Abstract
Background
The number of lymph nodes examined (LNe) is often insufficient in patients with rectal cancer (RC) treated with neoadjuvant therapy; however, its prognostic value remains controversial. Thus, we retrospectively explored whether LNe had an influence on staging and prognosis and investigated whether there was a cut-off value for better prognosis in patients with RC treated with neoadjuvant therapy.
Methods
Data were collected from seven prospective hospital databases in China from July 2002 to May 2018. Binary logistic regression models were used to predict lymph node metastasis. The cut-off value for LNe was determined using X-tile 3.6.1. Survival outcomes and risk factors were analyzed using the log-rank test and Cox regression model.
Results
A total of 482 patients were included, of whom 459 had complete overall survival (OS) information. Using the percentile method, the total number of lymph nodes examined (TLNe) was 14–16 (40th–60th percentile), and the proportion of patients with lymph node metastasis reached a maximum of 48.1%. Cox multivariate analysis showed that the odds ratio (OR) remained the highest when TLNe was 14–16 (OR = 3.379, P = 0.003). The 3-year and 5-year OS were 85.4% and 77.8%, respectively. Negative lymph nodes examined (NLNe) of ≤6 was an independent risk factor for 3-year and 5-year OS (3-year OS 71.1% vs. 85.9%, P = 0.004; 5-year OS 66.3% vs. 74.3%, P = 0.035). Subgroup analysis for patients with ypN + showed that higher 3-year and 5-year OS were achieved when the TLNe was >10, 78.8% vs. 54.0% (P = 0.005), and 60.8% vs. 36.0% (P = 0.012), respectively. Patients with ypN0M0 had a higher 5-year OS when the TLNe was >19 (P = 0.055).
Conclusion
The TLNe and NLNe influenced the staging accuracy and demonstrated prognostic value in patients with RC treated with neoadjuvant therapy.
Keywords: Lymph nodes examined, Prognosis, Staging accuracy, Rectal cancer, Neoadjuvant therapy
Graphical abstract
Highlights
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Many lymph nodes should be examined in patients with rectal cancer treated with neoadjuvant therapy.
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The number of lymph nodes examined might have prognostic value.
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Study conclusions should be drawn based on a sufficient or entire number of lymph nodes examined.
Introduction
Colorectal cancer is one of the most common malignancies in China, leading to approximately 180,000 deaths in 2014.1 The number of metastatic lymph nodes is regarded as an essential factor in staging and is based on a sufficient number of lymph nodes examined (LNe).2,3 According to the Eighth American Joint Committee on Cancer (AJCC) guideline, at least 12 lymph nodes should be examined for colorectal cancer.4 Neoadjuvant therapy has become the standard treatment for locally advanced rectal cancer (RC), but only about 20% of these patients have sufficient LNe.2,3,5 Both radiation and chemotherapy decrease the examined number of lymph nodes, which might influence staging accuracy, as positive lymph nodes might be missed.6, 7, 8 Moreover, the postoperative chemotherapy decision was made based on staging, and whether ypN0 disease requires further treatment remains controversial. Therefore, the number of LNe might have an impact on prognosis, but the results of existing studies differed significantly.9, 10, 11, 12 Moreover, all the lymph nodes in the specimens should be examined, but it is quite difficult in patients with RC who underwent treatment with neoadjuvant therapy, and there is no unified standard with regard to the minimum number of LNe in these patients; therefore, the prognostic value of the number of LNe has been unclear to date.8,13, 14, 15, 16, 17, 18, 19
Hence, this study aimed to explore whether the number of LNe had an influence on staging and prognosis and to investigate whether there was a cut-off value for better prognosis in patients with RC treated with neoadjuvant therapy.
Methods
Patients
A total of 482 patients with RC treated with neoadjuvant therapy from seven prospective hospital databases in China from July 2002 to May 2018 were retrospectively reviewed. Perioperative evaluation was performed by the respective colorectal cancer multiple-disciplinary team (MDT) in each hospital. All patients underwent curative surgery after neoadjuvant therapy. The patients received treatments based on the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines, and the final decision was made based on the patient's choice. Patients with a history of other types of cancers, those who required emergency surgical procedures, and those who had distant metastasis during the first clinical visit were excluded from the study.
Data collection
Data regarding patient demographics, clinicopathological characteristics, and treatment were retrospectively collected from the prospective databases. Follow-up evaluation assessments were conducted every 3–6 months until the third postoperative year and every year thereafter for at least 5 years. Overall survival (OS) was calculated from the time of surgery until the last follow-up visit or date of death.
Statistical analysis
Statistical analyses were performed using the SPSS 24.0 software (IBM Corp., Armonk, NY, USA). Categorical variables were presented as frequencies with percentages and assessed using the chi-square or Fisher's exact test, as appropriate. Multivariable binary logistic regression models were used to predict metastatic lymph nodes. The optimal cut-off points of total number of lymph nodes examined (TLNe), negative lymph nodes examined (NLNe), and positive lymph nodes examined (PLNe) were calculated and determined using X-tile 3.6.1 (https://medicine.yale.edu/lab/rimm/research/software.aspx). This identified the cut-off with minimum P values from log-rank χ2 statistics for categorical lymph nodes in terms of survival.20 Survival outcomes were analyzed using Kaplan–Meier method and compared by log-rank test. A Cox regression model was utilized to determine the risk factors for OS. Survival analyses were performed using R version 3.5.1 software (The R Foundation for Statistical Computing, Vienna, Austria) with “survival” and “survminer” packages. P values of <0.05 were considered to be significant.
Results
Patient characteristics
A total of 482 patients met the selection criteria, including 287 males and 195 females, with a median age of 58 (22–88) years. The median distance from the distal margin of the tumor to the anal verge was 5.0 cm (1.0–12.0). There were 24 patients with cT1-2 stage (5.0%), 406 patients with cT3 (84.2%), 51 patients with cT4 (10.6%), and one missing data. There were 89 patients with cN0 stage (18.5%), 392 patients with cN + stage (81.3%), and one missing data. Of all patients, 382 (79.2%) received 30 Gy (Gy)/10f preoperative radiation, 77 (16%) received ≥45 Gy radiation, and 23 (4.8%) received 25 Gy/5 f radiation. The downstaging rate was 4.8% during clinical evaluation and 55.2% during pathological evaluation.
A total of 324 patients (67.2%) underwent low anterior resection (LAR), 152 patients (31.5%) underwent abdominoperineal resection (APR), and six patients (1.3%) underwent the Hartmann procedure. There were 35 (7.3%), 24 (5.0%), 134 (27.8%), 261 (54.1%), and 28 (5.8%) patients with ypT stages 0, 1, 2, 3, and 4, respectively. There were 291 ypN0 patients (60.4%), 115 patients (23.9%) with 1–3 lymph node metastases (ypN1a-1b), and 69 patients (14.3%) with ≥4 lymph node metastases. The median number of metastatic lymph nodes was 2.0 (1–24). A total of 16 (3.3%) patients had tumor deposits, and seven of these had tumor deposits without lymph node metastasis (ypN1c). There were 35 patients (7.3%) with positive circumferential resection margin (CRM). No complete clinical response (cCR) was observed in any patient, and a partial clinical response (pCR) ratio was observed in 6.4% (31 patients). There were 123 (25.5%) patients with stage ypI, 137 (28.4%) with stage ypII, and 184 (38.2%) with stage ypIII. Seven (1.5%) patients had distant metastases during neoadjuvant treatment, two of whom had no lymph node metastasis, and five patients had lymph node metastasis.
Among the 392 cN + patients, 42.3% (166 patients) and 56.4% (221 patients) were with and without lymph node metastasis during pathological evaluation, respectively. Among 291 ypN0 patients, 75.6% (220) had clinical lymph node metastases. Among 191 patients who had lymph node metastases or tumor deposits, 9.9% (19 patients) did not have lymph node metastases during the initial clinical evaluation. The median number of TLNe was 14 (0–61) in the entire cohort and 15 (5–61) in patients with lymph node metastases, and the median number of metastatic lymph nodes was 2 (range, 1–24). The other clinicopathological characteristics are shown in Table 1.
Table 1.
Patient characteristics and univariate analysis of risk factors for lymph node metastasis.
| Parameters | Entire cohort (n = 482) | ypN0 (n = 291) | ypN+ (n = 191) | χ2 value | P value |
|---|---|---|---|---|---|
| Gender | 1.181 | 0.277 | |||
| Male | 287 (59.5) | 179 (61.5) | 108 (56.5) | ||
| Female | 195 (40.5) | 112 (38.5) | 83 (43.5) | ||
| Age (years) | 1.868 | 0.172 | |||
| <65 | 333 (69.1) | 194 (66.7) | 139 (72.8) | ||
| ≥65 | 148 (30.7) | 96 (33.0) | 52 (27.2) | ||
| Missing | 1 (0.2) | 1 (0.3) | 0 | ||
| CEA | 6.171 | 0.013 | |||
| Normal | 312 (64.7) | 201 (69.1) | 111 (58.1) | ||
| Abnormal | 165 (34.2) | 87 (29.9) | 78 (40.8) | ||
| Missing | 5 (1.1) | 3 (1.0) | 2 (1.1) | ||
| Dis to AV (cm) | 1.048 | 0.653 | |||
| ≤5 | 284 (58.9) | 176 (60.6) | 108 (56.5) | ||
| >5 and ≤10 | 194 (40.3) | 113 (38.8) | 81 (42.5) | ||
| >10 and ≤15 | 2 (0.4) | 1 (0.3) | 1 (0.5) | ||
| Missing | 2 (0.4) | 1 (0.3) | 1 (0.5) | ||
| cT stage | 0.429 | 0.513 | |||
| cT1–2 | 24 (5.0) | 16 (5.5) | 8 (4.2) | ||
| cT3–4 | 457 (94.8) | 274 (94.2) | 183 (95.8) | ||
| Missing | 1 (0.2) | 1 (0.3) | 0 | ||
| cN stage | 15.377 | <0.001 | |||
| cN0 | 89 (18.5) | 70 (24.1) | 19 (9.9) | ||
| cN+ | 392 (81.3) | 220 (75.6) | 172 (90.1) | ||
| Missing | 1 (0.2) | 1 (0.3) | 0 | ||
| Radiation (Gy) | 5.794 | 0.055 | |||
| ≥45 | 77 (16.0) | 55 (18.9) | 22 (11.5) | ||
| 30 | 382 (79.2) | 225 (77.3) | 157 (82.2) | ||
| 25 | 23 (4.8) | 11 (3.8) | 12 (6.3) | ||
| ycT stage | 2.644 | 0.104 | |||
| ycT0–2 | 28 (5.8) | 21 (7.3) | 7 (3.7) | ||
| ycT3–4 | 452 (93.8) | 269 (92.4) | 183 (95.8) | ||
| Missing | 2 (0.4) | 1 (0.3) | 1 (0.5) | ||
| ycN stage | 24.860 | <0.001 | |||
| ycN0 | 110 (22.8) | 89 (30.6) | 21 (11.0) | ||
| ycN+ | 371 (77.0) | 202 (69.4) | 169 (88.5) | ||
| Missing | 1 (0.2) | 0 | 1 (0.5) | ||
| Surgery | 0.200 | 0.950 | |||
| LAR | 324 (67.2) | 194 (66.7) | 130 (68.1) | ||
| APR | 152 (31.5) | 93 (31.9) | 59 (30.9) | ||
| Hartmann | 6 (1.3) | 4 (1.4) | 2 (1.0) | ||
| ypT stage | 58.332 | <0.001 | |||
| ypT0 | 35 (7.3) | 31 (10.7) | 4 (2.1) | ||
| ypT1–2 | 158 (32.8) | 127 (43.6) | 31 (16.2) | ||
| ypT3–4 | 289 (59.9) | 133 (45.7) | 156 (81.7) | ||
| TLNe | 22.680 | <0.001 | |||
| ≤9 | 107 (22.2) | 85 (29.2) | 22 (11.5) | ||
| 10–13 | 113 (23.4) | 62 (21.3) | 51 (26.7) | ||
| 14–16 | 77 (16.0) | 39 (13.4) | 38 (19.9) | ||
| 17–24 | 93 (19.3) | 56 (19.3) | 37 (19.4) | ||
| ≥25 | 92 (19.1) | 49 (16.8) | 43 (22.5) | ||
| M stage | 2.943 | 0.119 | |||
| M0 | 475 (98.5) | 289 (99.3) | 186 (97.4) | ||
| M1 | 7 (1.5) | 2 (0.7) | 5 (2.6) | ||
| ypTNM stage | – | – | |||
| 0 | 31 (6.4) | 31 (10.6) | 0 | ||
| I–II | 260 (53.9) | 258 (88.7) | 2 (1.1) | ||
| III | 184 (38.2) | 0 | 184 (96.3) | ||
| IV | 7 (1.5) | 2 (0.7) | 5 (2.6) | ||
| Differentiation | 18.596 | <0.001 | |||
| High | 18 (3.7) | 13 (4.5) | 5 (2.6) | ||
| Moderate | 318 (66.0) | 200 (68.7) | 118 (61.8) | ||
| Low | 103 (21.4) | 41 (14.1) | 62 (32.5) | ||
| Missing | 43 (8.9) | 37 (12.7) | 6 (3.1) | ||
| Tumor deposit | – | – | |||
| Negative | 466 (96.7) | 291 (100) | 175 (91.6) | ||
| Positive | 16 (3.3) | 0 | 16 (8.4) | ||
| LVI | 25.251 | <0.001 | |||
| Negative | 426 (88.4) | 274 (94.2) | 152 (79.6) | ||
| Positive | 55 (11.4) | 16 (5.5) | 39 (30.4) | ||
| Missing | 1 (0.2) | 1 (0.3) | 0 | ||
| CRM | 4.368 | 0.037 | |||
| Negative | 417 (86.5) | 254 (87.3) | 163 (85.3) | ||
| Positive | 35 (7.3) | 15 (5.1) | 20 (10.5) | ||
| Missing | 30 (6.2) | 22 (7.6) | 8 (4.2) |
Data were presented as n (%). APR: Abdominoperineal resection; AV: Anal verge; CEA: Carcinoembryonic antigen; CRM: Circumferential resection margin; Dis: Distance; LAR: Low anterior resection; LVI: Lymphovascular invasion; TLNe: Total number of lymph nodes examined.
There were 459 patients with complete OS information, including 374 cN+, 174ypN + M0, and 278 ypN0M0 patients. The median follow-up time was 64.3 months, and the 3-year and 5-year OS rates were 85.4% and 77.8%, respectively.
Correlation between lymph node metastasis and total number of lymph nodes examined
The median numbers of TLNe in ypN0 and ypN + patients were 13 and 15, respectively, showing significant differences (Mann–Whitney U test, U = 22,680, Z = −3.420, P = 0.001). Spearman's correlation analysis showed a slightly positive linear correlation between the number of metastatic lymph nodes and TLNe (rs = 0.173, P < 0.001).
Using the percentile method(20th, 40th, 60th, and 80th percentiles), TLNe was divided into five groups according to the percentiles (≤9, 10–13, 14–16, 17–24, and ≥25). The proportions of patients with metastatic lymph nodes were 19.6%, 42.5%, 48.1%, 37.6%, and 46.7%, respectively. In addition, the proportion was significantly increased in the group with 10–13 (χ2 = 13.332, P < 0.001) and 14–16 (χ2 = 0.576, P = 0.448) LNe.
Univariate and multivariate analysis of risk factors for lymph node metastasis
There were 191 ypN+ and 291 ypN0 patients. Univariate analysis showed that the carcinoembryonic antigen (CEA) level (χ2 = 6.171, P = 0.013), cN status (χ2 = 15.377, P < 0.001), radiotherapy method (χ2 = 5.794, P = 0.055), ycN status (χ2 = 24.860, P < 0.001), ypT stage (χ2 = 58.332, P < 0.001), TLNe (χ2 = 22.680, P < 0.001), tumor differentiation (χ2 = 18.596, P < 0.001), lymphovascular invasion (LVI) status (χ2 = 25.251, P < 0.001), and CRM status (χ2 = 4.368, P = 0.037) showed significant differences between the two groups [Table 1]. Binary logistic regression showed that 414 patients were finally included in the multivariate analysis (with no ypT0 patient), and ypT stage, TLNe, LVI status, and tumor differentiation were considered risk factors [Table 2]. When the TLNe was 14–16, then the OR was maximum (3.379 [95% CI 1.533–7.448, P = 0.003]).
Table 2.
Multivariate analysis of risk factors for lymph node metastasis.
| Parameters | B | SE | Wald | P | OR | 95% CI |
|---|---|---|---|---|---|---|
| ypT stage | ||||||
| I–II | 1.000 | |||||
| III–IV | 1.331 | 0.268 | 24.624 | <0.001 | 3.787 | 2.238–6.407 |
| TLNe | 11.808 | 0.019 | ||||
| ≤9 | 1.000 | |||||
| 10–13 | 1.042 | 0.372 | 7.855 | 0.005 | 2.836 | 1.368–5.879 |
| 14–16 | 1.218 | 0.403 | 9.119 | 0.003 | 3.379 | 1.533–7.448 |
| 17–24 | 0.702 | 0.385 | 3.324 | 0.068 | 2.017 | 0.949–4.287 |
| ≥25 | 1.030 | 0.380 | 7.357 | 0.007 | 2.801 | 1.331–5.897 |
| LVI | ||||||
| Negative | 1.000 | |||||
| Positive | 1.241 | 0.373 | 11.097 | 0.001 | 3.459 | 1.667–7.180 |
| Differentiation | 5.848 | 0.054 | ||||
| High | 1.000 | |||||
| Moderate | 0.548 | 0.688 | 0.634 | 0.426 | 1.730 | 0.449–6.665 |
| Low | 1.133 | 0.713 | 2.529 | 0.112 | 3.106 | 0.768–12.554 |
| Constant | −3.636 | 0.868 | 17.531 | <0.001 | 0.026 |
LVI: Lymphovascular invasion; TLNe: Total number of lymph nodes examined.
Cut-off value calculated by X-tile
As shown in Table 3 and Figure 1, X-tile plots were constructed and identified six as the cut-off value for NLNe to divide the entire cohort; the cN + cohort was divided into low (>6) and high (≤6) risk subsets in terms of OS, and five as the cut-off value for NLNe to divide the ypN + cohort into low (>5) and high (≤5) risk subsets in terms of OS. The results showed significant differences between the low- and high-risk subsets in the three cohorts in 3-year OS (87.2% vs. 76.0%, 88.3% vs. 74.6%, 81.5% vs. 41.2%, P = 0.003, 0.001, and <0.001, respectively), and the cN+ and ypN + M0 cohorts in 5-year OS (79.4% vs. 71.2%, 67.6% vs. 35.3%, P = 0.040, <0.001, respectively). A cut-off value of 10 for TLNe was identified to divide the ypN + M0 cohort into low (>10) and high (≤10) risk subsets in terms of OS, in which the 3-year OS were 80.4% and 60.0% (P = 0.007), and the 5-year OS were 66.4% and 52.0% (P = 0.030), respectively. A cut-off value of 19 for TLNe was identified to divide the ypN0M0 cohort into low- (>19) and high-risk (≤19) subsets in terms of OS, in which the 3-year OS were 96.0% and 86.8% (P = 0.031), and the 5-year OS were 92.3% and 84.0% (P = 0.030), respectively.
Table 3.
Details of cut-off values for the entire cN+, ypN+, and ypN0 cohort, 3-year and 5-year OS calculated by X-tile.
| Patients | Factors | Cut-off value | Overall Survival (%) | P value |
|---|---|---|---|---|
| Entire Cohort | TLNe | ≤14 | 3-year: 83.8 | 0.129 |
| >14 | 3-year: 87.0 | |||
| TLNe | ≤6 | 5-year: 87.2 | 0.237 | |
| >6 | 5-year: 76.7 | |||
| NLNe | ≤6 | 3-year: 76.0 | 0.003 | |
| >6 | 3-year: 87.2 | |||
| NLNe | ≤6 | 5-year: 73.3 | 0.078 | |
| >6 | 5-year: 78.7 | |||
| cN + Cohort | TLNe | ≤14 | 3-year: 85.1 | 0.317 |
| >14 | 3-year: 86.9 | |||
| TLNe | ≤20 | 5-year: 81.4 | 0.192 | |
| >20 | 5-year: 70.3 | |||
| NLNe | ≤6 | 3-year: 74.6 | 0.001 | |
| >6 | 3-year: 88.3 | |||
| NLNe | ≤6 | 5-year: 71.2 | 0.040 | |
| >6 | 5-year: 79.4 | |||
| ypN + M0 Cohort | TLNe | ≤10 | 3-year: 60.0 | 0.007 |
| >10 | 3-year: 80.4 | |||
| TLNe | ≤10 | 5-year: 52.0 | 0.030 | |
| >10 | 5-year: 66.4 | |||
| NLNe | ≤5 | 3-year: 41.2 | <0.001 | |
| >5 | 3-year: 81.5 | |||
| NLNe | ≤5 | 5-year: 35.3 | <0.001 | |
| >5 | 5-year: 67.6 | |||
| ypN0M0 Cohort | TLNe | ≤19 | 3-year: 86.8 | 0.031 |
| >19 | 3-year: 96.0 | |||
| TLNe | ≤19 | 5-year: 84.0 | 0.030 | |
| >19 | 5-year: 92.3 |
NLNe: Negative lymph nodes examined; TLNe: Total number of lymph nodes examined.
Figure 1.
Cut-off points for TLNe and NLNe counts determined by the X-tile program. X-tile analysis divided the entire cohort into the training sets and matched validation sets based on patient surgical data. The cohort was divided into low and high-count groups based on the optimal cut-points, as was shown on a histogram of the cohort, and a Kaplan–Meier curve. The cut-off value for NLNe of the entire cohort in 3-year OS (A) and 5-year OS (B), NLNe of the cN + cohort in 3-year OS (C), TLNe of the ypN0 cohort in 5-year OS (D), TLNe of the yPN + cohort in 3-year OS (E) and 5-year OS (F), NLNe of the yPN + cohort in 3-year OS (G) and 5-year OS (H). NLNe: Negative lymph nodes; OS: Overall survival; TLNe: Total number of lymph nodes examined.
Prognostic value of lymph nodes examined
Cox regression was performed to identify the prognostic value of the number of LNe, and any variable achieving a P value < 0.10 in the univariate analysis or clinically considered to be statistically significant, was proposed [Table 4, Table 5]. In the entire cohort, when the NLNe was >6, better 3-year and 5-year OS were achieved (hazard ratio [HR] 0.432, 95% CI 0.242–0.770, P = 0.004; HR 0.564, 95% confidence interval [CI] 0.331–0.961, P = 0.035, respectively) [Figure 2A and B]. Similar results were also observed in the cN + cohort [Figure 2C and D]. In the ypN + M0 cohort, better results were obtained when the TLNe was >10, achieving better 3-year and 5-year OS (HR 0.333, 95% CI 0.154–0.718, P = 0.005; HR 0.424, 95% CI 0.218–0.826, P = 0.012, respectively) [Figure 2E and F]. In the ypN0M0 cohort, a trend of better 5-year OS was shown when the TLNe was >19 (HR 0.420, 95% CI 0.173–1.020, P = 0.055) [Figure 2G and H].
Table 4.
Univariate analysis for OS in the entire cohort and cN + cohort.
| Factors | Entire cohort |
cN + cohort |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 3-year OS (%) | χ2 value | P value | 5-year OS (%) | χ2 value | P value | N | 3-year OS (%) | χ2 value | P value | 5-year OS (%) | χ2 value | P value | |
| Gender | 1.056 | 0.304 | 0.148 | 0.701 | 1.049 | 0.306 | 0.069 | 0.792 | ||||||
| Male | 272 | 82.2 | 72.6 | 225 | 82.9 | 73.3 | ||||||||
| Female | 187 | 85.7 | 73.8 | 149 | 76.6 | 73.5 | ||||||||
| Age (years) | 0.190 | 0.663 | 0.649 | 0.420 | 0.227 | 0.634 | 0.011 | 0.917 | ||||||
| <65 | 315 | 84.2 | 74.8 | 263 | 83.6 | 73.9 | ||||||||
| ≥65 | 143 | 82.9 | 69.9 | 111 | 86.0 | 71.8 | ||||||||
| CEA | 8.230 | 0.004 | 15.929 | <0.001 | 5.144 | 0.023 | 12.173 | <0.001 | ||||||
| Normal | 296 | 87.1 | 79.1 | 242 | 87.4 | 79.2 | ||||||||
| Abnormal | 159 | 76.2 | 60.8 | 128 | 77.9 | 61.3 | ||||||||
| Dis to AV (cm) | 0.757 | 0.685 | 0.233 | 0.890 | 0.785 | 0.675 | 0.378 | 0.828 | ||||||
| ≤5 | 268 | 82.6 | 72.9 | 208 | 82.9 | 72.5 | ||||||||
| >5 and ≤10 | 188 | 85.6 | 73.9 | 164 | 86.4 | 74.4 | ||||||||
| >10 and ≤15 | 1 | 100 | 100 | 1 | 100 | 100 | ||||||||
| cT stage | 0.072 | 0.788 | 0.507 | 0.476 | 0.037 | 0.848 | 0.504 | 0.477 | ||||||
| cT1–2 | 23 | 86.1 | 79.5 | 23 | 86.1 | 79.5 | ||||||||
| cT3–4 | 435 | 83.7 | 72.9 | 351 | 84.3 | 72.8 | ||||||||
| cN stage | 0.567 | 0.451 | 0.035 | 0.851 | – | – | – | – | – | – | – | |||
| cN0 | 84 | 81.4 | 73.1 | |||||||||||
| cN+ | 374 | 84.4 | 73.3 | |||||||||||
| Radiation (Gy) | 5.142 | 0.076 | 6.090 | 0.048 | 7.219 | 0.027 | 8.667 | 0.013 | ||||||
| ≥45 | 72 | 91.0 | 91.0 | 60 | 95.8 | 95.8 | ||||||||
| 30 | 382 | 83.5 | 72.5 | 309 | 84.0 | 72.4 | ||||||||
| 25 | 5 | 50.0 | 50.0 | 5 | 50.0 | 50.0 | ||||||||
| ycT stage | 1.025 | 0.311 | 1.795 | 0.180 | 0.780 | 0.377 | 1.658 | 0.198 | ||||||
| ycT0–2 | 28 | 91.0 | 84.5 | 27 | 90.9 | 84.4 | ||||||||
| ycT3–4 | 430 | 83.2 | 72.4 | 346 | 83.9 | 72.5 | ||||||||
| ycN stage | 0.003 | 0.960 | 0.330 | 0.566 | 1.870 | 0.171 | 2.872 | 0.090 | ||||||
| ycN0 | 105 | 83.7 | 76.1 | 22 | – | – | ||||||||
| ycN+ | 353 | 83.6 | 72.3 | 351 | 83.9 | 72.5 | ||||||||
| Surgery | 16.647 | <0.001 | 7.612 | 0.022 | 6.520 | 0.038 | 2.787 | 0.248 | ||||||
| LAR | 311 | 86.4 | 74.4 | 268 | 87.2 | 75.0 | ||||||||
| APR | 143 | 79.3 | 72.2 | 104 | 78.3 | 70.4 | ||||||||
| Hartmann | 5 | 40.0 | 40.0 | 2 | 50.0 | 50.0 | ||||||||
| ypT stage | 9.898 | 0.007 | 84.3 | 16.446 | <0.001 | 12.407 | 0.002 | 18.893 | <0.001 | |||||
| ypT0 | 34 | 89.6 | 84.5 | 26 | 95.5 | 95.5 | ||||||||
| ypT1–2 | 156 | 91.1 | 64.8 | 114 | 93.3 | 86.1 | ||||||||
| ypT3–4 | 269 | 78.4 | 234 | 78.9 | 64.8 | |||||||||
| ypN stage | 28.834 | <0.001 | 41.478 | <0.001 | 34.630 | <0.001 | 41.602 | <0.001 | ||||||
| ypN0 | 280 | 89.2 | 83.4 | 213 | 92.6 | 86.2 | ||||||||
| ypN1a–1b | 109 | 84.1 | 64.1 | 97 | 82.1 | 61.7 | ||||||||
| ypN1c | 6 | 83.3 | 83.3 | 5 | 80.0 | 80.0 | ||||||||
| ypN2 | 64 | 62.0 | 45.2 | 59 | 62.1 | 48.0 | ||||||||
| NLNe | 9.038 | 0.003 | 3.073 | 0.080 | 10.588 | 0.001 | 4.257 | 0.039 | ||||||
| ≤6 | 75 | 71.1 | 66.3 | 59 | 69.4 | 63.4 | ||||||||
| >6 | 384 | 85.9 | 74.3 | 315 | 86.9 | 75.0 | ||||||||
| M stage | 5.860 | 0.015 | 13.065 | <0.001 | 6.931 | 0.009 | 14.515 | 0.001 | ||||||
| M0 | 452 | 84.0 | 73.7 | 367 | 84.8 | 74.0 | ||||||||
| M1 | 7 | 42.9 | 0 | 7 | 42.9 | 0 | ||||||||
| ypTNM stage | 18.154 | <0.001 | 39.180 | <0.001 | 28.079 | <0.001 | 46.885 | <0.001 | ||||||
| 0 | 31 | 92.1 | 86.4 | 23 | 100 | 100 | ||||||||
| I–II | 247 | 89.3 | 83.5 | 188 | 92.4 | 85.2 | ||||||||
| III | 174 | 75.5 | 57.7 | 156 | 74.2 | 57.5 | ||||||||
| IV | 7 | 42.9 | 0 | 7 | 42.9 | 0 | ||||||||
| Differentiation | 5.144 | 0.076 | 10.806 | 0.005 | 5.875 | 0.053 | 11.521 | 0.003 | ||||||
| High | 12 | 83.3 | 83.3 | 8 | 87.5 | 87.5 | ||||||||
| Moderate | 307 | 85.9 | 77.0 | 249 | 86.6 | 77.2 | ||||||||
| Low | 98 | 75.7 | 58.6 | 85 | 75.1 | 57.0 | ||||||||
| Tumor deposit | 8.409 | 0.004 | 10.148 | 0.001 | 9.990 | 0.002 | 11.336 | <0.001 | ||||||
| Negative | 445 | 84.3 | 73.9 | 361 | 85.2 | 74.3 | ||||||||
| Positive | 14 | 50.5 | 33.7 | 13 | 50.1 | 33.4 | ||||||||
| LVI | 0.519 | 0.471 | 4.375 | 0.036 | 0.333 | 0.564 | 3.793 | 0.051 | ||||||
| Negative | 405 | 84.0 | 74.8 | 324 | 84.8 | 75.3 | ||||||||
| Positive | 53 | 80.5 | 59.5 | 50 | 81.7 | 60.4 | ||||||||
| CRM | 6.956 | 0.008 | 7.799 | 0.005 | 10.737 | 0.001 | 9.968 | 0.002 | ||||||
| Negative | 394 | 84.7 | 74.5 | 320 | 85.9 | 75.0 | ||||||||
| Positive | 35 | 66.8 | 53.0 | 28 | 62.1 | 48.9 | ||||||||
APR: Abdominoperineal resection; AV: Anal verge; CEA: Carcinoembryonic antigen; CRM: Circumferential resection margin; Dis: Distance; LAR: Low anterior resection; LVI: Lymphovascular invasion; NLNe: Negative lymph nodes examined; OS: Overall survival.
Table 5.
Univariate analysis for OS in ypN + cohort and ypN0 cohort.
| Factors | ypN + cohort |
ypN0 cohort |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 3-year OS (%) | χ2 value | P value | 5-year OS (%) | χ2 value | P value | N | 3-year OS (%) | χ2 value | P value | 5-year OS (%) | χ2 value | P value | |
| Gender | 1.469 | 0.225 | 1.032 | 0.310 | 0.243 | 0.622 | 0 | 0.990 | ||||||
| Male | 97 | 71.6 | 54.4 | 171 | 88.9 | 83.8 | ||||||||
| Female | 77 | 80.3 | 61.9 | 107 | 90.5 | 83.7 | ||||||||
| Age (years) | 0.001 | 0.977 | 0.122 | 0.727 | 0.145 | 0.704 | 1.013 | 0.314 | ||||||
| <65 | 125 | 75.9 | 59.3 | 186 | 90.2 | 86.1 | ||||||||
| ≥65 | 49 | 73.5 | 53.4 | 91 | 89.1 | 79.9 | ||||||||
| CEA | 0.705 | 0.401 | 2.916 | 0.088 | 9.715 | 0.002 | 9.216 | 0.002 | ||||||
| Normal | 100 | 77.5 | 63.7 | 192 | 93.3 | 87.7 | ||||||||
| Abnormal | 72 | 72.4 | 49.9 | 84 | 79.7 | 73.3 | ||||||||
| Dis to AV (cm) | 0.059 | 0.809 | 0.105 | 0.746 | 1.173 | 0.556 | 0.246 | 0.884 | ||||||
| ≤5 | 98 | 74.5 | 56.5 | 165 | 88.3 | 83.6 | ||||||||
| >5 and ≤10 | 75 | 76.6 | 59.3 | 111 | 92.4 | 84.8 | ||||||||
| >10 and ≤15 | 1 | 100 | 100 | |||||||||||
| cT stage | 1.691 | 0.193 | 0.133 | 0.716 | 1.654 | 0.198 | 0.870 | 0.351 | ||||||
| cT1–2 | 7 | 57.1 | 57.1 | 16 | 100 | 90.0 | ||||||||
| cT3–4 | 167 | 76.3 | 57.6 | 261 | 89.3 | 83.7 | ||||||||
| cN stage | 1.410 | 0.235 | 0.518 | 0.472 | 9.300 | 0.002 | 4.973 | 0.026 | ||||||
| cN0 | 18 | 87.1 | 59.4 | 66 | 79.8 | 75.7 | ||||||||
| cN+ | 156 | 74.2 | 57.5 | 211 | 93.1 | 86.7 | ||||||||
| Radiation (Gy) | 0.375 | 0.829 | 1.284 | 0.527 | 6.640 | 0.036 | 6.565 | 0.038 | ||||||
| ≥45 | 18 | 93.3 | 93.3 | 50 | 89.8 | 89.8 | ||||||||
| 30 | 155 | 74.9 | 56.5 | 224 | 90.1 | 83.9 | ||||||||
| 25 | 1 | 100 | 100 | 4 | 50.0 | 50.0 | ||||||||
| ycT stage | 0.171 | 0.680 | 0.100 | 0.752 | 2.046 | 0.153 | 1.257 | 0.262 | ||||||
| ycT0–2 | 7 | 68.6 | 68.6 | 21 | 100 | 90.9 | ||||||||
| ycT3–4 | 167 | 75.8 | 57.2 | 257 | 88.8 | 83.2 | ||||||||
| ycN stage | 1.455 | 0.228 | 0.543 | 0.461 | 4.488 | 0.034 | 1.784 | 0.182 | ||||||
| ycN0 | 20 | 87.1 | 59.4 | 85 | 82.9 | 79.3 | ||||||||
| ycN+ | 154 | 74.2 | 57.5 | 193 | 92.2 | 85.5 | ||||||||
| Surgery | 11.912 | 0.003 | 8.852 | 0.012 | 12.420 | 0.002 | 6.838 | 0.033 | ||||||
| LAR | 117 | 81.4 | 61.2 | 187 | 90.8 | 84.4 | ||||||||
| APR | 56 | 64.3 | 52.8 | 87 | 88.9 | 84.1 | ||||||||
| Hartmann | 1 | 0 | 0 | 4 | 50.0 | 50.0 | ||||||||
| ypT stage | 4.450 | 0.107 | 4.033 | 0.133 | 1.375 | 0.503 | 1.953 | 0.377 | ||||||
| ypT0 | 3 | 66.7 | 66.7 | 31 | 92.1 | 86.4 | ||||||||
| ypT1–2 | 28 | 92.0 | 76.4 | 125 | 91.7 | 86.7 | ||||||||
| ypT3–4 | 143 | 72.4 | 54.1 | 122 | 86.5 | 79.7 | ||||||||
| ypN stage | 10.288 | 0.005 | 7.345 | 0.025 | – | – | – | – | – | – | – | |||
| ypN0 | 106 | 84.1 | 64.1 | |||||||||||
| ypN1a–1b | 6 | 83.3 | 83.3 | |||||||||||
| ypN1c | 62 | 62.3 | 46.9 | |||||||||||
| ypN2 | ||||||||||||||
| TLNe | 7.025 | 0.008 | 4.604 | 0.032 | – | – | – | – | – | – | – | |||
| ≤10 | 27 | 54.0 | 36.0 | |||||||||||
| >10 | 147 | 78.8 | 60.8 | |||||||||||
| TLNe | – | – | – | – | – | – | – | 4.311 | 0.038 | 4.384 | 0.036 | |||
| ≤19 | 201 | 86.9 | 80.4 | |||||||||||
| >19 | 77 | 95.9 | 91.5 | |||||||||||
| Differentiation | 6.715 | 0.035 | 8.049 | 0.018 | 0.238 | 0.888 | 0.057 | 0.972 | ||||||
| High | 3 | 66.7 | 66.7 | 9 | 88.9 | 88.9 | ||||||||
| Moderate | 109 | 81.7 | 64.9 | 194 | 89.2 | 84.0 | ||||||||
| Low | 57 | 65.5 | 45.6 | 39 | 91.5 | 81.5 | ||||||||
| Tumor deposit | 4.947 | 0.026 | 4.830 | 0.028 | – | – | – | – | – | – | – | |||
| Negative | 161 | 76.8 | 59.0 | |||||||||||
| Positive | 13 | 50.1 | 33.4 | |||||||||||
| LVI | 0.067 | 0.793 | 0.547 | 0.460 | 0.094 | 0.759 | 0.004 | 0.947 | ||||||
| Negative | 140 | 75.6 | 58.6 | 261 | 89.4 | 83.8 | ||||||||
| Positive | 34 | 75.0 | 53.9 | 16 | 92.9 | 81.2 | ||||||||
| CRM | 3.873 | 0.049 | 4.242 | 0.039 | 1.580 | 0.209 | 1.589 | 0.207 | ||||||
| Negative | 147 | 77.6 | 60.1 | 241 | 89.8 | 84.1 | ||||||||
| Positive | 20 | 58.2 | 37.7 | 15 | 78.6 | 71.4 | ||||||||
APR: Abdominoperineal resection; AV: Anal verge; CEA: Carcinoembryonic antigen; CRM: Circumferential resection margin; Dis: Distance; LAR: Low anterior resection; LVI: Lymphovascular invasion; TLNe: Total number of lymph nodes examined; -: No available; OS: Overall survival.
Figure 2.
Cox regression results of the entire cohort, the cN+, ypN+, and ypN0 cohorts, showed with forest plots. (A) Multivariate analysis of 3-year OS in the entire cohort; (B) multivariate analysis of 5-year OS in the entire cohort; (C) multivariate analysis of 3-year OS in the cN + cohort; (D) multivariate analysis of 5-year OS in the cN + cohort; (E) multivariate analysis of 3-year OS in the ypN + cohort; (F) multivariate analysis of 5-year OS in the ypN + cohort; (G) multivariate analysis of 3-year OS in the ypN0 cohort; (H) multivariate analysis of 5-year OS in the ypN0 cohort. CEA: Carcinoma embryonic antigen; CRM: Circumferential resection margin; Diff: Differentiation; LNC: Lymph node count; LVI: Lymphovascular invasion; NLNC: Negative lymph nodes count; TLNe: Total number of lymph nodes examined.
Discussion
In our study, the number of lymph node metastases demonstrated a positive correlation with TLNe in patients with RC treated with neoadjuvant therapy, regardless of CRM status. When the TLNe was 14–16, then the proportion of patients with lymph node metastasis remained the highest. In these patients, TLNe may be influenced by the experience of the pathologist, tumor aggressiveness, and tumor staging. The increase in TLNe levels may also be related to the immune response. The results from the studies conducted by Parsons et al. and Van Erning et al. showed that an increase in TLNe in colon cancer did not increase the proportion of patients with positive lymph nodes.21,22 However, Kim et al. showed that an increase in TLNe would increase the positive rate of lymph nodes, and at least 10 LNe could avoid staging shifts in colorectal cancer.15 In 2014, Bhangu et al. showed that the proportion of patients with lymph node metastasis gradually increased with increasing TLNe in patients with RC treated with neoadjuvant therapy, and the proportion did not increase beyond this when it reached 16.8 In 2018, Gao et al. showed that when the TLNe reached 10, the rate of proportion increase tended to be gentle, achieving accurate staging.16 They recommended examination of at least 10 lymph nodes in patients with RC treated with neoadjuvant therapy.16 In our study, multivariate analysis after adjusting for related clinicopathological factors showed that TLNe was still an independent, influential factor. When examination of 14–16 lymph nodes was achieved, the OR was the highest (OR = 3.379, 95% CI 1.533–7.448, P = 0.003). Therefore, we believe that the TLNe in patients with RC treated with neoadjuvant therapy should be at least 14 for accurate staging.
In addition, multivariate analysis showed that positive LVI, ypT3–4, and tumor differentiation were independent risk factors for lymph node metastasis. In our study, 11.4% of patients were LVI-positive, and 21.2% were LVI-positive among patients with lymph node metastases, but only 5.4% were LVI-positive in patients without lymph node metastases. Moreover, among LVI-positive patients, 70.9% had lymph node metastases. ypT stage represents the depth of tumor invasion and increases the area between tumor tissue and lymphatic vessels with increasing depth, resulting in an increased probability of lymph node metastases. Among the ypT0, T1, T2, T3, and T4 patients, the proportions of lymph node metastases were 11.4%, 12.5%, 20.1%, 52.5%, and 46.4%, respectively.
cN status and ycN status were not considered independent risk factors for lymph node metastases. Among the cN+ and ycN + patients, 43.9% and 45.6% of patients had lymph node metastases, respectively. The consistency of the preoperative evaluation of lymph node metastases included in this study was not high, and the assessment of lymph node metastatic status by preoperative imaging should be further strengthened.
When the prognostic value of the number of LNe was taken into account, X-tile was used to find the cut-off value, followed by Cox regression to validate the prognostic value with clinicopathological factors together. Most previous studies focused on the relationship between TLNe and prognosis, and the log-rank test was used to compare prognosis.8,17 The cut-off value was mostly 12, which was determined according to the AJCC guidelines, while some studies used the median number of LNe in their series.18,23 Currently, an increasing number of studies have used an enumeration method to determine the cut-off values. In our study, the results showed that TLNe was not a prognostic factor in the entire cN + cohort, but the 3-year and 5-year OS were better when NLNe was >6.
Li et al. included 6068 patients with RC treated with neoadjuvant therapy from the SEER database from 2004 to 2010 and used X-tile to identify the cut-off value of nine for NLNe in terms of tumor-specific survival, and a better tumor-specific survival was observed when NLNe was >9.24 However, in our study, subgroup analysis showed NLNe as an unstable factor, whereas TLNe was an important factor in terms of 3-year and 5-year OS. In the ypN + M0 cohort, when TLNe was >10, then the 3-year and 5-year OS increased significantly, but when CRM was positive, no significant difference in terms of 5-year OS was observed. Sun et al. analyzed 158 ypN + patients and found that NLNe significantly influenced the 3-year disease-free survival (DFS) rate.25 They identified 4 and 16 as cut-off values to divide the patients into high-, middle-, and low-risk subsets, and the 3-year DFS was 15.2%, 55.5%, and 73.1%, respectively (P = 0.017). However, the 3-year OS were 62.1%, 79.8%, and 83.2%, respectively (P = 0.076), with no significant differences.25 While the results in our study showed that when NLNe was >6, a better 5-year OS was observed, NLNe did not influence the 3-year OS.
For ypN + patients, regardless of TLNe, current opinions mostly support that adjuvant chemotherapy is essential.9,10 However, whether adjuvant chemotherapy should be administered to patients with ypN0 status remains controversial. Loree et al. conducted a retrospective study, and the results after short-term radiation therapy revealed that patients with ypII stage RC did not benefit from adjuvant chemotherapy after multivariate analysis.26 Subgroup analysis showed that adjuvant chemotherapy improved only disease-specific survival and recurrence-free survival in patients with at least two risk factors: pT4, poor differentiation, less than 12 lymph nodes, LVI, perineural invasion (PNI), and obstructed or perforated condition. However, previous studies did not consider TLNe and did not verify the effect of adjuvant chemotherapy on prognosis when TLNe reached a specific number. The method of predicting prognosis based on the number of LNe is somewhat controversial, but it is important to accurately distinguish ypN0 patients to determine postoperative treatment.18
In our study, subgroup analysis in the ypN0M0 cohort showed, regardless of the CRM status, an increasing trend in 5-year OS when the lymph node count (LNC) was >19. Unfortunately, we failed to collect information on adjuvant chemotherapy; therefore, it was not possible to assess whether patients with TLNe of more than 19 needed adjuvant chemotherapy. Moreover, an increase in TLNe might reflect a stronger immune response to neoadjuvant therapy, resulting in a better prognosis. In addition, the tumor regression grade (TRG) was also considered an indicator of the effect of neoadjuvant treatment, and the relationship between TRG and TLNe remains unclear. However, existing evidence also could not prove that a decreased number of LNe in patients has better TRG.27 Patients who received neoadjuvant therapy showed greater heterogeneity. Different data sources and statistical methods might have caused differences in the results, and the results of our study support that TLNe is an independent prognostic factor of OS in patients with RC treated with neoadjuvant therapy.
However, our study has some limitations. First, this was a retrospective study and lacked information on adjuvant chemotherapy, which might have impacted the accuracy of the conclusions. Second, approximately 80% of the patients included in this study received 30 Gy radiotherapy, which was more than that in other studies, and the heterogeneity of patients and treatment methods might lead to differences in conclusions. Finally, all continuous variables, such as CEA level, age, and LNe, were converted into categorical variables, and a reduction in statistical power might have occurred.
In conclusion,the numbers of TLNe and NLNe influenced the staging accuracy and had prognostic value in patients with RC treated with neoadjuvant therapy.
Funding
This work was supported by the Beijing Chinese Society of Clinical Oncology Research Foundation (No. Y-Young2020-0468) and the Peking University People's Hospital Research and Development Funds (No. RDL2020-06).
Author contributions
Contributions to conception and design, or acquisition of data, or analysis and interpretation of data: Liyu Zhu, Lin Wang, Yujian Zeng, Kaixiong Tao, Quan Wang, Xinming Li, Huanhu Zhang, Zhanlong Shen, Kai Shen, Zhidong Gao, Yingjiang Ye, and Aiwen Wu. Drafting the article or revising it critically for important intellectual content: Liyu Zhu, Lin Wang, Zhidong Gao, Yingjiang Ye, and Aiwen Wu. Final approval of the version to be published: Aiwen Wu, Zhidong Gao, and Yingjiang Ye.
Ethics statement
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Peking University People's Hospital, Beijing, China (No. 2021PHD010-001). Written informed consent was obtained from all patients prior to their enrollment in the study.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Conflict of interest
None.
Acknowledgments
We thank the Organ Function Protection Committee of the Chinese Society of Colon and Rectal Surgeons.
Managing Editor: Peng Lyu
Contributor Information
Zhidong Gao, Email: gaozhidong@pkuph.edu.cn.
Yingjiang Ye, Email: yeyingjiang@pkuph.edu.cn.
Aiwen Wu, Email: wuaw@foxmail.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.