The present study was performed to investigate the effects of local complications (LC) on long-term survival and cancer recurrence in patients undergoing curative gastrectomy for gastric cancer.
We analyzed 2,627 patients after curative gastrectomy for gastric cancer between January 2001 and December 2006. Patients were classified into groups no complications (NC), LC, or systemic complications (SC).
Among the 2,627 patients, 475 patients developed complications (LC group [n=374, 14.2%] and SC group [n=101, 3.9%]). The 5-year cancer-specific survival rate was significantly poorer in the LC group compared to the NC and SC groups (LC, 78.0%; NC, 85.4%; SC, 80.2%; P=0.007). The occurrence of LC was identified as a significant independent prognostic factor for overall and cancer-specific survival (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.46–2.97; P=0.001 and HR, 1.77; 95% CI, 1.12–2.81; P=0.015). The tumor recurrence rates were higher in the LC group than the in other two groups (LC, 23.5%; NC, 15.4%; SC, 15.8%; P<0.001). The occurrence of LC was an independent predictor of tumor recurrence in patients undergoing curative gastrectomy for gastric cancer (HR, 1.55; 95% CI, 1.11–2.17; P=0.011).
LC are associated with adverse long-term outcomes in patients after curative gastrectomy for advanced gastric cancer.
Despite its decreasing incidence rate, gastric cancer remains a common malignancy worldwide. In particular, gastric cancer is the second most common cause of cancer death in Korea, although the number of patients diagnosed with early gastric cancer has increased due to the development of gastroscopy and mass screening tests [
Anastomotic leakage, which is one of the most serious complications after gastrointestinal surgery, is related to poor outcome despite improvements in surgical techniques and perioperative management of cancer surgery [
This study was performed to investigate the impact of postoperative local and systemic complications (SC) on long-term survival and recurrence rates in patients following curative gastrectomy for gastric cancer.
This was a retrospective multicenter observational cohort study of patients who underwent gastrectomy for gastric cancer between January 2001 and December 2006 at nine surgical centers: Soonchunhyang University Bucheon Hospital, Keimyung University Hospital, National Cancer Center, Dong-A University Hospital, Yonsei University Hospital, Chonbuk National University Hospital, Seoul National University Hospital, Hallym University Dongtan Sacred Heart Hospital, Samsung Medical Center, and Sungkyunkwan University. Consecutive patients who underwent gastrectomy for gastric cancer were prospectively registered over the study period. This study was granted Institutional Review Board approval (IRB No. SCHBC 2014-07-011) and informed consent was waived because of the retrospective observational design and the anonymous nature of the study.
The inclusion criteria required patients to be histologically diagnosed with gastric cancer and to be receiving surgical treatment during the study period. Patients diagnosed with synchronous primary malignancy, those undergoing non-curative surgery, and those receiving preoperative chemotherapy were excluded.
Postoperative complications were defined by a combination of clinical findings based on symptoms and physical examination of patients, as well as the results of laboratory and radiological studies, including X-ray, ultrasonography, and computed tomography (CT). In this study, patients were divided into groups exhibiting no complications (NC), local complications (LC), or SC. LC included wound infection, fluid collection/abscess, intraabdominal bleeding, intraluminal bleeding, intestinal obstruction, ileus, stenosis, anastomotic leakage, pancreatitis, wound dehiscence, and cholecystitis. SC consisted of pulmonary, hepatic, cardiac, urinary tract infections, splenic infarction, transient ischemic attack, and delirium. The Clavien-Dindo classification was used to assess the severity of surgical complications, using the following definitions based on its contracted form: grade I: any complication not requiring medical or surgical treatment; grade II: a complication requiring pharmacological treatment but no active intervention; grade III: a complication requiring surgical, radiological, or endoscopic treatment; grade IV: complications that are potentially life-threatening and require intensive care. In this study, we proceeded to record the complications observed in our patients, distribute them according to the type of treatment required, and classify them on this scale during hospitalization after surgery. In case of wound repair, when the wound was approximated at bedside, it was classified as grade I, when repaired under local anesthesia in an operation theater as grade III. Severe complications were defined as those graded as >III [
The follow-up schedule and indications for adjuvant chemotherapy were not standardized among the various institutions. However, most patients with advanced gastric cancer at TNM stage II or higher received fluorouracil-based adjuvant treatment. No patients were given postoperative or perioperative radiotherapy. Follow-up observations were performed at 3- or 6-month intervals for the first 2 years, at 6-month intervals for the next 3 years, and then annually until the patient’s death. The follow-up program consisted of physical examination, laboratory blood tests, endoscopy, CT, and positron emission tomography-CT (PET-CT). Recurrence was diagnosed from imaging findings, including CT, magnetic resonance imaging, PET-CT, endoscopy, biopsies, or cytology.
The following data were obtained from electronic medical records and the prospectively collected gastric cancer registry from each hospital: general characteristics of the patients, including demographic data, tumor site and size, type of surgical procedure, and extent of lymph node dissection. Overall survival was calculated from the time of surgery to death due to any cause, or to the last follow-up that ended without death. Cancer-specific survival was calculated as the date of a diagnosis of stomach cancer until date of death, and was censored if the primary or underlying cause of death was not stomach cancer. The primary outcome was the 5-year survival rate and the secondary outcome was the 5-year cancer recurrence rate.
All results and tables are presented as medians and interquartile ranges (IQRs) or as numbers (percentages) of patients because the majority of the data did not follow a normal distribution. The Mann-Whitney U test and Kruskal-Wallis one-way analysis of variance were used for comparison of continuous variables, and comparisons of categorical data were performed using the chi-squared or Fisher exact test where appropriate. Multivariate Cox regression analysis was used to determine independent predictors of the 5-year overall survival rate and the 5-year cancer recurrence rate in a forward stepwise manner. Covariates included univariate predictors with P<0.20 and those that we considered clinically relevant. Survival curves were constructed using Kaplan-Meier estimates and compared with the log-rank test. All tests were two-tailed and P<0.05 was considered statistically significant. Statistical tests were performed using SPSS software, version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).
During the study period, a total of 3,284 patients who underwent gastrectomy for gastric cancer were entered into the registry. Of these, 417 patients were excluded according to the exclusion criteria: palliative gastrectomy (n=287), insufficient medical records (n=126), and reasons unrelated to cancer death (suicide and death due to traffic accidents, n=4). Ultimately, a total of 2,867 patients who underwent curative gastrectomy for gastric cancer were included in this study. Of the eligible patients, 240 (8%) who died of other diseases were excluded when analyzing cancer-specific survival. A total of 2,627 patients were categorized according to postoperative complication type into the NC group (n=2,152, 81.9%), the LC group (n=374, 14.2%), and the SC group (n=101, 3.8%) (
The clinicopathological characteristics of the 2,867 patients at the time of curative gastrectomy for gastric cancer are presented in
Of the 2,867 patients who underwent gastrectomy for gastric cancer, 543 patients (18.9%) developed complications. The numbers of Clavien-Dindo grade I, II, III, and IV complications were 155 (5.4%), 182 (6.3%), 132 (4.6%), and 74 (2.6%), respectively.
The median follow-up period of the surviving patients was 59.0 months (IQR, 48.0–73.0 months), and ranged from 1 to 106 months. The 5-year overall survival rate of the SC group was lower than those of the LC group and NC group (NC, 79.4%, LC, 70.7%; P<0.001, SC, 66.7%; P<0.001). The 5-year cancer-specific survival rates of NC, LC, and SC groups were 85.4%, 78.3% (P<0.001), and 80.2% (P=0.159), respectively, indicating that the occurrence of LC is related to poor survival (P=0.007) (
In the analysis of patients in different severity of complications, increasing Clavien-Dindo scores from II to IV compared to no complication was significantly associated with a corresponding decrease in overall survival (80.4%, 71.4%, 66.5%, 29.5%, P<0.001) and cancer-specific survival (86.5%, 78.4%, 74.3%, 39.6% P< 0.001) (
In the univariate analysis of the 5-year cancer-specific survival in 2,627 patients after curative gastrectomy for gastric cancer, age, total gastrectomy, combine resection, lymph node dissection ≥D2, tumor size, tumor in the whole stomach, histological differentiation, T category, N category, stage, lymphatic invasion, vascular invasion, adjuvant chemotherapy, and complication occurrence were identified as prognostic factors. Multivariate analysis of 5-year overall survival and cancer-specific survival rate after curative gastrectomy for gastric cancer are presented in
Recurrence rates were higher in the LC group (n=88, 23.5%) than in the NC and SC groups (n=332, 15.4% and n=16, 15.8%; P=0.017) (
This is the largest multicenter study to examine the impact of postoperative complications on overall and cancer-specific survival rates in patients undergoing curative resection for gastric cancer. The results of the present study, along with previous reports in the literature, showed that LC following curative gastrectomy for gastric cancer are associated with high morbidity and mortality compared to other groups. In addition, the increase in the Clavien- Dindo classification proportionally deteriorate survival outcomes. Prognostic factors of the 5-year overall and cancer-specific survival in patients undergoing curative gastrectomy included LC as well as patient age, tumor size, total gastrectomy as the surgical procedure, more advanced stage of gastric cancer, vascular and lymphatic invasion, and adjuvant chemotherapy. Among the three groups, only the LC group was associated with higher recurrence rates, and the occurrence of LC was identified as one of the major independent prognostic factors of the 5-year cancer recurrence.
A number of recent studies have reported that the development of postoperative complications, especially intraabdominal sepsis, results in poorer long-term survival and increased risk of recurrence in patients undergoing resection of esophageal and colorectal cancer [
The incidence of postoperative complications is an important surrogate marker for measuring the quality of surgery. Dindo et al. [
As mentioned above, several previous studies pertaining to gastrointestinal malignancies have indicated that postoperative complications increase cancer-specific mortality rates [
Subset analyses indicated no significant differences in cancer-specific survival in stage I, but significant differences between the LC group and the other groups were identified in advanced stage II and III disease. In early gastric cancer, tumor cells are confined to the mucosal layer, and tumor cells are mostly removed by curative radical gastrectomy. However, spreading or spillage of viable exfoliated tumor cells occurs frequently in advanced compared to early gastric cancer [
Our study had several limitations. First, this was a non-randomized observational study and had a retrospective design. As such studies cannot be based on a randomized controlled experiment due to ethical issues, it is essential to perform a multicenter observational study. However, all consecutive patients undergoing curative gastrectomy for gastric cancer were prospectively included in a multicenter registry, and continuing data collection will improve the generalizability of our findings. Second, with respect to type of complications, we could not investigate the postoperative biological status, such as proinflammatory cytokines, including tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-18, and we could not estimate the degree or duration of immune suppression in this study. Third, grade I complications present any complication not requiring medical or surgical treatment, such as nausea, vomiting, and fever. In fact, since grade I complications were not always considered as complications in clinical practice, data of grade I complications would be unreliable and the overall incidence of grade I complications could be underestimated. Thus, we did not evaluate grade I complications after curative gastrectomy for gastric cancer. Finally, LC delay or prohibit patients from receiving adjuvant chemotherapy to a greater extent than SC. This may account for worse survival in the LC group, but our study could not investigate the percent of patients in each group who delayed or failed to receive adjunctive chemotherapy.
In conclusion, the postoperative occurrence of LC was an independent prognostic factor associated with poor overall and cancer-specific survival, and a high recurrence rate in patients undergoing curative gastrectomy for advanced gastric cancer, especially stage II and III diseases. The negative effect on survival outcomes were also increased with higher Clavien-Dindo grades. These findings suggest that surgeons should implement surgical procedures with careful perioperative care to minimize the occurrence of postoperative complications.
No potential conflict of interest relevant to this article was reported.
Patient flowchart.
Comparison of 5-year overall survival and cancer-specific survival rates among groups with no complications (NC), local complications (LC), and systemic complications (SC). (A) Overall survival. (B) Cancer-specific survival.
Comparison of the 5-year cancer-specific survival rates among groups with no complications (NC), local complications (LC) and systemic complications (SC) according to stage. (A) Stage I. (B) Stage II. (C) Stage III. (D) Stage IV.
Comparison of survival outcomes based on the Clavien-Dindo classification. (A) Overall survival. (B) Cancer-specific survival.
Comparison of 5-year cancer recurrence rates among groups with no complications (NC), local complications (LC) and systemic complications (SC) after curative gastrectomy for gastric cancer.
Clinicopathological characteristics of 2,867 patients undergoing curative gastrectomy for gastric cancer
Characteristics | No complications (n=2,324) | Local complications (n=420) | Systemic complications (n=123) | P-value |
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Male sex | 1,569 (67.5) | 307 (73.1) | 84 (68.3) | 0.077 |
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Age ≥65 yr | 792 (34.1) | 145 (34.5) | 56 (45.5) | 0.034 |
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Body mass index ≥25 kg/m2 | 572 (24.8) | 137 (32.9) | 30 (25.0) | 0.002 |
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Co-morbidity | 0.031 | |||
None | 1,438 (61.9) | 232 (55.2) | 70 (56.9) | |
Hypertension | 446 (19.2) | 90 (21.4) | 29 (23.6) | |
Diabetes mellitus | 123 (5.3) | 29 (6.9) | 9 (7.3) | |
Pulmonary disease | 86 (3.7) | 12 (2.9) | 3 (2.4) | |
Heart disease | 31 (1.3) | 11 (2.6) | 1 (0.8) | |
Liver disease | 86 (3.7) | 20 (4.8) | 3 (2.4) | |
Cerebrovascular disease | 17 (0.7) | 3 (0.7) | 2 (1.6) | |
Renal disease | 5 (0.2) | 2 (0.5) | 0 | |
Others | 92 (4.0) | 21 (5.0) | 6 (4.9) | |
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Surgical procedure | 0.001 | |||
Subtotal | 1,694 (72.9) | 268 (63.8) | 81 (65.9) | |
Total | 630 (27.1) | 152 (36.2) | 42 (34.1) | |
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Lymph node dissection ≥D2 | 2,010 (86.8) | 374 (89.3) | 109 (90.1) | 0.193 |
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Combine resection | 314 (13.5) | 74 (17.6) | 22 (17.9) | 0.044 |
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Tumor size ≥5 cm | 960 (41.3) | 212 (50.6) | 54 (43.9) | 0.002 |
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Tumor site | 0.023 | |||
Upper | 318 (13.7) | 87 (20.7) | 23 (18.7) | |
Middle | 676 (29.1) | 111 (26.4) | 42 (34.1) | |
Lower | 1,297 (55.8) | 204 (48.6) | 56 (45.5) | |
Whole | 33 (1.4) | 18 (4.3) | 2 (1.6) | |
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Histology, undifferentiated | 1,336 (57.5) | 245 (58.3) | 70 (56.9) | 0.948 |
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Tumor depth | <0.001 | |||
T1 | 1,041 (44.8) | 144 (34.3) | 52 (42.3) | |
T2 | 320 (13.8) | 45 (10.7) | 19 (15.4) | |
T3 | 482 (20.7) | 113 (26.9) | 26 (21.1) | |
T4 | 478 (20.6) | 117 (27.9) | 26 (21.1) | |
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Nodal involvement | 0.004 | |||
N0 | 1,251 (53.9) | 193 (46.0) | 64 (52.0) | |
N1 | 296 (12.7) | 56 (13.3) | 17 (13.8) | |
N2 | 324 (13.9) | 62 (14.8) | 18 (14.6) | |
N3 | 452 (19.5) | 109 (26.0) | 24 (19.5) | |
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TNM stage | <0.001 | |||
I | 1,131 (48.7) | 159 (37.9) | 61 (49.6) | |
II | 468 (20.1) | 83 (19.8) | 21 (17.1) | |
III | 689 (29.6) | 168 (40.0) | 39 (31.7) | |
IV | 33 (1.4) | 9 (2.1) | 2 (1.6) | |
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Adjuvant chemotherapy | 1,002 (51.1) | 200 (55.4) | 40 (40.8) | 0.023 |
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Cancer recurrence | 375 (16.3) | 109 (26.1) | 24 (19.5) | <0.001 |
Values are presented as number (%).
Incidence of local and systemic complications and grade ≥III according to the Clavien-Dindo classification of 2,867 patients undergoing curative gastrectomy for gastric cancer
Complications | No. of patients | Grade ≥III |
---|---|---|
Local complications | 421 | 174 |
Wound problems | 141 (4.9) | 39 (1.4) |
Fluid collection/abscess | 70 (2.4) | 31 (1.1) |
Intraabdominal bleeding | 20 (0.7) | 9 (0.3) |
Intraluminal bleeding | 14 (0.5) | 4 (0.1) |
Intestinal obstruction | 25 (0.9) | 16 (0.6) |
Ileus | 43 (1.5) | 5 (0.2) |
Stenosis | 39 (1.4) | 34 (1.2) |
Anastomotic leakage | 30 (1.0) | 28 (1.0) |
Pancreatitis | 14 (0.5) | 2 (0.1) |
Others | 25 (0.9) | 6 (0.1) |
| ||
Systemic complications | 122 | 32 |
Pulmonary | 60 (2.1) | 11 (0.4) |
Hepatic | 15 (0.5) | 3 (0.1) |
Cardiac | 5 (0.2) | 1 (0.0) |
Renal | 3 (0.1) | 1 (0.0) |
Splenic infarction | 5 (0.2) | 3 (0.1) |
Colitis | 4 (0.1) | 2 (0.1) |
Transient ischemic attack | 2 (0.1) | 0 |
Delirium | 9 (0.3) | 0 |
Others | 19 (0.7) | 11 (0.4) |
Values are presented as number (%).
Multivariate analyses of 5-year overall survival and cancer-specific survival rate after curative gastrectomy for gastric cancer
Variable | Overall survival | Cancer-specific survival | ||
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|
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HR (95% CI) | P-value | HR (95% CI) | P-value | |
Age (compared to <65 yr) | 1.57 (1.32–1.87) | <0.001 | 1.48 (1.21–1.82) | <0.001 |
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Tumor size (compared to <5 cm) | 1.26 (1.02–1.57) | 0.034 | 1.30 (1.01–1.66) | 0.041 |
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Surgical procedure, total (compared to subtotal) | 1.59 (1.27–1.84) | <0.001 | 1.35 (1.10–1.166 | 0.005 |
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Lymph node dissection (compared to <D2) | 0.67 (0.51–0.88) | 0.005 | 0.71 (0.51–0.99) | 0.048 |
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Cancer stage (compared to I) | <0.001 | <0.001 | ||
II | 1.95 (1.36–2.79) | <0.001 | 2.77 (1.75–4.39) | <0.001 |
III | 6.12 (4.43–8.47) | <0.001 | 9.40 (6.17–14.32) | <0.001 |
IV | 14.23 (8.80–22.99) | <0.001 | 25.67 (14.39–45.80) | <0.001 |
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Vascular invasion | 1.57 (1.22–2.03) | 0.001 | 1.68 (1.27–2.23) | <0.001 |
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Lymphatic invasion | 1.63 (1.24–2.12) | <0.001 | 1.69 (1.24–2.32) | 0.001 |
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Complications (compared to no complications) | <0.001 | 0.016 | ||
Local complications | 2.08 (1.46–2.97) | 0.001 | 1.77 (1.12–2.81) | 0.015 |
Systemic complications | 1.21 (0.97–1.52) | 0.061 | 1.26 (0.98–1.63) | 0.076 |
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Adjuvant chemotherapy | 1.29 (1.03–1.61) | 0.024 | 1.35 (1.05–1.73) | 0.021 |
HR, hazard ratio; CI, confidence interval.
Initial recurrence site according to complications in 2,627 patients undergoing curative gastrectomy for gastric cancer
Variable | No complications (n=2,152) | Local complications (n=374) | Systemic complications (n=101) | P-value |
---|---|---|---|---|
No recurrence | 1,820 (84.6) | 286 (76.5) | 85 (84.2) | <0.001 |
Locoregional recurrence | 91 (4.2) | 16 (4.3) | 1 (1.0) | |
Peritoneal recurrence | 132 (6.1) | 33 (8.8) | 10 (9.9) | |
Distant recurrence | 109 (5.0) | 39 (10.4) | 5 (5.0) |
Values are presented as number (%).
Univariate and multivariate analyses of factors associated with cancer recurrence in 2,627 patients after curative gastrectomy for gastric cancer
Variable | Univariate analysis | Multivariate analysis | ||
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|
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HR (95% CI) | P-value | HR (95% CI) | P-value | |
Sex (male) | 1.01 (0.81–1.26) | 0.92 | ||
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Age (compared to <65 yr) | 1.19 (0.96–1.48) | 0.11 | 1.37 (1.04–1.80) | 0.024 |
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Surgical procedure (compared to subtotal) | 2.48 (2.01–3.07) | <0.001 | ||
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Combine resection | 1.65 (1.25–2.16) | <0.001 | ||
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Tumor size (compared to <5 cm) | 4.19 (3.36–5.23) | <0.001 | ||
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Tumor site (compared to lower) | <0.001 | |||
Upper | 0.99 (0.78–1.27) | 0.96 | ||
Middle | 1.35 (1.01–1.80) | 0.51 | ||
Whole | 6.65 (3.56–12.41) | <0.001 | ||
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Histology, undifferentiated | 2.04 (1.64–2.55) | <0.001 | ||
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Cancer stage (compared to I) | <0.001 | <0.001 | ||
II | 5.08 (3.42–7.56) | <0.001 | 3.27 (2.09–5.11) | <0.001 |
III | 18.98 (13.49–26.70) | <0.001 | 10.13 (6.70–15.34) | <0.001 |
IV | 53.19 (31.54–89.70) | <0.001 | 27.64 (15.31–49.91) | <0.001 |
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Lymphatic invasion | 7.41 (5.68–9.66) | <0.001 | 1.86 (1.37–2.54) | <0.001 |
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Vascular invasion | 4.98 (3.80–6.52) | <0.001 | 1.53 (1.17–1.99) | 0.002 |
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Adjuvant chemotherapy | 4.92 (3.81–6.36) | <0.001 | 1.44 (1.10–1.87) | 0.007 |
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Complications (compared with no complications) | 0.001 | 0.017 | ||
Local complications | 1.68 (1.29–2.19) | <0.001 | 1.55 (1.11–2.17) | 0.011 |
Systemic complications | 1.03 (0.60–1.78) | 0.92 | 1.69 (0.86–3.35) | 0.126 |
HR, hazard ratio; CI, confidence interval.