Is there a survival benefit from adjuvant chemotherapy for patients with liver oligometastases from colorectal cancer after curative resection?

Is there a survival benefit from adjuvant chemotherapy for patients with liver oligometastases... Background: Although colorectal oligometastases to the liver can potentially be cured with aggressive local abla- tion, the efficacy of adjuvant chemotherapy (ACT ) for such metastasis remains unclear. The present study explored the effects of ACT on patients with colorectal liver oligometastases (CLO) after curative resections and aimed to iden- tify patients who could benefit from ACT. Methods: We retrospectively analyzed 264 eligible patients with CLO who underwent curative resection between September 1999 and June 2015. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan–Meier method and log-rank test; prognostic factors were a by Cox regression modeling. Results: Among 264 patients, 200 (75.8%) patients received ACT and 64 (24.2%) did not receive ACT. These two groups did not significantly differ in clinicopathologic characteristics, and had comparable 3-year OS and RFS rates (RFS: 42.1% vs. 45.7%, P = 0.588; OS: 69.7% vs. 62.7%, P = 0.446) over a median follow-up duration of 35.5 months, irrespective of preoperative chemotherapy. ACT markedly improved 3-year OS in high-risk patients with Memorial Sloan-Kettering Cancer Center clinical risk scores (MSKCC-CRS) of 3–5 (68.2% vs. 33.8%, P = 0.015), but presented no additional benefit in patients with MSKCC-CRS of 0–2 (72.2% vs. 78.6%, P = 0.834). In multivariate analysis, ACT was independently associated with improved OS in patients with MSKCC-CRS of 3–5. Conclusions: ACT might offer a prognostic benefit in high-risk patients with CLOs after curative liver resection, but not in low-risk patients. Therefore, patients’ risk status should be determined before ACT administration to optimize postoperative therapeutic strategies. Keywords: Colorectal cancer, Oligometastases, Adjuvant chemotherapy, Liver resection, Benefit *Correspondence: wands@sysucc.org.cn Zhizhong Pan, Jianhong Peng and Junzhong Lin contributed equally to this work Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, Guangdong, P. R. China © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pan et al. Cancer Commun (2018) 38:29 Page 2 of 10 primary and metastatic tumors; and (5) a minimum Introduction follow-up duration of 3  months. Tumor stage was clas- The liver is the most common site of metastasis in sified according to the 2010 American Joint Committee patients with colorectal cancer (CRC). At diagnosis, on Cancer staging system. Eligible patients’ clinicopatho- approximately 25% of patients present with synchronous logic data and treatment information were reviewed metastases, and approximately 50% patients ultimately using an electronic medical record system. All proce- develop metachronous metastases [1, 2]. Liver resec- dures were performed according to the ethical standards tion is the most effective curative treatment for patients of the World Medical Association Declaration of Hel- with CRC liver metastasis, with a 5-year survival rate sinki of 2013. We obtained approval from the independ- of 40%–50% [3, 4]. However, ~ 60% of patients develop ent ethics committee at Sun Yat-sen University Cancer recurrent liver metastases after initial liver resection [5, Center, and requested the informed consents before ini- 6]. Because of this high recurrence rate, adjuvant chemo- tial treatments. therapy (ACT) has been investigated for patients with CRC metastasis to the liver. Although several studies have indicated the potential efficacy of ACT in prolong - Patient treatments ing survival, its benefits had not been definitively shown The treatment strategy for every patient in the current until now [7–9]. study was determined by a multidisciplinary team (MDT) The latest version of the European Society for Medical as previously described [15]. Preoperative (neoadjuvant) Oncology Guidelines highlights oligometastatic disease— chemotherapy (NAC) and ACT regimens were deter- a disease state that links localized and systemic disease mined based on evaluations by oncologists, and included [2]. Notably, oligometastatic disease confined to the liver XELOX (130  mg/m intravenous [i.v.] oxaliplatin on is potentially curable. Aggressive locally ablative treat- Day 1 and 1000  mg/m oral capecitabine twice daily on ments, including liver resection, may prolong survival of Days 1–14 for a 3-week cycle), FOLFOX (85  mg/m i.v. patients with colorectal liver oligometastasis (CLO), with oxaliplatin and 400 mg/m i.v. leucovorin [LV] on Day 1; a 5-year overall survival (OS) rate of 45.9% as shown in 400  mg/m i.v. 5-fluorouracil (5-FU) on Day 1 and then our previous study [10]. Because complete resection is 1200  mg/m i.v. 5-FU for Day 1–2 for a 2-week cycle), 2 2 technically easy to perform, with usually good oncologic FOLFIRI (180  mg/m i.v. irinotecan and 400  mg/m i.v. outcomes, the suitability of ACT for patients with CLO LV on Day 1; 400  mg/m i.v. 5-FU on Day 1 and then is unclear [2, 11]. Additionally, even among CRC patients 1200 mg/m i.v. 5-FU for Day 1–2 for a 2-week cycle) and with the same disease stage, ACT benefits are deter - capecitabine (1000  mg/m oral capecitabine twice daily mined by such characteristics as preoperative carcinoem- on Days 1–14 for a 3-week cycle). During NAC, tumor bryonic antigen (CEA) level, need for emergent surgery, response was assessed using computerized tomography lymphovascular invasion, T stage and lymph node metas- (CT) or magnetic resonance imaging (MRI), by Response tasis [12, 13]. To our knowledge, the value of ACT has Evaluation Criteria in Solid Tumors, version 1.1 [16]. not been reported for patients who develop CLO after Patients underwent non-anatomical hepatectomy with curative resection. R0 resection (tumor-free margin > 1  mm). Decisions to Therefore, the present study explored whether ACT use ACT were based on patients’ tolerances and prefer- had a survival benefit for patients with CLO who had ences, and was recommended to begin 4–6  weeks after undergone curative liver resections, with particular liver resection. Among patients who underwent NAC, respect to patients’ risk classification according to the their ACT regimens were consistent with NAC. Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS) [14]. Risk status assessment Recurrence risk in patients after liver resection was eval- uated by the MSKCC-CRS [14]. The scoring system is Patients and methods based the following 5 clinical factors: (1) node-positive Patient selection primary tumor, (2) largest metastasis > 5 cm, (3) multiple We reviewed medical records of consecutive patients liver metastases, (4) preoperative CEA level > 200 ng/mL, with CRC liver metastases who underwent liver resection and (5) disease-free interval from primary tumor resec- between September 1999 and June 2015 at Sun Yat-sen tion to the diagnosis of liver metastasis < 12  months. University Cancer Center, China. Patients were included Based on the number of the risk factors, patients were in the present study according to the following criteria: classified into six risk subgroups (MSKCC-CRS 0–5). (1) histologically confirmed colorectal adenocarcinoma; Patients with a MSKCC-CRS of 0–2 were classified into (2) preoperative metastases confined to the liver; (3) no the low-risk subgroup, while patients with a MSKCC- more than 5 liver metastases; (4) R0 resection for both CRS of 3–5 were classified into the high-risk subgroup. Pan et al. Cancer Commun (2018) 38:29 Page 3 of 10 Follow‑up (Table  1). Overall, 171 (64.8%) patients had synchronous Follow-up data were collected from a tracking system. metastases at the time of diagnosis. Of the 225 (85.2%) Patients were monitored through subsequent visits every patients for whom MSKCC-CRS could be evaluated, 3  months for the first 2  years and then semiannually for 162 (72.0%) were low-risk (MSKCC-CRS 0–2), and 63 5 years after liver resection. Evaluations included clinical (28.0%) were high-risk (MSKCC-CRS 3–5). In total, 122 examination and assessment of CEA and carbohydrate (46.2%) patients received NAC, including 47 (38.5%) who antigen (CA) 19-9 levels, and CT imaging of the chest, received FOLFOX, 32 (26.2%) who received XELOX, abdomen and pelvis at 3, 6, 12, and 18  months, 2  years, 36 (29.5%) who received FOLFIRI, and 7 (5.7%) who and annually thereafter. Liver MRI was used to confirm received capecitabine. Additionally, 200 (75.8%) patients suspicious lesions indicated on CT or in patients with received ACT, including 57 (28.5%) who received FOL- increased CEA or CA19-9 level but negative CT results. FOX, 82 (41.0%) who received XELOX, 46 (23.0%) who The final follow-up visit occurred in June 2017. OS was received FOLFIRI, and 15 (7.5%) who received capecit- defined as the interval from liver resection to the date of abine. The median duration of ACT was 3.0  months death from any cause or the date of last follow-up. Recur- (range 1.0–6.0 months). rence-free survival (RFS) was defined as the interval from liver resection to the date of disease recurrence, death Relationships of ACT with clinicopathologic characteristics from disease or last follow-up. Random censoring was The ACT and non-ACT groups did not significantly dif - applied to patients without recurrence or death at the last fer in clinicopathologic characteristics (Table  1), or in follow-up date. Early recurrence was defined as disease receiving NAC, or radiological tumor response (Table 2). recurrence or death within 6 months after liver resection, and late recurrence was defined as disease recurrence or Eec ff t of ACT on survival outcomes death at least 6 months after liver resection [17, 18]. After their primary liver resections, all patients were followed up for a median of 35.5  months (range 2.0– Statistical analysis 126.0  months). Median follow-up time did not sig- All statistical analyses were performed using Statisti- nificantly differ between the ACT group (36.2  months; cal Package for the Social Sciences (SPSS, version 21.0, range 2.0–126.0  months) and the non-ACT group Chicago, IL, USA) and GraphPad Prism version 6.01 (30.5  months; range 2.0–117.0  months; P = 0.315; (GraphPad, Inc., USA). Values are shown as median Table 3). Overall, 157 (59.5%) patients experienced tumor (range) or percentage. Continuous and categorical data recurrence, and 104 (39.4%) patients died of tumor pro- were compared with the Mann–Whitney U-test, and gression. The ACT and non-ACT groups did not signifi - the Chi square test or Fisher’s exact test, respectively, as cantly differ in postoperative recurrence (60.5% vs. 56.3%, appropriate. OS and RFS rates were estimated with the P = 0.547), early recurrence (24.8% vs. 27.8%, P = 0.718), Kaplan–Meier method; differences between groups were or the most common recurrence pattern—intrahepatic assessed with the log-rank test. Parameters for which metastasis (51.0% vs. 60.9%, P = 0.389). P < 0.10 for OS in univariate Cox models were included Three-year RFS was 43.0%, and OS was 68.1%, for the in multivariate Cox models. Hazard ratios (HRs) and 95% entire cohort, and did not significantly differ between confidence intervals (CIs) were subsequently calculated. the ACT and non-ACT groups (RFS: 42.1% vs. 45.7%, P < 0.05 (two-sided) was considered significant. P = 0.588, Fig. 1a; OS: 69.7% vs. 62.7%, P = 0.446, Fig. 1b). Among patients who received NAC, 3-year RFS and OS rates were not significantly different between the ACT Results and non-ACT groups (RFS: 27.5% vs. 35.1%, P = 0.621, Patient characteristics Fig. 2a; OS: 59.6% vs. 61.2%, P = 0.674, Fig. 2b). Likewise, We reviewed data from 365 patients with CRC liver 3-year RFS and OS rates were also comparable between metastases who underwent liver resections. After the ACT and non-ACT groups in the absence of NAC excluding patients with extrahepatic disease or incom- (RFS: 56.1% vs. 52.0%, P = 0.747, Fig.  2c; OS: 79.5% vs. plete resections, 283 patients were identified for careful 63.8%, P = 0.265, Fig. 2d). review. We then excluded 17 patients with more than The patients were further stratified as high risk for 5 liver metastases and 2 patients with follow-up of less recurrence (MSKCC-CRS 0–2) or low risk (MSKCC-CRS than 3  months for a final study cohort of 264 patients. 3–5). Among the low-risk patients, 3-year DFS and OS They included 171 (64.8%) men and 93 (35.2%) women, rates were comparable between the ACT and non-ACT with a median age of 57  years (range 25–85  years). groups (RFS: 50.5% vs. 55.8%, P = 0.709, Fig.  3a; OS: Their primary tumors were located in the colon for 163 72.2% vs. 78.6% P = 0.834, Fig.  3b). Among the high-risk (61.7%) patients and rectum for 101 (38.3%) patients patients, although no significant difference was found in Pan et al. Cancer Commun (2018) 38:29 Page 4 of 10 Table 1 Clinicopathologic characteristics of  patients with  colorectal oligometastasis to  the  liver after  curative liver resection Parameters Total (n) With ACT (n, %) Without ACT (n, %) P value Number of patients 264 200 64 Age, years ≤ 60 164 129 (64.5) 35 (54.7) 0.159 > 60 100 71 (35.5) 29 (45.3) Sex Male 171 128 (64.0) 43 (67.2) 0.895 Female 93 72 (36.0) 21 (32.8) Primary tumor location Colon 163 126 (63.0) 37 (57.8) 0.457 Rectum 101 74 (37.0) 27 (42.8) Primary tumor differentiation Well to moderate 206 155 (77.5) 51 (79.7) 0.713 Poor 58 45 (22.5) 13 (20.3) T stage 1–3 157 122 (65.2) 35 (66.5) 0.707 4 86 65 (34.8) 21 (33.5) N stage 0 103 78 (42.9) 25 (45.3) 0.814 1–2 135 104 (57.1) 31 (55.4) Timing of metastasis Synchronous 171 136 (68.0) 35 (54.7) 0.052 Metachronous 93 64 (32.0) 29 (45.3) Number of metastatic tumors 1 140 102 (51.0) 38 (59.4) 0.501 2–3 99 78 (39.0) 21 (32.8) 4–5 25 20 (10.0) 5 (7.8) Metastases diameter (cm) ≤ 3 173 134 (68.0) 39 (61.9) 0.371 > 3 87 63 (32.0) 24 (38.1) Preoperative CEA (ng/mL) ≤ 50 200 156 (81.7) 44 (73.3) 0.161 > 50 51 35 (18.3) 16 (26.7) Preoperative CA19-9 (U/mL) ≤ 35 166 128 (68.8) 38 (66.7) 0.760 > 35 77 58 (31.2) 19 (33.3) Preoperative chemotherapy Yes 122 98 (49.0) 24 (37.5) 0.108 No 142 102 (51.0) 40 (62.5) MSKCC-CRS 0–2 162 127 (73.4) 35 (67.3) 0.390 3–5 63 46 (26.6) 17 (32.7) ACT adjuv ant chemotherapy, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, MSKCC-CRS Memorial Sloan-Kettering Cancer Center clinical risk score Data were available for 243 patients Data were available for 238 patients Data were available for 260 patients Data were available for 251 patients Data were available for 225 patients Pan et al. Cancer Commun (2018) 38:29 Page 5 of 10 Table 2 Clinicopathologic characteristics of patients stratified by both neoadjuvant and adjuvant chemotherapy Parameters With preoperative chemotherapy (n = 122) P value Without preoperative chemotherapy (n = 142) P value With ACT (n, %) Without ACT (n, %) With ACT (n, %) Without ACT (n, %) Number of patients 98 24 102 40 Age, years ≤ 60 69 (70.4) 16 (66.7) 0.721 60 (58.8) 19 (47.5) 0.222 > 60 29 (29.6) 8 (33.3) 42 (41.2) 21 (52.5) Sex Male 65 (66.3) 17 (70.8) 0.673 63 (61.8) 26 (65.0) 0.720 Female 33 (33.7) 7 (29.2) 39 (38.2) 14 (35.0) Primary tumor location Colon 55 (56.1) 15 (62.5) 0.571 71 (69.6) 22 (55.0) 0.100 Rectum 43 (43.9) 9 (37.5) 31 (30.4) 18 (45.0) Primary tumor differentiation Well to moderate 72 (73.5) 20 (83.3) 0.315 83 (81.4) 31 (77.5) 0.602 Poor 26 (26.5) 4 (16.7) 19 (18.6) 9 (22.5) T stage 1–3 50 (53.2) 12 (54.5) 0.909 72 (77.4) 23 (67.6) 0.261 4 44 (46.8) 10 (45.5) 21 (22.6) 11 (32.4) N stage 0 41 (45.6) 12 (54.5) 0.449 37 (40.2) 13 (38.2) 0.840 1–2 49 (54.4) 10 (45.5) 55 (59.8) 21 (61.8) Timing of metastasis Synchronous 74 (75.5) 15 (62.5) 0.198 62 (60.8) 20 (50.0) 0.242 Metachronous 24 (24.5) 9 (37.5) 40 (39.2) 20 (50.0) Number of metastatic tumors 1 29 (29.6) 9 (37.5) 0.453 73 (71.6) 29 (72.5) 0.912 2–5 69 (70.4) 15 (62.5) 29 (28.4) 11 (27.5) Metastases diameter (cm) ≤ 3 59 (62.1) 14 (58.3) 0.735 75 (73.5) 25 (64.1) 0.270 > 3 36 (37.9) 10 (41.7) 27 (26.5) 14 (35.9) Preoperative CEA (ng/mL) ≤ 50 78 (82.1) 17 (81.0) 0.901 78 (81.3) 27 (69.2) 0.128 > 50 17 (17.9) 4 (19.0) 18 (18.8) 12 (30.8) Preoperative CA19-9 (U/mL) ≤ 35 70 (76.9) 15 (75.0) 1.000 58 (61.1) 23 (62.2) 0.906 > 35 21 (23.1) 5 (25.0) 37 (38.9) 14 (37.8) MSKCC-CRS 0–2 54 (63.5) 9 (47.4) 0.193 73 (83.0) 26 (78.8) 0.597 3–5 31 (36.5) 10 (52.6) 15 (17.0) 7 (21.2) Preoperative chemotherapy regimen FOLFOX + XELOX 61 (62.2) 18 (75.0) 0.503 FOLFIRI 31 (31.6) 5 (20.8) Capecitabine 6 (6.1) 1 (4.2) Radiological response to preoperative chemotherapy PR 57 (58.8) 13 (54.2) 0.683 SD 30 (30.9) 7 (29.2) PD 10 (10.3) 4 (16.7) Pan et al. Cancer Commun (2018) 38:29 Page 6 of 10 Table 2 (continued) ACT adjuv ant chemotherapy, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, MSKCC-CRS Memorial Sloan-Kettering Cancer Center clinical risk score, PD progressive disease, PR partial response, SD stable disease Data were available for 243 patients Data were available for 238 patients Data were available for 260 patients Data were available for 251 patients Data were available for 243 patients Data were available for 225 patients Data were available for 121 patients Among high-risk patients, univariate analysis associ- Table 3 Postoperative recurrence in patients with colorectal oligometastases to  liver after  curative liver resection, ated ACT with a higher 3-year OS rate (HR: 0.402; 95% with or without adjuvant chemotherapy CI 0.188–0.858; P = 0.018; Table  4); and multivariate analysis showed ACT (HR: 0.350; 95% CI 0.161–0.759; Parameters With ACT (n, %) Without ACT (n, %) P value P = 0.008) and T stage (HR: 2.247; 95% CI 1.093–4.622; Postoperative recurrence (n = 264) P = 0.028) to be independent predictors of higher 3-year Yes 121 (60.5) 36 (56.2) 0.547 OS rates. No 79 (39.5) 28 (43.8) Recurrence period (n = 157) Discussion Early recurrence 30 (24.8) 10 (27.8) 0.718 The efficacy of ACT in prolonging survival of patients Latter recurrence 91 (75.2) 26 (72.2) after curative resection of CRC liver metastases remains Recurrence pattern (n = 127) unknown, especially in patients with CLO, who could Intrahepatic metas- 53 (51.0) 14 (60.9) 0.389 potentially achieve longer survival after curative treat- tases ment. As evidence of whether ACT after curative liver Extrahepatic metas- 51 (49.0) 9 (39.1) resection is worthwhile is lacking, we investigated the tases role of ACT in patients with CLO after curative liver ACT adjuv ant chemotherapy resection. Although we saw no significant benefit from Data of recurrence pattern were unavailable for 30 patients ACT on RFS and OS (irrespective of NAC), it notably improved OS in high-risk patient. 3-year DFS rates (25.4% vs. 21.2%, P = 0.978, Fig. 3c), the Based on the beneficial effects of ACT on patients with 3-year OS rate was significantly higher in the ACT group resected stage III colon cancer [19, 20], several studies than in the non-ACT group (68.2% vs. 33.8%, P = 0.015, have assessed its efficacy in eliminating micrometastatic Fig. 3d). disease in patients with CRC liver metastases after liver Fig. 1 Kaplan–Meier survival curves comparing 3-year (a) recurrence-free survival (RFS) and (b) overall survival (OS) rates, based on administration of adjuvant chemotherapy (ACT ) in patients who develop colorectal oligometastases to liver after curative liver resection Pan et al. Cancer Commun (2018) 38:29 Page 7 of 10 Fig. 2 Kaplan–Meier survival curves of patients with or without neoadjuvant chemotherapy (NAC) stratified by the administration of adjuvant chemotherapy (ACT ). a Recurrence-free survival (RFS) in the NAC group; b overall survival (OS) in the NAC group; c RFS in the non-NAC group; and d OS in the non-NAC group resection. The EORTC trial 40983 first showed that peri - current study, differences between the ACT and non- operative chemotherapy with FOLFOX4 (folinic acid, ACT groups in 3-year RFS (42.1% vs. 45.7%, P = 0.588) 5-FU, and oxaliplatin) improved 3-year progression-free and OS (69.7% vs. 62.7%, P = 0.446) among patients with survival (PFS) in patients with initially resectable CRC CLO were smaller than those in the pooled analysis. In liver metastases who underwent liver resection, com- addition, ACT did not significantly decrease the rate of pared with surgery alone (HR: 0.73, 95% CI 0.55–0.97, postoperative recurrence or affect the recurrence pattern. P = 0.025) [21]. After a median follow-up of 8.5  years The selected group of patients in our study experienced in EORTC trial 40983, the 5-year OS rate was slightly favorable survival outcomes after liver resection irrespec- higher in the perioperative chemotherapy group than in tive of ACT administration (3-year RFS: 43.0% and 3-year the surgery-alone group, but not significantly so (5-year OS rates: 68.1%), which implies that ACT has no effect OS rate: 57.3% vs. 54.4%, P = 0.350) [7]. However, the on long-term survival. potential benefits of NAC and ACT could not be dis - NAC has been shown to benefit some patients by cerned in that setting. Although an analysis of pooled allowing conversion to stable or resectable disease, data from the EORTC 40923 trial and FFCD trial 9002 which can translate into better long-term survival [22, showed potential improvement in the 5-year RFS (36.7% 23]. Here, we explored the effect of ACT, with or with - vs. 27.7%, P = 0.058) and OS (52.8% vs. 39.6%, P = 0.095) out NAC, on patient survival. No significant differences in response to ACT with a 5-FU bolus-based regimen were observed in the 3-year RFS and OS between the in patients after complete resection of CRC liver metas- ACT and non-ACT groups, with or without NAC. Thus, tases, the differences between the ACT group and ACT did not provide a survival benefit, irrespective of surgery-alone group were non-significant [11]. In the NAC. Contrary to our results, a recent study by Wang Pan et al. Cancer Commun (2018) 38:29 Page 8 of 10 Fig. 3 Kaplan–Meier survival curves of patients with lower risk (Memorial Sloan-Kettering Cancer Center clinical risk score [MSKCC-CRS] of 0–2) or higher risk (MSKCC-CRS 3–5) for chemotherapy, stratified by the administration of adjuvant chemotherapy (ACT ). a Recurrence-free survival (RFS) in the lower-risk group; b overall survival (OS) in the lower-risk group 2; c RFS in the higher risk group; and d OS in the higher risk group Table 4 Univariate and multivariate analyses of prognostic factors for overall survival in patients with MSKCC-CRS 3–5 Variable Univariate Multivariate HR (95% CI) P value HR (95% CI) P value Age (≤ 60 years vs. > 60 years) 0.945 (0.457–1.955) 0.880 Sex (male vs. female) 1.014 (0.492–2.090) 0.970 Primary tumor location (rectum vs. colon) 1.562 (0.754–3.236) 0.230 Primary tumor differentiation (poor vs. well to moderate) 1.601 (0.732–3.502) 0.160 T stage (4 vs. 1–3) 1.957 (0.964–3.973) 0.063 2.247 (1.093–4.622) 0.028 N stage (positive vs. negative) 1.139 (0.345–3.760) 0.831 Timing of metastasis (synchronous vs. metachronous) 1.190 (0.456–3.106) 0.722 Number of metastatic tumors (> 1 vs. 1) 0.930 (0.279–3.095) 0.906 Metastases diameter( > 3 cm vs. ≤ 3 cm) 1.625 (0.795–3.321) 0.183 Preoperative CEA (> 50 ng/mL vs. ≤ 50 ng/mL) 0.727 (0.334–1.585) 0.423 Preoperative CA19-9 (> 35 U/mL vs. ≤ 35 U/mL) 0.972 (0.444–2.129) 0.943 Preoperative chemotherapy (yes vs. no) 1.470 (0.687–3.148) 0.321 ACT (yes vs. no) 0.402 (0.188–0.858) 0.018 0.350 (0.161–0.759) 0.008 ACT adjuv ant chemotherapy, CA19-9 carbohydrate antigen 19-9, CEA carcinoembryonic antigen, CI confidence interval, HR hazard ratio, MSKCC-CRS Memorial Sloan- Kettering Cancer Center clinical risk score Pan et al. Cancer Commun (2018) 38:29 Page 9 of 10 et  al. [24] demonstrated the efficacy of ACT in patients have exerted specific prognostic effects that were not with CRC liver metastases who received NAC and liver analyzed in the current study [30, 31]. Third, the short resection, and suggested that ACT was an effective post - follow-up periods were insufficient to evaluate 5-year operative management strategy. Notably, the discrepancy survival outcomes, and may also have led to underes- in the results between the present study and the study timation of the effect of ACT on long-term survival. by Wang et  al. may be attributable to patient selection Moreover, the effect of microsatellite instability, and and the type of liver resection. In our study, only 28.0% mutations on such biomarkers as KRAS proto-onco- of patients were classified as high-risk group, based on a gene, NRAS proto-oncogene, B-Raf proto-oncogene, limited number of liver metastasis, while in the study by and phosphatidylinositol-4,5-bisphosphate 3-kinase Wang et al. 43.3% of patients were identified as high risk. catalytic subunit alpha on the efficacy of ACT was not In addition, 23.9% of patients underwent R1 resection in assessed in the present study. Future studies should the study by Wang et al. Therefore, these data preliminar - examine these biomarkers. Despite these limitations, ily indicate that the benefit of ACT might mainly depend our study shows a basis for further clinical trials to on patients’ risk factors, but not on their acceptance of evaluate the efficacy of ACT in patients with CLO after NAC. curative resection. Subgroup analyses based on various risk factors showed that ACT may not be the best treatment strat- egy for all patients with CLO. The efficacy of ACT was Conclusion mainly observed in high-risk patients; ACT failed to ACT provides prognostic benefits in high-risk patients, prolong survival of patients with low risk of recur- but not low-risk patients, who develop CLO after rence, which was consistent with many previous stud- undergoing curative liver resection. To optimize use of ies. A study by Rahbari et  al. [25] demonstrated that ACT, patients’ risk status should be determined while ACT markedly improved survival in high-risk patients forming early management plans. Further prospective with MSKCC-CRS > 2 (HR: 0.40; 95% CI 0.23–0.69, studies are warranted to validate our results. P = 0.001), but failed to provide any benefit to patients with a MSKCC-CRS ≤ 2 (HR: 0.90; 95% CI 0.57–1.43, Abbreviations P = 0.670). Likewise, ACT provided no benefit for 5-year 5-FU: 5-fluorouracil; ACT : adjuvant chemotherapy; CA-19-9: carbohydrate DFS (55.7% vs. 62.7%, P = 0.93) or OS (81.1% vs. 71.7%, antigen-19-9; CEA: carcinoembryonic antigen; CI: confidence interval; CLO: colorectal liver oligometastases; CRC: color ectal cancer; CT: computerized P = 0.460) in patients with low MSKCC-CRS in the study tomography; HR: hazard ratio; LV: leucovorin; MDT: multidisciplinary team; by Nakai et  al. [26]. Interestingly, by examining baseline MRI: magnetic resonance imaging; MSKCC-CRS: Memorial Sloan-Kettering parameters that predicted beneficial effects of periop - Cancer Center clinical risk scores; NAC: neoadjuvant chemotherapy; OS: overall survival; RFS: recurrence-free survival. erative chemotherapy on PFS in the EORTC 40983 trial, Sorbye et al. [27] demonstrated that patients with higher Authors’ contributions CEA levels (> 5  ng/mL) had better 3-year PFS than did ZP and JP carried out the data analysis and drafted the manuscript; JP, YD, YZ and QS participated in clinical data collection; GC, XW and ZL supervised the patients who were treated with surgery alone (35% vs. research program and edited the manuscript; DW had significant roles in the 20%, P = 0.002). Hirokawa et al. [28] also found that ACT study design and manuscript review. All authors read and approved the final increased OS and RFS in 110 patients with CRC liver manuscript. metastases who underwent initial liver resections and Acknowledgements had > 2 risk factors, including H2 classification, invasive We would like to thank the all colleagues of Department of Colorectal Surgery tumors (pT4), and positive lymph nodes. Based on the in Sun Yat-sen University Cancer Center, who have involved with performing the treatment for current study. overall results of the study, early engagement by a MDT was needed to carefully evaluate patients’ risk status Competing interests before receiving ACT, to increase chances of cure [29]. The authors declare that they have no competing interests. u Th s, ACT could be considered a standard treatment Availability of data and materials strategy after liver resection for high-risk patients, but The key raw data have been deposited into the Research Data Deposit (http:// not for low-risk patients.www.resea rchda ta.org.cn), with the Approval Number of RDDA2017000391. The present study had some limitations. First, this Consent for publication retrospective study employed an uncontrolled method- Not applicable. ology with a limited number of patients from a single Ethics approval and consent to participate institution. Therefore, the findings need to be validated The present study was undertaken in accordance with the ethical standards in a prospective study with a larger sample size. Sec- of the World Medical Association Declaration of Helsinki of 2013. Informed ond, the various ACT regimens and durations might consents before initial treatment were requested and the study approval Pan et al. Cancer Commun (2018) 38:29 Page 10 of 10 was obtained from independent ethics committees at Sun Yat-sen University neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for colorec- Cancer Center. tal liver-only metastases survival. Onco Targets Ther. 2017;10:3789–99. 16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Funding et al. New response evaluation criteria in solid tumours: revised RECIST The present study was funded by the National Natural Science Foundation of guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. China (No. 81772595), Sun Yat-sen University Clinical Research 5010 Program 17. Jung SW, Kim DS, Yu YD, Han JH, Suh SO. Risk factors for cancer recur- (2015024), Sun Yat-sen University Clinical Research 5010 Program (2013013) rence or death within 6 months after liver resection in patients with and Science and Technology Planning Project of Guangdong Province (Grant colorectal cancer liver metastasis. Ann Surg Treat Res. 2016;90(5):257–64. No. 2013B021800146). 18. Malik HZ, Gomez D, Wong V, Al-Mukthar A, Toogood GJ, Lodge JP, et al. Predictors of early disease recurrence following hepatic resection for Received: 18 October 2017 Accepted: 8 March 2018 colorectal cancer metastasis. Eur J Surg Oncol. 2007;33(8):1003–9. 19. Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–71. 20. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. References Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as 1. O’Reilly DA, Poston GJ. Colorectal liver metastases: current and future adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin perspectives. Future Oncol. 2006;2(4):525–31. Oncol. 2009;27(19):3109–16. 2. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, 21. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. ESMO consensus guidelines for the management of patients with et al. Perioperative chemotherapy with FOLFOX4 and surgery versus metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422. surgery alone for resectable liver metastases from colorectal cancer 3. Dexiang Z, Li R, Ye W, Haifu W, Yunshi Z, Qinghai Y, et al. Outcome of (EORTC Intergroup trial 40983): a randomised controlled trial. 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Is there a survival benefit from adjuvant chemotherapy for patients with liver oligometastases from colorectal cancer after curative resection?

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Abstract

Background: Although colorectal oligometastases to the liver can potentially be cured with aggressive local abla- tion, the efficacy of adjuvant chemotherapy (ACT ) for such metastasis remains unclear. The present study explored the effects of ACT on patients with colorectal liver oligometastases (CLO) after curative resections and aimed to iden- tify patients who could benefit from ACT. Methods: We retrospectively analyzed 264 eligible patients with CLO who underwent curative resection between September 1999 and June 2015. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan–Meier method and log-rank test; prognostic factors were a by Cox regression modeling. Results: Among 264 patients, 200 (75.8%) patients received ACT and 64 (24.2%) did not receive ACT. These two groups did not significantly differ in clinicopathologic characteristics, and had comparable 3-year OS and RFS rates (RFS: 42.1% vs. 45.7%, P = 0.588; OS: 69.7% vs. 62.7%, P = 0.446) over a median follow-up duration of 35.5 months, irrespective of preoperative chemotherapy. ACT markedly improved 3-year OS in high-risk patients with Memorial Sloan-Kettering Cancer Center clinical risk scores (MSKCC-CRS) of 3–5 (68.2% vs. 33.8%, P = 0.015), but presented no additional benefit in patients with MSKCC-CRS of 0–2 (72.2% vs. 78.6%, P = 0.834). In multivariate analysis, ACT was independently associated with improved OS in patients with MSKCC-CRS of 3–5. Conclusions: ACT might offer a prognostic benefit in high-risk patients with CLOs after curative liver resection, but not in low-risk patients. Therefore, patients’ risk status should be determined before ACT administration to optimize postoperative therapeutic strategies. Keywords: Colorectal cancer, Oligometastases, Adjuvant chemotherapy, Liver resection, Benefit *Correspondence: wands@sysucc.org.cn Zhizhong Pan, Jianhong Peng and Junzhong Lin contributed equally to this work Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, Guangdong, P. R. China © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pan et al. Cancer Commun (2018) 38:29 Page 2 of 10 primary and metastatic tumors; and (5) a minimum Introduction follow-up duration of 3  months. Tumor stage was clas- The liver is the most common site of metastasis in sified according to the 2010 American Joint Committee patients with colorectal cancer (CRC). At diagnosis, on Cancer staging system. Eligible patients’ clinicopatho- approximately 25% of patients present with synchronous logic data and treatment information were reviewed metastases, and approximately 50% patients ultimately using an electronic medical record system. All proce- develop metachronous metastases [1, 2]. Liver resec- dures were performed according to the ethical standards tion is the most effective curative treatment for patients of the World Medical Association Declaration of Hel- with CRC liver metastasis, with a 5-year survival rate sinki of 2013. We obtained approval from the independ- of 40%–50% [3, 4]. However, ~ 60% of patients develop ent ethics committee at Sun Yat-sen University Cancer recurrent liver metastases after initial liver resection [5, Center, and requested the informed consents before ini- 6]. Because of this high recurrence rate, adjuvant chemo- tial treatments. therapy (ACT) has been investigated for patients with CRC metastasis to the liver. Although several studies have indicated the potential efficacy of ACT in prolong - Patient treatments ing survival, its benefits had not been definitively shown The treatment strategy for every patient in the current until now [7–9]. study was determined by a multidisciplinary team (MDT) The latest version of the European Society for Medical as previously described [15]. Preoperative (neoadjuvant) Oncology Guidelines highlights oligometastatic disease— chemotherapy (NAC) and ACT regimens were deter- a disease state that links localized and systemic disease mined based on evaluations by oncologists, and included [2]. Notably, oligometastatic disease confined to the liver XELOX (130  mg/m intravenous [i.v.] oxaliplatin on is potentially curable. Aggressive locally ablative treat- Day 1 and 1000  mg/m oral capecitabine twice daily on ments, including liver resection, may prolong survival of Days 1–14 for a 3-week cycle), FOLFOX (85  mg/m i.v. patients with colorectal liver oligometastasis (CLO), with oxaliplatin and 400 mg/m i.v. leucovorin [LV] on Day 1; a 5-year overall survival (OS) rate of 45.9% as shown in 400  mg/m i.v. 5-fluorouracil (5-FU) on Day 1 and then our previous study [10]. Because complete resection is 1200  mg/m i.v. 5-FU for Day 1–2 for a 2-week cycle), 2 2 technically easy to perform, with usually good oncologic FOLFIRI (180  mg/m i.v. irinotecan and 400  mg/m i.v. outcomes, the suitability of ACT for patients with CLO LV on Day 1; 400  mg/m i.v. 5-FU on Day 1 and then is unclear [2, 11]. Additionally, even among CRC patients 1200 mg/m i.v. 5-FU for Day 1–2 for a 2-week cycle) and with the same disease stage, ACT benefits are deter - capecitabine (1000  mg/m oral capecitabine twice daily mined by such characteristics as preoperative carcinoem- on Days 1–14 for a 3-week cycle). During NAC, tumor bryonic antigen (CEA) level, need for emergent surgery, response was assessed using computerized tomography lymphovascular invasion, T stage and lymph node metas- (CT) or magnetic resonance imaging (MRI), by Response tasis [12, 13]. To our knowledge, the value of ACT has Evaluation Criteria in Solid Tumors, version 1.1 [16]. not been reported for patients who develop CLO after Patients underwent non-anatomical hepatectomy with curative resection. R0 resection (tumor-free margin > 1  mm). Decisions to Therefore, the present study explored whether ACT use ACT were based on patients’ tolerances and prefer- had a survival benefit for patients with CLO who had ences, and was recommended to begin 4–6  weeks after undergone curative liver resections, with particular liver resection. Among patients who underwent NAC, respect to patients’ risk classification according to the their ACT regimens were consistent with NAC. Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS) [14]. Risk status assessment Recurrence risk in patients after liver resection was eval- uated by the MSKCC-CRS [14]. The scoring system is Patients and methods based the following 5 clinical factors: (1) node-positive Patient selection primary tumor, (2) largest metastasis > 5 cm, (3) multiple We reviewed medical records of consecutive patients liver metastases, (4) preoperative CEA level > 200 ng/mL, with CRC liver metastases who underwent liver resection and (5) disease-free interval from primary tumor resec- between September 1999 and June 2015 at Sun Yat-sen tion to the diagnosis of liver metastasis < 12  months. University Cancer Center, China. Patients were included Based on the number of the risk factors, patients were in the present study according to the following criteria: classified into six risk subgroups (MSKCC-CRS 0–5). (1) histologically confirmed colorectal adenocarcinoma; Patients with a MSKCC-CRS of 0–2 were classified into (2) preoperative metastases confined to the liver; (3) no the low-risk subgroup, while patients with a MSKCC- more than 5 liver metastases; (4) R0 resection for both CRS of 3–5 were classified into the high-risk subgroup. Pan et al. Cancer Commun (2018) 38:29 Page 3 of 10 Follow‑up (Table  1). Overall, 171 (64.8%) patients had synchronous Follow-up data were collected from a tracking system. metastases at the time of diagnosis. Of the 225 (85.2%) Patients were monitored through subsequent visits every patients for whom MSKCC-CRS could be evaluated, 3  months for the first 2  years and then semiannually for 162 (72.0%) were low-risk (MSKCC-CRS 0–2), and 63 5 years after liver resection. Evaluations included clinical (28.0%) were high-risk (MSKCC-CRS 3–5). In total, 122 examination and assessment of CEA and carbohydrate (46.2%) patients received NAC, including 47 (38.5%) who antigen (CA) 19-9 levels, and CT imaging of the chest, received FOLFOX, 32 (26.2%) who received XELOX, abdomen and pelvis at 3, 6, 12, and 18  months, 2  years, 36 (29.5%) who received FOLFIRI, and 7 (5.7%) who and annually thereafter. Liver MRI was used to confirm received capecitabine. Additionally, 200 (75.8%) patients suspicious lesions indicated on CT or in patients with received ACT, including 57 (28.5%) who received FOL- increased CEA or CA19-9 level but negative CT results. FOX, 82 (41.0%) who received XELOX, 46 (23.0%) who The final follow-up visit occurred in June 2017. OS was received FOLFIRI, and 15 (7.5%) who received capecit- defined as the interval from liver resection to the date of abine. The median duration of ACT was 3.0  months death from any cause or the date of last follow-up. Recur- (range 1.0–6.0 months). rence-free survival (RFS) was defined as the interval from liver resection to the date of disease recurrence, death Relationships of ACT with clinicopathologic characteristics from disease or last follow-up. Random censoring was The ACT and non-ACT groups did not significantly dif - applied to patients without recurrence or death at the last fer in clinicopathologic characteristics (Table  1), or in follow-up date. Early recurrence was defined as disease receiving NAC, or radiological tumor response (Table 2). recurrence or death within 6 months after liver resection, and late recurrence was defined as disease recurrence or Eec ff t of ACT on survival outcomes death at least 6 months after liver resection [17, 18]. After their primary liver resections, all patients were followed up for a median of 35.5  months (range 2.0– Statistical analysis 126.0  months). Median follow-up time did not sig- All statistical analyses were performed using Statisti- nificantly differ between the ACT group (36.2  months; cal Package for the Social Sciences (SPSS, version 21.0, range 2.0–126.0  months) and the non-ACT group Chicago, IL, USA) and GraphPad Prism version 6.01 (30.5  months; range 2.0–117.0  months; P = 0.315; (GraphPad, Inc., USA). Values are shown as median Table 3). Overall, 157 (59.5%) patients experienced tumor (range) or percentage. Continuous and categorical data recurrence, and 104 (39.4%) patients died of tumor pro- were compared with the Mann–Whitney U-test, and gression. The ACT and non-ACT groups did not signifi - the Chi square test or Fisher’s exact test, respectively, as cantly differ in postoperative recurrence (60.5% vs. 56.3%, appropriate. OS and RFS rates were estimated with the P = 0.547), early recurrence (24.8% vs. 27.8%, P = 0.718), Kaplan–Meier method; differences between groups were or the most common recurrence pattern—intrahepatic assessed with the log-rank test. Parameters for which metastasis (51.0% vs. 60.9%, P = 0.389). P < 0.10 for OS in univariate Cox models were included Three-year RFS was 43.0%, and OS was 68.1%, for the in multivariate Cox models. Hazard ratios (HRs) and 95% entire cohort, and did not significantly differ between confidence intervals (CIs) were subsequently calculated. the ACT and non-ACT groups (RFS: 42.1% vs. 45.7%, P < 0.05 (two-sided) was considered significant. P = 0.588, Fig. 1a; OS: 69.7% vs. 62.7%, P = 0.446, Fig. 1b). Among patients who received NAC, 3-year RFS and OS rates were not significantly different between the ACT Results and non-ACT groups (RFS: 27.5% vs. 35.1%, P = 0.621, Patient characteristics Fig. 2a; OS: 59.6% vs. 61.2%, P = 0.674, Fig. 2b). Likewise, We reviewed data from 365 patients with CRC liver 3-year RFS and OS rates were also comparable between metastases who underwent liver resections. After the ACT and non-ACT groups in the absence of NAC excluding patients with extrahepatic disease or incom- (RFS: 56.1% vs. 52.0%, P = 0.747, Fig.  2c; OS: 79.5% vs. plete resections, 283 patients were identified for careful 63.8%, P = 0.265, Fig. 2d). review. We then excluded 17 patients with more than The patients were further stratified as high risk for 5 liver metastases and 2 patients with follow-up of less recurrence (MSKCC-CRS 0–2) or low risk (MSKCC-CRS than 3  months for a final study cohort of 264 patients. 3–5). Among the low-risk patients, 3-year DFS and OS They included 171 (64.8%) men and 93 (35.2%) women, rates were comparable between the ACT and non-ACT with a median age of 57  years (range 25–85  years). groups (RFS: 50.5% vs. 55.8%, P = 0.709, Fig.  3a; OS: Their primary tumors were located in the colon for 163 72.2% vs. 78.6% P = 0.834, Fig.  3b). Among the high-risk (61.7%) patients and rectum for 101 (38.3%) patients patients, although no significant difference was found in Pan et al. Cancer Commun (2018) 38:29 Page 4 of 10 Table 1 Clinicopathologic characteristics of  patients with  colorectal oligometastasis to  the  liver after  curative liver resection Parameters Total (n) With ACT (n, %) Without ACT (n, %) P value Number of patients 264 200 64 Age, years ≤ 60 164 129 (64.5) 35 (54.7) 0.159 > 60 100 71 (35.5) 29 (45.3) Sex Male 171 128 (64.0) 43 (67.2) 0.895 Female 93 72 (36.0) 21 (32.8) Primary tumor location Colon 163 126 (63.0) 37 (57.8) 0.457 Rectum 101 74 (37.0) 27 (42.8) Primary tumor differentiation Well to moderate 206 155 (77.5) 51 (79.7) 0.713 Poor 58 45 (22.5) 13 (20.3) T stage 1–3 157 122 (65.2) 35 (66.5) 0.707 4 86 65 (34.8) 21 (33.5) N stage 0 103 78 (42.9) 25 (45.3) 0.814 1–2 135 104 (57.1) 31 (55.4) Timing of metastasis Synchronous 171 136 (68.0) 35 (54.7) 0.052 Metachronous 93 64 (32.0) 29 (45.3) Number of metastatic tumors 1 140 102 (51.0) 38 (59.4) 0.501 2–3 99 78 (39.0) 21 (32.8) 4–5 25 20 (10.0) 5 (7.8) Metastases diameter (cm) ≤ 3 173 134 (68.0) 39 (61.9) 0.371 > 3 87 63 (32.0) 24 (38.1) Preoperative CEA (ng/mL) ≤ 50 200 156 (81.7) 44 (73.3) 0.161 > 50 51 35 (18.3) 16 (26.7) Preoperative CA19-9 (U/mL) ≤ 35 166 128 (68.8) 38 (66.7) 0.760 > 35 77 58 (31.2) 19 (33.3) Preoperative chemotherapy Yes 122 98 (49.0) 24 (37.5) 0.108 No 142 102 (51.0) 40 (62.5) MSKCC-CRS 0–2 162 127 (73.4) 35 (67.3) 0.390 3–5 63 46 (26.6) 17 (32.7) ACT adjuv ant chemotherapy, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, MSKCC-CRS Memorial Sloan-Kettering Cancer Center clinical risk score Data were available for 243 patients Data were available for 238 patients Data were available for 260 patients Data were available for 251 patients Data were available for 225 patients Pan et al. Cancer Commun (2018) 38:29 Page 5 of 10 Table 2 Clinicopathologic characteristics of patients stratified by both neoadjuvant and adjuvant chemotherapy Parameters With preoperative chemotherapy (n = 122) P value Without preoperative chemotherapy (n = 142) P value With ACT (n, %) Without ACT (n, %) With ACT (n, %) Without ACT (n, %) Number of patients 98 24 102 40 Age, years ≤ 60 69 (70.4) 16 (66.7) 0.721 60 (58.8) 19 (47.5) 0.222 > 60 29 (29.6) 8 (33.3) 42 (41.2) 21 (52.5) Sex Male 65 (66.3) 17 (70.8) 0.673 63 (61.8) 26 (65.0) 0.720 Female 33 (33.7) 7 (29.2) 39 (38.2) 14 (35.0) Primary tumor location Colon 55 (56.1) 15 (62.5) 0.571 71 (69.6) 22 (55.0) 0.100 Rectum 43 (43.9) 9 (37.5) 31 (30.4) 18 (45.0) Primary tumor differentiation Well to moderate 72 (73.5) 20 (83.3) 0.315 83 (81.4) 31 (77.5) 0.602 Poor 26 (26.5) 4 (16.7) 19 (18.6) 9 (22.5) T stage 1–3 50 (53.2) 12 (54.5) 0.909 72 (77.4) 23 (67.6) 0.261 4 44 (46.8) 10 (45.5) 21 (22.6) 11 (32.4) N stage 0 41 (45.6) 12 (54.5) 0.449 37 (40.2) 13 (38.2) 0.840 1–2 49 (54.4) 10 (45.5) 55 (59.8) 21 (61.8) Timing of metastasis Synchronous 74 (75.5) 15 (62.5) 0.198 62 (60.8) 20 (50.0) 0.242 Metachronous 24 (24.5) 9 (37.5) 40 (39.2) 20 (50.0) Number of metastatic tumors 1 29 (29.6) 9 (37.5) 0.453 73 (71.6) 29 (72.5) 0.912 2–5 69 (70.4) 15 (62.5) 29 (28.4) 11 (27.5) Metastases diameter (cm) ≤ 3 59 (62.1) 14 (58.3) 0.735 75 (73.5) 25 (64.1) 0.270 > 3 36 (37.9) 10 (41.7) 27 (26.5) 14 (35.9) Preoperative CEA (ng/mL) ≤ 50 78 (82.1) 17 (81.0) 0.901 78 (81.3) 27 (69.2) 0.128 > 50 17 (17.9) 4 (19.0) 18 (18.8) 12 (30.8) Preoperative CA19-9 (U/mL) ≤ 35 70 (76.9) 15 (75.0) 1.000 58 (61.1) 23 (62.2) 0.906 > 35 21 (23.1) 5 (25.0) 37 (38.9) 14 (37.8) MSKCC-CRS 0–2 54 (63.5) 9 (47.4) 0.193 73 (83.0) 26 (78.8) 0.597 3–5 31 (36.5) 10 (52.6) 15 (17.0) 7 (21.2) Preoperative chemotherapy regimen FOLFOX + XELOX 61 (62.2) 18 (75.0) 0.503 FOLFIRI 31 (31.6) 5 (20.8) Capecitabine 6 (6.1) 1 (4.2) Radiological response to preoperative chemotherapy PR 57 (58.8) 13 (54.2) 0.683 SD 30 (30.9) 7 (29.2) PD 10 (10.3) 4 (16.7) Pan et al. Cancer Commun (2018) 38:29 Page 6 of 10 Table 2 (continued) ACT adjuv ant chemotherapy, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, MSKCC-CRS Memorial Sloan-Kettering Cancer Center clinical risk score, PD progressive disease, PR partial response, SD stable disease Data were available for 243 patients Data were available for 238 patients Data were available for 260 patients Data were available for 251 patients Data were available for 243 patients Data were available for 225 patients Data were available for 121 patients Among high-risk patients, univariate analysis associ- Table 3 Postoperative recurrence in patients with colorectal oligometastases to  liver after  curative liver resection, ated ACT with a higher 3-year OS rate (HR: 0.402; 95% with or without adjuvant chemotherapy CI 0.188–0.858; P = 0.018; Table  4); and multivariate analysis showed ACT (HR: 0.350; 95% CI 0.161–0.759; Parameters With ACT (n, %) Without ACT (n, %) P value P = 0.008) and T stage (HR: 2.247; 95% CI 1.093–4.622; Postoperative recurrence (n = 264) P = 0.028) to be independent predictors of higher 3-year Yes 121 (60.5) 36 (56.2) 0.547 OS rates. No 79 (39.5) 28 (43.8) Recurrence period (n = 157) Discussion Early recurrence 30 (24.8) 10 (27.8) 0.718 The efficacy of ACT in prolonging survival of patients Latter recurrence 91 (75.2) 26 (72.2) after curative resection of CRC liver metastases remains Recurrence pattern (n = 127) unknown, especially in patients with CLO, who could Intrahepatic metas- 53 (51.0) 14 (60.9) 0.389 potentially achieve longer survival after curative treat- tases ment. As evidence of whether ACT after curative liver Extrahepatic metas- 51 (49.0) 9 (39.1) resection is worthwhile is lacking, we investigated the tases role of ACT in patients with CLO after curative liver ACT adjuv ant chemotherapy resection. Although we saw no significant benefit from Data of recurrence pattern were unavailable for 30 patients ACT on RFS and OS (irrespective of NAC), it notably improved OS in high-risk patient. 3-year DFS rates (25.4% vs. 21.2%, P = 0.978, Fig. 3c), the Based on the beneficial effects of ACT on patients with 3-year OS rate was significantly higher in the ACT group resected stage III colon cancer [19, 20], several studies than in the non-ACT group (68.2% vs. 33.8%, P = 0.015, have assessed its efficacy in eliminating micrometastatic Fig. 3d). disease in patients with CRC liver metastases after liver Fig. 1 Kaplan–Meier survival curves comparing 3-year (a) recurrence-free survival (RFS) and (b) overall survival (OS) rates, based on administration of adjuvant chemotherapy (ACT ) in patients who develop colorectal oligometastases to liver after curative liver resection Pan et al. Cancer Commun (2018) 38:29 Page 7 of 10 Fig. 2 Kaplan–Meier survival curves of patients with or without neoadjuvant chemotherapy (NAC) stratified by the administration of adjuvant chemotherapy (ACT ). a Recurrence-free survival (RFS) in the NAC group; b overall survival (OS) in the NAC group; c RFS in the non-NAC group; and d OS in the non-NAC group resection. The EORTC trial 40983 first showed that peri - current study, differences between the ACT and non- operative chemotherapy with FOLFOX4 (folinic acid, ACT groups in 3-year RFS (42.1% vs. 45.7%, P = 0.588) 5-FU, and oxaliplatin) improved 3-year progression-free and OS (69.7% vs. 62.7%, P = 0.446) among patients with survival (PFS) in patients with initially resectable CRC CLO were smaller than those in the pooled analysis. In liver metastases who underwent liver resection, com- addition, ACT did not significantly decrease the rate of pared with surgery alone (HR: 0.73, 95% CI 0.55–0.97, postoperative recurrence or affect the recurrence pattern. P = 0.025) [21]. After a median follow-up of 8.5  years The selected group of patients in our study experienced in EORTC trial 40983, the 5-year OS rate was slightly favorable survival outcomes after liver resection irrespec- higher in the perioperative chemotherapy group than in tive of ACT administration (3-year RFS: 43.0% and 3-year the surgery-alone group, but not significantly so (5-year OS rates: 68.1%), which implies that ACT has no effect OS rate: 57.3% vs. 54.4%, P = 0.350) [7]. However, the on long-term survival. potential benefits of NAC and ACT could not be dis - NAC has been shown to benefit some patients by cerned in that setting. Although an analysis of pooled allowing conversion to stable or resectable disease, data from the EORTC 40923 trial and FFCD trial 9002 which can translate into better long-term survival [22, showed potential improvement in the 5-year RFS (36.7% 23]. Here, we explored the effect of ACT, with or with - vs. 27.7%, P = 0.058) and OS (52.8% vs. 39.6%, P = 0.095) out NAC, on patient survival. No significant differences in response to ACT with a 5-FU bolus-based regimen were observed in the 3-year RFS and OS between the in patients after complete resection of CRC liver metas- ACT and non-ACT groups, with or without NAC. Thus, tases, the differences between the ACT group and ACT did not provide a survival benefit, irrespective of surgery-alone group were non-significant [11]. In the NAC. Contrary to our results, a recent study by Wang Pan et al. Cancer Commun (2018) 38:29 Page 8 of 10 Fig. 3 Kaplan–Meier survival curves of patients with lower risk (Memorial Sloan-Kettering Cancer Center clinical risk score [MSKCC-CRS] of 0–2) or higher risk (MSKCC-CRS 3–5) for chemotherapy, stratified by the administration of adjuvant chemotherapy (ACT ). a Recurrence-free survival (RFS) in the lower-risk group; b overall survival (OS) in the lower-risk group 2; c RFS in the higher risk group; and d OS in the higher risk group Table 4 Univariate and multivariate analyses of prognostic factors for overall survival in patients with MSKCC-CRS 3–5 Variable Univariate Multivariate HR (95% CI) P value HR (95% CI) P value Age (≤ 60 years vs. > 60 years) 0.945 (0.457–1.955) 0.880 Sex (male vs. female) 1.014 (0.492–2.090) 0.970 Primary tumor location (rectum vs. colon) 1.562 (0.754–3.236) 0.230 Primary tumor differentiation (poor vs. well to moderate) 1.601 (0.732–3.502) 0.160 T stage (4 vs. 1–3) 1.957 (0.964–3.973) 0.063 2.247 (1.093–4.622) 0.028 N stage (positive vs. negative) 1.139 (0.345–3.760) 0.831 Timing of metastasis (synchronous vs. metachronous) 1.190 (0.456–3.106) 0.722 Number of metastatic tumors (> 1 vs. 1) 0.930 (0.279–3.095) 0.906 Metastases diameter( > 3 cm vs. ≤ 3 cm) 1.625 (0.795–3.321) 0.183 Preoperative CEA (> 50 ng/mL vs. ≤ 50 ng/mL) 0.727 (0.334–1.585) 0.423 Preoperative CA19-9 (> 35 U/mL vs. ≤ 35 U/mL) 0.972 (0.444–2.129) 0.943 Preoperative chemotherapy (yes vs. no) 1.470 (0.687–3.148) 0.321 ACT (yes vs. no) 0.402 (0.188–0.858) 0.018 0.350 (0.161–0.759) 0.008 ACT adjuv ant chemotherapy, CA19-9 carbohydrate antigen 19-9, CEA carcinoembryonic antigen, CI confidence interval, HR hazard ratio, MSKCC-CRS Memorial Sloan- Kettering Cancer Center clinical risk score Pan et al. Cancer Commun (2018) 38:29 Page 9 of 10 et  al. [24] demonstrated the efficacy of ACT in patients have exerted specific prognostic effects that were not with CRC liver metastases who received NAC and liver analyzed in the current study [30, 31]. Third, the short resection, and suggested that ACT was an effective post - follow-up periods were insufficient to evaluate 5-year operative management strategy. Notably, the discrepancy survival outcomes, and may also have led to underes- in the results between the present study and the study timation of the effect of ACT on long-term survival. by Wang et  al. may be attributable to patient selection Moreover, the effect of microsatellite instability, and and the type of liver resection. In our study, only 28.0% mutations on such biomarkers as KRAS proto-onco- of patients were classified as high-risk group, based on a gene, NRAS proto-oncogene, B-Raf proto-oncogene, limited number of liver metastasis, while in the study by and phosphatidylinositol-4,5-bisphosphate 3-kinase Wang et al. 43.3% of patients were identified as high risk. catalytic subunit alpha on the efficacy of ACT was not In addition, 23.9% of patients underwent R1 resection in assessed in the present study. Future studies should the study by Wang et al. Therefore, these data preliminar - examine these biomarkers. Despite these limitations, ily indicate that the benefit of ACT might mainly depend our study shows a basis for further clinical trials to on patients’ risk factors, but not on their acceptance of evaluate the efficacy of ACT in patients with CLO after NAC. curative resection. Subgroup analyses based on various risk factors showed that ACT may not be the best treatment strat- egy for all patients with CLO. The efficacy of ACT was Conclusion mainly observed in high-risk patients; ACT failed to ACT provides prognostic benefits in high-risk patients, prolong survival of patients with low risk of recur- but not low-risk patients, who develop CLO after rence, which was consistent with many previous stud- undergoing curative liver resection. To optimize use of ies. A study by Rahbari et  al. [25] demonstrated that ACT, patients’ risk status should be determined while ACT markedly improved survival in high-risk patients forming early management plans. Further prospective with MSKCC-CRS > 2 (HR: 0.40; 95% CI 0.23–0.69, studies are warranted to validate our results. P = 0.001), but failed to provide any benefit to patients with a MSKCC-CRS ≤ 2 (HR: 0.90; 95% CI 0.57–1.43, Abbreviations P = 0.670). Likewise, ACT provided no benefit for 5-year 5-FU: 5-fluorouracil; ACT : adjuvant chemotherapy; CA-19-9: carbohydrate DFS (55.7% vs. 62.7%, P = 0.93) or OS (81.1% vs. 71.7%, antigen-19-9; CEA: carcinoembryonic antigen; CI: confidence interval; CLO: colorectal liver oligometastases; CRC: color ectal cancer; CT: computerized P = 0.460) in patients with low MSKCC-CRS in the study tomography; HR: hazard ratio; LV: leucovorin; MDT: multidisciplinary team; by Nakai et  al. [26]. Interestingly, by examining baseline MRI: magnetic resonance imaging; MSKCC-CRS: Memorial Sloan-Kettering parameters that predicted beneficial effects of periop - Cancer Center clinical risk scores; NAC: neoadjuvant chemotherapy; OS: overall survival; RFS: recurrence-free survival. erative chemotherapy on PFS in the EORTC 40983 trial, Sorbye et al. [27] demonstrated that patients with higher Authors’ contributions CEA levels (> 5  ng/mL) had better 3-year PFS than did ZP and JP carried out the data analysis and drafted the manuscript; JP, YD, YZ and QS participated in clinical data collection; GC, XW and ZL supervised the patients who were treated with surgery alone (35% vs. research program and edited the manuscript; DW had significant roles in the 20%, P = 0.002). Hirokawa et al. [28] also found that ACT study design and manuscript review. All authors read and approved the final increased OS and RFS in 110 patients with CRC liver manuscript. metastases who underwent initial liver resections and Acknowledgements had > 2 risk factors, including H2 classification, invasive We would like to thank the all colleagues of Department of Colorectal Surgery tumors (pT4), and positive lymph nodes. Based on the in Sun Yat-sen University Cancer Center, who have involved with performing the treatment for current study. overall results of the study, early engagement by a MDT was needed to carefully evaluate patients’ risk status Competing interests before receiving ACT, to increase chances of cure [29]. The authors declare that they have no competing interests. u Th s, ACT could be considered a standard treatment Availability of data and materials strategy after liver resection for high-risk patients, but The key raw data have been deposited into the Research Data Deposit (http:// not for low-risk patients.www.resea rchda ta.org.cn), with the Approval Number of RDDA2017000391. The present study had some limitations. First, this Consent for publication retrospective study employed an uncontrolled method- Not applicable. ology with a limited number of patients from a single Ethics approval and consent to participate institution. Therefore, the findings need to be validated The present study was undertaken in accordance with the ethical standards in a prospective study with a larger sample size. Sec- of the World Medical Association Declaration of Helsinki of 2013. Informed ond, the various ACT regimens and durations might consents before initial treatment were requested and the study approval Pan et al. Cancer Commun (2018) 38:29 Page 10 of 10 was obtained from independent ethics committees at Sun Yat-sen University neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for colorec- Cancer Center. tal liver-only metastases survival. Onco Targets Ther. 2017;10:3789–99. 16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Funding et al. New response evaluation criteria in solid tumours: revised RECIST The present study was funded by the National Natural Science Foundation of guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. 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Cancer CommunicationsSpringer Journals

Published: May 29, 2018

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