Study population
A total of 573 patients who underwent hepatectomy for CRLM at the National Cancer Center Hospital between January 2000 and December 2017 were enrolled. Nineteen patients were excluded because of missing clinicopathological data. Five hundred and nine patients had initially resectable CRLM at the time of diagnosis and underwent hepatectomy (primary resection group). Fourteen of these patients did not have features suggesting unresectable disease at the time of initial diagnosis but had tumors that were considered to be progressing rapidly and chemotherapy was administered preoperatively. Forty-five patients had initially unresectable CRLM at the time of diagnosis and underwent hepatectomy followed by chemotherapy (conversion group) (Fig. 1).
Patient characteristics
The clinical characteristics of the primary resection group (n=509) and the conversion group (n=45) are shown in Table 1. The median age of the total study population was 62 years (range, 21–88), the median number of liver metastases was 2 (range, 1–19), and the median size of the largest liver metastatic lesion was 3.0 cm (range, 0.1–23). Postoperative chemotherapy was administered in 62 patients (11%), many of whom were also participants in the JCOG0603 study[18]. Compared with the primary resection group, the conversion group had a significantly higher proportion of patients aged under 65 years (60% vs 76%, p=0.042) and significantly greater numbers of patient with a T4 tumor (16% vs 33%, p=0.003), synchronous liver metastasis (47% vs 80%, p<0.001), and extrahepatic metastasis (4% vs 18%, p<0.001). Furthermore, the conversion group also had a higher proportion of patients with ≥2 liver metastases (48% vs 78%, p<0.001) and a higher proportion with the largest liver metastatic lesion measuring >5.1 cm (16% vs 38%, p<0.001) compared with the primary resection group.
Treatment course in the conversion group
The treatment course of patients with CRLM who underwent conversion hepatectomy is shown in Table 2. The median interval between the start of chemotherapy and hepatectomy was 9.6 months (range, 3–45). The most common first-line regimen was oxaliplatin-based (n=29, 65%). Chemotherapy regimens differed depending on the treatment year. Until 2006, the most common regimen was 5-fluorouracil (5-FU)-based systemic chemotherapy or hepatic arterial infusion; thereafter, the most common regimen was oxaliplatin-based or irinotecan-based systemic chemotherapy combined with molecular targeted agents. The median response rate was 32% (range, -23, 79). Ten patients (22%) had microscopic tumor invasion of the resection margin (R1 resection).
Relapse-free survival
The Kaplan-Meier curves for RFS are compared between the primary resection group and the conversion group in Figure 2a. Median survival time was 14.8 months in the primary resection group and 9.3 months in the conversion group. The 3-year and 5-year RFS rates were 33.5% and 30.0%, respectively, in the primary resection group and 22.2% and 19.8% in the conversion group. In both groups, the RFS curve decreased sharply in the first 2 years after hepatectomy. The gap in the RFS curve between the primary resection group and the conversion group increased in the first year after hepatectomy and reached a plateau at 3 years while maintaining the gap (p=0.042).
Overall survival
The Kaplan-Meier curves for OS are compared between the primary resection group and the conversion group in Figure 2b. Median survival time was 99.0 months in the primary resection group and 64.7 months in the conversion group. The 3-year and 5-year RFS rates were 79.1% and 62.0%, respectively, in the primary resection group and 74.8% and 52.4% in the conversion group. The gap in the OS curves between the primary resection group and the conversion group was close during the first 4 years after hepatectomy, and gradually increased thereafter, although the difference was not significant (p=0.253).
Clinical factors affecting the prognosis of all patients with CRLM
The results of univariable and multivariable analyses for RFS and OS in all patients with CRLM who underwent hepatectomy are shown in Table 3. Multivariable analysis for RFS with adjustment for key clinical factors revealed the following as independent predictors of RFS: location of the primary tumor (right-sided: HR 1.28, 95% CI 1.01–1.63, p=0.040); N category of the primary tumor (N1/N2: HR 1.45, 95% CI 1.17–1.81, p<0.001); timing of liver metastasis (synchronous: HR 1.66, 95% CI 1.34–2.06, p<0.001); preoperative CEA level (>5 ng/ml: HR 1.45, 95% CI 1.14–1.84, p=0.002); postoperative chemotherapy (No: HR 1.66, 95% CI 1.19–2.33, p=0.003); and number of liver metastases (≥2: HR 1.69, 95% CI 1.37–2.08, p<0.001). In univariable analysis, RFS was significantly worse in the conversion group than in the primary resection group (HR 1.43, 95% CI 1.01–2.01, p=0.042; data not shown), whereas no significant difference in RFS was found in multivariable analysis (HR 0.95, 95% CI 0.65–1.38, p=0.787).
Multivariable analysis for OS with adjustment for key clinical factors revealed the independent predictors of OS as location of the primary tumor (right-sided: HR 1.43, 95% CI 1.05–1.94, p=0.024), N category of the primary tumor (N1/N2: HR 1.48, 95% CI 1.11–1.99, p=0.008), and preoperative CEA level (>5 ng/ml: HR 1.40, 95% CI 1.03–1.91, p=0.032). There was no significant difference in OS between the conversion group and the primary resection group (HR 1.12, 95% CI 0.69–1.83, p=0.643).
Clinical factors affecting prognosis of the conversion group
Univariable and multivariable analyses for RFS and OS in patients with CRLM who underwent conversion hepatectomy are shown in Table 4. On multivariable analyses for RFS using variables with a p-value of <0.2 on univariate analyses, independent predictors were timing of liver metastasis (synchronous: HR 3.14, 95% CI 1.20–8.24, p=0.020) and preoperative CEA level (>5 ng/ml: HR 3.10, 95% CI 1.45–6.61, p=0.003). On multivariable analyses for OS, preoperative CEA level (>5 ng/ml: HR 3.29, 95% CI 1.18–9.17, p=0.023) was an independent predictor.
Recurrence pattern
In total, 342 patients in the primary resection group and 36 in the conversion group developed recurrence during the study period. There was no significant difference in the pattern of first recurrence between the groups. Recurrence localized to the liver was observed in 139 patients (41%) in the primary resection group and 17 (47%) in the conversion group (p=0.548).
After first recurrence, surgical treatment was performed in 140 patients (41%) in the primary resection group and in 16 (44%) in the conversion group. Although there was no significant between-group difference, the proportion of patients who underwent hepatectomy tended to be higher in the conversion group than in the primary resection group (31% vs 23%, p=0.893; Table 5).