Osteopenia predicts outcomes in pancreatic cancer
Study Background
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States and is projected to become the second by 2030. The unfavorable prognosis of PDAC can be attributed to late diagnosis, poor metabolic status, and the resistance of cancer stem cells to drugs. Furthermore, up to 85% of pancreatic cancer patients present with cachexia, a complex metabolic and behavioral syndrome characterized by extreme weight loss and progressive muscle wasting. Cancer cachexia has a significant impact on the patient’s physical wellbeing and quality of life, and the patient’s ability to tolerate therapies, especially cytotoxic chemotherapy.
Evidence from several studies suggested that chemotherapy causes bone loss. Recent findings suggest that soluble factors released during bone resorption directly contribute to loss of muscle mass and complicate survival among cancer patients. Some reports have described factors contributing to bone wasting, but none have focused on osteopenia in PDAC. Therefore, this study aimed to evaluate anthropometric measures in surgical PDAC patients and control individuals.
Methods
This study was a retrospective evaluation of all PDAC patients who underwent surgery between October 2011 and January 2018 at the University of Florida. 152 of the 162 patients identified were included in the study and compared to sex, age, and comorbidity matched controls. Preoperative data collected included: i) Demographics: age, sex, race, and ethnicity, ii) blood chemistries: complete blood count, comprehensive metabolic panel, and CA19-9, iii) PDAC signs and symptoms iv) neoadjuvant therapy regimen if applicable v) comorbidities, if any vi) medication history and vii) basic body measurements. Preoperative data collected included tumor grade, tumor size, lymph nodes positive for PDAC, and surgical margin status.
CT Analysis
Pre-operative computed tomography scans, Muscle mass, and quality were measured at the L3 level for each patient. Manual image segmentation was performed using sliceOmatic™ 5.0 (Tomovision, Magog, Quebec). Cross-sectional skeletal muscle area (SMA, cm2) was calculated by the summative area between -29 and 150 Hounsfield Units (HU). Visceral, subcutaneous, and inter-/intra- muscular adipose cross-sectional areas were measured between −150 and −50 HU. Patients were grouped myopenic and not myopenic according to sex and BMI dependent cutoffs: SMI <43 cm2/m2 for men with a BMI <25 kg/m2, SMI <53 cm2/m2 for obese men, and SMI <41 cm2/m2 for women. BMI dependent cutoffs of muscle radiation attenuation (MRA) were used to analyze muscle health, degenerative and steatotic changes typical of atrophy, and cachexia of 41 HU for patients with a BMI <25 kg/m2 and 33 HU for patients with a BMI >25 kg/m2. Patients with PDAC were classified according to weight loss in the preceding 6 months. Significant body weight loss, low muscle mass, and low muscle quality were used as parameters to stratify patients as cachectic. Bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies (L1-L5). Patients were classified as osteopenic if the lumbar vertebral radiodensity (LVR) was <145 HU.
Statistical analysis
Data analyses were performed using SPAA version 22.0 (IBM Corp., Armonk, NY) and GraphPad Prism version 5.02 (GraphPad Software, San Diego, CA). T-test was used to compare the means of two groups, and a one-way analysis of variance tests for multiple means. Correlations were assessed with Pearson’s coefficient of correlation. Median survival was determined using Cox-Mantel tests.
Hazard ratios (HR) with 95% confidence intervals (CI) according to the presence or absence of osteopenia were evaluated using the Cox proportional hazard model.
Sensitivity and specificity for LVR and cachexia measures were calculated to predict postoperative survival. P < 0.05 was considered statistically significant.
RESULTS
A total of 152 PDAC patients were included in this study, of which the majority were male (57.2%) and Caucasian (88.8%). The mean age was 69.0 (±9.61) years. In this study, the mean age, gender ratio, race, medication, or comorbidity status between two control and PDAC patient groups were not statistically different.
Furthermore, both groups had a similar prevalence of osteoporosis and Vitamin D and calcium supplement use. Smoking status, a risk factor for PDAC and osteopenia, was also similar in both groups. No PDAC patients in this study were on anti-osteoporotic drugs such as bisphosphonates or denosumab.
Patients with PDAC showed typical signs of cachexia such as weight loss and radiologically appreciable skeletal muscle atrophy. Notably, 104 patients (68.4%) lost greater than 5% of their body weight in 6 months of diagnosis; 38 patients (25%) were classified as cachectic. The mean age of cachectic patients vs control was 70.0 (±7.01) years vs 64.2 (± 12.6) years.
Biochemical markers of cachexia
- Cachectic patients presented lower hemoglobin, albumin, and platelet count than controls. 21.1% of control subjects and 50.0% of PDAC patients were classified as anemic. All PDAC patients had high corpuscular volume (MCV, 93.0 ± 5.63 fl) compared to control individuals (89.6 ± 3.27 fl, p = 0.0122). It was also noted that MCV was particularly high in PDAC patients with weight loss (93.2 ± 5.10 fl, p = 0.0039) and cachexia (92.8 ± 5.73 fl, p = 0.0310). Notably, most PDAC patients showed signs of normocytic anemia, characteristic of chronic disease. Similarly, the mean albumin level was lower in the PDAC group compared to controls. Patients with less than 5% body weight loss (3.78 ± 0.555 g/dl, p = 0.0364) and cachexia (3.79 ± 0.459 g/dl, p = 0.0325) had lower serum albumin than controls (4.11 ± 0.597 g/dl).
- When measured, mean platelet level remained higher and consistent across all PDAC groups compared to control group: less than 5% body weight loss (259 ± 95.8, p = 0.0172), more than 5% body weight loss (261 ± 104, p = 0.0167), and cachexia (253 ± 89.0, p = 0.0243).
- Creatinine, sodium, and potassium levels were similar between both groups.
- Though aspartate aminotransferase (AST) levels were higher in PDAC patients (64.4 ± 85.3 U/L) compared to controls (37.8 ± 46.1 U/L), it was not significant.
- Serum calcium levels were also higher in most PDAC patients (9.31 ± 0.707 mmol/L) than in controls (9.07 ± 0.825 mmol/L), as would be expected when osteopenia progresses.
Body composition
Body mass index (BMI) was lower in PDAC patients (26.6 ± 5.00 kg/m2, p = 0.0254) than controls (29.4 ± 4.69 kg/m2); cachectic group showed the most significant decrement (25.7 ± 4.99 kg/m2, p = 0.0084).
SMI at the L3 vertebral level was lower in all subjects with PDAC, significantly so in the cohort with cachexia (38.7 ± 5.99 cm2/m2), p < 0.0001 compared to controls (46.1 ± 5.77 cm2/m2).
Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1- and 2- year disease-specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2- year mortality with a sensitivity of 76% and specificity of 58%.
Quantified bone density
PDAC patients had significantly lower bone mineral density than controls; 61.2% of PDAC patients were categorized as osteopenic compared to 36.8% of controls.
Body mass composition
Low BMI and SMI were prominent in PDAC patients, significantly so in the cohort with cachexia (p = < 0.0001). MRA was also found to be significantly altered between controls and PDAC patients.
Signs of bone loss
Patients with PDAC displayed severe bone degeneration (49.3% vs. 10.5%, p = 0.0012). Radiological scans also showed evidence of cortical bone remodeling and compression in the lumbar vertebra, notably in L5 compared to L1, L2, L3, and L4.
Survivor outcomes
Among the PDAC patients, the ones categorized as osteopenic had significantly lower survival (1.01 years) compared to patients without osteopenia (2.8 years). Postoperative osteopenia was the strongest clinical predictor of 1 and 2-year survival, increasing the risk of death by 107% and 80%, respectively. Furthermore, preoperative osteopenia served as a predictor of 2-year mortality with 76% sensitivity and 58% specificity.
DISCUSSION
Key findings of this study include significant reductions in weight, skeletal muscle mass, and bone density in patients with PDAC, compared to age-matched patients. Furthermore, the low bone density strongly correlates with anthropometric measurements of cachexia, including SMO, MRA, and inter-and intramuscular fat infiltration.
Among the different nutritional markers studies, osteopenia, a bone condition characterized by decreased bone density, has recently received attention with respect to pancreatic ductal adenocarcinoma. Sharma et al have shown for the first time that osteopenia has a negative impact on long-term outcomes after liver transplantation in patients with hepatocellular carcinoma. The current study is the first to show an association of osteopenia with worse survival after PDAC resection. The authors found that low bone density serves as the predictor of long-term outcomes in PDAC patients who underwent curative resection. According to the results, osteopenic patients had an increased risk of death by 107% and 80% within 1 and 2 years of surgery, respectively. Though the mechanism of this relationship is unclear, osteopenia might be associated with inflammatory cytokines – GF- β, IL- 6, and tumor necrosis factor-alpha (TNF- alpha), as with sarcopenia.
The study is limited by its retrospective and its small cohort comprising surgical patients with PDAC cases from one geographical region. The inclusion of non-cancer controls is another limitation. Therefore, future studies with healthy controls are needed. This study did not attempt to ascertain the mechanisms of the paraneoplastic element of cancer. Furthermore, since the majority of the observations were preoperative, the authors were unable to place the onset of cachexia in the continuum.
Oncology Related Tools
Other
Latest Research
