Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Level 7, NUHS Tower Block, 1E Kent Ridge Road, Singapore, 119228, Singapore.
University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
BMC Cancer. 2020 Nov 17;20(1):1118. doi: 10.1186/s12885-020-07616-4.
We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC.
Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).
We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51-1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792).
The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.
The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.
我们之前报道过，在新辅助多柔比星环磷酰胺（AC）治疗前使用低剂量、短疗程的舒尼替尼可以使肿瘤血管正常化并改善灌注，但会导致中性粒细胞减少，并延迟乳腺癌患者随后的周期。本研究将舒尼替尼与多西他赛联合使用，后者的中性粒细胞最低点比 AC 更早。
将晚期实体瘤患者按原发肿瘤部位分层，1:1 随机分为每周 3 次多西他赛 75mg/m2，联合或不联合舒尼替尼 12.5mg/d，共 7 天，在多西他赛前使用。主要终点为客观缓解率（CR+PR）和临床获益率（CR+PR+SD）；次要终点为毒性和无进展生存期（PFS）。
我们从 2 个研究中心共纳入 68 例患者；33 例接受多西他赛舒尼替尼治疗，35 例接受多西他赛单药治疗，其中 33 例为乳腺癌，25 例为肺癌，10 例为其他癌症。客观缓解率无差异（30.3% vs 28.6%，p=0.432，比值比[OR] 1.10，95%CI 0.38-3.18）；多西他赛舒尼替尼组的临床获益率较低（48.5% vs 71.4%，p=0.027，OR 0.37，95%CI 0.14-1.01）。多西他赛舒尼替尼组的中位 PFS 较短（2.9 与 4.9 个月，风险比[HR] 2.00，95%CI 1.15-3.48，p=0.014），总体情况如此，乳腺癌也是如此（4.2 与 5.6 个月，p=0.048）和其他癌症（2.0 与 5.3 个月，p=0.009），但肺癌则不然（2.9 与 4.1 个月，p=0.597）。两组的中位总生存期相似（9.9 与 10.5 个月，HR 0.92，95%CI 0.51-1.67，p=0.789），乳腺癌（18.9 与 25.8 个月，p=0.354），肺癌（7.0 与 6.7 个月，p=0.970）和其他癌症（4.5 与 8.8 个月，p=0.449）亚组中也是如此。多西他赛舒尼替尼组 3/4 级血液学毒性较低（18.2% vs 34.3%，p=0.132），这归因于更自由地使用预防性 G-CSF（90.9% vs 63.0%，p=0.024）。3/4 级非血液学毒性相似（12.1% vs 14.3%，p=0.792）。
多西他赛联合舒尼替尼耐受性良好，但未改善结局。在转移性乳腺癌患者中可能产生的负面影响与新辅助 AC 中加入舒尼替尼的结果相反。这些阴性结果表明，在晚期实体瘤中，特别是乳腺癌中，以目前的剂量和方案间歇性给予舒尼替尼联合多西他赛并不有益。
该研究于 2013 年 3 月 4 日前瞻性地在 clinicaltrials.gov 上注册（NCT01803503）。
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