Patients Characteristics
Among 8,376 patient with RC received TME surgery at FUSCC from May 2015 to June 2019, a total of 74 patients diagnosed with concurrent LR and DM were included in our study. The diagnostic rate of concurrent LR and DM in RC patients was 0.88%. Median time between date of LR and DM and date of primary tumor diagnosis was 16 months (range, 1 to 60 months) (Fig. 1).
The clinicopathological characteristics of 74 eligible patients were summarized in Table 1. Among all patients, male patients were more likely to be diagnosed with concurrent LR and DM (male 60.8% v. female 39.2%, P = 0.081, by binomial test). Half were aged over 60 years old. The primary tumor of 62.2% (46/74) patients were located over 5cm from the anal verge. In terms of characteristics for the primary tumor, 91.9% (68/74) were diagnosed as T3-4, 60.8% as positive lymph nodes involved and 23.0% as G3 tumors. 74.3% (55/74) had anterior resection and 31.1% (23/74) had preoperative CRT or RT. For the type of local recurrence, 47.3% (35/74) of patients were diagnosed as regional lymph node recurrence while 31.1% (23/74) as anastomotic recurrence and 21.6% (16/74) as undetermined pelvic recurrence. For the type of distant metastasis, 71.6% (53/76) of patients were diagnosed with OMD and 28.4% (21/74) of patients were diagnosed to have metastases in 3 or more organs or in peritoneal. 73.0% and 85.1% of observed LR and DM had occurred within 2 and 3 years.
Table 1
Baseline characteristics of all eligible patients (n = 74).
Characteristics | No. (%) |
Gender | |
Male | 45 (60.8) |
Female | 29 (39.2) |
Age (years) | |
< 60 | 37 (50.0) |
≥ 60 | 37 (50.0) |
Primary tumor location: distance from the anal verge (cm) | |
> 5 | 46 (62.2) |
≤ 5 | 28 (37.8) |
Type of local recurrence | |
Anastomotic recurrence | 23 (31.1) |
Regional lymph node recurrence | 35 (47.3) |
Undetermined pelvic recurrence | 16 (21.6) |
Distant metastasis | |
Liver/lung/localized lymph node | 53 (71.6) |
3 or more organs/structures involved or peritoneal metastases | 21 (28.4) |
Type of resection of primary tumor | |
Anterior resection | 55 (74.3) |
Abdominoperineal resection | 19 (17.6) |
Others | 6 (8.1) |
T stage of primary tumor | |
T1-2 | 6 (8.1) |
T3 | 41 (55.4) |
T4 | 27 (36.5) |
N stage of primary tumor | |
N0 | 29 (39.2) |
N1 | 36 (48.6) |
N2 | 9 (12.2) |
Tumor grade of primary tumor | |
G1-2 | 57 (77.0) |
G3 | 17 (23.0) |
Preoperative CRT or RT of primary tumor | |
Yes | 23 (31.1) |
No | 51 (68.9) |
Time to recurrence | |
< 24 months | 52 (70.3) |
24–36 months | 10 (13.5) |
> 36 months | 12 (16.2) |
Treatment Modalities
Treatment modalities for 74 RC patients with concurrent LR and DM were listed in Table 2. 70 patients (94.6%) underwent at least one of the local treatments including surgical resection, RT and RFA. 48 patients (64.9%) received systemic treatments such as perioperative chemotherapy and palliative chemotherapy. 59 patients (79.7%) underwent multiple treatments. The results suggested that the vast majority of patients with LR and DM received comprehensive treatment no matter aggressively or palliatively.
Table 2
Treatment modalities of patients.
Treatment modality | | | | | | | | | | |
Surgical resection | √ | √ | √ | √ | √ | | | | | |
Perioperative chemotherapy | | | √ | √ | | | | | | |
Palliative chemotherapy | | | | | | √ | √ | √ | | √ |
Radiotherapy | | √ | | | | √ | √ | | √ | |
Radiofrequency ablation | | | √ | | √ | | √ | √ | | |
Cases | 8 | 12 | 5 | 16 | 3 | 10 | 9 | 4 | 3 | 4 |
Percentage (%) | 10.8 | 16.2 | 6.8 | 21.6 | 4.1 | 13.5 | 12.2 | 5.4 | 4.1 | 5.4 |
Survival
During follow-up, 30 patients (40.5%) died and for the remaining 44 patients, median time between date of LR and DM diagnosis and date of last contact was 27 months (range, 17 to 48 months). Median survival after LR and DM diagnosis was 34 months (95% CI, 28.6 to 39.4 months) and three-year survival after LR and DM was estimated at 49.3% (Fig. 2).
In univariate analysis, type of distant metastasis (HR, 2.464; 95%CI, 1.132–5.362;P = 0.023), number of peritoneal metastases (HR, 2.637; 95%CI, 1.140–2.229; P = 0.023) and NED status (HR, 2.727; 95%CI, 1.229–6.049; P = 0.014) were associated with survival (Table 3). Kaplan-Meier analysis showed that patients achieving NED (P = 0.009), diagnosed with OMD (P = 0.017) and five or less peritoneal metastases (P = 0.017) tended to have longer survival after LR and DM diagnosis (Fig. 3).
Table 3
Univariate and multivariate Cox regression analysis for survival.
Related factors | Univariate | | Multivariate |
HR | 95% CI | P value | | HR | 95% CI | P value |
Gender | | | 0.296 | | | | |
Male | 1.000 | | | | | | |
Female | 0.658 | 0.300-1.433 | | | | | |
Age (years) | | | 0.333 | | | | |
< 60 | 1.000 | | | | | | |
≥ 60 | 0.691 | 0.327–1.460 | | | | | |
Primary tumor location: distance from the anal verge (cm) | | | 0.856 | | | | |
> 5 | 1.000 | | | | | | |
≤ 5 | 0.933 | 0.443–1.965 | | | | | |
Type of local recurrence | | | 0.159 | | | | |
Anastomotic recurrence | 1.000 | | | | | | |
Regional lymph node metastasis | 0.461 | 0.205–1.038 | | | | | |
Undetermined pelvic recurrence | 0.565 | 0.182–1.751 | | | | | |
Distant metastasis | | | 0.023 | | | | 0.068 |
Liver/lung/localized lymph node | 1.000 | | | | 1.000 | | |
3 or more organs/structures involved or peritoneal metastases | 2.464 | 1.132–5.362 | | | 2.106 | 0.947–4.684 | |
Localized abdominal recurrence | | | 0.060 | | | | |
0 | 1.000 | | | | | | |
1–3 | 0.695 | 0.279–1.734 | | | | | |
> 3 | 2.011 | 0.696–5.806 | | | | | |
Peritoneal metastases | | | 0.023 | | | | 0.513 |
0–5 | 1.000 | | | | 1.000 | | |
> 5 | 2.637 | 1.140–6.099 | | | 1.380 | 0.526–3.623 | |
Type of surgery of primary tumor | | | 0.268 | | | | |
Anterior resection | 1.000 | | | | | | |
Abdominoperineal resection | 2.064 | 0.857–4.971 | | | | | |
Others | 1.111 | 0.257–4.815 | | | | | |
T stage of primary tumor | | | 0.362 | | | | |
T1-2 | 1.000 | | | | | | |
T3 | 1.668 | 0.220-12.624 | | | | | |
T4 | 0.965 | 0.121–7.668 | | | | | |
N stage of primary tumor | | | 0.424 | | | | |
N0 | 1.000 | | | | | | |
N1 | 0.979 | 0.441–2.174 | | | | | |
N2 | 1.904 | 0.652–5.565 | | | | | |
Tumor grade of primary tumor | | | 0.199 | | | | |
G1-2 | 1.000 | | | | | | |
G3 | 0.551 | 0.222–1.368 | | | | | |
Preoperative treatment of primary tumor | | | 0.242 | | | | |
Chemoradiotherapy or radiotherapy | 1.000 | | | | | | |
None | 1.801 | 0.673–4.822 | | | | | |
Time to recurrence | | | 0.233 | | | | |
< 24 months | 1.000 | | | | | | |
24–36 months | 3.074 | 0.835–11.315 | | | | | |
> 36 months | 1.779 | 0.599–5.290 | | | | | |
No evidence of disease | | | 0.014 | | | | 0.032 |
NED | 1.000 | | | | 1.000 | | |
Non-NED | 2.727 | 1.229–6.049 | | | 2.419 | 1.078–5.427 | |
After multiple variables adjustment in the Cox proportional hazards regression model, number of peritoneal metastases lost its statistically significance (HR, 1.380; 95%CI, 0.526–3.623;P = 0.513) and type of distant metastasist was marginal statistically significant for predicting survival (HR, 2.106; 95%CI, 0.947–4.684; P = 0.068) (Table 3). NED status was the only independent factor for survival after LR and DM diagnosis (HR, 2.419; 95%CI, 1.078–5.427; P = 0.032) (Table 3).
Ned Status
The relationship between clinicopathological features and NED status was then analyzed (Table 4). The type of distant metastasis (P = 0.003), number of localized abdominal recurrence (P = 0.005), number of peritoneal metastases were all significantly related with NED status (P = 0.001). Thus, patients with OMD can achieve NED status more frequently.
Table 4
Association of NED status and clinicopathological features in 74 eligible patients.
Characteristics | NED, n (%) (n = 41) | Non-NED, n (%) (n = 33) | χ2 | P value |
Gender | | | | |
Male | 25 (33.8) | 20 (27.0%) | 0.001 | 0.974 |
Female | 16 (21.6) | 13 (17.6%) | | |
Age (years) | | | | |
< 60 | 17 (23.0) | 20 (27.0%) | 2.680 | 0.102 |
>/= 60 | 24 (32.4) | 13 (17.6%) | | |
Primary tumor location: distance from the anal verge (cm) | | | | |
> 5 | 26 (35.1) | 20 (27.0%) | 0.061 | 0.804 |
≤ 5 | 15 (20.3) | 13 (17.6%) | | |
Type of local recurrence | | | | |
Anastomotic recurrence | 10 (13.5) | 13 (17.6%) | 2.115 | 0.347 |
Regional lymph node metastasis | 22 (29.7) | 13 (17.6%) | | |
Undetermined pelvic recurrence | 9 (12.2) | 7 (9.5%) | | |
Distant metastasis | | | | |
Liver/lung/localized lymph node | 35 (47.3) | 18 (24.3%) | 8.525 | 0.003 |
3 or more organs/structures involved or peritoneal metastases | 6 (8.1) | 15 (20.3%) | | |
Localized abdominal recurrence | | | | |
None | 10 (13.5) | 4 (5.4%) | 10.636 | 0.005 |
</=3 | 29 (39.2) | 18 (24.3%) | | |
> 3 | 2 (2.7) | 11 (14.9%) | | |
Peritoneal metastases | | | | |
None or </=5 | 39 (52.7) | 22 (29.7%) | 10.223 | 0.001 |
> 5 | 2 (2.7) | 11 (14.9%) | | |
T stage of primary tumor | | | | |
T1-2 | 3 (4.1) | 3 (4.1%) | 1.161 | 0.560 |
T3 | 25 (33.8) | 16 (21.6%) | | |
T4 | 13 (17.6) | 14 (18.9%) | | |
N stage of primary tumor | | | | |
N0 | 17 (23.0) | 12 (16.2%) | 2.920 | 0.232 |
N1 | 17 (23.0) | 19 (25.7%) | | |
N2 | 7 (9.5) | 2 (2.7%) | | |
Tumor grade of primary tumor | | | | |
G1-2 | 30 (40.5) | 27 (36.5%) | 0.773 | 0.379 |
G3 | 11 (14.9) | 6 (8.1%) | | |
Preoperative treatment of primary tumor | | | | |
Chemoradiotherapy or radiotherapy | 16 (21.6) | 7 (9.5%) | 2.708 | 0.100 |
None | 25 (33.8) | 26 (35.1%) | | |
Treatment modality | | | | |
Single treatment | 8 (10.8) | 7 (9.5%) | 0.033 | 0.857 |
Multiple treatment | 33 (44.6) | 26 (35.1%) | | |
Further survival analysis showed that 11 patients (26.8%) in NED group and 19 patients (57.6%) in non-NED group died during follow-up (Table 5). Three-year survival after LR and DM was estimated to be 61.8% in NED group and 29.6% in non-NED group. Patients in NED group have longer median survival after LR and DM diagnosis of 46 months (95% CI, 37.5 to 54.5 months), compared with that of 32 months (95% CI, 24.2 to 39.8 months) in non-NED group. Consequently, RC patients with concurrent LR and DM after TME have a poor prognosis, but reaching NED status after treatments can improve patients’ survival.
Table 5
Survival outcome of NED and non-NED group
Survival outcome | NED (n = 41) | Non-NED (n = 33) |
Number of patients followed until death | 11 (26.8%) | 19 (57.6%) |
3-year survival rate | 61.8% | 29.6% |
Median survival time (month) | 46 | 32 |