Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio; Systems Biology and Bioinformatics Program, Department of Nutrition, Case Western Reserve School of Medicine, Cleveland, Ohio.
Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida.
Int J Radiat Oncol Biol Phys. 2021 Jun 1;110(2):371-381. doi: 10.1016/j.ijrobp.2020.12.044. Epub 2021 Jan 21.
In the treatment of patients with metastatic cancer, the current paradigm states that metastasis-directed therapy does not prolong life. This paradigm forms the basis of clinical trial null hypotheses, where trials are built to test the null hypothesis that patients garner no overall survival benefit from targeting metastatic lesions. However, with advancing imaging technology and increasingly precise techniques for targeting lesions, a much larger proportion of metastatic disease can be treated. As a result, the life-extending benefit of targeting metastatic disease is becoming increasingly clear.
In this work, we suggest shifting this qualitative null hypothesis and describe a mathematical model that can be used to frame a new, quantitative null. We begin with a very simple formulation of tumor growth, an exponential function, and illustrate how the same intervention (removing a given number of cells from the tumor) at different times affects survival. Additionally, we postulate where recent clinical trials fit into this parameter space and discuss the implications of clinical trial design in changing these quantitative parameters.
Our model shows that although any amount of cell kill will extend survival, in many cases the extent is so small as to be unnoticeable in a clinical context or is outweighed by factors related to toxicity and treatment time.
Recasting the null in these quantitative terms will allow trialists to design trials specifically to increase understanding of the circumstances (patient selection, disease burden, tumor growth kinetics) that can lead to improved overall survival when targeting metastatic lesions, rather than whether targeting metastases extends survival for patients with (oligo-) metastatic disease.
在转移性癌症患者的治疗中，目前的范式认为针对转移灶的治疗并不能延长生存期。该范式构成了临床试验无效假设的基础，这些试验旨在检验针对转移性病变患者不会获得总体生存获益的无效假设。然而，随着成像技术的进步和针对病变的靶向治疗技术越来越精确，更多的转移性疾病可以得到治疗。因此，针对转移性疾病的延长生命获益变得越来越明显。
在这项工作中，我们建议改变这种定性无效假设，并描述一个可用于构建新的定量无效假设的数学模型。我们从肿瘤生长的一个非常简单的公式——指数函数开始，并说明了在不同时间进行相同干预（从肿瘤中去除一定数量的细胞）如何影响生存。此外，我们假设最近的临床试验在这个参数空间中的位置，并讨论了临床试验设计在改变这些定量参数方面的影响。
我们的模型表明，尽管任何数量的细胞杀伤都会延长生存期，但在许多情况下，这种程度非常小，在临床环境中难以察觉，或者被与毒性和治疗时间相关的因素所抵消。
用这些定量术语重新定义无效假设将使试验设计者能够专门设计试验，以增加对靶向转移性病变可导致总体生存改善的情况（患者选择、疾病负担、肿瘤生长动力学）的理解，而不是针对转移性疾病是否延长（寡）转移性疾病患者的生存期。
