Medical Oncology Service, University Hospital del Mar-IMIM, Barcelona, Spain.
Lancet Oncol. 2010 Apr;11(4):350-7. doi: 10.1016/S1470-2045(09)70383-3. Epub 2010 Feb 15.
Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC).
Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m(2) (days 1 and 8), oral capecitabine 500 mg/m(2) twice a day (final dose after adjustment, days 1-14), and oral sorafenib 400 mg twice a day (days 1-21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301.
44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11.1 months (95% CI 7.9-17.1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand-foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug.
PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration.
Spanish Oncology Genitourinary Group (SOGUG).
最大耐受剂量（MTD）化疗后进行节拍化疗（频繁给予低剂量）通过增加抗血管生成药物的抗肿瘤作用来作用于肿瘤血管内皮细胞。这项多中心、2 期研究调查了 MTD 吉西他滨联合节拍卡培他滨加多激酶抑制剂索拉非尼治疗转移性肾细胞癌（RCC）的疗效。
2006 年 12 月 13 日至 2008 年 4 月 17 日，在西班牙的 8 个中心招募了患者。患者年龄在 18 岁或以上，患有明确的伴有透明细胞组织学的转移性 RCC，东部合作肿瘤学组（ECOG）表现状态为 0 或 1，未接受过先前的治疗，且不适合或不能耐受免疫治疗。治疗包括静脉注射吉西他滨 1000mg/m2（第 1 天和第 8 天），口服卡培他滨 500mg/m2，每日两次（最终剂量调整后，第 1-14 天），口服索拉非尼 400mg，每日两次（第 1-21 天），共 6 个周期，随后根据临床获益情况，由研究者决定是否继续使用索拉非尼单药治疗。主要终点是所有接受治疗的患者的中位无进展生存期（PFS）。该试验在 ClinicalTrials.gov 上注册，编号为 NCT00496301。
44 例患者入组该研究，其中 40 例患者接受了治疗。这些患者的中位 PFS 为 11.1 个月（95%CI 7.9-17.1）。20 例患者部分缓解，17 例患者病情稳定。大多数不良事件为 1 级或 2 级。3 级不良事件包括疲劳或乏力（n=9）、手足皮肤反应（n=11）、黏膜炎（n=3）、腹泻（n=2）、感染（n=2）和过敏反应、高血压和皮疹（均 n=1）。9 例患者出现 3 级血液学毒性。1 例因肺栓塞导致的 5 级呼吸困难死亡，可能与研究药物有关。
与转移性 RCC 患者接受吉西他滨和卡培他滨或索拉非尼单药治疗相比，PFS 和缓解率更高。大多数患者的不良事件可以得到控制。这些发现初步证实了临床前研究中观察到的化疗转换概念的协同作用，值得进一步探索。
西班牙肿瘤泌尿生殖学组（SOGUG）。
