Abstract
Background
This study examined the relationship between the magnitude of the postoperative systemic inflammatory response (SIR), the severity of complications, and long-term outcomes following surgery for colorectal cancer.
Methods
Data were recorded prospectively for patients undergoing potentially curative surgery for colorectal cancer in a single centre between 2008 and 2013. The magnitude of the SIR was measured using C-reactive protein (CRP). Complications were classified by Clavien-Dindo grade. The impact on disease specific and overall survival was assessed using univariate and multivariate Cox regression.
Results
Of 377 patients included, the majority were male (55 %), older than age 65 years (68 %), with colonic (63 %) and node-negative disease (66 %). A total of 138 patients (37 %) had a complication, of which 26 (6 %) were Clavien-Dindo grade 3 or 4 severity. Complication severity was significantly associated with the established CRP thresholds of 150 mg/L on postoperative day (POD) 3 (p < 0.001) and POD 4 (p < 0.001). Median follow-up was 42 months with disease-specific survival 86 % and overall survival 78 %. On univariate analysis, complication severity [hazard ratio (HR) 1.66, 95 % confidence interval (CI) 1.13–2.43, p = 0.009], and POD 4 CRP > 150 mg/L (HR 2.53, 95 % CI 1.43–4.48, p = 0.001) were associated with disease-specific survival. On multivariate survival analysis, POD 4 CRP > 150 mg/L (HR 2.00, 95 % CI 1.12–3.59, p = 0.020), but not complication severity, was significantly associated with disease-specific survival independent of TNM stage (HR 2.46, 95 % CI 1.52–4.12, p < 0.001).
Conclusions
The magnitude of the postoperative SIR, evidenced by CRP, was significantly associated with long-term outcomes following surgery for colorectal cancer, independent of complications and stage.
Colorectal cancer is a significant burden of disease in the developed world.1 Surgical resection continues to form the cornerstone of management of this disease. However, surgery is not without problems in terms of postoperative morbidity and mortality.2 Furthermore, it has become clear that postoperative complications following surgery for colorectal cancer are not only associated with poor short-term outcomes but also with poorer long-term outcomes.3–6
Postoperative complications have previously been defined as “deviation from the normal postoperative course.”7 They have been classified by type, primarily as infective or noninfective, or by severity using the Clavien-Dindo scale.3,7–10 There is good evidence that the type of complication, in particular infective complications, has a significant negative impact on cancer-specific and overall survival following surgery for colorectal cancer.11,12 Fewer studies have examined the impact of complication severity on long-term outcomes, although those that have reported poorer disease-free and overall survival.13,14 Indeed, a recent meta-analysis reported that severe complications had a greater impact on long-term outcomes following surgery for colorectal cancer.15
The magnitude of the systemic inflammatory response, as evidenced by postoperative CRP thresholds of 190 mg/L on postoperative day (POD) 2, 170 mg/L on POD 3, and 145 mg/L on POD 4, have been reported to be associated with the development of infective complications.16–18 More recently, a comprehensive review suggested that CRP concentrations above a threshold of 150 mg/L on POD 3–5 should prompt investigation and or treatment of potential postoperative complications in colorectal surgery.19 Two recent studies have examined the relationship between the magnitude of the postoperative systemic inflammatory response, as measured by CRP, and the severity of complications following surgery for colorectal cancer.20,21 Moreover, two recent studies in oesophagogastric cancer have suggested that CRP concentrations in the postoperative period are significantly associated with survival independent of postoperative complications.22,23 To the authors knowledge, no study investigating the interaction between the magnitude of the postoperative systemic inflammatory response and complication severity, and their impact on long-term outcomes has been performed in colorectal cancer surgery.
Therefore, the purpose of the present study was to examine the relationship between the magnitude of the postoperative systemic inflammatory response and complication severity and to determine which, if any, had the greatest impact on long-term outcomes following surgery for colorectal cancer.
Patients and Methods
Patients
This observational study included patients who underwent elective, potentially curative surgery for histologically confirmed colorectal cancer in a single centre between March 2008 and May 2013. Patients with metastatic disease who underwent palliative procedures or had existing inflammatory conditions were excluded.
All patients received prophylactic antibiotics and venous thromboprophylaxis prior to the induction of anaesthesia as per hospital policy. All patients were cared for in line with a unit standardised enhanced recovery after surgery (ERAS) protocol, which included preoperative carbohydrate drinks, early mobilisation, and early enteral nutrition, with the avoidance of routine peritoneal and/or nasogastric drainage. On each POD, patients were clinically assessed and had blood samples, including serum CRP, obtained as standard until discharged. Further postoperative investigation and intervention was at the discretion of the patient’s surgical team who were not blind to postoperative blood results.
Methods
All data were collected prospectively in a database, anonymised, and subsequently analysed. Recorded information included patient demographics, tumour site, TNM stage (TNM, AJCC), surgical approach, whether adjuvant or neoadjuvant treatment was given, whether the presentation was elective or emergency, the presence of complications, preoperative serum CRP, and albumin measurements. Data regarding the nature, severity, and management of complications was retrospectively categorised using the Clavien-Dindo scale.7 Any uncertainties were addressed by review of electronic and/or physical case notes. Date and cause of death were crosschecked with the Registrar General (Scotland). Death records were complete until June 30, 2015, which served as the censor date. The study was approved by the West of Scotland Research Ethics Committee, Glasgow.
Serum concentrations of CRP (mg/L) were measured using an autoanalyzer (Architect; Abbot Diagnostics, Maidenhead, UK) with a lower detectable limit of 0.2 mg/L as was serum albumin (normal range 35–50 g/L). The preoperative modified Glasgow Prognostic Score (mGPS) was calculated from preoperative serum CRP and albumin.24
Statistical Analysis
Categorical data regarding patient characteristics were compared using the Chi square test and Chi square test for linear association where appropriate. Patients who underwent colonic resection were analysed as a subgroup due to significant differences in postoperative complication rates between those with colonic and rectal cancers. Those patients who died within 30 days of surgery or during the same admission (Clavien-Dindo grade 5 complications) were excluded from survival analysis. Univariate and multivariate survival data were analysed using Cox’s proportional hazards model. Variables associated with disease-specific or overall survival at a significance level of p < 0.1 on univariate analysis were included in multivariate modelling using backward conditional regression where a two-sided p value <0.05 was considered statistically significant. Disease-specific survival was defined as time from date of surgery to date of cancer-specific death. Overall survival was defined as time from date of surgery to date of death from any cause. Statistical analyses were performed using IBM SPSS version 22 for Windows (Chicago, IL).
Results
Patients
A total of 377 patients were included having undergone potentially curative surgery for colorectal cancer in the absence of metastatic disease. The majority were male (55 %), older than age 65 years (68 %), with colonic (63 %) and node-negative disease (66 %). In total, 110 patients (29 %) had a laparoscopic resection, and the remainder had open surgery. Amongst the 138 patients with rectal cancer, 65 (47 %) with locally advanced or margin-threatening disease had neoadjuvant treatment, of which 10 (15 %) were subsequently found to have had a pathological complete response. Of all included patients, 29 % had adjuvant treatment following surgery.
Complications
Of 377 patients, 138 (37 %) experienced complications (Table 1). Four patients (1 %) died within 30 days of surgery or during the same admission. When classified using the Clavien-Dindo scale, 108 (30 % of all patients) were grade 1–2 (i.e., required minor intervention) and 26 (6 %) were grade 3–4 (i.e., necessitated major intervention). When patient’s demographic, pathological, and clinical characteristics were compared across complication severity (Table 2), male gender (p < 0.01), ASA grade (p < 0.05), smoking status (p < 0.05), and rectal cancer (p < 0.05) were significantly associated with Clavien-Dindo grade. There was a significant association between complication severity and the proportion of patients breaching the established CRP threshold of 150 mg/L on POD 2 (p = 0.004), POD 3, and POD 4 (both p < 0.001).
Table 1.
Postoperative complications by severity
| Complication | n | % |
|---|---|---|
| No complication | 239 | 63 |
| Any complication | 138 | 37 |
| Complication type | ||
| Infective | ||
| All infective complications | 94 | 25 |
| SSI | ||
| Wound infection | 43 | 11.5 |
| Anastomotic leak | 16 | 4 |
| Intra-abdominal abscess | 6 | 2 |
| RSI | ||
| Pneumonia | 23 | 6 |
| Septicaemia | 2 | 0.5 |
| UTI | 4 | 1 |
| Noninfective | ||
| All noninfective complications | 44 | 12 |
| Wound | ||
| Seroma | 2 | 0.5 |
| Dehiscence | 4 | 1 |
| Surgical site | ||
| Haemorrhage | 1 | 0.25 |
| Cardiac | ||
| MI | 4 | 1 |
| Arrhythmia | 9 | 2.5 |
| Vascular | ||
| VTE | 3 | 0.75 |
| CVA | 2 | 0.5 |
| Urinary | ||
| Renal failure | 4 | 1 |
| Acute urinary retention | 3 | 0.75 |
| Gastrointestinal | ||
| Diarrhoea (noninfective) | 4 | 1 |
| Ileus | 8 | 2.25 |
| Complication severity | ||
| Clavien-Dindo Grade | ||
| 0 | 239 | 63 |
| 1 | 36 | 10 |
| 2 | 72 | 20 |
| 3 | 18 | 4 |
| 4 | 8 | 2 |
| 5 | 4 | 1 |
SSI surgical site infection, RSI remote site infection, UTI urinary tract infection, MI myocardial infarction, VTE venous thromboembolism, CVA cerebrovascular accident
Table 2.
Patient characteristics by severity of complication following surgery for colorectal cancer
| Characteristic | All | Clavien-Dindo complication grade | ||||
|---|---|---|---|---|---|---|
| 0a | 1–2b | 3–4c | 5d | p | ||
| N (%) | 377 (100) | 239 (63) | 108 (30) | 26 (7) | 4 (1) | – |
| Age (<65/65–74/>74) | 122/149/106 | 82/96/61 | 31/44/33 | 9/7/10 | 0/2/2 | 0.451 |
| Sex (male/female) | 208/169 | 116/123 | 74/34 | 15/11 | 3/1 | 0.005 |
| BMI (<20/20–25/36–30/>30) | 16/112/114/90 | 12/69/75/55 | 3/32/31/28/94 | 1/8/8/6 | 0/3/0/1 | 0.833 |
| ASA (1/2/3/4) | 48/169/145/14 | 36/112/83/7 | 9/45/48/6 | 3/11/12/0 | 0/1/2/1 | 0.014 |
| Smoking (never/ex/current) | 159/150/61 | 114/89/31 | 37/46/23 | 8/11/7 | 0/4/0 | 0.015 |
| Preop mGPS (0/1/2) | 284/37/56 | 180/23/36 | 82/9/17 | 18/5/3 | 4/0/0 | 0.636 |
| Site (colon/rectum) | 239/138 | 160/79 | 63/45 | 16/10 | 0/4 | 0.024 |
| TNM stage (0/I/II/III) | 10/80/159/128 | 8/54/101/76 | 1/20/43/44 | 0/5/14/7 | 1/1/1/1 | 0.120 |
| Neoadjuvant treatment (no/yes) | 299/65 | 191/40 | 84/19 | 21/5 | 3/1 | 0.970 |
| Approach (open/laparoscopic) | 266/110 | 162/77 | 83/24 | 18/8 | 3/1 | 0.323 |
| Surgery > 4 h (yes/no) | 83/247 | 51/154 | 22/76 | 9/16 | 1/1 | 0.456 |
| Stoma (yes/no) | 115/262 | 65/174 | 39/69 | 8/18 | 1/1 | 0.087 |
| POD 2 CRP > 150 mg/L (yes/no) | 205/162 | 114/117 | 72/35 | 16/9 | 3/1 | 0.004 |
| POD 3 CRP > 150 mg/L (yes/no) | 187/169 | 100/124 | 67/38 | 19/5 | 1/2 | <0.001 |
| POD 4 CRP > 150 mg/L (yes/no) | 126/200 | 58/137 | 51/51 | 16/10 | 1/2 | <0.001 |
| Adjuvant treatment (no/yes) | 269/108 | 171/68 | 73/35 | 21/5 | 4/0 | 0.323 |
mGPS preoperative modified Glasgow Prognostic score (0 = CRP < 10 mg/L, 1 = CRP ≥ 10 mg/L and albumin ≥ 35 g/L, 2 = CRP ≥ 10 mg/L and albumin < 35 g/L)
POD postoperative day
a0 = no complication
b1–2 = complication requiring minor intervention
c3–4 = complication requiring significant intervention
d5 = death
Follow-Up
After exclusion of postoperative mortality (4, 1 %), death due to any cause occurred in 81 patients (22 %); 53 (14 %) were cancer-specific. The median follow-up for patients alive at the time of their censoring was 46 (range 24–86) months.
Disease-Specific Survival
On univariate analysis (Table 3), age [hazard ratio (HR) 1.54, 95 % confidence interval (CI) 1.08–2.21, p = 0.018], ASA grade (HR 1.69, 95 % CI 1.16–2.46, p = 0.007), TNM stage (HR 2.50, 95 % CI 1.63–3.85, p < 0.001), mGPS (HR 1.67, 95 % CI 1.23–2.26, p = 0.001), breaching the established CRP threshold of 150 mg/L on POD 3 (HR 1.84, 95 % CI 1.01–3.35, p = 0.047) and POD 4 (HR 2.53, 95 % CI 1.43–4.48, p = 0.001) and complication severity (HR 1.66, 95 % CI 1.13–2.43, p = 0.009) were associated with disease-specific survival and included in multivariate analysis. On multivariate analysis (Table 3), ASA grade (HR 1.52, 95 % CI 1.01–2.28, p = 0.044), mGPS (HR 1.49, 95 % CI 1.08–2.07, p = 0.016), TNM stage (HR 2.46, 95 % CI 1.52–3.96, p < 0.001), and breaching the established CRP threshold of 150 mg/L on POD 4 (HR 2.00, 95 % CI 1.12–3.59, p = 0.020) remained independently associated with poorer disease-specific survival. Breaching the established CRP threshold of 150 mg/L on POD 3 was not included in multivariate analysis, because it was directly associated with breaching the established CRP thresholds of 150 mg/L on POD 4, which had a greater statistical significance on univariate analysis.
Table 3.
Impact of the severity of postoperative complications on survival following surgery for colorectal cancer, univariate and multivariate survival analysis
| Survival | Variable | Univariate HR (95 % CI) | p | Multivariate HR (95 % CI) | p |
|---|---|---|---|---|---|
| DSS | Age | 1.54 (1.08–2.21) | 0.018 | – | 0.225 |
| Sex | 0.77 (0.45–1.32) | 0.344 | – | – | |
| BMI | 0.88 (0.62–1.23) | 0.446 | – | – | |
| ASA | 1.69 (1.16–2.46) | 0.007 | 1.52 (1.01–2.28) | 0.044 | |
| Smoking | 1.00 (0.69–1.46) | 0.984 | – | – | |
| mGPS | 1.67 (1.23–2.26) | 0.001 | 1.49 (1.08–2.07) | 0.016 | |
| Rectal | 1.00 (0.57–1.74) | 0.998 | – | – | |
| TNM stage | 2.50 (1.63–3.85) | <0.001 | 2.46 (1.52–3.96) | <0.001 | |
| Neoadjuvant treatment | 1.23 (0.63–2.39) | 0.548 | – | – | |
| POD 2 CRP > 150 mg/L | 1.62 (0.91–2.89) | 0.101 | – | – | |
| POD 3 CRP > 150 mg/L | 1.84 (1.01–3.35) | 0.047 | – | – | |
| POD 4 CRP > 150 mg/L | 2.53 (1.43–4.48) | 0.001 | 2.00 (1.17–3.59) | 0.020 | |
| Clavien-Dindo grade | 1.66 (1.13–2.43) | 0.009 | 1.51 (0.98–2.33) | 0.061 | |
| Adjuvant treatment | 0.78 (0.42–1.46) | 0.432 | – | – | |
| OS | Age | 1.83 (1.36–2.48) | <0.001 | 1.35 (0.97–1.87) | 0.074 |
| Sex | 1.06 (0.68–1.64) | 0.799 | – | – | |
| BMI | 0.85 (0.65–1.12) | 0.242 | – | – | |
| ASA | 1.92 (1.41–2.61) | <0.001 | 1.49 (1.05–2.10) | 0.024 | |
| Smoking | 1.20 (0.89–1.61) | 0.238 | – | – | |
| mGPS | 1.52 (1.18–1.96) | 0.001 | – | 0.170 | |
| Rectal | 0.78 (0.49–1.25) | 0.308 | – | – | |
| TNM stage | 1.70 (1.25–2.31) | 0.001 | 2.12 (1.45–3.41) | <0.001 | |
| Neoadjuvant treatment | 0.97 (0.54–1.73) | 0.914 | – | – | |
| POD 2 CRP > 150 mg/L | 1.99 (1.22–3.26) | 0.006 | – | – | |
| POD 3 CRP > 150 mg/L | 1.76 (1.08–2.85) | 0.022 | – | – | |
| POD 4 CRP > 150 mg/L | 2.02 (1.27–3.20) | 0.003 | 2.14 (1.34–3.41) | 0.001 | |
| Clavien-Dindo grade | 1.30 (0.93–1.81) | 0.127 | – | – | |
| Adjuvant treatment | 0.64 (0.37–1.09) | 0.098 | 0.33 (0.17–0.64) | 0.001 |
HR hazard ratio, CI confidence interval, DSS disease-specific survival, OS overall survival, mGPS modified Glasgow Prognostic score, POD postoperative day
Overall Survival
On univariate analysis (Table 3), age (HR 1.83, 95 % CI 1.36–2.48, p < 0.001), ASA grade (HR 1.92, 95 % CI 1.41–2.61, p < 0.001), mGPS (HR 1.52, 95 % CI 1.18–1.96, p = 0.001), TNM stage (HR 1.70, 95 % CI 1.25–2.31, p = 0.001), breaching the established CRP threshold of 150 mg/L on POD 2 (HR 1.99, 95 % CI 1.22–3.26, p = 0.006, POD 3 (HR 1.76, 95 % CI 1.08–2.85, p = 0.022), and POD 4 (HR 2.02, 95 % CI 1.27–3.20, p = 0.003), and adjuvant treatment (HR 0.64, 95 % CI 0.37–1.09, p = 0.098) were associated with overall survival and included in multivariate analysis. On multivariate analysis (Table 3), ASA grade (HR 1.49, 95 % CI 1.05–2.10, p = 0.024), TNM stage (HR 2.12, 95 % CI 1.45–3.09, p < 0.001), breaching the established CRP threshold of 150 mg/L on POD 4 (HR 2.14, 95 % CI 1.34–3.41, p = 0.001), and adjuvant treatment (HR 0.33, 95 % CI 0.17–0.64, p = 0.001) all remained independently associated with overall survival. Breaching the established CRP threshold of 150 mg/L on POD 2 and 3 were not included in multivariate analysis, because they were directly associated with breaching the established CRP thresholds of 150 mg/L on POD 4, which had a greater statistical significance on univariate analysis.
Colonic Resection
When the subgroup of 239 patients who underwent surgery for colonic cancer were considered, 79 (33 %) experienced complications (Table 4). No patients died within 30 days of surgery or during the same admission. When classified using the Clavien-Dindo scale, 63 were grade 1–2 and 16 were grade 3–4. When patient’s demographic, pathological, and clinical characteristics were compared across complication severity (Table 3), only smoking status (p = 0.047) was significantly associated. There was a significant association between complication severity and the proportion of patients breaching the established CRP threshold of 150 mg/L on POD 2 (p = 0.032), POD 3 (p = 0.002), and POD 4 (p = 0.005).
Table 4.
Patient characteristics by severity of complication following surgery for colonic cancer
| Characteristic | All | Clavien-Dindo complication grade | ||||
|---|---|---|---|---|---|---|
| 0a | 1–2b | 3–4c | 5d | p | ||
| N (%) | 239 | 160 | 63 | 16 | 0 | – |
| Age (<65/65–74/>74) | 66/88/85 | 48/59/53 | 14/24/25 | 4/5/7 | 0/0/0 | 0.724 |
| Sex (male/female) | 127/112 | 77/83 | 42/21 | 8/8 | 0/0/0 | 0.111 |
| BMI (<20/20–25/36–30/>30) | 11/64/68/60 | 9/41/50/38 | 1/19/12/19 | 1/4/6/3 | 0/0/0/0 | 0.430 |
| ASA (1/2/3/4) | 24/99/105/11 | 20/70/63/7 | 2/23/34/4 | 2/6/8/0 | 0/0/0/0 | 0.227 |
| Smoking (never/ex/current) | 103/91/40 | 79/54/23 | 20/30/12 | 4/7/5 | 0/0/0 | 0.047 |
| Preop mGPS (0/1/2) | 170/28/41 | 115/18/27 | 46/6/11 | 9/4/3 | 0/0/0 | 0.513 |
| TNM stage (0/I/II/III) | 0/50/112/77 | 0/33/73/54 | 0/14/29/20 | 0/3/10/3 | 0/0/0/0 | 0.734 |
| Approach (open/laparoscopic) | 83/156 | 57/103 | 20/43 | 6/10 | 0/0 | 0.836 |
| Surgery > 4 h (yes/no) | 28/179 | 17/118 | 7/50 | 4/11 | 0/0 | 0.303 |
| Stoma (yes/no) | 14/158 | 7/113 | 6/37 | 1/8 | 0/0 | 0.277 |
| POD 2 CRP > 150 mg/L (yes/no) | 129/105 | 78/78 | 43/19 | 8/8 | 0/0 | 0.032 |
| POD 3 CRP > 150 mg/L (yes/no) | 121/105 | 69/81 | 41/20 | 11/4 | 0/0 | 0.002 |
| POD 4 CRP > 150 mg/L (yes/no) | 81/117 | 41/84 | 31/26 | 9/7 | 0/0 | 0.005 |
| Adjuvant treatment (no/yes) | 69/170 | 48/112 | 18/45 | 3/13 | 0/0 | 0.638 |
mGPS preoperative modified Glasgow Prognostic score (0 = CRP < 10 mg/L, 1 = CRP ≥ 10 mg/L and albumin ≥ 35 g/L, 2 = CRP ≥ 10 mg/L and albumin < 35 g/L)
POD postoperative day
a0 = no complication
b1–2 = complication requiring minor intervention
c3–4 = complication requiring significant intervention
d5 = death
On multivariate analysis (Table 5) mGPS (HR 1.81, 95 % CI 1.20–2.72, p = 0.005), TNM stage (HR 2.28, 95 % CI 1.23–4.21, p = 0.009), and breaching the established CRP threshold of 150 mg/L on POD 4 (HR 2.42, 95 % CI 1.13–5.18, p = 0.023) were independently associated with disease specific survival after surgery for colonic cancer. ASA grade (HR 1.99, 95 % CI 1.28–3.10, p = 0.002), mGPS (HR 1.53, 95 % CI 1.11–2.10, p = 0.010), and breaching the established CRP threshold of 150 mg/L on POD 4 (HR 2.32, 95 % CI 1.29–4.20, p = 0.005) were independently associated with overall survival after surgery for colonic cancer.
Table 5.
Impact of the severity of postoperative complications on survival following surgery for colonic cancer, univariate and multivariate survival analysis
| Survival | Variable | Univariate HR (95 % CI) | p | Multivariate HR (95 % CI) | p |
|---|---|---|---|---|---|
| DSS | Age | 1.52 (0.96–2.41) | 0.073 | – | 0.316 |
| Sex | 0.72 (0.37–1.44) | 0.356 | – | – | |
| BMI | 0.69 (0.44–1.09) | 0.109 | – | – | |
| ASA | 1.63 (1.00–2.67) | 0.051 | 1.70 (0.99–2.93) | 0.057 | |
| Smoking | 0.94 (0.58–1.52) | 0.792 | – | – | |
| mGPS | 1.95 (1.34–2.82) | <0.001 | 1.81 (1.20–2.72) | 0.005 | |
| TNM stage | 2.27 (1.32–3.90) | 0.003 | 2.28 (1.23–4.21) | 0.009 | |
| POD 2 CRP > 150 mg/L | 1.69 (0.82–3.48) | 0.157 | – | – | |
| POD 3 CRP > 150 mg/L | 1.97 (0.89–4.36) | 0.094 | – | – | |
| POD 4 CRP > 150 mg/L | 2.78 (1.31–5.91) | 0.008 | 2.42 (1.13–5.18) | 0.023 | |
| Clavien-Dindo grade | 1.34 (1.01–1.78) | 0.043 | – | 0.164 | |
| Adjuvant treatment | 0.77 (0.35–1.70) | 0.516 | – | – | |
| OS | Age | 1.78 (1.23–2.57) | 0.002 | 1.43 (0.94–2.15) | 0.092 |
| Sex | 1.04 (0.61–1.78) | 0.873 | – | – | |
| BMI | 0.75 (0.53–1.06) | 0.100 | – | – | |
| ASA | 1.98 (1.34–2.93) | 0.001 | 1.99 (1.28–3.10) | 0.002 | |
| Smoking | 1.19 (0.83–1.70) | 0.354 | – | – | |
| TNM stage | 1.53 (1.04–2.25) | 0.030 | – | 0.114 | |
| mGPS | 1.66 (1.23–2.23) | 0.001 | 1.53 (1.11–2.10) | 0.010 | |
| POD 2 CRP > 150 mg/L | 2.18 (1.20–3.96) | 0.010 | – | – | |
| POD 3 CRP > 150 mg/L | 1.88 (1.03–3.42) | 0.040 | – | – | |
| POD 4 CRP > 150 mg/L | 2.33 (1.31–4.17) | 0.004 | 2.32 (1.29–4.20) | 0.005 | |
| Clavien-Dindo grade | 1.08 (0.84–1.39) | 0.548 | – | – | |
| Adjuvant treatment | 0.67 (0.35–1.27) | 0.205 | – | – |
HR hazard ratio, CI confidence interval, DSS disease-specific survival, OS overall survival, mGPS modified Glasgow Prognostic score, POD postoperative day
Discussion
The results of the present study report a significant association between the magnitude of the postoperative systemic inflammatory response and complication severity, using the Clavien-Dindo grade, following surgery for colorectal cancer. Furthermore, the magnitude of the postoperative systemic inflammatory response, in particular CRP on POD 4, was significantly associated with disease-specific and overall survival independent of postoperative complications. These relationships remained in a subgroup of patients who underwent colonic surgery. Therefore, the present results would suggest that the relationship between postoperative complication severity and poorer long-term survival is, at least in part, dependent on the magnitude of the postoperative systemic inflammatory response.
The results of the present study are consistent with previous studies showing an association between male gender, preoperative ASA grade, smoking status, and complication severity following colorectal surgery.19,25,26 Moreover, with two recent studies reporting the association between complication severity and the magnitude of the postoperative systemic inflammatory response in patients with colorectal cancer and also in patients undergoing surgery for gastric and oesophageal cancer.20–23
A recent meta-analysis reported that complication type and severity were independently associated with poorer oncologic outcomes following colorectal surgery and liver resection for colorectal cancer.15 However, the present study is the first to include a measure of the magnitude of the systemic inflammatory response together with the severity of complication in survival analysis following surgery for colorectal cancer. Although the relationship between postoperative infective complications and poorer survival in patients with colorectal cancer has been extensively documented, complication severity using the Clavien-Dindo scale provides a validated, objective framework for the definition of such postoperative complications.10
Taken together the implications of these results are important. They would suggest that the mechanisms that link the magnitude of the postoperative systemic inflammatory response, postoperative complications, and poorer oncological outcomes are inflammatory in aetiology.27 In previous work, it has been reported that the presence of preoperative systemic inflammation, as measured by the mGPS, but not postoperative complication, was associated with poorer long-term outcomes following surgery for colorectal cancer.8 However, the magnitude of the postoperative systemic inflammatory response was not considered. More recently, it is now recognised that the magnitude of the systemic inflammatory response following surgery for colorectal cancer is associated with the extent of postoperative complications.17,18,20,21 The present study shows that both the pre- and postoperative systemic inflammatory responses are associated with oncologic outcomes independent of tumour stage and postoperative complications.
The exact mechanisms underlying these relationships are unclear. However, the presence of an innate immune driven systemic inflammatory response can suppress cytotoxic immunity and may promote the development of postoperative complications and tumour progression.28–30 If this were proven to be the case, it therefore would be rational to consider the postoperative systemic inflammatory response a target for therapeutic intervention. Clearly, such therapeutic intervention also would test the above hypothesis, because it would be anticipated that a reduction in the postoperative systemic inflammatory response would not only result in a reduction in the severity of postoperative complications but also improve long-term outcomes, not only in colorectal cancer surgery, but in surgery for all solid tumours. It remains to be determined whether the modulation of the postoperative systemic inflammatory response may reduce the frequency and/or severity of postoperative complications or improve long-term outcomes following surgery for colorectal cancer.
Therefore, it is of interest that several meta-analyses investigating trials of preoperative corticosteroids in major abdominal and gastrointestinal surgery have suggested a reduction in both the magnitude of the postoperative systemic inflammatory response and postoperative complications.31–33 The long-term outcomes of these trials however is less clear; two, small follow-up studies suggested that preoperative corticosteroids had a potentially negative oncologic impact.34,35 However, preoperative corticosteroids have been widely incorporated into perioperative care guidelines for colorectal surgery due to their efficacy in the reduction of rates of postoperative nausea and vomiting.36 Other strategies might include the use of NSAIDs, H2 receptor antagonists, or statins in the perioperative period, each of which have been suggested to attenuate the systemic inflammatory response in patients with cancer.29,37 Additionally, laparoscopic surgery has been associated with a reduction in the magnitude of the postoperative systemic inflammatory response where technically appropriate.38
A main limitation of the present study was the relatively short follow-up period. In addition, a relatively small number of Clavien-Dindo grade 3–4 complications occurred. The significant difference in frequency of severe complication between colonic and rectal resection led to the separate analysis of patients undergoing colonic resection. Nevertheless, comparative analysis showed similar significant relationships with survival compared with the whole cohort.
In summary, the results of the present study show that the magnitude of the postoperative systemic inflammatory response was associated with oncologic outcome following surgery for colorectal cancer, independent of postoperative complications, or disease stage.
Acknowledgments
Conflict of interest
None.
References
- 1.Cancer Stats, Cancer Research UK. 2014. http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/commoncancers/.
- 2.Ghaferi LG, Birkmeyer JD, Dimick JB. Hospital volume and failure to rescue with high-risk surgery. Med Care. 2011;49:1076–1081. doi: 10.1097/MLR.0b013e3182329b97. [DOI] [PubMed] [Google Scholar]
- 3.McArdle CS, McMillan DC, Hole DJ. Impact of anastomotic leakage on long-term survival of patients undergoing curative resection for colorectal cancer. Br J Surg. 2005;92:1150–1154. doi: 10.1002/bjs.5054. [DOI] [PubMed] [Google Scholar]
- 4.Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg. 2005;242(3):326–341. doi: 10.1097/01.sla.0000179621.33268.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Law WL, Choi HK, Lee YM, Ho JWC. The impact of postoperative complications on long-term outcomes following curative resection for colorectal cancer. Ann Surg Oncol. 2007;14(9):2559–2566. doi: 10.1245/s10434-007-9434-4. [DOI] [PubMed] [Google Scholar]
- 6.Law WL, Choi HK, Lee YM, Ho JW, Seto CL. Anastomotic leakage is associated with poor long-term outcome in patients after curative colorectal resection for malignancy. J Gastrointest Surg. 2007;11:8–15. doi: 10.1007/s11605-006-0049-z. [DOI] [PubMed] [Google Scholar]
- 7.Dindo D, Demartines N, Clavien P. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213. doi: 10.1097/01.sla.0000133083.54934.ae. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Richards CH, Platt JJ, Anderson JH, McKee RF, Horgan PG, McMillan DC. The impact of perioperative risk, tumor pathology and surgical complications on disease recurrence following potentially curative resection of colorectal cancer. Ann Surg. 2011;254:83–89. doi: 10.1097/SLA.0b013e31821fd469. [DOI] [PubMed] [Google Scholar]
- 9.Mrak K, Eberl T, Laske A, Jagoditsch M, Fritz J, Tschmelitsch J. Impact of postoperative complications on long-term survival after resection for rectal cancer. Dis Colon Rectum. 2013;56(1):20–28. doi: 10.1097/DCR.0b013e31826f2672. [DOI] [PubMed] [Google Scholar]
- 10.Clavien P, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five year experience. Ann Surg. 2009;250:187–196. doi: 10.1097/SLA.0b013e3181b13ca2. [DOI] [PubMed] [Google Scholar]
- 11.Artinyan A, Orcutt ST, Anaya DA, Richardson P, Chen GJ, Berger DH. Infectious postoperative complications decrease long-term survival in patients undergoing curative surgery for colorectal cancer. Ann Surg. 2015;261(3):497–505. doi: 10.1097/SLA.0000000000000854. [DOI] [PubMed] [Google Scholar]
- 12.Mirzenami A, Mirzenami R, Chandrakumaran K, Sasapu K, Sagar P, Finan P. Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann Surg. 2011;253(5):890–899. doi: 10.1097/SLA.0b013e3182128929. [DOI] [PubMed] [Google Scholar]
- 13.Xia X, Wu W, Zhang K, et al. Prognostic significance of complications after laparoscopic colectomy for colon cancer. PLOS One. 2014;9(10):e108348. doi: 10.1371/journal.pone.0108348. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Odermatt M, Miskovic D, Flashman K, et al. Major postoperative complications following elective resection for colorectal cancer decrease long-term survival but not the time to recurrence. Colorectal Dis. 2014 doi: 10.1111/codi.12757. [DOI] [PubMed] [Google Scholar]
- 15.McSorley ST, Horgan PG, McMillan DC. The impact of the type and severity of postoperative complications on long-term outcomes following surgery for colorectal cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015 doi: 10.1016/j.critrevonc.2015.08.013. [DOI] [PubMed] [Google Scholar]
- 16.Ramanathan ML, MacKay G, Platt J, Horgan PG, McMillan DC. Impact of day 2 c-reactive protein on day 3 and 4 thresholds associated with infective complications following curative surgery for colorectal cancer. World J Surg. 2013;37:2705–2710. doi: 10.1007/s00268-013-2177-4. [DOI] [PubMed] [Google Scholar]
- 17.Singh PP, Zeng IS, Srinivasa S, Lemanu DP, Connolly AB, Hill AG. Systematic review and meta-analysis of use of serum C-reactive protein levels to predict anastomotic leak after colorectal surgery. Br J Surg. 2014;101(4):339–346. doi: 10.1002/bjs.9354. [DOI] [PubMed] [Google Scholar]
- 18.Platt JJ, Ramanathan ML, Crosbie RA, Anderson JH, McKee RF, Horgan PG, McMillan DC. C-reactive protein as a predictor of postoperative infective complications after curative resection in patients with colorectal cancer. Ann Surg Oncol. 2012;19:4168–4177. doi: 10.1245/s10434-012-2498-9. [DOI] [PubMed] [Google Scholar]
- 19.McDermott FD, Heeney A, Kelly ME, Steele RJ, Carlson GJ, Winter DC. Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks. Br J Surg. 2015;102:462–479. doi: 10.1002/bjs.9697. [DOI] [PubMed] [Google Scholar]
- 20.Selby J, Prabhudesai A. Can C-reactive protein predict the severity of post-operative complication after elective resection of colorectal cancer? Int J Colorectal Dis. 2014;29(10):1211–1215. doi: 10.1007/s00384-014-1977-9. [DOI] [PubMed] [Google Scholar]
- 21.McSorley ST, Ramanathan ML, Horgan PG, McMillan DC. Postoperative C-reactive protein measurement predicts the severity of complications following surgery for colorectal cancer. Int J Colorectal Dis. 2015;30(7):913–917. doi: 10.1007/s00384-015-2229-3. [DOI] [PubMed] [Google Scholar]
- 22.Matsuda S, Takeuchi H, Kawakubo H, et al. Correlation between intense postoperative inflammatory response and survival of esophageal cancer patients who underwent transthoracic esophagectomy. Ann Surg Oncol. 2015 doi: 10.1245/s10434-015-4557-5. [DOI] [PubMed] [Google Scholar]
- 23.Saito T, Kurokawa Y, Miyazaki Y, 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 doi: 10.1002/jso.24067. [DOI] [PubMed] [Google Scholar]
- 24.McMillan DC. The systemic inflammation based glasgow prognostic score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534–540. doi: 10.1016/j.ctrv.2012.08.003. [DOI] [PubMed] [Google Scholar]
- 25.Kirchhoff P, Dincler S, Buchmann P. A multivariate analysis of potential risk factors for intra- and post-operative complications in 1316 elective laparoscopic colorectal procedures. Ann Surg. 2008;248:259–265. doi: 10.1097/SLA.0b013e31817bbe3a. [DOI] [PubMed] [Google Scholar]
- 26.Lipska MA, Bissett IP, Parry BR, Merrie AE. Anastomotic leakage after lower gastrointestinal anastomosis: men are at a higher risk. ANZ J Surg. 2006;76:579–585. doi: 10.1111/j.1445-2197.2006.03780.x. [DOI] [PubMed] [Google Scholar]
- 27.Powell DR, Huttenlocher A. Neutrophils in the tumour microenvironment. Trends Immunol. 2015 doi: 10.1016/j.it.2015.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Roxburgh CS, McMillan DC. Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer. Transl Res. 2015 doi: 10.1016/j.trsl.2015.08.013. [DOI] [PubMed] [Google Scholar]
- 29.Roxburgh CS, Horgan PG, McMillan DC. The perioperative immune/inflammatory insult in cancer surgery: time for intervention? OncoImmunology. 2013;2:e27324. doi: 10.4161/onci.27324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014;16(8):717–727. doi: 10.1038/ncb3015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Srinvasa S, Kahoker AA, Yu TC, Hill AG. Preoperative glucocorticoid use in major abdominal surgery: a systematic review and meta-analysis of randomized trials. Ann Surg. 2011;254(2):183–191. doi: 10.1097/SLA.0b013e3182261118. [DOI] [PubMed] [Google Scholar]
- 32.Richardson AJ, Laurence JM, Lam VWT. Use of pre-operative steroids in liver resection: a systematic review and meta-analysis. HPB. 2014;16:12–19. doi: 10.1111/hpb.12066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Gao Q, Mok HP, Wang WP, Xiao-Feizuo Z, Chen LQ. Effect of perioperative glucocorticoid administration on postoperative complications following esophagectomy: a meta-analysis. Oncol Lett. 2014;7:349–356. doi: 10.3892/ol.2013.1748. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Singh PP, Lemanu DP, Taylor MH, Hill AG. Association between pre-operative glucocorticoids and long-term survival and cancer recurrence after colectomy: follow-up analysis of a previously randomized trial. Br J Anaesth. 2014;113(S1):i68–i73. doi: 10.1093/bja/aet577. [DOI] [PubMed] [Google Scholar]
- 35.Yu HC, Luo YX, Peng H, Kang L, Huang MJ, Wang JP. Avoiding perioperative dexamethasone may improve the outcomes of patients with rectal cancer. Eur J Surg Oncol. 2015;41:667–673. doi: 10.1016/j.ejso.2015.01.034. [DOI] [PubMed] [Google Scholar]
- 36.Feldheiser A, Aziz O, Baldini G, et al. Enhanced recover after surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice. Acta Anaesthesiol Scand. 2016;60(3):289–334. doi: 10.1111/aas.12651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Park JH, McMillan DC, Horgan PG. The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer. Cancer Treat Rev. 2014;40(1):68–77. doi: 10.1016/j.ctrv.2013.05.006. [DOI] [PubMed] [Google Scholar]
- 38.Watt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review. Surgery. 2015;157(2):362–380. doi: 10.1016/j.surg.2014.09.009. [DOI] [PubMed] [Google Scholar]