Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.
Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.
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DOI：
10.1158/1078-0432.ccr-10-0054
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Melcher AA
中科院分区：
文献类型：
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作者：
Harrington KJ;Karapanagiotou EM;Roulstone V;Twigger KR;White CL;Vidal L;Beirne D;Prestwich R;Newbold K;Ahmed M;Thway K;Nutting CM;Coffey M;Harris D;Vile RG;Pandha HS;Debono JS;Melcher AA
确定呼肠孤病毒联合放射治疗晚期癌症患者的安全性和可行性，并评估病毒的生物分布、呼肠孤病毒在肿瘤中的复制和抗病毒免疫反应。可测量疾病的患者可接受姑息性放疗。在第一阶段，患者接受放疗（20 Gy，分五次）加两次瘤内注射RT3D，剂量在1 × 108 ~ 1 × 1010 TCID50之间。在第二阶段，增加放疗剂量（36 Gy，分12次），患者接受2、4、6次RT3D治疗，剂量为1 × 1010 TCID50。终点是安全性、病毒复制、免疫原性和抗肿瘤活性。对23例不同类型的实体瘤进行了治疗。未见剂量限制性毒性。最常见的毒性是2级（或更低）发热、流感样症状、呕吐、无症状淋巴细胞减少和中性粒细胞减少。急性放射反应未见加重。血液、尿液、粪便和痰液的逆转录pcr （RT-PCR）研究均未发现病毒脱落。在低剂量（5次20 Gy）放疗组，7名可评估患者中有2名有部分反应，5名病情稳定。在高剂量（12次36 Gy）放疗组，7例可评估患者中有5例部分缓解，2例病情稳定。肿瘤内RT3D联合放疗耐受性良好。良好的毒性特征和缺乏载体脱落意味着这种组合应该在接受放射治疗的新诊断患者中进行评估。
To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity. Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.