Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications?

Kazunari Sasaki; Georgios A Margonis; Nikolaos Andreatos; Ana Wilson; Faiz Gani; Neda Amini; Timothy M Pawlik

doi:10.1016/j.hpb.2016.09.004

. 2016 Oct 18;18(12):1000–1009. doi: 10.1016/j.hpb.2016.09.004

Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications?

Kazunari Sasaki ¹, Georgios A Margonis ¹, Nikolaos Andreatos ¹, Ana Wilson ¹, Faiz Gani ¹, Neda Amini ¹, Timothy M Pawlik ^1,^∗

PMCID: PMC5144549 PMID: 27769662

Abstract

Background

The impact of prehepatectomy carcinoembryonic antigen (CEA) levels in the era of modern chemotherapy and expanded surgical indications for colorectal liver metastasis (CRLM) remains not well defined.

Methods

484 patients were identified and divided into two groups by surgical time period (group 1: 2000–2007 vs. group 2: 2008–2015). The prognostic significance of pre-hepatectomy CEA was determined by assessing the HRs associated with various cut-off levels ranging from 5 to 200 ng/mL.

Results

Median CRLM number was comparable in both groups (group 1: 2 vs. group 2: 2, P = 0.504). Bilobar disease was more frequent in group 2 (30.1% vs. 42.5%, P = 0.006). The administration of modern chemotherapy and/or biologic agents increased over time (49.5% vs. 67.9%, P < 0.001). Preoperative CEA independently predicted OS in group 1, even with a cut-off as low as >5 ng/mL. However, in group 2 it predicted recurrence and survival only after exceeding 70 and 50 ng/mL, respectively. Of note, in group 2, CEA was strongly associated with survival when CEA levels exceeded 70 ng/mL (HR 4.84).

Conclusions

While pre-hepatectomy CEA level may still have prognostic utility in CRLM resection, the optimal cut-off value has increased in the era of modern chemotherapy.

Introduction

Hepatic resection remains the only potentially curative treatment for patients with colorectal liver metastasis (CRLM) with reported 5-year survival of up to 50–58%.¹^,²^,³ Traditionally, primary colorectal cancer (CRC) stage, hepatic tumor size, number of CRLMs, presence of extrahepatic disease and pre-hepatectomy carcinoembryonic antigen (CEA) levels have been reported to be independent predictors of long-term survival after resection.⁴^,⁵^,⁶^,⁷ In addition, CEA levels are widely used to monitor tumor recurrence following resection of CRC and CRLM.⁸^,⁹^,¹⁰ In fact, high levels of pre-hepatectomy CEA have been associated with long-term post-operative outcomes and have been incorporated into clinical risk scores.⁵^,⁶^,¹¹^,¹²^,¹³ Many of these studies have, however, reported different pre-operative CEA cut-off levels (i.e. >5, ≥10, >30, >60, >100 and >200 ng/mL) as being independently predictive of prognosis.⁴^,⁶^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸

The introduction of novel multi-drug combination chemotherapeutic regimens, including oxaliplatin, irinotecan, and biologic agents has made curative-intent hepatectomy among initially unresectable CRLM patients feasible.¹⁹^,²⁰^,²¹ Advances in systemic therapy have also changed the treatment strategy for resectable CRLM. Regarding resectable synchronous CRLM, current National Cancer Center Network (NCCN) guidelines recommend several approaches for patients with colon cancer metastases including neo-adjuvant chemotherapy, staged resection with adjuvant chemotherapy after CRC surgery, and surgery alone (category 2A).²²^,²³ Moreover, neo-adjuvant chemotherapy is recommended for many patients with metachronous CRLM (category 2A).²²^,²³ As such, many candidates for resection of CRLM have already received some kind of chemotherapy at the time of liver surgery. A favorable response to chemotherapy before hepatectomy may decrease preoperative CEA levels, as is often the case when highly effective regimens are utilized.²⁴^,²⁵^,²⁶ On the other hand, advances in CRLM management have expanded the indications for CRLM resection.²⁷^,²⁸^,²⁹ This expansion has resulted in inclusion of more patients with advanced disease as surgical candidates, which in turn has likely shifted preoperative CEA levels upward. Therefore, the clinical implications of pre-hepatectomy CEA levels in an era of expanded indications and modern chemotherapy for CRLM are no longer clearly defined. Given this, we hypothesized that the prognostic value of pre-hepatectomy CEA level has changed in the era of modern chemotherapy and operative strategy.

The objective of this study was to test this hypothesis by analyzing pre-hepatectomy CEA levels concurrently with clinicopathological factors. In particular, we sought to define the impact of pre-hepatectomy CEA levels as a function of changes in modern chemotherapy and expanded CRLM surgical indications over time.

Methods

Patients

Patients who underwent curative-intent surgery for CRLM between January 2000 and March 2015 at Johns Hopkins Hospital with available pre-hepatectomy CEA levels were identified. Patients with unknown pre-hepatectomy CEA levels, patients who only underwent ablation, and individuals who underwent palliative surgery (R2 resection) were excluded. The Institutional Review Board of the Johns Hopkins Medical Institution approved the study.

Detailed information was obtained on age, gender, site of primary tumor (primary tumors located from the cecum to the end of transverse colon were defined as right-sided, while tumors located from the splenic flexure to the rectum were defined as left-sided), primary tumor American Committee on Cancer (AJCC) T stage and nodal metastases status, history of chemotherapy and type of chemotherapy, operative details, KRAS mutation status, as well as preoperative CEA level. Pre-operative CEA levels were assessed within one week prior to hepatic resection after all pre-operative therapy had concluded. Resected primary CRC characteristics and CRLM tumor size and number were determined based on the resected specimen. Modern cytotoxic chemotherapy was defined as a fluorouracil-based regimen combined with oxaliplatin and/or irinotecan. Prior history of chemotherapy included all history of chemotherapy before hepatectomy such as perioperative chemotherapy for CRC patients without liver metastases. In contrast, neoadjuvant chemotherapy for CRLM was defined as chemotherapy administered following the diagnosis of metastatic liver disease, but before the lesions were resected (irrespective of primary CRC treatment). The largest lesion was used as the index lesion in the case of multifocal disease. A major hepatectomy was defined as a resection of at least 3 Couinaud liver segments.³⁰ An R1 margin was defined as microscopic tumor invasion at the margin of the pathological specimen. Long-term clinical outcomes were obtained, including data on recurrence and overall survival (OS) at last follow-up. Recurrence was defined as the presence of a biopsy-proven tumor showing colorectal adenocarcinoma cells or a lesion deemed suspicious on follow-up CT imaging in the setting of an elevated CEA.

Statistical analysis

To assess the impact of pre-hepatectomy CEA level, the patient cohort was divided into two groups according to the time period of surgery (group 1: 2000–2007 vs. group 2: 2008–2015). Demographic, clinicopathological, and perioperative features of the study population were stratified according to the time period of hepatectomy. Summary statistics for the population were presented as totals and frequencies for categorical variables or as median values with interquartile ranges (IQR) for continuous variables. The differences between the two groups were assessed by Chi-square test, Fisher's exact test, and Mann–Whitney U test, as appropriate. Cumulative recurrence rates and OS were estimated using the Kaplan–Meier method calculated from the date of surgery and differences in cumulative recurrence and OS were assessed with the log-rank test. The Cox proportional hazards regression model was used to identify independent predictors of prognosis on multivariable analyses and reported as hazard ratio (HR) with 95% confidence intervals (95% CI). The following factors were included in multivariate analysis: (i) variables that were significant on univariate analysis (P < 0.10) (Supplemental Table 1) (ii) clinically relevant characteristics such as bilobar disease, and location of CRC.⁴^,⁵^,⁶^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ The prognostic significance of pre-hepatectomy CEA level was determined by assessing the HRs associated with various CEA cut-off levels ranging from 5 to 200 ng/mL.⁴^,⁶^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ HRs and P values for each individual CEA cut-off level were calculated after adjusting for other relevant clinicopathological variables on multivariate analysis. The corresponding HRs and P values obtained from each multivariate analysis were then graphically depicted. All analyses were carried out with SPSS software version 20 (IBM SPSS, Chicago, IL, USA).

Results

Clinicopathologic characteristics and surgical outcomes of the study group

A total of 595 patients underwent curative intent hepatectomy during the study period; from this cohort a total of 484 patients (81.3%) who met inclusion criteria were identified and included in the analysis. Table 1 shows the baseline characteristics of the entire cohort. Median patient age was 58.0 years (IQR, 49.0–66.0 years) and most patients were male (n = 290; 59.9%). The majority of patients had left-sided primary CRC (n = 321; 66.3%), T3 or T4 primary tumors (n = 368; 83.5%) and nodal metastases (n = 331; 68.4%). Most patients had a prior history of chemotherapy before hepatectomy (n = 356; 73.6%); the majority of patients received a modern combination cytotoxic chemotherapy regimen (n = 289; 81.2%) and nearly 50% of patients received a monoclonal antibody agent (n = 158; 44.4%). Among patients with a prior history of chemotherapy, 303 received neoadjuvant therapy (62.6% of all patients and 85.1% of those with prior history of chemotherapy); the use of modern cytotoxic chemotherapy and biological agents was not different among patients receiving neoadjuvant therapy (modern cytotoxic chemotherapy n = 249, 82.2% and biological agent n = 147, 48.5%). The median preoperative CEA level was 7.4 ng/mL (IQR, 3.0–25.1 ng/mL). The median number of metastatic lesions was 2 (IQR, 1–3) and the median size of the largest metastatic lesion was 2.5 cm (IQR, 1.5–4.0 cm). Bilobar disease was present in nearly one-third of patients (n = 179, 37.0%). The majority of patients had synchronous CRLM presentation (58.7%) and more than half of these patients underwent staged hepatectomy (176 out of 284, 62.0%), rather than simultaneous CRLM/CRC resection. A minority of patients underwent concurrent ablation (n = 77, 15.9%) or major hepatectomy (n = 180, 37.2%). On histopathology, an R1 resection margin was present in a minority of patients (n = 46, 9.5%). Less than half of patients harbored KRAS mutations (n = 147; 36.6%). Postoperative chemotherapy was administered to 305 (69.8%) patients.

Table 1.

Patients characteristics according to the time period

	No. (%)
	Total (n = 484)	2000–2007 (n = 216)	2008–2015 (n = 268)	P
Patient characteristics
Gender
Male	290 (59.9)	137 (63.4)	153 (57.1)
Female	194 (40.1)	79 (36.6)	115 (42.9)	0.163
Age, years
Median	58.0	59.0	57.0
(IQR)	(49.0–66.0)	(50.3–66.0)	(48.0–66.0)	0.134
Primary tumor characteristics
Tumor site
Right	163 (33.7)	70 (32.4)	93 (34.7)
Left	321 (66.3)	146 (67.6)	175 (65.3)	0.629
T stage (n = 441)
T1 or T2 stage	73 (16.6)	32 (15.6)	41 (17.4)
T3 or T4 stage	368 (83.5)	173 (84.4)	195 (82.6)	0.700
Nodal metastases
Positive	331 (68.4)	141 (65.3)	190 (70.9)
Negative	153 (31.6)	75 (34.7)	78 (29.1)	0.202
Preoperative factors
Prior history of chemotherapy
Total	356 (73.6)	154 (71.3)	202 (75.4)	0.351
-Modern cytotoxic regimen^a	289 (81.2)	107 (69.5)	182 (90.0)	*<0.001*
-Biological agent^a	158 (44.4)	47 (30.5)	111 (55.0)	*<0.001*
Neo-adjuvant for CRLM	303 (62.6)	135 (62.5)	168 (62.7)	1.00
-Modern cytotoxic regimen^b	249 (82.2)	96 (71.1)	153 (91.1)	*<0.001*
-Biological agent^b	147 (48.5)	44 (32.6)	103 (61.3)	*<0.001*
Preoperative CEA, ng/mL	7.4	7.0	7.7
Median, (IQR)	(3.0–25.1)	(3.0–28.9)	(3.0–22.2)	0.801
CRLM characteristics and operation
CRLM resection
Synchronized surgery with CRC	108 (22.3)	33 (15.3)	75 (28.0)
Staged resection for synchronous CRLM	176 (36.4)	95 (44.0)	81 (30.2)
Resection for metachronous CRLM	200 (41.3)	88 (40.7)	112 (41.8)	*<0.001*
No. of CRLM	2.0	2.0	2.0
	(1.0–3.0)	(1.0–4.0)	(1.0–3.0)	0.504
Size of largest CRLM, cm
Median	2.5	3.0	2.6
(IQR)	(1.5–4.0)	(2.0–4.5)	(1.7–4.4)	*0.025*
Bilobar disease	179 (37.0)	65 (30.1)	114 (42.5)	*0.006*
Resection only	407 (84.1)	176 (81.5)	231 (86.2)
Resection plus ablation	77 (15.9)	40 (18.5)	37 (13.8)	0.171
Major hepatectomy	180 (37.2)	103 (47.7)	77 (28.7)	*<0.001*
Resection margin width, mm
Median	5.0 (1–10)	8.0 (2–15)	4.0 (0.5–9)	*<0.001*
R1	46 (9.5)	25 (11.6)	21 (7.8)	0.212
KRAS mutation status (n = 402)
Wild-type	255 (63.4)	111 (69.8)	144 (59.3)
Mutated	147 (36.6)	48 (30.2)	99 (40.7)	*0.035*
Postop chemotherapy (n = 437)	305 (69.8)	128 (64.0)	177 (74.7)	*0.016*

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CEA, carcinoembryonic antigen; CRC, colorectal cancer; CRLM, colorectal liver metastases; IQR, interquartile range; R1, resection margin exposure in final pathological specimen.

Statistical significant values are indicted in bold italics.

Percentage in total prior history of chemotherapy.

Percentage in total chemotherapy for liver lesion.

At a median follow up of 31.4 months, 265 patients had recurred and 197 patients had died. The 1-, 3-, and 5-year cumulative recurrence for the entire cohort was 33.5%, 68.4%, and 71.0%, respectively. Median, 1-, 3-, and 5-year OS was 65.0 months, 94.2%, 70.5%, and 52.6%, respectively.

Clinicopathologic characteristics and prognosis stratified by time period

The baseline characteristics of group 1 (n = 216) and group 2 (n = 268) patients are shown in Table 1. Many patient and primary tumor characteristics were similar between the two groups (all P > 0.050). For example, the median number of metastatic lesions was comparable between the two groups (group 1: 2 vs. group 2: 2, P = 0.504). However, the median size of the largest lesion was slightly greater in group 1 (group 1: 3.0 vs. group 2: 2.6 cm, P = 0.025). In contrast, the presence of bilobar disease was more frequent in group 2 (group 1: 30.1% vs. group 2: 42.5%, P = 0.006). Of note, the proportion of patients with a prior history of chemotherapy did not differ between the two groups (P = 0.351); however, patients in group 2 were more likely to have received modern cytotoxic chemotherapy (group 1: 69.5% vs. group 2: 90.0%, P < 0.001) and biological agents (group 1: 30.5% vs. group 2: 55.0%, P < 0.001, respectively). Although, modern cytotoxic chemotherapy was more frequently administered to group 2 patients, median preoperative CEA level was no different between the two groups (group 1: 7.0 ng/mL vs. group 2: 7.7 ng/mL, P = 0.801).

Regarding surgical approach, the frequency of a simultaneous CRC and CRLM operation was higher in group 2 (group 1: 15.3% vs. group 2: 28.0%, P < 0.001). In contrast, major resection was less often performed among patients in the latter time period (group 1: 47.7% vs. group 2: 28.7%, P < 0.001). While there was no difference in the incidence of R1 resection (group 1: 7.8% vs. group 2: 11.6%, P = 0.212), the width of the resection margin was less among patients undergoing surgery in the latter time period (group 1: 8.0 mm vs. group 2: 4.0 mm, P < 0.001). In addition, the presence of a KRAS mutation was more frequent in group 2 patients (group 1: 30.2% vs. group 2: 40.7%, P = 0.035). Furthermore, administration of adjuvant chemotherapy was more common in the more recent time period (group 1: 64.0% vs. group 2: 74.7%, P = 0.016).

The 1-, 3-, and 5-year cumulative recurrence rates were comparable among the two time periods (group 1: 30.2%, 68.4%, and 70.5%, respectively, vs. group 2: 36.2%, 68.3%, and 71.3%, respectively; P = 0.550). In contrast, group 2 patients had a slightly improved long-term 1-, 3-, and 5-year OS (group 1: 91.1%, 67.1%, and 48.0%, respectively, vs. group 2: 97.0%, 74.0%, and 59.2%; P = 0.025) (Fig. 1a and b).

(a) Cumulative incidence of recurrence stratified by time period. (b) Overall survival stratified by time period

The prognostic significance of CEA stratified by time period of hepatectomy

Plots of HRs corresponding to recurrence and overall survival for various preoperative CEA levels are shown in Fig. 2a–d. Among patients undergoing hepatic resection between 2000 and 2007 (group 1), CEA level was an independent predictor of recurrence, with the HR associated with the CEA level always being above 2.0 when the CEA cut-off level was set at >30 ng/mL. Similarly, the preoperative CEA level was an independent predictor of OS among all patients treated between 2000 and 2007, even when the CEA cut-off was a low as >5 ng/mL. In contrast, among patients treated between 2008 and 2015 (group 2), preoperative CEA level was only independently predictive of recurrence and survival when the cut-off values were >70 ng/mL and 50 ng/mL, respectively. Of note, among patients treated in the later time period, CEA was most strongly associated with survival when the CEA level cut-off was >70 ng/mL (HR 4.84, 95% CI 1.97–11.88) (Fig. 2d).

Plots of the P values and hazard ratios corresponding to recurrence and overall survival for various preoperative CEA levels. (a) recurrence in 2000–2007 (b) survival in 2000–2007 (c) recurrence 2008–2015 (d) survival in 2008–2015. (abbreviations: CEA, carcinoembryonic antigen; HR, hazard ratio)

To investigate possible factors associated with the temporal changes in the predictive CEA cut-off values, additional analyses comparing preoperative CEA levels with clinicopathological variables were performed (Table 2). The chronological changes in surgical and CRLM descriptive factors are shown in Fig. 3a. The proportion of patients with bilobar disease increased as time progressed, but remained stable at approximately 40% after 2008. Of note, resection in patients with 10 or more CRLMs was more frequent in the group 2 time period (group 1: 1.9% vs. group 2: 6.3%, P = 0.023).

Table 2.

Preoperative CEA level according to patients characteristics and time period

	CEA, median
	2000–2007 (n = 216)	P	2008–2015 (n = 268)	P
Patient characteristics
Gender
Male	7	0.906	7.6	0.488
Female	7.1		8.4
Age, years
> 55	7.3	0.366	7.7	0.335
≤ 55	7.0		7.6
Primary tumor characteristics
Tumor site
Right	7.4	0.816	7	0.637
Left	7		7.8
T stage (n = 441)
T1 or T2 stage	9.6	0.297	7.6	0.639
T3 or T4 stage	7		8.8
Nodal metastases
Positive	7	0.992	7.5	0.234
Negative	7.1		8.5
Preoperative factors
Prior history of chemotherapy
Yes	7	0.480	7.7	0.562
No	8.6		7.6
-Modern cytotoxic regimen
Yes	5.8	*0.009*	7.6	0.901
No	10.5		8.2
-Biological agent
Yes	5	0.420	9.0	0.145
No	7.4		7.1
CRC at hepatectomy
Present	14.0	0.202	7.8	0.741
Resected	7.0		7.6
CRLM characteristics
No. of CRLM
>2	6.4	0.840	7.4	0.060
≤2	7.5		10.1
Size of largest CRLM, cm
>3	11.1	*<0.001*	12.1	*<0.001*
≤3	5.0		6.8
Bilateral disease
Positive	7.1	0.770	7.6	0.522
Negative	6.3		7.4
K-ras mutation status (n = 402)
Wild-type	6.4	0.624	10.5	0.110
Mutated	7.5		7.0

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CEA, carcinoembryonic antigen; CRC, colorectal cancer; CRLM, colorectal liver metastases.

Statistical significant values are indicted in bold italics.

(a) Chronological changes of operative indication and CRLM size. (abbreviations: CEA, carcinoembryonic antigen; CRLM, colorectal liver metastases) (b) Changes in use of pre-hepatectomy chemotherapy over time (c) Distribution of CEA levels in the patients who received modern cytotoxic chemotherapy

Perhaps not surprisingly, pre-hepatectomy median CEA level was associated with tumor size in both the early (group 1: ≤3 cm, 5.0 ng/mL vs. >3 cm, 11.1 ng/mL; P < 0.001) and late (group 2: ≤3 cm, 6.8 ng/mL vs. >3 cm, 12.1 ng/mL; P < 0.001) time periods. The temporal changes in chemotherapy protocols utilized are shown in Fig. 3b; the distribution of pre-hepatectomy CEA levels among patients with prior history of modern cytotoxic regimen administration is depicted in Fig. 3c. While the median CEA was different among patients in group 1 who received modern cytotoxic regimens versus patients who did not (pre-therapy: 10.5 ng/mL vs. post-therapy: 5.8 ng/mL; P = 0.009), there was no difference in CEA levels among patients in group 2 who received modern cytotoxic regimen versus those who did not (pre-therapy: 8.2 ng/mL vs. post-therapy: 7.6 ng/mL; P = 0.901).

Discussion

CEA level has been proposed as an important prognostic factor for patients treated for CRLM.⁴^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ In fact, CEA levels have been incorporated into the Fong clinical risk score, as well as in several prognostic nomograms utilized to estimate long-term prognosis of patients with CRLM.⁵^,⁶^,¹¹ While the pre-hepatectomy CEA level is influenced by primary CRC status and CRLM tumor burden, several studies have reported that pre-hepatectomy CEA levels remained independently predictive of prognosis even after adjusting for clinicopathological variables.⁴^,⁵^,⁶^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ Pre-hepatectomy CEA levels can, however, also be influenced by receipt and response to chemotherapy,¹¹^,¹²^,²³^,²⁴ and detailed data on the impact of CEA on prognosis in the era of modern chemotherapy are lacking.⁴^,⁵^,⁶^,¹⁴^,¹⁵^,¹⁶ Therefore, the objective of the current study was to reappraise the prognostic implications of CEA levels in a contemporary clinical environment characterized by the use of modern chemotherapy regimens. The current study was important because it demonstrated that the prognostic implications of the pre-hepatectomy CEA level varied over time. Specifically, while pre-hepatectomy CEA was independently associated with survival outcomes between 2000 and 2007 irrespective of the chosen cut-off levels, the association of CEA was less evident in the time period between 2008 and 2015. For example, while even a modestly elevated CEA >5 ng/mL was associated with outcomes among patients in group 1, CEA only became an independent prognostic factor at a much higher cut-off value of >50 ng/mL in the later time period. Interestingly, once CEA levels increased above this cut-off threshold, the resulting HR associated with risk of death was almost double that observed in the earlier time period.

Several differences were noted among patients treated in the earlier (2000–2007) versus later (2008–2015) time period. In particular, the frequency of modern cytotoxic regimen and biologic agent administration was markedly higher in the later period (Fig. 3b). The U.S Food and Drug Administration approved irinotecan and oxaliplatin as first-line treatments for metastatic colorectal cancer in 2000 and 2002, respectively. After the MOSAIC trial confirmed the prognostic benefit of adding oxaliplatin to fluorouracil based treatment protocols for stage II and III CRC in 2004, modern cytotoxic regimens became the standard for adjuvant CRC treatment.³¹^,³² Subsequently, the applications of modern cytotoxic regimens have continued to expand to both the adjuvant and neo-adjuvant settings for resectable CRLM.²²^,²³^,³³ In fact, in the current study, 67.9% (182/268) of patients received modern cytotoxic regimen prior to hepatectomy, with two-thirds of these patients concurrently receiving a biologic agent in the later period. Furthermore, among patients with a history of pre-hepatectomy chemotherapy, patients in group 2 were more likely to receive modern cytotoxic chemotherapy regimens (group 1: 69.5% vs. group 2: 90.0%, P < 0.001) and biological agents (group 1: 30.5% vs. group 2: 55.0%, P < 0.001, respectively). Changes in resection strategy were also noted, likely reflecting the expanding indications for resection of CRLM over time. For example, as depicted in Fig. 3a, resection of patients with bilobar and/or disseminated disease increased markedly in the later time period. Moreover, simultaneous resection of CRC and CRLM also increased. At the same time, major resection and resection margin width decreased in the later period, in line with a general shift in surgical strategies to adopt a parenchymal sparing approach with less resection margin.²⁷^,²⁸^,³⁴ Resection of CRLM with a more aggressive biological behavior characterized by an increase in KRAS mutant-type tumors was also more common in group 2.³⁵ Interestingly, although patients in the later time period had a higher burden of disease, the median pre-hepatectomy CEA level was similar among patients undergoing surgical resection of CRLM in both the early and later time periods (P = 0.801). The causes of this observation are undoubtedly multifactorial and may be related to improvements in preoperative chemotherapy with higher response rates and a greater decrease in pre-treatment CEA levels following therapy.

Although the median pre-hepatectomy CEA level was similar between the two periods studied, pre-hepatectomy CEA levels following treatment with modern cytotoxic chemotherapy differed by time period (Table 2). In the earlier period, preoperative CEA level was lower among patients treated with modern chemotherapy (P = 0.009), whereas no difference was evident in the later period (P = 0.901). One possible explanation for this finding may be related to patients in the later time period having a much higher burden of disease. Given the expansion of surgical indications in the later period to include patients with more extensive metastatic disease, initially unresectable patients may have become candidates for hepatectomy without complete normalization of their CEA levels, thus shifting the median pre-hepatectomy CEA levels upwards. As such, while modern cytotoxic chemotherapy and concurrent biological agent use facilitated the employment of surgery on patients with more extensive disease in the later time period, it did not result in normalization of the CEA level.¹⁹^,²⁰^,²¹ This point is further emphasized by the finding that, among patients with prior history of modern cytotoxic chemotherapy, the number of patients with a CEA that was between 10 and 30 ng/mL was much higher in the later period (P < 0.001) (Fig. 3c). Interestingly, tumor size and number were higher among patients with a CEA between 10 and 30 ng/mL compared with other patients (median tumor number: 3 vs. 2, P = 0.047 and median tumor size: 3.0 cm vs. 2.6 cm, P = 0.037, respectively). As such, while the median pre-hepatectomy CEA level was relatively comparable among patients treated in the two time periods, the clinical implications of an elevated pre-hepatectomy CEA levels were different.

Data from the current study suggest that the prognostic implications of pre-hepatectomy CEA levels have changed over time. In the earlier time period, preoperative CEA level was a strong independent predictor of prognosis irrespective of the particular cut-off value chosen. These data were consistent with previous reports that included patients from a similar time span, which demonstrated the prognostic relevance a wide range of CEA cut-off values.⁴^,⁵^,⁶^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ In contrast, in the current study, in the later time period of 2008–2015 pre-hepatectomy CEA levels had no prognostic significance, until a much higher-cutoff value was utilized. Of interest, in the later period, the HRs associated with OS increased sharply when the CEA level exceeded 70 ng/mL. Thus, while CEA was still a relevant prognostic factor in the recent time period, its relative prognostic importance at most commonly employed cut-off values was marginal. As such, CEA levels may still be prognostically important among patients with more extensive disease who are being treated with modern chemotherapy, but only at a much higher cut-off threshold.

Several limitations should be considered when interpreting the current study. The study did not specifically examine response to chemotherapy relative to changes in CEA levels.²⁴^,²⁵^,³⁶^,³⁷ In addition, no sub-analysis of patients who received neo-adjuvant chemotherapy for CRLM was performed. Given that many patients had therapy initiated at an outside hospital, review of the pre-treatment scans was not possible and thereby response to systemic therapy could not be assessed in some cases. In addition, information on the dosing of chemotherapy was not available. However, the unavailability of these data should not affect the main aim of our study, which was to investigate temporal changes in the prognostic impact of the pre-hepatectomy CEA level. Finally, it should be noted that this analysis was restricted to the ‘modern’ period of CRLM treatment that followed the introduction of modern cytotoxic regimens in 2000; we did not assess potential differences in the prognostic implications of CEA among patients treated prior to 2000, as the advent of multiple changes in clinical practice since that time would serve to hinder any potential comparison.

In conclusion, over the past 15 years many important changes have taken place in the management of patients with CRLM. Specifically, more patients with an extensive disease burden underwent surgery, resection more often involved a parenchymal sparing approach, and a higher proportion of patients received modern chemotherapy before hepatectomy. Over this time period, the clinical implications of the pre-hepatectomy CEA level changed. Specifically, while CEA was prognostic of long-term outcome regardless of the threshold value utilized in the early time period, the impact of CEA level was much less evident in the later time period. In fact, CEA levels were only associated with recurrence and OS when a much higher threshold of >70 ng/mL and >50 ng/mL, respectively, was used. However, when patients in the latter time period did have CEA levels that were elevated past these cut-off values, these patients had a much worse prognosis. Collectively, the data suggest that the pre-hepatectomy CEA level may still play a role in estimating prognosis following resection of CRLM, but the relative prognostic cut-off value utilized has shifted upwards in the era of modern chemotherapy.

Conflicts of interest

None declared.

Footnotes

^{Appendix A}

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.hpb.2016.09.004.

Appendix A. Supplementary data

The following is the supplementary data related to this article:

mmc1.docx^{(42.1KB, docx)}

References

1.Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
2.House M.G., Ito H., Gönen M., Fong Y., Allen P.J., DeMatteo R.P. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210:744–752. doi: 10.1016/j.jamcollsurg.2009.12.040. [DOI] [PubMed] [Google Scholar]
3.Kopetz S., Chang G.J., Overman M.J., Eng C., Sargent D.J., Larson D.W. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–3683. doi: 10.1200/JCO.2008.20.5278. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Nordlinger B., Guiguet M., Vaillant J.C., Balladur P., Boudjema K., Bachellier P. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer. 1996;77:1254–1262. [PubMed] [Google Scholar]
5.Fong Y., Fortner J., Sun R.L., Brennan M.F., Blumgart L.H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–318. doi: 10.1097/00000658-199909000-00004. discussion 318–321. [DOI] [PMC free article] [PubMed] [Google Scholar]
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8.Bast R.C., Jr., Ravdin P., Hayes D.F., Bates S., Fritsche H., Jr., Jessup J.M. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–1878. doi: 10.1200/JCO.2001.19.6.1865. [DOI] [PubMed] [Google Scholar]
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12.Ueno H., Konishi T., Ishikawa Y., Shimazaki H., Ueno M., Aosasa S. Prognostic value of poorly differentiated clusters in the primary tumor in patients undergoing hepatectomy for colorectal liver metastasis. Surgery. 2015;157:899–908. doi: 10.1016/j.surg.2014.12.025. [DOI] [PubMed] [Google Scholar]
13.Pawlik T.M., Choti M.A. Shifting from clinical to biologic indicators of prognosis after resection of hepatic colorectal metastases. Curr Oncol Rep. 2007 May;9:193–201. doi: 10.1007/s11912-007-0021-4. [DOI] [PubMed] [Google Scholar]
14.de Haas R.J., Wicherts D.A., Flores E., Azoulay D., Castaing D., Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–637. doi: 10.1097/SLA.0b013e31818a07f1. [DOI] [PubMed] [Google Scholar]
15.Dexiang Z., Li R., Ye W., Haifu W., Yunshi Z., Qinghai Y. Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. Ann Surg Oncol. 2012;19:2860–2868. doi: 10.1245/s10434-012-2356-9. [DOI] [PubMed] [Google Scholar]
16.Adam R., Bhangui P., Poston G., Mirza D., Nuzzo G., Barroso E. Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases? Ann Surg. 2010;252:774–787. doi: 10.1097/SLA.0b013e3181fcf3e3. [DOI] [PubMed] [Google Scholar]
17.Margonis G.A., Spolverato G., Kim Y., Karagkounis G., Choti M.A., Pawlik T.M. Effect of KRAS mutation on long-term outcomes of patients undergoing hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2015;22:4158–4165. doi: 10.1245/s10434-015-4587-z. [DOI] [PubMed] [Google Scholar]
18.John S.K., Robinson S.M., Rehman S., Harrison B., Vallance A., French J.J. Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study. Dig Surg. 2013;30:293–301. doi: 10.1159/000354310. [DOI] [PubMed] [Google Scholar]
19.Adam R., Wicherts D.A., de Haas R.J., Ciacio O., Lévi F., Paule B. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–1835. doi: 10.1200/JCO.2008.19.9273. [DOI] [PubMed] [Google Scholar]
20.Folprecht G., Gruenberger T., Bechstein W.O., Raab H.R., Lordick F., Hartmann J.T. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47. doi: 10.1016/S1470-2045(09)70330-4. [DOI] [PubMed] [Google Scholar]
21.Ye L.C., Liu T.S., Ren L., Wei Y., Zhu D.X., Zai S.Y. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931–1938. doi: 10.1200/JCO.2012.44.8308. [DOI] [PubMed] [Google Scholar]
22.NCCN Guidelines Version 2. 2016 Colon Cancer. New York: National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon. Accessed Mar 28, 2016.
23.NCCN Guidelines Version 1. 2016 Rectal Cancer. New York: National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#rectal. Accessed Mar 28, 2016.
24.Huang S.C., Lin J.K., Lin T.C., Chen W.S., Yang S.H., Wang H.S. Concordance of carcinoembryonic antigen ratio and response evaluation criteria in solid tumors as prognostic surrogate indicators of metastatic colorectal cancer patients treated with chemotherapy. Ann Surg Oncol. 2015;22:2262–2268. doi: 10.1245/s10434-014-4228-y. [DOI] [PubMed] [Google Scholar]
25.Stremitzer S., Stift J., Graf A., Singh J., Starlinger P., Gruenberger B. CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases. Ann Surg Oncol. 2015;22:1315–1323. doi: 10.1245/s10434-014-4158-8. [DOI] [PubMed] [Google Scholar]
26.Nagai Y., Beppu T., Sakamoto Y., Miyamoto Y., Hayashi H., Nitta H. Carcinoembryonic antigen half-life is an early predictor of therapeutic effects in induction chemotherapy for liver metastases from colorectal cancer. Anticancer Res. 2014;34:5529–5535. [PubMed] [Google Scholar]
27.Pawlik T.M., Schulick R.D., Choti M.A. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008;13:51–64. doi: 10.1634/theoncologist.2007-0142. [DOI] [PubMed] [Google Scholar]
28.Gold J.S., Are C., Kornprat P., Jarnagin W.R., Gönen M., Fong Y. Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann Surg. 2008;247:109–117. doi: 10.1097/SLA.0b013e3181557e47. [DOI] [PubMed] [Google Scholar]
29.Siriwardena A.K., Mason J.M., Mullamitha S., Hancock H.C., Jegatheeswaran S. Management of colorectal cancer presenting with synchronous liver metastases. Nat Rev Clin Oncol. 2014;11:446–459. doi: 10.1038/nrclinonc.2014.90. [DOI] [PubMed] [Google Scholar]
30.Strasberg S.M. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg. 2005;12:351–355. doi: 10.1007/s00534-005-0999-7. [DOI] [PubMed] [Google Scholar]
31.André T., Boni C., Mounedji-Boudiaf L., Navarro M., Tabernero J., Hickish T. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351. doi: 10.1056/NEJMoa032709. [DOI] [PubMed] [Google Scholar]
32.André T., Boni C., Navarro M., Tabernero J., Hickish T., Topham C. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–3116. doi: 10.1200/JCO.2008.20.6771. [DOI] [PubMed] [Google Scholar]
33.Nordlinger B., Sorbye H., Glimelius B., Poston G.J., Schlag P.M., Rougier P. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–1016. doi: 10.1016/S0140-6736(08)60455-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Pawlik T.M., Scoggins C.R., Zorzi D., Abdalla E.K., Andres A., Eng C. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715–722. doi: 10.1097/01.sla.0000160703.75808.7d. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Brudvik K.W., Kopetz S.E., Li L., Conrad C., Aloia T.A., Vauthey J.N. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015;102:1175–1183. doi: 10.1002/bjs.9870. [DOI] [PubMed] [Google Scholar]
36.Viganò L., Capussotti L., De Rosa G., De Saussure W.O., Mentha G., Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258:731–740. doi: 10.1097/SLA.0b013e3182a6183e. [DOI] [PubMed] [Google Scholar]
37.Shindoh J., Loyer E.M., Kopetz S., Boonsirikamchai P., Maru D.M., Chun Y.S. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30:4566–4572. doi: 10.1200/JCO.2012.45.2854. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.docx^{(42.1KB, docx)}

[bib1] 1.Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]

[bib2] 2.House M.G., Ito H., Gönen M., Fong Y., Allen P.J., DeMatteo R.P. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210:744–752. doi: 10.1016/j.jamcollsurg.2009.12.040. [DOI] [PubMed] [Google Scholar]

[bib3] 3.Kopetz S., Chang G.J., Overman M.J., Eng C., Sargent D.J., Larson D.W. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–3683. doi: 10.1200/JCO.2008.20.5278. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib4] 4.Nordlinger B., Guiguet M., Vaillant J.C., Balladur P., Boudjema K., Bachellier P. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer. 1996;77:1254–1262. [PubMed] [Google Scholar]

[bib5] 5.Fong Y., Fortner J., Sun R.L., Brennan M.F., Blumgart L.H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–318. doi: 10.1097/00000658-199909000-00004. discussion 318–321. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib6] 6.Rees M., Tekkis P.P., Welsh F.K., O'Rourke T., John T.G. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247:125–135. doi: 10.1097/SLA.0b013e31815aa2c2. [DOI] [PubMed] [Google Scholar]

[bib7] 7.Pawlik T.M., Abdalla E.K., Ellis L.M., Vauthey J.N., Curley S.A. Debunking dogma: surgery for four or more colorectal liver metastases is justified. J Gastrointest Surg. 2006;10:240–248. doi: 10.1016/j.gassur.2005.07.027. [DOI] [PubMed] [Google Scholar]

[bib8] 8.Bast R.C., Jr., Ravdin P., Hayes D.F., Bates S., Fritsche H., Jr., Jessup J.M. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–1878. doi: 10.1200/JCO.2001.19.6.1865. [DOI] [PubMed] [Google Scholar]

[bib9] 9.Duffy M.J., van Dalen A., Haglund C., Hansson L., Holinski-Feder E., Klapdor R. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007;43:1348–1360. doi: 10.1016/j.ejca.2007.03.021. [DOI] [PubMed] [Google Scholar]

[bib10] 10.Nicholson B.D., Shinkins B., Pathiraja I., Roberts N.W., James T.J., Mallett S. Blood CEA levels for detecting recurrent colorectal cancer. Cochrane Database Syst Rev. 2015;12:CD011134. doi: 10.1002/14651858.CD011134.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib11] 11.Watine J., Miédougé M., Friedberg B. Carcinoembryonic antigen as an independent prognostic factor of recurrence and survival in patients resected for colorectal liver metastases: a systematic review. Dis Colon Rectum. 2001 Dec;44:1791–1799. doi: 10.1007/BF02234457. [DOI] [PubMed] [Google Scholar]

[bib12] 12.Ueno H., Konishi T., Ishikawa Y., Shimazaki H., Ueno M., Aosasa S. Prognostic value of poorly differentiated clusters in the primary tumor in patients undergoing hepatectomy for colorectal liver metastasis. Surgery. 2015;157:899–908. doi: 10.1016/j.surg.2014.12.025. [DOI] [PubMed] [Google Scholar]

[bib13] 13.Pawlik T.M., Choti M.A. Shifting from clinical to biologic indicators of prognosis after resection of hepatic colorectal metastases. Curr Oncol Rep. 2007 May;9:193–201. doi: 10.1007/s11912-007-0021-4. [DOI] [PubMed] [Google Scholar]

[bib14] 14.de Haas R.J., Wicherts D.A., Flores E., Azoulay D., Castaing D., Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–637. doi: 10.1097/SLA.0b013e31818a07f1. [DOI] [PubMed] [Google Scholar]

[bib15] 15.Dexiang Z., Li R., Ye W., Haifu W., Yunshi Z., Qinghai Y. Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. Ann Surg Oncol. 2012;19:2860–2868. doi: 10.1245/s10434-012-2356-9. [DOI] [PubMed] [Google Scholar]

[bib16] 16.Adam R., Bhangui P., Poston G., Mirza D., Nuzzo G., Barroso E. Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases? Ann Surg. 2010;252:774–787. doi: 10.1097/SLA.0b013e3181fcf3e3. [DOI] [PubMed] [Google Scholar]

[bib17] 17.Margonis G.A., Spolverato G., Kim Y., Karagkounis G., Choti M.A., Pawlik T.M. Effect of KRAS mutation on long-term outcomes of patients undergoing hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2015;22:4158–4165. doi: 10.1245/s10434-015-4587-z. [DOI] [PubMed] [Google Scholar]

[bib18] 18.John S.K., Robinson S.M., Rehman S., Harrison B., Vallance A., French J.J. Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study. Dig Surg. 2013;30:293–301. doi: 10.1159/000354310. [DOI] [PubMed] [Google Scholar]

[bib19] 19.Adam R., Wicherts D.A., de Haas R.J., Ciacio O., Lévi F., Paule B. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–1835. doi: 10.1200/JCO.2008.19.9273. [DOI] [PubMed] [Google Scholar]

[bib20] 20.Folprecht G., Gruenberger T., Bechstein W.O., Raab H.R., Lordick F., Hartmann J.T. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47. doi: 10.1016/S1470-2045(09)70330-4. [DOI] [PubMed] [Google Scholar]

[bib21] 21.Ye L.C., Liu T.S., Ren L., Wei Y., Zhu D.X., Zai S.Y. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931–1938. doi: 10.1200/JCO.2012.44.8308. [DOI] [PubMed] [Google Scholar]

[bib22] 22.NCCN Guidelines Version 2. 2016 Colon Cancer. New York: National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon. Accessed Mar 28, 2016.

[bib23] 23.NCCN Guidelines Version 1. 2016 Rectal Cancer. New York: National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#rectal. Accessed Mar 28, 2016.

[bib24] 24.Huang S.C., Lin J.K., Lin T.C., Chen W.S., Yang S.H., Wang H.S. Concordance of carcinoembryonic antigen ratio and response evaluation criteria in solid tumors as prognostic surrogate indicators of metastatic colorectal cancer patients treated with chemotherapy. Ann Surg Oncol. 2015;22:2262–2268. doi: 10.1245/s10434-014-4228-y. [DOI] [PubMed] [Google Scholar]

[bib25] 25.Stremitzer S., Stift J., Graf A., Singh J., Starlinger P., Gruenberger B. CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases. Ann Surg Oncol. 2015;22:1315–1323. doi: 10.1245/s10434-014-4158-8. [DOI] [PubMed] [Google Scholar]

[bib26] 26.Nagai Y., Beppu T., Sakamoto Y., Miyamoto Y., Hayashi H., Nitta H. Carcinoembryonic antigen half-life is an early predictor of therapeutic effects in induction chemotherapy for liver metastases from colorectal cancer. Anticancer Res. 2014;34:5529–5535. [PubMed] [Google Scholar]

[bib27] 27.Pawlik T.M., Schulick R.D., Choti M.A. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008;13:51–64. doi: 10.1634/theoncologist.2007-0142. [DOI] [PubMed] [Google Scholar]

[bib28] 28.Gold J.S., Are C., Kornprat P., Jarnagin W.R., Gönen M., Fong Y. Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann Surg. 2008;247:109–117. doi: 10.1097/SLA.0b013e3181557e47. [DOI] [PubMed] [Google Scholar]

[bib29] 29.Siriwardena A.K., Mason J.M., Mullamitha S., Hancock H.C., Jegatheeswaran S. Management of colorectal cancer presenting with synchronous liver metastases. Nat Rev Clin Oncol. 2014;11:446–459. doi: 10.1038/nrclinonc.2014.90. [DOI] [PubMed] [Google Scholar]

[bib30] 30.Strasberg S.M. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg. 2005;12:351–355. doi: 10.1007/s00534-005-0999-7. [DOI] [PubMed] [Google Scholar]

[bib31] 31.André T., Boni C., Mounedji-Boudiaf L., Navarro M., Tabernero J., Hickish T. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351. doi: 10.1056/NEJMoa032709. [DOI] [PubMed] [Google Scholar]

[bib32] 32.André T., Boni C., Navarro M., Tabernero J., Hickish T., Topham C. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–3116. doi: 10.1200/JCO.2008.20.6771. [DOI] [PubMed] [Google Scholar]

[bib33] 33.Nordlinger B., Sorbye H., Glimelius B., Poston G.J., Schlag P.M., Rougier P. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–1016. doi: 10.1016/S0140-6736(08)60455-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib34] 34.Pawlik T.M., Scoggins C.R., Zorzi D., Abdalla E.K., Andres A., Eng C. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715–722. doi: 10.1097/01.sla.0000160703.75808.7d. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib35] 35.Brudvik K.W., Kopetz S.E., Li L., Conrad C., Aloia T.A., Vauthey J.N. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015;102:1175–1183. doi: 10.1002/bjs.9870. [DOI] [PubMed] [Google Scholar]

[bib36] 36.Viganò L., Capussotti L., De Rosa G., De Saussure W.O., Mentha G., Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258:731–740. doi: 10.1097/SLA.0b013e3182a6183e. [DOI] [PubMed] [Google Scholar]

[bib37] 37.Shindoh J., Loyer E.M., Kopetz S., Boonsirikamchai P., Maru D.M., Chun Y.S. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30:4566–4572. doi: 10.1200/JCO.2012.45.2854. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications?

Kazunari Sasaki

Georgios A Margonis

Nikolaos Andreatos

Ana Wilson

Faiz Gani

Neda Amini

Timothy M Pawlik