This study examined the efficacy of doublet AC after curative hepatectomy in patients with CRC, and identified the patient types in which doublet AC had a positive effect on prognosis. Multivariate analysis predicting RFS and OS revealed the doublet regimen as an independent prognostic factor. Among patients with a high risk of recurrence (MSKCC-CRS 3–5), 5-year RFS and OS were higher in patients who received doublet AC compared with surgery alone. In low-risk patients (MSKCC-CRS 0–2), however, 5-year RFS and OS were similar between the groups.
Several guidelines have recommended AC using doublet AC of 5FU plus oxaliplatin for improving long-term outcomes in pathological stage III patients . In contrast, there is no consensus regarding the effectiveness of doublet AC for patients who have undergone curative liver resection, and who have a much higher recurrence rate compared with Stage III patients. The FFCD9002 trial studied 173 patients who underwent complete resection of liver metastases from CRC . Their evaluation of long-term outcomes between patients who had surgery alone (n=87) and those treated with 5FU and folinic acid (n=86) revealed significantly higher 5-year disease-free survival (DFS) in the AC group compared with the surgery-alone group (33.5% vs 26.7%, p=0.028). However, 5-year OS was similar between the groups (51.1% vs 41.1%, p=0.13). Hasegawa et al. examined oncological outcomes between patients in a surgery-alone group and an AC (tegafur-uracil//leucovorin) group . Also in the FFCD9002 trial, OS was similar between the groups, but RFS at 3 years was higher in the AC group (38.6%) than in the surgery-alone group (32.3%).
A recent RCT (JCOG0603) reported that doublet AC (mFOLFOX6) was superior to surgery alone in CRC patients who underwent complete resection of liver metastases (21). Five-year DFS was 38.7% for hepatectomy alone compared with 71.2% for hepatectomy followed by AC (p=0.006), and 5-year OS was similar between the groups (83.1% vs 71.2%). In contrast to previous studies, oxaliplatin was used for AC in JCOG0603; however, 5-year DFS did not correlate with OS for liver metastatic CRC.
One explanation for the discrepancies in effect of AC for RFS and OS is the low completion rate of AC after hepatectomy. Indeed, it might be difficult for patients to tolerate systemic chemotherapy after hepatectomy, because hepatectomy is usually more invasive compared with colectomy. Regarding AC using 5FU monotherapy, previous studies have reported completion rates ranging from 54.9% to 66.7% (19, 20, 22). The incidence of grade 3 or 4 adverse events ranged from 12.2% to 24.7%, and dose reduction was 12%–25%. In contrast, for doublet AC using 5FU plus oxaliplatin, the incidence of Grade 3 and 4 events has been reported as 63% and 11%, respectively, with a dose reduction rate of 77%, delayed cycle rate of 95%, and total 6 months completion rate of 55% . In the present study, the grade 3 or 4 adverse effect rate and the dose reduction rate were 18.7% and 56.2%, respectively, for single AC; and 78.9% and 89.5%, respectively, for doublet AC. Overall, the present 6-month completion rate was 68.7% for single AC and 31.6% for doublet AC, in agreement with results reported previously .
Another possible explanation for the discrepancies in effect of AC for RFS and OS is that hepatectomy alone may have been curative in some cases. Indeed, the JCOG0603 trial reported an imbalance between the surgery-alone group and the surgery followed by doublet AC group, with 7% more R0-1 resections in the surgery-alone group . In a study of CRC patients who underwent initial hepatectomy for CRLM by Hirokawa et al., multivariate analysis revealed pT4, lymph node metastasis, and H2-classifiction as predictors of poor prognosis . They subdivided CRLM patients into low-score (score 0–1) and high-score (score 2–3) groups, and concluded that AC did not improve OS or DFS in patients who had no more than two risk factors.
Pan et al. reported risk-stratified indicators for AC after hepatectomy for CRLM using MSKCC-CRS (24). AC markedly improved the 3-year OS rate in high-risk patients with MSKCC-CRS score 3–5, but provided no additional benefit in those with MSKCC-CRS 0–2. Among the present high-risk patients (MSKCC-CRS 3–5), 5-year RFS and OS was higher for doublet AC than for surgery alone; however, in low-risk patients (MSKCC-CRS 0–2), 5-year RFS and OS were similar among the groups, in agreement with the study of Pan et al. . Of note, that study reported AC as an independent prognostic factor for OS only in high-risk patients, whereas the present study revealed doublet AC as an independent preferable prognostic factor in the overall patient cohort . This discrepancy might be explained by the greater number of MSKCC-CRS high-risk patients (58.3%) in our cohort compared with the previous study (28.0%). As mentioned above, patients who undergo doublet AC after hepatectomy usually experience severe side effects, which may have caused a prolonged reduction in quality of life. Appropriate patient selection that takes the risk of recurrence into consideration is crucial for AC after hepatectomy of CRLM.
There were several limitations in the present study. First, the study was retrospective in design, with a small number of patients. Second, the choice of whether or not to undergo AC and the choice of regimen was at the discretion of the surgeon, without clear selection criteria. Third, the appropriate duration of doublet AC after hepatectomy remains controversial. In stage III CRC, 6 months of doublet AC has been recommended for high-risk patients (pT4 and/or N2); however, 3 months of AC has been considered sufficient for low-risk patients . In the present study, only 31.6% of patients completed 6 months of doublet AC, but >70% of patients completed at least 3 months of treatment, which might have had a positive effect on long-term outcomes. Further studies are required to clarify these issues.