Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Acta Oncol. 2021 Dec;60(12):1557-1564. doi: 10.1080/0284186X.2021.1971294. Epub 2021 Sep 23.
A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination.
Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as ≤5% viable cells.
25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3+ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3+ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension.
Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.
一项前期 I 期研究表明，帕唑帕尼联合放疗的新辅助治疗方案具有良好的耐受性，并诱导软组织肉瘤患者产生有前景的病理缓解。本文呈现了随后前瞻性、多中心的 PASART-2 试验的结果，进一步研究了该联合方案的疗效和安全性。
高风险局限性软组织肉瘤患者接受新辅助放疗，50Gy/25 次（PASART-2A）或随后剂量减少至 36Gy/18 次（PASART-2B）。放疗前一周开始联合 800mg 帕唑帕尼每日一次治疗，同时结束。4-8 周后进行手术切除。主要终点是病理完全缓解率（pCR），定义为≤5%存活细胞。
该研究共登记了 25 例患者，其中 21 例患者入组 PASART-2A，4 例患者入组 PASART-2B。经中心病理复查，联合治疗导致 5 例患者（20%）出现 pCR。17 例患者（68%）在新辅助治疗期间出现 3+级毒性，最常见的是丙氨酸转氨酶（ALT）升高、天冬氨酸转氨酶（AST）升高和高血压，均为无症状。5 例患者（20%）发生 3+级急性术后毒性，最常见的是伤口感染。所有患者均完成了全剂量放疗，并接受了手术。9 例患者（36%）因 ALT 和/或 AST 升高而在完成前停用帕唑帕尼，2 例患者（8%）因高血压而短暂中断。
除无症状性肝毒性外，该研究方案具有良好的耐受性。尽管未达到预设的疗效终点（30%pCR），但单独接受新辅助放疗后 pCR 率显著提高（增加一倍以上），值得进一步研究。
