Effects of a Pragmatic Home-based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial.

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer. BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer. METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes. RESULTS: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes. CONCLUSIONS: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery.

The Role of Home-Based Exercise in Maintaining Skeletal Muscle During Preoperative Pancreatic Cancer Treatment.

Loss of skeletal muscle and inferior muscle quality are associated with poor prognosis in patients undergoing preoperative treatment for pancreatic cancer, so maintaining skeletal muscle health before surgery may help accelerate patients' functional recovery and improve their quality of life following surgery. While exercise helps maintain or increase skeletal muscle in individuals undergoing cancer treatment, its efficacy during pancreatic cancer treatment is unclear. Accordingly, in this study we compared changes in skeletal muscle quantity (skeletal muscle index [SMI]) and quality (skeletal muscle density [SMD]) during preoperative pancreatic cancer treatment in participants in a home-based exercise program (EP) and a historical cohort of patients who received the usual care (UC) with no formal exercise programming. Recommendations for the EP cohort included both aerobic and resistance exercise. We assessed changes in SMI and SMD using computed tomography scans administered at treatment planning (T0, prior to EP enrollment) and preoperative restaging (T1) for 33 EP and 64 UC patients and compared changes between groups. The UC patients had statistically significant SMI decreases from T0 to T1 (-1.4 ± 3.8 cm2/m2; p = .005), while the EP patients did not (0.2 ± 3.2 cm2/m2; p = .7). The SMI loss was significantly worse for the UC than for the EP patients (p = .03). Neither group demonstrated statistically significant changes in SMD from T0 to T1, nor did the groups differ in the amount of change in SMD. An adjusted linear regression model demonstrated that EP participation was significantly associated with better SMI maintenance (p = .02). These results suggest that participation in a home-based EP during preoperative treatment may help improve skeletal muscle health and clinical and quality of life outcomes for pancreatic cancer survivors.

Home-Based Exercise Prehabilitation During Preoperative Treatment for Pancreatic Cancer Is Associated With Improvement in Physical Function and Quality of Life.

Purpose: To investigate relationships among physical activity, changes in physical function, and health-related quality of life (HRQOL) among patients with pancreatic adenocarcinoma enrolled in a home-based exercise prehabilitation program. Methods: Patients with resectable pancreatic adenocarcinoma receiving preoperative chemotherapy and/or chemoradiation were enrolled on this prospective, single-arm trial and were advised to perform ≥60 minutes each of moderate-intensity aerobic exercise and strengthening exercise weekly. Activity was measured via self-report and accelerometers, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary activity (SA). Physical function measures at baseline and restaging follow-up included 6-minute walk test (6MWT), 5 times sit-to-stand (5×STS), handgrip strength (HGS), 3-m walk for gait speed (GS), and the PROMIS Physical Function Short Form. HRQOL was measured via the FACT-Hep questionnaire. Results: Fifty participants with mean age 66 years (standard deviation = 8 years) were enrolled. The 6MWT, 5×STS, and GS significantly improved from baseline to restaging follow-up (P=.001, P=.049, and P=.009, respectively). Increases in self-reported aerobic exercise, weekly MVPA, and LPA were associated with improvement in 6MWT (ß=.19, P=.048; ß=.18, P=.03; and ß=.08, P=.03, respectively) and self-reported physical functioning (ß=.02, P=.03; ß=.03, P=.005; and ß=.01, P=.02, respectively). Increased weekly LPA was associated with increased HRQOL (ß=.03, P=.02). Increased SA was associated with decreased HRQOL (ß=-.02,P=.01). Conclusions: Patients with potentially resectable pancreatic cancer exhibit meaningful improvement in physical function with prehabilitation; physical activity was associated with improved physical function and HRQOL. These data highlight the importance of physical activity during treatment for pancreatic cancer.

Supports and Barriers to Home-Based Physical Activity During Preoperative Treatment of Pancreatic Cancer: A Mixed-Methods Study.

BACKGROUND: Physical activity and exercise appear to benefit patients receiving preoperative treatment for cancer. Supports and barriers must be considered to increase compliance with home-based exercise prescriptions in this setting. Such influences have not been previously examined. METHODS: The authors used quantitative and qualitative methods to examine potential physical activity influences among patients who were prescribed home-based aerobic and strengthening exercises concurrent with preoperative chemotherapy or chemoradiation for pancreatic cancer. Physical activity was measured using exercise logs and accelerometers. Social support for exercise and perceived neighborhood walkability were measured using validated surveys. Relationships between influences and physical activity were evaluated using linear regression analyses and qualitative interviews. RESULTS: Fifty patients received treatment for a mean of 16 (9) weeks prior to planned surgical resection. Social support from friends and neighborhood esthetics were positively associated with physical activity (P < .05). In interviews, patients confirmed the importance of these influences and cited encouragement from health care providers and desire to complete and recover from treatment as additional motivators. CONCLUSIONS: Interpersonal and environmental motivators of exercise and physical activity must be considered in the design of future home-based exercise interventions designed for patients receiving preoperative therapy for cancer.

Exercise during preoperative therapy increases tumor vascularity in pancreatic tumor patients.

The efficacy of chemotherapy is reduced by dysfunctional tumor vasculature, which may limit chemotherapy delivery to tumors. Preclinical studies have shown that moderate aerobic exercise improves tumor vascular function and increases chemotherapy efficacy in mouse models, but the effect of exercise on human tumor vasculature has not yet been determined. Here, we demonstrate that exercise remodels the tumor vasculature, accelerates the regression, and delays the regrowth of pancreatic ductal adenocarcinoma in a patient-derived xenograft mouse model treated with gemcitabine. By evaluating pancreatic adenocarcinoma specimens from patients treated with preoperative chemotherapy or chemoradiation therapy, we also demonstrate for the first time that tumor vascular remodeling occurs in association with exercise in humans. Future studies will evaluate whether exercise-induced vascular remodeling improves gemcitabine or other chemotherapy efficacy in patients, as this study evaluated only changes in tumor vascular structure.

Association between frailty syndrome and survival in patients with pancreatic adenocarcinoma.

BACKGROUND: Frailty is a syndrome characterized by weakness, slow gait, weight loss, exhaustion, and low activity. We sought to determine whether frailty was associated with age or stage in newly diagnosed patients with pancreatic ductal adenocarcinoma (PDAC), and determine its association with survival. METHODS: Consecutive patients with newly diagnosed PDAC of all stages underwent baseline assessment. Frailty (per Fried criteria) was defined as having three or more abnormalities in: grip strength, gait speed, weight loss, self-reported exhaustion, or self-reported physical activity. Baseline clinicodemographic characteristics, anatomic stage, performance status, and laboratory markers of prognosis were included. The association between baseline characteristics, frailty, and survival was determined. The associations of individual frailty measures with age, stage, comorbidities, and performance status were examined. Body composition was measured from computed tomographic images using SliceOMatic software. RESULTS: Of 150 patients enrolled, 8 were excluded because they did not have PDAC on final diagnosis. The median age was 65 years (range, 32-89). Seventy-nine patients (55.6%) were sarcopenic, and 36 (25.4%) were frail. Frailty was associated with increasing comorbidities (P = 0.03) and worse performance status (P < 0.01). During follow-up, 79 patients (56%) died. Frailty was significantly associated with death during the follow-up period (P < 0.001) for the entire cohort, including patients with curative (P = 0.038) and palliative (P = 0.003) treatment plans. CONCLUSIONS: Frailty was seen frequently in patients with newly diagnosed PDAC and was not associated with increasing age or more advanced stage. Frailty was a predictor of survival, including patients treated with curative intent.

Pancreas Cancer-Associated Weight Loss.

Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.

Physical activity and exercise during preoperative pancreatic cancer treatment.

PURPOSE: Guidelines recommend exercise to cancer survivors, but limited data exists regarding exercise among patients undergoing preoperative cancer treatment. We examined differences in weekly self-reported exercise and accelerometer-measured physical activity among participants in a home-based exercise program administered during preoperative treatment for pancreatic cancer. METHODS: Participants were encouraged to perform at least 60 min/week of moderate-intensity aerobic exercise and at least 60 min/week of full-body strengthening exercises concurrent with chemotherapy, chemoradiation therapy or both sequentially and received resistance equipment, program instruction, and biweekly follow-up calls to encourage adherence. Self-reported aerobic and strengthening exercise minutes were measured using daily logs, and physical activity was measured objectively using accelerometers. RESULTS: Fifty participants (48% female, mean age 66 ± 8 years) participated for an average of 16 ± 9 preoperative weeks. Participants reported overall means of 126 ± 83 weekly minutes of aerobic exercise and 39 ± 33 weekly minutes of strengthening exercise in daily logs. Participants performed 158.7 ± 146.7 weekly minutes of accelerometer-measured moderate-to-vigorous physical activity. There were no significant differences in exercise or physical activity between treatment phases. CONCLUSIONS: These findings suggest that it is feasible to target the entire preoperative course for exercise prescription. Although participants exceeded aerobic exercise recommendations on average, we observed low strengthening exercise adherence and wide variability in self-reported exercise and accelerometer physical activity variables. These findings suggest that additional support, including program adaptations, may be necessary to overcome barriers to exercise or improve motivation when prescribing exercise in this clinical scenario.

Anthropometric Changes in Patients with Pancreatic Cancer Undergoing Preoperative Therapy and Pancreatoduodenectomy.

BACKGROUND: The changes in body composition that occur in response to therapy for localized pancreatic ductal adenocarcinoma (PDAC) and during the early survivorship period, as well as their clinical significance, are poorly understood. METHODS: One hundred twenty-seven consecutive patients with PDAC who received preoperative therapy followed by pancreatoduodenectomy (PD) at a single institution between 2009 and 2012 were longitudinally evaluated. Changes in skeletal muscle (SKM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured on serial computed tomography images obtained upon presentation, prior to pancreatectomy, and approximately 3 and 12 months after surgery. RESULTS: Prior to therapy, patients' mean baseline BMI was 26.5 ± 4.7 kg/m2 and 63.0% met radiographic criteria for sarcopenia. During a mean 5.4 ± 2.3 months of preoperative therapy, minimal changes in SKM (- 0.5 ± 7.8%, p > 0.05), VAT (- 1.8 ± 62.6%, p < 0.001), and SAT (- 4.8 ± 27.7%, p < 0.001) were observed. In contrast, clinically significant changes were observed on postoperative CT compared to baseline anthropometry: SKM - 4.1 ± 10.7%, VAT - 38.7 ± 30.2%, and SAT - 24.1 ± 22.6% (all p < 0.001) and these changes persisted at one year following PD. While anthropometric changes during preoperative therapy were not independently associated with survival, SKM gain between the postoperative period and one-year follow-up was associated with improved overall survival (OR 0.50, 95% CI 0.29-0.87). CONCLUSIONS: In contrast to the minor changes that occur during preoperative therapy for PDAC, significant losses in key anthropometric parameters tend to occur over the first year following PD. Ongoing SKM loss in the postoperative period may represent an early marker for worse outcomes.

Symptom Management and Palliative Care in Pancreatic Cancer.

Evidence documents the benefits of palliative care to ameliorate the symptoms of pancreatic cancer as well as those from its treatment. Professional organizations now recommend palliative care for all patients with pancreatic cancer early in the course of illness and concurrently with active treatment. Scrupulous symptom management as well as sensitive communication and advance care planning allow oncologists to provide "primary palliative care" and to care well for patients with pancreatic cancer throughout the course of their illness.

Nutrition Implications for Long-Term Survivors of Pancreatic Cancer Surgery [Formula: see text].

With slowly increasing survival rates in pancreatic cancer and international consensus guidelines recommending surgical resection of premalignant lesions, survival post-pancreatic resection is increasing. With longer survival time, the significant comorbidities of such major surgery have far-reaching effects on the nutrition status of the survivor of pancreatic cancer. This review describes the many nutrition-related side effects of pancreatic surgery, including the development of pancreatic enzyme insufficiency, micronutrient deficiencies, diabetes, fatty liver, and metabolic bone disease. Beyond causing additional medical problems, each of these can have significant effects on quality of life and functional status. The potential mechanisms, diagnosis criteria, and potential treatments of these conditions are described. Overall, little literature exists to fully describe the effects of these comorbidities, and even less is able to guide effective treatments for this population. Clinicians caring for these patients should begin incorporating goals for promotion of long-term health and reduction of these known and reported comorbidities in patients who have undergone pancreatic surgery. Treatment plans in this population remain understudied, and clinicians may need to consider recommendations for similar disease states when developing interventions for these patients.

Home-based exercise during preoperative therapy for pancreatic cancer.

PURPOSE: Exercise concurrent with neoadjuvant chemotherapy and/or chemoradiation for pancreatic adenocarcinoma (PDAC) may mitigate the decline in function that may occur as a result of the disease or its treatment in the preoperative period. The primary objective of this single-arm prospective trial was to determine adherence to a home-based exercise program administered during preoperative therapy. METHODS: Twenty patients from a quaternary cancer center with potentially resectable PDAC were enrolled. Patients were prescribed a minimum of 120 min of moderate-intensity exercise weekly: at least 60 min of aerobic exercise and 60 min of resistance exercise. Self-reported exercise was recorded in daily logs. Functional and survey measures were collected upon enrollment, following preoperative therapy, and 1 month after surgery. RESULTS: Fifteen out of 20 patients participated in the program. They reported a mean (standard deviation (SD)) of 98.6 (69.8) min of aerobic exercise weekly and 57.4 (36.0) min of strengthening exercise weekly over a median of 17 weeks (range, 5-35 weeks) of preoperative therapy, for a mean (SD) of 156.0 (64.5) min of total exercise weekly. Eighty percent reported a mean of least 120 min of total exercise weekly during preoperative therapy. Patients with low baseline physical activity based on the International Physical Activity Questionnaire significantly increased their preoperative physical activity (p = .01). There were no adverse events associated with the exercise program. CONCLUSIONS: Patients with PDAC will participate in a home-based exercise program of aerobic and strengthening exercise and will increase physical activity, concurrent with preoperative chemotherapy and/or chemoradiation.

Impact of pancreatectomy on long-term patient-reported symptoms and quality of life in recurrence-free survivors of pancreatic and periampullary neoplasms.

BACKGROUND: Long term patient-reported symptoms and quality of life (QOL) are important outcome metrics following cancer operations, but have been poorly described in patients who have previously undergone pancreatectomy. METHODS: We conducted a cross-sectional survey of recurrence-free survivors of pancreatic ductal adenocarcinoma, periampullary carcinomas, and pancreatic neuroendocrine tumors who had undergone prior pancreatectomy. QOL and symptom burden were measured using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire, and psychosocial distress was measured using the Hospital Anxiety and Depression Scale. RESULTS: Of 331 eligible patients surveyed, 217 (66%) participated at a median of 53.3 (range, 7.6-214.8) months following pancreatoduodenectomy (PD, n = 165) or distal pancreatectomy (DP, n = 52). Among all patients, overall QOL scores were favorable and influenced by race, histology, and type of surgery. The most common significant symptoms reported were fatigue (82%), back pain (32%), and difficulty with digestion (31%). In general, PD survivors reported better QOL, lower levels of anxiety/depression, greater levels of diarrhea, and improved appetite, constipation, fatigue, anxiety, and depression (P < 0.05) than DP survivors. On both univariate and multivariate regression analysis, DP was negatively associated with QOL. CONCLUSIONS: Most disease-free survivors of pancreatic neoplasms report favorable QOL, but gastrointestinal and psychosocial symptoms may exist long after pancreatectomy. J. Surg. Oncol. 2017;115:144-150. © 2016 Wiley Periodicals, Inc.

Nutrition Implications for Long-Term Survivors of Pancreatic Cancer Surgery.

With slowly increasing survival rates in pancreatic cancer and international consensus guidelines recommending surgical resection of premalignant lesions, survival post-pancreatic resection is increasing. With longer survival time, the significant comorbidities of such major surgery have far-reaching effects on the nutrition status of the survivor of pancreatic cancer. This review describes the many nutrition-related side effects of pancreatic surgery, including the development of pancreatic enzyme insufficiency, micronutrient deficiencies, diabetes, fatty liver, and metabolic bone disease. Beyond causing additional medical problems, each of these can have significant effects on quality of life and functional status. The potential mechanisms, diagnosis criteria, and potential treatments of these conditions are described. Overall, little literature exists to fully describe the effects of these comorbidities, and even less is able to guide effective treatments for this population. Clinicians caring for these patients should begin incorporating goals for promotion of long-term health and reduction of these known and reported comorbidities in patients who have undergone pancreatic surgery. Treatment plans in this population remain understudied, and clinicians may need to consider recommendations for similar disease states when developing interventions for these patients.

Fear of cancer recurrence after curative pancreatectomy: a cross-sectional study in survivors of pancreatic and periampullary tumors.

BACKGROUND: Fear of disease recurrence is well documented among cancer survivors, but its significance among patients treated for solid pancreatic and periampullary neoplasms is unknown despite the known risk of recurrence associated with these tumors. We hypothesized that fear of cancer recurrence (FCR) represents a common source of psychosocial distress in this population and sought to characterize subgroups for whom FCR might represent a target for intervention to improve quality of life. METHODS: We conducted a cross-sectional study of FCR in patients who were disease-free after potentially curative pancreatectomy for ductal or periampullary adenocarcinoma or pancreatic neuroendocrine tumor. We assessed seven discrete dimensions of FCR using the Fear of Recurrence Inventory and evaluated quality of life and psychosocial distress using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire and the Hospital Anxiety and Depression Scale. RESULTS: Of 354 eligible patients, 240 (68 %) participated in the study a median of 48 months after potentially curative pancreatectomy. An FCR severity score indicative of frequent fearful thoughts, emotional disturbance and functional impairment was identified in 37, 28, and 35 % of patients with pancreatic adenocarcinoma, nonpancreatic periampullary adenocarcinoma, and pancreatic neuroendocrine tumor, respectively. Anxiety (P < 0.001) and low quality of life (P = 0.028) were independently associated with a clinically significant level of FCR, but histopathologic diagnosis and clinicopathologic markers of prognosis were not. CONCLUSIONS: FCR represents a significant concern for one-third of patients after curative surgery for a pancreatic or periampullary tumor, regardless of their actual likelihood of recurrence or disease-related death.

Influence of obesity on cancer-related outcomes after pancreatectomy to treat pancreatic adenocarcinoma.

OBJECTIVE: To examine the influence of obesity, as measured by body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), on clinicopathologic factors and survival after pancreatectomy to treat adenocarcinoma. DESIGN: Retrospective review and statistical analysis using prospectively collected data. SETTING: Referral center with a dedicated multidisciplinary pancreas cancer program. PATIENTS: Two hundred eighty-five consecutive patients with data available for BMI calculation who underwent potentially curative pancreas resection to treat adenocarcinoma from January 1, 1999, to October 31, 2006. MAIN OUTCOME MEASURE: Influence of BMI and other known prognostic variables on the incidence of lymph node metastasis and disease-free and overall survival. RESULTS: We identified a subset of obese patients (BMI >35) who were at 12-fold risk of lymph node metastasis compared with nonobese patients (BMI < or =35). The estimated disease-free and overall survival rates were decreased in the obese patients, and the risk of cancer recurrence and death after pancreatectomy was nearly twice that in nonobese patients. CONCLUSIONS: Obese patients with a BMI of more than 35 are more likely to have node-positive pancreatic cancer and decreased survival after surgical resection. Data suggest that the negative influence of BMI of more than 35 on cancer-related end points is unrelated to the potential complexity of performing major oncologic surgery in obese patients.