Patient Characteristics and Recurrent Pattern
A cohort of 2,329 patients diagnosed with locally advanced rectal cancer who underwent radical TME procedures, with or without NAT was collated. Over a follow-up period averaging 30.5 ± 24.5 months, 381 cases presented with recurrence or distant metastatic disease (Fig. 1). The mean age of these recurrent patients was 56.6 ± 13.0 years, with females comprising 33.1 percent (n = 126). Based on the clinicopathological data of the primary rectal cancer, 187 patients (49.1%) were classified as local high-risk according to MRI-defined risk stratification, and 192 (50.4%) had undergone NAT prior to surgery. Detailed information regarding the primary tumor is presented in Table 1. Recurrent tumors were situated at multiple sites in 36.2% (n = 138) of cases, with single-site recurrence locations being the lung (n = 104; 27.3%), local recurrence (n = 94; 24.7%) and liver (n = 45; 11.8%).
Table 1
Baseline Characteristics and Recurrent Details of the 381 cases of Recurrent Patients from Locally Advanced Rectal Cancer Cohort
Characteristics | | No. (%) |
Gender | Female | 126 (33.1) |
| Male | 255 (66.9) |
Age | < 60 | 199 (52.2) |
| >=60 | 182 (47.8) |
MRI-defined Local Risk | High | 187 (49.1) |
| Low | 194 (50.9) |
Baseline Serum CEA level | > 5ng/ml | 125 (32.8) |
| <=5ng/ml | 256 (67.2) |
Baseline Serum CA19-9 level | >37ng/ml | 51 (13.4) |
| <=37ng/ml | 330 (86.6) |
Mismatch Repair Status | dMMR | 15 ( 3.9) |
| pMMR | 302 (79.3) |
| Unknown | 64 (16.8) |
Tumor Differentiation | High/Moderate | 280 (73.5) |
| Low/Undifferentiated | 53 (13.9) |
| Unknown | 48 (12.6) |
Tumor Distance from Anal Verge | Mid-Rectum | 220 (57.7) |
| Low-Rectum | 161 (42.3) |
Tumor deposit | Absent | 234 (61.4) |
| Present | 147 (38.6) |
Vascular cancer embolus | Absent | 325 (85.3) |
| Present | 56 (14.7) |
PNI | Absent | 301 (79.0) |
| Present | 80 (21.0) |
MRI-N stage | N0 | 89 (23.4) |
| N1-2 | 284 (74.5) |
| Unknown | 8 ( 2.1) |
MRI-T stage | T1-T2 | 8 ( 2.1) |
| T3 | 298 (78.2) |
| T4 | 64 (16.8) |
| Unknown | 11 ( 2.9) |
Initial Treatment for Primary Tumor | Primary Surgery | 189 (49.6) |
| NAT | 192 (50.4) |
Pathological margin | Negative | 328 (86.1) |
| Positive | 6 ( 1.6) |
| Unknown | 47 (12.3) |
Adjuvant Chemotherapy for Primary Tumor | No | 84 (22.0) |
| Yes | 297 (78.0) |
Adjuvant Radiotherapy for Primary Tumor | No | 294 (77.2) |
| Yes | 87 (22.8) |
Recurrence site | Liver-only | 45 (11.8) |
| Locoregional-only | 94 (24.7) |
| Lung-only | 104 (27.3) |
| Multiple sites | 138 (36.2) |
Stage of recurrence time | Early recurrence (< 8 months) | 152 (39.9) |
| Late recurrence ( > = 8 months) | 229 (60.1) |
Treatment after recurrence | Palliative treatment | 255 (66.9) |
| Surgery treatment | 126 (33.1) |
Chemotherapy after recurrence | No | 165 (43.3) |
| Yes | 216 (56.7) |
Radiotherapy after recurrence | No | 349 (91.6) |
| Yes | 32 ( 8.4) |
CEA, carcinoembryonic antigen; CA199, Carbohydrate antigen199; NAT, Neoadjuvant therapy; MMR, Mismatch Repair; PNI, Perineural Invasion |
Correlation Between Recurrence Site, Salvage Surgery, and Post-Recurrence Survival
Of the patients with recurrent cancer, 72 cases (18.8%) underwent salvage surgery, 49 cases (12.8%) received tumor ablation treatment, and 5 cases (1.3%) received both. A subsequent 19.5 ± 17.3 month follow-up revealed that 121 cases (31.8%) of patients died. According to the log-rank test depicted in Fig. 2a-b patients who underwent salvage surgery/ablation or experienced single-site recurrence manifested extended post-recurrence survival compared to patients who solely received palliative treatment (26.2 ± 19.1 months vs. 17.9 ± 14.9 months, P < 0.001) or experienced multiple recurrence sites (23.7 ± 17.9 months vs. 15.0 ± 13.2 months, P < 0.001). Table 2 illustrates that patients who developed a single-site recurrence (OR 3.58, 95% CI 2.07–6.43, P < 0.001) or had mid-rectum tumor (OR 1.67, 95% CI 1.02–2.76, P = 0.042) were significantly more likely to undergo salvage surgery/ablation, while patients with perineural invasion (PNI) (OR 2.03, 95% CI 1.16–3.55, P = 0.013), high/moderate differentiation tumor (OR 1.87, 95% CI 1.01–3.49, P = 0.047) or tumor deposit (OR 1.70, 95% CI 1.05–2.76, P = 0.031) in the primary tumor exhibited an elevated risk of recurrence at multiple sites.
Table 2
Logistic analysis of impact factors for salvage treatment and single-site recurrence in recurrent locally advanced rectal cancer patients
Characteristics | Factors for Salvage Treatment | Factors for Single-site Recurrence |
Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis |
| OR | CI | P | OR | CI | P | OR | CI | P | OR | CI | P |
Gender (Female vs Male) | 0.91 | 0.58–1.44 | 0.699 | 0.91 | 0.54–1.52 | 0.730 | 1.15 | 0.73–1.79 | 0.550 | 0.95 | 0.57–1.58 | 0.839 |
Age ( > = 60 vs < 60) | 0.86 | 0.56–1.32 | 0.487 | 0.67 | 0.41–1.08 | 0.100 | 1.37 | 0.90–2.09 | 0.140 | 1.07 | 0.66–1.72 | 0.780 |
Baseline Serum CEA level (> 5ng/ml vs < = 5ng/ml) | 0.79 | 0.49–1.25 | 0.315 | | | | 1.13 | 0.72–1.76 | 0.606 | | | |
Baseline Serum CA19-9 level ( < = 37ng/ml vs > 37ng/ml) | 1.09 | 0.58–2.06 | 0.782 | | | | 1.40 | 0.77–2.55 | 0.271 | | | |
MRI-N stage (N0 vs N1-2) | 0.73 | 0.44–1.19 | 0.206 | | | | 1.67 | 0.99–2.80 | 0.054 | | | |
MRI-T stage (T1-2 vs T3-4) | 0.50 | 0.12–2.03 | 0.331 | | | | 1.61 | 0.320–8.11 | 0.565 | | | |
Differentiation (High/Moderate vs Low/Undifferentiated) | 0.59 | 0.30–1.16 | 0.129 | 1.53 | 0.77–3.22 | 0.240 | 2.27 | 1.25–4.11 | 0.007 | 1.87 | 1.01–3.49 | 0.047 |
Tumor site (Low-Rectum vs Mid-Rectum) | 0.67 | 0.43–1.03 | 0.070 | 0.60 | 0.36–0.98 | 0.042 | 1.22 | 0.80–1.87 | 0.352 | | | |
Vascular Cancer Embolus (Present vs Absent) | 0.95 | 0.51–1.72 | 0.873 | | | | 1.03 | 0.57–1.85 | 0.932 | | | |
Perineural Invasion (Absent vs Present) | 0.84 | 0.49–1.43 | 0.512 | | | | 2.36 | 1.43–3.90 | 0.001 | 2.03 | 1.16–3.55 | 0.013 |
Tumor deposit (Absent vs Present) | 0.79 | 0.51–1.23 | 0.302 | | | | 1.83 | 1.20–2.81 | 0.005 | 1.70 | 1.05–2.76 | 0.031 |
Pathological margin (Negative vs Positive) | 0.41 | 0.05–3.58 | 0.422 | | | | 1.78 | 0.35–8.96 | 0.485 | | | |
MMR status (dMMR vs pMMR) | 0.38 | 0.13–1.07 | 0.067 | | | | 1.62 | 0.50–5.21 | 0.418 | | | |
Initial Treatment for Primary Tumor (Primary Surgery vs NAT) | 0.95 | 0.61–1.47 | 0.808 | | | | 1.27 | 0.83–1.95 | 0.270 | | | |
Recurrence site (Single site vs Multiple sites) | 3.44 | 2.09–5.81 | < 0.001 | 3.58 | 2.07–6.43 | < 0.001 | | | | | | |
Recurrence Interval (< 8 months vs > = 8 months) | 0.94 | 0.60–1.45 | 0.778 | | | | 1.00 | 0.65–1.54 | 0.990 | | | |
MRI-defined Local Risk (Low vs High) | 1.53 | 0.99–2.35 | 0.055 | | | | 1.39 | 0.92–2.12 | 0.122 | | | |
CEA, carcinoembryonic antigen; CA199, Carbohydrate antigen199; NAT, Neoadjuvant therapy; MMR, Mismatch Repair; CI, Confidence Interval |
Impact of Local Risk and Initial Treatment of the primary rectal cancer on the Overall Survival after Recurrence
To investigate whether the local risk associated with primary rectal cancer and initial treatment impact the subsequent treatment and prognosis of recurrent tumors, patients were categorized into four groups (LoS, LoN, HiS, HiN) according to the MRI-defined local risk and initial treatment for the primary tumor. As shown in Table 3, patients in the HiS group exhibited older age (P = 0.021) and exposed to fewer chemotherapy or radiotherapy (P = 0.001) during the initial treatment for the rectal cancer, when compared with the HiN and LoN groups. Additionally, this subset of patients received less adjuvant chemotherapy for the recurrent disease (P = 0.001), and higher proportion of patients in the HiS group experienced earlier recurrences within the first 8 weeks after surgery (P = 0.001). This group of patients demonstrated a shorter survival time after recurrence than the other groups, according to the log-rank test in Fig. 3 (P = 0.034). The proportion of patients receiving salvage surgery and recurrent site did not markedly differ among groups (P > 0.05).
Table 3
Comparison of Baseline characteristics of recurrent locally advanced rectal cancer patients in four subgroups according to their MRI-defined local Risk and initial Treatment
Characteristics
|
|
HiN
|
HiS
|
LoN
|
LoS
|
P Value
|
Gender
|
Female
|
35 (30.7)
|
26 (35.6)
|
21 (26.9)
|
44 (37.9)
|
0.381
|
|
Male
|
79 (69.3)
|
47 (64.4)
|
57 (73.1)
|
72 (62.1)
|
|
Age
|
< 60
|
71 (62.3)a
|
33 (45.2)a,b
|
44 (56.4)a,b
|
51 (44.0)b
|
0.021
|
|
≥ 60
|
43 (37.7)
|
40 (54.8)
|
34 (43.6)
|
65 (56.0)
|
|
Recurrence Interval
|
< 8 months
|
52 (45.6)a
|
40 (54.8)a
|
27 (34.6)a,b
|
33 (28.4)b
|
0.001
|
|
>= 8 months
|
62 (54.4)
|
33 (45.2)
|
51 (65.4)
|
83 (71.6)
|
|
Recurrence Site
|
Liver-only
|
11 (9.6)
|
10 (13.7)
|
8 (10.3)
|
16 (13.8)
|
0.271
|
|
Locoregional-only
|
23 (20.2)
|
21 (28.8)
|
15 (19.2)
|
35 (30.2)
|
|
|
Lung-only
|
34 (29.8)
|
13 (17.8)
|
26 (33.3)
|
31 (26.7)
|
|
|
Multiple sites
|
46 (40.4)
|
29 (39.7)
|
29 (37.2)
|
34 (29.3)
|
|
Adjuvant Chemotherapy for Primary Tumor
|
No
|
1 (0.9)a
|
30 (41.1)b
|
1 (1.3)a
|
52 (44.8)b
|
< 0.001
|
|
Yes
|
113 (99.1)
|
43 (58.9)
|
77 (98.7)
|
64 (55.2)
|
|
Radiotherapy for Primary Surgery
|
No
|
62 (54.4)a
|
71 (97.3)b
|
47 (60.3)a
|
114 (98.3)b
|
< 0.001
|
|
Yes
|
52 (45.6)
|
2 (2.7)
|
31 (39.7)
|
2 (1.7)
|
|
Radiotherapy for Recurrence Disease
|
No
|
104 (91.2)
|
68 (93.2)
|
71 (91.0)
|
106 (91.4)
|
0.962
|
|
Yes
|
10 (8.8)
|
5 (6.8)
|
7 (9.0)
|
10 (8.6)
|
|
Chemotherapy for Recurrence
|
No
|
33 (28.9)a
|
41 (56.2)b
|
38 (48.7)b
|
53 (45.7)a,b
|
0.001
|
|
Yes
|
81 (71.1)
|
32 (43.8)
|
40 (51.3)
|
63 (54.3)
|
|
Treatment after Recurrence
|
Palliative Treatment
|
80 (70.2)
|
54 (74.0)
|
51 (65.4)
|
70 (60.3)
|
0.209
|
|
Surgery Treatment
|
34 (29.8)
|
19 (26.0)
|
27 (34.6)
|
46 (39.7)
|
|
HiN, MRI-defined High Risk and received Neoadjuvant therapy; HiS, MRI-defined High Risk and received Primary Surgery; LoN, MRI-defined Low Risk and received Neoadjuvant therapy; LoS, MRI-defined Low Risk and received Primary Surgery
a,bThe different letters represent a statistical difference between the two groups
|
Cox hazard regression analysis, utilized to discern risk factors affecting survival after recurrence, was showed in Table 4. It was revealed that salvage treatment (Salvage surgery vs. Palliative treatment, HR = 0.37, 95% CI: 0.21–0.61, P < 0.001) and longer recurrence interval ( > = 8 months vs < 8 months, HR = 0.44, 95% CI: 0.27–0.70, P < 0.001) emerged as independent predictors favoring overall survival post-recurrence.
Table 4
Cox Hazard Regression Analysis for Risk Factors Affecting Survival after Recurrence
Factors | Univariate analysis | Multivariate analysis |
| HR | 95%CI | P | HR | 95%CI | P |
Gender (Female vs Male) | 0.82 | 0.59–1.13 | 0.224 | 0.77 | 0.46–1.27 | 0.302 |
Age ( > = 60 vs < 60) | 1.04 | 0.77–1.40 | 0.818 | 1.34 | 0.83–2.17 | 0.235 |
Baseline Serum CEA level ( < = 5ng/ml vs > 5ng/m) | 0.90 | 0.65–1.23 | 0.503 | | | |
Baseline Serum CA19-9 level (> 37ng/ml vs < = 37ng/ml) | 0.99 | 0.62–1.61 | 0.983 | | | |
MMR status (dMMR vs pMMR) | 0.62 | 0.19, 1.78 | 0.391 | | | |
MRI-defined Local Risk (Low vs High) | 0.85 | 0.63–1.15 | 0.287 | | | |
Differentiation (Well/Moderately vs Poor/undifferentiated) | 0.54 | 0.29–0.97 | 0.039 | 0.63 | 0.32–1.22 | 0.168 |
Tumor Site (Mid-rectum vs Low-rectum) | 0.85 | 0.63–1.16 | 0.305 | | | |
Initial Treatment for Primary Tumor (NAT vs Primary Surgery) | 0.81 | 0.59–1.10 | 0.169 | | | |
Vascular Cancer Embolus (Absent vs Present) | 0.68 | 0.45–1.03 | 0.068 | 1.22 | 0.60–2.50 | 0.586 |
Tumor deposit (Absent vs Present) | 0.73 | 0.54–0.99 | 0.045 | 0.81 | 0.49–1.33 | 0.398 |
Perineural Invasion (Absent vs Present) | 0.74 | 0.52–1.06 | 0.096 | | | |
Recurrence site (Single Site vs Multiple sites) | 0.41 | 0.30–0.56 | < 0.001 | 0.64 | 0.39–1.07 | 0.090 |
Recurrence Interval(>=8 months vs < 8 month) | 0.69 | 0.51–0.94 | 0.017 | 0.46 | 0.28–0.73 | < 0.001 |
Treatment after recurrence (Salvage Surgery vs Palliative treatment) | 0.37 | 0.26–0.54 | < 0.001 | 0.37 | 0.21–0.62 | < 0.001 |
Subgroup | | | 0.172 | | | |
HiN vs HiS | 0.67 | 0.44–1.02 | 0.060 | | | |
LoN vs HiS | 0.68 | 0.44–1.04 | 0.077 | | | |
LoS vs HiS | 0.65 | 0.41–1.02 | 0.060 | | | |
HiN, MRI-defined High Risk and received Neoadjuvant therapy; HiS, MRI-defined High Risk and received Primary Surgery; LoN, MRI-defined Low Risk and received Neoadjuvant therapy; LoS, MRI-defined Low Risk and received Primary Surgery; CEA, carcinoembryonic antigen; CA199, Carbohydrate antigen199; NAT, Neoadjuvant therapy; MMR, Mismatch Repair |