World J Surg DOI 10.1007/s00268-015-3019-3
ORIGINAL SCIENTIFIC REPORT
Postoperative Complications Affect Long-Term Survival Outcomes Following Hepatic Resection for Colorectal Liver Metastasis Zi Yin • Xiande Huang • Tingting Ma • Haosheng Jin • Ye Lin • Min Yu • Zhixiang Jian
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background The impact of postoperative complications (POCs) on long-term survival outcomes following hepatic resection for colorectal liver metastasis (CRLM) is in controversy. The aim of the present meta-analysis was to systematically evaluate the POC effect on overall survival (OS) and disease-free survival (DFS) in patients undergoing hepatic resection for CRLM. Methods We conducted a systematic review and meta-analysis of all observational studies to evaluate the POC effect on OS and DFS in patients undergoing hepatic resection for CRLM. A search for all major databases and relevant journals from inception to January 2014 without restriction on languages or regions was performed. POCs were extracted and graded according to a validated system of classification. Outcome measures were postoperative 1-, 2-, 3-, and 10-year OSs and DFSs. Both random-effects and fixed-effect models were used to pool the hazard ratios (HRs) of the survival outcomes. Test of heterogeneity was performed with the Q statistic. Results A total of 2370 patients were included in the meta-analysis. Both 5- and 10-year postoperative OSs showed significant decreases in patients with POCs (HR = 1.52; 95 % CI 1.27–1.83; P \ 0.001 and HR = 1.36; 95 % CI 1.18–1.58; P \ 0.001, respectively). Similar outcomes were also observed in terms of DFSs, with the 5- and 10-year HRs found to be 1.37 (95 % CI 1.23–1.53; P \ 0.001) and 1.34 (95 % CI 1.17–1.53; P \ 0.001), respectively, compared to no POC group. Conclusions POCs are strongly related to long-term oncologic outcomes following hepatic resection for CRLM. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients.
Introduction Zi Yin, Xiande Huang and Tingting Ma contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s00268-015-3019-3) contains supplementary material, which is available to authorized users. Z. Yin (&) H. Jin Y. Lin M. Yu Z. Jian (&) General Surgery Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd., Guangzhou 510080, China e-mail: [email protected] Z. Jian e-mail: [email protected]
Hepatic resection is the most effective treatment in patients with colorectal liver metastases (CRLM). However, postoperative morbidity is common and its impact on long-term X. Huang Department of Urology, Gansu Provincial Hospital, Lanzhou, China T. Ma Gynaecology and Obstetrics Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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survival outcome is still in controversy. Although there have been improvements in the 5-year overall survival (OS) for this disease over the past several decades due to advances in surgical techniques, staging, and perioperative care, the disease-free survival (DFS) has not significantly improved [1–4]. Neoadjuvant chemotherapy prior to hepatectomy may facilitate the resectability of the liver lesions and treat occult metastasis, but may also lead to hepatic parenchyma damage in patients with resectable CRLM [5]. It is noted that significantly improved mortality rate for liver surgery in many high-volume centers has been reported, yet the morbidity remains high [6–10]. As we know that identifying determinants of therapeutic response is a major focus of research in oncology, especially the recognition of modifiable factors that affect oncologic outcomes is of great importance [4, 11]. Prognostic factors predicting the postoperative survival outcome include the characteristics of primary tumor (stage, carcinoembryonic antigen) and liver metastases (number, size, and lymph node metastases), the presence of extrahepatic disease, the type of operation (curative/palliative), and also perioperative chemotherapy in CRLM resection [1, 4, 10, 12–18]. Currently, negative impact of postoperative complications (POCs) on long-term survival outcomes in various cancers has been indicated [19–22]. Khuri et al. analyzed the National Surgical Quality Improvement Program data with the conclusion that POC was associated with a poor long-term survival after selected major operations [23]. CRLM is a common malignancy in 20–25 % of colorectal carcinoma individuals at initial presentation, with a further metachronous incidence of 20–30 % following colorectal surgery [11, 24–26]. Following hepatic resection for CRLM, the influences of POC on hospital stay and resource usage have been identified; however, its effectiveness on long-term oncological outcome is eagerly awaited to clarify. The aim of the present meta-analysis was to systematically evaluate the POC effect on OS and DFS in CRLM patients.
SpringerLink. We combined the database-specific search terms of CRLM, hepatic resection, complication, and survival as well as truncated search terms utilizing the wildcard (‘‘*’’) character for CRLM patients. Additionally, the ‘‘related articles’’ function was also used to broaden the search, and computer search was supplemented with manual searches for reference lists of all retrieved review articles, primary studies, and abstracts from meetings to identify other studies not found in the computer search. When the results of a single study were reported in more than one publication, only the most recent and complete data were included. Study selection All clinical studies reporting on the influence of POCs on long-term survival following hepatic resection for CRLM were selected (in addition, the comparisons in postoperative long-term oncological outcomes between postoperative CRLM patients with POCs and without POCs were performed). All of the studies included in the meta-analysis met the following criteria: (1)
(2)
(3)
(4) (5)
Liver metastasis as the first manifestation of M1 disease accompanied by no documented non-hepatic disseminated disease in preoperative imaging; intraoperative histologically proven colorectal carcinoma. No prior history of liver-directed treatment such as hepatectomy, radiofrequency ablation, or other local modalities; no extrahepatic disease. Perioperative results and long-term results of survival were assessed as outcome measures of the treatment effects. They had been published or accepted for publication as full-length articles. The study included at least 30 patients. Smaller studies were excluded because of poor reliability.
The exclusion criteria were non-human studies, experimental trials, review articles, editorials, letters/case reports, and articles not reporting outcomes of interest.
Methods Outcome measures The methods of literature search, inclusion and exclusion criteria, outcome measures, and methods of statistical analysis were defined in a protocol according to the metaanalysis of observational studies in epidemiology recommendations for study reporting [27]. Data sources and searches The primary sources of the reviewed studies through January 2014, without restriction on the languages or regions, were Pubmed, Embase, Science Citation Index, and
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Outcomes assessed were primary parameters of 1-, 3-, 5-, and 10-year OS and DFS, POCs [those directly related to primary colorectal cancer resection (ileus, anastomotic leak, pelvic abscess, and rectovaginal fistula), to hepatectomy (hepatic insufficiency/failure, subphrenic/ perihepatic abscess, bile leakage, bleeding, etc.), to laparotomy (wound infection, intra-abdominal collection, and pulmonary and cardiac diseases), and others], and postoperative mortality within 60 days. Accessorial outcomes reported in some of the articles were also reviewed.
World J Surg Table 1 The Clavien–Dindo complication classification [28] Grades
Definitions
I
Any deviation from normal postoperative course without pharmacological, surgical, endoscopic, and radiological interventions. Antiemetics, antipyretics, analgesics, diuretics, electrolytes, physiotherapy, and wound infections opened at bedside were allowed
II
Drug treatment other than in grade I. Blood transfusions and total parenteral nutrition included
III
Requiring surgical, endoscopic, or radiological interventions
IIIa
Intervention not under general anesthesia
IIIb
Intervention under general anesthesia
IV
Life threatening complications (inc CNS complicationsa) requiring HDU/ICU care
IVa
Single organ dysfunction (including dialysis)
IVb
Multi-organ dysfunction
V
Death of patient
a
Brain hemorrhage, ischemic stroke, subarachnoid bleed, but excluding transient ischemic attacks
Data extraction and quality assessment Two reviewers (YZ and JZ) independently considered the eligibility of potential titles and abstracts. When there was a disagreement about a study or a lack of information for an accurate assessment of eligibility, the study was carried to the full-text stage for evaluation. Data were extracted independently and in duplicate by two reviewers (HXD and JHS); discrepancies were resolved by mutual discussion. We extracted the inclusion and exclusion criteria and the characteristics for each included study. POCs were further graded using a validated system of classification (Table 1) [28]. The quality of observational studies was assessed by modified criteria suggested by the Newcastle–Ottawa quality assessment tool [29]. We also assessed the loss to follow up and the ways in which missing data were handled for all studies. Data synthesis and analysis The hazard ratio (HR) was used as a summary statistic for long-term outcomes (survival analysis) as described by Parmar et al. [30]. An HR of less than 1 represented a survival benefit favoring the simultaneous group. Medians were converted to means using the technique described by Hozo et al. [31]. The fixed-effect model was first used to pool the results, which assumes that all the studies share the same common (fixed or non-random) effect. Variance was used to calculate the weight of each study. Heterogeneity was considered not statistically significant when the Cochrane Q test P value was [0.1. A transformation of Q test, the I2 statistic (I2 = 100 % 9 (Q - df)/Q), was
used to assess the consistency of the effect sizes. In case of heterogeneity, meta-analysis was performed applying the random-effects model. In addition, an I2 value of less than 25 % was defined to represent low heterogeneity, a value between 25 and 50 % was defined as moderate heterogeneity, and a value [50 % was defined as high heterogeneity [32]. The studies were weighted in the metaanalysis by the inverse variances of their effect estimates, that is, the validities of the included studies. Subgroup analyses, which considered more homogeneous studies, were performed to identify subsets of patients more likely to benefit from the treatment and to assess the efficacy of different studies. To determine the extent to which the combined risk estimate might be affected by individual studies, sensitivity analysis was performed by consecutively omitting every study from the meta-analysis (leave-one-out procedure). Funnel plots were not used to screen for publication bias due to the limited study numbers. Meta-analysis was conducted by Review Manager (RevMan) Meta-analysis software, version 5.3.5. [33]. The 95 % CIs were calculated as estimates of precision for HR. The statistical tests were two-sided, and P values of \0.05 were considered statistically significant.
Results Literature search Database searches and other resources (mainly conference proceedings) yielded 1717 entries (see Fig. 1), of which 666 were excluded as duplicates. Of the 1051 publications that qualified for abstract review, 907 were excluded primarily because they were not controlled trials, other comparisons, open choledochotomy, or with no comparison group. The remaining 94 publications underwent full article review, and further 89 publications were excluded mainly because they were other comparisons, not controlled trials, or duplicate studies. Finally, a total of 5 studies qualified for inclusion in this review with a total of 2370 patients [34–38]. Characteristics of the included studies Table 2 listed the characteristics of the included studies and details of the enrolled participants. Of 2370 patients included in the meta-analysis, 829 (35 %) suffered from POCs and 1541 (65 %) did not. Of the five studies included in the meta-analysis, four were prospective [34–36, 38] and one retrospective [37]. Four were carried out in a single center with no randomized control trials [35–38], one was multicenter [34], three studies originated from Europe [34, 36, 37], and two from the US [35, 38]. POCs were graded
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Pubmed, Embase and other secondary sources
Overall number of search result n = 1717 Search Overlap n = 666 Abstract Review n = 1051 Excluded: n = 907 Not A Controlled trial: n = 489 Other Comparison: n = 307 No Comparison Group: n = 111 Full Paper Review n = 94 Excluded: n = 89 Other Comparison: n = 49 Not A Controlled Trials: n = 33 No Comparison Group: n = 5 Duplicate Study: n = 2 Included Trials n=5
Fig. 1 Flow chart of publication search and selection
using a validated system of classification in the included trials except one [37]. Two studies [34, 35] provided data on the impact of POCs on 10-year survival after hepatic resection for CRLM. All studies conducted multivariate analyses to extract the independent prognostic factors on 5-year DFS and OS. Variables were collected from patient medical records, operative reports, anesthesia reports, and pathology reports. Preoperative tumor staging was performed using contrastenhanced computer tomography or magnetic resonance imaging. Positron emission tomography was used selectively, in the latter part of the series, to rule out extra hepatic disease. Major hepatectomy was defined as resection of C3 segments. Disease extent was quantified using a previously validated five-point clinical-risk score (CRS), which includes carcinoembryonic antigen level, diseasefree interval, nodal status (primary tumor), number of liver lesions, and size of greatest lesion. Resection was considered in selected patients with limited extrahepatic disease
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and typically in those with proven chemotherapy-sensitive tumors. OS was measured from the time of liver resection to death and DFS from the time of liver resection to the period when the first recurrence was detected. Quality assessments for the included studies The agreement between two reviewers for study selection was 0.96 and for quality assessment of trials was 0.94. We evaluated the risk of bias in the five observational studies by modification of the Newcastle–Ottawa scale (Supplementary Table 1) [32]. Detailed descriptions of follow-up were available in most studies. The outcomes may have been influenced by various selection biases in these trials for patient allocation, including age, major hepatectomy, sex ratio, colorectal primary location, the distribution, total number, and the largest size of liver metastases, and preoperative chemotherapy. More colorectal surgery combined with hepatectomy was performed in metachronous
World J Surg Table 2 Characteristics of the included studies Authors
Enrolled participants and study design
Tumor characteristics and hepatic resection
Complication gradea
UV/MV analysis of complications presentb
Schiesser et al. [34]
No. patients 197
Synchronous CRLM (%) 35 (18)
I/II: 32 (16)
Overall survival:
Australia (multicenter)
No. tumor (range) NA
III/IV: 22 (11)
UV: P \ 0.01
(Australia)
PCS: (1992–2005)
Size (cm) (range/SD) NA
V: 5 (3)
MV: P = 0.003, HR (95 % CI) 2.2 (1.3–3.7)
Patient age (range) 64 (22–92)
Major liver resection (%) NA R0 (%): NAPBT (%) 82 (42)
UV: P = 0.041
M (%) 124 (63)
Preop. chemotherapy (%) 67(34)
MV: P = 0.006, HR (95 % CI) 1.8 (1.2–2.8)
Disease free survival:
Follow-up period (month) 54
Postop. chemotherapy (%) NA
Ito et al. [35]
No. patients 1067
Synchronous CRLM (%) 380 (36)
I/II: 258 (24)
Overall survival:
(USA)
USA (single centre)
No. tumor (range) 3.4 (NA)
PCS (1991–2002)
Size (cm) (range/SD) 5 ± 3.7
III/IV: 192 (18)
MV: P = 0.10, HR (95 % CI) 1.2 (0.96–1.5)
Patient age (range) 61 (20–89)
Major liver resection (%) 620 (58)
M (%) 596 (56)
R0 (%) 921 (86), PBT (%) 476 (45)
Follow-up period (month) 41
Preop. chemotherapy (%) 319 (30)
UV: P = 0.0059 Disease free survival: UV: P = 0.0042 MV: P = 0.083, HR (95 % CI) 1.2 (0.98–1.5)
Postop. chemotherapy (%) 909 (85) Farid et al. [36]
No. patients 705
Synchronous CRLM (%) 290 (41)
I/II: 74 (37)
Overall survival:
(UK)
UK (single centre)
No. tumor (range) 3 (1–21)
III/IV: 98 (49)
PCS (1993–2007)
Size (cm) (range/SD) 4 (0.1–23)
V: 25 (13)
UV: P \ 0.001, HR (95 % CI) 1.6 (1.46–1.72)
Patient age (range) 46 (23–91)
Major liver resection (%) 443 (63)
M (%) 442 (63)
R0 (%) 447 (63), PBT (%) 149 (21)
Follow-up period (month) 38
Preop. chemotherapy (%) 88 (13)
MV: P = 0.026, HR (95 % CI) 1.4 (1.04–1.86) Disease free survival: UV: P = 0.004, HR (95 % CI) 1.4 (1.10–1.67)
Postop. chemotherapy (%) 705 (100) NA
Overall survival:
Laurent et al. [37]
No. patients 311
Synchronous CRLM (%) NA
(France)
France (single centre)
No. tumor (range) 2 (1–8)
UV: P \ 0.001
RCS (1985–2000)
Size (cm) (range/SD) 5 (0.4–28)
Patient age (range) 63 (31–86)
Major liver resection (%) 194 (62)
MV: P = 0.001, HR (95 % CI) 1.79 (1.28–2.52)
R0 (%) 305 (98), PBT (%) 49 (16)
Disease free survival:
M (%) 209 (67)
Preop. chemotherapy (%) none
UV: NA
Follow-up period (month) 29
Postop. chemotherapy (%) 138 (44)
MV: P = 0.006, HR (95 % CI) 1.52 (1.13–2.06)
Correa-Gallego et al. [38]
No. patients 90
Synchronous CRLM (%) 14 (16)
I/II: 9
USA (single centre)
No. tumor (range) NA
III/IV: 21
(USA)
PCS (2004–2007)
Size (cm) (range/SD) NA
MV: P = 0.007, HR (95 % CI) 3.0 (1.3–6.5)
Patient age (range) 53 (49–63)
Major liver resection (%) 90 (100)
Disease free survival:
R0 (%) 69 (77), PBT (%) NA
UV: P \ 0.003, HR (95 % CI) 2.4 (1.4–4.2)
M (%) 50 (56)
Preop. chemotherapy (%) 75 (83)
MV: P = 0.004, HR (95 % CI) 2.7 (1.4–5.4)
Follow-up period (month) 71
Postop. chemotherapy (%) 78 (87)
Overall survival: UV: P \ 0.01, HR (95 % CI) 2.7 (1.5–4.8)
UV univariate, MV multivariate, RCS retrospective cohort study, PCS prospective cohort study, M male, CRLM colorectal liver metastases, NA not available, No. number of, R0 margin zero, preop. preoperative, postop. postoperative, SD standard deviation, PBT perioperative blood transfusion, HR hazard ratio, CI confidence interval a
Incidence and severity of complications according to a standardized complication classification. Grade I minor deviation from the normal postoperative course without the need for any specific treatment, grade II complications that can be treated solely by drugs, blood transfusion, physiotherapy, or nutritional support, grade III complications that require interventional or surgical treatment, grade IV complications that are life-threatening and require ICU management, grade V death of the patient
b
The hazard ratios are specifically referring to the group of patients with complications
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World J Surg Fig. 2 Forest plots depicting the meta-analysis of postoperative complication (POC) versus no postoperative complication (NPOC) following hepatic resection for CRLM in long-term 1-, 3-, 5-, and 10-year overall survivals (OSs)
resection. In addition, no study described adequately the patient flow. Methods for handling missing data were not adequately described in most studies. Meta-analysis including subgroup and sensitivity analyses To evaluate the long-term oncological outcomes for CRLM resection, HRs of OS and DFS were calculated and combined in the present study using the data extracted from Kaplan–Meier curves (Fig. 2). Five studies with a total of 2370 patients were included, and the postoperative duration for survival analysis ranged from 6 to 120 months. Analysis for the 1264 patients from two studies with 10-year postoperative OS showed a significantly decreased outcome in POC group (HR: 1.36; 95 % CI 1.18–1.58; P \ 0.001; I2 = 7 %). Similarly, final pooled estimates of 1-, 3-, and 5-year OSs were found to be 2.14 (95 % CI 1.57–2.92; P \ 0.001; I2 = 13 %), 1.49 (95 % CI 1.23–1.80; P \ 0.001; I2 = 39 %), and 1.52 (95 % CI 1.27–1.83; P \ 0.001; I2 = 55 %), respectively. Likely,
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the 1-, 3-, 5-, and 10-year pooled HRs of DFSs for POC were found to be 1.52 (95 % CI 1.32–1.75; I2 = 0 %), 1.33 (95 % CI 1.20–1.48; I2 = 19 %), 1.37 (95 % CI 1.23–1.53; I2 = 50 %), and 1.34 (95 % CI 1.17–1.53; I2 = 0 %), respectively, compared to no POC group with all the P values less than 0.001 (Fig. 3). Sensitivity analysis did not significantly alter the ultimate results by the leave-one-out procedures, which indicated the stability and reliability of the meta-analysis.
Discussion Hepatic resection as the standard treatment for patients with CRLM was associated with a relatively high postoperative morbidity rate of 26–56 %, although the mortality rate has been dramatically reduced over the recent decade to less than 5 % in large-volume centers with experienced hepatic surgeons [5, 6, 8]. One of the major concerns is whether, from medical or surgical point of view, POC itself is associated with longer hospital stay, increased
World J Surg Fig. 3 Forest plots depicting the meta-analysis of postoperative complication (POC) versus no postoperative complication (NPOC) following hepatic resection for CRLM in long-term 1-, 3-, 5-, and 10-year disease-free survivals (DFSs)
reoperative rate, and subsequent higher inpatient stay costs. Further, POCs are associated with the more extent of resection and more complexity of surgery, which could result in more frequent use of blood product transfusion. It has been reported that long-term outcomes were affected by POC following curative resection, which was a well-recognized concept for patients with esophageal, colorectal, oral, and lung tumors [19–22]. POCs such as infections, anastomotic leakage, and multiorgan failure have been shown to be associated with decreased survival after tumor resection in previous studies [39–42]. Improved surgical and anesthetic techniques, as well as better measures that might minimize complications (accurate mobilization of the liver, limited vascular clamping, extrahepatic control of hepatic vessels, and meticulous parenchymal transection), have been responsible for a decline in perioperative mortality from as high as 35–0.1–3 %. Nevertheless, overall postoperative morbidity reaches 45 % currently, and grade III/IV morbidity ranges from 28 to 30 % based on the present experiences of several high-volume medical centers [8, 43, 44]. The major finding of this meta-analysis was that patients suffering from POCs after liver resection for CRLM had reduced long-term survival rates. Negative impacts of POCs on postoperative 5- and 10-year OS and DFS were
observed. The present study found that patients experiencing POCs had higher HRs with 1-, 3-, 5-, and 10-year OS of 2.14, 1.49, 1.52, and 1.36 compared with patients without POCs (all P values \0.001), respectively, and 1-, 3-, 5-, and 10-year DFS of 1.52, 1.33, 1.37, and 1.34 (all P values \0.001). Burdened by various operation extent, blood loss and transfusion rates, as well as comorbid conditions between patients who developed POCs and those who did not, the analysis of perioperative morbidity as an oncologic variable particularly in retrospective studies was difficult. Several preoperative variables including patient age, body mass index, platelet count, and albumin level were found to be associated with POCs, and some of these factors have been shown to be associated with postoperative mortality as well [6]. Also, mortality is an objective parameter; whereas inconsistency exists in defining POCs, accurately comparing morbidity rates across institutions is difficult. This shortcoming has severely hampered conclusive analysis of its impact on survival outcome. Therefore, an objective surgical complication classification was applied [28], which graded the complications according to their therapeutic relevance in four of these included studies [34–36, 38]. Potential benefits in performing the surgery with meticulous technique to minimize complications were
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indicated. Schiesser et al. firstly correlated the findings of this classification to the outcome in patients undergoing liver resection for SCRM, and showed a statistically significant difference in outcome of patients with grade I and II versus III and IV [34]. Thus, instinctively, the association between perioperative morbidity and oncologic outcomes in patients with CRLM may suggest that severe POCs may have a higher negative impact on postoperative long-term oncological results than mild POCs. In contrary to Schiesser et al.’s research, Farid et al. demonstrated similar survival outcomes of patients with grade I/II versus III/IV [36]. The same observation was also noted in Correa-Gallego et al.’s study, although given the small size of the groups in this analysis, it was possible that failure to identify a difference represented a type-II error rather than an equivalent impact of morbidity on survival. This may represent the heterogeneity in the types of complications implicated in these grades. Furthermore, a system classification based on the therapy required to correct complications has the benefit of eliminating inconsistency in definitions not by focusing on etiopathology would be unable to provide a meaningful differentiation, at least in disease- or cancer-specific survival. Regardless of the type or severity, in Ito’s study, the overall POC was 42 %, and complications requiring moderate (grade II) or invasive interventions (grade III) represented 80 % of the total, which was at the higher end of the range reported in the literature [35]. Further work is needed to resolve the relationship of severity of the POCs and survival outcomes. Furthermore, the observation that patients who developed POCs after liver resection had shorter long-term survival which was independent of other variables including CRS, which was itself an independent predictor of outcome. Ito et al. demonstrated a negative impact of POC on OS and DFS in an analysis only seen in 1067 patients with low CRS. Correa-Gallego et al. showed a stronger and much clearer association by differing from Ito et al.’s which included only patients submitted to major hepatic resections and retrospectively analyzes an independent, contemporary cohort of prospectively evaluated patients [35, 38]. The question that why POCs within 30 days following surgery endowed with a negative impact on patient’s longterm survival outcomes is interesting and deserving deep investigation. To date, the precise mechanism remains to be elucidated. Inflammatory response has been highlighted and may play a central role in potentially exacerbating this problem. In a more detailed analysis aimed at evaluating the impact of the specific type of sepsis, Farid et al. have shown that although wound infection was a common complication after hepatic resection, it did not have exhibited a negative impact on either DFS or OS when compared with the other patients without POCs. However,
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in the presence of more systemic inflammatory insult (either respiratory or intra-abdominal infection), the negative effect becomes significant [36]. Major surgery could cause a certain degree of systemic inflammatory response and even immunosuppression in patients and thus creates a favorable environment for faster progression of microscopic cancer, or that POCs are the consequence of poor functional status, which independently predicts shorter survival in patients with various malignancies. Particularly, severe POCs like septicemia lead to an extended period of immunosuppression, which allows residual tumor cells to further proliferate and survive in the host [45–47]. It has been reported that patients with elevated C-reactive protein (CRP) had a poorer prognosis after liver resection for CRLM compared with those with normal CRP. Other researches on positive effect of various cytokines, such as interleukin-1 and -8 (IL-1 and IL-8) on cancer cell proliferation in vitro, also supported the speculation that prolonged systemic inflammation and attenuated immune defense by POCs may be a factor promoting survival and subsequent growth of the micrometastatic cells [48, 49]. In summary, this systematic review and meta-analysis was conducted at appropriate time because enough data have accumulated for inspection by meta-analytical methods when hepatic resection strategy for CRLM patients is used more commonly. The postoperative course represents a vulnerable period in which infective complications and secondary immunosuppression negatively influence cancer-related prognosis. POCs are strongly related to the long-term oncologic outcomes. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients. Acknowledgments The authors thank Prof. Yuan-Tao Hao, Department of Medical Statistics, Sun Yat-sen University, Guangdong, China, for statistical advice; Yu Bai, Department of Gastroenterology of Affiliated Changhai Hospital, Second Military Medical University, Shanghai, China, for research comments; and Yan Jia, Medical Library of North Campus, Sun Yat-sen University, Guangdong, China, for literature search. None of these persons received compensation for the work performed. This study was not supported by any pharmaceutical company or Grants; the cost was borne by the authors’ institutions. Conflicts of interest Consents to publication were all available for all authors. The authors declare no conflicts of interest.
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22. Chok KS, Ng KK, Poon RT et al (2009) Impact of postoperative complications on long-term outcome of curative resection for hepatocellular carcinoma. Br J Surg 96:81–87 23. Khuri SF, Henderson WG, DePalma RG et al (2005) Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg 242:326–341 24. Cancer Research UK Information Centre (2003) CancerStats. http://www.info.cancerresearch.org/cancerstats. Accessed 15 Dec 2014 25. Doci R, Gennari L, Bignami P et al (1995) Morbidity and mortality after hepatic resection of metastases from colorectal cancer. Br J Surg 82:377–381 26. Malik HZ, Prasad KR, Halazun KJ et al (2007) Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases. Ann Surg 246:806–814 27. Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 283:2008–2012 28. Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213 29. Wells GA, Shea B, O’Connell D et al (2013) The Newcastle– Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_ epidemiology/oxford.asp. Accessed 29 Feb 30. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834 31. Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:13 32. Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. March 2011. Cochrane Collaboration. http://www.cochrane-handbook.org. Accessed 29 March 2014 33. Review Manager (RevMan) (2014) [Computer program]. Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen 34. Schiesser M, Chen JW, Maddern GJ et al (2008) Perioperative morbidity affects long-term survival in patients following liver resection for colorectal metastases. J Gastrointest Surg 12:1054–1060 35. Ito H, Are C, Gonen M et al (2008) Effect of postoperative morbidity on long-term survival after hepatic resection for metastatic colorectal cancer. Ann Surg 247:994–1002 36. Farid SG, Aldouri A, Morris-Stiff G et al (2010) Correlation between postoperative infective complications and long-term outcomes after hepatic resection for colorectal liver metastasis. Ann Surg 251:91–100 37. Laurent C, Sa Cunha A, Couderc P (2003) Influence of postoperative morbidity on long-term survival following liver resection for colorectal metastases. Br J Surg 90:1131–1136 38. Correa-Gallego C, Gonen M, Fischer M et al (2013) Perioperative complications influence recurrence and survival after resection of hepatic colorectal metastases. Ann Surg Oncol 20:2477–2484 39. Nagano Y, Tanaka K, Togo S et al (2005) Efficacy of hepatic resection for hepatocellular carcinomas larger than 10 cm. World J Surg 29:66–71. doi:10.1007/s00268-004-7509-y 40. Howard TJ, Krug JE, Yu J et al (2006) A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon’s contribution to long-term survival in pancreatic cancer. J Gastrointest Surg 10:1338–1345 41. Fujita S, Teramoto T, Watanabe M et al (1993) Anastomotic leakage after colorectal cancer surgery: a risk factor for recurrence and poor prognosis. Jpn J Clin Oncol 23:299–302
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World J Surg 42. Hirai T, Yamashita Y, Mukaida H et al (1998) Poor prognosis in esophageal cancer patients with postoperative complications. Surg Today 28:576–579 43. Kamiyama T, Nakanishi K, Yokoo H et al (2010) Perioperative management of hepatic resection toward zero mortality and morbidity: analysis of 793 consecutive cases in a single institution. J Am Coll Surg 211:443–449 44. Fan ST, Mau Lo C, Poon RT (2011) Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: a 20-year experience. Ann Surg 253:745–758 45. Lundy J, Ford CM (1983) Surgery, trauma and immune suppression. Evolving the mechanism. Ann Surg 197:434–438
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46. Morise Z, Sugioka A, Fujita J et al (2006) Does repeated surgery improve the prognosis of colorectal liver metastases? J Gastrointest Surg 10:6–11 47. Mynster T, Christensen IJ, Moesgaard F et al (2000) Effects of the combination of blood transfusion and postoperative infectious complications on prognosis after surgery for colorectal cancer. Danish RANXOS Colorectal Cancer Study Group. Br J Surg 87:1553–1562 48. Wong VK, Malik HZ, Hamady ZZ et al (2007) C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases. Br J Cancer 96:222–225 49. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
ORIGINAL SCIENTIFIC REPORT
Postoperative Complications Affect Long-Term Survival Outcomes Following Hepatic Resection for Colorectal Liver Metastasis Zi Yin • Xiande Huang • Tingting Ma • Haosheng Jin • Ye Lin • Min Yu • Zhixiang Jian
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background The impact of postoperative complications (POCs) on long-term survival outcomes following hepatic resection for colorectal liver metastasis (CRLM) is in controversy. The aim of the present meta-analysis was to systematically evaluate the POC effect on overall survival (OS) and disease-free survival (DFS) in patients undergoing hepatic resection for CRLM. Methods We conducted a systematic review and meta-analysis of all observational studies to evaluate the POC effect on OS and DFS in patients undergoing hepatic resection for CRLM. A search for all major databases and relevant journals from inception to January 2014 without restriction on languages or regions was performed. POCs were extracted and graded according to a validated system of classification. Outcome measures were postoperative 1-, 2-, 3-, and 10-year OSs and DFSs. Both random-effects and fixed-effect models were used to pool the hazard ratios (HRs) of the survival outcomes. Test of heterogeneity was performed with the Q statistic. Results A total of 2370 patients were included in the meta-analysis. Both 5- and 10-year postoperative OSs showed significant decreases in patients with POCs (HR = 1.52; 95 % CI 1.27–1.83; P \ 0.001 and HR = 1.36; 95 % CI 1.18–1.58; P \ 0.001, respectively). Similar outcomes were also observed in terms of DFSs, with the 5- and 10-year HRs found to be 1.37 (95 % CI 1.23–1.53; P \ 0.001) and 1.34 (95 % CI 1.17–1.53; P \ 0.001), respectively, compared to no POC group. Conclusions POCs are strongly related to long-term oncologic outcomes following hepatic resection for CRLM. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients.
Introduction Zi Yin, Xiande Huang and Tingting Ma contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s00268-015-3019-3) contains supplementary material, which is available to authorized users. Z. Yin (&) H. Jin Y. Lin M. Yu Z. Jian (&) General Surgery Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd., Guangzhou 510080, China e-mail: [email protected] Z. Jian e-mail: [email protected]
Hepatic resection is the most effective treatment in patients with colorectal liver metastases (CRLM). However, postoperative morbidity is common and its impact on long-term X. Huang Department of Urology, Gansu Provincial Hospital, Lanzhou, China T. Ma Gynaecology and Obstetrics Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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survival outcome is still in controversy. Although there have been improvements in the 5-year overall survival (OS) for this disease over the past several decades due to advances in surgical techniques, staging, and perioperative care, the disease-free survival (DFS) has not significantly improved [1–4]. Neoadjuvant chemotherapy prior to hepatectomy may facilitate the resectability of the liver lesions and treat occult metastasis, but may also lead to hepatic parenchyma damage in patients with resectable CRLM [5]. It is noted that significantly improved mortality rate for liver surgery in many high-volume centers has been reported, yet the morbidity remains high [6–10]. As we know that identifying determinants of therapeutic response is a major focus of research in oncology, especially the recognition of modifiable factors that affect oncologic outcomes is of great importance [4, 11]. Prognostic factors predicting the postoperative survival outcome include the characteristics of primary tumor (stage, carcinoembryonic antigen) and liver metastases (number, size, and lymph node metastases), the presence of extrahepatic disease, the type of operation (curative/palliative), and also perioperative chemotherapy in CRLM resection [1, 4, 10, 12–18]. Currently, negative impact of postoperative complications (POCs) on long-term survival outcomes in various cancers has been indicated [19–22]. Khuri et al. analyzed the National Surgical Quality Improvement Program data with the conclusion that POC was associated with a poor long-term survival after selected major operations [23]. CRLM is a common malignancy in 20–25 % of colorectal carcinoma individuals at initial presentation, with a further metachronous incidence of 20–30 % following colorectal surgery [11, 24–26]. Following hepatic resection for CRLM, the influences of POC on hospital stay and resource usage have been identified; however, its effectiveness on long-term oncological outcome is eagerly awaited to clarify. The aim of the present meta-analysis was to systematically evaluate the POC effect on OS and DFS in CRLM patients.
SpringerLink. We combined the database-specific search terms of CRLM, hepatic resection, complication, and survival as well as truncated search terms utilizing the wildcard (‘‘*’’) character for CRLM patients. Additionally, the ‘‘related articles’’ function was also used to broaden the search, and computer search was supplemented with manual searches for reference lists of all retrieved review articles, primary studies, and abstracts from meetings to identify other studies not found in the computer search. When the results of a single study were reported in more than one publication, only the most recent and complete data were included. Study selection All clinical studies reporting on the influence of POCs on long-term survival following hepatic resection for CRLM were selected (in addition, the comparisons in postoperative long-term oncological outcomes between postoperative CRLM patients with POCs and without POCs were performed). All of the studies included in the meta-analysis met the following criteria: (1)
(2)
(3)
(4) (5)
Liver metastasis as the first manifestation of M1 disease accompanied by no documented non-hepatic disseminated disease in preoperative imaging; intraoperative histologically proven colorectal carcinoma. No prior history of liver-directed treatment such as hepatectomy, radiofrequency ablation, or other local modalities; no extrahepatic disease. Perioperative results and long-term results of survival were assessed as outcome measures of the treatment effects. They had been published or accepted for publication as full-length articles. The study included at least 30 patients. Smaller studies were excluded because of poor reliability.
The exclusion criteria were non-human studies, experimental trials, review articles, editorials, letters/case reports, and articles not reporting outcomes of interest.
Methods Outcome measures The methods of literature search, inclusion and exclusion criteria, outcome measures, and methods of statistical analysis were defined in a protocol according to the metaanalysis of observational studies in epidemiology recommendations for study reporting [27]. Data sources and searches The primary sources of the reviewed studies through January 2014, without restriction on the languages or regions, were Pubmed, Embase, Science Citation Index, and
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Outcomes assessed were primary parameters of 1-, 3-, 5-, and 10-year OS and DFS, POCs [those directly related to primary colorectal cancer resection (ileus, anastomotic leak, pelvic abscess, and rectovaginal fistula), to hepatectomy (hepatic insufficiency/failure, subphrenic/ perihepatic abscess, bile leakage, bleeding, etc.), to laparotomy (wound infection, intra-abdominal collection, and pulmonary and cardiac diseases), and others], and postoperative mortality within 60 days. Accessorial outcomes reported in some of the articles were also reviewed.
World J Surg Table 1 The Clavien–Dindo complication classification [28] Grades
Definitions
I
Any deviation from normal postoperative course without pharmacological, surgical, endoscopic, and radiological interventions. Antiemetics, antipyretics, analgesics, diuretics, electrolytes, physiotherapy, and wound infections opened at bedside were allowed
II
Drug treatment other than in grade I. Blood transfusions and total parenteral nutrition included
III
Requiring surgical, endoscopic, or radiological interventions
IIIa
Intervention not under general anesthesia
IIIb
Intervention under general anesthesia
IV
Life threatening complications (inc CNS complicationsa) requiring HDU/ICU care
IVa
Single organ dysfunction (including dialysis)
IVb
Multi-organ dysfunction
V
Death of patient
a
Brain hemorrhage, ischemic stroke, subarachnoid bleed, but excluding transient ischemic attacks
Data extraction and quality assessment Two reviewers (YZ and JZ) independently considered the eligibility of potential titles and abstracts. When there was a disagreement about a study or a lack of information for an accurate assessment of eligibility, the study was carried to the full-text stage for evaluation. Data were extracted independently and in duplicate by two reviewers (HXD and JHS); discrepancies were resolved by mutual discussion. We extracted the inclusion and exclusion criteria and the characteristics for each included study. POCs were further graded using a validated system of classification (Table 1) [28]. The quality of observational studies was assessed by modified criteria suggested by the Newcastle–Ottawa quality assessment tool [29]. We also assessed the loss to follow up and the ways in which missing data were handled for all studies. Data synthesis and analysis The hazard ratio (HR) was used as a summary statistic for long-term outcomes (survival analysis) as described by Parmar et al. [30]. An HR of less than 1 represented a survival benefit favoring the simultaneous group. Medians were converted to means using the technique described by Hozo et al. [31]. The fixed-effect model was first used to pool the results, which assumes that all the studies share the same common (fixed or non-random) effect. Variance was used to calculate the weight of each study. Heterogeneity was considered not statistically significant when the Cochrane Q test P value was [0.1. A transformation of Q test, the I2 statistic (I2 = 100 % 9 (Q - df)/Q), was
used to assess the consistency of the effect sizes. In case of heterogeneity, meta-analysis was performed applying the random-effects model. In addition, an I2 value of less than 25 % was defined to represent low heterogeneity, a value between 25 and 50 % was defined as moderate heterogeneity, and a value [50 % was defined as high heterogeneity [32]. The studies were weighted in the metaanalysis by the inverse variances of their effect estimates, that is, the validities of the included studies. Subgroup analyses, which considered more homogeneous studies, were performed to identify subsets of patients more likely to benefit from the treatment and to assess the efficacy of different studies. To determine the extent to which the combined risk estimate might be affected by individual studies, sensitivity analysis was performed by consecutively omitting every study from the meta-analysis (leave-one-out procedure). Funnel plots were not used to screen for publication bias due to the limited study numbers. Meta-analysis was conducted by Review Manager (RevMan) Meta-analysis software, version 5.3.5. [33]. The 95 % CIs were calculated as estimates of precision for HR. The statistical tests were two-sided, and P values of \0.05 were considered statistically significant.
Results Literature search Database searches and other resources (mainly conference proceedings) yielded 1717 entries (see Fig. 1), of which 666 were excluded as duplicates. Of the 1051 publications that qualified for abstract review, 907 were excluded primarily because they were not controlled trials, other comparisons, open choledochotomy, or with no comparison group. The remaining 94 publications underwent full article review, and further 89 publications were excluded mainly because they were other comparisons, not controlled trials, or duplicate studies. Finally, a total of 5 studies qualified for inclusion in this review with a total of 2370 patients [34–38]. Characteristics of the included studies Table 2 listed the characteristics of the included studies and details of the enrolled participants. Of 2370 patients included in the meta-analysis, 829 (35 %) suffered from POCs and 1541 (65 %) did not. Of the five studies included in the meta-analysis, four were prospective [34–36, 38] and one retrospective [37]. Four were carried out in a single center with no randomized control trials [35–38], one was multicenter [34], three studies originated from Europe [34, 36, 37], and two from the US [35, 38]. POCs were graded
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Pubmed, Embase and other secondary sources
Overall number of search result n = 1717 Search Overlap n = 666 Abstract Review n = 1051 Excluded: n = 907 Not A Controlled trial: n = 489 Other Comparison: n = 307 No Comparison Group: n = 111 Full Paper Review n = 94 Excluded: n = 89 Other Comparison: n = 49 Not A Controlled Trials: n = 33 No Comparison Group: n = 5 Duplicate Study: n = 2 Included Trials n=5
Fig. 1 Flow chart of publication search and selection
using a validated system of classification in the included trials except one [37]. Two studies [34, 35] provided data on the impact of POCs on 10-year survival after hepatic resection for CRLM. All studies conducted multivariate analyses to extract the independent prognostic factors on 5-year DFS and OS. Variables were collected from patient medical records, operative reports, anesthesia reports, and pathology reports. Preoperative tumor staging was performed using contrastenhanced computer tomography or magnetic resonance imaging. Positron emission tomography was used selectively, in the latter part of the series, to rule out extra hepatic disease. Major hepatectomy was defined as resection of C3 segments. Disease extent was quantified using a previously validated five-point clinical-risk score (CRS), which includes carcinoembryonic antigen level, diseasefree interval, nodal status (primary tumor), number of liver lesions, and size of greatest lesion. Resection was considered in selected patients with limited extrahepatic disease
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and typically in those with proven chemotherapy-sensitive tumors. OS was measured from the time of liver resection to death and DFS from the time of liver resection to the period when the first recurrence was detected. Quality assessments for the included studies The agreement between two reviewers for study selection was 0.96 and for quality assessment of trials was 0.94. We evaluated the risk of bias in the five observational studies by modification of the Newcastle–Ottawa scale (Supplementary Table 1) [32]. Detailed descriptions of follow-up were available in most studies. The outcomes may have been influenced by various selection biases in these trials for patient allocation, including age, major hepatectomy, sex ratio, colorectal primary location, the distribution, total number, and the largest size of liver metastases, and preoperative chemotherapy. More colorectal surgery combined with hepatectomy was performed in metachronous
World J Surg Table 2 Characteristics of the included studies Authors
Enrolled participants and study design
Tumor characteristics and hepatic resection
Complication gradea
UV/MV analysis of complications presentb
Schiesser et al. [34]
No. patients 197
Synchronous CRLM (%) 35 (18)
I/II: 32 (16)
Overall survival:
Australia (multicenter)
No. tumor (range) NA
III/IV: 22 (11)
UV: P \ 0.01
(Australia)
PCS: (1992–2005)
Size (cm) (range/SD) NA
V: 5 (3)
MV: P = 0.003, HR (95 % CI) 2.2 (1.3–3.7)
Patient age (range) 64 (22–92)
Major liver resection (%) NA R0 (%): NAPBT (%) 82 (42)
UV: P = 0.041
M (%) 124 (63)
Preop. chemotherapy (%) 67(34)
MV: P = 0.006, HR (95 % CI) 1.8 (1.2–2.8)
Disease free survival:
Follow-up period (month) 54
Postop. chemotherapy (%) NA
Ito et al. [35]
No. patients 1067
Synchronous CRLM (%) 380 (36)
I/II: 258 (24)
Overall survival:
(USA)
USA (single centre)
No. tumor (range) 3.4 (NA)
PCS (1991–2002)
Size (cm) (range/SD) 5 ± 3.7
III/IV: 192 (18)
MV: P = 0.10, HR (95 % CI) 1.2 (0.96–1.5)
Patient age (range) 61 (20–89)
Major liver resection (%) 620 (58)
M (%) 596 (56)
R0 (%) 921 (86), PBT (%) 476 (45)
Follow-up period (month) 41
Preop. chemotherapy (%) 319 (30)
UV: P = 0.0059 Disease free survival: UV: P = 0.0042 MV: P = 0.083, HR (95 % CI) 1.2 (0.98–1.5)
Postop. chemotherapy (%) 909 (85) Farid et al. [36]
No. patients 705
Synchronous CRLM (%) 290 (41)
I/II: 74 (37)
Overall survival:
(UK)
UK (single centre)
No. tumor (range) 3 (1–21)
III/IV: 98 (49)
PCS (1993–2007)
Size (cm) (range/SD) 4 (0.1–23)
V: 25 (13)
UV: P \ 0.001, HR (95 % CI) 1.6 (1.46–1.72)
Patient age (range) 46 (23–91)
Major liver resection (%) 443 (63)
M (%) 442 (63)
R0 (%) 447 (63), PBT (%) 149 (21)
Follow-up period (month) 38
Preop. chemotherapy (%) 88 (13)
MV: P = 0.026, HR (95 % CI) 1.4 (1.04–1.86) Disease free survival: UV: P = 0.004, HR (95 % CI) 1.4 (1.10–1.67)
Postop. chemotherapy (%) 705 (100) NA
Overall survival:
Laurent et al. [37]
No. patients 311
Synchronous CRLM (%) NA
(France)
France (single centre)
No. tumor (range) 2 (1–8)
UV: P \ 0.001
RCS (1985–2000)
Size (cm) (range/SD) 5 (0.4–28)
Patient age (range) 63 (31–86)
Major liver resection (%) 194 (62)
MV: P = 0.001, HR (95 % CI) 1.79 (1.28–2.52)
R0 (%) 305 (98), PBT (%) 49 (16)
Disease free survival:
M (%) 209 (67)
Preop. chemotherapy (%) none
UV: NA
Follow-up period (month) 29
Postop. chemotherapy (%) 138 (44)
MV: P = 0.006, HR (95 % CI) 1.52 (1.13–2.06)
Correa-Gallego et al. [38]
No. patients 90
Synchronous CRLM (%) 14 (16)
I/II: 9
USA (single centre)
No. tumor (range) NA
III/IV: 21
(USA)
PCS (2004–2007)
Size (cm) (range/SD) NA
MV: P = 0.007, HR (95 % CI) 3.0 (1.3–6.5)
Patient age (range) 53 (49–63)
Major liver resection (%) 90 (100)
Disease free survival:
R0 (%) 69 (77), PBT (%) NA
UV: P \ 0.003, HR (95 % CI) 2.4 (1.4–4.2)
M (%) 50 (56)
Preop. chemotherapy (%) 75 (83)
MV: P = 0.004, HR (95 % CI) 2.7 (1.4–5.4)
Follow-up period (month) 71
Postop. chemotherapy (%) 78 (87)
Overall survival: UV: P \ 0.01, HR (95 % CI) 2.7 (1.5–4.8)
UV univariate, MV multivariate, RCS retrospective cohort study, PCS prospective cohort study, M male, CRLM colorectal liver metastases, NA not available, No. number of, R0 margin zero, preop. preoperative, postop. postoperative, SD standard deviation, PBT perioperative blood transfusion, HR hazard ratio, CI confidence interval a
Incidence and severity of complications according to a standardized complication classification. Grade I minor deviation from the normal postoperative course without the need for any specific treatment, grade II complications that can be treated solely by drugs, blood transfusion, physiotherapy, or nutritional support, grade III complications that require interventional or surgical treatment, grade IV complications that are life-threatening and require ICU management, grade V death of the patient
b
The hazard ratios are specifically referring to the group of patients with complications
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World J Surg Fig. 2 Forest plots depicting the meta-analysis of postoperative complication (POC) versus no postoperative complication (NPOC) following hepatic resection for CRLM in long-term 1-, 3-, 5-, and 10-year overall survivals (OSs)
resection. In addition, no study described adequately the patient flow. Methods for handling missing data were not adequately described in most studies. Meta-analysis including subgroup and sensitivity analyses To evaluate the long-term oncological outcomes for CRLM resection, HRs of OS and DFS were calculated and combined in the present study using the data extracted from Kaplan–Meier curves (Fig. 2). Five studies with a total of 2370 patients were included, and the postoperative duration for survival analysis ranged from 6 to 120 months. Analysis for the 1264 patients from two studies with 10-year postoperative OS showed a significantly decreased outcome in POC group (HR: 1.36; 95 % CI 1.18–1.58; P \ 0.001; I2 = 7 %). Similarly, final pooled estimates of 1-, 3-, and 5-year OSs were found to be 2.14 (95 % CI 1.57–2.92; P \ 0.001; I2 = 13 %), 1.49 (95 % CI 1.23–1.80; P \ 0.001; I2 = 39 %), and 1.52 (95 % CI 1.27–1.83; P \ 0.001; I2 = 55 %), respectively. Likely,
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the 1-, 3-, 5-, and 10-year pooled HRs of DFSs for POC were found to be 1.52 (95 % CI 1.32–1.75; I2 = 0 %), 1.33 (95 % CI 1.20–1.48; I2 = 19 %), 1.37 (95 % CI 1.23–1.53; I2 = 50 %), and 1.34 (95 % CI 1.17–1.53; I2 = 0 %), respectively, compared to no POC group with all the P values less than 0.001 (Fig. 3). Sensitivity analysis did not significantly alter the ultimate results by the leave-one-out procedures, which indicated the stability and reliability of the meta-analysis.
Discussion Hepatic resection as the standard treatment for patients with CRLM was associated with a relatively high postoperative morbidity rate of 26–56 %, although the mortality rate has been dramatically reduced over the recent decade to less than 5 % in large-volume centers with experienced hepatic surgeons [5, 6, 8]. One of the major concerns is whether, from medical or surgical point of view, POC itself is associated with longer hospital stay, increased
World J Surg Fig. 3 Forest plots depicting the meta-analysis of postoperative complication (POC) versus no postoperative complication (NPOC) following hepatic resection for CRLM in long-term 1-, 3-, 5-, and 10-year disease-free survivals (DFSs)
reoperative rate, and subsequent higher inpatient stay costs. Further, POCs are associated with the more extent of resection and more complexity of surgery, which could result in more frequent use of blood product transfusion. It has been reported that long-term outcomes were affected by POC following curative resection, which was a well-recognized concept for patients with esophageal, colorectal, oral, and lung tumors [19–22]. POCs such as infections, anastomotic leakage, and multiorgan failure have been shown to be associated with decreased survival after tumor resection in previous studies [39–42]. Improved surgical and anesthetic techniques, as well as better measures that might minimize complications (accurate mobilization of the liver, limited vascular clamping, extrahepatic control of hepatic vessels, and meticulous parenchymal transection), have been responsible for a decline in perioperative mortality from as high as 35–0.1–3 %. Nevertheless, overall postoperative morbidity reaches 45 % currently, and grade III/IV morbidity ranges from 28 to 30 % based on the present experiences of several high-volume medical centers [8, 43, 44]. The major finding of this meta-analysis was that patients suffering from POCs after liver resection for CRLM had reduced long-term survival rates. Negative impacts of POCs on postoperative 5- and 10-year OS and DFS were
observed. The present study found that patients experiencing POCs had higher HRs with 1-, 3-, 5-, and 10-year OS of 2.14, 1.49, 1.52, and 1.36 compared with patients without POCs (all P values \0.001), respectively, and 1-, 3-, 5-, and 10-year DFS of 1.52, 1.33, 1.37, and 1.34 (all P values \0.001). Burdened by various operation extent, blood loss and transfusion rates, as well as comorbid conditions between patients who developed POCs and those who did not, the analysis of perioperative morbidity as an oncologic variable particularly in retrospective studies was difficult. Several preoperative variables including patient age, body mass index, platelet count, and albumin level were found to be associated with POCs, and some of these factors have been shown to be associated with postoperative mortality as well [6]. Also, mortality is an objective parameter; whereas inconsistency exists in defining POCs, accurately comparing morbidity rates across institutions is difficult. This shortcoming has severely hampered conclusive analysis of its impact on survival outcome. Therefore, an objective surgical complication classification was applied [28], which graded the complications according to their therapeutic relevance in four of these included studies [34–36, 38]. Potential benefits in performing the surgery with meticulous technique to minimize complications were
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indicated. Schiesser et al. firstly correlated the findings of this classification to the outcome in patients undergoing liver resection for SCRM, and showed a statistically significant difference in outcome of patients with grade I and II versus III and IV [34]. Thus, instinctively, the association between perioperative morbidity and oncologic outcomes in patients with CRLM may suggest that severe POCs may have a higher negative impact on postoperative long-term oncological results than mild POCs. In contrary to Schiesser et al.’s research, Farid et al. demonstrated similar survival outcomes of patients with grade I/II versus III/IV [36]. The same observation was also noted in Correa-Gallego et al.’s study, although given the small size of the groups in this analysis, it was possible that failure to identify a difference represented a type-II error rather than an equivalent impact of morbidity on survival. This may represent the heterogeneity in the types of complications implicated in these grades. Furthermore, a system classification based on the therapy required to correct complications has the benefit of eliminating inconsistency in definitions not by focusing on etiopathology would be unable to provide a meaningful differentiation, at least in disease- or cancer-specific survival. Regardless of the type or severity, in Ito’s study, the overall POC was 42 %, and complications requiring moderate (grade II) or invasive interventions (grade III) represented 80 % of the total, which was at the higher end of the range reported in the literature [35]. Further work is needed to resolve the relationship of severity of the POCs and survival outcomes. Furthermore, the observation that patients who developed POCs after liver resection had shorter long-term survival which was independent of other variables including CRS, which was itself an independent predictor of outcome. Ito et al. demonstrated a negative impact of POC on OS and DFS in an analysis only seen in 1067 patients with low CRS. Correa-Gallego et al. showed a stronger and much clearer association by differing from Ito et al.’s which included only patients submitted to major hepatic resections and retrospectively analyzes an independent, contemporary cohort of prospectively evaluated patients [35, 38]. The question that why POCs within 30 days following surgery endowed with a negative impact on patient’s longterm survival outcomes is interesting and deserving deep investigation. To date, the precise mechanism remains to be elucidated. Inflammatory response has been highlighted and may play a central role in potentially exacerbating this problem. In a more detailed analysis aimed at evaluating the impact of the specific type of sepsis, Farid et al. have shown that although wound infection was a common complication after hepatic resection, it did not have exhibited a negative impact on either DFS or OS when compared with the other patients without POCs. However,
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in the presence of more systemic inflammatory insult (either respiratory or intra-abdominal infection), the negative effect becomes significant [36]. Major surgery could cause a certain degree of systemic inflammatory response and even immunosuppression in patients and thus creates a favorable environment for faster progression of microscopic cancer, or that POCs are the consequence of poor functional status, which independently predicts shorter survival in patients with various malignancies. Particularly, severe POCs like septicemia lead to an extended period of immunosuppression, which allows residual tumor cells to further proliferate and survive in the host [45–47]. It has been reported that patients with elevated C-reactive protein (CRP) had a poorer prognosis after liver resection for CRLM compared with those with normal CRP. Other researches on positive effect of various cytokines, such as interleukin-1 and -8 (IL-1 and IL-8) on cancer cell proliferation in vitro, also supported the speculation that prolonged systemic inflammation and attenuated immune defense by POCs may be a factor promoting survival and subsequent growth of the micrometastatic cells [48, 49]. In summary, this systematic review and meta-analysis was conducted at appropriate time because enough data have accumulated for inspection by meta-analytical methods when hepatic resection strategy for CRLM patients is used more commonly. The postoperative course represents a vulnerable period in which infective complications and secondary immunosuppression negatively influence cancer-related prognosis. POCs are strongly related to the long-term oncologic outcomes. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients. Acknowledgments The authors thank Prof. Yuan-Tao Hao, Department of Medical Statistics, Sun Yat-sen University, Guangdong, China, for statistical advice; Yu Bai, Department of Gastroenterology of Affiliated Changhai Hospital, Second Military Medical University, Shanghai, China, for research comments; and Yan Jia, Medical Library of North Campus, Sun Yat-sen University, Guangdong, China, for literature search. None of these persons received compensation for the work performed. This study was not supported by any pharmaceutical company or Grants; the cost was borne by the authors’ institutions. Conflicts of interest Consents to publication were all available for all authors. The authors declare no conflicts of interest.
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