Murray Louise, Longo Joseph, Wan Jonathan, Chung Caroline, Wang Lisa, Dawson Laura, Milosevic Michael, Oza Amit, Brade Anthony
Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Canada.
Radiother Oncol. 2017 Jul;124(1):74-79. doi: 10.1016/j.radonc.2017.06.007. Epub 2017 Jun 28.
To evaluate the tolerability and maximum tolerated dose (MTD) of sorafenib administered concurrently with palliative radiotherapy.
In patients with incurable cancer, sorafenib was escalated independently in three cohorts based on irradiation site: thorax, abdomen or pelvis. Sorafenib was administered days 1-28 and radiotherapy (30Gy in 10 fractions) was delivered days 8-12 and 15-19. Dose-limiting toxicities (DLT) were acute grade 3+ toxicities attributable to radiotherapy.
For the thorax, abdomen and pelvis cohorts, 14, 16 and 4 patients were recruited, and Dose Levels 3, 3 and 2 were reached, respectively. Sorafenib-related systemic toxicity led to significant sorafenib interruption in 10 patients. There were 3 DLTs in total, one per cohort: grade 3 oesophagitis (thoracic), transaminase elevation (abdominal) and grade 5 bowel perforation (pelvic; patient with tumour invading bowel). Grade 2 radiation dermatitis developed in 12 patients. The trial was terminated early as slow accrual and sorafenib-related systemic toxicity prevented efficient evaluation of RT-related DLTs.
The MTD of sorafenib when used with 30Gy in 10 fractions was not established due to sorafenib-related systemic toxicity. Severe radiotherapy-related toxicities were also observed. These events suggest this concurrent combination does not warrant further study.
评估索拉非尼与姑息性放疗同时使用时的耐受性和最大耐受剂量（MTD）。
在无法治愈的癌症患者中，根据照射部位将索拉非尼在三个队列中独立递增：胸部、腹部或骨盆。索拉非尼在第1 - 28天给药，放疗（10次分割，共30Gy）在第8 - 12天和第15 - 19天进行。剂量限制毒性（DLT）为归因于放疗的急性3级及以上毒性。
胸部、腹部和骨盆队列分别招募了14、16和4名患者，分别达到了剂量水平3、3和2。与索拉非尼相关的全身毒性导致10名患者的索拉非尼显著中断。总共出现3例DLT，每个队列各1例：3级食管炎（胸部）、转氨酶升高（腹部）和5级肠穿孔（骨盆；肿瘤侵犯肠道的患者）。12名患者出现2级放射性皮炎。由于入组缓慢以及与索拉非尼相关的全身毒性妨碍了对放疗相关DLT的有效评估，试验提前终止。
由于与索拉非尼相关的全身毒性，未确定索拉非尼与10次分割30Gy放疗联合使用时的MTD。还观察到严重的放疗相关毒性。这些事件表明这种联合方案不值得进一步研究。
