首页期刊导航|Journal of clinical oncology :
期刊信息/Journal information
Journal of clinical oncology :
Grune & Stratton,
Journal of clinical oncology :

Grune & Stratton,

0732-183X

Journal of clinical oncology :/Journal Journal of clinical oncology :
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    Statistics in Oncology

    Devlin SIasonos A
    3页
    查看更多>>摘要：In this special series, we aimed to include a wide perspective from regulators, bioethicists, statisticians, and clinician-scientists on the drug development continuum, focusing on challenges raised by new classes of therapies: immunotherapy, targeted agents, and cellular therapy. The review articles discuss the challenges raised by dose optimization in the phase I setting, and the ethics of early-phase trials that file for US Food and Drug Administration (FDA) expedited programs such as accelerated approval or breakthrough therapy designation. The series also includes reviews discussing efficient designs, such as basket trials, to assess efficacy in the setting of targeted agents, and window-of-opportunity studies that use the time gap before cancer resection to evaluate pharmacodynamic and pharmacokinetic signals of novel agents. Finally, there are review articles covering the methodologic challenges of later-phase trials, such as testing treatment effects in randomized studies where the benefit of therapy might not be constant over time, and how additional patient-level data can be used to generalize the treatment benefit of randomized trials to a broader population. These articles outline areas for future research and provide insight into the dynamically changing field of oncology drug development.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Ethical Considerations for Phase I Trials in Oncology

    Bittlinger MBicer SPeppercorn JKimmelman J...
    15页
    查看更多>>摘要：Phase I trials often represent the first occasion where new cancer strategies are tested in patients. Various developments in cancer biology, methodology, regulation, and medical ethics have altered the ethical landscape of such trials. We provide a narrative review of contemporary ethical challenges in design, conduct, and reporting of phase I cancer trials and outline recommendations for addressing each. We organized our review around four topics, supplementing the first three with scoping reviews: (1) benefit/risk, (2) research biopsies, (3) therapeutic misconception and misestimation, and (4) reporting. The main ethical challenges of conducting phase I trials stem from three issues. First, phase I trials often involve higher research burden and scientific uncertainty compared with other cancer trials. Second, many patients arrive at phase I trials at a transitional point in their illness trajectory where they have exhausted standard survival-extending options. Third, phase I trial results play a major role in informing downstream drug development and regulatory decisions. Together, these issues create distinct pressures for study design, ethical review, informed consent, and reporting. Developments in methodology, regulation, cancer biology, and ethical awareness have helped mitigate some of these challenges, while introducing others. We conclude our review with a series of recommendations regarding trial design, ethical review, consent, and reporting. We also outline several unresolved questions that, if addressed, would strengthen the ethical foundation of phase I cancer trials.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients

    Pazdur RTheoret M.RFourie Zirkelbach JShah M...
    12页
    查看更多>>摘要：This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Summary of US Food and Drug Administration Chimeric Antigen Receptor (CAR) T-Cell Biologics License Application Approvals From a Statistical Perspective

    Shiowjen LeePoornima SharmaXue LinBindu George...
    9页
    查看更多>>摘要：The approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 marked a milestone in the development of oncology therapies. Since 2017, the breakthrough in treatment or even cure of previously intractable diseases represented by this new class of cancer treatments has continued with subsequent chimeric antigen receptor T (CAR T)-cell approvals. To date, the US Food and Drug Administration has approved five autologous CAR T-cell products for seven indications. A feature of autologous CAR T-cell products that differentiates them from traditional oncology drugs is that they need to be manufactured specifically for each patient. This feature has implications in study design, statistical analyses, and interpretation of study results. In this article, we share our experiences in the statistical review of CAR T-cell products and provide considerations for the design and statistical analyses of CAR T-cell trials. We also describe how the newly adopted estimand framework for clinical trials can help clarify nuanced issues in CAR T-cell trial design.
      原文链接:
    • NSTL

    Balancing Risk and Efficiency in Drug Development for Rare and Challenging Tumors: A New Paradigm for Glioma

    Mellinghoff I.KCloughesy T.F
    10页
    查看更多>>摘要：The process of developing cancer therapies is well established and has enabled the incorporation of many new drugs and classes of agents into the standard of care for common cancers. Clinical drug development is fundamentally different for rare and difficult-to-treat solid tumors, such as glioma or pancreatic cancer. The failure to develop effective new agents for the latter diseases has discouraged the development of therapeutics for these cancers. Using glioma as an example, we describe a process toward obtaining more reliable early-stage signals of drug activity and a process toward translating those signals into clinical benefits with more efficient late-stage development. If linked together, these processes should increase the likelihood of benefit in late-stage settings at a lower cost and encourage more drug development for patients with rare and difficult-to-treat cancers.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Basket Trials: Review of Current Practice and Innovations for Future Trials

    Brian P HobbsRoberto Carmagnani PestanaEmily C ZaborAlexer M Kaizer...
    9页
    查看更多>>摘要：Advances in biology and immunology have elucidated genetic and immunologic origins of cancer. Innovations in sequencing technologies revealed that distinct cancer histologies shared common genetic and immune phenotypic traits. Pharmacologic developments made it possible to target these alterations, yielding novel classes of targeted agents whose therapeutic potential span multiple tumor types. Basket trials, one type of master protocol, emerged as a tool for evaluating biomarker-targeted therapies among multiple tumor histologies. Conventionally conducted within the phase II setting and designed to estimate high and durable objective responses, basket trials pose challenges to statistical design and interpretation of results. This article reviews basket trials implemented in oncology studies and discusses issues related to their statistical design and analysis.
      原文链接:
    • NSTL

    Early-Phase Oncology Trials: Why So Many Designs?

    Clertant M
    8页
    查看更多>>摘要：The past 30 years have seen a considerable effort on the part of statisticians to improve the design and accuracy of early-phase oncology trials. Some of this effort has been rewarded via successful implementation in actual trials, yet it would be fair to say that among clinicians, there remains some reluctance to fully embrace more efficient model-based approaches. One reason for such reticence is the difficulty in understanding exactly what is being offered by more modern designs. Although it is generally accepted that these designs offer improvements over the old standard 3 + 3 design, a new question has then to be addressed: How should we decide among the new proposals which one is the best for our purpose? In this study, we recall 15 designs that are currently proposed and in use. We show that among these 15 designs, many are operationally identical. These 15 designs reduce to three broad classes of designs. This review helps summarize their properties and differences and highlights that certain designs require ad hoc modifications to ensure satisfactory performance.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Testing for Differences in Survival When Treatment Effects Are Persistent, Decaying, or Delayed

    O'quigley J
    9页
    查看更多>>摘要：A statistical test for the presence of treatment effects on survival will be based on a null hypothesis (absence of effects) and an alternative (presence of effects). The null is very simply expressed. The most common alternative, also simply expressed, is that of proportional hazards. For this situation, not only do we have a very powerful test in the log-rank test but also the outcome is readily interpreted. However, many modern treatments fall outside this relatively straightforward paradigm and, as such, have attracted attention from statisticians eager to do their best to avoid losing power as well as to maintain interpretability when the alternative hypothesis is less simple. Examples include trials where the treatment effect decays with time, immunotherapy trials where treatment effects may be slow to manifest themselves as well as the so-called crossing hazards problem. We review some of the solutions that have been proposed to deal with these issues. We pay particular attention to the integrated log-rank test and how it can be combined with the log-rank test itself to obtain powerful tests for these more complex situations.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins

    Novel Use of Patient-Specific Covariates From Oncology Studies in the Era of Biomedical Data Science: A Review of Latest Methodologies

    Xu RChen GConnor MMurphy J...
    8页
    查看更多>>摘要：In this article, we review different applications of how to incorporate individual patient variables into clinical research within oncology. These methodologies range from the more traditional use of baseline covariates from randomized clinical trials, as well as observational studies, to using covariates to generalize the results of randomized clinical trials to other populations. Individual patient variables also allow for the consideration of heterogeneity in treatment effects and individualized treatment rules. We primarily consider two treatment groups and mostly focus on time-to-event outcomes where such methodologies have been well established and widely applied. We also discuss more conceptually newer statistical research that has not been widely applied in clinical oncology, but is likely to make an impact in future oncology research. With the increasing amount of biomedical data available for analysis, it is inevitable that more methods are developed to make best use of information, to advance oncology research.
      原文链接:
    • NSTL
    • Lippincott Williams & Wilkins