Brady-Nicholls Renee, Enderling Heiko
Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Cancers (Basel). 2022 Oct 28;14(21):5319. doi: 10.3390/cancers14215319.
Adaptive therapy with abiraterone acetate (AA), whereby treatment is cycled on and off, has been presented as an alternative to continuous therapy for metastatic castration resistant prostate cancer (mCRPC). It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for whom this competition can be enhanced through slight modifications. Here, we investigate how adaptive AA can be modified to extend time to progression using a simple mathematical model of stem cell, non-stem cell, and prostate-specific antigen (PSA) dynamics. The model is calibrated to longitudinal PSA data from 16 mCRPC patients undergoing adaptive AA in a pilot clinical study at Moffitt Cancer Center. Model parameters are then used to simulate range-bounded adaptive therapy (RBAT) whereby treatment is modulated to maintain PSA levels between pre-determined patient-specific bounds. Model simulations of RBAT are compared to the clinically applied adaptive therapy and show that RBAT can further extend time to progression, while reducing the cumulative dose patients received in 11/16 patients. Simulations also show that the cumulative dose can be reduced by up to 40% under RBAT. Through small modifications to the conventional adaptive therapy design, our study demonstrates that RBAT offers the opportunity to improve patient care, particularly in those patients who do not respond well to conventional adaptive therapy.
醋酸阿比特龙（AA）的适应性疗法，即治疗循环开启和关闭，已被提出作为转移性去势抵抗性前列腺癌（mCRPC）持续治疗的替代方案。据推测，通过治疗循环可使敏感细胞竞争性抑制耐药细胞，从而延长治疗有效的时间。有人提出，存在一部分患者，通过轻微调整可增强这种竞争。在此，我们使用干细胞、非干细胞和前列腺特异性抗原（PSA）动力学的简单数学模型，研究如何调整适应性AA疗法以延长疾病进展时间。该模型根据莫菲特癌症中心一项试点临床研究中16名接受适应性AA治疗的mCRPC患者的纵向PSA数据进行校准。然后使用模型参数模拟范围受限的适应性疗法（RBAT），即调整治疗以将PSA水平维持在预先确定的患者特异性范围内。将RBAT的模型模拟结果与临床应用的适应性疗法进行比较，结果表明RBAT可进一步延长疾病进展时间，同时减少11/16患者接受的累积剂量。模拟还表明，在RBAT下累积剂量可减少多达40%。通过对传统适应性疗法设计进行微小调整，我们研究表明RBAT为改善患者护理提供了机会，特别是对于那些对传统适应性疗法反应不佳的患者。
