Abstract
Background
The impact of body composition on outcomes after surgery for colorectal liver metastases (CRLM) remains unclear. The aim of the present study was to determine the influence of sarcopenia, obesity and sarcopenic obesity on morbidity, disease-free (DFS) and overall survival (OS).
Method
Between 2005 and 2012, all patients undergoing a partial liver resection for CRLM in the Maastricht University Medical Centre, and who underwent computed tomography (CT) imaging within 3 months before liver surgery, were included. Body composition was primarily based on pre-operative CT measurements. Sarcopenia was based on total muscle area at the level of the third lumbar vertebra and predefined body mass index (BMI)- and gender-specific cut-off values for sarcopenia were used. Body fat percentages were calculated and the top 40% for men and women were considered obese.
Results
Of the 171 included patients undergoing liver surgery for CRLM, 80 (46.8%) patients were sarcopenic, 69 (40.4%) obese and 49 (28.7%) sarcopenic obese. The presence of sarcopenia, obesity or sarcopenic obesity did not affect the complication rates. However, readmission rates were significantly increased in patients with (sarcopenic) obesity (P < 0.05). Surprisingly, obesity seemed to prolong OS (P = 0.021) and was identified as an independent predictor [hazard ratio (HR):0.58 and P = 0.046] for better OS. Sarcopenia and sarcopenic obesity did not affect DFS or OS.
Conclusion
Sarcopenia, obesity and sarcopenic obesity did not worsen DFS, OS and complication rates after a partial liver resection for CRLM.
Introduction
A liver resection for colorectal liver metastases (CRLM) is increasingly being performed. The criteria for resectability have been expanded as a result of improved surgical possibilities, more effective chemotherapy and improved peri-operative care.1–3 As a result, more extensive parenchymal resections are now performed. As a consequence the risk of post-resectional liver failure and other major complications has increased. Therefore the role of pre-operative assessment has gained more importance. Liver volumetry and functional liver assessment are widely accepted in the workup of patients undergoing a major liver resection.4–6 In this context body composition is increasingly being brought to the attention, as it was reported to be associated with impaired outcome.7–10 Currently, there are not many studies that investigated the impact of body composition on outcome and survival after surgery for CRLM.
Cancer-related weight loss (cachexia) occurs in up to 30% of patients with colorectal liver metastases.11 The effect of reduced muscle mass (sarcopenia) on outcome and survival after liver surgery has been analysed in relatively small studies, but so far there is no consensus about its influence on outcome.8–10,12 Some previous studies have identified sarcopenia as an independent predictor negatively influencing overall survival (OS) and disease-free survival (DFS),8,10 but others did not.9 Some authors concluded that sarcopenia is associated with higher morbidity rates after liver surgery.9 Recently it has been demonstrated that total liver volume in sarcopenic patients was disproportionally smaller compared with patients without sarcopenia,13 and this could contribute to increased morbidity after liver surgery.
At the other extreme of physiognomy, the effect of obesity on outcome in patients with malignant disease also remains controversial.14 Obesity seems to be associated with a higher risk of post-operative morbidity and mortality after liver surgery.7 There is, however, no consensus on the impact of obesity on DFS and OS. Depending on the underlying malignant disease, conflicting results have been reported on OS in patients with obesity versus patients with a normal weight,10,15 with some even reporting there was a protective effect of obesity.16,17
The combination of sarcopenia and obesity (sarcopenic obesity) is an independent predictor of worse OS in patients undergoing pulmonary, gastrointestinal and pancreatic cancer surgery.18–20 However, to the authors' knowledge the effect of sarcopenic obesity on complications and long-term outcomes after liver surgery has not been described.
The aim of the present study was to explore whether sarcopenia, obesity and sarcopenic obesity predispose for morbidity, early recurrence and reduced OS in patients undergoing a partial liver resection for CRLM.
Material and methods
Patients
A prospective database was used to identify patients that underwent a partial hepatectomy at the Maastricht University –Medical Centre Hepato-Pancreato-Biliary (HPB) unit between 2005 and 2012. Only patients with CRLM, staged by a four-phase contrast enhanced abdominal computed tomography (CT) scan up to 3 months before resection, were included. Patients with CT scans of poor quality were excluded as body composition measurements could not be performed in these patients. Moreover, patients who eventually did not undergo a liver resection were excluded. Patients without information on weight, height and body mass index (BMI) were also excluded. All patients were discussed at a pre-operative multidisciplinary liver board. Patient-specific co-morbidities and diagnostic procedures were assessed and the definitive treatment strategy was decided in consensus. Induction chemotherapy in patients with irresectable tumours, liver resection combined with tumour ablation, pre-operative portal vein embolization (PVE), liver first policy in rectal cancer and a repeat hepatectomy were all among potential treatment options. Vascular reconstructions were occasionally used. All patients were treated within an Enhanced Recovery After Surgery (ERAS®) peri-operative care programme.21
Liver resections
All liver resections were classified in accordance with the IHPBA Brisbane nomenclature.22 Liver resection was performed as described previously.23 After mobilization of the liver, intra-operative ultrasound gave insight in the feasibility of the pre-operatively planned surgical procedure. A transection was performed using a Cavitron Ultrasonic Surgical Aspirator (CUSA system 200 Macrodissector; Cavitron Surgical Systems, Stamford, CT, USA). To prevent excessive blood loss the central venous pressure was maintained below 5 cm H2O during transection. Hilar inflow occlusion (Pringle manoeuvre) was performed for a maximum of 30 min in case of increased bleeding risk. Haemostasis was achieved using bipolar coagulation (Force GSU System; Valleylab, Boulder, CO, USA), sutures and clips.
Methods
Body composition
The presence of sarcopenia was assessed through measurements of skeletal muscle areas by one researcher (T.J.A.v.N.) with the use of the OsiriX® programme on contrast-enhanced pre-operative CT scans on a 2.8-GHz Intel Core 2 Duo 24” iMac (Apple Inc., Cupertino, CA, USA). A threshold range between −30 and 110 Hounsfield Units was set to semi-automatically outline muscle areas at the transversal level of the third lumbar vertebra (L3) as recently described. The mean of measurements on two adjacent CT slices at the L3 level was used to calculate the L3 skeletal muscle index (L3 MI) by correcting it for height. Sarcopenia was defined as an L3 MI <41 cm2/m2 in women, <43 cm2/m2 in men with a BMI <25, and <53 cm2/m2 in men with a BMI >25 as these cut-off values showed an association with mortality.20 The body surface area was estimated using the Mosteller formula, {[height (cm) * weight (kg)]/3600}1/2.24 Total fat-free body mass (kg) was estimated as: 0.30 * (skeletal muscle surface area at L3 in cm2) + 6.06.18 Body fat percentage was calculated as: [body weight (kg) – fat free body mass (kg)]/body weight (kg). Obesity was based on body fat percentages. Cut-off values for obesity were >44.4% for women and >35.7% for men, based on the top two body fat percentage quintiles in our study as is conventional for studies evaluating sarcopenic obesity.25–27 Sarcopenic obesity was defined as the presence of both sarcopenia and obesity according to these definitions.
Outcome parameters
The primary endpoint of the study was OS. Secondary endpoints were complications, post-operative mortality, hospital length of stay (LOS) and DFS. Complications were registered daily using National Surgical Adverse Event Registration (LHCR) software28 of the Dutch Association of General Surgery before 2009 and the hospital information system (SAP, Walldorf, Germany) afterwards. The post-operative course of all discharged patients was discussed at the surgical morbidity meeting. Post-operative 90-day morbidity was graded according to the Dindo–Clavien classification.29 Complications requiring readmission were also included in the complication registration. Complications with a Dindo–Clavien score ≤2 were considered minor complications whereas complications with a score ≥3a were considered major complications. Moreover, the liver surgery-specific composite endpoint (LSSCEP), composed of ascites, post-resectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and mortality, was used to assess liver surgery-specific morbidity.30 Patient demographics were registered and information on co-morbidity, location and TNM stage of the primary tumour and time point of occurrence of liver metastases were retrieved from patient charts. The size of the metastases and the resection margins were retrieved from pathology reports. R0 resections were defined as resections with a tumour-free resection surface.
Follow-up consisted of outpatient visits with plasma carcinoembryonic antigen levels every 3 months and liver imaging twice in the first 2 years and annually up to 5 years after surgery. In case of recurrence, patients were assessed with positron emission tomography (PET)-CT and the indication for repeat liver or lung surgery was again discussed at a multidisciplinary liver meeting. OS and DFS after liver resection were calculated in percentages and registered in months using the time period between the date of surgery and death or recurrence, respectively. In the case of two-stage hepatectomies, DFS was calculated as the time period between the first stage operation and the recurrence of metastases after the second stage operation.
Statistical analysis
Data were analysed using SPSS version 21.0 (SPSS Inc., Chicago, IL). Data are expressed as the median and range or percentages or survival in months (95% confidential interval). The chi-square test was used to analyse categorical data whereas continuous data were analysed using the Mann–Whitney U-test. Time to recurrence and OS were calculated with the Kaplan–Meier (censored) method using the date of liver surgery as a reference date. A level of P < 0.05 was considered to be statistically significant. Relevant clinicopathological variables associated with OS and DFS were examined using univariable and, where applicable, multivariable Cox proportional hazards regression. For the multivariable models, a univariable inclusion criterion of P ≤ 0.15 was used.
Results
Four out of 175 patients (2.3%) were excluded for various reasons (1 patient because no resection was performed, 1 patient due to a poor quality CT scan and 2 patients due to a lack of information on weight, height or BMI.). A total of 171 patients with a median follow-up of 21 [1–90] months, were included. Demographics are shown in Table 1. Complications are shown in Table 2. The median hospital LOS was 8 [2–92] days. The median DFS was 16 [confidence interval (CI) 9–22] months with a 1 and 3 year DFS rate of 57.1% and 36.0%, respectively. The median OS was 54 months (CI 45–62) and 1, 3 and 5 year OS rates were 91.8%, 65.6% and 43.1%, respectively.
Table 1.
Patient characteristics
| Variables, median [range] | All patients n = 171 |
|---|---|
| Patient characteristics | |
| Median age [range], y | 64 [24–86] |
| ASA >2 | 28 (16.4) |
| Patients with PVE (%) | 4 (2.3) |
| Weight [range], kg | 75 [47–119] |
| Height [range], (cm) | 172 [149–195] |
| BMI [range], (kg/m2) | 25.7 [18.4–42.8] |
| Body composition | |
| L3 MI [range] (cm2/m2) | 46.4 [31.7–71.1] |
| Sarcopenia (%) | 80 (46.8) |
| Fat free body mass [range] (kg) | 48.1 [29.9–79.9] |
| Fat mass [range] (kg) | 28.4 [3.7–73.4] |
| Body fat % [range] | 36.9 [6.8–62.2] |
| Obesity (%) | 69 (40.4) |
| Sarcopenic obesity (%) | 49 (28.7) |
| Body surface area [range] (m2) | 1.89 [1.42–2.53] |
| Laboratory testing [range] (normal) | |
| Bilirubin (mg/dl) (<20.0) | 11.6 [2.7–47.0] |
| INR ratio (0.80-1.20) | 0.99 [0.91–2.91] |
| Platelets (10E9/l) (130–350) | 226 [3–635] |
| Prothrombin time (s) (9.9–11.5) | 10.6 [9.7–31.7] |
| Tumour | |
| Size of largest tumour [range] (mm) | 25 [2–130] |
| Patients with tumour >5 cm (%) | 21 (12.5) |
| Bilateral (%) | 77 (45.0) |
| Number of tumours [range] | 2 [1–13] |
| Patients with tumours >3 (%) | 32 (18.7) |
| Concomittant extrahepatic disease | 14 (8.2) |
| Resection type (%) | |
| Left hemihepatectomy (%) | 4 (2.3) |
| Right hemihepatectomy (%) | 45 (26.3) |
| Extended right hepatectomy (%) | 4 (2.3) |
| Central (%) | 6 (3.5) |
| (Multiple) segmentectomy (%) | 110 (64.3) |
ASA, American Society of Anesthesiologists; PVE, portal vein embolization; BMI, body mass index; MI, muscle index; INR, International Normalized Ratio.
Table 2.
Complications
| Variables | All patients N = 171 |
|---|---|
| Grading of complications | |
| Number of patients with complications (%) | 78 (45.6) |
| Minor complications present | 40 (23.4) |
| Dindo–Clavien grade 1 | 9 (5.3) |
| Dindo–Clavien grade 2 | 31 (18.1) |
| Major complications present | 38 (22.2) |
| Dindo–Clavien grade 3a | 27 (15.8) |
| Dindo–Clavien grade 3b | 4 (2.3) |
| Dindo–Clavien grade 4a | 5 (2.9) |
| Dindo–Clavien grade 4b | 1 (0.6) |
| Dindo–Clavien grade 5 | 1 (0.6) |
| Liver surgery-specific composite endpoint (LSSCEP) | |
| Number of patients with 1 or more items of LSSCEP | 28 (16.4) |
| Ascites | 5 (2.9) |
| Post-resectional liver failure | 4 (2.3) |
| Bile leak | 8 (4.7) |
| Intra-abdominal haemorrhage | 1 (0.6) |
| Intra-abdominal abscess | 21 (12.3) |
| Mortality | 1 (0.6) |
| Other complications | |
| Cardiovascular | 9 (5.3) |
| Pulmonary | 14 (8.2) |
| Renal | 5 (2.9) |
| Gastro-intestinal | 34 (19.1) |
| Neurological | 4 (2.4) |
| Haematological | 4 (2.4) |
| Sepsis | 6 (3.5) |
| Wound infection | 12 (7.0) |
| Readmissions | |
| Number of patients readmitted | 23 (13.5) |
Sarcopenia
According to the predefined cut-off values for sarcopenia, 80 (46.8%) patients were considered sarcopenic (Table 1). Patients with sarcopenia had a significantly increased percentage body fat (42.2 [26.1–57.3] versus 32.2 [6.8–62.2]%, P < 0.001). Major complications were equally common in sarcopenic and non-sarcopenic patients (26.3 versus 18.7%, P = 0.235). Moreover, the presence of the LSSCEP (P = 0.230), initial hospital LOS (P = 0.202) and readmission rates (P = 0.283) did not differ significantly between the groups (Table 3). The median DFS and OS were not significantly different between patients with and patients without sarcopenia (Fig. 1).
Table 3.
Features associated with sarcopenia, obesity and sarcopenic obesity
| Sarcopenia | Obesity | Sarcopenic-obesity | |||||||
|---|---|---|---|---|---|---|---|---|---|
| No (n = 91) | Yes (n = 80) | P | No (n = 102) | Yes (n = 69) | P | No (n = 122) | Yes (n = 49) | P | |
| Patient characteristics | |||||||||
| Median age [range] (years) | 64 [24–83] | 65 [39–86] | 0.628 | 64 [24–83] | 66 [41–86] | 0.184 | 64 [24–83] | 67 [41–86] | 0.262 |
| Sex, number of males (%) | 59 (64.8) | 45 (56.3) | 0.251 | 62 (60.8) | 42 (60.9) | 0.991 | 71 (58.2) | 33 (67.3) | 0.268 |
| Patients with ASA >2 (%) | 15 (16.5) | 13 (16.3) | 0.967 | 18 (17.6) | 10 (14.5) | 0.582 | 21 (17.2) | 7 (14.3) | 0.640 |
| Co-morbidities present (%) | 47 (51.6) | 36 (45.0) | 0.385 | 52 (51.0) | 31 (44.9) | 0.437 | 60 (49.2) | 23 (46.9) | 0.791 |
| Patients with PVE (%) | 2 (2.2) | 2 (2.5) | 0.896 | 2 (2.0) | 2 (2.9) | 0.691 | 3 (2.5) | 1 (2.0) | 0.870 |
| Surgery | |||||||||
| Major liver resections (≥3 liver segments) (%) | 28 (30.8) | 33 (41.3) | 0.153 | 34 (33.3) | 27 (39.1) | 0.438 | 45 (36.9) | 16 (32.7) | 0.601 |
| R0 resections (%) | 65 (71.4) | 58 (72.5) | 0.876 | 75 (73.5) | 48 (69.6) | 0.571 | 86 (70.5) | 37 (75.5) | 0.509 |
| Admission | |||||||||
| Initial hospital length of stay [range] (days) | 8 [2–90] | 8 [4–92] | 0.202 | 8 [2–92] | 8 [5–90] | 0.746 | 8 [2–92] | 8 [5–84] | 0.579 |
| Complications present (%) | 45 (49.5) | 33 (41.3) | 0.283 | 46 (45.1) | 32 (46.4) | 0.869 | 55 (45.1) | 23 (46.9) | 0.826 |
| Minor complications (%) | 28 (30.8) | 12 (15.0) | 0.015 | 26 (25.5) | 14 (20.3) | 0.431 | 31 (25.4) | 9 (18.4) | 0.325 |
| Major complications (%) | 17 (18.7) | 21 (26.3) | 0.235 | 20 (19.6) | 18 (26.1) | 0.317 | 24 (19.7) | 14 (28.6) | 0.206 |
| Liver specific composite endpoint present (%) | 12 (13.2) | 16 (20.0) | 0.230 | 16 (15.7) | 12 (17.4) | 0.768 | 18 (14.8) | 10 (20.4) | 0.366 |
| Readmissions | |||||||||
| Patients readmitted (%) | 10 (11.0) | 13 (16.3) | 0.314 | 8 (7.8) | 15 (21.7) | 0.009 | 12 (9.8) | 11 (22.4) | 0.029 |
ASA, American Society of Anesthesiologists; PVE, portal vein embolization.
Figure 1.
Kaplan–Meier curves of disease-free (DFS) (top) and overall survival (OS) (bottom) for patients with and without sarcopenia. The median DFS was 20 [6–34] and 14 [9–18] months with 1/3 years DFS rates of 62.7/40.9% and 52.3/31.7% in patients with and without sarcopenia. The median OS was 54 [36–71] and 49 [34–64] months with 1/3/5 years OS rates of 92.5/69.0/45.8% and 91.2/62.6/40.8% in patients with and without sarcopenia
Obesity
Based on our definition 69 (40.4%) patients met the criteria for obesity. General patient characteristics, not related with obesity, were comparable between the two groups. Obese men had significantly lower L3 muscle indices compared with men without obesity (46.5 [34.9–63.2] versus 52.5 [40.2–71.1] cm2/m2, P < 0.001) indicating a higher incidence of sarcopenia. There was no difference in morbidity between the two groups. However, the readmission rate was significantly higher in obese patients (21.7 versus 7.8%, P = 0.009) (Table 3). Moreover, readmissions tended to be more often as a result of infection in the obese (53.3 versus 12.5%, P = 0.056). DFS did not differ significantly between obese and non-obese patients. OS was significantly longer in obese patients compared with non-obese patients [79 (CI 45–113) versus 46 (CI 37–57) months, P = 0.021] (Fig. 2). Non-obese women showed decreased OS compared with obese women [40 (CI 22–58) versus 79 (CI 48–109) months, P = 0.012], whereas non-obese men did not (P = 0.325).
Figure 2.
Kaplan–Meier curves of disease-free (DFS) (top) and overall survival (OS) (bottom) for patients with and without obesity. The median DFS was 22 [2–42] and 13 [9–17] months with 1/3 years DFS rates of 65.1/45.5% and 51.5/29.5% in patients with and without obesity. The median OS was 79 [45–113] and 46 [37–57] months with 1/3/5 years OS rates of 92.8/75.7/60.9% and 91.1/59.5/32.4% in patients with and without obesity
Sarcopenic-obesity
Sarcopenic obesity was present in 49 patients (28.7%). Major complications (P = 0.206), the occurrence of one or more of the items of the liver surgery-specific composite endpoint (P = 0.225) and the initial hospital LOS (P = 0.579) were all comparable between sarcopenic-obese patients and patients without sarcopenic obesity. Readmissions were more frequent in patients with sarcopenic obesity (22.4 versus 9.8%, P = 0.029) (Table 3) and were caused by infections in 45.5% of the sarcopenic obese and 33.3% of patients without sarcopenic obesity (P = 0.552). The median DFS (22 [0–45] versus 15 [11–18] months, P = 0.337) and OS (71 [38–58] versus 48 [38–58] months, P = 0.135) were not significantly different between sarcopenic-obese patients and patients without sarcopenic obesity, respectively.
Predictors of DFS and OS
Univariable analyses showed that having >3 metastases, concomitant extrahepatic disease and pre-operative chemotherapy were significant prognostic factors of DFS (P < 0.05). Four more factors (P < 0.15) were added to the multivariable analysis. As the before-mentioned results indicated that obesity might be a protective factor for OS, obesity was also added to the multivariable analysis. After multivariable analysis obesity (HR: 0.73 and P = 0.161) could not be identified as an independent factor for better DFS. The only significant independent negative prognostic factors affecting DSF was having concomitant extrahepatic disease (HR: 2.48 and P = 0.006) (Table 4).
Table 4.
Predictors for disease free survival, uni- and multivariable analysis
| Prognostic factor | Univariable | Multivariable | ||
|---|---|---|---|---|
| P value | HR (95% CI) | P value | HR (95% CI) | |
| Age (years) | 0.483 | 0.993 (0.975–1.012) | ||
| Female gender | 0.166 | 1.317 (0.892–1.945) | ||
| ASA 3 (versus ASA 1/2) | 0.130 | 0.628 (0.344–1.147) | 0.359 | 0.738 (0.386–1.412) |
| Co-morbidities present | 0.176 | 0.764 (0.518–1.128) | ||
| Primary site | ||||
| Colon | Reference | |||
| Rectum | 0.635 | 1.110 (0.721–1.710) | ||
| Primary CRC T stage | ||||
| T1-2 | Reference | |||
| T3-4 | 0.735 | 1.106 (0.616–1.987) | ||
| Positive primary CRC lymph nodes | 0.120 | 1.408 (0.915–2.166) | 0.189 | 1.347 (0.863–2.102) |
| Sarcopenia* | 0.483 | 0.871 (0.591–1.283) | ||
| Obesity | 0.211 | 0.775 (0.520–1.156) | 0.161 | 0.727 (0.466–135) |
| Sarcopenic obesity* | 0.338 | 0.807 (0.519–1.252) | ||
| >3 CRLM | 0.017 | 1.736 (1.104–2.732) | 0.175 | 1.414 (0.857–2.333) |
| Diameter of largest lesion ≥5 cm | 0.360 | 0.754 (0.411–1.381) | ||
| Concomitant extrahepatic disease | 0.001 | 2.697 (1.464–4.971) | 0.006 | 2.483 (1.296–4.756) |
| Bilateral | 0.202 | 1.288 (0.873–1.899) | ||
| Major liver resection (versus minor) | 0.404 | 0.842 (0.562–1.261) | ||
| Duration of surgery (hours) | 0.986 | 1.001 (0.880–1.139) | ||
| Blood loss during surgery (1000 ml) | 0.982 | 1.000 (1.000–1.000) | ||
| Positive surgical margin (R1 versus R0) | 0.090 | 1.433 (0.945–2.172) | 0.118 | 1.437 (0.913–2.263) |
| Liver surgery-specific CEP | 0.063 | 1.581 (0.975–2.563) | 0.216 | 1.374 (0.830–2.276) |
| Complications* | ||||
| None | Reference | |||
| Minor (Dindo–Clavien grade 1–2) | 0.724 | 1.092 (0.669–1.782) | ||
| Major (Dindo–Clavien grade ≥3a) | 0.062 | 1.558 (0.978–2.481) | ||
| Pre-operative chemotherapy | 0.033 | 1.651 (1.042–2.618) | 0.385 | 1.249 (0.756–2.062) |
| Adjuvant chemotherapy | 0.332 | 0.825 (0.560–1.217) | ||
*/**Excluded from multivariable analysis owing to collinearity with obesity (*) or the liver surgery-specific composite endpoint (**).
ASA, American Society of Anesthesiologists; CEP, composite endpoint; CRC, colorectal cancer.
Significant prognostic factors for OS after univariable analyses were female gender, obesity, concomitant extrahepatic disease, major complications and the liver surgery specific composite endpoint (P < 0.05). One more factor (positive primary colorectal cancer lymph nodes) was added to the multivariable analysis because of borderline significance (P < 0.15). After multivariable analysis, obesity (HR: 0.58 and P = 0.046) was identified as an independent protective factor for OS. Concomitant extrahepatic disease (HR: 2.32 and P = 0.020) was the only significant negative prognostic factors affecting OS. Moreover, the LSSCEP (HR: 1.65 and P = 0.076), positive primary colorectal lymph nodes (HR: 1.60 and P = 0.078) and female gender (HR: 1.54 and P = 0.071) all showed tendencies to be negative prognostic factors for OS (Table 5).
Table 5.
Predictors for overall survival, uni- and multivariable analysis
| Prognostic factor | Univariable | Multivariable | ||
|---|---|---|---|---|
| P-value | HR (95% CI) | P-value | HR (95% CI) | |
| Age (years) | 0.364 | 1.010 (0.988–1.033) | ||
| Female gender | 0.090 | 1.478 (0.941–2.321) | 0.071 | 1.542 (0.964–2.465) |
| ASA 3 (versus 1/2) | 0.934 | 0.973 (0.513–1.847) | ||
| Co-morbidities present | 0.412 | 1.208 (0.769–1.898) | ||
| Primary site | ||||
| Colon | Reference | |||
| Rectum | 0.863 | 0.958 (0.590–1.555) | ||
| Primary CRC T stage | ||||
| T1-2 | Reference | |||
| T3-4 | 0.420 | 0.774 (0.415–1.442) | ||
| Positive primary CRC lymph nodes | 0.145 | 1.468 (0.876–2.458) | 0.078 | 1.599 (0.949–2.693) |
| Sarcopenia* | 0.644 | 0.899 (0.571–1.414) | ||
| Obesity | 0.023 | 0.562 (0.342–0.925) | 0.046 | 0.584 (0.345–0.991) |
| Sarcopenic obesity* | 0.138 | 0.663 (0.386–1.141) | ||
| >3 CRLM | 0.390 | 1.282 (0.728–2.260) | ||
| Diameter of largest lesion ≥5 cm | 0.551 | 0.800 (0.384–1.666) | ||
| Concomitant extrahepatic disease | 0.002 | 2.887 (1.464–5.693) | 0.020 | 2.322 (1.144–4.712) |
| Bilateral | 0.340 | 0.800 (0.505–1.265) | ||
| Major liver resection (versus minor) | 0.874 | 0.963 (0.606–1.531) | ||
| Duration of surgery (hours) | 0.396 | 0.929 (0.785–1.101) | ||
| Blood loss during surgery (1000 ml) | 0.960 | 1.000 (1.000–1.000) | ||
| Positive surgical margin (R1 versus R0) | 0.232 | 1.352 (0.825–2.217) | ||
| Liver surgery-specific CEP | 0.048 | 1.710 (1.004–2.912) | 0.076 | 1.646 (0.950–2.852) |
| Complications* | ||||
| None | Reference | |||
| Minor (Dindo–Clavien grade 1–2) | 0.433 | 1.260 (0.707–2.246) | ||
| Major (Dindo–Clavien grade ≥3a) | 0.043 | 1.717 (1.016–2.901) | ||
| Pre-operative chemotherapy | 0.223 | 1.375 (0.823–2.297) | ||
| Adjuvant chemotherapy | 0.792 | 0.940 (0.596–1.484) | ||
*/**Excluded from multivariable analysis owing to collinearity with obesity (*) or the liver surgery-specific composite endpoint (**).
ASA, American Society of Anesthesiologists; CRC, colorectal cancer; CRLM, colorectal liver metastases.
Discussion
To date, the influence of body composition on outcomes after liver surgery for colorectal liver metastases has not been described clearly. This study showed that sarcopenia, obesity and sarcopenic obesity did not seem to influence (major) complication rates after a liver resection for CRLM. Readmission rates, however, were significantly increased in patients with obesity or sarcopenic obesity. Sarcopenia, obesity and sarcopenic obesity did not seem to influence OS adversely. In obese patients, the median OS was nearly twice as long compared with patients without obesity. Moreover, after multivariable analysis, obesity was identified as an independent factor for better OS.
Peng et al. previously looked at the effect of sarcopenia on outcome in patients operated for CRLM and, in line with the present results, they concluded that sarcopenia did not result in worse DFS and OS.9 In contrast, others showed that sarcopenic patients undergoing a liver resection for hepatocellular carcinoma or CRLM had a worse prognosis concerning DFS and OS.8,10 Some studies showed increased morbidity after a liver resection in sarcopenic patients in contrast to the present study where morbidity and mortality were comparable in patients with and without sarcopenia.9
Differences in outcome between studies might well be explained by the different L3 muscle index cut-off values used to define sarcopenia. Martin et al. published sex-specific BMI dependent cut-off values for the L3 muscle index that were associated with mortality, based on >1400 patients with pulmonary and gastrointestinal cancer.18 Using these cut-off values, the present study reported an incidence of sarcopenia of 47%. Some studies used cut-off values calculated by Prado et al. that are based on obese patients only.18 Others used cut-off values for the L3 muscle index calculated by van Vledder et al. based on a relatively small series of patients with colorectal liver metastases without taking BMI into account. These cut-off values lead to an incidence of sarcopenia between 19% and 40%.8,10 A large epidemiological study by Baumgartner et al., using dual-energy X-ray (DXA), revealed an incidence of sarcopenia of about 20% in patients <70 years of age rising to over 50% in patients aged >80 years in a healthy population.31 It should be realized that cachexia (cancer-related loss of adipose tissue and skeletal muscle mass) also contributes to muscle wasting in up to 30% of patients with CRLM.11 Therefore this may increase the prevalence of sarcopenia substantially in studies including patients with colorectal liver metastases.32 We believe that muscle wasting is underreported in studies showing increased morbidity and worse long-term outcomes in sarcopenics, and these studies may have selected predominantly severe cases of muscle wasting.8,10
The present study showed a clear increase of the OS in obese patients compared with their non-obese counterparts. Moreover, obesity was an independent predictor positively affecting OS. These findings, also called the obesity paradox,33 are in line with recently published studies in patients with other malignancies and the elderly, also showing the survival benefit for the obese.16,17,33,34 To our knowledge this seemingly protective effect of increased percentage body fat has not yet been described for CRLM. Vigano et al. reported higher minor morbidity in the obese, but also concluded that major morbidity was comparable.35 Others found that obesity influenced major morbidity.36 Possibly the increased percentage body fat in this population was not as profound as needed to increase morbidity significantly,33 but just sufficient to increase the physiological reserve and have a positive effect on OS.
In order to prevent possible confounders, this study was performed among a homogenous population of only patients with CRLM. Moreover, we based sarcopenia on CT-based measurements, the gold standard for estimating muscle mass.37 The main drawbacks, however, of the present study are the retrospective design and the calculation of percentage body fat. Although calculation of percentage body fat based on the skeletal muscle area at the level of the third lumbar vertebra is believed reasonably accurate,18 measuring the body fat area on CT might be more reliable. Moreover, a bigger sample size might have enabled us to identify some factors as statistically significant that were now borderline significant.
In conclusion, the present study provides new insights in liver surgery for CRLM in relation to body composition. Sarcopenia, obesity and sarcopenic obesity do not seem to increase morbidity. However, obese and sarcopenic-obese patients were significantly more often readmitted. Increased body fat seemed to prolong OS and obesity was identified as an independent predictor of better OS. New studies on the effect of body composition disturbances on outcome after surgery should take the severity of obesity and sarcopenia into account as it might be that especially mild-to-moderate obesity has a protective effect on OS and severe obesity or severe sarcopenia have negative effects on complications, DFS and OS.
Conflicts of interest
None declared.
References
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