Abstract
Background:
Carcinoembryonic antigen (CEA) levels may vary with administration and discontinuation of pre-hepatectomy chemotherapy in patients undergoing resection of colorectal cancer liver metastases (CLM). The prognostic significance of these changes, termed CEA dynamics, is unclear.
Methods:
Consecutive patients undergoing hepatectomy for CLM (2001-2021) at a comprehensive cancer center were included. CEA dynamics were classified as CEA-normal (CEA <5 ng/mL before, during, and after chemotherapy); CEA-decrease (elevated CEA levels that drop during and after chemotherapy); and CEA-rebound (elevated CEA levels that drop during chemotherapy but rebound upon discontinuation). Recurrence-free (RFS), hepatic-specific disease-free (hDFS), and overall survival (OS) were compared across CEA dynamics groups.
Results:
Of 903 patients, 254 (28%) were CEA-normal, 423 (47%) CEA-decrease, and 226 (25%) CEA-rebound. Median RFS was 15.9 months, median hDFS not-reached, and median OS 11.9 years for CEA-normal patients. By comparison, CEA-decrease and CEA-rebound patients had shorter median RFS (12.2 months, P=0.002 and 7.4 months, P<0.001), shorter median hDFS (29.1 months, P=0.003 and 14.8 months, P<0.001), and shorter median OS (7.1 years, P=0.131, and 4.9 years, P<0.001). On multivariable analysis, CEA-rebound was an independent predictor of worse RFS (HR 1.50, 95%CI 1.16-1.93), hDFS (HR 1.39, 95%CI 1.03-1.88), and OS (HR 1.79, 95%CI 1.18-2.73). Among CEA-rebound patients, RAS-BRAF/TP53 co-mutation and multiple tumors predicted worse OS while APC mutation predicted improved OS.
Conclusion:
CEA rebound between pre-hepatectomy chemotherapy discontinuation and CLM resection is associated with worse oncologic outcomes, particularly in patients with aggressive tumor biology and may help frame patient and surgeon expectations ahead of CLM resection.
Keywords: Carcinoembryonic antigen, colorectal liver metastases, tumor marker, colorectal cancer, hepatobiliary surgery
INTRODUCTION
Survival of patients with colorectal cancer (CRC) even in the presence of liver metastases (CLM) has steadily improved in the past two decades due to optimization of operative and perioperative management, which have broadened the indications of surgery in patients with CLM.1-4 Pre-hepatectomy chemotherapy plays an important role in the management of CLM.5,6 Response to pre-hepatectomy chemotherapy3,7 and known biologic factors8-10 now influence the clinical decision-making for patients with CLM.
In patients with CLM, carcinoembryonic antigen (CEA) levels before and after surgery are an important prognostic factor.11-14 An elevated pre-hepatectomy CEA level is associated with recurrence after hepatectomy.15 Whereas normalization of an elevated CEA level after hepatectomy is a positive prognostic marker,16,17 a persistently elevated CEA level is associated with a higher 2-year recurrence rate.18,19 Current surveillance guidelines recommend measurement of CEA levels every 3 to 6 months following CRC resection as this permits early detection of disease recurrence and increases the opportunity for curative re-resection.20,21
When pre-hepatectomy therapy is administered, it is common practice to hold chemotherapy for a period of time (usually 3-6 weeks) before hepatectomy to allow for a washout period to facilitate safe surgery and optimal wound healing. CEA levels may vary with the administration and discontinuation of chemotherapy during this pre-hepatectomy period. These variations are referred to as CEA dynamics (Figure 1). Particularly, in the group of patients labeled CEA-normal, CEA levels remain within normal limits at baseline, throughout chemotherapy, and after its discontinuation. In the second group of patients labeled CEA-decrease, CEA levels drop with receipt of chemotherapy and continue to decrease once chemotherapy is held. In the third group of patients, termed CEA-rebound, CEA levels initially drop with receipt of chemotherapy, but rebound once chemotherapy is held. The different CEA dynamics with chemotherapy and during the washout period in preparation for CLM resection are regularly encountered in the clinical setting. Yet, their prognostic significance is an unexplored but deeply relevant question. In this study, we sought to evaluate the significance of CEA dynamics in the pre-hepatectomy chemotherapy period ahead of resection of CLM, and to identify factors associated with CEA rebound.
Figure 1.
Illustrations showing the possible variations of CEA levels before, during, and after pre-hepatectomy chemotherapy within the three groups. CEA, carcinoembryonic antigen.
METHODS
Patient Selection and Data Collection
This was a single-center retrospective cohort study of consecutive patients who underwent hepatectomy for CLM after receiving pre-hepatectomy chemotherapy during 2001-2021. Patients were excluded if CEA levels were not recorded before, during, and after chemotherapy ahead of resection of CLM. Finally, patients who received more than one line of chemotherapy but did not have CEA levels recorded before the last chemotherapy line administered before hepatectomy were excluded. Clinicopathologic and demographic characteristics were collected from a departmental database and electronic medical records (Epic, Verona, WI). The Institutional Review Board at The University of Texas MD Anderson Cancer Center approved this study protocol (#2023-0433) and waived the requirement for informed consent.
Institutional Approach to Management of CLM
The approach to patients with CLM at our institution was described previously.22 We routinely offer pre-hepatectomy multidrug chemotherapy including oxaliplatin and/or irinotecan in combination with anti-vascular endothelial growth factor (VEGF) therapy.1 During pre-hepatectomy chemotherapy, restaging is performed.23 In the case of disease progression or suboptimal tumor response after first-line chemotherapy, second-line chemotherapy is considered, which might include anti-epidermal growth factor receptor (EGFR) therapy for patients with RAS wild type tumors.24 CLM are deemed resectable when hepatectomy can achieve a negative margin and preserve ≥30% of the total liver volume standardized to the patient’s body surface area, sparing two contiguous hepatic segments and maintaining vascular inflow, vascular outflow, and biliary drainage.25,26 Parenchymal-sparing hepatectomy is preferred whenever possible.27,28 For patients with synchronous CLM and an intact primary tumor, decisions about the treatment sequence (primary tumor first, combined, or CLM first) are discussed at a multidisciplinary conference.29 For patients with an anticipated insufficient future liver remnant, pre-hepatectomy portal vein embolization and/or staged hepatectomy may be proposed. Postoperative chemotherapy is typically administered to complete a total of 12 cycles, including those given before hepatectomy.3 The interval between the last dose of chemotherapy and liver resection is typically 3 to 6 weeks. Patients are routinely followed after resection with history, physical examination, laboratory evaluation, and imaging every 3 to 4 months for the first 2 years and every 4 to 6 months for the subsequent 3 years.30
Definitions
Synchronous CLM were defined as metastases diagnosed within 12 months of primary tumor diagnosis. Positive surgical margin (i.e., R1 resection) was defined as presence of tumor cells within 1 mm of the transection line.31 The number and diameter of CLM were determined from examination of surgical pathology specimens. T-category was classified according to the staging system in the AJCC Cancer Staging Manual,32 eighth edition. Pre-hepatectomy chemotherapy regimens were recorded and categorized according to whether they included an anti-VEGF or anti–epidermal growth factor receptor agent and whether they included oxaliplatin or not. Major pathologic response was defined as tumor viability less than 50% on pathologic specimen evaluation.33,34 Recurrence-free survival (RFS) was defined as the duration from hepatectomy to last follow-up or first recurrence regardless of the location. Hepatic-specific disease-free survival (hDFS) was defined as the duration from hepatectomy to last follow-up or first liver recurrence. Overall survival (OS) was defined as the duration from hepatectomy to last follow-up or death.
For the purposes of this study, CEA levels at four specific time-points were recorded: 1) before first dose of the current line of pre-hepatectomy chemotherapy ahead of hepatectomy (pre-chemotherapy CEA); 2) at its peak, whether this occurred before, during or after chemotherapy (maximum CEA); 3) at its nadir, whether this is achieved during neoadjuvant chemotherapy or after its discontinuation (minimum CEA); and 4) the last value obtained before hepatectomy (pre-hepatectomy CEA). Patients were then divided into three groups based on the CEA dynamics during the pre-hepatectomy period according to these four levels (Figure 1). Patients with a CEA level <5 mg/dL at all times before, during, and after chemotherapy were considered to have a normal CEA level (CEA-normal group).35 Patients with any elevated CEA level (≥5 ng/mL) were categorized into two groups: patients with a continuous decline in CEA level after chemotherapy discontinuation – where minimum CEA = pre-hepatectomy CEA – were categorized as having a CEA decrease (CEA-decrease group) while patients with an initial drop in CEA during chemotherapy followed by a rebound increase in CEA level after chemotherapy discontinuation – where minimum CEA < pre-hepatectomy CEA – were categorized as having a CEA rebound (CEA-rebound group). Because a consistently rising CEA despite pre-hepatectomy chemotherapy represents a relative contraindication to hepatectomy, our cohort does not include any patient with a steadily increasing CEA throughout the pre-hepatectomy period except for those in whom CEA was always below the upper limit of normal.
Statistical Analyses
Continuous variables were presented as median and interquartile range (IQR) and compared using the Kruskal-Wallis test or Mann-Whitney U test. Categorical variables were presented as number (percentage) and compared using the χ2 test. Factors associated with CEA rebound were analyzed using binary logistic regression model. RFS, hDFS, and OS curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Deaths without recurrence were censored for the RFS analysis, and deaths without hepatic-specific recurrence were censored for the hDFS analysis. Univariable and multivariable analyses for RFS, hDFS, and OS were determined by Cox regression model. Odds ratios (ORs) or hazard ratios (HRs) with the respective 95% CIs were calculated for each factor on univariable analyses. Factors with P<0.05 on univariable analysis and those deemed clinically important by the authors based on previous literature were advanced to the multivariable regression model. A backward elimination with a threshold P value of 0.05 was used to select variables for the final models. P<0.05 was considered statistically significant, and all tests were 2-sided. Statistical analysis was performed using SPSS version 26 (IBM, Aramark, NY) and GraphPad Prism version 10.0.3 for Windows (GraphPad Software, Boston, MA).
RESULTS
Patient Characteristics
The cohort included 903 patients. The median age was 55 years, and 532 patients (59%) were male (Table 1). The median body mass index was 27.4 (24.2-31.7) kg/m2. Majorities of patients had left-sided primary tumors, T category 3 or greater, positive primary lymph nodes, and synchronous CLM. Extrahepatic metastases were present in 190 patients (21%). Median number of CLM was 2 (1-4), median maximum tumor diameter was 2.3 (1.4-3.8) cm, and 145 patients (16%) had a maximum tumor diameter greater than 5 cm.
Table 1.
Patient Characteristics According to CEA dynamics (n=903)
| Factor | Entire cohort (n=903) |
CEA-normal group (n=254) |
CEA-decrease (n=423) |
CEA-rebound (n=226) |
P value b |
|---|---|---|---|---|---|
| Patient factors | |||||
| Sex ratio (male: female) | 532:371 (59:41) | 171:83 (67:33) | 239:184 (57:43) | 122:104 (54:46) | 0.005 |
| Age, years c | 55 (47-63) | 54 (45-62) | 56 (48-63) | 57 (50-64) | 0.067 |
| BMI, kg/m2 a, c | 27.4 (24.2-31.7) | 27.6 (24.4-31.7) | 28.0 (24.2-31.9) | 26.4 (23.9-30.9) | 0.113 |
| Primary lesion factors | |||||
| Ascending colon | 236 (26) | 68 (27) | 107 (25) | 61 (26) | 0.863 |
| T category ≥3 a | 793 (89) | 223 (88) | 366 (88) | 204 (92) | 0.192 |
| Pathologically positive LN a | 616 (70) | 184 (73) | 273 (66) | 159 (74) | 0.093 |
| Extrahepatic metastases | 190 (21) | 47 (19) | 75 (18) | 68 (30) | 0.001 |
| Intact primary tumor | 297 (33) | 65 (26) | 155 (37) | 77 (34) | 0.011 |
| Liver metastases factors | |||||
| Synchronous CLM (≤1 year) | 699 (77) | 199 (78) | 322 (76) | 178 (79) | 0.683 |
| No. of tumors a, c | 2 (1-4) | 2 (1-3) | 2 (1-4) | 3 (1-5) | <0.001 |
| Multiple tumors a | 574 (64) | 135 (53) | 278 (66) | 161 (71) | <0.001 |
| Maximum diameter, cm a, c | 2.3 (1.4-3.8) | 1.6 (1.1-2.5) | 2.3 (1.4-4.0) | 3.3 (2.0-5.2) | <0.001 |
| Maximum diameter >5 cm a | 145 (16) | 8 (3.1) | 76 (18) | 61 (27) | <0.001 |
| Pre-hepatectomy chemotherapy | |||||
| No. of cycles a | 5 (4-7) | 4 (4-6) | 5 (4-6) | 6 (4-11) | <0.001 |
| Number of cycles >6 a | 254 (28) | 50 (20) | 99 (23) | 105 (47) | <0.001 |
| Oxaliplatin-containing | 729 (81) | 195 (77) | 362 (86) | 172 (76) | 0.002 |
| Anti-VEGF agent-containing | 684 (76) | 191 (75) | 325 (77) | 168 (74) | 0.757 |
| Anti-EGFR agent-containing | 67 (7.4) | 13 (5.1) | 24 (5.7) | 30 (13) | <0.001 |
| Post-hepatectomy chemotherapy a | 642 (73) | 184 (75) | 306 (75) | 152 (69) | 0.281 |
| Resection factors | |||||
| Portal vein embolization a | 124 (14) | 25 (10) | 50 (12) | 49 (22) | <0.001 |
| Major hepatectomy | 355 (39) | 78 (30) | 170 (40) | 107 (47) | 0.001 |
| R1 resection | 199 (22) | 40 (16) | 94 (22) | 65 (29) | 0.003 |
| Major pathologic response a | 323 (69) | 86 (72) | 171 (75) | 66 (54) | <0.001 |
| Somatic gene alterations | |||||
| RAS or BRAF mutation a | 383 (55) | 102 (58) | 181 (55) | 100 (52) | 0.555 |
| TP53 mutation a | 462 (74) | 106 (69) | 223 (75) | 133 (77) | 0.191 |
| RAS-BRAF/TP53 co-mutation a | 224 (36) | 47 (31) | 117 (39) | 60 (35) | 0.166 |
| APC mutation a | 261 (53) | 62 (51) | 124 (52) | 75 (56) | 0.737 |
| SMAD4 mutation a | 57 (9.2) | 21 (14) | 23 (7.8) | 13 (7.6) | 0.082 |
| FBXW7 mutation a | 45 (7.2) | 11 (7.2) | 20 (6.7) | 14 (8.2) | 0.843 |
| CEA factors | |||||
| Pre-chemotherapy CEA, ng/mL d | 12.3 (3.7-55.0) | 2.2 (1.3-3.3) | 27.0 (11.4-105.7) | 21.6 (8.3-87.9) | 0.075 |
| Pre-chemotherapy CEA <5 | 291 (32) | 254 (100) | 10 (2.4) | 27 (12) | <0.001 |
| Pre-chemotherapy CEA >100 | 162 (18) | 0 | 108 (26) | 54 (24) | <0.001 |
| Maximum CEA, ng/mL d | 13.7 (4.3-64.5) | 2.6 (1.8-3.7) | 28.6 (12.1-108.7) | 34.5 (11.1-118.2) | 0.905 |
| Maximum = Pre-chemo CEA | 655 (73) | 175 (69) | 355 (84) | 125 (55) | <0.001 |
| Minimum CEA, ng/mL d | 3.1 (1.6-7.1) | 1.0 (1.5-2.1) | 4.0 (2.4-10.5) | 4.9 (2.7-11.1) | 0.086 |
| Pre-hepatectomy CEA, ng/mL d | 3.5 (1.9-9.9) | 1.8 (1.2-2.5) | 4.0 (2.4-10.5) | 10.1 (4.6-30.5) | <0.001 |
Abbreviations: BMI, body mass index; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
Data not available for BMI in 5 patients, T category ≥3 in 12 patients, pathologically positive lymph node in 23 patients, tumor number in 1 patient, maximum tumor diameter in 1 patient, number of cycles in 4 patients, post-hepatectomy chemotherapy in 27 patients, portal vein embolization in 1 patient, major pathologic response in 29 patients, RAS mutation in 184 patients, RAS or BRAF mutation in 204 patients, TP53 mutation in 180 patients, APC mutation in 408 patients, SMAD4 mutation in 283 patients, and FBXW7 mutation in 282 patients.
Data presented as n (%), and P value obtained by Chi-square test..
Data presented as median (IQR) and P value obtained by Kruskal-Wallis or Mann-Whitney U tes.t
Data presented as median (IQR), and P value obtained by Kruskal-Wallis or Mann-Whitney U test comparing CEA-decrease and CEA-rebound groups.
The median number of chemotherapy cycles was 5 (4-7). Oxaliplatin-containing, anti-VEGF agent–containing, and anti-EGFR agent-containing regimens were administered to 729 patients (81%), 684 patients (76%), and 67 patients (7.4%) respectively. RAS or BRAF mutation was detected in 55% of patients and TP53 mutation was detected in 74% of patients with available data. RAS-BRAF/TP53 co-mutation was detected in 36% of patients. APC, SMAD4, and FBXW7 mutation were found in 53%, 9.2%, and 7.2%, of patients, respectively.
The median pre-chemotherapy CEA level was 12.3 (3.7-55.0) ng/mL. The median maximum CEA level was 13.7 (4.3-64.5) ng/mL, the median minimum CEA level achieved was 3.1 (1.6-7.1) ng/mL, and the median pre-hepatectomy CEA level was 3.5 (1.9-9.9) ng/mL. Median duration from chemotherapy discontinuation to pre-hepatectomy CEA was 37 (22-53) days, from pre-hepatectomy CEA to hepatectomy 5 (2-15) days, and from chemotherapy discontinuation to hepatectomy 45 (35-62) days for all patients (Supplemental Figure 1A). Linear regression analysis showed that there is a strong correlation between the duration from chemotherapy discontinuation to hepatectomy and the duration from chemotherapy discontinuation to pre-hepatectomy CEA indicating a consistent approach to timing of pre-hepatectomy CEA relative to hepatectomy (R2=0.999, P<0.001; Supplemental Figure 1B).
Patient Characteristics According to CEA Level Dynamics and Predictors of CEA Rebound
Among the 903 patients, 254 (28%) were CEA-normal, 423 (47%) CEA-decrease, and 226 (25%) CEA-rebound (Table 1). There were no differences in the rate of ascending colon primary tumor, synchronous CLM, and somatic gene mutations (RAS or BRAF, TP53, RAS-BRAF/TP53 co-mutation, APC, SMAD4, and FBXW7) across the three groups. Median duration from pre-hepatectomy CEA to hepatectomy was similar across the three groups (6 [2-15] days for CEA-normal, 5 [1-20] for CEA-decrease, and 5 [2-11] for CEA-rebound; P=0.068; Supplemental Figure 1A). However, there was a statistically significant difference in the durations from chemotherapy discontinuation to pre-hepatectomy CEA (35 [22-52] days for CEA-normal, 35 [20-48] days for CEA-decrease, and 43 [29-77] days for CEA-rebound; P<0.001) and from chemotherapy discontinuation to hepatectomy (44 [34-59] days for CEA-normal, 43 [35-58] days for CEA-decrease, and 51 [36-86] days for CEA-rebound; P<0.001) across the three groups. Compared with the CEA-decrease group, the CEA-rebound group had similar pre-chemotherapy, maximum CEA, and minimum CEA levels but higher pre-hepatectomy CEA levels.
In our entire study cohort, 612 patients presented with pre-chemotherapy CEA ≥5 ng/mL and 291 patients presented with pre-chemotherapy CEA levels <5 ng/mL (Table 1). Factors associated with CEA rebound were analyzed among the 612 patients with pre-chemotherapy CEA ≥5 ng/mL (Supplemental Table 1). On multivariable analysis, extrahepatic metastases, receipt of anti-EGFR agent containing-regimen, and receipt of more than 6 cycles of chemotherapy were associated with increased risk of CEA rebound, whereas minimum CEA level <5 ng/mL was associated with decreased risk of CEA rebound (Supplemental Table 1).
Association of CEA Dynamics with RFS and hDFS
After a median follow-up of 56.6 months, median RFS, hDFS, and OS were 11.4 (5.4-36.3) months, 29.0 (8.7-not reached) months, and 83.4 (37.0-not reached) months, respectively, for the whole cohort.
Median RFS was 15.9 (7.5-not reached) months for the CEA-normal group (reference), 12.2 (6.2-28.6) months for the CEA-decrease group (P=0.002), and 7.4 (3.9-15.1) months for the CEA-rebound group (P<0.001) (Figure 2A). Besides CEA dynamics, other factors associated with RFS on univariable analysis are shown in Supplemental Table 2. On multivariable analysis, CEA-rebound independently predicted RFS (HR 1.50, P=0.002), as did extrahepatic metastases, multiple CLM, R1 resection, and RAS-BRAF/TP53 co-mutation (Table 2).
Figure 2.
Recurrence-free survival (A), hepatic-specific disease-free survival (B), and overall survival (C) according to CEA dynamics after pre-hepatectomy chemotherapy. CEA, carcinoembryonic antigen; NR, not reached.
Table 2.
Multivariable Analysis of Oncologic Outcomes
| Recurrence-free survival c | Hepatic-specific disease-free survival d |
Overall survival e | ||||
|---|---|---|---|---|---|---|
| Factor | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value |
| Patient factors | ||||||
| Sex, male | 0.94 (0.78-1.13) | 0.504 | — | — | ||
| Age | — b | — | 1.01 (1.00-1.02) | 0.123 | ||
| Primary lesion factors | ||||||
| Ascending colon | — | — | 1.60 (1.15-2.24) | 0.006 | ||
| T category ≥3 a | 1.32 (0.96-1.83) | 0.090 | 1.13 (0.78-1.62) | 0.521 | — | |
| Pathologically positive lymph node a | 1.12 (0.91-1.38) | 0.277 | — | — | ||
| Extrahepatic metastases | 2.01 (1.64-2.46) | <0.001 | 1.16 (0.90-1.48) | 0.249 | 1.89 (1.35-2.66) | <0.001 |
| Intact primary tumor | — | |||||
| Liver metastases factors | ||||||
| Synchronous CLM (≤1 year) | — | 1.44 (1.08-1.91) | 0.012 | — | ||
| Multiple tumors a | 1.31 (1.07-1.60) | 0.010 | 1.44 (1.12-1.85) | 0.004 | 1.53 (1.09-2.15) | 0.014 |
| Maximum tumor diameter ≥5 cm a | 1.22 (0.95-1.57) | 0.121 | — | 0.86 (0.55-1.34) | 0.509 | |
| Pre-hepatectomy chemotherapy | ||||||
| Oxaliplatin-containing | — | 1.07 (0.79-1.45) | 0.665 | — | ||
| Anti-VEGF agent-containing | 1.04 (0.84-1.30) | 0.723 | — | — | ||
| Number of cycles >6 a | 1.09 (0.88-1.35) | 0.414 | 1.06 (0.84-1.35) | 0.611 | 1.15 (0.83-1.60) | 0.395 |
| Resection factors | ||||||
| Major hepatectomy | — | — | 1.17 (0.86-1.61) | 0.319 | ||
| R1 resection | 1.38 (1.12-1.69) | 0.002 | 1.42 (1.12-1.80) | 0.004 | 1.31 (0.93-1.84) | 0.117 |
| Somatic gene alterations | ||||||
| RAS-BRAF/TP53 co-mutation a | 1.44 (1.19-1.74) | <0.001 | 1.47 (1.19-1.82) | <0.001 | 1.55 (1.14-2.12) | 0.005 |
| APC mutation a | — | — | 0.58 (0.43-0.79) | <0.001 | ||
| SMAD4 mutation a | — | — | 2.39 (1.57-3.66) | <0.001 | ||
| CEA category | ||||||
| CEA-normal | Ref | Ref | Ref | |||
| CEA-decrease | 1.14 (0.90-1.43) | 0.284 | 1.08 (0.82-1.43) | 0.599 | 1.08 (0.73-1.61) | 0.704 |
| CEA-rebound | 1.50 (1.16-1.93) | 0.002 | 1.39 (1.03-1.88) | 0.03 | 1.79 (1.18-2.73) | 0.007 |
Abbreviations: CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
Data not available for T category ≥3 in 12 patients, pathologically positive lymph node in 23 patients, tumor number in 1 patient, maximum tumor diameter in 1 patient, number of cycles in 4 patients, RAS/TP53 or BRAF/TP53 co-mutation in 204 patients, TP53 mutation in 280 patients, and APC mutation in 410 patients.
— indicates that variable was not significant in univariable analysis and thus was not included in multivariable analysis.
601 patients were included in the multivariable analysis for recurrence-free survival
609 patients were included in the multivariate analysis for hepatic specific disease-free survival
490 patients were included in the multivariate analysis for overall survival
Median hDFS was not reached (12.8 months-not reached) for the CEA-normal group, 29.1 (9.3-not reached) months for the CEA-decrease group (P=0.003), and 14.8 (5.8-not reached) months for the CEA-rebound group (P<0.001) (Figure 2B). Besides CEA dynamics, other factors associated with hDFS on univariable analysis are shown in Supplemental Table 2. On multivariable analysis, CEA-rebound independently predicted hDFS (HR 1.39, P=0.03), as did synchronous presentation, multiple CLM, R1 resection, and RAS-BRAF/TP53 co-mutation (Table 2).
Association of CEA Dynamics with OS
Median OS was 11.9 (3.7-not reached) years for the CEA-normal group, 7.1 (3.5-not reached) years for the CEA-decrease group (P=0.131), and 4.9 (2.2-not reached) years for the CEA-rebound group (P<0.001) (Figure 2C). Besides CEA dynamics, other factors associated with OS on univariable analysis are shown in Supplemental Table 2. On multivariable analysis, CEA-rebound independently predicted worse OS (HR 1.79, P=0.007), as did ascending colon primary tumor, extrahepatic metastases, multiple CLM, RAS-BRAF/TP53 co-mutation, and SMAD4 mutation. Conversely, APC mutation independently predicted better OS (Table 2).
Association of CEA Dynamics with Oncologic Outcomes for Patients without Extrahepatic Metastases
We conducted a subset analysis for patients with CLM and NO extrahepatic metastases at the time of hepatectomy next (Supplemental Tables 3 and 4). Out of the 903 patients in our study, 190 had extrahepatic metastases; thus, 713 patients were included in this analysis. Median RFS, hDFS, and OS for all patients without extrahepatic metastases were 13.2 (7.0-not reached) months, 33.8 (9.1-not reached) months, and 8.3 (3.5-not reached) years, respectively. On univariable analysis, CEA-rebound and CEA-decrease were associated with worse outcomes compared to CEA-normal. On multivariable analysis, CEA-rebound had a HR (95% CI) of 1.36 (0.99-1.87) for RFS, 1.62 (1.13-2.32) for hDFS, and 1.79 (1.18-2.73) for OS.
Factors Associated with Survival in Patients with CEA Rebound
Factors associated with survival in patients with CEA rebound were analyzed to better identify patients at risk of worse prognosis and who may derive the least benefit from surgery (Table 3). On univariable analysis, APC mutation was associated with improved OS while multiple tumors, R1 resection, SMAD4, and RAS-BRAF/TP53 co-mutation were associated with worse OS (Figure 3). Among patients with CEA rebound, those with RAS-BRAF/TP53 co-mutation had a median OS of 2.7 years compared to 7 years in patients without RAS-BRAF/TP53 co-mutation. On multivariable analysis, APC mutation was associated with improved OS while multiple tumors and RAS-BRAF/TP53 co-mutation were associated with worse survival.
Table 3.
Factors associated with overall survival in patients with CEA rebound (n=226)
| Univariate Analysis | Multivariate Analysis b | |||
|---|---|---|---|---|
| Factor | HR (95% CI) | p-value | HR (95% CI) | p-value |
| Patient factors | ||||
| Sex, male | 1.25 (084-1.85) | 0.269 | ||
| Age | 1.01 (1.00-1.03) | 0.184 | ||
| Primary lesion factors | ||||
| Right colon | 1.41 (0.93-2.14) | 0.109 | ||
| T category ≥ 3 a | 0.64 (0.34-1.19) | 0.157 | ||
| Pathologically positive lymph node a | 1.13 (0.73-1.77) | 0.579 | ||
| Extrahepatic metastasis | 1.22 (0.79-1.86) | 0.372 | ||
| Synchronous presentation (≤1 year) | 0.91 (0.57-1.45) | 0.699 | ||
| Liver metastases factors | ||||
| Tumor number | 1.02 (0.97-1.08) | 0.412 | ||
| Multiple tumors | 1.90 (1.17-3.08) | 0.009 | 2.00 (1.04-3.89) | 0.038 |
| Maximum diameter | 1.04 (0.97-1.12) | 0.270 | ||
| Maximum Diameter ≥ 5 cm | 1.14 (0.73-1.77) | 0.569 | ||
| Pre-hepatectomy chemotherapy | ||||
| Oxaliplatin-containing | 0.83 (0.53-1.30) | 0.412 | ||
| Anti-VEGF agent-containing | 1.14 (0.72-1.80) | 0.588 | ||
| Anti-EGFR agent-containing | 1.31 (0.78-2.21) | 0.307 | ||
| Number of cycles a | 1.00 (0.98-1.02) | 0.825 | ||
| Number of cycles > 6 a | 0.93 (0.63-1.38) | 0.720 | ||
| Post-hepatectomy chemotherapy a | 0.87 (0.56-1.34) | 0.515 | ||
| Resection factors | ||||
| Major Hepatectomy | 1.10 (0.75-1.62) | 0.635 | ||
| R1 resection | 1.59 (1.04-2.42) | 0.031 | 1.49 (0.87-2.57) | 0.150 |
| Somatic gene alterations | ||||
| RAS or BRAF mutation a | 0.99 (0.64-1.54) | 0.975 | ||
| TP53 mutation a | 2.17 (1.11-4.25) | 0.024 | ||
| RAS or BRAF/TP53 co-mutation a | 1.94 (1.18-3.16) | 0.008 | 2.24 (1.30-3.85) | 0.004 |
| APC mutation a | 0.55 (0.33-0.91) | 0.019 | 0.52 (0.31-0.87) | 0.013 |
| SMAD4 mutation a | 2.40 (1.08-5.31) | 0.032 | ||
| FBXW7 mutation a | 1.65 (0.79-3.45) | 0.186 | ||
Abbreviations: CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor
Data not available for T category ≥ 3 in 5 patients, pathologically positive lymph node in 10 patients, number of cycles in 1 patient, post-hepatectomy chemotherapy in 6 patients, RAS or BRAF mutation in 33 patients, TP53 mutation in 54 patients, APC mutation in 91 patients, SMAD4 mutation in 55 patients, FBXW7 mutation in 55 patients.
135 patients were included in the multivariable analysis. Factors included in the multivariable analysis are multiple tumors, positive, liver margin, RAS-BRAF/TP53 co-mutation, and APC mutation. SMAD4 mutation was not included because of low number of patients with mutation (n=13/171), and TP53 mutation was not included because of collinearity with RAS-BRAF/TP53 co-mutation.
Figure 3.
Overall survival in patients with CEA rebound according to the presence or absence of RAS-BRAF/TP53 co-mutation. CEA, carcinoembryonic antigen; NR, not reached.
DISCUSSION
CEA is an inexpensive and widely available tumor marker used to assess prognosis in patients with CRC and CLM.18,21,36 Previous studies focused on the perioperative change in CEA level after resection of CRC and CLM.16-19 In this study, we focused on the change in CEA level after discontinuation of pre-hepatectomy chemotherapy but before hepatectomy. Our analysis of 903 patients who underwent hepatectomy after receiving systemic chemotherapy showed that CEA dynamics in this pre-hepatectomy period was a significant independent predictor of survival outcomes. In particular, CEA rising once pre-hepatectomy chemotherapy was discontinued ahead of hepatectomy – which we termed CEA rebound – was associated with worse RFS, hDFS, and OS compared to a CEA level that was always normal or stayed down with chemotherapy pause.
Although CEA rebound may intuitively signal more aggressive disease biology and/or less effective disease control, to our knowledge this is the first study to assess the significance of this phenomenon. In clinical practice, this scenario is encountered not uncommonly; in our series, nearly a quarter of patients with CLM treated with neoadjuvant chemotherapy ahead of hepatectomy experienced a CEA rebound. Normalization of CEA level (to <5 ng/mL) after chemotherapy was protective against CEA rebound. On the other hand, receiving more than 6 cycles of chemotherapy and receiving anti-EGFR agent-containing regimen were predictive of CEA rebound. These findings are in line with clinical decision-making processes at our center, where patients whose CLM do not respond to 4 to 6 cycles of first-line chemotherapy with oxaliplatin and an anti-VEGF agent receive more cycles or a different regimen before the decision about resection is made. The association of the receipt of anti-EGFR agents with worse outcomes for patients undergoing CLM resection was previously reported in the New EPOC trial.37 Whether the association of anti-EGFR with CEA-rebound in the current report reflects aggressive CLM at presentation or represents the development of more aggressive disease due to anti-EGFR therapy, as discussed in the New EPOC trial, is a topic of interest and perhaps further investigation.
Progression of CLM between pre-hepatectomy chemotherapy and hepatectomy has been previously shown to be associated with a very poor prognosis, and hepatectomy in patients with such progression should be undertaken only after careful consideration.38 In our practice, patients are not routinely offered hepatectomy in case of radiographic progression or development of new intra- or extra-hepatic metastases. Rebound increase in CEA level among CEA producers allows us to identify patients who do not exhibit obvious radiographic progression but have microscopic progression, in the liver or beyond, that would likely manifest on postoperative follow-up if hepatectomy was performed. Indeed, patients who experience CEA rebound after pre-hepatectomy chemotherapy discontinuation experienced both lower hepatic-specific disease-free survival and lower recurrence-free survival. In contrast, compared with the CEA-normal group, the CEA-decrease group had similar RFS and hDFS; that CEA would decrease and stay down, even after pausing chemotherapy, speaks to effective systemic therapy and a favorable tumor biology.
Even in this era of personalized medicine and circulating tumor DNA, dynamic changes in CEA level, which is ubiquitously measured and widely available, remain a valuable tool for prognostication because it allows surgeons and patients to frame their expectations regarding long-term outcomes before hepatectomy. CEA rebound was associated with worse OS, which may be partly due to the decreased RFS and hDFS seen with this phenomenon. It should be noted though that, despite the disappointing median RFS and hDFS of 7.4 months and 14.8 months, respectively, median OS for CEA-rebound patients still approached 5 years. This may be partly explained by more effective second- and beyond lines of therapy, but also by better multidisciplinary strategies focused on preserving opportunities for future repeat local therapies. In our practice, the increased implementation of parenchymal-sparing hepatectomy has expanded the option for repeat salvage local therapy for recurrence, which has previously been shown to prolong OS.4,39,40 Nevertheless, CEA-rebound patients with RAS-BRAF/TP53 co-mutation had a low median OS (2.7 years) compared to those without RAS-BRAF/TP53 co-mutation who had a median survival of 7 years. Thus, the decision to undergo surgery should be made only after careful consideration in patients with CEA rebound, especially if they have known RAS-BRAF/TP53 co-mutation. However, CEA rebound alone in our opinion should not contraindicate surgery.
The results presented here should be interpreted in the context of certain limitations. First, this is a single-center retrospective study with a highly selected patient cohort. Validation in a multicenter cohort would improve the generalizability of these results. Nonetheless, this remains the first study to evaluate the prognostic significance of CEA dynamics during the neoadjuvant therapy period. Second, data on somatic gene mutations were missing for many patients. However, genetic testing was not used to determine whether to measure CEA levels or not, so we chose to include patients in whom this information was not available. Third, our study does not provide further insight on the preferred management of patients with CEA rebound. Although the disappointing survival seen in CEA rebound patients with RAS-BRAF/TP53 co-mutation leaves much to be desired, how it compares to outcomes achieved with non-surgical management in this particular cohort of patients is unclear. Finally, our current study lacks granularity with regards to the rate and degree of CEA rebound relative to both the pre-chemotherapy level and the minimum CEA level achieved on chemotherapy. Because this phenomenon is unlikely to be a binary (yes/no) metric, we plan to evaluate in greater detail the extent of CEA rebound in future studies, when a larger sample size would provide the power necessary to do so.
CONCLUSION
CEA dynamics during pre-hepatectomy chemotherapy and upon its discontinuation may provide a more global or comprehensive assessment of the interplay between the nature of the disease biology and the effectiveness of systemic therapy. Rebound in CEA level after discontinuation of pre-hepatectomy chemotherapy is a novel predictor of poor long-term outcomes in patients undergoing resection for CLM. Although a rebound in CEA level after chemotherapy discontinuation does not contraindicate hepatectomy, it should inform patient counseling and clinical decision-making, especially in patients with aggressive tumor biology.
Supplementary Material
Supplemental Figure 1. A. Durations (in days) from chemotherapy discontinuation to hepatectomy according to CEA dynamics groups. B. Scatterplot showing the correlation between the durations from chemotherapy discontinuation to hepatectomy and to pre-hepatectomy CEA.
Supplemental Table 1. Predictors of CEA Rebound after Discontinuation of Chemotherapy Among Patients with Pre-chemotherapy CEA Level ≥5 ng/mL (n=612)
Supplemental Table 2. Univariable Analysis of Oncologic Outcomes
Supplemental Table 3. Univariable Analysis of Oncologic Outcomes for Patients without Extrahepatic Disease (n=713)
Supplemental Table 4. Multivariable Analysis of Oncologic Outcomes for Patients without Extrahepatic Disease
SYNOPSIS.
In patients with colorectal liver metastases, a rebound in CEA level once chemotherapy is held ahead of hepatectomy predicts poor long-term outcomes. CEA rebound does not contraindicate hepatectomy, but should inform patient counseling and clinical decision-making, especially in patients with RAS/TP53 co-mutation.
ACKNOWLEDGMENTS
The authors thank Ms. Ruth Haynes for administrative support in the preparation of this manuscript and Ms. Stephanie Deming, Research Medical Library, MD Anderson Cancer Center, for copyediting the manuscript.
FUNDING/SUPPORT
Supported by the National Cancer Institute under award number P30CA016672, which supports the MD Anderson Cancer Center Clinical Trials Support Resource.
Footnotes
CONFLICT OF INTEREST STATEMENT
The authors have no conflict of interest to disclose.
DATA AVAILABILITY
The authors are willing to make their data, analytical methods, and study materials available to other researchers upon reasonable request, including relevant ethical and legal statements, to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1. A. Durations (in days) from chemotherapy discontinuation to hepatectomy according to CEA dynamics groups. B. Scatterplot showing the correlation between the durations from chemotherapy discontinuation to hepatectomy and to pre-hepatectomy CEA.
Supplemental Table 1. Predictors of CEA Rebound after Discontinuation of Chemotherapy Among Patients with Pre-chemotherapy CEA Level ≥5 ng/mL (n=612)
Supplemental Table 2. Univariable Analysis of Oncologic Outcomes
Supplemental Table 3. Univariable Analysis of Oncologic Outcomes for Patients without Extrahepatic Disease (n=713)
Supplemental Table 4. Multivariable Analysis of Oncologic Outcomes for Patients without Extrahepatic Disease
Data Availability Statement
The authors are willing to make their data, analytical methods, and study materials available to other researchers upon reasonable request, including relevant ethical and legal statements, to the corresponding author.