Ramos-Cejudo, David Tuck, Danne Elbers, Mary Brophy, Nhan Do, Nathanael Fillmore

    Background: There is wide interest in developing prognostic models in non–small-cell lung cancer (NSCLC) due to the heterogeneity of the disease. Models developed at other healthcare institutions may not be directly applicable for patients treated at the Department of Veterans Affairs (VA). External validation of a candidate prognostic model among VA patients would be crucial before it can be implemented to aid clinical decision-making. Methods: A prognostic model for mortality developed in the Military Health System (MHS) was applied to data from the VA Precision Oncology Data Repository (VA-PODR), which is available to researchers inside and outside the VA at the Veterans Precision Oncology Data Commons (VPODC). Measures of discrimination and calibration were calculated for the MHS model. The MHS model was also refitted in VA-PODR data using the same risk factors to compare the effect of specific factors and predictive performance when the model is developed using VA data. Results: Time-dependent AUC of the MHS prognostic model was 0.788, 0.806, 0.780, and 0.779 for predicting survival at 1, 2, 3, and 5 years following diagnosis, respectively. Significant discrepancies were found between predicted and observed rates of survival, particularly for later years. When the model is refit in VA-PODR data, it achieved cross-validated AUCs of 0.739, 0.773, 0.769, and 0.807 at the same time points, and discrepancies between predicted and observed survival were reduced. Conclusions: Validation of the MHS prognostic model in VA-PODR demonstrates that its discrimination remains strong when applied to VA patients. Nevertheless, further calibration to VA data may be needed to improve its risk estimation performance. This study highlights the utility of VA-PODR and the VPODC as a national resource for developing analytic tools that are welladapted to the Veteran population.

    更新日期:2019-11-01
  • Old and new directions of Cardio-Oncology.
    Semin. Oncol. (IF 3.606) Pub Date : null
    Michael S Ewer,Joseph R Carver,Giorgio Minotti

    更新日期:2019-11-01
  • Changes to recognize--oncology billing and administration.
    Semin. Oncol. (IF 3.606) Pub Date : 2009-04-30
    Tony Crisafulli

    更新日期:2019-11-01
  • Novel enhanced delivery taxanes: an update.
    Semin. Oncol. (IF 3.606) Pub Date : 2007-06-30
    Edith A Perez

    Taxanes are widely used for many solid tumors, including metastatic breast cancer. Enhanced-delivery taxanes (EDTs) were specifically designed to improve the efficacy and tolerability of taxanes through the utilization of biocompatible, tumor-selective, taxane delivery vehicles, removing the need for drug delivery in toxic, conventional solvents. Nab-paclitaxel is a first-generation EDT that consists of paclitaxel encapsulated in albumin-bound nanoparticles that utilize a standard, endogenous serum albumin pathway to deliver paclitaxel to tumor cells. Second-generation EDTs, including Tocosol Paclitaxel (Sonus Pharmaceuticals, Inc., Bothell, Washington) and paclitaxel poliglumex, use biocompatible drug delivery vehicles that not only eliminate the need for toxic conventional solvents but also exploit tumor pathophysiological phenomena such as enhanced permeability and retention. Emerging evidence suggests that the use of EDTs may promote a more favorable and predictable pharmacokinetic profile with increased bioavailability of taxanes at the tumor site, limiting their exposure to normal tissues and improving the therapeutic benefits associated with taxane treatment.

    更新日期:2019-11-01
  • Docetaxel in the treatment of esophageal cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    James R Rigas,Konstantin H Dragnev,Jeffrey A Bubis

    Esophageal cancer is the ninth most common malignancy in the world and the seventh leading cause of death in American men. Because symptoms are often intermittent and vague, patients typically present at an advanced stage, with limited survival. In operable patients, standard care includes surgery with or without adjuvant chemotherapy and radiotherapy; chemotherapy and radiotherapy is the standard care for inoperable disease. Docetaxel, a taxane that promotes polymerization of tubules and inhibits depolymerization of microtubules, has shown in vitro and in vivo antitumor effects on human gastric cell lines and gastric cancer xenografts. These antitumor effects have led to the evaluation of docetaxel as a single agent and in combination with other agents and modalities in patients with esophageal cancer. Results of relevant trials are reviewed herein.

    更新日期:2019-11-01
  • Experience with docetaxel in the treatment of gastric cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Philip A Philip

    Gastric cancer is the second most common cause of cancer death worldwide. In operable patients, standard care includes surgery with or without adjuvant chemotherapy and radiotherapy; standard care for inoperable disease includes chemotherapy with or without radiotherapy. Docetaxel has shown in vitro and in vivo antitumor effects on human gastric cell lines and gastric cancer xenografts. Phase I through III trials of docetaxel alone and in combination with other chemotherapy agents have subsequently been conducted. This review provides an overview of these studies and suggestions for future directions in the treatment of gastric cancer.

    更新日期:2019-11-01
  • Docetaxel in the management of advanced pancreatic cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Gilberto Lopes,Caio Max S Rocha Lima

    The poor outcome of pancreatic cancer with conventional treatment options emphasizes the need for continued research. The benefits of gemcitabine in improving quality of life and survival have been established in patients with advanced pancreatic cancer. Randomized clinical trials studying the addition of a second drug to gemcitabine, either a classic cytotoxic (5-fluorouracil, cisplatin, irinotecan, pemetrexed, oxaliplatin, or exatecan) or targeted agents (ie, the farnesyl transferase inhibitor R115777 or the metalloproteinase inhibitor marimastat) have not resulted in improvement in survival compared with gemcitabine alone. Although limited activity of docetaxel in patients with pancreatic adenocarcinoma has been reported in single-agent studies, attractive efficacy results have been documented with docetaxel in combination with other chemotherapeutic agents for the management of advanced pancreatic cancer. Phase I and II trials of docetaxel in combination with gemcitabine, irinotecan, 5-fluorouracil, or thalidomide, as well as trials of docetaxel and radiotherapy, suggest that docetaxel combinations in pancreatic cancer should be further studied in randomized trials.

    更新日期:2019-11-01
  • Preclinical experience with docetaxel in gastrointestinal cancers.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Tanios S Bekaii-Saab,Miguel A Villalona-Calero

    Docetaxel is a semisynthetic taxane that acts primarily by promoting microtubule assembly and preventing the depolymerization of assembled microtubules, thereby inducing mitotic block and inhibition of cell proliferation. This agent also induces apoptosis and appears to prevent angiogenesis. Although docetaxel has shown efficacy in a wide variety of tumors, it has only recently been evaluated in the treatment of gastrointestinal cancers. Data from preclinical studies have shown that docetaxel has substantial in vitro and in vivo activity against gastric, esophageal, and pancreatic tumors. The cytotoxic activity of docetaxel is generally time- and dose-dependent, and greater than that produced by other chemotherapeutic agents, including paclitaxel and anthracyclines. Studies evaluating combination regimens suggest that docetaxel has additive-to-synergistic antitumor activity against gastrointestinal cancers over that produced by the individual agents, and the increased antitumor activity appears to be schedule-dependent. These data suggest that docetaxel has promising therapeutic activity in the treatment of gastrointestinal cancers and provides a rationale for its inclusion in therapeutic protocols either as a single agent or in combination regimens. In addition to combination regimens with conventional chemotherapeutic agents, early studies with a number of novel molecularly targeted therapies in combination with docetaxel have shown encouraging results. These studies provide a basis for pursuing future clinical trials with docetaxel-based combinations of novel therapies for improving response rates in the treatment of gastrointestinal cancers.

    更新日期:2019-11-01
  • Southwest Oncology Group: two decades of experience in non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Andrew T Turrisi,John Crowley,Kathy Albain,Laurie Gaspar,David Gandara

    Over the past two decades, studies of the Southwest Oncology Group have consistently reported stable esophagitis rates despite changing scales with concurrent chest radiotherapy and cisplatin/etoposide regimens. Patient selection has perhaps contributed to increased survival over this period. The Southwest Oncology Group has incorporated surgical questions and advanced the field with a steady use of consistent therapies (ie, cisplatin/etoposide plus radiotherapy of 45 Gy [induction therapy] and cisplatin/etoposide plus at least 61 Gy) in potentially operable or unresectable disease. Further studies examining the addition of either docetaxel or novel agents to such regimens are underway.

    更新日期:2019-11-01
  • Combined modality trials in unresectable stage III non-small cell lung cancer: the Cancer and Leukemia Group B experience.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Mark A Socinski

    Lung cancer remains the leading cause of cancer-related mortality in the United States and 30% to 40% of newly diagnosed patients with non-small cell lung cancer present with regionally advanced and unresectable stage III disease. Combined-modality therapy is the current standard of care in patients with good performance status at the time of diagnosis and recent trials have suggested a survival advantage for the concurrent use of chemotherapy and thoracic radiation therapy at the risk of increased toxicity (mainly esophagitis and myelosuppression). The Cancer and Leukemia Group B has been instrumental in shaping the standard of care in the combined-modality approach to unresectable stage III non-small cell lung cancer. Currently, Cancer and Leukemia Group B is conducting trials evaluating novel thoracic radiation therapy strategies as well as the incorporation of molecularly targeted agents, yielding encouraging preliminary data. In addition, a change in the therapeutic platform is planned that explores a full-dose systemic approach with the antifolate pemetrexed that possesses radiosensitizing properties.

    更新日期:2019-11-01
  • A review of radiation dose escalation trials for non-small cell lung cancer within the Radiation Therapy Oncology Group.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Jeffrey Bradley

    Chemotherapy and radiation therapy (RT) is the therapy of choice for patients with locally advanced, inoperable non-small cell lung cancer (with an expected 4-year survival rate of 21% for radiation doses to 60 Gy given with concurrent chemotherapy in patients with good performance status and minimal weight loss, as established by Radiation Therapy Oncology Group (RTOG) 9410. While a minimal tumor dose of 60 Gy has been considered "standard" for the past 30 years, this dose is insufficient to control local disease. For patients receiving RT alone or radiation following induction chemotherapy, data from RTOG 9311 established that doses of 83.8 Gy using 3-dimensional conformal RT techniques were tolerable, with excess mortality observed at 90.3 Gy. When concurrent chemotherapy and 3-dimensional conformal RT are used, the maximum tolerated dose of radiation is reduced, and current indications suggest that the maximum tolerated dose in this setting is in the range of 70 to 74 Gy.

    更新日期:2019-11-01
  • An overview of Eastern Cooperative Oncology Group stage III non-small cell lung cancer studies.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    David S Ettinger

    The Eastern Cooperative Oncology Group conducts phase II and III trials for the treatment of resectable and unresectable stage III non-small cell lung cancer, and also participates in a number of Intergroup studies. For resectable disease, the Eastern Cooperative Oncology Group is participating in a phase III prospective randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor antagonist gefitinib (ZD1839), a phase II trial for superior sulcus tumors of induction chemoradiotherapy with cisplatin/etoposide followed by surgical resection, followed by docetaxel. For unresectable disease, a phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide is underway. Proposed studies include a feasibility phase II study of chemotherapy/hyperfractionated accelerated radiation therapy (HART) + cetuximab (an antibody specific for epidermal growth factor receptor) and a phase II trial of pharmcogenomics-directed adjuvant chemotherapy for completely resected non-small cell lung cancer.

    更新日期:2019-11-01
  • Amifostine in chemoradiation therapy for non-small cell lung cancer: review of experience and design of a phase II trial assessing subcutaneous and intravenous bolus administration.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Maria Werner-Wasik,Corey Langer,Benjamin Movsas

    Esophagitis is a major complication of chemoradiation therapy in patients with non-small cell lung cancer, producing significant morbidity and resulting in treatment interruptions. Amifostine at different doses and schedules has been found to reduce frequency or severity of esophagitis in this setting. In the Radiation Therapy Oncology Group 98-01 trial in non-small cell lung cancer patients receiving chemoradiation therapy, amifostine given intravenously four times weekly did not significantly reduce the frequency of grade 3 or 4 esophagitis; however, a significant reduction in severity over time was observed in patient swallowing diaries. The potential benefits of amifostine may have been obscured by inability to provide full amifostine doses due to toxicity associated with infusion, scheduling of doses, and inadequate follow-up to monitor severity of esophagitis over time. These issues are to be addressed in a randomized phase II trial of amifostine given subcutaneously or via intravenous bolus in non-small cell lung cancer patients undergoing chemoradiation treatment.

    更新日期:2019-11-01
  • Reduction of treatment breaks and radiation-induced esophagitis and pneumonitis using amifostine in unresectable non-small cell lung cancer patients receiving definitive concurrent chemotherapy and radiation therapy: a prospective community-based clinical trial.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Raymond B Wynn,Vivek Mehta

    Concurrent chemotherapy with daily thoracic radiation therapy is a common regimen used in patients with non-small cell lung cancer resulting in excellent response rates but with appreciable morbidity. Radiation-induced toxicities may increase the number of treatment breaks and then may limit the use of this aggressive treatment approach for some patients. We are conducting an open-label, multicenter trial determining the incidence of radiation treatment breaks and severity of treatment-related toxicities with the concurrent use of a cytoprotective agent. Approximately 15 to 20 sites in the United States will participate with a total of 200 patients. Patients will receive one of two chemotherapy regimens and daily radiation (1.8 to 2.0 Gy daily; total dose, 60 to 70 Gy) and amifostine 500 mg subcutaneously or intravenous push daily over a 6- to 7-week period. Patients will receive amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) 500 mg daily. The route of amifostine administration chosen at the time of patient registration must be adhered to throughout the study. In addition, all patients may receive consolidation chemotherapy consisting of intravenous docetaxel 75 mg/m 2 once every 3 weeks for three courses, starting more than 30 but less than 60 days after the last dose of amifostine or thoracic radiation therapy, whichever is the last therapy discontinued. The objectives of this study are to determine the incidence of radiation treatment breaks and evaluate acute radiation esophagitis, acute radiation pneumonitis, chronic radiation pneumonitis, and pulmonary function in patients with measurable, medically inoperable non-small cell lung cancer stage II, unresectable stage IIIA, or IIIB disease receiving combined modality therapy and amifostine.

    更新日期:2019-11-01
  • Mutagen sensitivity may predict lung protection by amifostine for patients with locally advanced non-small cell lung cancer treated by chemoradiotherapy.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Ritsuko Komaki,Joe Y Chang,Xifeng Wu,Pamela K Allen,Luka Milas,Zhongxing Liao,Frank V Fossella,Elizabeth Travis,Margaret R Spitz

    Amifostine (AMF) has been shown to protect some normal tissues from acute effects of radiation therapy +/- chemotherapy. We enrolled 62 patients in a randomized study investigating the efficacy of AMF: 31 had concurrent chemoradiation for non-small cell lung cancer and 31 had the same treatment + AMF. AMF reduced the frequency and severity of esophagitis, pneumonitis, and neutropenic fever. We have tried to identify patients who get more benefit from AMF by checking their DNA repair capability of normal cells. It was hypothesized that DNA repair capacity from patients' lymphocytes damaged by bleomycin could predict their normal tissue sensitivity to chemoradiation and could be protected by AMF. Forty-six of the 62 patients provided pretreatment blood for assessment of mutagen sensitivity (MS) using a peripheral lymphocyte assay that infers DNA repair capacity from cellular damage remaining after in vitro mutagenic exposure and recovery. Bleomycin-induced chromosome breaks in 50 metaphases were counted and expressed as the mean number of breaks per cell. Patients with an average of more than one break/cell were deemed to exhibit the MS phenotype. Data analysis used Pearson's chi-square and Kaplan-Meier survival function estimates with Strata 8.2 statistical software. The Log-rank test was used to assess the equality of survival function using a P value of .05. Twelve patients (10 AMF, 2 control) exhibited the MS phenotype. The remaining 34 patients (13 AMF, 21 control) were considered to have normal DNA repair. There were no significant differences in overall survival, disease specific survival, or local control by MS. Those with high MS had shorter distant metastasis-free survival compared with low MS patients ( P = .029). There were no differences in severe esophagitis or neutropenic fever by MS. Both high and low MS patients from the control group developed severe lung fibrosis compared with five of 21 who had AMF ( P = .025). The incidence of grade 3/4 lung fibrosis was two of 10 with AMF compared with two of two in the control group ( P = .025) with higher MS. Higher MS was associated with shorter distant metastasis-free survival and more frequent grade 3/4 lung fibrosis. AMF reduced the incidence of grade 3/4 lung fibrosis among higher MS. These data suggest that MS might help identify subgroups of patients who could receive more benefit from AMF with respect to lung damage.

    更新日期:2019-11-01
  • Mechanisms and potential targets for prevention and treatment of normal tissue injury after radiation therapy.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Mitchell S Anscher,Zeljko Vujaskovic

    The ability to optimize treatment for cancer based on individual risk assessment for normal tissue injury has important implications in oncology because more aggressive therapy may improve outcome in the treatment of advanced non-small cell lung cancer. To achieve this goal, a thorough understanding of the molecular mechanisms responsible for radiation-induced toxicity will be essential. Recent research has shown that ionizing radiation triggers a series of genetic and molecular events that may lead to chronic, persistent alterations in the microenvironment, producing an aberrant wound healing response. Disrupted epithelial-stromal cell communication may also contribute to impaired wound healing. As a result of an improved understanding of these fundamental biologic responses to radiation, new approaches to the treatment and prevention of normal tissue injury will focus on correcting these disturbed molecular processes. Herein, we will summarize recent developments in this field, with an emphasis on the lung.

    更新日期:2019-11-01
  • Non-small cell lung cancer treatment-related bone marrow toxicities.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    David S Ettinger

    A major consequence of administering increasingly aggressive therapies (chemotherapy with or without radiation therapy) in the treatment of non-small cell lung cancer is the adverse effects on the bone marrow that may lead to neutropenia, thrombocytopenia, and/or anemia. Myelosuppression or bone marrow toxicity may also lead to dose reduction of chemotherapy and/or treatment delays in both chemotherapy and radiation therapy, diminishing the efficacy of therapy in the curative setting. In this setting, the use of hematopoietic growth factors may thus be beneficial.

    更新日期:2019-11-01
  • Cardiac toxicity following thoracic radiation.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Robert G Prosnitz,Yu Husuan Chen,Lawrence B Marks

    While the data regarding radiotherapy (RT)-induced cardiovascular disease in lung cancer patients is limited, the cardiotoxic effects of RT have been thoroughly documented in long-term survivors of breast cancer and Hodgkin's disease. Herein we review data illustrating the cardiotoxic effects of thoracic RT in lung and breast cancer patients. Older RT techniques for treating the breast/chest wall and draining lymph nodes resulted in a relatively high dose being delivered to a substantial volume of heart, and convincing evidence exists of excess cardiovascular morbidity and mortality in patients treated with these techniques. While modern RT techniques have reduced radiation exposure to the heart, they have not eliminated it. In patients treated with modern techniques, there are conflicting data regarding the impact of radiation on late cardiovascular morbidity and mortality. Thus, it is prudent to reduce cardiac exposure as much as possible. Techniques to reduce further cardiac exposure (eg, respiratory gating, intensity modulated radiation therapy) are currently under investigation. Further work is needed to quantify the frequency and severity of cardiac injury and develop preventative methods.

    更新日期:2019-11-01
  • Potential role of growth factors in diminishing radiation therapy neural tissue injury.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Nicolaus H Andratschke,Carsten Nieder,Roger E Price,Belinda Rivera,K Kian Ang

    Human growth factors are firmly established in treatment of cytopenias that are associated with cancer chemotherapy, and have been used successfully to reduce severe mucositis in patients receiving radiation therapy and chemotherapy in the setting of autologous bone marrow transplantation. The ability of growth factors that are involved in differentiation and proliferation of neural tissue cells to prevent or accelerate recovery from radiation injury currently is being evaluated in preclinical studies. Data from these studies indicate that brief therapeutic intervention with platelet-derived growth factor, insulin-like growth factor-1, vascular endothelial growth factor, and the combination of insulin-like growth factor-1 and basic fibroblast growth factor can prevent or delay radiation myelopathy after spinal cord irradiation. Additional investigation is required to define potentially clinically useful growth factor regimens in the clinic.

    更新日期:2019-11-01
  • Treatment-related esophagitis.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Maria Werner-Wasik

    Current therapeutic approaches for lung cancer favor treatment intensification, with the presumption that dose-intense chemotherapy regimens and/or higher radiation therapy (RT) doses or novel fractionation schemes will result in increased patient survival. Also, the trend for non-operative therapy has favored concurrent over sequential regimens. The incidence of severe acute esophagitis in patients treated for lung cancer with standard (once daily) RT alone is 1.3%, and induction chemotherapy increases the risk of severe acute esophagitis slightly over that of standard RT alone. In contrast, a strong radiosensitizing effect of chemotherapy given concurrently with standard thoracic RT (chemoRT) is associated with an incidence of severe esophagitis of 14% to 49%. Acute esophagitis may be severe and disabling, and result in hospitalization, placement of a feeding tube in the stomach or intravenous feedings, and steady supportive care. Also, RT may need to be halted temporarily to allow for healing of the esophageal lining; treatment breaks in turn decrease survival of patients with unresectable lung cancer. Therefore, esophagitis as a dose-limiting toxicity of chemoRT may have a direct impact on tumor control and survival. Aggressive types of RT fractionation have also been associated with worsening esophagitis grades and duration. Moreover, it is commonly assumed in the radiation oncology clinic that the longer the length of the esophagus segment included in the RT field the higher the probability of esophageal toxicity, although differing opinions are commonly expressed. Recent advances in 3-dimensional conformal RT allow a unique chance to gain volumetric data pertaining to organ damage rather than rely on older estimates based on organ length (eg, esophagus) or portion (ie, lung, spinal cord). The Radiation Therapy Oncology Group (RTOG) conducted a large phase III, randomized study RTOG 98-01 examining chemoRT with or without the amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD), a cyto- and radioprotectant in locally advanced non-small cell lung cancer (n = 243). While amifostine did not significantly reduce severe esophagitis based on National Cancer Institute Common Toxicity Criteria and weekly physician dysphagia logs, swallowing dysfunction over time (based on patient diaries, the equivalent of Esophagitis Index) was significantly lower in the amifostine arm ( P = .03). Therefore, significant progress has been accomplished in our understanding of the basis of esophageal injury resulting from thoracic RT, and future effort may find other effective strategies to either minimize or eliminate esophagitis.

    更新日期:2019-11-01
  • Pulmonary toxicity associated with the treatment of non-small cell lung cancer and the effects of cytoprotective strategies.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Ramesh Gopal

    Concurrent chemoradiation regimens for the treatment of non-small cell lung cancer have resulted in improved treatment outcomes. However, they are also more toxic. Acute esophagitis and pneumonitis are experienced by a large number of treated patients. Cytoprotective agents are used to reduce treatment-related toxicity. The cytoprotectant amifostine has been shown to reduce some of the toxicity associated with concurrent chemoradiation. Clinical studies of its role in reducing esophagitis and radiation pneumonitis are discussed. Lung irradiation also leads to a reduction in lung diffusion capacity (DLCO). The magnitude of this reduction is related to the volume of lung irradiated as well as to the use and timing of chemotherapy. Concurrent chemoradiation regimens result in a larger reduction in DLCO than radiation alone. Small changes in DLCO can be detected with sensitive pulmonary function tests, but are subclinical. Larger reductions in DLCO correlate with significant clinical symptoms. Preliminary data show that amifostine can significantly decrease the treatment-related reduction in DLCO associated with concurrent chemoradiation (42% v 24%; P = .004). Additional studies are being designed to verify these results and to further define the evolving role of cytoprotection in cancer care.

    更新日期:2019-11-01
  • Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Feng-Ming Kong,Randall Ten Haken,Avraham Eisbruch,Theodore S Lawrence

    Successful treatment of non-small cell lung cancer requires adequate local and systemic disease control. Although it has been shown to have superior results, high-dose radiation therapy is not a current practice largely because of concerns of normal tissue toxicity. This article reviews and updates the possible mechanism of radiation-induced pneumonitis and fibrosis, their associations with dose intensity, and the role they may play in making treatment decisions. The commonly used clinical terminology and grading systems are summarized. Pneumonitis and fibrosis after 3-dimensional conformal high-dose radiation are reviewed, including recent updates from radiation dose escalation trials. Chemotherapy- and chemoradiation-related lung toxicities are also discussed. Individual susceptibility and potential predictive models are examined; dose and 3-dimensional dosimetric parameters are reviewed along with estimation of normal tissue complication probability and biologic predictive assays. Based on the risk levels of toxicity for each patient, future clinical trials may be designed to maximize individual therapeutic gain.

    更新日期:2019-11-01
  • Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Neal Ready

    Epidermal growth factor receptor 1 (EGFR 1 ) is a 170-kd glycoprotein that plays many roles in the growth of non-small cell lung cancer (NSCLC). There are four known receptors in the EGFR family. Binding of a ligand such as epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) causes EGFR to undergo a conformational change leading to autophosphorylation of EGFR and activation of the EGFR growth factor pathway. The protein products of the genes that are then expressed increase cell proliferation and angiogenesis and inhibit programmed cell death. EGFR is expressed in 40% to 80% of NSCLC. EGFR tyrosine kinase activity can be inhibited by antibody therapy, such as cetuximab, against the extracellular domain of EGFR or small-molecule therapy, such as gefitinib or erlotinib that blocks the adenosine triphosphate (ATP) binding site of the cytoplasmic domain. Both forms of EGFR inhibition have single-agent antitumor activity against previously treated NSCLC. Interestingly, EGFR expression does not correlate with response to EGFR inhibition therapy. Increased likelihood of responding to small-molecule therapy is associated with female gender, never smoking, adenocarcinoma, and acquired mutations of the EGFR ATP binding site in tumor cells. In previously treated NSCLC, the small-molecule erlotinib improved both quality of life and median survival as a single agent compared with best supportive care. Southwest Oncology Group 0023 is a large, phase III, randomized trial comparing concurrent chemoradiotherapy and consolidation docetaxel with or without maintenance small-molecule therapy with gefitinib. There is also strong preclinical evidence that EGFR inhibition is additive or synergistic with radiotherapy in NSCLC. In locally advanced head and neck cancer, the addition of cetuximab antibody therapy to radiation increased median survival from 28 to 54 months. Cancer and Leukemia Group B 30106 and a multi-institutional Australian phase I trial have shown that gefitinib can be added to concurrent chemoradiotherapy for stage III NSCLC without excessive toxicity. A phase I trial at the University of Chicago (Chicago, IL) has evaluated erlotinib with concurrent chemoradiotherapy in stage III NSCLC. Radiation Therapy Oncology Group 0324 is an on-going phase II trial studying cetuximab and concurrent chemoradiotherapy in stage III NSCLC.

    更新日期:2019-11-01
  • Are more aggressive therapies able to improve treatment of locally advanced non-small cell lung cancer: combined modality treatment?
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Minesh Mehta,Rafael Manon

    Non-small cell lung cancer continues to be a major oncologic problem, with approximately 3-month increase in median survival per decade since the 1970s. Thus, newer strategies are needed to improve outcomes in non-small cell lung cancer. New treatment strategies include optimizing and intensifying radiation therapy (RT) delivery, as well as improving systemic therapy with newly developed targeted agents. Three-dimensional treatment planning is a key technology for optimizing RT delivery. Additionally, improvements in radiation therapy will clearly require better target delineation and dose-intensification of RT. With newer, possibly less toxic agents such as the epidermal growth factor receptor inhibitors, RT and systemic therapy (with chemo- and/or targeted therapies) may be optimized in the concurrent setting, perhaps reserving more cytotoxic regimens either for the induction or maintenance settings.

    更新日期:2019-11-01
  • Chemotherapeutic issues in the management of unresectable stage III non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Mark A Socinski,Julian G Rosenman

    The standard of care in unresectable stage IIIA/B non-small cell lung cancer is combined-modality therapy using both chemotherapy and thoracic radiation therapy. Although there is general agreement on this principle, there remain many controversies regarding the optimal combined-modality approach in this patient population. Both induction and concurrent chemoradiotherapy strategies were initially tested, with both approaches improving survival in randomized phase III trials. Several trials have now been completed comparing sequential versus concurrent approaches. There appears to be a modest and consistent advantage to the concurrent approach at the risk of an increase in the rates of acute toxicities, particularly esophagitis and myelosuppression. The concurrent approach used in the phase III trials evaluating the question of sequence has been the use of full-dose systemic chemotherapy rather than a low-dose radio-enhancing strategy. These approaches are distinctly different, and one must recognize this difference when evaluating results from clinical trials. A number of clinical trials have established the use of both induction and consolidation chemotherapy; however, the optimal approach remains unclear. What is clear is that this population of patients needs aggressive therapy directed at achieving locoregional control as well as control of occult micrometastatic disease that is present in the majority of cases. As treatment strategies have become more aggressive, survival outcomes have improved, although the differences have been modest at best, and the risk of severe toxicity has increased. Future aggressive approaches must enhance both locoregional and distant control of occult disease, with acceptable rates of both acute and long-term toxicities.

    更新日期:2019-11-01
  • Does more aggressive therapy improve outcomes in the treatment of unresectable stage III non-small cell lung cancer?
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Julian G Rosenman,Mark A Socinski

    Concurrent chemotherapy combined with radiation therapy currently offers the best treatment strategy in stage IIIA/IIIB non-small cell lung cancer. However, inadequate radiation dose may be a contributing factor in the resultant lack of adequate control of local disease. Hypothetically, radiation doses that are higher than "standard" (eg, 60 Gy) might increase patient morbidity without improving cure rates, and data from a University of North Carolina phase I/II trial suggested that at least 74 Gy can be given safely to patients receiving cytotoxic chemotherapy, with a trend toward improved survival. Also, clinical data indicate that the cytoprotective agent amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can be used to reduce esophagitis (and possibly pneumonitis) in patients treated with conventional radiation doses. Finally, a phase III clinical trial is proposed to: (1) test the hypothesis that higher radiation doses lead to a survival advantage in non-small cell lung cancer patients; and (2) discern the value of amifostine as a cytoprotective agent in the high-radiation dose range.

    更新日期:2019-11-01
  • Pilot study of accelerated radiotherapy with concurrent chemotherapy for stage III non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Mitchell Machtay,Cathi Washam,Pamela Devine

    The purpose of this pilot study was to determine the safety and feasibility of accelerated fractionation (via concomitant boost) radiotherapy (XRT) with concurrent carboplatin/paclitaxel chemotherapy for locally advanced stage III non-small cell lung carcinoma. Radiotherapy consisted of 3-dimensional conformal techniques to 60 Gy continuous course, over 4 weeks, via 3-dimensional conformal techniques. Once-daily treatments were used; the large field (including gross tumor and selected regional nodes) was given a daily dose of 2.2 Gy (to 44 Gy), with a 0.8 Gy concomitant boost (field within a field) for an additional 16 Gy to the gross tumor volume. Weekly carboplatin at an area under the curve (AUC) of 2 plus paclitaxel 50 mg/m2 were given during XRT, followed by two cycles of systemic-dose carboplatin AUC 6, every 4 weeks plus paclitaxel 100 mg/m2 , 3 weeks out of 4, were planned. The nutritional supplement glutamine 10 mg 3 times per day was prescribed in an effort to decrease esophagitis. Before the early closure of this study, five patients were enrolled, of whom four were evaluable for toxicity/feasibility. No patient experienced grade 3+ acute nonhematologic toxicity during concurrent chemoradiotherapy. Hematologic toxicity was significant in the post-XRT consolidation phase, resulting in dose reduction and/or discontinuation in three of four patients. More notably, two patients experienced serious nonhematologic late toxicity. One patient developed a grade 4 tracheoesophageal fistula that probably contributed to her death 6 months after treatment, and one patient developed grade 3 pulmonary complications including severe oxygen-dependent radiation pneumonopathy. Three patients are alive without disease progression at 14, 20, and 21 months follow-up. Despite the use of 3-dimensional conformal technology, this regimen of concomitant boost accelerated hypofractionated XRT with concurrent and systemic chemotherapy was excessively toxic and not feasible. Extreme caution must be exercised in designing studies of XRT dose intensification with concurrent chemotherapy.

    更新日期:2019-11-01
  • A case against surgery for most IIIa non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Andrew T Turrisi

    Stage IIIa non-small cell lung cancer remains categorically a heterogeneous hodgepodge without clear prospective mandates for clinical care. Poor outcome ensues for patients with mediastinal node-positive cancer when treated with surgery alone, but we are unclear how to define subsets that might benefit from surgery. This article reviews significant trials of surgery and chemoradiotherapy, including those using induction chemotherapy for stage III patients. While many continue to believe that chemotherapy without RT may provide equivalent pathologic complete response and survival rates, there is very little apparent difference in survival between patients managed with surgery or those managed to a higher dose of radiotherapy with concurrent chemotherapy (using an established chemotherapy regimen, 2-dimensional radiotherapy treatment planning, and a dose of only 61 Gy). If there is any benefit to surgery in the IIIa as currently staged, the benefit is very small and is counterbalanced by operative risk.

    更新日期:2019-11-01
  • Treatment of locally advanced non-small cell lung cancer: what we have and have not learned over the past decade.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-15
    Walter J Curran

    Over the past decade, clinical trials for good-performance status patients with unresectable stage III non-small cell lung cancer have shown that concurrent chemoradiation therapy (chemoRT) provides improved survival over sequential chemoradiation therapy. The available data suggest that induction chemotherapy preceding concurrent chemoRT does not further improve survival. Much remains to be learned about optimizing concurrent chemoRT in this setting, including identifying doses and schedules of chemotherapy that can maintain efficacy and reduce toxicity, as well determining optimal RT doses.

    更新日期:2019-11-01
  • New agents in the management of advanced mesothelioma.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Nicholas J Vogelzang,Camillo Porta,Luciano Mutti

    Malignant pleural mesothelioma (MPM) is a seemingly uncommon tumor whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual "epidemic" is expected in Europe over the next 20 years. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MPM patients remains dramatically poor (12 to 18 months' median survival from diagnosis), although exceptional cases of long-survivors are reported in all literature series. The current review will cover the dramatic improvements in the treatment of this rare disease that have been recently achieved, as well as the promise that new, molecular-targeted therapies, such as bortezomid, mTOR ( m ammalian t arget o f r apamycin) inhibitors, and Met inhibitors, seem to offer for the next few years. With pemetrexed we now have a drug that is able to impact patient survival. Together with the newer drugs, rapidly emerging from the laboratory to be applied in the clinic, we have the hope of making further advances in the struggle against this disease.

    更新日期:2019-11-01
  • Redefining bronchioloalveolar carcinoma.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Janessa J Laskin,Alan B Sandler,David H Johnson

    Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. Although BAC appears to be on a pathologic continuum with adenocarcinoma, the most recent World Health Organization (WHO) classification system has set stringent criteria for the diagnosis. Though malignant, these cancers tend to be peripheral and grow in a lepedic fashion along the alveolar septae without parenchymal invasion. This clear distinction based on histopathology allows for a more definite separation of the natural history and behavior of BAC in clinical studies. Recent clinical trials of molecular targeted anticancer therapies have led to a deeper understanding of the unique features of this cancer and suggest that BAC may require a different therapeutic paradigm from other NSCLCs.

    更新日期:2019-11-01
  • Current management of advanced non-small cell lung cancer: targeted therapy.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Takeshi Isobe,Roy S Herbst,Amir Onn

    Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.

    更新日期:2019-11-01
  • Advances in cytotoxic chemotherapy for the treatment of metastatic or recurrent non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Daniel T Milton,Vincent A Miller

    Improvements in drug development and clinical trial design have resulted in a wider range of treatment options for patients with advanced non-small cell lung cancer (NSCLC). Combination chemotherapy is the standard of care for medically fit patients. A variety of chemotherapeutic doublets, including nonplatinum combinations, with similar clinical activity are now available, allowing oncologists to match acceptable toxicity profiles to individual patients' comorbidities and preferences. Single-agent treatment of refractory or recurrent disease has been shown to improve survival and offer improved quality of life (QOL). For special patient populations, such as the elderly and patients with limited performance status (PS), treatment with single-agent chemotherapy results in modest survival benefits and combination chemotherapy may be appropriate for some of these patients.

    更新日期:2019-11-01
  • Prophylactic cranial irradiation with combined modality therapy for patients with locally advanced non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    L Chinsoo Cho,Jonathan E Dowell,Dan Garwood,Ann Spangler,Hak Choy

    Central nervous system (CNS) metastasis is a significant problem for many patients with non-small cell lung cancer (NSCLC). The earlier data reported a high incidence of CNS metastasis in patients with locally advanced NSCLC who were treated with radiotherapy alone. However, poor control of both thoracic and extracranial systemic disease dominated the results of the early trials. The risk for CNS metastasis as the first site of failure remains a significant concern for patients who have completed modern combined modality therapy. With improvements in the treatment of thoracic and systemic disease, there is renewed interest in prophylactic cranial irradiation (PCI). The results from the Radiation Therapy Oncology Group (RTOG) trial of PCI to prevent CNS relapse in patients with locally advanced NSCLC are anticipated.

    更新日期:2019-11-01
  • Current standards and ongoing controversies in the management of locally advanced non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Howard West,Kathy S Albain

    Despite the fact that nearly half of all patients with non-small cell lung cancer (NSCLC) present with stage III disease, this is the treatment setting with the least well-established standards. Generally treated with curative intent, patients with stage III disease usually receive more than one of the three main therapeutic approaches to lung cancer-surgery, radiation, and chemotherapy. In addition, the staging system encompasses a remarkably heterogeneous range of tumor burden and location within the rubric of stage III. Consequently, an individualized approach is often invoked to address particular concerns for resectability, toxicity, and patient and physician preferences. For patients with locally advanced NSCLC, therapeutic outcomes have improved overall for this population over the past few decades. While there exists a range of acceptable standard approaches to the treatment of stage III NSCLC, this review will describe several conclusions that have emerged and how they evolved.

    更新日期:2019-11-01
  • Adjuvant chemotherapy in early-stage non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Julien Dômont,Jean-Charles Soria,Thierry Le Chevalier

    Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.

    更新日期:2019-11-01
  • Mediastinal staging 2005: pictures, scopes, and scalpels.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Harvey I Pass

    Staging of the mediastinum for lung cancer has matured dramatically with the advent of newer technologies in imaging and endoscopic surveillance. Some of these technologies such as positron emission tomography (PET) scanning are becoming mainstream in the evaluation of patients with clinically suspicious mediastinal disease as seen on computed tomography (CT), while others such as endobronchial ultrasound are reserved for specialty expertise and await validation. While much improvement has been made in the accurate preoperative staging of patients having surgery as the primary modality in lung cancer, controversy exists regarding the restaging of locally advanced cases after induction chemotherapy or chemoradiotherapy. A major concentration on these restaging issues is warranted since it is now generally agreed that sterilization of the mediastinum after induction therapy has an impact on the prognosis of patients with stage IIIA disease, and accurate staging after therapy may rationally guide diverse therapeutic interventions in these patients.

    更新日期:2019-11-01
  • Novel strategies for the early detection and prevention of lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Noel R Wardwell,Pierre P Massion

    Lung cancer is the leading cause of cancer death in the United States. Despite evidence of molecular abnormalities in biological specimens, progress in this disease is hampered by the lack of diagnostic markers useful for clinical practice. The majority of patients with lung cancer are still diagnosed at an advanced stage, when prognosis is poor. This article reviews new strategies being studied for the early detection of lung cancer. These strategies involve new methods of imaging (including low-dose computed tomography [CT] scanning), DNA analysis, and proteomic-based techniques. These strategies have not only improved our understanding of lung cancer but show promise in offering better survival to patients with this deadly disease. Of paramount importance in the search for methods of early detection is the need for the identification of the ideal population to screen, a multidisciplinary approach, and validation of promising techniques.

    更新日期:2019-11-01
  • Screening for non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-07-01
    Rendell W Ashton,James R Jett

    Lung cancer is the leading cause of cancer mortality and is usually discovered at an advanced stage, when treatment is generally not effective. Many researchers have investigated the value of screening for lung cancer, which would theoretically allow earlier detection and more effective treatment. Unfortunately, no trials of screening strategies for lung cancer have shown a mortality benefit, and as a result, no major medical organization currently recommends screening. Research continues to seek proof of the benefit of screening as new techniques are developed, including low-dose spiral computed tomography (CT), autofluorescence bronchoscopy, and advanced techniques of sputum analysis. Although there are promising data on the sensitivity of these newer screening methods, especially low-dose CT, for detecting early lung cancer, none of the published trials are controlled, and they have not yet proven a decrease in mortality. There are ongoing randomized, controlled trials aiming to demonstrate a mortality benefit. Patients who are interested in being screened for lung cancer should be encouraged to participate in well-designed clinical trials whenever possible.

    更新日期:2019-11-01
  • Adjuvant and neoadjuvant therapy in non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-04-09
    Chandra P Belani

    The 5-year survival rates for patients with non-small cell lung cancer (NSCLC) ranges from 9% to 61% following resection, depending on clinical stage; survival rates post-surgery (pathologic stage) range from 25% to 67%. Most stage I and II patients eventually experience recurrent disease: two thirds occur systemically, one third locally. Surgical resection remains the standard of care in early stage NSCLC, although the role of surgery in stage IIIA [N 2 ] disease is controversial. Despite resection, the vast majority of lung cancer patients will experience recurrent and/or metastatic disease; therefore, supplementing surgery with adjuvant therapy is a rational treatment strategy. Recent data indicate that adjuvant chemotherapy should now be considered the standard of care for the treatment of patients with completely resected early stage NSCLC, with the single exception of patients with stage IA disease, where the prognosis is relatively favorable and there is currently no evidence supporting the efficacy of adjuvant therapy. While recent data from trials of adjuvant chemotherapy have shown promising results, no study has yet compared the utility of adjuvant versus neoadjuvant, or induction, chemotherapy. From the current data, more than 90% of patients receiving neoadjuvant chemotherapy undergo the planned surgical resection. Neoadjuvant chemotherapy may also downstage the disease before surgery and decrease perioperative tumor seeding, and molecularly targeted approaches with neoadjuvant therapy appear promising.

    更新日期:2019-11-01
  • Pemetrexed plus carboplatin or oxaliplatin in advanced non-small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-04-09
    Giorgio V Scagliotti

    Over the past decade many large randomized trials have been conducted in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC); however, no single regimen has shown clear superiority. Typical response rates of 17% to 32%, median survival times of 7 to 10 months, and 1-year survival rates of 30% to 45% are common in such studies. Nevertheless, metastatic NSCLC remains an incurable disease, with the development of drug resistance as a major impediment. New treatment regimens, such as the broadly used antifolate antimetabolites, target multiple metabolic functions and may lead to improvements in clinical outcome. Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate, distinguished by a unique nuclear structure and its ability to inhibit multiple folate-dependent enzymatic pathways. Typically, vitamin B 12 and folic acid supplementation are incorporated into the treatment regimen to ameliorate untoward toxicities. When used either as a single agent or in combination with cis-diamine platinums (eg, cisplatin, carboplatin) or diaminocyclohexane platinums (eg, oxaliplatin), pemetrexed has shown significant antitumor activity, with mild, manageable toxicity in patients with advanced NSCLC.

    更新日期:2019-11-01
  • The evolving role of pemetrexed (Alimta) in lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-04-09
    Mark A Socinski,Thomas E Stinchcombe,D Neil Hayes

    Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.

    更新日期:2019-11-01
  • Pemetrexed (Alimta) in small cell lung cancer.
    Semin. Oncol. (IF 3.606) Pub Date : 2005-04-09
    Mark A Socinski

    Small cell lung cancer (SCLC) comprises approximately 13% of all lung cancers. In limited stage (LS)-SCLC, combined-modality therapy represents the standard of care. Therapy should be approached curatively in fit patients with a good performance status because 5-year survival rates approach 26% in aggressively treated patients. In contrast, cure is not possible in extensive stage (ES)-SCLC with median 2-year survival rates with current therapy remaining at less than 10%. Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel, multi-targeted antifolate that inhibits several folate-dependent enzymes involved in purine and pyrimidine synthesis, and is active as a single-agent or in combination with a platinum in both non-small cell lung cancer and malignant pleural mesothelioma. Pemetrexed/platinum combinations appear active in ES-SCLC based on objective response rates observed in a randomized phase II trial. However, no survival data is yet available from this trial. The toxicity profile of both cisplatin and carboplatin in combination with pemetrexed was extremely favorable, as was the ability to deliver full doses of each of the component drugs. Given the limited options available for patients in the relapsed setting, the activity of single-agent pemetrexed is interesting. Also, preliminary data indicates that full doses of carboplatin/pemetrexed can be administered with thoracic radiation therapy, supporting a future clinical trial initiative in LS-SCLC.

    更新日期:2019-11-01
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