Prognostic Value of Postoperative Complication for Gastric Cancer

Abstract

Background:

The incidence of complications in gastric cancer (GC) patients after surgery was increasing, and it was not clear whether postoperative complications would have an impact on prognosis. The current study attempted to investigate the role of postoperative complication for prognosis on GC patients undergoing radical resection.

Materials and Methods:

Eligible studies were searched in three databases, including PubMed, Embase, and the Cochrane Library, in accordance with the searching strategy on September 4th, 2022. The survival values were most concerned; then, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled up. All prognostic values, including overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and recurrence-free survival (RFS), were allowed. Subgroup analysis based on complication types was used for further in-depth research.

Results:

A total of 29 studies involving 33,858 patients were included in this study. Intra-abdominal abscess (19.4%) was the most common complications in the included studies, followed by anastomotic leakage (17.0%) and pneumonia (16.4%). There were 23, 4, 6, and 10 studies that reported OS, DFS, DSS, and RFS, respectively. After analysis, postoperative complication was found to be an independent prognostic factor for OS (HR = 1.52, I² = 1.14%, 95% CI = 1.42–1.61, P = .00), DFS (HR = 1.71, I² = 0.00%,95% CI = 1.44–1.98, P < .05), DSS (HR = 1.60, I² = 54.58%, 95% CI = 1.26–1.93, P < .1), and RFS (HR = 1.26, I² = 0.00%, 95% CI = 1.11–1.41, P < .05). Subgroup analysis found that noninfectious complication was not significantly associated with OS (HR = 1.39, I² = 0.00%, 95% CI = 0.96–1.82, P > .05).

Conclusion:

Surgeons needed to pay more attention to GC patients who developed postoperative complications, especially infectious complications, and take proactive management to improve the prognosis.

Introduction

According to the International Agency for Research on Cancer, gastric cancer (GC) was the fifth most common cancer with 10.81 million new cases and the fourth leading cause of cancer death with 0.77 million deaths in 2020.¹ Although the medical level and technology improved greatly, radical surgery with lymph node dissection was still the most effective and preferred curative treatment option for GC.^2–5 The recurrence of cancer and survival time after surgery was a huge challenge, with ∼8.3% of patients experiencing recurrence and a 5-year relative survival rate of ∼30% nowadays.^6,7 However, there was also many patients suffering from postoperative complications, which might be related to the malnutrition in GC patients.^8–10 The short-term outcomes also needed to be of concern.

Postoperative complication was usually defined as any morbidity that developed within 30 days after surgery.^11,12 It could be categorized as local complications and systematic complications.¹³ Local complications included surgical-site infection, bleeding, anastomosis leakage, obstruction, etc. Systematic complications included pulmonary infection, diarrhea, liver dysfunction, heart failure, etc. Although perioperative mortality of GC patients declined over the past decades, the incidence of postoperative complications remained high that ranged from 10.5% to 40.1%.^14–16 Therefore, reducing the incidence and severity of postoperative complications might also have a potential role to improve long-term outcomes.

The prognostic value of postoperative complications for GC patients was reported by some previous studies.^17–45 Most studies demonstrated that there was a significant association between complications and survival rate.^{18,20,22–25,27–31,33,34,36–45} However, some other studies held a different view and revealed that the current evidence did not support a negative impact of postoperative complications on GC.^{17,19,21,26,32,35} Therefore, the purpose of this study was to solve the controversy.

Materials and Methods

This study was produced according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.⁴⁶

Search strategy

The search strategy included three key words: complications, GC, and prognosis. As for complications, the search terms were: “complications” OR “adverse events” OR “surgical outcomes” OR “harms.” As for GC, the search terms were: “gastric cancer” OR “gastric carcinoma” OR “gastric neoplasms” OR “stomach cancer” OR “stomach carcinoma” OR “stomach neoplasms.” As for prognosis, the search terms were: “survival” OR “mortality” OR “death” OR “prognosis” OR “period analysis” OR “long term” OR “survivors.” The searching scope was limited in titles and abstracts. Language was limited in English.

Inclusion and exclusion criteria

The inclusion criteria of the current study were: (1) patients who were diagnosed as GC and underwent radical surgery; (2) the types and incidence of postoperative complications were reported; (3) at least one prognostic indicator was reported; and (4) only the study type of article was allowed. The exclusion criteria of this study were: (1) insufficient data of postoperative complications and prognostic indicators; (2) the study types were case report, review, meta-analysis, letters to editor, comments, or conferences; and (3) data were repeated or overlapped.

Study selection

Two authors searched the eligible studies separately according to the search strategy in three databases (PubMed, Embase, and the Cochrane Library). First, duplicated studies were removed. Next, the study type, title, and abstract were viewed to remove nonarticle and irrelevant studies. Finally, full-text was read to eliminate studies without sufficient data and low quality. When there was a dispute about whether a study should be included, a third author would make a decision based on the inclusion and exclusion criteria.

Quality assessment

The quality of studies was assessed by Newcastle-Ottawa Scales (NOS) score.⁴⁷ A score of 9 meant high quality, 7 to 8 meant medium quality, below 7 meant low quality.

Definition

Each complication was defined based on the Common Terminology Criteria for Adverse Events (CTCAE) V4.0,⁴⁸ and the grade was evaluated using the Clavien-Dindo (CD) classification.¹¹ If multiple postoperative complications occurred, the higher grade was used. Due to the common denominator of cancer related death, disease-specific mortality (DSM), cancer-specific survival (CSS), and disease-specific survival (DSS) were collectively referred to as CSS. Same to the common denominator of relapse, time to recurrence (TTR) and recurrence-free survival (RFS) were collectively referred to as RFS.

Data collection

As for the 29 included studies, the characteristics included the first author, published year, published country, study period, sample size, complication incidence, types of complications, CD grade, prognostic indicators, conclusion, and NOS score.

Complication types of all patients included were requested. In this study, patients were divided into the complication group (C group) and noncomplication group (NC group). The data of patients in each group included personal characteristics, comorbidity, pathological characteristics, and treatment characteristics. Personal characteristics included mean age, gender, American Society of Anesthesiologists (ASA) score, and Eastern Cooperative Oncology Group (ECOG) status. Comorbidity included diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular, and liver cirrhosis. Pathological characteristics included histological type, Lauren type, tumor location, tumor depth, lymph node status, and pathological stage. Treatment characteristics included adjuvant chemotherapy, neoadjuvant chemotherapy, surgical approach, surgical procedure, lymphadenectomy, and multivisceral resection. As for prognostic indicators, whether overall survival (OS), disease-free survival (DFS), TTR, RFS, DSM, CSS, or DSS were allowed.

Statistical analysis

This study focused most on patients' prognosis; therefore, hazard ratios (HRs) and 95% confidence intervals (CIs) were added to assess the impact of postoperative complication on different prognostic indicators. As for other characteristics, dichotomous variables were expressed as odds ratios (ORs) and 95% CIs; continuous variables were expressed as mean difference (MD) and standardized difference. I² value and the chi-squared test were used to evaluate the statistical heterogeneity.^49,50 Random-effect model was used as the default model, and P < .1 meant statistically significant. When I² < 50%, the fixed-effect model was used, and P < .05 meant statistically significant. Stata V16.0 software was used for all of the data analyses.

Results

Study selection

After conducting the searching strategy, there were 11,220 studies (3861 in PubMed, 6263 in Embase, and 11 in the Cochrane Library). Three thousand nine hundred thirty-two studies were excluded for duplicates removed, 1009 studies were excluded for unqualified study type, and then, 2923 studies were left for record screening. After browsing the titles and abstracts, full-texts of 40 studies with relevant content were read. Finally, 29 studies^17–45 with sufficient data were included in this study (Fig. 1).

FIG. 1.

Flowchart of study selection.

Baseline characteristics of studies

This pooling up analysis included a total of 33,858 patients from 29 studies. The published time ranged from 2013 to 2022. Among the 29 studies, 13, 9, and 2 studies were published from Japan, China, and South Korea, respectively. Incidence of complications varied from 5.0% to 59.8%. Prognostic indicators that included OS, DFS, TTR, RFS, DSM, CSS, and DSS were reported from 23, 4, 1, 9, 1, 4, and 2 studies, respectively. More characteristics, including the first author, study period, sample size, complication types, CD grade, conclusion, and NOS score, are shown in Table 1.

Table 1.

Baseline Characteristics of Included Studies

Author	Year	Country	Study period	Patients (complications %)	Complication	CD grade	Prognostic indicators	Conclusion	NOS
Akimoto	2022	Japan	2010–2015	1223 (9.2%)	IAIC	≥II	OS	Postoperative IAIC adversely affects survival outcomes; however, its impact may be weakened by less invasive surgery.	8
Abdul	2016	Japan	1991–2010	265 (14.3%)	IAC	≥II	OS/DSS	Postoperative IACs were related to poorer survival for patients with stage II–III GC.	7
Climent	2016	Spain	1990–2009	271 (59.8%)	Any complications	≥II	OS/TTR	Evidence provided by this study does not support a negative impact of CD II PCs.	7
Fujiya	2016	Japan	2002–2009	1541 (11.3%)	IAIC	≥II	OS/RFS	IAIC adversely affected survival outcome when patients were matched by propensity scores, which included demographic data as covariates.	8
Galata	2019	Germany	1972–2014	1107 (25.3%)	Any complications	NA	OS	PCs influenced OS due to complication-related early postoperative deaths. In patients successfully rescued from early PCs, neither overall complications nor major surgical complications were risk factors for decreased survival.	8
Han	2020	South Korea	2002–2012	6585 (6.2%)	IC	≥II	OS	Postoperative IC was an independent prognostic factor for 5-year OS after curative gastrectomy, as well as known factors. A significant association between IC and recurrence was also noted.	9
Hayashi	2015	Japan	2000–2005	502 (10.4%)	IC	≥II	RFS	IC was a risk factor for GC recurrence.	7
Jiang	2014	China	2003–2008	386 (21.5%)	Any complications	NA	OS	PC was an independent factor associated with postoperative survival.	7
Kubota	2014	Japan	2005–2008	1395 (14.8%)	Any complications	≥II	OS/DSM	PCs that can cause prolonged inflammation have an obvious impact not only on the OS but also on the DSM of patients with GC even if the tumor is resected curatively.	8
Kurokawa	2020	Japan	2008–2010	1456 (12.2%)	IAIC	≥II	RFS	PC was not an independent prognostic factor.	8
Li	2013	China	2005–2006	432 (12.5%)	Any complications	I–V	OS	The occurrence of in-hospital PCs was an independent predictor of worse 5-year OS rate after radical resection of GC.	7
Li	2020	USA	2001–2015	206 (53.9%)	Any complications	Minor (I–II) Major (III-IV)	OS	Major PC adversely affects long-term survival after gastrectomy for GC, at least, in part, through lower completion rates of multimodality therapy.	7
Li	2018	China	2009–2015	3091 (13.3%)	Any complications	II–IV	OS/DFS/DSS	PCs had a negative impact on long-term survival outcomes after curative resection for GC. The negative effects were also increased with higher CD grades.	9
Li	2018	China	2008–2015	571 (17.9%)	Any complications	≥II	OS/CSS	Severe complications adversely affected long-term survival outcomes after laparoscopic total gastrectomy with D2 lymph node dissection for advanced GC.	8
Lui	2019	Singapore	2000–2015	405 (40%)	Any complications	NA	OS/DFS	PC is a significant predictor for long-term survival.	7
Migita	2013	Japan	2003–2009	548 (28.6%)	Any complications	I–V	OS	PCs were not independent prognostic factors for the OS.	7
Mohri	2016	Japan	2000–2011	404 (25.5%)	Any complications	NA	OS/CSS	Patients with postoperative IC had shorter OS and CSS than those without postoperative IC.	8
Pang	2021	China	2009–2014	1667 (10.08%)	Any complications	I–V	OS	Serious complications, particularly of an infectious type, may have a negative impact on OS of GC patients.	8
Saito	2015	Japan	2001–2012	305 (28.2%)	Any complications	≥II	RFS	C-reactive protein elevation is a more reliable indicator of survival after GC surgery than PC occurrence.	7
Saunders	2018	UK	2006–2016	1100 (13.7%)	Nonleak-related complications	III–IV	OS/DFS	Beyond the acute postoperative period, anastomotic leak does not adversely affect survival; however, other severe PCs do reduce long-term OS and DFS.	8
Song	2021	South Korea	2013–2015	939 (5.0%)	Any complications	≥III	OS/RFS	Serious complications after gastrectomy had a negative impact on the prognosis of stage II/III GC patients.	8
Takebayashi	2022	Japan	2014–2017	152 (21.1%)	IAC	≥II	OS/RFS	Patients with postoperative IACs had worse clinical outcomes.	7
Tokunaga	2013	Japan	2002–2006	765 (10.6%)	IAIC	≥II	OS/RFS	Postoperative IAIC adversely affects OS and RFS.	8
Tokunaga	2021	Japan	2010–2015	1204 (50%)	Any complications	I–IV	OS/RFS	PCs adversely affect the long-term survival outcomes of patients with cT3/4a GC. Any ≥C-D grade III complication seems to be the most suitable definition of complication for predicting negative long-term survival outcomes.	9
Tu	2018	China	1996–2014	5327 (14.4%)	Any complications	I–V	CSS	Complication after radical gastrectomy is an independent prognostic factor, and the complication severity reflects the difference of CSS in GC patients with PCs.	9
Watanabe	2020	Japan	2000–2011	226 (13.3%)	Any complications	≥II	RFS	PC of grade 2 or more was an independent risk factor for recurrence in patients with stage II GC who received adjuvant chemotherapy after curative gastrectomy.	7
Xiao	2020	China	2010–2019	2114 (7%)	IC	≥II	CSS	Independent of infections had an additive effect that was associated with even worse CSS.	9
Yu	2022	China	2010–2014	663 (20.8%)	Any complications	I–V	OS	PCs have a significant negative impact on the long-term survival in GC patients even if the tumor is resected curatively.	7
Yuan	2019	China	2012–2013	239 (24.7%)	Any complications	I–V	OS/DFS	Postoperative major complications adversely affect OS and DFS.	7

CD, Clavien-Dindo; CSS, cancer-specific survival; DFS, disease-free survival; DSM, disease-specific mortality; DSS, disease-specific survival; GC, gastric cancer; IAC, intra-abdominal complication; IAIC, intra-abdominal infectious complications; IC, infectious complications; NA, not applicable; NOS, Newcastle-Ottawa Scales; OS, overall survival; PC, postoperative complication; RFS, recurrence-free survival; TTR, time to recurrence.

Types of complications

After summarizing complications of all included patients, intra-abdominal abscess was the most common complications for 774 patients (19.4%). Six hundred seventy-nine (17.0%), 655 (16.4%), 356 (8.9%), and 313 (7.9%) patients suffered from anastomotic leakage, pneumonia, complicated fluid collection, and pancreatic fistula, respectively. Other postoperative complications such as pancreatitis, wound infection, cardiac complications, bleeding, and so on are shown in Table 2.

Table 2.

Summary of Complications

Complications	Studies	Patients
Intra-abdominal abscess	17	774 (19.4%)
Anastomotic leakage	19	679 (17.0%)
Pneumonia	14	655 (16.4%)
Complicated fluid collection	6	356 (8.9%)
Pancreatic fistula	11	313 (7.9%)
Pancreatitis	3	205 (5.1%)
Wound infection	12	201 (5.0%)
Cardiac complications	5	176 (4.4%)
Bleeding	10	112 (2.8%)
Bowel obstruction	6	67 (1.7%)
Paralytic ileus	7	62 (1.7%)
Anastomotic stenosis	8	75 (2.0%)
Wound dehiscence	5	52 (1.3%)
Cholecystitis	5	23 (0.6%)
Urinary tract infection	4	15 (0.4%)
Thrombosis	8	37 (0.9%)
Afferent loop syndrome	4	38 (1.0%)
Catheter-related infection	3	17 (0.4%)
Reflux esophagitis	2	10 (0.3%)
Gastric motility disorders	4	49 (1.2%)
Anemia	1	20 (0.5%)
Duodenal leak	3	11 (0.3%)
Renal complications	4	33 (0.8%)
Liver dysfunction	3	8 (0.2%)

Baseline characteristics of patients in the C group and NC group

After pooling up the OR, MD, and 95% CIs, the patients in the C group were older (MD = 2.75, I² = 80.14%, 95% CI = 0.47–5.04, P = .02) and had more males (OR = 1.61, I² = 66.01%, 95% CI = 1.36–1.90, P = .00) and more ASA score ≥3 (OR = 2.28, I² = 78.25%, 95% CI = 1.60–3.24, P = .00) than in the NC group. Tumor location was higher in the C group with less middle third located tumor (OR = 0.44, I² = 0.00%, 95% CI = 0.37–0.53, P = .00) and lower third located tumor (OR = 0.47, I² = 0.00%, 95% CI = 0.39–0.56, P = .00). Tumor stage was more advanced in the C group with more T2 (OR = 1.42, I² = 34.57%, 95% CI = 1.02–1.98, P = .04), T3 (OR = 2.24, I² = 21.01%, 95% CI = 1.75–2.87, P = .00), and T4 stage (OR = 2.38, I² = 62.66%, 95% CI = 1.60–3.53, P = .00), more N2 (OR = 1.47, I² = 57.59%, 95% CI = 1.10–1.97, P = .01) and N3 stage (OR = 1.60, I² = 52.66%, 95% CI = 1.23–2.08, P = .00), more Tumor Node Metastasis (TNM) II (OR = 1.41, I² = 76.44%, 95% CI = 1.09–1.83, P = .01) and III stage (OR = 1.76, I² = 64.86%, 95% CI = 1.46–2.12, P = .00), and more patients received neoadjuvant therapy (OR = 1.47, I² = 0.00%, 95% CI = 1.06–2.05, P = .02). The C group had less patients who underwent laparoscope surgery (OR = 0.76, I² = 77.41%, 95% CI = 0.60–0.98, P = .04) and total gastrectomy (OR = 0.54, I² = 83.46%, 95% CI = 0.44–0.66, P = .00); more patients accepted lymphadenectomy ≥D2 (OR = 1.76, I² = 83.22%, 95% CI = 1.13–2.74, P = .01) and multivisceral resection (OR = 2.36, I² = 93.99%, 95% CI = 1.16–4.79, P = .02) than the NC group. There was no significant difference in other characteristics, including ECOG status, comorbidities, histological type, Lauren type, N0 stage, and adjuvant chemotherapy between the two groups (Table 3).

Table 3.

Summary of Characteristics Between C Group and Noncomplication Group

Characteristics	Studies	Patients (C/NC)	OR/MD (95% CI)	Heterogeneity
Personal characteristics
Age	5	850/7892	2.75 (0.47–5.04); P = .02	I² = 80.14; P = .00
Gender, male	21	5768/23596	1.61 (1.36–1.90); P = .00	I² = 66.01%; P = .00
ASA score
1 or 2	9	2271/17652	Reference	Reference
≥3	9	2271/17652	2.28 (1.60–3.24); P = .00	I² = 78.25%; P = .00
ECOG status
0 or 1	3	368/3160	Reference	Reference
2 or 3	3	368/3160	1.19 (0.41–3.44); P = .75	I² = 0.00%; P = .81
Comorbidity
Diabetes	4	506/1925	1.11 (0.75–1.65); P = .59	I² = 33.60%; P = .21
COPD	3	447/1745	1.23 (0.88–1.72); P = .22	I² = 0.00%; P = .87
Cardiovascular	4	558/1840	1.29 (0.82–2.04); P = .27	I² = 51.19%; P = .10
Liver cirrhosis	2	336/1650	0.90 (0.25–3.27); P = .87	I² = 0.00%; P = .51
Pathological characteristics
Histological type
Differentiated	12	1873/14924	Reference	Reference
Undifferentiated	12	1873/14924	0.92 (0.80–1.06); P = .27	I² = 35.72%; P = .10
Lauren type
Intestinal	4	758/6926	Reference	Reference
Diffuse	4	688/6140	0.87 (0.55–1.36); P = .54	I² = 68.82%; P = .02
Mixed	4	451/4042	1.18 (0.88–1.57); P = .27	I² = 0.00%; P = .81
Tumor location
Upper third	5	804/8991	Reference	Reference
Middle third	5	537/5175	0.44 (0.37–0.53); P = .00	I² = 0.00%; P = .45
Lower third	5	547/5480	0.47 (0.39–0.56); P = .00	I² = 0.00%; P = .54
Tumor depth
T1	10	1190/6775	Reference	Reference
T2	11	470/4069	1.42 (1.02–1.98); P = .04	I² = 34.57%; P = .12
T3	11	705/4595	2.24 (1.75–2.87); P = .00	I² = 21.01%; P = .24
T4	11	647/4595	2.38 (1.60–3.53); P = .00	I² = 62.66%; P = .00
Lymph node status
N0	12	1335/7157	Reference	Reference
N1	12	801/5109	1.14 (0.91–1.41); P = .25	I² = 21.02%; P = .23
N2	12	829/4994	1.47 (1.10–1.97); P = .01	I² = 57.59%; P = .01
N3	12	889/5096	1.60 (1.23–2.08); P = .00	I² = 52.66%; P = .01
Pathological stage
I	16	3436/25751	Reference	Reference
II	20	3436/25751	1.41 (1.09–1.83); P = .01	I² = 76.44%; P = .00
III	20	3436/25751	1.76 (1.46–2.12); P = .00	I² = 64.86%; P = .00
Treatment characteristics
Adjuvant chemotherapy	9	2240/12906	1.19 (0.76–1.85); P = .45	I² = 92.87%; P = .00
Neoadjuvant chemotherapy	4	991/5150	1.47 (1.06–2.05); P = .02	I² = 0.00%; P = .63
Surgical approach
Open	10	2490/20441	Reference	Reference
Laparoscopy	10	2490/20441	0.76 (0.60–0.98); P = .04	I² = 77.41%; P = .00
Surgical procedure
Subtotal gastrectomy	19	3345/25016	Reference	Reference
Total gastrectomy	19	3345/25016	0.54 (0.44–0.66); P = .00	I² = 83.46%; P = .00
Lymphadenectomy
<D2	12	1575/10198	Reference	Reference
≥D2	12	1575/10198	1.76 (1.13–2.74); P = .01	I² = 83.22%; P = .00
Multivisceral resection	12	1223/7916	2.36 (1.16–4.79); P = .02	I² = 93.99%; P = .00

ASA, American Society of Anesthesiologists; C, complication; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; MD, mean difference; NC, noncomplication; OR, odds ratio.

OS of complication

After pooling up the HRs and 95% CIs, postoperative complication was found to be an independent prognostic factor for OS (HR = 1.52, I² = 1.14%, 95% CI = 1.42–1.61, P = .00) for GC patients (Fig. 2).

FIG. 2.

Overall survival of postoperative complications.

DFS, DSS, and RFS of complication

For other prognostic indicators, postoperative complication still had a prognostic value for DFS (HR = 1.71, I² = 0.00%, 95% CI = 1.44–1.98, P < .05), DSS (HR = 1.60, I² = 54.58%, 95% CI = 1.26–1.93, P < .1), and RFS (HR = 1.26, I² = 0.00%, 95% CI = 1.11–1.41, P < .05) (Fig. 3).

FIG. 3.

Other survival values, including disease-free survival, disease-specific survival, and recurrence-free survival of postoperative complications.

OS of complication classifications

All included studies were divided into four groups according to the definition of postoperative complications. Of the studies, 16, 9, 2, and 2 reported any complications, infectious complications, noninfectious complications, and other complications, respectively. After subgroup analysis, infectious complications still increased the risk of OS for GC patients (HR = 1.52, I² = 0.00%, 95% CI = 1.34–1.69, P < .05). However, noninfectious complication was found to have no relationship with OS (HR = 1.39, I² = 0.00%, 95% CI = 0.96–1.82, P > .05) (Fig. 4).

FIG. 4.

Subgroup analyses based on complication types for overall complications.

Sensitivity analysis

Each study was excluded at a time for sensitivity analysis, and there was no significant difference between every outcome.

Discussion

The present study enrolled a total of 29 studies involving 33,858 patients for analysis^17–45 and showed that postoperative complication adversely affected long-term outcomes after radical surgery for GC patients. Complication was an independent prognostic factor for all survival indicators, including OS, DFS, DSS, and RFS. However, further analysis found that noninfectious complications were not significantly associated with OS, while infectious complications still had a prognostic value.

Postoperative complication could decrease the OS and DFS in several cancers, including lung cancer, breast cancer, and colorectal cancer.^51–53 In particular, infectious complications such as wound infection and anastomotic leakage was associated with increased recurrence after breast cancer surgery and colon cancer surgery, respectively.^54–56 However, infectious complications were reported to decrease recurrence rate and lead to regression in head and neck cancers.^57,58

The impact of postoperative complication for GC patients undergoing surgery was also of concern. Some studies reported that infectious complication was a risk factor for recurrence and survival.^18,22,23 And more studies showed that overall complication had a negative impact on prognosis after radical resection,^{24,25,27,28,30,31} even the negative effects increased with higher CD grades.²⁹ However, some other studies revealed that complication was not a reliable indicator of survival; its impact might be weak.^{17,19,26,32,35} Galata C analyzed GC patients during a period of 42 years and concluded that postoperative complication influenced OS due to complication-related early postoperative deaths; it was not a risk factor for patients successfully rescued from early postoperative complications.²¹ Therefore, the prognostic role and potential mechanisms of postoperative complication in predicting the prognosis of GC patients were unclear.

Based on the current study, we hypothesized that postoperative complications, especially infectious postoperative complications, that resulted in worse prognosis and higher GC recurrence might be due to the following several mechanisms. It was proofed that the excessive surgical stress might increase the levels of inflammatory cytokines such as interleukin-6, and the inflammatory response would cause aggravated postoperative complications.^59–62 Otherwise, the inflammation after surgery could suppress cell-mediated immunity responses, particularly by impairing natural killer cells and cytotoxic T lymphocytes, that promoted the cancer cells' growth and metastasis.^63,64 Meanwhile, the occurrence of inflammatory complication, especially intra-abdominal infections, produced excessive catecholamine and prostaglandin, which also adversely affected the immune system and contributed to metastatic and worse outcomes.⁶⁵ Furthermore, infectious postoperative complication could activate the processes of bacterial antigen mediated; the inflammatory cytokines would lead to the adhesion of circulating cancer cells to vascular endothelium of distant organs, then directly affect the metastasis of cancer cells.^66,67

Based on the above mechanisms, we recommended that surgeons developed a multimodality approach for patients preoperatively,⁶⁸ made efforts to minimize intraoperative blood loss and transfusions intraoperatively,^69,70 and actively provided nutritional support^70,71 and correcting hypoproteinemia⁷² perioperatively. These measures might help to reduce the incidence of postoperative complications, further improved patient prognosis, and reduced postoperative recurrence.

To our knowledge, this was the first study that pooled up all the previous studies on the relationship between postoperative complication and GC patients' survival. The results were reliable with a large sample size and little heterogeneity. Furthermore, subgroup analysis identified infectious complication as a major prognostic risk factor. Meanwhile, there were some limitations in this study. First, subgroup analysis of more refined types of complications was lacking due to the insufficient data. Second, complications of different CD classifications might have different impact. Third, a majority of the included studies were published in Asian countries, which might lead to a bias. Therefore, more western countries studies on the influence of different CD grades and different types of complications for GC patients were needed.

In conclusion, GC patients with postoperative complication had a worse prognosis than those without postoperative complication, and the survival disadvantage seemed to be mainly driven by infectious complications rather than noninfectious complications. Thus, it was important to prevent postoperative complications, especially infectious complications.

Footnotes

Acknowledgments

We acknowledge all the authors in this article.

Authors' Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by L-F.R. and Y-H.X. The first draft of the article was written by L-F.R., the final draft of the article was written by J-G.L., and all authors commented on previous versions of the article. All authors read and approved the final article.

Ethics Approval

The current study was conducted in accordance with the PRISMA statement.

Data Availability Statement

The data were accessed from the database.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Sung

, Ferlay

, Siegel

, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021; 71(3):209–249; doi: 10.3322/caac.21660

Hashimoto

, Kurokawa

, Mori

, et al. Update on the treatment of gastric cancer. JMA J, 2018; 1(1):40–49; doi: 10.31662/jmaj.2018-0006

Tao

, Cheng

, Liu

, et al. A simple predictive index of the abdominal shape for postoperative complications after laparoscopy-assisted distal gastrectomy for gastric cancer. Front Surg, 2021; 8:768434; doi: 10.3389/fsurg.2021.768434

, Hsiung

, Lo

, et al. Nodal dissection for patients with gastric cancer: A randomised controlled trial. Lancet Oncol, 2006; 7(4):309–315; doi: 10.1016/S1470-2045(06)70623-4

Peng

, Zou

, Cheng

, et al. Effect of time (season, surgical starting time, waiting time) on patients with gastric cancer. Risk Manag Healthc Policy, 2021; 14:1327–1333; doi: 10.2147/RMHP.S294141

Zheng

, Wu

, Xi

, et al. The survival and the long-term trends of patients with gastric cancer in Shanghai, China. BMC Cancer, 2014; 14:300; doi: 10.1186/1471-2407-14-300

Sun

, Liu

, Chen

, et al. Early and late recurrences in lymph node-negative gastric cancer: A retrospective cohort study. Ann Saudi Med, 2021; 41(6):336–349; doi: 10.5144/0256-4947.2021.336

Ryu

, Kim

, Lee

, et al. Surgical complications and the risk factors of laparoscopy-assisted distal gastrectomy in early gastric cancer. Ann Surg Oncol, 2008; 15(6):1625–1631; doi: 10.1245/s10434-008-9845-x

Cheng

, Tao

, Kang

, et al. Impact of preoperative type 2 diabetes mellitus on the outcomes of gastric cancer patients following gastrectomy: A propensity score matching analysis. Front Surg, 2022; 9:850265; doi: 10.3389/fsurg.2022.850265

10.

Kanda

. Preoperative predictors of postoperative complications after gastric cancer resection. Surg Today, 2020; 50(1):3–11; doi: 10.1007/s00595-019-01877-8

11.

Dindo

, Demartines

, Clavien

. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg, 2004; 240(2):205–213; doi: 10.1097/01.sla.0000133083.54934.ae

12.

Cheng

, Tao

, Liu

, et al. The outcome of young vs. old gastric cancer patients following gastrectomy: A propensity score matching analysis. BMC Surg, 2021; 21(1):399; doi: 10.1186/s12893-021-01401-1

13.

Zhou

, Zhou

, Cao

, et al. Multivariate logistic regression analysis of postoperative complications and risk model establishment of gastrectomy for gastric cancer: A single-center cohort report. Scand J Gastroenterol, 2016; 51(1):8–15; doi: 10.3109/00365521.2015.1063153

14.

Degiuli

, Sasako

, Ponti

, et al. Morbidity and mortality in the Italian Gastric Cancer Study Group randomized clinical trial of D1 versus D2 resection for gastric cancer. Br J Surg, 2010; 97(5):643–649; doi: 10.1002/bjs.6936

15.

Kim

, Hyung

, Cho

, et al. Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: An interim report—A phase III multicenter, prospective, randomized Trial (KLASS Trial). Ann Surg, 2010; 251(3):417–420; doi: 10.1097/SLA.0b013e3181cc8f6b

16.

Lee

, Park

, Kim

, et al. Comparison of complications after laparoscopy-assisted distal gastrectomy and open distal gastrectomy for gastric cancer using the Clavien-Dindo classification. Surg Endosc, 2012; 26(5):1287–1295; doi: 10.1007/s00464-011-2027-0

17.

Akimoto

, Kinoshita

, Sato

, et al. Impact of postoperative intra-abdominal infectious complications on survival outcomes in patients with gastric cancer who underwent laparoscopic surgery. Surg Endosc, 2023; 37(1):382–390; doi: 10.1007/s00464-022-09522-1

18.

A T M Abdul

, Murakami

, Yoshimoto

, et al. Intra-abdominal complications after curative gastrectomies worsen prognoses of patients with stage II-III gastric cancer. Yonago Acta Med, 2016; 59,(3):210–216.

19.

Climent

, Hidalgo

, Vidal Ó, et al. Postoperative complications do not impact on recurrence and survival after curative resection of gastric cancer. Eur J Surg Oncol, 2016; 42(1):132–139; doi: 10.1016/j.ejso.2015.08.163

20.

Fujiya

, Tokunaga

, Mori

, et al. Long-term survival in patients with postoperative intra-abdominal infectious complications after curative gastrectomy for gastric cancer: A propensity score matching analysis. Ann Surg Oncol, 2016; 23(Suppl 5):809–816; doi: 10.1245/s10434-016-5577-5

21.

Galata

, Blank

, Weiss

, et al. Role of postoperative complications in overall survival after radical resection for gastric cancer: A retrospective single-center analysis of 1107 patients. Cancers (Basel), 2019; 11(12):1890; doi: 10.3390/cancers11121890

22.

Han

, Oh

, Eom

, et al. Prognostic impact of infectious complications after curative gastric cancer surgery. Eur J Surg Oncol, 2020; 46(7):1233–1238; doi: 10.1016/j.ejso.2020.04.032

23.

Hayashi

, Yoshikawa

, Aoyama

, et al. Impact of infectious complications on gastric cancer recurrence. Gastric Cancer, 2015; 18(2):368–374; doi: 10.1007/s10120-014-0361-3

24.

Jiang

, Deng

, Ding

, et al. Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer. World J Gastroenterol, 2014; 20(30):10537–10544; doi: 10.3748/wjg.v20.i30.10537

25.

Kubota

, Hiki

, Sano

, et al. Prognostic significance of complications after curative surgery for gastric cancer. Ann Surg Oncol, 2014; 21(3):891–898; doi: 10.1245/s10434-013-3384-9

26.

Kurokawa

, Yamashita

, Kawabata

, et al. Prognostic value of postoperative C-reactive protein elevation versus complication occurrence: A multicenter validation study. Gastric Cancer, 2020; 23(5):937–943; doi: 10.1007/s10120-020-01073-5

27.

, Li

, Tang

, et al. Impact of postoperative complications on long-term survival after radical resection for gastric cancer. World J Gastroenterol, 2013; 19(25):4060–4065; doi: 10.3748/wjg.v19.i25.4060

28.

, Udelsman

, Parikh

, et al. Impact of postoperative complication and completion of multimodality therapy on survival in patients undergoing gastrectomy for advanced gastric cancer. J Am Coll Surg, 2020; 230(6):912–924; doi: 10.1016/j.jamcollsurg.2019.12.038

29.

, Bai

, Ji

, et al. Relationship between Clavien-Dindo classification and long-term survival outcomes after curative resection for gastric cancer: A propensity score-matched analysis. Int J Surg, 2018; 60:67–73; doi: 10.1016/j.ijsu.2018.10.044

30.

, Bai

, Zhao

, et al. Severity of complications and long-term survival after laparoscopic total gastrectomy with D2 lymph node dissection for advanced gastric cancer: A propensity score-matched, case-control study. Int J Surg, 2018; 54(Pt A):62–69; doi: 10.1016/j.ijsu.2018.04.034

31.

Lui

, Tan

, Tai

, et al. Predictors of survival outcome following radical gastrectomy for gastric cancer. ANZ J Surg, 2019; 89(1–2):84–89; doi: 10.1111/ans.15011

32.

Migita

, Takayama

, Saeki

, et al. The prognostic nutritional index predicts long-term outcomes of gastric cancer patients independent of tumor stage. Ann Surg Oncol, 2013; 20(8):2647–2654; doi: 10.1245/s10434-013-2926-5

33.

Mohri

, Tanaka

, Toiyama

, et al. Impact of preoperative neutrophil to lymphocyte ratio and postoperative infectious complications on survival after curative gastrectomy for gastric cancer: A single institutional cohort study. Medicine (Baltimore), 2016; 95(11):e3125; doi: 10.1097/MD.0000000000003125

34.

Pang

, Zhao

, Wang

, et al. Impact of type of postoperative complications on long-term survival of gastric cancer patients: Results from a high-volume institution in china. Front Oncol, 2021; 11:587309; doi: 10.3389/fonc.2021.587309

35.

Saito

, Kurokawa

, Miyazaki

, et al. Which is a more reliable indicator of survival after gastric cancer surgery: Postoperative complication occurrence or C-reactive protein elevation?. J Surg Oncol, 2015; 112(8):894–899; doi: 10.1002/jso.24067

36.

Saunders

, Yanni

, Dorrington

, et al. Impact of postoperative complications on disease recurrence and long-term survival following oesophagogastric cancer resection. Br J Surg, 2020; 107(1):103–112; doi: 10.1002/bjs.11318

37.

Song

, Lee

, Choi

, et al. Adverse prognostic impact of postoperative complications after gastrectomy for patients with stage II/III gastric cancer: Analysis of prospectively collected real-world data. Front Oncol, 2021; 11:611510; doi: 10.3389/fonc.2021.611510

38.

Takebayashi

, Murata

, Kaida

, et al. Adverse impact of postoperative intra-abdominal infectious complications on cancer recurrence-related survival after curative gastric cancer surgery. Am J Surg, 2022; 224(3):949–954; doi: 10.1016/j.amjsurg.2022.05.009

39.

Tokunaga

, Tanizawa

, Bando

, et al. Poor survival rate in patients with postoperative intra-abdominal infectious complications following curative gastrectomy for gastric cancer. Ann Surg Oncol, 2013; 20(5):1575–1583; doi: 10.1245/s10434-012-2720-9

40.

Tokunaga

, Kurokawa

, Machida

, et al. Impact of postoperative complications on survival outcomes in patients with gastric cancer: Exploratory analysis of a randomized controlled JCOG1001 trial. Gastric Cancer, 2021; 24(1):214–223; doi: 10.1007/s10120-020-01102-3

41.

, Lin

, Li

, et al. Comprehensive complication index predicts cancer-specific survival of patients with postoperative complications after curative resection of gastric cancer. Gastroenterol Res Pract, 2018; 2018:4396018; doi: 10.1155/2018/4396018

42.

Watanabe

, Hayashi

, Komori

, et al. Impact of postoperative complications on recurrence in patients with stage II/III gastric cancer who received adjuvant chemotherapy with S-1. Anticancer Res, 2020; 40(3):1683–1690; doi: 10.21873/anticanres.14120

43.

Xiao

, Xiao

, Chen

, et al. Association among blood transfusion, postoperative infectious complications, and cancer-specific survival in patients with stage II/III gastric cancer after radical gastrectomy: Emphasizing benefit from adjuvant chemotherapy. Ann Surg Oncol, 2021; 28(4):2394–2404; doi: 10.1245/s10434-020-09102-4

44.

, Huang

, Cheng

, et al. Prognostic significance of postoperative complication after curative resection for patients with gastric cancer. J Cancer Res Ther, 2020; 16(7):1611–1616; doi: 10.4103/jcrt.JCRT_856_19

45.

Yuan

, Wu

, Li

, et al. Impact of postoperative major complications on long-term survival after radical resection of gastric cancer. BMC Cancer, 2019; 19(1):833; doi: 10.1186/s12885-019-6024-3

46.

Page

, McKenzie

, Bossuyt

, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol, 2021; 134:178–189; doi: 10.1016/j.jclinepi.2021.03.001

47.

Stang

. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010; 25(9):603–605; doi: 10.1007/s10654-010-9491-z

48.

Freites-Martinez

, Santana

, Arias-Santiago

, et al. Using the common terminology criteria for adverse events (CTCAE - Version 5.0) to evaluate the severity of adverse events of anticancer therapies. Actas Dermosifiliogr (Engl Ed). 2021; 112(1):90–92; doi: 10.1016/j.ad.2019.05.009

49.

Ioannidis

. Interpretation of tests of heterogeneity and bias in meta-analysis. J Eval Clin Pract, 2008; 14(5):951–957; doi: 10.1111/j.1365-2753.2008.00986.x

50.

Higgins

, Thompson

, Deeks

, et al. Measuring inconsistency in meta-analyses. BMJ, 2003; 327(7414):557–560; doi: 10.1136/bmj.327.7414.557

51.

Aoyama

, Oba

, Honda

, et al. Impact of postoperative complications on the colorectal cancer survival and recurrence: Analyses of pooled individual patients' data from three large phase III randomized trials. Cancer Med, 2017; 6(7):1573–1580; doi: 10.1002/cam4.1126

52.

Nojiri

, Hamasaki

, Inoue

, et al. Long-term impact of postoperative complications on cancer recurrence following lung cancer surgery. Ann Surg Oncol, 2017; 24(4):1135–1142; doi: 10.1245/s10434-016-5655-8

53.

de Glas

, Kiderlen

, Bastiaannet

, et al. Postoperative complications and survival of elderly breast cancer patients: A FOCUS study analysis. Breast Cancer Res Treat, 2013; 138(2):561–569; doi: 10.1007/s10549-013-2462-9

54.

Murthy

, Thomson

, Dodwell

, et al. Postoperative wound complications and systemic recurrence in breast cancer. Br J Cancer, 2007; 97(9):1211–1217; doi: 10.1038/sj.bjc.6604004

55.

Tanaka

, Kanemitsu

, Shida

, et al. Prognostic impact of intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer. Dis Colon Rectum, 2017; 60(8):827–836; doi: 10.1097/DCR.0000000000000853

56.

Goto

, Hasegawa

, Hida

, et al. Multicenter analysis of impact of anastomotic leakage on long-term oncologic outcomes after curative resection of colon cancer. Surgery, 2017; 162(2):317–324; doi: 10.1016/j.surg.2017.03.005

57.

Ramadan

, Wetmore

. Effect of wound infections on head and neck cancer. Arch Otolaryngol Head Neck Surg, 1992; 118(5):486–487; doi: 10.1001/archotol.1992.01880050032007

58.

Schantz

, Skolnik

, O'Neill

. Improved survival associated with postoperative wound infection in laryngeal cancer: An analysis of its therapeutic implications. Otolaryngol Head Neck Surg, 1980; 88(4):412–417; doi: 10.1177/019459988008800417

59.

Peng

, Cheng

, Zhang

. Does Roux-en-Y construction really bring benefit of type 2 diabetes mellitus remission after gastrectomy in patients with gastric cancer? A systematic review and meta-analysis. Diabetes Ther, 2020; 11(12):2863–2872; doi: 10.1007/s13300-020-00934-7

60.

Finnerty

, Mabvuure

, Ali

, et al. The surgically induced stress response. JPEN J Parenter Enteral Nutr, 2013; 37(5 Suppl):21S–9S; doi: 10.1177/0148607113496117

61.

Peng

, Cheng

, Tao

, et al. Onco-metabolic surgery: A combined approach to gastric cancer and hypertension. Cancer Manag Res, 2020; 12:7867–7873; doi: 10.2147/CMAR.S260147

62.

Alazawi

, Pirmadjid

, Lahiri

, et al. Inflammatory and immune responses to surgery and their clinical impact. Ann Surg, 2016; 264(1):73–80; doi: 10.1097/SLA.0000000000001691

63.

McMillan

. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care, 2009; 12(3):223–226; doi: 10.1097/MCO.0b013e32832a7902

64.

Mantovani

, Allavena

, Sica

, et al. Cancer-related inflammation. Nature, 2008; 454(7203):436–444; doi: 10.1038/nature07205

65.

Tao

, Cheng

, Zou

, et al. Aorta calcification increases the risk of anastomotic leakage after gastrectomy in gastric cancer patients. Cancer Manag Res, 2021; 13:3857–3865; doi: 10.2147/CMAR.S306942

66.

McDonald

, Spicer

, Giannais

, et al. Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms. Int J Cancer, 2009; 125(6):1298–1305; doi: 10.1002/ijc.24409

67.

Hsu

, Chan

, Spicer

, et al. LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res, 2011; 71(5):1989–1998; doi: 10.1158/0008-5472.CAN-10-2833

68.

Beeharry

, Zhang

, Liu

, et al. Optimization of perioperative approaches for advanced and late stages of gastric cancer: Clinical proposal based on literature evidence, personal experience, and ongoing trials and research. World J Surg Oncol, 2020; 18(1):51; doi: 10.1186/s12957-020-01819-6

69.

Osorio

, Jericó

, Miranda

, et al. Improved postoperative outcomes and reduced transfusion rates after implementation of a Patient Blood Management program in gastric cancer surgery. Eur J Surg Oncol, 2021; 47(6):1449–1457; doi: 10.1016/j.ejso.2020.11.129

70.

Nakanishi

, Kanda

, Kodera

. Long-lasting discussion: Adverse effects of intraoperative blood loss and allogeneic transfusion on prognosis of patients with gastric cancer. World J Gastroenterol, 2019; 25(22):2743–2751; doi: 10.3748/wjg.v25.i22.2743

71.

Deftereos

, Kiss

, Isenring

, et al. A systematic review of the effect of preoperative nutrition support on nutritional status and treatment outcomes in upper gastrointestinal cancer resection. Eur J Surg Oncol, 2020; 46(8):1423–1434; doi: 10.1016/j.ejso.2020.04.008

72.

, Tan

, Fan

, et al. Clinicopathologic characteristics of elderly with gastric cancer, and the risk factors of postoperative complications. J Invest Surg, 2017; 30(6):394–400; doi: 10.1080/08941939.2016.1265617