Abstract
Background
Incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are on the rise. Sarcopenia and sarcopenic obesity have proven to be prognostic factors in different types of cancers. In the context of previous findings, we evaluated the impact of body composition in patients undergoing surgery in a national pancreatic center.
Methods
Patient’s body composition (n = 133) was analyzed on diagnostic CT scans and defined as follows: Skeletal muscle index ≤38.5 cm2/m2 (women), ≤52.4 cm2/m2 (men); obesity was classified as BMI ≥25kg/m2.
Results
Sarcopenia showed a negative impact on overall survival (OS; 14 vs. 20 months, p = 0.016). Sarcopenic patients suffering from obesity showed poorer OS compared to non-sarcopenic obese patients (14 vs. 23 months, p = 0.007). Both sarcopenia and sarcopenic obesity were associated with sex (p<0.001 and p = 0.006; males vs. females 20% vs. 38% and 12% vs. 38%, respectively); sarcopenia was further associated with neoadjuvant treatment (p = 0.025), tumor grade (p = 0.023), weight loss (p = 0.02) and nutritional depletion (albumin, p = 0.011) as well as low BMI (<25 kg/m2, p = 0.038). Sarcopenic obese patients showed higher incidence of major postoperative complications (p<0.001). In addition, sarcopenia proved as an independent prognostic factor for OS (p = 0.031) in the multivariable Cox Regression model.
Conclusion
Patients with sarcopenia and sarcopenic obesity undergoing resection for PDAC have a significantly shorter overall survival and a higher complication rate. The assessment of body composition in these patients may provide a broader understanding of patients’ individual condition and guide specific supportive strategies in patients at risk.
Introduction
Pancreatic cancer is one of the most lethal malignancies. Even in times of multimodal treatment the prognosis remains poor[1]. In search of prognostic factors, the main focus lies on tumor-specific factors (TNM/UICC) rather than taking host-specific conditions into account[2]. Recently, body composition was evaluated in different oncologic patient cohorts; hereby, sarcopenia proved as a prognostic factor of morbidity, mortality and survival, especially in combination with obesity. It has also been associated with impaired response to chemo- and radiotherapy in a variety of cancers[3–6]. These insights started intensive research on therapeutic strategies including nutritional and pharmacological support as well as physical exercise[7–10]. Guidelines were elaborated to assess sex-specific body composition by measuring the cross-sectional muscle and visceral fat area at the level of the third lumbar vertebra on routinely available diagnostic computed tomography images and to analyze data using validated software[11–15]. Yet, in patients with pancreatic ductal adenocarcinoma (PDAC), data was controversially discussed[16–26]. However, a recent meta-analysis showed that sarcopenia and sarcopenic obesity was significantly associated with poorer overall survival; in patients with resectable PDAC, data on the impact of body composition on treatment-relevant postoperative complications are still rare, thus no conclusion could be drawn from these studies[27].
In the context of these previous findings, we aimed to explore the prevalence and clinical implications of sarcopenia and sarcopenic obesity in a patient cohort that underwent pancreatic resection in a national leading centre for PDAC treatment. Here we investigated the impact on survival as well as the relationship to nutritional status, conventional patient and tumor characteristics, comorbidities and postoperative complications.
Materials and methods
Ethical approval
We performed a retrospective analysis by summarizing patient and tumor characteristics anonymously from our institutional database at the Medical University of Vienna. Approval was obtained from the local Institutional Review Board (”Ethik Kommission”), Medical University of Vienna (IRB protocol #2012-P-000619/1).
Data collection
Patients who underwent pancreatic resection for PDAC between 2005 and 2010 were identified. Patients who received neoadjuvant chemo- or radiochemotherapy of various protocols due to borderline resectable disease were also included. After completion of neoadjuvant treatment, restaging scans were reviewed by an interdisciplinary panel/tumorboard. If resectable, patients were allocated to either pylorus-preserving pancreaticoduodenectomy or distal pancreatectomy depending on the location of the tumor. Patients with reported stable or progressive disease, despite completed neoadjuvant treatment who were directed towards further oncological treatment, were excluded from the study. Of these patients, those with preoperative diagnostic contrast enhanced computed tomographic (CT) scans, taken within 6 weeks prior to surgery, available in the electronic radiologic database, were included. Eligible patients were followed-up on for at least 24 months after surgery. Follow-up was conducted mostly within our outpatient clinic; for those who were followed-up on elsewhere, information was assessed via the Statistic Austria Death Index. If not available, patients or relatives were contacted via telephone and personally surveyed about the follow-up status.
Patient and tumor characteristics were recorded retrospectively. Variables included sex, age at the time of surgery, personal medical history, physical examination as well as routine laboratory testing. In addition, details on the surgical procedure, the postoperative course and the final pathological report were conducted. All data were extracted from our institutional database. Comorbidities were assessed using the Charlson age comorbidity index (CACI)[28], perioperative complications were reported according to the classification system defined by Clavien et al.[29] and fistulas were graded according to the latest consensus definitions[30]. Depleted nutritional status was defined as albumin <35mg/dl[31] and weight loss as >5% within 6 months prior to surgery[12]. Only patients whose data were completely available were selected for inclusion.
Anthropometric measures
Determination of body composition was conducted on preoperative contrast-enhanced, portal-venous-phase CT images as described by Mourtzakis et al.[11]. Images were analyzed using Osirix V5.8 software (Pixmeo Sarl, Switzerland).
CT Hounsfield unit thresholds were -29 to +150 for lean muscle (Fig 1)[32] and -190 to -30 HU and -150 to -50 HU for subcutaneous and intramuscular fat and visceral obese tissue[33], respectively. As necessary, a single-trained observer manually corrected the tissue boundaries.
Fig 1. Determination of body composition in patients with resectable pancreatic ductal adenocarcinoma.
Axial contrast-enhanced portal-venous phase CT image at the L3 level of a sarcopenic obese patient (A, 67-year old female, BMI 33 kg/m2, total muscle tissue cross-sectional area 109.2 cm2, skeletal muscle index 39.3 cm2/m2) compared to a non-sarcopenic obese patient (B, 71-year old female, BMI 31 kg/m2, total muscle tissue cross-sectional area 130.4 cm2, skeletal muscle index 47.7 cm2/m2). Marked red: psoas, paraspinal, transverse abdominal, external oblique, internal oblique and rectus abdominis muscles.
Two consecutive transverse CT images extending from the third lumbar vertebrae (L3) in the inferior direction were analyzed for total lean tissue, total lean muscle (psoas, erector spinae, quadratus lumborum, transverse abdominis, external and internal obliques and rectus abdominis) and adipose tissue (subcutaneous, intramuscular and visceral). Total fat-free tissue comprised soft tissue excluding intestinal contents and bones. In addition, tissue cross-sectional areas (cm2) were computed automatically by summing tissue pixels and multiplying by pixel surface area. Areas were normalized for stature (cm2/m2). Cut-offs for sarcopenia were based on the computed tomography-based sarcopenic obesity study of cancer patients conducted by Prado et al. (i.e., L3 skeletal muscle index ≤38.5 cm2/m2 for women and ≤52.4 cm2/m2 for men)[34]. Assessment of total body fat-free mass and total body fat mass was performed using the following regression equations defined by Mourtzakis et al.[11] Total body fat-free mass (FFM) (kg) = 0.3 × [skeletal muscle at L3 (cm2)] + 6.06 (r = 0.94); total body fat mass (FM) (kg) = 0.042 × [total adipose tissue at L3 (cm2)] + 11.2 (r = 0.88). Cut-off points for overweight and obesity were used as proposed by the World Health Organization (overweight—BMI ≥25kg/m2, obese—BMI ≥30kg/m2)[35].
Statistical analysis
Categorical variables were described by frequencies, numerical variables by median (range). For comparison of categorical variables between patient groups a Chi-squared test was used. Numerical variables were compared using the Mann-Whitney U test or a two-sample Student’s t-test, if normally distributed. Overall survival was defined as time of initial PDAC diagnosis until death from PDAC and recurrence-free survival (RFS) was defined as time from PDAC surgery until diagnosis of PDAC recurrence. Survival estimates were calculated by the Kaplan-Meier method (log-rank test for group comparisons). To estimate the median follow-up time, the reversed Kaplan-Meier method was used. Cox regression analysis was performed to estimate group differences between relative risks of death (hazard ratios, 95% confidence interval) and to adjust for effects. Established prognostic factors known to influence PDAC survival (T stage, N stage, grading) were included into the model next to sarcopenia. For explicit examination of the influence of sex and BMI on sarcopenia’s strength for survival prognostication, an interaction model was implemented. A two-sided p-value less than 0.05 was considered statistically significant. The SPSS version 24 software for Mac OsX and Sierra (IBM, USA) was used for analyses.
Results
Patient and tumor characteristics
A total of 179 patients underwent surgery for PDAC during the study period. In 46 patients, preoperative CT scans were not available due to technical reasons and were thus excluded from the study. Of the remaining 133 patients, analyzed data were fully available and they were thus included in the study. Of these, 78 patients suffered from sarcopenia and 25 from sarcopenic obesity. Sarcopenia was associated with sex (p<0.001), weight loss (p = 0.02), lower albumin levels (p = 0.011), higher tumor grading (p = 0.023) and neoadjuvant therapy (p = 0.035). Sarcopenic obesity was associated with sex (p = 0.006) and major postoperative complications (p<0.001). Patient and tumor characteristics are compiled in Tables 1 and 2.
Table 1. Patient and tumor characteristics comparing sarcopenic and non-sarcopenic patients.
| Total | Sarcopenia | No Sarcopenia | p-value | |
|---|---|---|---|---|
| n = 133 (100) | n = 78 (58.6) | n = 55 (41.4) | ||
| Age | 65 (34–87) | 66 (45–84) | 65 (34–87) | n.s. |
| Female | 65 (48.9) | 27 (20.3) | 38 (28.6) | <0.001 |
| Male | 68 (51.1) | 51 (38.3) | 17 (12.8) | |
| CACI* ≥5 | 20 (15.2) | 12 (9.1) | 8 (6.1) | n.s. |
| Postoperative complications (Clavien-Dindo ≥IIIB) | 20 (15.0) | 13 (9.8) | 7 (5.3) | n.s. |
| Fistula (≥grade B) | 27 (20.3) | 15 (11.3) | 12 (9.0) | n.s. |
| Weight loss (>5%) | 72 (54.1) | 49 (36.8) | 23 (17.3) | 0.017 |
| Albumin (g/l) | 40 (19–49) | 39 (24–48) | 41 (19–49) | 0.011 |
| CA 19–9 (kU/l) | 140 (0–2953) | 174 (0–2953) | 125 (0.7–2953) | n.s. |
| PPPD** | 112 (84.2) | 68 (51.1) | 44 (33.1) | n.s. |
| Distal PD*** | 21 (15.8) | 10 (7.5) | 11 (8.3) | |
| Neoadjuvant therapy | 20 (15.2) | 16 (12.1) | 4 (3.0) | 0.035 |
| Tumor grading (G3) | 54 (40.6) | 38 (28.6) | 16 (12.0) | 0.023 |
| Tumor stage ≥T3 | 108 (81.2) | 64 (48.1) | 44 (33.1) | n.s. |
| Nodal metastases (N1) | 91 (68.4) | 54 (40.6) | 37 (27.8) | n.s. |
| Distant metastases (M1) | 7 (5.3) | 4 (3.0) | 3 (2.3) | n.s. |
| UICC ≥IIB | 94 (70.7) | 55 (41.4) | 39 (29.3) | n.s. |
| Resection margin (R1) | 22 (16.5) | 12 (9.0) | 10 (7.5) | n.s. |
*Charlson Age-Comorbidity Index
**pylorus-preserving pancreaticoduodenectomy
***pancreatectomy; n.s. denotes not significant; nominal/ordinal variables are expressed by numbers and percentages, continuous variables by median and range.
Table 2. Patient and tumor characteristics comparing sarcopenic obese and non-sarcopenic obese patients.
| Total | Sarcopenic obesity | No sarcopenic obesity | p-value | |
|---|---|---|---|---|
| n = 133 (100) | n = 34 (25.6) | n = 99 (74.4) | ||
| Age | 68 (34–87) | 25 (45–84) | 108 (34–87) | n.s. |
| Female | 65 (48.9) | 8 (12.3) | 57 (87.7) | 0.006 |
| Male | 68 (51.1) | 26 (38.2) | 42 (61.8) | |
| CACI* ≥5 | 20 (15.2) | 1 (0.8) | 19 (14.4) | n.s. |
| Postoperative complications (Clavien-Dindo ≥IIIB) | 20 (15.0) | 18 (13.5) | 2 (1.5) | <0.001 |
| Fistula (≥grade B) | 27 (20.3) | 4 (3.0) | 23 171.3) | n.s. |
| Weight loss (>5%) | 72 (54.1) | 16 (12.0) | 56 (42.1) | n.s. |
| Albumin (g/l) | 40 (19–49) | 39 (24–48) | 35 (19–49) | n.s. |
| CA 19–9 (kU/l) | 81 (0–2953) | 22 (0–2953) | 59 (0.7–2953) | n.s. |
| PPPD** | 112 (84.2) | 22 (16.5) | 90 (67.7) | n.s. |
| Distal PD*** | 21 (15.8) | 3 (2.3) | 18 (13.5) | |
| Neoadjuvant therapy | 20 (15.2) | 5 (3.8) | 15 (11.4) | n.s. |
| Tumor grading G3 | 54 (40.6) | 13 (9.8) | 14 (30.8) | n.s. |
| Tumor stage ≥T3 | 108 (81.2) | 20 (15.0) | 88 (66.2) | n.s. |
| Nodal metastases (N1) | 91 (68.4) | 17 (12.8) | 74 (55.6) | n.s. |
| Distant metastases (M1) | 7 (5.3) | 2 (1.5) | 5 (3.8) | n.s. |
| UICC ≥IIB | 94 (70.6) | 18 (13.5) | 76 (57.1) | n.s. |
| Resection margin (R1) | 22 (16.5) | 6 (4.5) | 16 (12.0) | n.s. |
*Charlson Age-Comorbidity Index
**pylorus-preserving pancreaticoduodenectomy
***pancreatectomy; n.s. denotes not significant; nominal/ordinal variables are expressed by numbers and percentages, continuous variables by median and range.
Perioperative features
The majority of patients (112, 84.2%) underwent pylorus-preserving pancreaticoduodenectomy, (21, 15.8%) received distal pancreatectomy. Tangential or segmental venous resections were necessary in 22 (16%) patients. Operative mortality was 4%. The median length of stay was 13 days (6–85 days). There was no correlation between sarcopenia or sarcopenic obesity and postoperative morbidity (sarcopenia vs. no sarcopenia: 9.8% vs. 5.3%, p = 0.531 and sarcopenic obesity vs. no sarcopenic obesity: 7.5% vs. 9.5%, p = 0.876), mortality (sarcopenia vs. no sarcopenia: 3% vs. 0.8%, p = 0.323 and sarcopenic obesity vs. no sarcopenic obesity: 1.5% vs. 2.3%, p = 0.216) or median length of stay (sarcopenia vs. no sarcopenia: 14 vs. 11 days, p = 0.243 and sarcopenic obesity vs. no sarcopenic obesity: 16 vs. 13 days, p = 0.435).
Body composition analysis
Data on sarcopenia and sarcopenic obesity in relation to patient and tumor characteristics are shown in Tables 1 and 2. Sarcopenic obesity is defined as the presence of sarcopenia in patients with a BMI ≥30 kg/m2 according to Prado et al.[34]. Due to the relatively small number of obese patients (n = 7, 5%) in our cohort, we decided to fuse the WHO-defined groups “overweight” (BMI ≥25 kg/m2) and “obese” (BMI ≥30 kg/m2)[35]. Data on body composition in relation to sarcopenia are shown in Table 3. Due to significant sex differences between non-sarcopenic and sarcopenic as well as sarcopenic obese patients (p<0.001, Table 1 and p = 0.006, Table 2, respectively), body composition data are described separately in Table 4.
Table 3. Body composition data comparing sarcopenic and non-sarcopenic patients.
| Total | Sarcopenia | No Sarcopenia | p-value | |
|---|---|---|---|---|
| n = 133 (100) | n = 78 (58.6) | n = 55 (41.4) | ||
| WHO classification, n (%) | ||||
| Mean BMI (kg/m2) | 24 (±4.3) | 24 (±4.2) | 25 (±4.4) | 0.058 |
| Normal/underweight (BMI <25 kg/m2) | 65 (48.9) | 44 (33.1) | 21 (15.8) | 0.038 |
| Overweight/obese (BMI ≥25 kg/m2) | 68 (51.2) | 34 (25.6) | 34 (25.6) | |
| Absolute body composition data, cm2 (±SD) | ||||
| Lumbar total muscle tissue cross-sectional area | 126.5 (±28.6) | 122 (±27.9) | 132 (±28.7) | n.s. |
| Lumbar total adipose tissue cross-sectional area | 141.7 (±99.7) | 145.2 (±101.8) | 136.7 (±97.4) | n.s. |
| Relative body composition data, related to body surface area, cm2/m2 (±SD) | ||||
| Lumbar skeletal muscle index | 43.8 (±7.8) | 40.7 (±6.7) | 48.3 (±7.2) | n.s. |
| Lumbar adipose tissue index | 49.2 (±34.4) | 48.2 (±31.9) | 50.7 (±37.9) | n.s. |
| Estimated body composition data, kg (±SD) | ||||
| Estimated total fat-free mass | 44 (±8.6) | 42.7 (±8.4) | 45.9 (±8.6) | n.s. |
| Estimated total fat mass | 17.1 (±4.2) | 17.3 (±4.3) | 16.9 (±4.1) | n.s. |
n.s. denotes not significant; ±SD denotes standard deviation.
Table 4. Overall and sex-specific body composition data.
| Body composition | Cohort | Overall | Sarcopenia | No Sarcopenia |
|---|---|---|---|---|
| Overall | n = 133 (100) | n = 78 (58.6) | n = 55 (41.4) | |
| Female | n = 65 (48.9) | n = 27 (20.3) | n = 38 (28.6) | |
| Male | n = 68 (51.1) | n = 51 (38.3) | n = 17 (12.8) | |
| WHO classification, n (%) | ||||
| Mean BMI (kg/m2) | Overall | 24 (±4.3) | 24 (±4.2) | 25 (±4.4) |
| Female | 24 (±4.7) | 22.7 (±4.1) | 24.8 (±4.9) | |
| Male | 25 (±3.9) | 24.5 (±4.1) | 26.1 (±2.8) | |
| Normal/underweight (BMI <25 kg/m2) | Overall | 65 (48.9) | 44 (33.1) | 21 (15.8) |
| Female | 37 (56.9) | 19 (29.2) | 18 (27.2) | |
| Male | 28 (41.2) | 25 (36.8) | 3 (4.4) | |
| Overweight/obese (BMI ≥25 kg/m2) | Overall | 68 (51.2) | 34 (25.6) | 34 (25.6) |
| Female | 28 (43.1) | 8 (12.3) | 20 (30.8) | |
| Male | 40 (58.8) | 26 (38.2) | 14 (20.6) | |
| Absolute body composition data, cm2 (±SD) | ||||
| Lumbar total muscle tissue cross-sectional area | Overall | 126.5 (±28.6) | 122 (±27.9) | 132 (±28.7) |
| Female | 106.2 (±17.6) | 91.9 (±12.1) | 116.3 (±13.3) | |
| Male | 146.0 (±23.1) | 138.1 (±19.3) | 169.5 (±17.2) | |
| Lumbar total adipose tissue cross-sectional area | Overall | 141.7 (±99.7) | 145.2 (±101.8) | 136.7 (±97.4) |
| Female | 110.0 (±83.4) | 195.3 (±65.4) | 120.4 (±93.6) | |
| Male | 172.1 (±105.1) | 171.7 (±108.1) | 173.4 (±98.5) | |
| Relative body composition data, related to body surface area, cm2/m2 (±SD) | ||||
| Lumbar skeletal muscle index | Overall | 43.8 (±7.8) | 40.7 (±6.7) | 48.3 (±7.2) |
| Female | 40.1 (±6.8) | 34.0 (±4.0) | 44.5 (±4.6) | |
| Male | 47.5 (±7.0) | 44.4 (±4.7) | 56.9 (±3.2) | |
| Lumbar adipose tissue index | Overall | 49.2 (±34.4) | 48.2 (±31.9) | 50.7 (±37.9) |
| Female | 44.3 (±13.9) | 25.3 (±24.5) | 46.9 (±38.7) | |
| Male | 44.1 (±14.0) | 43.4 (±15.4) | 46.0 (±8.6) | |
| Estimated body composition data, kg (±SD) | ||||
| Estimated total fat-free mass | Overall | 44 (±8.6) | 42.7 (±8.4) | 45.9 (±8.6) |
| Female | 37.9 (±5.3) | 33.6 (±3.6) | 40.9 (±4.0) | |
| Male | 50.0 (±6.9) | 47.5 (±5.8) | 56.9 (±5.2) | |
| Estimated total fat mass | Overall | 17.1 (±4.2) | 17.3 (±4.3) | 16.9 (±4.1) |
| Female | 15.8 (±3.5) | 15.2 (±2.8) | 16.3 (±3.9) | |
| Male | 18.4 (±4.4) | 8.4 (±4.5) | 18.5 (±0.6) | |
n.s. denotes not significant; ±SD denotes standard deviation.
Sarcopenia, sarcopenic obesity and survival
The median follow-up was 134 months, the median survival was 16 months (13–19 months) in the entire cohort and 103 patients (77%) relapsed during the follow-up period. Sarcopenic patients showed impaired overall survival (OS) compared to non-sarcopenic patients (Kaplan Meier/log rank; 14 vs. 20 months, p = 0.016, Fig 2). Multivariable Cox regression analysis revealed sarcopenia as an independent prognostic factor for OS (p = 0.031, adjusted for tumor grading, stage and nodal metastases; p = 0.023, adjusted for tumor grading/stage and nodal metastases as well as BMI; p = 0.045, adjusted for tumor grading/stage and nodal metastases as well as sex). Furthermore, as demonstrated by an interaction model, the prognostic effect of sarcopenia is modified by the patient’s BMI level and sex (p-value for interaction term: p = 0.018 and p = 0.032, respectively). Thus, survival analysis for sarcopenic vs. non-sarcopenic patients was performed separately for sexes (Kaplan Meier/log rank: male sarcopenic vs. non-sarcopenic: 15 vs. 25 months, p = 0.023, and female sarcopenic vs. non-sarcopenic: 14 vs. 20 months, p = 0.387, respectively; Figs 3 and 4) and BMI groups (Kaplan Meier/log rank: BMI ≥25 kg/m2 (sarcopenic obese vs. non-sarcopenic obese): 14 vs. 23 months, p = 0.007 and BMI <25 kg/m2 (sarcopenic normal/underweight vs. non-sarcopenic normal/underweight): 14 vs. 16 months, p = 0.679, respectively; Figs 5 and 6). Overall survival data, according to Kaplan Meier and Cox Regression analysis are compiled in Tables 5 and 6.
Fig 2. Kaplan Meier curve for overall survival in sarcopenic vs. non-sarcopenic patients.
Sarcopenia diminishes overall survival in patients with resectable PDAC (14 vs. 20 months, p = 0.016).
Fig 3. Kaplan Meier curve for overall survival in sarcopenic vs. non-sarcopenic male patients.
Sarcopenia diminishes overall survival in male patients with resectable PDAC (15 vs. 25 months, p = 0.023).
Fig 4. Kaplan Meier curve for overall survival in sarcopenic vs. non-sarcopenic female patients.
Sarcopenia does not diminish overall survival in female patients with resectable PDAC (14 vs. 20 months, p = 0.378).
Fig 5. Kaplan Meier curve for overall survival in obese sarcopenic vs. non-sarcopenic patients (BMI ≥25 kg/m2).
Sarcopenia diminishes overall survival in obese patients with resectable PDAC (14 vs. 23 months, p = 0.007).
Fig 6. Kaplan Meier curve for overall survival in normal/underweight sarcopenic vs. non-sarcopenic patients (BMI <25 kg/m2).
Sarcopenia does not diminish overall survival in normal/underweight patients with resectable PDAC (14 vs. 16 months, p = 0.679).
Table 5. Kaplan Meier estimates for overall survival.
| Kaplan Meier estimates | Median (range) | p-value |
|---|---|---|
| Total (n = 133) | 16 months (13–19) | n.a. |
| Sarcopenia | ||
| Yes (n = 78) vs. no (n = 55) | 14 (11–17) vs. 20 (14–26) | 0.016 |
| Sex-specific sarcopenia | ||
| Female: Yes (n = 27) vs. no (n = 38) | 14 (9–19) vs. 20 (14–26) | n.s. |
| Male: Yes (n = 51) vs. no (n = 17) | 15 (12–19) vs. 25 (2–48) | 0.023 |
| Sarcopenic obesity (BMI ≥25 kg/m2) | ||
| Yes (n = 25) vs. no (n = 108) | 14 (11–17) vs. 23 (16–30) | 0.007 |
| Serum albumin | ||
| <35 (n = 18) vs. ≥35 mg/dl (n = 115) | 12 (9–15) vs. 18 (14–21) | 0.044 |
| Neoadjuvant therapy | ||
| Yes (n = 113) vs. no (n = 20) | 28 (22–25) vs. 24 (16–32) | n.s. |
| CACI* | ||
| ≥5 (n = 43) vs. <5 (n = 90) | 15 (12–18) vs. 18 (14–22) | 0.032 |
| Tumor grading | ||
| G3 (n = 54) vs. G1-2 (n = 79) | 20 (16–24) vs. 12 (11–13) | 0.012 |
| Tumor stage | ||
| T≥3 (n = 108) vs. T<3 (n = 25) | 23 (13–33) vs. 16 (13–19) | n.s. |
| Nodal metastases | ||
| N1 (n = 91) vs. N0 (n = 42) | 20 (8–32) vs. 16 (13–19) | 0.005 |
| Distant metastases | ||
| M1 (n = 7) vs. M0 (n = 126) | 16 (13–19) vs. 13 (5–21) | n.s. |
| Resection margin | ||
| R1 (n = 22) vs. R0 (n = 111) | 18 (14–21) vs. 15 (12–18) | n.s. |
*Charlson Age-Comorbidity Index; n.a. denotes not applicable; n.s. denotes not significant.
Table 6. Uni- and multivariable Cox-Regression analyses and interaction models for overall survival.
| Univariable analysis | HR (95% CI) | p-value |
| Sarcopenia | 1.55 (1.07–2.23) | 0.016 |
| Sarcopenic obesity | 1.02 (1.00–1.03) | 0.007 |
| Serum albumin | 1.63 (1.0–2.7) | 0.044 |
| BMI | 0.86 (0.60–1.22) | n.s. |
| CACI* | 1.68 (1.03–2.73) | 0.032 |
| Neoadjuvant therapy | 1.0 (0.6–1.62) | n.s. |
| Tumor grading | 1.16 (1.03–1.31) | 0.012 |
| Tumor stage | 1.41 (1.0–2.0) | n.s. |
| Nodal metastases | 1.75 (1.17–2.62) | 0.005 |
| Distant metastases | 1.04 (0.46–2.36) | n.s. |
| Resection margin | 1.47 (0.91–2.35) | n.s. |
| Multivariable models | HR (95% CI) | p-value |
| Sarcopenia** | 1.51 (1.04–2.19) | 0.031 |
| Tumor grading | 1.17 (1.04–1.33) | 0.011 |
| Tumor stage | 1.3 (0.92–1.85) | n.s. |
| Nodal metastases | 1.76 (1.16–2.66) | 0.008 |
| Sarcopenic obesity** | 1.46 (0.92–2.3) | n.s. |
| Tumor grading | 1.18 (1.04–1.33) | 0.01 |
| Tumor stage | 1.31 (0.92–1.85) | n.s. |
| Nodal metastases | 1.19 (1.18–2.72) | 0.007 |
| Sarcopenia*** | 1.55 (1.1–2.3) | 0.023 |
| Tumor grading | 1.18 (1.04–1.33) | 0.010 |
| Tumor stage | 1.31 (0.92–1.85) | n.s. |
| Nodal metastases | 1.79 (1.18–2.72) | 0.007 |
| BMI | 1.02 (0.98–1.06) | n.s. |
| Sarcopenia**** | 1.49 (1.01–2.19) | 0.045 |
| Tumor grading | 1.17 (1.04–1.33) | 0.011 |
| Tumor stage | 1.30 (0.91–1.84) | n.s. |
| Nodal metastases | 1.75 (1.16–2.66) | 0.008 |
| Sex | 1.04 (0.72–1.52) | n.s. |
| Interaction models** | p-value | |
| Sarcopenia*BMI | n.a. | 0.018 |
| Sarcopenia*sex | n.a. | 0.032 |
*Charlson Age-Comorbidity Index
**adjusted for tumor grading, stage and nodal metastases
***adjusted for tumor grading/stage and nodal metastases as well as BMI
****adjusted for tumor grading/stage and nodal metastases as well as sex; n.s. denotes not significant, n.a. denotes not applicable.
Recurrence-free survival (RFS) was not impaired in sarcopenic vs. non-sarcopenic patients (Kaplan Meier/log rank: 9 vs. 10 months, p = 0.275, S1 Fig). Furthermore, no differences were found between male and female sarcopenic vs. non-sarcopenic patients (Kaplan Meier/log rank: male: 9 vs. 9 months, p = 0.216, and female: 10 vs. 11 months, p = 0.709; S2 and S3 Figs) or sarcopenic obese vs. non-sarcopenic obese as well as sarcopenic normal/underweight vs. non-sarcopenic normal/underweight patients (Kaplan Meier/log rank: BMI ≥25kg/m2: 9 vs. 13 months, p = 0.173 and BMI <25kg/m2: 9 vs. 10 months, p = 0.698, respectively, S4 and S5 Figs).
Discussion
Surgery is considered to be the mainstay of curative treatment for patients with PDAC. However, despite multimodal treatment strategies survival remains poor[1]. Yet, approved markers for predicting survival in PDAC are limited to tumor-specific features without considering host-specific body composition as significant determinant of outcome[2, 36–38]. In the present study, we aimed to validate sarcopenia and sarcopenic obesity as prognostic factors in a series of 133 patients undergoing surgery for PDAC in a national pancreatic centre. Our findings confirmed a negative impact of sarcopenia as well as sarcopenic obesity on overall survival (OS).
PDAC is associated with an excessive catabolic state that leads to progressive physical deterioration, known as cachexia, that reduces the tolerance to preoperative treatment and increases the likelihood of complications[39, 40]. PDAC patients are diagnosed with cachexia at a high rate and up to 80% suffered from severe cachexia at the time of death[41–43]. Cachexia is defined as a significant degree of weight loss depending on the prevalence of sarcopenia (generalized muscle disorder) and/or individual BMI[12] and is currently understudied in patients with PDAC[44]. In this study we demonstrate that preoperative sarcopenia and weight loss were significantly associated, whereby 62.8% of the sarcopenic patients suffered from weight loss >5% prior to surgery and hence suffered from cachexia[12].
Initially known as depletion of skeletal muscle mass, strength and physical performance, sarcopenia has recently been re-defined as a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes and mortality[45] that results in high personal, social and economic costs[46]. Recent studies using computertomography for body composition analysis, validate that PDAC patients frequently suffer from sarcopenia[27, 44] and whenever possible, tumor resection is the best way to stop further muscle wasting[47]. In this study, more than half the patients (58.6%) with resectable pancreatic cancer were sarcopenic at the time of diagnosis, with male patients more likely to be affected (65.4%). Interestingly, we found a strong association of sarcopenia with neoadjuvant therapy, poor tumor differentiation and low serum albumin levels; all of these factors are known to further promote physical deterioration[31, 47].
Over the course of this past decade the clinical importance of sarcopenia as part of the cancer cachexia syndrome has been widely recognized and efforts have been made to define therapeutic improvements[48–54]. While originally a measure of frailty in geriatric non-cancer patients, the prognostic impact of sarcopenia has recently been observed in several gastrointestinal malignancies including PDAC[4, 5, 27]. The prevalence of sarcopenia found in these previous studies was consistent with our findings[27, 44].
We further validate that sarcopenia is an independent prognostic factor of OS and that its prognostic significance is associated with BMI. Patients suffering from sarcopenia who had a BMI ≥25 kg/m2 died sooner than normal or underweight patients. Peng et al. showed that sarcopenic patients undergoing pancreatic resection suffered from impaired OS[55]; still, no conclusion can be drawn as to the role of obesity in this study, since body composition data was not compared between BMI groups. Only a relatively small subset of studies report sarcopenia in the context of overweight patients and outline that the development of sarcopenic obesity and its modification options are barely understood[13, 34, 56]. Sarcopenic obesity has been found to be connected to aging and lifestyle. It is understood to be a complex syndrome that is based on reduced physical activity and results in accelerated loss of muscle mass and in decreased energy consumption. In cancer patients, increased body fat mass was associated with dissatisfactory pain management[13, 57]. In patients with resectable PDAC, sarcopenia, as well as sarcopenic obesity have been confirmed as crucial determinants of overall survival[56]; yet, compared to other gastrointestinal cancers, convincing data on the impact of body composition on postoperative complications are rare[58–60]. Here, we demonstrate that sarcopenic patients suffering from obesity (BMI ≥25kg/m2) have a higher rate of treatment-relevant postoperative complications. Similar findings have recently been reported by Sandini et al. revealing that sarcopenic obesity (referred to as visceral fat to skeletal muscle ratio) was an independent determinant of major complications after pancreaticoduodenectomy[24]. In the past, sarcopenic obesity has often been referred to as visceral fat to skeletal muscle ratio. Pecorelli et al. showed that the ratio of visceral fat to skeletal muscle (as an equivalent to sarcopenic obesity) was higher in patients who died after pancreatic resection compared to survivors[22]. However, the relationship between fat and muscle compartments seems to have an impact on outcome of PDAC patients and is currently understudied[18, 19, 25, 61]. Patients with sarcopenic obesity are less likely to be recognized as “high risk” patients, and hence less likely to receive (perioperative) nutritional support. Whether these patients should be supplied with tailored nutritional support in accordance with normal or underweight sarcopenic patients remains to be clarified by prospective clinical investigations. In fact, 64% of sarcopenic obese patients in this study indicated weight loss at the time of hospital admission, still weight loss was not significantly associated with sarcopenic obesity. Ultimately, these findings underline the importance of carefully screening this subgroup of patients.
According to previous findings, we found a strong association of sex with sarcopenia as well as sarcopenic obesity in patients with resectable PDAC[62]. In our patient cohort, males suffer from sarcopenia and sarcopenic obesity at a significantly higher rate. In fact, men experience greater muscle loss during the process of physiological aging[63]. We here demonstrate that the prognostic significance of sarcopenia is associated with sex. Male sarcopenic patients died sooner than male non-sarcopenic patients; in females, no differences were found between sarcopenic and non-sarcopenic patients. Studies in cancer patients show that men lose skeletal muscle mass and strength over time and at a faster rate when compared to women[64] implicating sex differences in body composition. Accordingly, sex-specific cut-offs have been recommended for body composition analysis[11].
The negative sequelae of sarcopenia have shown an increased awareness in regard to cancer treatment and studies exploring nutritional and pharmacological support as well as exercise programs to prevent physical deterioration are under investigation [7, 10, 65, 66]. Further results need to be looked at in order to define patient cohorts amenable for such multimodal approaches.
A considerable limitation of the study design is that since it was not based on a power calculation, subgroup analyses in particular have to be interpreted deliberately.
Our findings confirm that sarcopenia and sarcopenic obesity are independent prognostic factors for OS in patients with resectable PDAC. In sarcopenic patients, neoadjuvant therapy and tumor grade as well as sex, nutritional status, weight loss and BMI play a crucial role for postoperative outcome. These data underline the importance of body composition in addition to other determinants of the disease in differentiating a “high risk” situation from a conditional perspective and selecting specifically those patients that might benefit from additional support strategies.
Supporting information
Sarcopenia does not impair recurrence-free survival in patients with resectable PDAC (15 vs. 25 months, p = 0.275).
(TIFF)
Sarcopenia does not impair recurrence-free survival in male patients with resectable PDAC (9 vs. 9 months, p = 0.216).
(TIFF)
Sarcopenia does not impair recurrence-free survival in female patients with resectable PDAC (10 vs. 11 months, p = 0.709).
(TIFF)
Sarcopenia does not impair recurrence-free survival in obese patients with resectable PDAC (9 vs. 10 months, p = 0.698).
(TIFF)
Sarcopenia does not impair recurrence-free survival in normal/underweight patients with resectable PDAC (9 vs. 13 months, p = 0.173).
(TIFF)
Acknowledgments
We thank Alexandra Kaider for statistical advice and Gretchen Simms for proofreading of the manuscript.
Data Availability
All relevant data are within the manuscript and its Supporting Information files.
Funding Statement
The authors received no specific funding for this work.
References
- 1.Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann Oncol. 2014;25(8):1650–6. 10.1093/annonc/mdu138 [DOI] [PubMed] [Google Scholar]
- 2.Akerberg D, Ansari D, Andersson R. Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas. World J Gastroenterol. 2016;22(28):6424–33. 10.3748/wjg.v22.i28.6424 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Daly LE, Ni Bhuachalla EB, Power DG, Cushen S, James K, Ryan A. Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancer. J Cachexia Sarcopenia Muscle. 2018;9(2):315–25. 10.1002/jcsm.12267 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Joglekar S, Nau PN, Mezhir JJ. The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature. J Surg Oncol. 2015;112(5):503–9. 10.1002/jso.24025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Levolger S, van Vugt JL, de Bruin RW, IJzermans J. Systematic review of sarcopenia in patients operated on for gastrointestinal and hepatopancreatobiliary malignancies. Br J Surg. 2015;102(12):1448–58. 10.1002/bjs.9893 [DOI] [PubMed] [Google Scholar]
- 6.Wagner D, DeMarco MM, Amini N, Buttner S, Segev D, Gani F, et al. Role of frailty and sarcopenia in predicting outcomes among patients undergoing gastrointestinal surgery. World J Gastrointest Surg. 2016;8(1):27–40. 10.4240/wjgs.v8.i1.27 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clinical Nutrition. 2017;36(1):11–48. 10.1016/j.clnu.2016.07.015 [DOI] [PubMed] [Google Scholar]
- 8.Mochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, et al. A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project. Journal of Cachexia, Sarcopenia and Muscle. 2017;8(1):25–39. 10.1002/jcsm.12127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Rooks D, Praestgaard J, Hariry S, Laurent D, Petricoul O, Perry R, et al. Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof-of-Concept Study. J Am Geriatr Soc. 2017. [DOI] [PubMed] [Google Scholar]
- 10.Yoh K, Nishikawa H, Enomoto H, Ishii N, Iwata Y, Ishii A, et al. Effect of exercise therapy on sarcopenia in pancreatic cancer: a study protocol for a randomised controlled trial. BMJ Open Gastroenterol. 2018;5(1):e000194 10.1136/bmjgast-2017-000194 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mourtzakis M, Prado CMM, Lieffers JR, Reiman T, McCargar L, Baracos V. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Applied Physiology, Nutrition, and Metabolism. 2008;33(5):997–1006. [DOI] [PubMed] [Google Scholar]
- 12.Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger R, et al. Definition and classification of cancer cachexia: an international consensus. The Lancet Oncology. 2011;12(5):489–95. 10.1016/S1470-2045(10)70218-7 [DOI] [PubMed] [Google Scholar]
- 13.Baracos VE, Arribas L. Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol. 2018;29. [DOI] [PubMed] [Google Scholar]
- 14.van Vugt JLA, Levolger S, Gharbharan A, Koek M, Niessen W, Burger J, et al. A comparative study of software programmes for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed tomography scan of rectal cancer patients. Journal of Cachexia, Sarcopenia and Muscle. 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–23. 10.1093/ageing/afq034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Choi Y, Oh D, Kim T, Lee K, Han S, Im S, et al. Skeletal Muscle Depletion Predicts the Prognosis of Patients with Advanced Pancreatic Cancer Undergoing Palliative Chemotherapy, Independent of Body Mass Index. Plos One. 2015;10(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cooper AB, Slack R, Fogelman D, Holmes H, Petzel M, Parker N, et al. Characterization of Anthropometric Changes that Occur During Neoadjuvant Therapy for Potentially Resectable Pancreatic Cancer. Ann Surg Oncol. 2015;22(7):2416–23. 10.1245/s10434-014-4285-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Dalal S, Hui D, Bidaut L, Lem K, Del Fabbro E, Crane C, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage. 2012;44(2):181–91. 10.1016/j.jpainsymman.2011.09.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ninomiya G, Fujii T, Yamada S, Yabusaki N, Suzuki K, Iwata N, et al. Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma: A retrospective cohort study. International Journal of Surgery. 2017;39:45–51. 10.1016/j.ijsu.2017.01.075 [DOI] [PubMed] [Google Scholar]
- 20.Nishida Y, Kato Y, Kudo M, Aizawa H, Okubo S, Takahashi D, et al. Preoperative Sarcopenia Strongly Influences the Risk of Postoperative Pancreatic Fistula Formation After Pancreaticoduodenectomy. Journal of Gastrointestinal Surgery. 2016;20(9):1586–94. 10.1007/s11605-016-3146-7 [DOI] [PubMed] [Google Scholar]
- 21.Okumura S, Kaido T, Hamaguchi YF, Y., Masui T, Mizumoto M, Hammad A, et al. Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer. Ann Surg Oncol. 2017;24(12):3732–40. 10.1245/s10434-017-6077-y [DOI] [PubMed] [Google Scholar]
- 22.Pecorelli N, Carrara G, De Cobelli F, Cristel G, Damascelli A, Balzano G, et al. Effect of sarcopenia and visceral obesity on mortality and pancreatic fistula following pancreatic cancer surgery. Br J Surg. 2016;103(4):434–42. 10.1002/bjs.10063 [DOI] [PubMed] [Google Scholar]
- 23.Rollins KE, Tewari N, Ackner A, Awwad A, Madhusudan SM, IA, Fearon K, et al. The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma. Clinical Nutrition. 2015;35(5):1103–9. 10.1016/j.clnu.2015.08.005 [DOI] [PubMed] [Google Scholar]
- 24.Sandini M, Bernasconi DP, Fior D, Molinelli M, Ippolito D, Nespoli L, et al. A high visceral adipose tissue-to-skeletal muscle ratio as a determinant of major complications after pancreatoduodenectomy for cancer. Nutrition. 2016;32(11–12):1231–7. 10.1016/j.nut.2016.04.002 [DOI] [PubMed] [Google Scholar]
- 25.Tan BH, Birdsell LA, Martin L, Baracos V, Fearon K. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res. 2009;15(22):6973–9. 10.1158/1078-0432.CCR-09-1525 [DOI] [PubMed] [Google Scholar]
- 26.Van Dijk DB MJAM Coolson MME, Rensen S, van Dam R, Bours MW, Dejong MP, CH, Olde Damink S. Low skeletal muscle radiation attenuation and visceral adiposity are associated with overall survival and surgical site infections in patients with pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle. 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mintziras I, Miligkos M, Waechter S, Manoharan J, Maurer E, Bartsch D. Sarcopenia and sarcopenic obesity are significantly associated with poorer overall survival in patients with pancreatic cancer: Systematic review and meta-analysis. Int J Surg. 2018;59:19–26. 10.1016/j.ijsu.2018.09.014 [DOI] [PubMed] [Google Scholar]
- 28.Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51. [DOI] [PubMed] [Google Scholar]
- 29.Clavien PA, Barkun J, de Oliveira ML, Vauthey J, Dindo D, Schulick R, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250(2):187–96. 10.1097/SLA.0b013e3181b13ca2 [DOI] [PubMed] [Google Scholar]
- 30.Bassi C, Marchegiani G, Dervenis C, Sarr M, Abu Hilal M, Adham M, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After. Surgery. 2017;161(3):584–91. 10.1016/j.surg.2016.11.014 [DOI] [PubMed] [Google Scholar]
- 31.Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: A systematic review of the epidemiological literature. Nutrition Journal. 2010;9(1). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol (1985). 1998;85(1):115–22. 10.1152/jappl.1998.85.1.115 [DOI] [PubMed] [Google Scholar]
- 33.Vehmas T, Kairemo KJ, Taavitsainen MJ. Measuring visceral adipose tissue content from contrast enhanced computed tomography. International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity. 1996;20(6):570–3. [PubMed] [Google Scholar]
- 34.Prado CMM, Lieffers JR, McCargar LJ, Reiman T, Sawyer M, Martin L, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. The Lancet Oncology. 2008;9(7):629–35. 10.1016/S1470-2045(08)70153-0 [DOI] [PubMed] [Google Scholar]
- 35.WHO. Physical Status: The Use and Interpretation of Anthropometry. WHO Technical Report Series. 1995. [PubMed]
- 36.Chun YS, Pawlik TM, Vauthey JN. 8th Edition of the AJCC Cancer Staging Manual: Pancreas and Hepatobiliary Cancers. Ann Surg Oncol. 2017. [DOI] [PubMed] [Google Scholar]
- 37.Epstein JD, Kozak G, Fong ZV, He J, Javed AA, Joneja U, et al. Microscopic lymphovascular invasion is an independent predictor of survival in resected pancreatic ductal adenocarcinoma. J Surg Oncol. 2017;116(6):658–64. 10.1002/jso.24723 [DOI] [PubMed] [Google Scholar]
- 38.Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goéré D, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v56–68. [DOI] [PubMed] [Google Scholar]
- 39.Bachmann J, Buechler MW, Friess H, Martignoni M. Cachexia in patients with chronic pancreatitis and pancreatic cancer: impact on survival and outcome. Nutr Cancer. 2013;65(6):827–33. 10.1080/01635581.2013.804580 [DOI] [PubMed] [Google Scholar]
- 40.Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler M, Friess H, Martignoni M. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg. 2008;12(7):1193–201. 10.1007/s11605-008-0505-z [DOI] [PubMed] [Google Scholar]
- 41.Dewys WD, Begg C, Lavin PT, Band P, Bennett J, Bertino J, et al. Prognostic effect of weight loss prior tochemotherapy in cancer patients. The American Journal of Medicine. 1980;69(4):491–7. [DOI] [PubMed] [Google Scholar]
- 42.Viganó A, Bruera E, Jhangri GS, Newman S, Fields A, Suarez-Almazor M. Clinical Survival Predictors in Patients With Advanced Cancer. Archives of Internal Medicine. 2000;160(6):861–8. [DOI] [PubMed] [Google Scholar]
- 43.Wigmore SJ, Plester CE, Richardson RA, Fearon K. Changes in nutritional status associated with unresectable pancreatic cancer. British Journal Of Cancer. 1997;75:106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ozola Zalite I, Zykus R, Francisco Gonzalez M, Saygili F, Pukitis A, Gaujoux S, et al. Influence of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma: a systematic review. Pancreatology. 2015;15(1):19–24. 10.1016/j.pan.2014.11.006 [DOI] [PubMed] [Google Scholar]
- 45.Cruz-Jentoft AJ, Bahat G, Bauer JM, Boirie Y, Bruyère O, Cederholm TC, C, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age and Ageing. 2019;48(1):16–31. 10.1093/ageing/afy169 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mijnarends DM, Luiking YC, Halfens RJ, Evers SMAA, Lenaerts ELA, Verlaan S, et al. Muscle, Health and Costs: A Glance at their Relationship. The journal of nutrition, health & aging. 2018;22(7):766–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Aslani A, Gill AJ, Roach PJ, B.J. A, Smith RC. Preoperative body composition is influenced by the stage of operable pancreatic adenocarcinoma but does not predict survival after Whipple's procedure. HPB (Oxford). 2010;12(5):325–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Pausch T, Hartwig W, Hinz U, Swolana T, Bundy BD, Hackert T, et al. Cachexia but not obesity worsens the postoperative outcome after pancreatoduodenectomy in pancreatic cancer. Surgery. 2012;152(3 Suppl 1):S81–8. [DOI] [PubMed] [Google Scholar]
- 49.Ní Bhuachalla ÉB, Daly LE, Power DG, Cushen SJ, MacEneaney P, Ryan AM. Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition? Journal of cachexia, sarcopenia and muscle. 2018;9(2):295–305. 10.1002/jcsm.12258 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Mueller TC, Burmeister MA, Bachmann J, Martignoni ME. Cachexia and pancreatic cancer: are there treatment options? World J Gastroenterol. 2014;20(28):9361–73. 10.3748/wjg.v20.i28.9361 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Solheim TS, Laird BJA, Balstad TR, Stene GB, Bye A, Johns N, et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J Cachexia Sarcopenia Muscle. 2017;8(5):778–88. 10.1002/jcsm.12201 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Tan CR, Yaffee PM, Jamil LH, Lo SK, Nissen N, Pandol SJ, et al. Pancreatic cancer cachexia: a review of mechanisms and therapeutics. Front Physiol. 2014;5:88 10.3389/fphys.2014.00088 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Solheim TS, Laird BJA, Balstad TR, Bye A, Stene G, Baracos V, et al. Cancer cachexia: rationale for the MENAC (Multimodal—Exercise, Nutrition and Anti-inflammatory medication for Cachexia) trial. BMJ Supportive & Palliative Care. 2018;8(3):258. [DOI] [PubMed] [Google Scholar]
- 54.Fearon KC, Baracos VE. Cachexia in pancreatic cancer: new treatment options and measures of success. HPB (Oxford). 2010;12(5):323–4. 10.1111/j.1477-2574.2010.00178.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Peng P, Hyder O, Firoozmand A, Kneuertz P, Schulick RD, Huang D, et al. Impact of sarcopenia on outcomes following resection of pancreatic adenocarcinoma. J Gastrointest Surg. 2012;16(8):1478–86. 10.1007/s11605-012-1923-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Mintziras I, Miligkos M, Wächter S, Manoharan J, Maurer E, Bartsch DK. Sarcopenia and sarcopenic obesity are significantly associated with poorer overall survival in patients with pancreatic cancer: Systematic review and meta-analysis. International Journal of Surgery. 2018;59:19–26. 10.1016/j.ijsu.2018.09.014 [DOI] [PubMed] [Google Scholar]
- 57.Prado CM, Sawyer MB, Ghosh S, Lieffers JRE, N. Antoun S., Baracos VE. Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential? Am J Clin Nutr. 2013;98(4):1012–9. 10.3945/ajcn.113.060228 [DOI] [PubMed] [Google Scholar]
- 58.Feliciano EMC, Kroenke CH, Meyerhardt JA, Prado CM, Bradshaw PT, Kwan ML, et al. Association of Systemic Inflammation and Sarcopenia With Survival in Nonmetastatic Colorectal Cancer: Results From the C SCANS StudySystemic Inflammation, Sarcopenia, and Survival in Colorectal CancerSystemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer. JAMA Oncology. 2017;3(12):e172319–e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Elliott JA, Doyle SL, King S, Guinan EM, Beddy P, Ravi N, et al. Sarcopenia: Prevalence, and Impact on Operative and Oncologic Outcomes in the Multimodal Management of Locally Advanced Esophageal Cancer. Ann of Surg. 2017;266(5):822–30. [DOI] [PubMed] [Google Scholar]
- 60.Shen Y, Hao Q, Zhou J, Dong B. The impact of frailty and sarcopenia on postoperative outcomes in older patients undergoing gastrectomy surgery: a systematic review and meta-analysis. BMC Geriatrics. 2017;17(1):188 10.1186/s12877-017-0569-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Okumura S, Kaido T, Hamaguchi Y. Impact of preoperative quality as well as quantity of skeletal muscle on survival after resection of pancreatic cancer. Surgery. 2015;157(6):1088–98. 10.1016/j.surg.2015.02.002 [DOI] [PubMed] [Google Scholar]
- 62.Nakamura NH, Hara T, Shibata YM, Nakamura T., Ninomiya H., S., Kito Y, Kitagawa J, Kanemura N, et al. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma. Ann Hematol. 2015;94(12):2043–53. 10.1007/s00277-015-2499-4 [DOI] [PubMed] [Google Scholar]
- 63.Doherty T. The influence of aging and sex on skeletal muscle mass and strength. Current Opinion in Clinical Nutrition and Metabolic Care. 2001;4(6):503–8. [DOI] [PubMed] [Google Scholar]
- 64.Stephens NA, Gray C, MacDonald AJ, Tan BH, Gallagher IJS, R.J., Ross JA, et al. Sexual dimorphism modulates the impact of cancer cachexia on lower limb muscle mass and function. Clin Nutr. 2012;31(4):499–505. 10.1016/j.clnu.2011.12.008 [DOI] [PubMed] [Google Scholar]
- 65.Argiles JM, Busquets S, Lopez-Soriano FJ, Costelli P, Penna F. Are there any benefits of exercise training in cancer cachexia? Journal of cachexia, sarcopenia and muscle. 2012;3(2):73–6. 10.1007/s13539-012-0067-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Cormie P, Spry N, Jasas K, Johansson M, Yusoff IF, Newton RU, et al. Exercise as medicine in the management of pancreatic cancer: a case study. Medicine and science in sports and exercise. 2014;46(4):664–70. 10.1249/MSS.0000000000000160 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Sarcopenia does not impair recurrence-free survival in patients with resectable PDAC (15 vs. 25 months, p = 0.275).
(TIFF)
Sarcopenia does not impair recurrence-free survival in male patients with resectable PDAC (9 vs. 9 months, p = 0.216).
(TIFF)
Sarcopenia does not impair recurrence-free survival in female patients with resectable PDAC (10 vs. 11 months, p = 0.709).
(TIFF)
Sarcopenia does not impair recurrence-free survival in obese patients with resectable PDAC (9 vs. 10 months, p = 0.698).
(TIFF)
Sarcopenia does not impair recurrence-free survival in normal/underweight patients with resectable PDAC (9 vs. 13 months, p = 0.173).
(TIFF)
Data Availability Statement
All relevant data are within the manuscript and its Supporting Information files.