Abstract
Background:
Little is known about changes in body composition that may occur during neoadjuvant therapy for pancreatic cancer. This study aimed to characterize these changes and their potential relationships with therapeutic outcomes.
Methods:
The study population consisted of patients with potentially resectable pancreatic cancer treated on a phase II trial of neoadjuvant chemotherapy and chemoradiation. Skeletal muscle and adipose tissue compartments were measured before and after administration of neoadjuvant therapy using SliceOMatic software (TomoVision, 2012) and protocol-mandated CT scans. Sarcopenia was defined using gender-adjusted norms.
Results:
Among 89 eligible patients, 46 (52%) patients met anthropometric criteria for sarcopenia prior to the initiation of neoadjuvant therapy. Further depletion of skeletal muscle, visceral adipose tissue, and subcutaneous adipose tissue occurred during neoadjuvant therapy but these losses did not preclude the performance of potentially curative surgery. Degree of skeletal muscle loss correlated with disease-free survival while visceral adipose loss was associated with overall and progression-free survival. However, completion of all therapy including pancreatectomy was the only independently significant predictor of outcome in a multivariate analysis of overall survival.
Discussion:
These data suggest that body composition analysis of standard CT images may provide clinically relevant information for patients with potentially resectable pancreatic cancer who receive neoadjuvant therapy. Anthropometric changes must be considered in the design of preoperative therapy regimens and further efforts should focus on maintenance of muscle and visceral adipose tissue in the preoperative setting.
Background
Weight loss, muscle wasting and cachexia are hallmarks of pancreatic ductal adenocarcinoma (PDAC) that may be associated with depletion of both skeletal muscle and adipose tissue. Sarcopenia—loss of skeletal muscle which typically occurs with age and disease 1—has been shown to adversely impact the survival of pancreatic cancer patients following both de novo resection of early stage tumors 2 and palliative therapy for advanced disease 3,4. Visceral adipose tissue loss has also been associated with a poor survival duration among patients with a range of pancreatic cancer stages 5. These findings suggest that characterization of changes in the composition of various body compartments may provide important prognostic information for patients with PDAC in a variety of clinical scenarios.
The administration of neoadjuvant chemotherapy and/or chemoradiation to patients with advanced breast 6,7, rectal 8,9, and esophageal cancer 10,11, is a well-established therapeutic paradigm. However, the changes in body composition that occur during such therapy, and the influence of those changes on post-operative outcomes, have only recently begun to be evaluated. Among patients with breast cancer, sarcopenic patients who received preoperative therapy were more likely to have a pathologic complete response than non-sarcopenic patients, and both lower skeletal muscle index and higher visceral adipose tissue index were associated with a decreased risk of death 12. Among patients with gastroesophageal cancer, the incidence of sarcopenia increased and fat mass decreased during neoadjuvant therapy; however, these body composition changes were not correlated with failure to complete therapy or higher mortality 13. Among patients with rectal cancer, patients with a high visceral to subcutaneous fat ratio had shorter disease-free (DFS) and overall survival (OS) 14.
The administration of neoadjuvant therapy prior to planned pancreatectomy is increasingly gaining acceptance for patients with both resectable and borderline resectable pancreatic cancer 15. To date, however, no prior studies have evaluated the incidence or significance of changes in body composition that may occur in the preoperative period. Understanding such changes might allow better patient selection for surgery, help determine response to neoadjuvant therapies, or inform the design of novel preoperative adjuvant “prehabilitation” strategies employing exercise, dietary modifications, or drugs.
In this study, we sought to explore and characterize the changes in body composition that occur during neoadjuvant chemotherapy and chemoradiation for localized PDAC, and to determine their potential relationship with resectability and survival. To meet these aims, we performed an anthropometric analysis of patients with potentially resectable PDAC who received an identical preoperative regimen of chemotherapy and chemoradiation on a previously reported phase II trial.
MATERIALS AND METHODS
Patients
Patients with PDAC treated on a previously published phase II trial of neoadjuvant chemotherapy followed by chemoradiation 16 comprised the study population. The MD Anderson Institutional Review Board approved both the original trial and the retrospective body composition analysis reported in this manuscript. Consent was waived by the IRB for this retrospective body composition analysis.
Protocol eligibility criteria for the original clinical trial were previously reported 17. Briefly, all patients had previously untreated, potentially resectable PDAC of the head or uncinate process, a Karnovsky performance status of at least 70 and a serum bilirubin level <5 mg/dL. Additional eligibility criteria for this study of body composition included the availability of CT images from an initial staging scan and/or a restaging scan after the completion of neoadjuvant therapy.
Neoadjuvant Regimen
The 12-week neoadjuvant therapy regimen has been described in detail 16. In brief, it consisted of four cycles of every other week gemcitabine and cisplatin, followed by a three week break prior to external beam radiation to a total dose of 30 Gy in 10 fractions with concurrent gemcitabine. Patients then had a four to six week period of rest prior to preoperative restaging. Patients without evidence of disease progression underwent subsequent resection of their primary tumor 18,19.
Patient Follow Up
Following surgery, patients were evaluated every 3–4 months for the first 2 years with physical exam, chest X-ray, and abdominal CT scan per protocol. From years 2–5 patients were followed every 6 months and then yearly thereafter.
Anthropometric Analysis
The cross sectional areas of the skeletal muscle (SKM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) compartments were determined using CT images obtained using a pancreatic protocol both prior to and following the administration of preoperative therapy. Dicom images corresponding to the midpoint of the L3 vertebral body were analyzed using SliceOMatic software (TomoVision, 2012). Cross sectional areas were standardized to the square of the height in meters 5. Sarcopenia was defined as SKM ≤38.9 cm2/m2 for women and SKM ≤55.4 cm2/m2 for men 20.
Statistical Analysis
Differences between groups were tested using the chi-square test, exact chi-square test, or paired t-test 21. OS was calculated from the date of tissue diagnosis. DFS was calculated for patients who underwent surgical resection from the date of surgery until the date of recurrence or death from other cause. Progression-free survival (PFS) was calculated for all patients from the date of tissue diagnosis until the date of the first evidence of tumor progression. Kaplan-Meier 22 estimates of the median and 95% confidence interval were provided for comparisons of OS, DFS and PFS. Comparisons were made with the log rank test. Cox regression 23 was implemented to show hazard ratios and their 95% confidence intervals for univariate and multivariate models of overall survival. A CART analysis 24 was performed to identify any cut points in the adjusted continuous SKM and adjusted VAT that might predict overall survival when combined with other patient factors. The smallest allowed node was 20 patients, and each split was controlled at a 5% significance level. CART analysis and the Kaplan-Meier figures were produced in Stata 13 (StataCorp, College Station, TX). All other analyses were performed in SAS 9.3 (The SAS Institute, Cary, NC).
Results
Among the 90 patients enrolled in the original phase II trial, 89 patients had evaluable images from CT scans obtained prior to and/or following the administration of neoadjuvant therapy, of whom 84 had pretreatment scans, 86 had post-treatment scans, and 82 had both (Table 1). Following the administration of chemotherapy and chemoradiation, 57 (64%) patients underwent surgical resection.
Table 1.
Patient Characteristics (n=89)
| All | |
|---|---|
| Patient Characteristics | n (%) |
|
| |
| All Patients | 89 (100%) |
| Age - median (min,max) | 63 (38, 79) |
| Gender | |
| F | 40 (45%) |
| M | 49 (55%) |
| Race Ethnicity | |
| White/Non-Hispanic | 77 (87%) |
| White/Hispanic | 6 (7%) |
| Asian/Non-Hispanic | 3 (3%) |
| Black/Non-Hispanic | 3 (3%) |
| Smoking History* | |
| Yes | 54 (61%) |
| No | 34 (38%) |
| Surgical Resection Following Neoadjuvant Therapy | |
| Yes | 57 (64%) |
| No | 32 (36%) |
1 patient missing smoking history data
Anthropometric Changes During Preoperative Therapy and Association with Resection
The mean changes in the cross-sectional areas of the muscle and adipose tissue compartments that occurred during neoadjuvant therapy are presented in Table 2. SKM decreased on average 1.2 cm2/m2 (p=<0.01). VAT decreased on average 4.0 cm2/m2 (p=0.01). SAT was measurable at both time points in only 47 (57%) patients; among them, the cross-sectional area of SAT declined on average 4.2 cm2/m2 (p=0.02). The extent of adjusted SKM, VAT and SAT loss did not differ significantly between patients who did and did not ultimately undergo resection (p =0.87, p=0.07 and p=0.11, respectively).
Table 2.
Absolute Changes in Skeletal Muscle and Adipose Tissue Compartments During Neoadjuvant Chemoradiation and Their Association with Resection
| Pretreatment | Posttreatment | Difference | |||
|---|---|---|---|---|---|
|
| |||||
| Tissue Type | Mean (SE) | Mean (SE) | Mean (SE) | P-value | |
| Skeletal Muscle | |||||
|
| |||||
| All Patients | n=82 | 47.5 (1.0) | 46.3 (1.0) | −1.2 (0.4) | 0.01 |
| Resected | n=53 | 48.2 (1.1) | 46.9 (1.1) | −1.3 (0.5) | 0.01 |
| Non-Resected | n=29 | 46.2 (2.0) | 45.1 (2.1) | −1.1 (0.9) | 0.24 |
| P-value for Resected vs. Non-Resected | 0.40 | 0.45 | 0.87 | ||
|
| |||||
| Visceral Adipose | |||||
|
| |||||
| All Patients | n=82 | 45.1 (3.1) | 41.2 (2.8) | −4.0 (1.6) | 0.01 |
| Resected | n=53 | 44.5 (4.1) | 42.6 (3.8) | −2.0 (2.0) | 0.33 |
| Non-Resected | n=29 | 46.3 (4.6) | 38.6 (4.3) | −7.6 (2.3) | 0.003 |
| P-value for Resected vs. Non-Resected | 0.78 | 0.49 | 0.07 | ||
|
| |||||
| Subcutaneous Adipose | |||||
|
| |||||
| All Patients | n=47 | 53.0 (4.0) | 48.7 (3.5) | −4.2 (1.7) | 0.02 |
| Resected | n=31 | 53.5 (5.1) | 51.4 (3.9) | −2.1 (1.9) | 0.29 |
| Non-Resected | n=16 | 51.9 (6.4) | 43.6 (7.1) | −8.4 (3.3) | 0.02 |
| P-value for Resected vs. Non-Resected | 0.85 | 0.34 | 0.11 | ||
Note, median (min, max) treatment time was 4.2 months (2.2, 11.5 months), n=87. Units are cm2/m2.
The relationships of BMI categories, sarcopenia status and changes thereof with surgical outcomes are presented in Table 3. Prior to the initiation of therapy, 1 (1%) patient was underweight, 36 (40%) patients had a normal BMI, 30 (34%) patients were overweight and 22 (25%) patients were obese. Forty-six (55%) patients were sarcopenic at baseline, of whom 21 (40%) were overweight or obese.
Table 3.
Relationship of BMI category and sarcopenia status with resection
| Resection | ||||
|---|---|---|---|---|
| Patient Characteristic | n (%) | n (%) | P-Value | |
|
| ||||
| All Patients | 89 (100%) | 57 (64%) | ||
| Pretreatment BMI | 0.30 | |||
| Normal/Underweight | 37 (41%) | 26 (70%) | ||
| Overweight/Obese | 52 (58%) | 31 (60%) | ||
|
| ||||
| Pretreatment Sarcopenia* | 0.79 | |||
| No | 38 (45%) | 25 (66%) | ||
| Yes | 46 (55%) | 29 (63%) | ||
|
| ||||
| Pretreatment Sarcopenia and Overweight/Obese | 0.07 | |||
| No | 66 (76%) | 46 (70%) | ||
| Yes | 21 (24%) | 10 (48%) | ||
|
| ||||
| Post-treatment Sarcopenia | 0.53 | |||
| No | 35 (41%) | 21 (60%) | ||
| Yes | 51 (59%) | 34 (67%) | ||
|
| ||||
| Weight Loss | 0.42 | |||
| No | 33 (38%) | 23 (70%) | ||
| Yes | 54 (62%) | 33 (61%) | ||
|
| ||||
| Pre/Post-treatment Sarcopenia | 0.50 | |||
| No/No | 30 (37%) | 18 (60%) | ||
| No/Yes | 8 (10%) | 7 (88%) | ||
| Yes/No | 4 (5%) | 3 (75%) | ||
| Yes/Yes | 40 (49%) | 25 (63%) | ||
Defined as L3 skeletal muscle cross-sectional area ≤38.9 cm2/m2 for women and ≤55.4 cm2/m2 for men. Sufficient information is available for 84 of the 89 patients for pretreatment sarcopenia determination.
Fifty-four (62%) patients lost weight during, and 51 (59%) patients met anthropometric criteria for sarcopenia following the administration of preoperative therapy. No significant associations between BMI category, or sarcopenia status or changes thereof and surgical outcomes were identified, but patients who were both obese and sarcopenic upon presentation had a lower probability of undergoing successful surgical resection that did not reach statistical significance (70% vs. 48%; p=0.07).
Body Composition and Long-term Outcomes
The top portion of Table 4A presents estimates for OS, PFS, and DFS and the effect of weight and sarcopenia status on these outcomes. Pretreatment sarcopenic obesity was significantly associated with OS (p=0.04) but neither PFS nor DFS.
Table 4A.
Overall, Progression-Free, and Disease-Free Survival (in Months) for Planned Subgroup Analyses
| Patient Status | OS | PFS | DFS | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||||
| Deaths/n | Median (95% CI) | P-Value | Events/n | Median (95% CI) | P-Value | Events/n | Median (95% CI) | P-Value | ||
|
| ||||||||||
| All Patients | 78/89 | 17.2 (14.4, 21.3) | 78/89 | 11.2 (8.7, 13.8) | 46/57 | 11.0 (8.5, 15.8) | ||||
|
| ||||||||||
| Pretreatment BMI | 0.47 | 0.35 | 0.68 | |||||||
| Normal/Underweight | 32/37 | 20.9 (14.2, 35.4) | 32/37 | 13.8 (8.7, 18.1) | 21/26 | 11.2 (8.5, 27.0) | ||||
| Overweight/Obese | 46/52 | 16.0 (13.2, 19.4) | 46/52 | 10.9 (5.8, 12.8) | 25/31 | 9.7 (7.1, 15.6) | ||||
|
| ||||||||||
| Pretreatment Sarcopenia | 0.08 | 0.20 | 0.13 | |||||||
| Yes | 42/46 | 16.8 (12.8, 20.9) | 42/46 | 10.6 (6.4, 14.2) | 25/29 | 9.8 (7.5, 15.6) | ||||
| No | 31/38 | 20.4 (14.9, 40.7) | 31/38 | 12.6 (6.5, 17.8) | 18/25 | 20.2 (7.6, 75.0) | ||||
|
| ||||||||||
| Pretreatment Sarcopenia and Overweight/Obese | 0.04 | 0.11 | 0.54 | |||||||
| Yes | 19/21 | 12.9 (10.0, 17.1) | 19/21 | 6.5 (5.4, 12.0) | 8/10 | 8.6 (0.1, 15.6) | ||||
| No | 57/66 | 20.7 (15.1, 28.5) | 57/66 | 12.6 (9.4, 14.9) | 37/46 | 11.2 (8.5, 20.2) | ||||
|
| ||||||||||
| Post-treatment Sarcopenia | 0.30 | 0.89 | 0.38 | |||||||
| Yes | 45/51 | 17.1 (12.9, 23.5) | 45/51 | 12.0 (6.7, 14.2) | 28/34 | 10.5 (7.3, 15.6) | ||||
| No | 30/35 | 19.4 (14.9, 35.4) | 30/35 | 11.0 (5.7, 14.9) | 16/21 | 20.0 (7.6, 27.0) | ||||
|
| ||||||||||
| Weight Loss | 0.14 | 0.34 | 0.39 | |||||||
| Yes | 49/54 | 16.0 (13.2, 19.4) | 49/54 | 11.0 (7.5, 12.9) | 28/33 | 11.0 (7.1, 15.8) | ||||
| No | 27/33 | 21.3 (13.8, 37.9) | 27/33 | 12.6 (6.1, 15.4) | 17/23 | 11.5 (7.6, 33.2) | ||||
|
| ||||||||||
| Pre/Post-treatment Sarcopenia | 0.46 | 0.56 | 0.40 | |||||||
| No/No | 25/30 | 20.4 (14.9, 44.4) | 25/30 | 11.3 (5.7, 24.5) | 13/18 | 22.3 (7.6, 75.0) | ||||
| No/Yes | 6/8 | 22.5 (5.4, NR) | 6/8 | 14.6 (5.4, NR) | 5/7 | 12.1 (0.4, NR) | ||||
| Yes/No | 4/4 | 25.1 (9.1, 55.9) | 4/4 | 10.6 (4.4, 23.9) | 3/3 | 9.5 (0.1, 20.0) | ||||
| Yes/Yes | 36/40 | 16.7 (12.8, 20.9) | 36/40 | 10.6 (6.5, 14.0) | 21/25 | 10.0 (7.5, 15.8) | ||||
|
| ||||||||||
| HR (95% CI) | HR (95% CI) | HR (95% CI) | ||||||||
|
| ||||||||||
| Adjusted SKM | ||||||||||
| Pretreatment | 73/84 | 0.99 (0.97, 1.02) | 0.47 | 73/84 | 1.00 (0.97, 1.03) | 0.93 | 43/54 | 1.01 (0.97, 1.04) | 0.75 | |
| Post-treatment | 75/86 | 0.99 (0.96, 1.01) | 0.29 | 75/86 | 0.99 (0.97, 1.02) | 0.71 | 44/55 | 1.00 (0.96, 1.03) | 0.84 | |
| Difference* | 71/82 | 0.95 (0.88, 1.03) | 0.22 | 71/82 | 0.95 (0.88, 1.03) | 0.19 | 42/53 | 0.89 (0.80, 1.00) | 0.04 | |
| Percent Difference | 71/82 | 0.98 (0.94, 1.01) | 0.24 | 71/82 | 0.98 (0.94, 1.02) | 0.25 | 42/53 | 0.95 (0.90, 1.01) | 0.08 | |
|
| ||||||||||
| Adjusted VAT | ||||||||||
| Pretreatment | 73/84 | 1.01 (1.00, 1.01) | 0.09 | 73/84 | 1.01 (1.00, 1.01) | 0.10 | 43/54 | 1.01 (1.00, 1.02) | 0.14 | |
| Post-treatment | 75/86 | 1.00 (0.99, 1.01) | 0.96 | 75/86 | 1.00 (0.99, 1.01) | 0.74 | 44/55 | 1.00 (0.99, 1.01) | 0.53 | |
| Difference* | 71/82 | 0.97 (0.95, 0.99) | 0.001 | 71/82 | 0.98 (0.96, 0.99) | 0.01 | 42/53 | 0.98 (0.95, 1.00) | 0.07 | |
| Percent Difference | 71/82 | 1.00 (1.00, 1.00) | 0.37 | 71/82 | 1.00 (1.00, 1.00) | 0.38 | 42/53 | 1.00 (1.00, 1.00) | 0.63 | |
OS=Overall Survival; PFS=Progression-Free Survival; DFS=Disease-Free Survival; CI=Confidence Interval; NR=Median or CI limit is Not Reached
The difference was calculated as the difference between post- minus pre-treatment measures. Positive values mean patients gained SKM following treatment. For example, an increase of one unit indicates either a gain of one unit or a smaller loss by one unit.
The lower portion of Table 4A explores the relationships of adjusted SKM and adjusted VAT with survival outcomes. The absolute difference between pre- and post-treatment SKM was associated with DFS (HR=0.89; p=0.04) with higher values being associated with improved DFS. In this case higher values indicate that SKM increased over time, or patients with less loss did better than patients with more loss. Similarly, the absolute change of adjusted VAT was associated with both OS (HR=0.97; p=0.001) and PFS (HR=0.98; p=0.01) with gains or smaller losses associated with better outcome compared to those with greater losses. This trend was visible for DFS (HR=0.98; p=0.07) but was not statistically significant.
Table 4B explores additional clinical factors and their association with overall survival individually, and in combination. Only adjusted VAT difference [HR 0.97 (95% CI; 0.95, 0.99), p=0.001] and successful resection [HR 0.09 (95% CI: 0.05, 0.17), p<0.001] were associated with overall survival.
Table 4B.
Relationships of Selected Patient Characteristics with Overall Survival
| Univariate | Multivariate (n=86) | ||||
|---|---|---|---|---|---|
| HR (95% CI) | P-Value | HR (95% CI) | P-Value | ||
| BMI | Overweight/Obese vs. Normal/Underweight | 1.18 (0.75, 1.86) | 0.47 | 0.89 (0.53, 1.51) | 0.67 |
| Lost Weight | Yes vs No | 1.43 (0.89, 2.29) | 0.14 | 1.36 (0.77, 2.39) | 0.29 |
| Adjusted SKM Difference | Unit=1 | 0.95 (0.88, 1.03) | 0.22 | 1.00 (0.93, 1.08) | 0.94 |
| Adjusted VAT Difference | Unit=1 | 0.97 (0.95, 0.99) | 0.001 | 0.99 (0.97, 1.01) | 0.46 |
| Months on Treatment | Unit=1 | 0.90 (0.74, 1.09) | 0.28 | 0.85 (0.68, 1.07) | 0.17 |
| Successful Resection* | Yes vs No | 0.09 (0.05, 0.17) | <0.001 | 0.08 (0.04, 0.18) | <0.001 |
Only 55 patients had non-missing values for all specific surgery variables since patients had to have successful resection for tumor size or nodal status to be recorded. Therefore the models omit the specific surgical features in order to test the effect of surgery. Univariate and multivariate analyses which included tumor size, LN positivity, and surgical margin were performed for the 55 patients with complete data and none of these factors was significant (data not shown).
Figure 1 presents the overall survival of groups identified by an exploratory, multivariate CART analysis. Factors entered into the analysis included: age; adjusted SKM difference pre vs. post treatment; adjusted VAT pre and post treatment and the difference; BMI category; whether the patient lost weight; and resection status. When all of these characteristics were included, 81 patients had full information to be included in the model. The first split was identified based on resection status. The second split occurred only among patients who underwent resection and divided adjusted pretreatment VAT at 37.01 cm2/m2 (≤37 [low VAT], vs. >37 [high VAT]). These 2 splits produced 3 nodes with median OS times of 10.8 (9.1, 12.9) months, 21.3 (17.1, 40.7) months, and 40.4 (27.7, NR) months for patients who did not undergo resection, did undergo resection and had a high pretreatment VAT, and did undergo resection and had a low pretreatment VAT, respectively. To confirm the robustness of this split, an ad hoc CART analysis of just the surgery status and adjusted pretreatment VAT was performed. It produced similar splits, but with a slightly larger cut-off of 44 instead of 37 for the adjusted pretreatment VAT among patients who underwent resection (data not shown).
Figure 1.
Overall Survival by Risk Groups Identified by CART Analysis.
SR=Successful Resection=Pancreaticoduodenectomy; VAT = pretreatment adjusted visceral adipose tissue; Low= Below 37.01 cm2/m2; High=Above 37.01 cm2/m2.
The identification of these 3 groups includes a multivariate model including: age; adjusted SKM difference between pre and post treatment; adjusted VAT pre and post treatment and the difference; BMI category; whether the patient lost weight; and successful resection status. N=81 with available information for included variables. Changes in the variables included in the model may result in slightly different groupings.
Discussion
This study, the first to characterize changes in body composition that occur among patients with potentially resectable PDAC during neoadjuvant therapy and their association with relevant oncologic outcomes, produced several important findings. First, even among these highly functional patients selected for protocol-based therapy, underlying sarcopenia was common at baseline. Subsequent weight loss, as well as further depletion of skeletal muscle and both visceral and subcutaneous adipose tissue, routinely occurred during the neoadjuvant therapy period. Such changes did not preclude the performance of potentially curative resection. Both high pretreatment visceral adipose levels and progressive loss of visceral adipose during neoadjuvant therapy were associated with shorter OS, and loss of skeletal muscle was associated with shorter DFS. Ultimately, completion of all therapy including surgery was the only independently significant predictor of OS, but all these initial findings together suggest that body composition analysis may provide valuable clinical information in the preoperative setting.
The results of this study demonstrate that radiographic data acquired as a routine part of care can potentially be used to identify high-risk anthropometric phenotypes among patients treated with neoadjuvant therapy. These profiles include the presence of sarcopenic obesity, high visceral adipose mass, and ongoing loss of muscle and/or fat. These profiles cannot be identified using traditional measures. Only one patient in this series was underweight, for example, but 55% of all patients and 40% of overweight and obese patients met anthropometric criteria for sarcopenia. Although other methods of body composition analysis exist, such as dual energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis 20, the CT-based method used in this study is associated with several advantages—foremost among them being that it may be performed without the patient having to undergo any additional procedures 20,25,26.
That anthropometric changes are associated with therapeutic outcomes among patients treated with preoperative therapy suggests that both the direct and indirect effects of cytotoxic regimens on fat and muscle mass must be considered in the design of neoadjuvant regimens 27,28. Furthermore, efforts to maintain both muscle and adipose tissue might represent a critical adjuvant strategy in the preoperative period. Such efforts might include dietary or physical prehabilitation programs 29,30, the concurrent administration of nutritional supplements 31,32, or drugs targeting chronic inflammation and cachexia 33,34.
It is noteworthy that our findings are discordant from those of Peng 2, who found that preoperative sarcopenia was an independent predictor of survival following pancreatectomy, and the likely reasons for this discrepancy should be considered. First, the patients reported herein, unlike those reported by Peng, received preoperative therapy prior to intended resection, and the absence of a clear association between sarcopenia and outcome may be an artifact of the selective effects of that therapy, as patients with particularly poor physiology or rapidly progressive disease did not ultimately undergo resection. Second, the two studies utilized different definitions for sarcopenia. The gender-specific cutoffs we used were generated using data from 50 cancer patients where cutoffs for low appendicular muscle mass defined using DXA analysis were associated with physical disability, falls, and mortality in elderly adults 20. In contrast, Peng used a non-standard definition, characterizing patients as sarcopenic if they had a gender-specific skeletal muscle mass in the lowest quartile among patients examined 2.
The major strengths of this study include its use of data that were collected from patients enrolled on a prospective clinical trial. Indeed, evaluated this group to reduce the potential bias associated with variation in therapeutic regimens and their associated variability in cytotoxic effect, treatment durations and toxicity profiles. However, as a result, the study population reported herein is both fairly homogeneous and relatively robust. This may limit the ability to generalize our results to the entire population of patients with pancreatic cancer, or to patients treated with other neoadjuvant regimens. It could be expected, however, that the depletion of skeletal muscle and visceral adipose tissue observed in a broader population of pancreatic cancer patients would be, if anything, more pronounced than those seen in the current study. Also, the regimen described here is similar to other multimodality regimens used for resectable and borderline resectable disease 35. Other potential limitations must also be acknowledged. First, the small sample size in this study mandates that the results be interpreted somewhat cautiously. Second, this study is unable to elucidate the extent to which these changes were attributable to underlying disease, the therapies administered, or a combination of both. Further studies must focus on the etiology of these changes, and must determine whether these changes are reversible and targetable.
In this study, successful completion of all therapy including pancreatectomy was ultimately the only independently significant predictor of outcome among patients with potentially resectable PDAC who received preoperative therapy. However, even among a homogenous group of relatively robust patients, ongoing depletion of both skeletal muscle and visceral adipose tissue was common and appeared to be associated with treatment outcomes. Although further studies are needed to confirm these findings and to further explore their significance, the data herein suggest that careful consideration of anthropometric changes may provide insight into the role of preoperative interventions designed to improve outcomes for the vulnerable population of patients undergoing neoadjuvant therapy for PDAC.
Synopsis.
Body composition changes during neoadjuvant therapy for pancreatic cancer were characterized using CT anthropometry. Depletion of muscle and adipose tissue was common but did not preclude subsequent resection. Disease-free survival correlated with degree of skeletal muscle loss and overall and progression-free survival correlated with degree of visceral adipose loss.
Supported by:
The Khalifa Bin Zayed Al Nahyan Foundation and by the Various Donor Pancreatic Research Fund at the University of Texas MD Anderson Cancer Center. ABC is also supported by a grant from the Foundation of Surgical Fellowships. RS is part of the Biostatistics Shared Resource supported by the NIH/NCI under award number P30CA016672
Footnotes
Disclosures: There are no relevant financial disclosures.
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