These authors have contributed equally to this work
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Colorectal cancer (CRC) is the third most common type of cancer worldwide, with estimated 1.8 million new cases and 0.91 million deaths in 2020 [
Many clinical factors have been used to predict the survival of patients with CRLM after hepatectomy, including the tumor size and number of lesions [
In this study, we applied a novel method to evaluate the pathologic response of CRLM patients. We defined the pathologic complete response ratio of liver metastases (PCRRLM) as the number of liver metastases exhibiting PCR divided by the number of total resected liver metastases. Then, we explored the value of the PCRRLM as an indicator of recurrence after preoperative chemotherapy and the need for liver resection in patients with CRLM.
In this retrospective study, we reviewed the medical records of consecutive patients with CRLM who underwent liver resection between September 1999 and August 2020 at Sun Yat-sen University Cancer Center. A total of 305 patients who underwent curative liver resection for CRLM following preoperative chemotherapy were included in this study. The inclusion criteria were as follows: 1) radical resection of both the colorectal primary tumor and liver metastases; 2) histologically confirmed colorectal adenocarcinoma; 3) preoperative chemotherapy before hepatectomy; and 4) complete clinical and pathological information. Clinical information including patient demographics, tumor characteristics, treatment details, and follow-up data was collected from the electronic medical record system. All procedures performed in this study were in conducted accordance with the ethical standards of the World Medical Association Declaration of Helsinki and were approved by the Institutional Research Ethics Committee of Sun Yat-sen University Cancer Center (approval number: 2020-309-01). Informed consent was waived because of the observational and retrospective nature of the study, and all patient data were kept strictly confidential.
All included patients received preoperative chemotherapy according to the recommendations of a multidisciplinary team (MDT). XELOX (oxaliplatin and capecitabine), FOLFOX (oxaliplatin, leucovorin [LV] and 5-fluorouracil [5-FU]), FOLFIRI (irinotecan, LV and 5-FU) and capecitabine were used based on the recommended doses in the NCCN guidelines. Computerized tomography (CT) or magnetic resonance imaging (MRI) was performed every 3 months to assess the tumor response according to Response Evaluation Criteria in Solid Tumors, version 1.1 [
CRLM was localized by imaging before the operation. All resected tumors in each CRLM patient were sampled. The hepatectomy specimens were sectioned into 5 µm-thick slices. The hematoxylin-eosin-stained sections were carefully examined by two independent pathologists who were blinded to the patient data, treatment regimen and outcome. PCR was defined as the absence of any residual cancer cells in each tissue section, and PCRRLM was defined as the number of liver metastases exhibiting PCR divided by the number of total resected liver metastases of each patient.
Primary tumors were staged according to the eighth edition of the American Joint Committee of Cancer (AJCC) TNM staging system. The liver metastasis characteristics such as number, size, and distribution were assessed by enhanced abdominal nuclear MRI at the time of diagnosis. Synchronous metastases were defined as liver metastases detected at the time of diagnosis or within 6 months after radical resection of the primary tumor, while metachronous metastases were defined as liver metastases detected more than 6 months after radical resection of the primary colorectal tumor [
After liver resection, follow-up was conducted through clinical visits every 3 months for the first 2 years and then semiannually until 5 years. The evaluations included the clinical examination and assessment of CEA levels and CT imaging of the chest, abdomen, and pelvis at 3, 6, 12, and 18 months, 2 years, and annually thereafter. Liver MRI was applied to confirm suspicious lesions indicated on CT or in patients with negative CT results but increased CEA levels. The final follow-up visit was performed in June 2022. Overall survival (OS) was defined as the time interval from liver resection to the date of death due to any cause or the date of the last follow-up visit, while recurrence-free survival (RFS) was calculated as the time interval from liver resection to disease recurrence, death from disease, or last follow-up. Random censoring was applied to patients without recurrence or death at the last follow-up. According to previous studies [
Categorical variables are expressed as numbers with percentages, and continuous variables are expressed as medians with interquartile ranges. Intergroup comparisons were performed using the chi-square test. The chi-square test and Fisher’s exact test were used for categorical variables, and Student’s t test was used for continuous variables to compare baseline characteristics. Univariate and multivariate logistic regression analyses were performed to determine the predictors of recurrence and PCRRLM, and odds ratios (ORs) and 95% confidence intervals (CIs) were subsequently calculated. Survival curves were plotted using the Kaplan–Meier method, and differences between groups were assessed with the log-rank test. Univariate and multivariate analyses of Cox proportional hazards regression models were performed to evaluate the association of the relevant clinicopathological factors with prognosis. Hazard ratios (HRs) with 95% CIs were then calculated. All statistical analyses were conducted using SPSS software version 25.0 (IBM Corp., Armonk, NY, United States) and GraphPad Prism version 7.0, and
The clinicopathological characteristics of the patients are summarized in
Clinicopathological characteristics of the CRLM patients.
Characteristics | N (%) |
---|---|
Age (years, median [range]) | 55 (26–82) |
Sex | |
Female | 92 (30.2) |
Male | 213 (69.8) |
LM number (median [range]) | 3 (1–14) |
LM diameter (cm, median [range]) | 3 (0–14) |
CRS (median [range]) | 2 (0–4) |
TBS (median [range]) | 4.72 (1–15.23) |
Primary tumor location | |
Colon | 187 (61.3) |
Rectum | 118 (38.7) |
Pathology | |
Adenocarcinoma | 276 (90.5) |
Mucinous adenocarcinoma | 17 (5.6) |
Unknown | 12 (3.9) |
Lymph node metastases | |
Negative | 139 (45.6) |
Positive | 166 (54.4) |
CEA (ng/ml) | |
≤5 | 119 (39.0) |
>5 | 186 (61.0) |
Preoperative chemotherapy regimen | |
Irinotecan-based | 116 (38.0) |
Oxaliplatin-based | 169 (55.4) |
Others | 20 (6.6) |
Preoperative targeted therapy | |
Bevacizumab | 84 (27.5) |
Cetuximab | 51 (16.7) |
No | 170 (55.7) |
Interventional therapy | |
No | 226 (74.1) |
Yes | 79 (25.9) |
Synchronous liver metastases | |
No | 60 (19.7) |
Yes | 245 (80.3) |
Hepatic lobe involvement | |
Double | 166 (54.4) |
Single | 139 (45.6) |
Postoperative chemotherapy | |
No | 74 (24.3) |
Yes | 231 (75.7) |
Abbreviations: CEA, carcinoembryonic antigen; CRLM, colorectal liver metastases; CRS, clinical risk score; LM, liver metastases; TBS, tumor burden score.
In this study, 15 patients (4.9%) achieved a complete pathologic response (PCRRLM = 1), 29 patients (9.5%) achieved a PCRRLM ≥0.50 but <1, 44 patients (14.4%) achieved a PCRRLM <0.50 but >0, and 217 patients (71.1%) showed no sign of pathologic response (PCRRLM = 0). Considering the frequency of PCRRLM and its influence on RFS and OS, the whole cohort was divided into two groups for further analyses: the PCRRLM ≥0.50 group (
Baseline characteristics of the patients with a PCRRLM ≥0.50 and <0.50.
Characteristics | PCRRLM ≥0.50 ( |
PCRRLM <0.50 ( |
|
---|---|---|---|
Age (years) |
|
||
<55 | 29 (65.9) | 118 (45.2) | |
≥55 | 15 (34.1) | 143 (54.8) | |
Sex | 0.796 | ||
Female | 14 (31.8) | 78 (29.9) | |
Male | 30 (68.2) | 183 (70.1) | |
LM number | 0.762 | ||
<3 | 23 (52.3) | 130 (49.8) | |
≥3 | 21 (47.7) | 131 (50.2) | |
LM diameter (cm) |
|
||
<3 | 30 (68.2) | 118 (45.2) | |
≥3 | 14 (31.8) | 143 (54.8) | |
Primary site |
|
||
Colon | 20 (45.5) | 167 (64.0) | |
Rectum | 24 (54.5) | 94 (36.0) | |
Lymph node metastases | 0.335 | ||
Negative | 23 (52.3) | 116 (44.4) | |
Positive | 21 (47.7) | 145 (55.6) | |
Synchronous liver metastases | 0.276 | ||
No | 6 (13.6) | 54 (20.7) | |
Yes | 38 (86.4) | 207 (79.3) | |
CEA (ng/ml) |
|
||
≤5 | 32 (72.7) | 87 (33.3) | |
>5 | 12 (27.3) | 174 (66.7) | |
Hepatic lobe involvement | 0.196 | ||
Double | 20 (45.5) | 146 (55.9) | |
Single | 24 (54.5) | 115 (44.1) | |
Preoperative chemotherapy regimen | 0.97 | ||
Irinotecan-based | 16 (36.364) | 100 (38.314) | |
Oxaliplatin-based | 25 (56.818) | 144 (55.172) | |
Others | 3 (6.818) | 17 (6.513) | |
Postoperative chemotherapy | 0.902 | ||
No | 11 (25.0) | 63 (24.1) | |
Yes | 33 (75.0) | 198 (75.9) | |
CRS |
|
||
<3 | 29 (65.9) | 130 (49.8) | |
≥3 | 15 (34.1) | 131 (50.2) | |
TBS |
|
||
<5 | 29 (65.9) | 125 (47.9) | |
≥5 | 15 (34.1) | 136 (52.1) |
Abbreviations: CEA, carcinoembryonic antigen; CRS, clinical risk score; LM, liver metastases; PCRRLM, pathologic complete response ratio of liver metastases; TBS, tumor burden score. The bold values in table indicate
The univariable and multivariable logistic regression (
Univariable and multivariable logistic regression analyses predicting risk factors for PCRRLM.
Variables | Univariable | Multivariable | ||
---|---|---|---|---|
OR (95% CI) |
|
OR (95% CI) |
|
|
Age (years): ≥ 55 vs. < 55 | 0.43 (0.22, 0.84) |
|
0.47 (0.23, 0.96) |
|
Sex: male vs. female | 0.91 (0.46, 1.82) | 0.796 | ||
Primary tumor site: rectum vs. colon | 2.13 (1.12, 4.07) |
|
0.53 (0.27–1.06) | 0.072 |
Lymph node metastases: positive vs. negative | 0.73 (0.38, 1.39) | 0.336 | ||
Pathology: adenocarcinoma vs. mucinous adenocarcinoma | 2.79 (0.36–21.63) | 0.326 | ||
CEA (ng/ml): > 5 vs. ≤ 5 | 0.19 (0.09, 0.38) |
|
0.23 (0.11, 0.48) |
|
Chemotherapy regimen: irinotecan-based vs. oxaliplatin-based | 0.92 (0.47–1.81) | 0.813 | ||
Chemotherapy cycles: > 4 vs. ≤ 4 | 1.10 (0.58–2.11) | 0.767 | ||
Synchronous LM: Yes vs. No | 1.65 (0.66, 4.13) | 0.280 | ||
LM number: ≥ 3 vs. < 3 | 0.75 (0.40, 1.43) | 0.386 | ||
LM diameter (cm): ≥ 3 vs. < 3 | 0.39 (0.19, 0.76) |
|
0.57 (0.25–1.31) | 0.183 |
Hepatic lobe involvement: single vs. double | 1.52 (0.80, 2.90) | 0.199 | ||
CRS: ≥ 3 vs. < 3 | 0.51 (0.26, 1.00) | 0.051 | ||
TBS: ≥ 5 vs. < 5 | 0.48 (0.24, 0.93) |
|
0.88 (0.38–2.06) | 0.775 |
Abbreviations: CEA, carcinoembryonic antigen; CI, confidence interval; CRS, clinical risk score; LM, liver metastases; OR, odds ratio; PCRRLM, pathologic complete response ratio of liver metastases; TBS, tumor burden score. The bold values in table indicate
The median follow-up durations for patients with a PCRRLM ≥0.50 and those with a PCRRLM <0.50 were 84.23 and 63.33 months, respectively. Both RFS and OS were significantly better in patients with a PCRRLM ≥0.50 than in those with a PCRRLM <0.50 (5-year OS rates, 62.75% vs. 41.06%,
Plots of patient survival stratified by the PCRRLM.
Compared to patients with a PCRRLM ≥0.50, those with a PCRRLM <0.50 were more likely to experience intrahepatic recurrence rather than extrahepatic recurrence (intrahepatic recurrence,
Death percent of patients with different recurrence rates stratified by the PCRRLM.
The results of univariate and multivariate Cox analyses predicting OS and RFS are shown in
Univariable and multivariable Cox regression analyses of the predictors of overall survival.
Variables | Univariable | Multivariable | ||
---|---|---|---|---|
HR (95% CI) |
|
HR (95% CI) |
|
|
Age (years): ≥55 vs. < 55 | 0.93 (0.68–1.27) | 0.644 | ||
Sex: male vs. female | 1.12 (0.79–1.57) | 0.532 | ||
PCRRLM: ≥ 0.50 vs. < 0.50 | 0.61 (0.38–0.99) |
|
0.75 (0.46, 1.23) | 0.256 |
Primary site: colon vs. rectum | 0.88 (0.64–1.21) | 0.427 | ||
Lymph node status: positive vs. negative | 1.61 (1.17–2.21) |
|
1.47 (0.97, 2.24) | 0.070 |
CEA (ng/ml): >5 vs. ≤ 5 | 1.28 (0.93–1.77) | 0.135 | ||
Chemotherapy regimen: oxaliplatin-based vs. irinotecan-based | 0.69 (0.50–0.95) | 0.076 | ||
Chemotherapy cycles: > 4 vs. ≤ 4 | 0.88 (0.65–1.21) | 0.441 | ||
Synchronous LM: yes vs. no | 0.60 (0.42–0.86) |
|
0.59 (0.41, 0.85) |
|
LM number: ≥ 3 vs. < 3 | 1.56 (1.14–2.15) |
|
1.18 (0.76, 1.83) | 0.462 |
LM diameter (cm): ≥ 3 vs. < 3 | 1.37 (1.00–1.87) |
|
1.01 (0.69, 1.50) | 0.944 |
Hepatic lobe involvement: double vs. single | 1.54 (1.13–2.12) |
|
1.11 (0.75, 1.64) | 0.617 |
CRS: ≥ 3 vs. < 3 | 1.84 (1.35–2.52) |
|
1.29 (0.84, 1.98) | 0.246 |
TBS: ≥ 5 vs. < 5 | 1.88 (1.37–2.58) |
|
1.58 (1.02, 2.45) |
|
Postoperative chemotherapy: yes vs. no | 0.72 (0.51–1.03) | 0.068 |
Abbreviations: CEA, carcinoembryonic antigen; CI, confidence interval; CRS, clinical risk score; LM, liver metastases; HR, hazard ratio; PCRRLM, pathologic complete response ratio of liver metastases; TBS, tumor burden score. The bold values in table indicate
Univariable and multivariable Cox regression analyses of the predictors of recurrence-free survival.
Variables | Univariable | Multivariable | ||
---|---|---|---|---|
HR (95% CI) |
|
HR (95% CI) |
|
|
Age (years): ≥55 vs. < 55 | 0.90 (0.70–1.16) | 0.407 | ||
Sex: male vs. female | 1.16 (0.88–1.53) | 0.300 | ||
PCRRLM: ≥ 0.50 vs. < 0.50 | 0.63 (0.43–0.92) |
|
0.67 (0.46, 0.99) |
|
Primary site: colon vs. rectum | 1.17 (0.90–1.51) | 0.238 | ||
Lymph node status: positive vs. negative | 1.38 (1.07–1.79) |
|
1.46 (1.04, 2.05) |
|
CEA (ng/ml): > 5 vs. ≤ 5 | 1.29 (0.99–1.68) | 0.055 | ||
Chemotherapy regimen: oxaliplatin-based vs. irinotecan-based | 0.64 (0.49–0.83) |
|
0.78 (0.59, 1.02) | 0.073 |
Chemotherapy cycles: > 4 vs. ≤ 4 | 0.65 (0.50–0.84) |
|
0.80 (0.61, 1.05) | 0.102 |
Synchronous LM: yes vs. no | 0.84 (0.61–1.15) | 0.267 | ||
LM number: ≥ 3 vs. < 3 | 1.69 (1.31–2.18) |
|
1.42 (0.99, 2.05) | 0.059 |
LM diameter (cm): ≥ 3 vs. < 3 | 1.34 (1.04–1.72) |
|
1.10 (0.81, 1.49) | 0.550 |
Hepatic lobe involvement: double vs. single | 1.50 (1.16–1.94) |
|
1.03 (0.75, 1.41) | 0.864 |
CRS: ≥ 3 vs. < 3 | 1.56 (1.21–2.01) |
|
1.03 (0.73, 1.44) | 0.884 |
TBS: ≥ 5 vs. < 5 | 1.93 (1.49–2.49) |
|
1.44 (1.02, 2.04) |
|
Postoperative chemotherapy: yes vs. no | 1.03 (0.76–1.39) | 0.846 |
Abbreviations: CEA, carcinoembryonic antigen; CI, confidence interval; CRS, clinical risk score; LM, liver metastases; HR, hazard ratio; PCRRLM, pathologic complete response ratio of liver metastases; TBS, tumor burden score. The bold values in table indicate
In this study, we retrospectively analyzed the accumulated cases of CRLM in our hospital in an attempt to identify potential prognostic indicators for these patients. We proposed the PCRRLM, a new and potentially better measurement of pathologic response in patients with CRLM after preoperative chemotherapy and resection, and assessed its value for predicting prognosis and recurrence. Detailed analysis confirmed that patients with a PCRRLM ≥0.50 had a highly favorable prognosis and a significantly lower incidence of recurrence, suggesting that PCRRLM could be a feasible clinicopathological indicator.
Although the strength of the pathologic response after preoperative chemotherapy has generally been accepted as a prognostic factor over the years, the optimal grading system to evaluate this parameter is still a matter of debate. A conventional assessment was semi-quantitatively estimating the proportion of residual cancer cells in relation to the total tumor area, and the mean of the values was used when there was more than one metastasis [
Another popular index for pathologic response was tumor regression grade (TRG), a 5-point scoring system firstly proposed for esophageal tumor and then introduced into the field of colorectal cancer by Dworak
One of the inherent drawbacks of applying the PCRRLM in clinical practice is the difficulty of assessing it in a noninvasive manner prior to surgery. Therefore, it would be considerably valuable to preoperatively identify patients who are likely to achieve a favorable pathologic response. In this study, we determined that age <55 years old and preoperative CEA ≤5 ng/ml are strong predictors of PCRRLM ≥0.50. In addition, a primary tumor site in the rectum, CRLM diameter of <3 cm, and TBS <5 points were all identified as predictors in the univariate analysis. The correlations among small tumor size, low CEA levels, and PCR have been well confirmed by previous studies [
The long-term prognosis was much better for patients who had a higher PCRRLM than for those who did not. In our study, the proportion of patients who achieved pathologic complete response (PCR) was 4.9% (15/305), which is similar to previous studies [
The response to chemotherapy was limited among patients with a PCRRLM less than 0.50, and their prognosis was relatively poor. Hence, for these patients, the follow-up interval should be shortened, as closer clinical monitoring is needed. A low PCRRLM also suggests that the chemotherapy regimen should be modified. Some studies have reported a relatively higher tumor response after oxaliplatin-based preoperative chemotherapy than irinotecan-based preoperative chemotherapy [
This study had some limitations, which should be acknowledged. First, this was a retrospective analysis that included only a limited number of patients from a single institution. Incorporating the grouped chemotherapy and targeted therapy regimens into the analyses would make it difficult to obtain good reproducible results, as this was a small cohort study. Therefore, the findings need further validation in a larger prospective cohort of patients. Second, the mutation status of some genes, such as
In conclusion, we proposed the PCRRLM as a novel grading system for the pathologic response of patients after the resection of CRLM treated with preoperative chemotherapy. The long-term RFS of patients who achieved a PCRRLM ≥0.50 was extremely favorable, and most of them showed a significantly lower tendency toward recurrence. The PCRRLM may provide an objective and precise evaluation of the pathologic response of patients with CRLM.
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below:
The studies involving human participants were reviewed and approved by the Institutional Research Ethics Committee of Sun Yat-sen University Cancer Center. The patients/participants provided their written informed consent to participate in this study.
Study concept and design: JL, JP, and YX. Acquisition of data: JH, YX, WL, and WZ. Analysis and interpretation of data: YX and JH. Drafting of the manuscript: JH. Critical revision of the manuscript for important intellectual content: JL, JP, ZL, and ZP. Hematoxylin-eosin-stained sections examination: SL and JH. Study supervision: JL, JP, and ZP. All authors have made a significant contribution to this study and have approved the final manuscript.
This study was funded by grants from the National Natural Science Foundation of China (no. 82003051 and no. 82072606), the Fundamental Research Funds for the Central Universities of Sun Yat-sen University (no. 22qntd4001), and Medical Scientific Research Foundation of Guangdong Province, China (no. A2021130).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.