Changes in motor function and quality of life after surgery in patients with pancreatic cancer

概要

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Changes in motor function and quality of life after surgery in patients with pancreatic cancer

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Yuki Nakashima,1,5) Toshihiro Kawae,2) Daisuke Iwaki,1) Kenichi Fudeyasu,1) Hiroaki Kimura,3)

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Kenichiro Uemura,4) Hitoshi Okamura5)

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Japan

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University, Hiroshima, Japan

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Sciences, Hiroshima University, Japan

Division of Rehabilitation, Department of Clinical Support, Hiroshima University Hospital,

Department of Physical Therapy, Faculty of Makuhari Human Care, Tohato University, Japan
Department of Rehabilitation Medicine, Hiroshima University Hospital, Japan
Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima

Department of Psychosocial Rehabilitation, Graduate School of Biomedical and Health

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Abstract

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Objective: To determine the changes in motor function and health-related quality of life after

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pancreatectomy and identify factors influencing postoperative quality of life.

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Methods: This study was a single-center prospective observational study. The 6-min walking

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distance, grip strength, knee extension strength, and health-related quality of life variables were

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measured in patients with pancreatic cancer before and after surgery. The paired t-test and the

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Wilcoxon signed-rank test were used to compare the pre-and postoperative motor function and

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health-related quality of life variables. Factors associated with postoperative health-related

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quality of life were assessed using multiple regression analysis.

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Results: Fifty-nine individuals were enrolled. Motor function values decreased significantly

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postoperatively compared with preoperatively, including the 6-min walking distance (mean ±

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standard deviation: 402.5 ± 95.4 vs. 497.7 ± 80.4 m, P＜0.001), knee-extensor strength (0.42 ±

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0.10 vs. 0.47 ± 0.10 kgf/kg, P＜0.001), and grip strength (22.0 ± 8.9 vs. 24.5 ± 9.2 kg, p <

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0.001). Multiple regression analysis showed significant association between 6-min walking

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distance change and postoperative physical functioning scores of health-related quality of

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life (p = 0.036).

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Conclusion: Motor function decreased postoperatively. Our findings suggest that a decrease in 6min walking distance after surgery may be associated with postoperative physical functioning scores of
EORTC QLQ-C30 in pancreatic cancer patients.

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Key words: Pancreatectomy, cancer, muscle strength, surgery, quality of life, walking

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Introduction

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Pancreatic cancer is one of the leading causes of cancer-related mortality in developed

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countries (Ferlay et al, 2013). Actually, more than 331,000 deaths per year - accounting for

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4.0% of all cancer-related deaths - are attributed to this disease, making it the seventh leading

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cause of such deaths in men and women combined (Ferlay et al, 2013). In recent years, the

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death rate from pancreatic cancer has been increasing, and it is anticipated that this rate will

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continue to increase in the future (Rahib et al, 2014; Katanoda et al, 2015).

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Surgical resection is the only curative treatment for pancreatic cancer (Tempero et al, 2017),

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and postoperative adjuvant chemotherapy has been shown to improve life expectancy in

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randomized controlled trials (Oettle et al, 2007; Oettle et al, 2013). Adjuvant chemotherapy is

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initiated approximately 2–10 weeks after the surgery, although the Karnofsky performance

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status score is required to be >50 for its administration (Ueno et al, 2009; Oettle et al, 2007;

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Oettle et al, 2013). Early postoperative mobilization is strongly recommended to prevent

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postoperative complications; however, there have been no studies on the influence of

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perioperative exercise therapy and motor function on the postoperative courses of patients who

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underwent pancreatic cancer surgery. Therefore, there exists a lack of established exercise

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therapy programs for such patients (Lassen et al, 2013).

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In recent years, the importance of health-related quality of life (QOL) has been emphasized in

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patients with cancer (Esbensen et al, 2004; Morishita et al, 2018; Hawthorn, 1993). It has been

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shown that pancreatectomy reduces the health-related QOL in patients with pancreatic cancer

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(Lounis et al, 2019; Halloran et al, 2011); these studies also found that pancreatectomy has a

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major impact on motor and psychological functions.

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Previous studies revealed that surgery is associated with decreased motor function in patients

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with esophageal and colorectal cancers (Tatematsu et al, 2013; Inoue et al, 2016; Olsén et al,

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2005; Sánchez-Jiménez et al, 2015). Therefore, given that surgery for pancreatic cancer is more
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invasive than that for colorectal cancer, motor function is also expected to decrease after

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pancreatectomy. However, very few studies have objectively investigated motor function in

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patients with pancreatic cancer(Hayashi et al, 2017), and there are no longitudinal studies that

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have compared motor function before and after surgery despite their potential importance in

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establishing perioperative rehabilitation programs. Additionally, health-related QOL is also

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expected to decrease after surgery; however, the effect of motor function on the postoperative

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health-related QOL is also unclear.

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Therefore, we aimed to determine the effect of surgery on the motor function and health-

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related QOL in patients with pancreatic cancer, and to identify factors that influence the

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postoperative health-related QOL.

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Methods

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We conducted a single-center prospective study to investigate the effect of pancreatic

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resection on the motor function and health-related QOL in patients with pancreatic cancer. This

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study was approved by the redacted Epidemiological Ethics Review Board (approval number:

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E-656), and the patients provided written and verbal informed consent. All persons gave their

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informed consent prior to their inclusion in the study. The survey period spanned from June

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2017 to June 2019.

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The inclusion criteria were: 1) pancreatectomy performed for suspected invasive ductal

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carcinoma of the pancreas at our hospital during the aforementioned period; and 2) immediate

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referral to the rehabilitation department. Patients who required assistance while walking owing

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to motor organ and/or central nervous system disease, and those for whom the evaluation of

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motor function was difficult, were excluded from the study.

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As 6-min walking distance was primary endpoint. The 6-min walking distance was measured
as an index of exercise tolerance. Secondary endpoint as hand grip, knee extension strengths,
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Health-related QOL. Hand grip and knee extension strengths were measured as indices of upper

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and lower extremity muscle strength, respectively. Health-related QOL measures were assessed

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by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life

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Questionnaire (QLQ-C30) version 3.0. The investigations were conducted by physical

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therapists. Patient information including age, sex, body weight, body mass index (BMI),

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diagnosis, chemotherapy regimens received before surgery, preoperative blood levels of C-

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reactive protein and albumin, surgical method, operation time, amount of blood loss, and

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postoperative hospitalization duration were obtained from medical records.

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Details of the administered evaluation tests are as follows:

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1) In the 6-min walking test, 30-m walking courses were created in an indoor corridor according

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to the guidelines of the American Thoracic Society statement (2002), with a cone installed to

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indicate the turnaround point. Patients were instructed to walk the longest distance they could

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cover during the 6-min period. Walking for 6 min is reportedly associated with peak oxygen

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uptake in patients with cancer, and is, therefore, a valuable indicator (Schmidt et al, 2013).

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2) Knee extensor muscle strength, which is considered an index of lower limb muscle strength,

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was measured using an isometric muscle strength measuring device (μTas M-1, Anima Inc.,

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Tokyo, Japan), while the isometric knee extensor strength was measured with a sensor pad

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immobilized on a belt at the distal lower leg (Nomura et al, 2018). The measurement posture

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was sitting at the edge of a chair, with both hands paired in front of the chest while the trunk

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was kept in an upright position. The sensor pad was placed distal to the participant’s lower leg;

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the height of the sitting surface and length of the fixation belt were adjusted to place the knee

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joint at a 90° flexion, whereupon the belt was secured to the examination table. Isometric knee

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extension exercises with maximum effort were performed for approximately 5 s twice on each

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side, and the maximum value was adopted as the recorded knee extension strength. To eliminate

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the effect of body weight, the knee extension strength-to-weight ratio divided by the maximum

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isometric knee extension strength was calculated for normalization.
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3) Grip strength measurement was performed using Smedley-type grip dynamometer while

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being in the standing position with the upper extremity in a drooping stance. The grip size of a

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dynamometer was adjusted until the second joint of the participant’s index finger was at a 90°

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angle on the handle by examiner. The participants were instructed to grasp the device with their

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maximum strength; the right and left hand strength was each tested twice, and the maximum

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value was considered the grip strength.

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4) The EORTC QLQ-C30 version 3.0, which comprises 30 questions for patients with cancer,

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was used to investigate the health-related QOL. The scores were classified according to the

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guidelines into five functional scales (physical, roles, cognitive, emotional, and social

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functioning), three symptom scales (fatigue, pain, nausea/vomiting), and six single items

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(constipation, diarrhea, insomnia, dyspnea, anorexia, and economic difficulties) and were

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converted to an overall score ranging from 0 to 100 (Fayers et al, 2001).

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Motor function and EORTC QLQ-C30 were evaluation at two points before and after

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surgery. All participants in this study received the same physical therapy regimen during the

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perioperative period. Preoperative guidance included respiratory training, postoperative physical

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therapy orientation, and preoperative evaluation between 7 and 1 day(s) before surgery.

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Postoperative rehabilitation was performed starting on postoperative day 1 and continued until

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discharge. From the first postoperative day, the participants performed sputum drainage

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exercises and rose from their beds. Resistance and aerobic exercises were performed starting on

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postoperative day 4. Each patient performed a combination of resistance and aerobic exercise

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for 20 to 40 minutes. The focus was on lower extremity resistance exercises such as leg presses,

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leg extensions, hip adductions, hip abductions, and heel raises. Aerobic exercise included

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bicycle ergometer and walking for 10 to 20 minutes. Postoperative evaluation was performed 14

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days after surgery.

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The sample sizes were calculated using a standard deviation of 88 m based on a previous

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study, which examined the changes in 6-min walking times before and after gastrointestinal
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surgery (Inoue et al, 2016). A decrease of 80 m during the 6-min walking test was considered

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clinically meaningful (Wise and Brown, 2005). The required sample size for an α error of 0.05

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and a β error of 0.2 was calculated to be 41 participants.

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Statistical Analysis

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Continuous variables were checked for normality using the Shapiro–Wilk test. Comparisons

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between the two matched groups were performed using the paired t-tests for the 6-min walking

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distance, grip strength, and knee-extension strength based on a normal distribution, and using

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the Wilcoxon signed-rank tests for the EORTC QLQ-C30 without a normal distribution.

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Pearson correlation coefficients were then calculated to assess relations among preoperative

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motor function parameters and physical functioning scores of EORTC QLQ-C30, and the

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relation between the delta change in physical functioning scores and motor function parameters.

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Single regression analysis was followed by multiple regression analysis to investigate factors

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associated with physical function scores, as determined by the postoperative QLQ-C30. We

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chose physical functioning scores because physical functioning scores have been reported as an

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independent prognostic factor in patients with pancreatic cancer (Gupta et al, 2006). In addition,

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the 6 minutes walking distance for in patients with cancer correlates with the EORTC physical

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functioning scores (K Schmidt et al, 2013, Morishita et al, 2018).

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The JMP® 14 software (SAS Institute Inc., Cary, NC, USA) was used for all statistical

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processing and analyses. All hypothesis tests were two-tailed. Single regression analysis was

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performed to select explanatory variables for multiple regression analysis; variables with P-

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values <0.20 were used as explanatory variables for multiple regression analysis. P-values

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<0.05 were considered statistically significant.

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Results

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The patients’ selection process is presented in Figure 1. The patients’ characteristics and

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surgical information are presented in Table 1. The median age was 66.5 years and the median

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BMI was 21.5 kg/m2; 25(42%) and 34 (58%) participants were men and women, respectively.

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Seventeen patients (29%) underwent preoperative chemotherapy. The median postoperative

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hospital stay was 19 days and the median postoperative assessment time was at 14 days

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postoperatively.

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Table 2 shows the preoperative and postoperative 6-min walking distances, grip strength, and

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knee-extensor strength test results; all variables significantly decreased after surgery. The

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postoperative 6-min walking distance, grip strength, and knee extension strength were at 81%,

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90%, and 89% of their presurgical values, respectively. In the EORTC QLQC-30, significant

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decreases in physical, role, cognitive, social, and global functioning, fatigue, nausea and

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vomiting, pain, insomnia, appetite loss, and diarrhea scores were observed after surgery

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compared with their preoperative values (Table 3).

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Regarding relations among preoperative motor function parameters and physical functioning

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scores of EORTC QLQ-C30, except for the relationship between hand grip strength and

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physical functioning scores, there was a significant relationship between each score (Table 4).

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The delta change in physical functioning of EORTC QLQC30 was significant correlated with

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the delta change in 6-min walk distance (r = 0.257; p = 0.0495), but not with the delta change

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in % knee extension force (r = 0.048; p = 0.718) and hand grip strength (r = 0.075; p = 0.575).

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To investigate the factors associated with the physical function scores, as derived from the

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postoperative QLQ-C30, we performed a single-regression analysis using age, preoperative

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serum albumin, preoperative C-reactive protein, surgical duration, blood loss, preoperative and

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postoperative body weights, grip strength changes, knee-extension muscle strength changes, and

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6-min walking distance changes as explanatory factors (Table 5). Subsequently, multiple
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regression analyses were performed using blood loss, body weight change, and 6-min walking

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distance change (i.e., factors with P-values < 0.20 on single-regression analyses) as explanatory

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variables. Only the 6-min walking distance was found to be related to postoperative physical

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function on multiple regression analysis (Table 4).

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Discussion

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This was the first prospective study to investigate motor function before and after surgery in

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patients with pancreatic cancer. Our key finding was that motor functions, such as 6-min

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walking distance, grip strength, and knee extension strength, decreased after pancreatectomy,

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affecting the health-related QOL.

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A previous study in patients with esophageal cancer revealed a decrease in the 6-min walking

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length, grip strength, and knee-extensor strength following surgical treatment (Tatematsu et al,

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2013). Moreover, another work showed that grip strength and lower extremity muscle strength

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decreased in patients with colorectal carcinoma after surgery (Jensen et al, 2011). Furthermore,

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in a cross-sectional study of patients with pancreatic cancer performed 107.9 ± 53.6 days after

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pancreatectomy, muscle weakness of the upper and lower limbs was reported (Clauss et al,

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2017). In our study, postoperative evaluation was performed after a median of 14 days

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postoperatively, indicating that motor functions, such as muscle strength and exercise tolerance,

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decline at an earlier stage.

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Preventing such functional declines is important; despite receiving interventions, such as,

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preoperative instruction included respiratory training and postoperative physical therapy

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orientation. Postoperatively, patients were given walking from day 1 and resistance and aerobic

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exercises from day 4. Each patient performed a combination of resistance and aerobic exercises

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for 20 to 40 minutes. In spite of our participants experienced lower motor function, as

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evidenced by decreases to 81%, 90%, and 89% of their 6-min walking distance, grasping power,
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and knee extension muscle force, respectively, when compared to their preoperative values.

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This was similar to previous studies in patients with other types of cancer (Tatematsu et al,

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2013; Inoue et al, 2016), suggesting that the currently used in-hospital rehabilitation

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interventions may not be sufficient to fully restore motor function after surgery. Additionally,

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we found that many health-related QOL variables decreased postoperatively; this was consistent

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with data from previous studies that found a significant reduction in the QOL immediately after

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surgery (Schniewind et al, 2006; Heerkens et al, 2016). Moreover, our data also showed that the

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change in 6-min walking distance was significantly associated with the postoperative physical

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function scores as determined via the QLQ-C30. We hypothesized that the amount of change in

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motor function after surgery compared to the amount of change in preoperative physical function in the

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EORTC QLQ-C30 would affect postoperative physical function, and the amount of change in motor

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function was used as an explanatory factor. This suggests that some rehabilitation for preventing a

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decrease in the 6-min walking distance is needed to avert a decline in the postoperative QOL.

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As aforementioned, our results suggest that commonly-used exercise therapies during

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hospitalization, may not be sufficient to prevent the postoperative deterioration of motor

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function. Recent studies have demonstrated the effectiveness of preoperative exercise therapy in

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preventing postoperative motor dysfunction. In patients with colorectal carcinoma, undergoing

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preoperative exercise therapy for approximately 1 month has been reported to improve the

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postoperative 6-min walking distance (Li et al, 2013, Minnella, E. M et al, 2013). Preoperative

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exercise has also been shown to be feasible in pancreatic cancer (Ngo-Huang, A et al, 2017),

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and increasing physical activity has been shown to increase preoperative 6-minute walking

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distance (Ngo-Huang, A et al, 2019).

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In addition, significant weight loss was observed in the subjects of this study after surgery.

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This was similar to previous studies in patients with pancreatic cancer after surgery (Hashimoto,

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D et al, 2015). As weight has been used as one of the indicators of nutritional status in cancer

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patients (Bauer, J et al, 2002), it can be inferred that the subjects in this study are in worse

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nutritional status after surgery. Deterioration in nutritional status may affect motor function.

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Such data suggest that preoperative exercise therapy and nutrition management may be

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necessary for the early improvement of motor function in patients with pancreatic cancer.

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There were some limitations in this study. First, it was a single-center investigation and,

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therefore, did not necessarily reflect the general population. Second, although all participants in

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this study received rehabilitation interventions during their hospitalization, the Enhanced

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recovery after surgery(ERAS) protocol was not implemented at the hospital, as the ERAS

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protocol facilitates recovery and reduces postoperative hospital stay (Ji, H. B et al, 2018), which

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may help patients recover motor function and quality of life. Third, the duration of this study

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encompassed only a short period of time before and after surgery. However, it would be more

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informative to investigate the factors that impede motor function and QOL in a longitudinal

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study spanning a longer period of time before and after surgery.

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In conclusion, we found that the motor functions of patients with pancreatic cancer decreased

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after surgery, and that the decrease in the 6-min walking distance was significantly associated

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with a lower health-related QOL. Our data suggest that additional perioperative rehabilitation

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should be considered to maintain postoperative motor function and health-related QOL in such

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patients.

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Table 1. Patient baseline characteristics
n=59
Age; years, mean (SD)

66.5 (11.6)

Body mass index; kg/m2, mean (SD)

21.5 (2.7)

Sex; n (%)
Male

25 (42)

Female

34 (58)

Hypertension; n (%)

18 (31)

Diabetes; n (%)

23 (39)

Hyperlipidemia; n (%)

16 (27)

Preoperative adjuvant therapy; n (%)
Yes

17 (29)

No

42 (71)

Preoperative serum albumin; g/dL, median (IQR)

3.60 (3.30–3.90)

Preoperative C-reactive protein; mg/dL, median (IQR)

0.11 (0.04–0.29)

Surgical procedure; n (%)
PPPD

34 (58)

DP

17 (29)

PD

4 (7)

DP-CAR

3 (5)

TP

1 (2)

Operative time; min, median (IQR)

304 (209–344)

Estimated blood loss; mL, median (IQR)

515 (277–795)

Postoperative hospital stays; days, median (IQR)

19 (17–25)

Postoperative evaluation day; days, median (IQR)

14 (12–17)

n: number, SD: standard deviation, IQR: interquartile range, PPPD: pylorus preserving
pancreaticoduodenectomy, DP: distal pancreatectomy, PD: pancreatoduodenectomy, DP-CAR:
distal pancreatectomy with celiac axis resection, TP: transduodenal papillectomy

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Table 2. Differences in physical fitness and body weight before and after surgery
Preoperative

Postoperative

95% CI

P-value†

6MWD; m, mean (SD)

497.7 (80.4)

402.5 (95.4)

-110.8 – -79.6

<0.001

HGS; kg, median (IQR)

24.5 (9.2)

22.0 (8.9)

-3.8 – -2.3

<0.001

0.47 (0.10)

0.42 (0.10)

-0.06 – -0.03

<0.001

53.2 (10.9)

52.2 (10.1)

-3.6 – -2.2

<0.001

%KEF; kgf/kg, mean
(SD)
BW; kg, median (IQR)

6MWD: 6-min walk distance, HGS: hand grip strength, KEF: knee extension force, BW: body
weight, SD: standard deviation, IQR: interquartile range, CI: confidence interval, †: paired ttest

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Table 3. Postoperative changes as determined using the EORTC QLQ‐C30
Condition

Preoperative

Postoperative

95% CI

P-value†

93.3 (86.7–100)

80.0 (66.7–86.7)

-19.0 – -10.6

<0.001

100.0 (66.7–100)

66.7 (33.3–66.7)

-34.0 – -19.7

<0.001

Cognitive functioning

83.3 (66.7–100)

66.7 (66.7–83.3)

-15.6 – -5.3

0.002

Emotional functioning

83.3 (66.7–91.7)

83.3 (66.7–91.7)

-10.0 – 5.5

0.620

Social functioning

83.3 (66.7–100)

66.7 (50.0–100)

-21.5 – -6.7

<0.001

Global functioning

66.7 (41.7–83.3)

50.0 (33.3–58.3)

-21.4 – -7.4

<0.001

Fatigue

22.2 (11.1–33.3)

44.4 (33.3–55.6)

16.5–27.9

<0.001

Physical functioning
Role functioning

Nausea and vomiting

0 (0–0)

16.7 (0–16.7)

-5.1–15.9

<0.001

Pain

0 (0–16.7)

33.3 (16.7–50)

16.2–29.0

<0.001

Dyspnea

0 (0–33.3)

33.3 (0–33.3)

3.1–16.1

0.007

Insomnia

0 (0–33.3)

33.3 (0–33.3)

8.5–23.1

<0.001

Appetite loss

0 (0–33.3)

33.3 (33.3–66.7)

26.7–45.6

<0.001

Constipation

33.3 (0–33.3)

33.3 (0–66.7)

-9.3–10.5

0.860

Diarrhea

0 (0–0)

33.3 (0–66.7)

23.0–43.6

<0.001

Financial difficulties

0 (0–33.3)

0 (0–33.3)

-0.02–13.6

0.020

Values are presented as the median (IQR). EORTC: European Organisation for Research and
Treatment of Cancer; QLQ-30: quality of life questionnaire-C30, IQR: interquartile range, CI:
confidence interval, †: Wilcoxon signed-rank test

20

Table 4. Relations among preoperative motor function parameters and physical functioning scores
of EORTC QLQ-C30
PF
PF

6MWD

-

6MWD

%KEF

HGS

0.397

0.279

0.173

(P=0.002)

(P=0.033)

(P=0.189)

0.323

0.374

(P=0.013)

(P=0.004)

-

%KEF

-

HGS

0.296
(P=0.023)
-

6MWD, 6-min walk distance; HGS, hand grip strength;KEF, knee extension force; PF,
physical functioning scores of EORTC QLQ-C30.

21

Table 5. Associations between indicators of relative decline in physical functioning score in the
EORTC QLQ-C30
Simple regression analysis
β

SE

-0.070

0.181

0.600

-0.161

4.619

0.223

0.120

5.576

0.366

Operative time

-0.016

0.020

0.902

Estimated blood loss

-0.222

0.002

δBW

-0.185

δHGS

Multiple regression analysis
β

SE

P-value

0.091

-0.105

0.003

0.437

0.793

0.160

-0.178

0.756

0.158

0.107

0.760

0.419

δKEF

0.018

29.342

0.895

δ6MWD

0.332

0.033

0.010

0.289

0.036

0.036

Age

P-value

Preoperative serum
albumin
Preoperative C-reactive
protein

BW: body weight, HGS: hand grip strength, KEF: knee extension force, 6MWD: 6-min walking
distance, SE: standard error

22

Surgery for suspected pancreatic cancer
(n=72)
Refusal of participate(n=3)

Preoperative survey (n=69)

Withdraw consent (n=5)
Lack of data (n=4)
Benign pathology (n=1)

Postoperative survey (n=59)
Excluded from analysis (n=0)

Figure 1. Flow diagram showing the selection of study participants

23