Kakizawa Nao, Suzuki Koichi, Fukui Taro, Takayama Yuji, Ichida Kosuke, Muto Yuta, Hasegawa Fumi, Watanabe Fumiaki, Kikugawa Rina, Tsujinaka Shingo, Futsuhara Kazushige, Miyakura Yasuyuki, Noda Hiroshi, Rikiyama Toshiki
Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
Oncol Rep. 2017 Apr;37(4):2506-2512. doi: 10.3892/or.2017.5456. Epub 2017 Feb 15.
Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.
瑞戈非尼已在所有标准治疗后病情恶化的转移性结直肠癌患者中显示出生存获益。然而，一些患者会出现严重不良事件（AE），导致治疗中断。因此，选择可能从瑞戈非尼中获益的患者至关重要。20例转移性结直肠癌患者接受了瑞戈非尼治疗；从其中16例患者采集了122份血浆样本，用于监测血液中的循环肿瘤DNA（ctDNA）。评估了治疗反应、AE、总生存期（OS）、无进展生存期（PFS）以及CT图像上的肿瘤形态学变化。使用数字PCR测定KRAS突变ctDNA。中位PFS和OS分别为2.5个月和5.9个月。10例患者因疾病进展（PD）中断治疗，另外10例患者因AE中断治疗。AE包括高胆红素血症、严重疲劳和皮疹。2例有多发性双侧肝转移的患者出现高胆红素血症，另外2例身体状况较差（PS）的患者出现严重疲劳。这些严重AE导致治疗中断。10例因AE相关中断治疗的患者中位PFS为2.1个月；PD发生在3.5个月（p = 0.00334）。4例患者出现形态学反应，PFS时间更好，分别为3.5、5.3、5.6和14.2个月。11例KRAS野生型肿瘤患者中有3例在抗EGFR抗体治疗期间ctDNA中出现KRAS突变；在影像学检测到PD之前血液中即可检测到。此外，2例患者在瑞戈非尼单药治疗期间KRAS突变下降。这些患者再次接受抗EGFR抗体治疗。有广泛多发性肝转移或PS较差的患者不太可能从瑞戈非尼中获益。有形态学反应的患者在对其他AE进行适当管理的情况下可能从瑞戈非尼中获益。ctDNA中的KRAS监测对于治疗反应和确定治疗策略可能有用。
