Haas Rick L M, Gelderblom Hans, Sleijfer Stefan, van Boven Hester H, Scholten Astrid, Dewit Luc, Borst Gerben, van der Hage Jos, Kerst J Martijn, Nout Remi A, Hartgrink Henk H, de Pree Ilse, Verhoef Cornelis, Steeghs Neeltje, van Coevorden Frits
a Department of Radiotherapy , the Netherlands Cancer Institute , Amsterdam , The Netherlands.
Acta Oncol. 2015;54(8):1195-201. doi: 10.3109/0284186X.2015.1037404. Epub 2015 Apr 29.
Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting.
Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II).
A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases.
Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.
越来越多的证据表明，放射治疗（RT）与血管生成靶向治疗联合使用具有显著的协同作用。这项多中心前瞻性I期临床试验确定了在根治性治疗中，帕唑帕尼与术前放疗同时用于肢体软组织肉瘤（ESTS）患者的安全性概况，并推荐了进一步研究的剂量。
患有深部中高级别肉瘤、肿瘤直径≥5 cm的患者，每天接受一次帕唑帕尼治疗（剂量递增队列分别为400 mg、600 mg和800 mg），持续6周，并从第8天开始进行50 Gy的术前放疗。5至7周后进行手术。毒性根据CTC标准4.0进行评分。剂量限制毒性（DLT）分为两组；DLT-I是指在放疗范围内6周的放化疗期间直至手术当天出现的毒性（称为DLT-I），以及围手术期直至术后第21天出现的毒性（DLT-II）。
共招募了12名患者，11名可评估（3名女性和8名男性，中位年龄58岁，范围24 - 78岁，中位肿瘤大小9 cm，范围5 - 15 cm）。10名患者接受了手术。放疗区域内未观察到毒性增加，但10名患者中有2名（400 mg和600 mg队列各1名）术后伤口愈合延迟。RT后没有患者出现明显的体积缩小。对切除标本的评估显示，10例中有4例出现病理（接近）完全缓解（坏死率≥95%）。出乎意料的是，11例中有3例（27%）因3级以上肝毒性导致帕唑帕尼提前中断。
除肝毒性外，每天800 mg的新辅助帕唑帕尼联合50 Gy似乎是可耐受的；该方案在ESTS中似乎显示出有前景的活性，是进一步研究的推荐剂量。
