Quality of Life, Fatigue, and Sleep Problems in Pancreatic Cancer Patients: A Randomized Trial on the Effects of Exercise
A randomized trial on the effects of exercise
; ; ; ; ; ; ; ;
Background: Improving quality of life (QoL) is an important treatment goal in pancreatic cancer patients. Although the beneficial effects of exercise on QoL are well understood, few studies have investigated more aggressive cancers such as pancreatic cancer.
Methods: Within a randomized trial, we assessed the efficacy of 6-month resistance training on physical functioning (primary outcome) and further QoL-related outcomes. 65 pancreatic cancer patients were assigned to home-based training, supervised training, or a usual care control group. Analysis-of-covariance models on changes from baseline to 6 and 3 months were applied.
Results: 47 patients completed the intervention period. After 6 months, no effects of resistance training were observed. However, after 3 months, explorative analyses showed significant between-group mean differences (MD) in favor for resistance training for physical functioning (pooled group: MD=11.0; p=0.016; effect size[ES]=0.31), as well as for global QoL (MD=12.1; p=0.016; effect size=0.56), and other outcomes, such as sleep problems and fatigue. Multiple imputation analyses yielded similar results. Home-based and supervised training performed similarly.
Conclusion: This first randomized resistance training trial in pancreatic cancer patients indicated clinically relevant improvements in QoL after 3 but not after 6 months. Given the severity of pancreatic cancer, exercise recommendations may already commence at surgery.
Pancreatic cancer is characterized by aggressive tumor growth with early metastases (1, 2). Further, cancer cachexia and sarcopenia are both ubiquitous characteristics which limit the ability to perform daily activities, compromise patients’ quality of life (QoL), and have been associated with poor overall survival (3, 4). Therefore, preservation of physical functioning and health-related QoL are the main treatment goals of supportive cancer care.
Patient QoLvaries significantly depending on stage of disease and treatment phase. Thus, patients in a metastatic disease situation were found to have a lower QoL compared to surgically treated patients (5). Furthermore, patients shortly after surgery have a lower QoL than patients at two months after surgery (6). In the further course—three to six months postoperatively—the patients’ QoL seems to stabilize (7, 8).
Physical activity plays an important role in supportive cancer care, as it has positive effects on physical and psychological well-being, both during and after cancer therapy (9). However, most studies on this topic investigated patients in an early stage of the disease, with less aggressive tumors and with a lower symptom burden. Studies including patients with more aggressive or advanced cancers are rare and most of them were conducted with small sample sizes and mixed entities (10, 11).
To date, only two randomized controlled trials (RCTs) have been published on exercise and QoL in pancreatic cancer patients (12, 13). A 6-week multimodal intervention (nutritional counseling, aerobic and resistance training, anti-inflammatory medication) in inoperable pancreatic cancer patients (n=20) observed no significant differences for fatigue and physical fitness (12). The second RCT conducted a 3-month home-based walking program among 102 pancreatic cancer patients (13). Although the intervention group improved with respect to fatigue, physical functioning, and QoL between-group comparisons did not reach significance.
The aim of the current study was to investigate the effects of a 6-month resistance training intervention on QoL and fatigue in pancreatic cancer patients. We hypothesized that patients who regularly perform resistance training experience better QoL, better physical functioning, fewer disease-related symptoms, and lower levels of fatigue.
Our study, the SUPPORT (Supervised Progressive Resistance Training for Pancreatic Cancer Patients) trial, is a three-arm exercise RCT comparing a supervised progressive resistance training group (RT1), a home-based progressive resistance training group (RT2), and a usual care control group (CON) over a 6-month intervention period. The primary outcome was the subscale physical functioning of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) core module (C30) (14) at 6 months.
The study was approved by the Ethics Committee of the Medical Faculty of Heidelberg University (S-409/2013) and has been registered on ClinicalTrials.gov (NCT01977066). Trials were conducted in accordance with the Declaration of Helsinki and International Council for Harmonization guidelines for good clinical practice. All patients provided written informed consent.
Participants were recruited between December 2013 and December 2015. The inclusion criteria were: resectable or non-resectable pancreatic cancer (stage I-IV); mostly treated at Heidelberg University Hospital or National Center for Tumor Diseases in Heidelberg; age ≥18 years and sufficient German language skills.
As they received identical treatment regimes, patients with adenocarcinoma of the distal bile duct (pancreatic biliary) and with ampullary ductal adenocarcinoma were also eligible. Patients were excluded from the study if they showed insufficient wound healing, impaired hematological capacity (either hemoglobin value <8g/dl or thrombocytes <50 000), heart failure or uncertain arrhythmia, uncontrolled hypertension, severe renal dysfunction (glomerular filtration rate <30%, creatinine >3mg/dl), reduced standing or walking ability, or any other comorbidities, that precluded their participation.
Patients living close to the study center (about <20 km) were randomized to RT1 or CON, while patients living further away were randomly assigned to RT2 or CON. A 2:1 block randomization, stratified by sex and age, with a random number generator and varying block sizes of 3 and 6 was used. Randomization of a patient was done by an independent biometrician according to the pre-specified allocation list.
Outcome measures were collected via self-reported questionnaires prior to the intervention (T0, baseline), at mid-intervention (T1, after 3 months) and post-intervention (T2, after 6 months). Baseline assessments took place at the earliest 3 months after surgical resection to allow for adequate wound healing. For practicability and safety reasons, parts of the study personnel were unblinded.
The patients of the two resistance training groups RT1 and RT2 exercised twice a week for approximately 60 minutes for 6 months, according to the exercise guidelines of the American College of Sports Medicine for cancer survivors (15). Both resistance training interventions addressed major muscle groups of the upper and lower extremities. After a four-week adaptation phase, patients performed 8 exercises/session with 2–3 sets with 8–12 repetitions. Exercise intensities were of 60–80% One-Repetition Maximum in RT1 and 14–16 on the Borg Scale of Perceived Exertion (16) in RT2.
Detailed information and results on feasibility and efficacy of the resistance training on muscle strength are described elsewhere (17). Both interventions differed primarily by the mode of delivery (therapist-supervised at an exercise facility on weight machines vs. home-based with a training manual exercising at home supported by weekly phone calls). Patients of the control group received usual care in line with their cancer treatment and were advised not to change exercise behavior. Patients were called once a month and asked about possible treatment-related side effects.
Changes in QoL were assessed using the EORTC C30 (14) and the pancreas-specific module (PAN26) (18). The C30 questionnaire covers a total of 30 items with 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional and social functioning) and 8 symptom scales (fatigue, pain, nausea/vomiting, dyspnea, sleep problems, appetite loss, constipation, and diarrhea), as well as a global health status and QoL scale. The PAN26 consists of 26 items covering 7 multi-item scales.
Cronbach’s alpha ranged from 0.7 to 0.9 for all subscales in our study, except for diarrhea (Cronbach’s alpha=0.5). After standard transformations, all scales ranged from 0–100. Higher scores indicated more symptoms and worse health-related QoL, with the exception of global health status, C30 functioning scales, and PAN26 satisfaction with health care scale with higher scores indicating better function and better QoL.
Fatigue was assessed using the German version of the Multidimensional Fatigue Inventory (MFI) (19). The validated 20-item questionnaire consists of 5 subscales (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) ranging from 0 to 20, with higher scores indicating more fatigue (Cronbach’s alpha=0.63–0.87).
Clinical data and patient characteristics were extracted and validated from the medical records or assessed by self-report of the patients. Weight and height were measured during the assessments. Additionally, patients reported their exercise behavior in the year before the pancreatic cancer diagnosis.
Sample size calculations were based on a two-sided F-test (significance level: p<0.05) comparing normal mean differences of 3 groups. Assuming effect sizes (ES) of 0.6 and 0.5 in RT1 and RT2, respectively, and a 25% drop-out rate, recruiting 67 patients per group corresponded to a power (probability of detecting an effect, given that the effect is really there) of 0.82.
Descriptive analyses were based on frequencies or mean values and standard deviations, depending on the scale of the variables. The primary dataset included all patients for which analyzable data were available after 6 months (complete–case analysis). Stability was investigated by comparing results from the complete-case dataset with those from multiple imputation methods (25 datasets). Data for patients who died or had disease progression, preventing further participation, within 6 months, were not substituted during the multiple imputation procedure.
For the primary endpoint (T2), an analysis of covariance (ANCOVA) was performed, with the changes since T0 as the dependent variable, group assignment (according to the intention-to-treat principle) as the independent variable, and the value of the variable at T0 as a covariable. In case of a significant difference between the three groups in the global F-test, paired t-tests were performed within the ANCOVA.
In addition, comparisons of the pooled resistance training group (RT), combining RT1 and RT2, with CON were conducted as exploratory analyses. The ES per training group was calculated by dividing the change from the pretest values to the posttest values by the pretest standard deviation (20, 21). Furthermore, the effects of an additional adjustment to age, sex, body mass index (BMI), time since first chemotherapy, and exercise behavior in the year prior to being diagnosed with pancreatic cancer were investigated. Similar exploratory analyses were performed for all secondary endpoints. The statistical software SAS 9.3 was used for all analyses.
A total of 304 pancreatic cancer patients were approached (Figure 1). Of these, 65 patients were randomized in the study and 47 completed the 6-month intervention phase. The drop-out rate was 22.7% in CON, 25% in RT1 and 32.3% in RT2.
Patients were on average 60.5 years (standard deviation [SD] = 8.4) old. Most patients had a normal weight (mean BMI = 23.7; SD=4.3) and were diagnosed with stage IIB cancer (67.4%) (Table 1). More than half of the patients (53.2%) experienced a weight loss of >10% within 6 months before T0. Patients random^zed to the exercise groups performed on average 1.3 weekly training sessions (out of 2) which corresponds to an overall training adherence rate of 66.5%. Among the 47 patients who completed the 6-month intervention phase, training adherence dropped steadily over the 6 months in RT1 and RT2, from initially 73.6% and 87.5%, respectively, to 41.5% and 62.0% (Figure 2). No adverse events occurred during exercise sessions.
For the primary endpoint, physical functioning, the global test did not indicate an overall between-group difference at 6 months (p=0.93, Table 2). However, at month 3, explorative analyses revealed significant global between-group differences (Table 2). Descriptively, physical functioning increased from baseline to the end of the 6-month intervention similarly in both training groups with reaching the maximum after 3 months (eTable 1). In contrast, CON showed a steady increase during intervention. Mean differences (MD) were statistically significant at 3 months compared to CON for the pooled RT group (MD=11.0; p<0.05), as well as for RT2 (MD=11.8; p=0.02), with a similar but non-significant effect for RT1 (MD=9.1; p=0.14) (Table 2, eTable 1). Sensitivity analyses based on further adjustments and multiple imputations yielded similar results (eTable 2).
For secondary outcomes, all global tests were non-significant at 6 months. At 3 months, the global tests and the comparisons of RT with CON indicated significant differences for global QoL, cognitive functioning, sleep problems, physical fatigue, and reduced activity (Table 2, eTable 3).
The subsequently performed pairwise-comparisons with CON showed similar effects for RT1 and RT2 (eTable 1, Figure 3). The absolute values of effect sizes ranged from 0.16 to 1.14. RT2 showed significant between-group changes for all variables but sleep problems (MD=-14.9; p=0.07; ES=-0.66), RT1 for cognitive functioning (MD=17.9; p=0.01; ES=0.74), sleep problems (MD=-28.2; p=0.01; ES=-1.14), and the PAN26 hepatic (MD= –14.5; p=0.003; ES=-1.10). None of the other PAN26 scales indicated additional differences at any time (eTable 4).
Sensitivity analyses yielded similar results (eTable 2). Two variables with significant results in the complete-case analysis showed no significant differences in the imputed analyses (cognitive function and reduced activity), however, with p-values still between 0.05 and 0.1. Vice-versa, two variables had non-significant p-values ≤0.1 in the complete-case analyses with significant p-values after multiple imputation (role function and fatigue).
This is the first RCT that investigated the effects of resistance training on QoL in pancreatic cancer patients. After the 6-month intervention period, there were no effects of resistance training on the primary endpoint physical functioning as well as on the other assessed QoL parameters. However, after 3 months, favorable effects of resistance training compared to usual care were observed for physical functioning, as well as global QoL, cognitive functioning, sleep problems, physical fatigue, and reduced activity. Between-group differences and the corresponding absolute effect sizes of up to 1.14 after 3 months demonstrated the clinical and practical relevance of resistance training on QoL with moderate-to-large effect sizes (20). Both modes of delivery—supervised and home-based resistance training—showed similar effects.
We did not detect any between-group differences after 6 months. One explanation might be that mid-term training effects after 3 months were later cancelled out to some extent by disease progression. In addition, the adherence rate showed a continuous decline over the course of the intervention period.
Our results after 6 months were comparable with those of the previous exercise RCTs which also reported no between-group effects (12, 13). Our results at mid-intervention were in accordance with research regarding QoL and resistance training in cancer patients with other cancer entities (22–24). Meta-analyses, mainly based on breast and prostate cancer, demonstrated that resistance training held beneficial effects for QoL and physical functioning (25, 26). However, our study revealed higher effect sizes that are rather in line with a recent study on patients with colon cancer (27).
The 3-month results of our study on QoL indicate overall positive effects of resistance training. Here, the pairwise analyses for each parameter found comparable effects in the supervised and home-based resistance training groups. This result is highly relevant for the implementation of resistance training interventions in clinical practice, because not all cancer patients have easy access to training facilities, offering supervised training for patients living with cancer.
The present study has several strengths, especially the randomized controlled design, a good adherence rate to the standardized intervention, intention-to-treat analysis, and the use of a multidimensional assessment tool for QoL and fatigue.
A methodological limitation of this study is the limited sample size, resulting in a reduced generalizability. Recruitment difficulties resulted in lower numbers than originally planned (65 randomized patients instead of 201). Comparable recruitment experiences have been reported in a recent study on lung and pancreatic cancer patients (12). On the other hand, the observed effect sizes were partially higher and we applied more powerful statistical methods for the analyses than were used for the sample size calculations. Consequently, our study design was rather conservative. Nevertheless, the interpretation of the study, especially of non-significant results, need to be performed with caution. Another limitation is the monocentric study design. Further, both resistance training groups were not randomized to each other, resulting in unbalanced group sizes.
This RCT was the first to show that resistance training may be a promising modality to relieve symptoms, improve physical functioning and QoL in pancreatic cancer patients. Given the high symptom burden and the limited survival time of these patients, we consider even the 3-month results as relevant, so that corresponding exercise recommendations should already be given at diagnosis. Future studies need to focus on prolonging the positive mid-term exercise effects, potentially by maintaining regular training.
We would like to thank the patients who participated in this clinical trial. We also thank Lena Kempf and Marcel Bannasch for training support of the supervised training group, Emanuel Schembri for support in the assessments, and Prof. Dr. Jens Werner for clinical advice on designing the trial.
This work was supported by a grant of the German Cancer Aid (SUPPORT-Study Grant No. 110513 and 110552) as well as by additional financial support of the German Cancer Research Center and the University Hospital Heidelberg.
Upon completion of further analyses of the study, the authors are willing to share data with other researchers for scientific purposes. Please address your requests regarding the dataset to the corresponding author.
Conflict of interest
Prof. Steindorf received consultancy fees from Pfizer. She is co-author of the Breast Cancer and Sports brochure published by Pfizer. She received authorship/co-authorship fees for a publication related to the topic from Thieme-Verlag. She received reimbursement of travel expenses and lecture fees form BIC-Krankenkasse Dortmund, from Audi, Bosch, Adviva, and from Asklepios.
Dr. Wiskemann received reimbursement of congress fees and travel expenses as well as lecture fees from Pfizer, Celgene and MSD.
The remaining authors declare no conflict of interest.
Manuscript received on 28 December 2018, revised version accepted on 29 April 2019
Prof. Dr. rer. nat. Karen Steindorf
Abteilung Bewegung, Präventionsforschung und Krebs
Deutsches Krebsforschungszentrum (DKFZ) und Nationales Centrum für
Tumorerkrankungen (NCT) Heidelberg
Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
Cite this as:
Steindorf K, Clauss D, Tjaden C, Hackert T, Herbolsheimer F, Bruckner T,
Schneider L, Ulrich CM, Wiskemann J: Quality of life, fatigue, and sleep problems in pancreatic cancer patients—a randomized trial on the effects of exercise.
Dtsch Arztebl Int 2019; 116: 471–8. DOI: 10.3238/arztebl.2019.0471
Division of Physical Activity, Prevention and Cancer, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Germany: Prof. Dr. rer. nat Karen Steindorf, Dr. sc. hum. Dorothea Clauss, Dr. sc. hum. Florian Herbolsheimer
Division of Medical Oncology, National Center for Tumor Diseases and Heidelberg University Hospital, Heidelberg, Germany: Dr. sc. hum. Dorothea Clauss, PD Dr. phil. Joachim Wiskemann
Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany: Dr. med. Christine Tjaden, Prof. Dr. med. Thilo Hackert, Prof. Dr. med. Lutz Schneider
Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany: Dr. sc. hum. Thomas Bruckner
Department of Population Health Sciences, Huntsman Cancer Institute and University of Utah, Salt Lake City, USA: Prof. Dr. rer. nat. Cornelia M. Ulrich
|1.||Gong J, Tuli R, Shinde A, Hendifar AE: Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 2016; 4: 315–25 CrossRef MEDLINE PubMed Central|
|2.||Oberstein PE, Olive KP: Pancreatic cancer: why is it so hard to treat? Therap Adv Gastroenterol 2013; 6: 321–37 CrossRef MEDLINEPubMed Central|
|3.||Choi MH, Yoon SB, Lee K, et al.: Preoperative sarcopenia and post-operative accelerated muscle loss negatively impact survival after resection of pancreatic cancer. J Cachexia Sarcopenia Muscle 2018; 9: 326–34 CrossRef MEDLINE PubMed Central|
|4.||Pausch T, Hartwig W, Hinz U, et al.: Cachexia but not obesity worsens the postoperative outcome after pancreatoduodenectomy in pancreatic cancer. Surgery 2012; 152: S81–8 CrossRef MEDLINE|
|5.||Crippa S, Dominguez I, Rodriguez JR, et al.: Quality of life in pancreatic cancer: analysis by stage and treatment. J Gastrointest Surg 2008; 12: 783–94 CrossRef MEDLINE PubMed Central|
|6.||Eaton AA, Gonen M, Karanicolas P, et al.: Health-related quality of life after pancreatectomy: results from a randomized controlled trial. Ann Surg Oncol 2016; 23: 2137–45 CrossRef MEDLINE PubMed Central|
|7.||Nieveen van Dijkum EJ, Kuhlmann KF, Terwee CB, Obertop H, de Haes JC, Gouma DJ: Quality of life after curative or palliative surgical treatment of pancreatic and periampullary carcinoma. Br J Surg 2005; 92: 471–7 CrossRef MEDLINE|
|8.||Schniewind B, Bestmann B, Henne-Bruns D, Faendrich F, Kremer B, Kuechler T: Quality of life after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head. Br J Surg 2006; 93: 1099–107 CrossRef MEDLINE|
|9.||Burke S, Wurz A, Bradshaw A, Saunders S, West MA, Brunet J: Physical activity and quality of life in cancer survivors: a meta-synthesis of qualitative research. Cancers (Basel) 2017; 9. doi:10.3390/cancers9050053 CrossRefMEDLINE PubMed Central|
|10.||Dittus KL, Gramling RE, Ades PA: Exercise interventions for individuals with advanced cancer: a systematic review. Prev Med 2017; 104: 124–32 CrossRef MEDLINE|
|11.||Titz C, Hummler S, Thomas M, Wiskemann J: Physical exercise in advanced cancer patients undergoing palliative treatment. Expert Review of Quality of Life in Cancer Care 2016; 1: 433–42 CrossRef|
|12.||Solheim TS, Laird BJA, Balstad TR, 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: 778–88 CrossRef MEDLINE PubMed Central|
|13.||Yeo TP, Burrell SA, Sauter PK, et al.: A progressive postresection walking program significantly improves fatigue and health-related quality of life in pancreas and periampullary cancer patients. J Am Coll Surg 2012; 214: 463–75; discussion 75–7 CrossRef MEDLINE|
|14.||Aaronson NK, Ahmedzai S, Bergman B, et al.: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–76 CrossRef MEDLINE|
|15.||Schmitz KH, Courneya KS, Matthews C, et al.: American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 2010; 42: 1409–26 CrossRef MEDLINE|
|16.||Borg G: Perceived exertion and pain scales. Champaign, IL: Human Kinetics Pub Inc; 1998.|
|17.||Wiskemann J, Clauss D, Tjaden C, et al.: Progressive resistance training to impact physical fitness and body weight in pancreatic cancer patients: a randomized controlled trial. Pancreas 2019; 48: 257–66 CrossRef MEDLINE|
|18.||Eaton AA, Karanicolas P, MChir CDJB, Allen PJ, Gonen M: Psychometric validation of the EORTC QLQ-PAN26 Pancreatic Cancer Module for assessing health related quality of life after pancreatic resection. J Pancreas 2017; 18: 19–25.|
|19.||Krauß O: Multidimenional Fatigue Inventory. In: Schumacher J, Klaiberg A, Brähler E (eds.): Diagnostische Verfahren zu Lebensqualität und Wohlbefinden. Göttingen: Hogrefe Verlag; 2003.|
|20.||Cohen J: Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, New York: Lawrence Erlbaum Associates; 1988.|
|21.||Morris SB, DeShon RP: Combining effect size estimates in meta-analysis with repeated measures and independent-groups designs. Psychological Methods 2002; 7: 105–25 CrossRef|
|22.||Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O: Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev 2012; 8: CD008465 CrossRef|
|23.||Steindorf K, Wiskemann J, Ulrich CM, Schmidt ME: Effects of exercise on sleep problems in breast cancer patients receiving radiotherapy: a randomized clinical trial. Breast Cancer Res Treat 2017; 162: 489–99 CrossRef MEDLINE|
|24.||Hojan K, Kwiatkowska-Borowczyk E, Leporowska E, Milecki P: Inflammation, cardiometabolic markers, and functional changes in men with prostate cancer. A randomized controlled trial of a 12month exercise program. Pol Arch Intern Med 2017; 127: 25–35 CrossRef MEDLINE|
|25.||Buffart LM, Kalter J, Sweegers MG, et al.: Effects and moderators of exercise on quality of life and physical function in patients with cancer: an individual patient data meta-analysis of 34 RCTs. Cancer Treat Rev 2017; 52: 91–104 CrossRef MEDLINE|
|26.||Cramp F, James A, Lambert J: The effects of resistance training on quality of life in cancer: a systematic literature review and meta-analysis. Support Care Cancer 2010; 18: 1367–76 CrossRef MEDLINE|
|27.||Van Vulpen JK, Velthuis MJ, Steins Bisschop CN, et al.: Effects of an exercise program in colon cancer patients undergoing chemotherapy. Med Sci Sports Exerc 2016; 48: 767–75 CrossRef MEDLINE|