Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients.

OBJECTIVES: Loss of body weight is often seen in pancreatic cancer and also predicts poor prognosis. Thus, maintaining muscle mass is an essential treatment goal. The primary aim was to investigate whether progressive resistance training impacts muscle and adipose tissue compartments. Furthermore, the effect of body composition on overall survival (OS) was investigated.
METHODS: In the randomized SUPPORT-study, 65 patients were assigned to 6-month resistance training (2x/week) or a usual care control group. As secondary endpoint, muscle strength of the upper and lower extremities was assessed before and after the intervention period. Routine CT scans were assessed on lumbar L3/4 level for quantification of total-fat-area, visceral-fat-area, subcutaneous-fat-area, intramuscular-fat-area, visceral-to-subcutaneous fat ratio (VFR), muscle-area (MA), muscle-density and skeletal-muscle-index (SMI). OS data were retrieved.
RESULTS: Of 65 patients, 53 had suitable CT scans at baseline and 28 completed the intervention period with suitable CT scans. There were no significant effects observed of resistance training on body composition (p>0.05; effect sizes ω2p <0.02). Significant moderate to high correlations were found between MA and muscle strength parameters (r = 0.57-0.85; p<0.001). High VFR at baseline was a predictor of poor OS (VFR≥1.3 vs. <1.3; median OS 14.6 vs. 45.3 months; p = 0.012). Loss of muscle mass was also a predictor of poor OS (loss vs. gain of SMI; median OS 24.6 vs. 50.8 months; p = 0.049).
CONCLUSION: There is anabolic potential in patients with resectable pancreatic cancer. A progressive resistance training may help patients to maintain their muscle mass and avoid muscle depletion. CT-quantified muscle mass at the level of L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. A high VFR at baseline and a high loss of muscle mass are predictors of poor OS. Registered on ClinicalTrials.gov (NCT01977066).

RCT Entities:   Population Interventions Outcomes

Introduction

In many cancer patients, weight loss is frequently already present at the time of diagnosis [1]. Patients with pancreatic cancer in particular often suffer from severe weight loss and loss of muscle mass [2].

Pancreatic cancer is a frequent highly malignant disease with a very poor prognosis and consecutive high mortality with a 5-year survival rate across all stages of 6% [3]. Most pancreatic cancers are diagnosed at a late stage due to very late and unspecific symptoms [4]. In up to 74% of pancreatic cancer patients, cachexia, a multifactorial wasting syndrome characterized by an ongoing loss of muscle mass with or without the loss of fat mass, systemic inflammation and usually weight loss [5] is present [6]. Further, the loss of muscle mass and weight loss leads to reduced muscle strength which additionally worsens functional capacity. Besides functional impairments, patients with cachexia tend to have more fatigue and a poor prognosis [5, 7, 8]. The loss of muscle mass (MA) and body composition with a high ratio of visceral fat tissue to subcutaneous fat tissue (VFR) were reported as predictors of poor prognosis in patients with lung cancer [9]. Therefore, maintaining MA, physical functioning and quality of life are among the main treatment goals in pancreatic cancer patients.

Exercise is known to have positive effects on disease- and treatment-related side effects in cancer patients during and after cancer treatment such as improvements in physical fitness [10], quality of life [11] and fatigue [12]. Resistance training in particular is reported to have a positive effect on improving MA due to increased muscle protein synthesis and improving muscle metabolism [13]. Recently, our group showed that pancreatic cancer patients can benefit from progressive resistance training with regard to muscle strength and quality of life as part of the SUPPORT-study [14, 15]. First evidence also suggests that exercise plays an important role in the recurrence and survival of cancer [16].

Here we present an explorative analysis of muscle and adipose tissue compartments using CT scans to investigate the effects of resistance training on muscle and adipose tissue compartments in the above mentioned randomized controlled SUPPORT-study.

Primary aim was to investigate whether the intervention group showed a better course of body composition with increased muscle tissue compartments than the control group. Secondary aim was to identify predictive factors in body composition that influence the survival of patients with pancreatic cancer.

Materials & methods

Study population

Data from the SUPPORT-study (Supervised Progressive Resistance Training for Pancreatic Cancer Patients), a randomized controlled intervention trial investigating the effects of a 6-month lasting progressive resistance training on patients with pancreatic cancer, were used in a post-hoc manner for the present analysis to investigate the effects of the training intervention on muscle and adipose tissue compartments. The study was approved by the Ethics Committee of the Medical Faculty of the University of Heidelberg (S-409/2013) and has been registered on ClinicalTrials.gov (NCT01977066). The methods, the study design and the main results of the SUPPORT-study with regards to the pre-specified primary and secondary outcomes have been published in detail recently [14, 15, 17].

In brief, from 12/2013 until 12/2015 65 out of 304 eligible patients were recruited with following inclusion criteria: age ≥18 years, resectable or non-resectable cancer (stage I-IV), treatment at Heidelberg University Hospital in Germany, sufficient German language skills and informed consent. Patients with adenocarcinoma of the distal bile duct and with ampullary ductal adenocarcinoma were also eligible because of the same medical treatment regime. Following eligibility criteria were changed very early of recruitment to improve the low recruitment rate: patients who performed sports more than 150 minutes per week, stage III and IV and patients who had their surgical resection within the last 12 months were also included. Exclusion criteria were: heart insufficiency more than grade III of the New York Heart Association (NYHA) or uncertain arrhythmia, uncontrolled hypertension, severe renal dysfunction (GFR <30%, creatinine >3 mg/dl), uncompleted wound healing, insufficient hematological capacity (either hemoglobin value <8 g/dl or thrombocytes <50,000), reduced standing or walking ability, or any other comorbidities that precluded their participation.

Patients living close to the study center (<20km) were randomized to a supervised progressive resistance training group (RT1) or to the control group (CON). Patients living further away were randomized to a home-based progressive resistance training group (RT2) or to 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. Assessment for outcome parameters took place prior to the intervention start (T0, baseline) and post-intervention after 6 months (T2). 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.

Intervention

RT1 and RT2 performed a resistance training program over a 6-month period with training sessions of approximately 60 minutes twice a week. The sessions included resistance exercises for the major muscle groups of the upper and lower extremities with performance adapted increasing weights. After a four-week adaptation phase, patients performed 8 exercises/session with 2–3 sets with 8–12 repetitions. The training of patients in RT1 took place at an exercise facility at the Heidelberg University’s campus on weight machines under supervision of a specialized exercise therapist with exercise intensities of 60–80% One-Repetition Maximum. Patients in RT2 exercised with a training manual on their own at home with exercise intensities of 14–16 on the Borg Scale of Perceived Exertion [18] supported through the exercise therapist by weekly phone calls. Each training session carried out was documented on a training sheet.

CON received usual care in line with their cancer treatment. Patients were called once a month and asked about possible treatment-related side effects and were advised not to change exercise behaviour.

Outcome assessment

For this analysis CT scans at T0 and T2 were analysed. All of the CT scans were performed in the clinical routine with clinical indication without additional CT scans being performed in the context of the SUPPORT-study. Inclusion criteria for patients of the SUPPORT-study into this post-hoc analysis were: CT scans suitable in quality and time for T0 and T2 (date of the baseline CT scan -120 days before and +35 days after T0; date for the follow-up CT at T2–35 days before and +35 days after T2), technically evaluable CT scans, level between lumbar vertebral body 3 and 4 (L3/4) included in scans, patient in field of view.

Quantification of body compartments via CT scans

Contrast-enhanced CT scans were retrieved from the institutional PACS (GE Medical Systems, Buckinghamshire, UK) and area-based quantification was performed with a semiautomatic volume tool (Syngo Volume Tool, Siemens Healthineers, Munich, Berlin, Germany). Quantification of body compartments was performed on a single slice between lumbar vertebral body 3 and 4 (L3/4) at the lower endplate of L3 by manually defining specific regions of interest (ROI) [9, 19, 20]. These ROIs were measured using threshold values (in Hounsfield-Units; HU) and the obtained volumes (cm3) were divided by slice-thickness (cm) to get area values (cm2). Of totally 81 CT scans, 90% (n = 73) had a slice-thickness of 0.3cm (5 with 0.5cm; 2 with 0.2cm and 1 with 0.4cm).

The adipose tissue was divided into Total-Fat-Area (TFA), Visceral-Fat-Area (VFA) and Subcutaneous-Fat-Area (SFA). TFA was measured by drawing the ROI around the whole body circumference. VFA was measured by drawing the ROI along the inside of the abdominal wall. The measurement for adipose tissue was restricted to an upper threshold of -30HU and a lower threshold of -190HU [9, 20].

The muscle tissue was quantified on the same slice by drawing a ROI including all muscles on that level (M. erector spinae, M. psoas major, M. rectus abdominis, M. obliquus internus abdominis, M. obliquus externus abdominis, M. transversus abdominis, M. quadratus lumborum, M. latissimus dorsi). The first measurement of Muscle-Area (MA150) was performed with a wide range of an upper threshold of +150HU and a lower threshold of -29HU [21, 22], containing the fatty infiltration of muscle tissue as well. The second measurement of Muscle-Area (MA100) in the same ROI was with a smaller range of an upper threshold of +100HU and a lower threshold of +40HU, hereby excluding the fatty infiltrated muscle fraction. Mean muscle density of the muscle quantifications in HU was obtained (MD150 and MD100). Thirdly, the adipose tissue within the muscle-ROI (IMFA, intramuscular-fat-area) was quantified with an upper threshold of -30HU and a lower threshold of -190HU.

SFA was calculated by subtracting VFA and IMFA from the TFA. Visceral-to-subcutaneous-Fat-Ratio (VFR) was calculated by dividing VFA/SFA [9]. Skeletal-Muscle-Index (SMI) was calculated by adjusting MA150 with body height (MA150/body-height2; Unit cm2/m2) [21]. Differences of parameters were calculated by: parameterdiff = parameterT2 –parameterT0.

Strength parameters

Muscle strength was assessed bilaterally for extensors and flexors of the elbow, knee and hip with an isokinetic dynamometer (IsoMed2000; D&R Ferstl GmbH, Hemau, Germany). Maximal isokinetic peak torque (MIPT) was assessed with angular velocity of 60°/s. Patients were instructed to move the machine arm as strong and as fast as they can for 10 repetitions. Maximal voluntary isometric contraction (MVIC) was measured at the strongest angle position each (elbow flexor 80°, knee extensor 36°, hip flexor 33°). Patients were instructed to exert maximum force and to keep it for 6 seconds. Only values of the dominant side were included in the analysis.

Clinical data and patient characteristics were extracted from the medical records or by self-report of the patients. Weight and height were measured during the assessments. Smoking habits and exercise behaviour in the year before the pancreatic cancer diagnosis were assessed by self-report. Patient exercise behaviour was converted into MET/hours per week (metabolic equivalent) according to the Ainsworth compendium of physical activities [23].

Survival data

For survival analysis, data was taken from the hospitals information system I.S-H. med. (SAP, Walldorf, Germany). If available, date of death was retrieved. If date of death was not available, date of last contact with the hospital was retrieved. Time between date of first diagnosis and death or last contact with the hospital was calculated.

Statistical analysis

Data was collected using Microsoft Office ACCESS and Excel 2010 (Microsoft Corporation, Redmond, WA, USA). Statistical analyses were performed using SPSS Statistics 21 (IBM, Armonk, NY, USA) and SAS Enterprise Guide (version 6.1, SAS statistics, Cary, North Carolina, USA).

For the explorative analysis, RT1 and RT2 were combined to a pooled resistance training group (RT) due to small sample sizes. The dataset included all patients for which evaluable data were available after 6 months (complete-case analysis). Analyses of covariance (ANCOVA) were used to analyse the differences in body composition between groups from pre- to post-intervention. The group assignment (according to intention-to-treat analysis) was used as independent variable, the change since baseline as dependent variable and the baseline measure as covariate. Effect sizes were analysed by computing the partial omega-squared (ω2p) coefficient using analyses of covariance. To compare parameters from T0 and T2 paired t-test were used.

For the correlation of CT acquired muscle parameters with muscle strength parameters Spearman correlation coefficients were used. For survival analysis at baseline univariate cox regressions were used. Bivariable Cox regression models were used to assess the risk factor for death using values that have changed over time as time-dependent covariates and intervention group as fixed factor. Kaplan-Meier-curves with log-rank-test were used to compare overall survival of patients with high vs. low VFR and patients with muscle loss vs. muscle gain.

For the presented explorative analysis on routine CT scans no further power calculation was performed.

Results were considered statistically significant at p<0.05.

Results

Patient characteristics

In total, 53 of 65 randomized pancreatic cancer patients had eligible CT scans at baseline. Out of these, 28 patients completed the 6-month intervention period and showed eligible CT scans at T2, 19 patients in RT and 9 patients in CON (Fig 1). Patient characteristics for all patients (n = 53) as well as for the patients with eligible CT scans before and after the intervention (n = 28) are described in Table 1. Mean age was 62.1 years (SD = 9.0 years) and mean body mass index (BMI) was 23.9 kg/m2 (SD = 4.1 kg/m2). Overall the most common cancer type was pancreatic ductal adenocarcinoma (88.7%) and most patients were diagnosed with stage II (77.4%). The most common treatment regime was surgery combined with adjuvant chemotherapy (83.0%). Most patients were non-smoker (83.0%). The training adherence rate dropped steadily over the 6 months from initially 81.7% to 62.9%. On average, patients performed 1.4 weekly training sessions out of 2. One adverse event occurred, incisional hernia temporally after baseline assessment (CON), no adverse events occurred during exercise sessions.

Fig 1

Patient flow chart.

T0 = baseline; T2 = after 6-month resistance training; * Combining RT1 and RT2.

Table 1

Patient characteristics of all patients and divided by group.

	All patients		RT		CON
	(n = 53)		(n = 28)
TOTAL, n (%)	53	(100)	19	(100)	9	(100)
Age, years, mean (SD)	62.1	(9.0)	61.0	(9.2)	60.6	(7.9)
Gender, n (%)
Male	33	(62.3)	13	(68.4)	6	(66,7)
Female	20	(37.7)	6	(31.6)	3	(33.3)
BMI, mean (SD)	23.9	(4.1)	23.3	(3.3)	25.7	(2.9)
Cancer Type, n (%)
Pancreatic ductal adenocarcinoma	47	(88.7)	17	(89.5)	7	(77.8)
Distal bile duct adenocarcinoma	4	(7.5)	2	(10.5)	1	(11.1)
Papillary ductal adenocarcinoma	2	(3.8)			1	(11.1)
Tumor stage, n (%)
Not available	3	(5.7)	1	(5.3)
IA	1	(1.9)
IB	6	(11.3)	2	(10.5)	2	(22.2)
IIA	7	(13.2)	4	(21.1)	2	(22.2)
IIB	34	(64.2)	11	(57.9)	5	(55.6)
IV	2	(3.8)	1	(5.3)
Operative procedures, n (%)
Total pancreatectomy	6	(11.3)	3	(15.8)
Distal pancreatectomy	8	(15.1)	2	(10.5)	1	(11.1)
Whipple	16	(30.2)	5	(26.3)	3	(33.3)
Pylorus-preserving Whipple	20	(37.7)	8	(42.1)	5	(55.6)
No operation	3	(5.7)	1	(5.3)
Treatment, n (%)
Surgery, adj. CHT	44	(83.0)	15	(78.9)	9	(100)
Neoadj. CHT, Surgery	2	(3.8)	2	(10.5)
Neoadj. CHT, Surgery, adj. CHT	3	(5.7)	1	(5.3)
CHT	3	(5.7)	1	(5.3)
Surgery	1	(1.9)
Smoking, n (%)
Non-smoker	40	(75.5)	14	(73.7)	9	(100)
Recent smoker	10	(18.9)	3	(15.8)
Still smoker	3	(5.7)	2	(10.5)
Exercise in the year before diagnosis, n (%)
None	24	(45.3)	9	(47.4)	6	(66.7)
0 - <9 MET*h/week	10	(18.9)	3	(15.8)	1	(11.1)
9 - <18 MET*h/week	10	(18.9)	5	(26.3)	2	(22.2)
≥ 18 MET*h/week	7	(13.2)	2	(10.5)
Missing	2	(3.8)
Time between CT scans, months, mean (SD)	-	-	7.2	(1.7)	7.4	(1.8)
Surgery between CT scans, n (%)	-	-
In between			3	(15.8)	3	(33.3)
Before			16	(84.2)	6	(66.6)

Baseline patient characteristics of patients with CT at T0 (n = 53) and patients with CT at T0 and T2 (n = 28) classified by progressive resistance training group (RT) and control group (CON). MET = metabolic equivalent; CHT = chemotherapy; SD = standard deviation; CT = computed tomography.

Change in body composition

Adipose tissue compartments

Table 2 presents the distribution and change in body composition of adipose tissue compartments of RT and CON from T0 to T2.

Table 2

Distribution of adipose tissue across compartments before (T0) and after 6-month resistance training (T2).

Outcome	Group	N	T0	T2	Adjusted mean change* (95% CI) from T0 to T2	Adjusted difference between groups, mean (95% CI)		p‡	ω2p ‡‡
			Mean (SD)	Mean (SD)
TFA (cm2)	RT	19	299.0 (136.1)	242.6 (120.6)	-75.8 (-127, -24.5)	RT-CON	-47.3 (-143, 48.0)	0.317	0.002
	CON	9	411.0 (123.9)	341.4 (120.0)	-28.5 (-105, 48.2)
VFA (cm2)	RT °	19	134.8 (82.6)	96.9 (50.8)	-45.4 (-68.4, -22.4)	RT-CON	-22.3 (-63.6, 19.0)	0.276	0.009
	CON °	9	174.0 (74.1)	135.2 (70.2)	-23.1 (-56.8, 10.6)
SFA (cm2)	RT	19	153.4 (65.0)	137.1 (74.1)	-24.3 (-52.9, 4.3)	RT-CON	-12.6 (-67.1, 41.8)	0.636	-0.028
	CON	9	220.6 (61.0)	192.0 (59.1)	-11.7 (-55.0, 31.7)
VFR	RT	19	0.9 (0.4)	0.9 (0.5)	-0.0 (-0.2, 0.2)	RT-CON	0.1 (-0.2, 0.5)	0.441	-0.014
	CON °	9	0.8 (0.2)	0.7 (0.3)	-0.1 (-0.4, 0.1)
BMI (kg/m2)	RT	17	23.5 (3.2)	23.8 (3.6)	0.3 (-0.5, 1.1)	RT-CON	0.6 (-0.8, 2.0)	0.361	-0.005
	CON	8	25.5 (3.0)	25.2 (3.5)	-0.3 (-1.5, 0.8)
Body weight (kg)	RT	17	72.8 (9.2)	73.7 (11.0)	1.1 (-1.1, 3.3)	RT-CON	1.9 (-2.0, 5.8)	0.330	-0.000
	CON	8	78.3 (13.9)	77.9 (15.9)	-0.8 (-4.0, 2.4)

ANCOVA; n = 28; compartments quantified at level L3/4. TFA = total fat area, VFA = visceral fat area, SFA = subcutaneous fat area, VFR = visceral fat ratio, BMI = body mass index, RT = resistance training group, CON = usual care control group

* Adjusted for baseline value

‡ diff

‡‡ effect size partial omega squared

° Significant differences T0 vs. T2 (paired t-test; p<0.05).

There were no between-group differences for the assessed adipose tissue parameters at 6 months (p>0.05; (ω2p<0.02). Descriptively, CON showed higher values for CT quantified parameters TFA, VFA and SFA as well as for body weight and BMI at baseline. VFR was slightly higher in RT. During the intervention, RT and CON showed a similar decrease in TFA, VFA and SFA. For VFR, no change was observed in RT, while a slight decrease was observed in CON (-0.1; Table 2). RT showed a slight increase of BMI and body weight while CON showed a slight decrease of BMI and body weight.

Muscle tissue compartments

Table 3 presents the distribution and change in body composition of muscle tissue compartments of RT and CON from T0 to T2.

Table 3

Distribution of muscle tissue compartments and mean attenuation before (T0) and after 6-month resistance training (T2).

Outcome	Group	N	T0	T2	Adjusted mean change* (95% CI) from T0 to T2	Adjusted difference between groups, mean (95% CI)		p ‡	ω2p ‡‡
			Mean (SD)	Mean (SD)
MA150 (cm2)	RT	19	143.5 (26.1)	143.7 (28.8)	0.3 (-5.7, 6.2)	RT-CON	-5.4 (-16.0, 5.1)	0.298	0.005
	CON	9	146.2 (32.3)	151.8 (33.3)	5.7 (-3.0, 14.4)
MA100 (cm2)	RT	19	97.5 (21.0)	106.4 (30.0)	9.4 (-0.8, 19.6)	RT-CON	-1.7 (-20.3, 16.9)	0.851	-0.036
	CON	9	82.9 (21.8)	95.1 (22.9)	11.1 (-3.9, 26.2)
IMFA (cm2)	RT °	19	10.7 (5.0)	8.6 (4.4)	-3.1 (-4.9, -1.3)	RT-CON	-2.9 (-6.4, 0.6)	0.097	0.066
	CON	9	16.4 (5.5)	14.2 (4.1)	-0.2 (-2.9, 2.6)
SMI150 (cm2/m2)	RT	19	46.3 (7.3)	46.4 (8.5)	0.1 (-1.8, 2.0)	RT-CON	-1.8 (-5.2, 1.6)	0.288	0.006
	CON	9	47.5 (8.3)	49.4 (8.5)	1.9 (-0.9, 4.7)
SMI100 (cm2/m2)	RT	19	31.4 (6.0)	34.3 (8.9)	3.1 (-0.1, 6.4)	RT-CON	-0.3 (-6.3, 5.7)	0.909	-0.037
	CON	9	27.0 (6.0)	31.0 (6.5)	3.5 (-1.4, 8.3)
MD150 (HU)	RT	19	46.4 (7.1)	48.9 (6.5)	3.7 (1.1, 6.4)	RT-CON	3.0 (-2.1, 8.1)	0.233	0.017
	CON	9	39.6 (3.2)	42.9 (4.3)	0.7 (-3.3, 4.7)
MD100 (HU)	RT	19	58.7 (3.5)	59.5 (2.8)	1.4 (0.3, 2.6)	RT-CON	1.0 (-1.1, 3.2)	0.341	-0.002
	CON	9	56.2 (1.6)	57.8 (1.8)	0.4 (-1.3, 2.1)

ANCOVA; n = 28; compartments quantified at level L3/4. MA = muscle area, IMFA = inter-muscular-fat area, SMI = skeletal muscle index, MD = muscle density (in HU), RT = resistance training group, CON = usual care control group

* Adjusted for baseline value

‡ diff

‡‡ effect size partial omega squared; ° Significant differences T0 vs. T2 (paired t-test; p<0.05).

All assessed muscle tissue parameters showed no between-group differences at 6 months (p>0.05; (ω2p<0.02). Descriptively, CON showed higher values for all muscle parameters but MA100 and SMI100 compared to RT at baseline. From baseline to the end of the 6-month intervention period RT and CON showed a noticeable increase of MA100 and SMI100, while there was just a small increase of muscle density (MD150, MD100) in both groups. For MA150 and SMI150 CON showed a higher increase than RT. IMFA decreased in both groups equally.

Surgery between CT scans

22 out of 28 patients (78.6%) had surgery before the baseline CT and showed a significant increase in muscle parameters between T0 and T2 (see S1 Table; difference in SMI = 1.4; p = 0.03). No significant change in fat parameters was observed. 6 patients (21.4%) had surgery after the baseline CT (see S2 Table) and therefore between the CT scans. Those patients showed a significant decrease in fat parameters (difference of TFA = -219.8; p = 0.013). No significant difference in muscle parameters was found.

Muscle mass and muscle strength

Table 4 presents the correlations of the measured muscle strength parameters and the CT acquired muscle parameters using Spearman correlation coefficients. The calculation was performed with baseline values at T0, n = 53.

Table 4

Correlations of muscle strength parameters with CT acquired muscle parameters.

	Knee extensors	Knee extensors	Elbow flexors	Elbow flexors	Hip flexors	Hip flexors
	MIPT	MVIC	MIPT	MVIC	MIPT	MVIC
MA150 (cm2)	0.71	0.73	0.82	0.85	0.62	0.57
p-value	< .001*	< .001*	< .001*	< .001*	< .001*	< .001*
n	53	53	53	53	51	51
SMI150 (cm2/m2)	0.50	0.54	0.66	0.69	0.45	0.40
p-value	0.001*	< .001*	< .001*	< .001*	<0.001**	0.004*
n	53	53	53	53	51	51
MD150 (HU)	0.23	0.15	0.17	0.18	0.20	0.21
p-value	0.099	0.292	0.211	0.191	0.158	0.136
n	53	53	53	53	51	51
MA100 (cm2)	0.65	0.63	0.70	0.73	0.57	0.52
p-value	< .001*	< .001*	< .001*	< .001*	< .001*	<0.001*
n	53	53	53	53	51	51
SMI100 (cm2/m2)	0.52	0.48	0.55	0.56	0.47	0.42
p-value	< .001*	<0.001*	< .001*	< .001*	<0.001*	0.002*
n	53	53	53	53	51	51
MD100 (HU)	-0.01	-0.12	-0.12	-0.10	-0.06	-0.03
p-value	0.964	0.411	0.405	0.458	0.671	0.855
n	53	53	53	53	51	51
IMFA (cm2)	0.04	0.05	0.01	0.02	-0.13	-0.21
p-value	0.770	0.716	0.967	0.886	0.365	0.145
n	53	53	53	53	51	51

All patients at baseline (T0), n = 53. Calculation of Spearman correlation coefficients. MIPT: maximal isokinetic peak torque (in Newton Meter); MVIC: maximal voluntary isometric contraction (in Newton); MA = muscle area, SMI = skeletal muscle index, MD = muscle density (in HU), IMFA = inter-muscular-fat area

* = significant

° = strength-measurement of hip flexors could not be performed in n = 2 patients, thus correlation of hip flexion was calculated with n = 51 patient.

There were moderate to high positive correlations between MA150 and the muscle strength parameters (r = 0.57–0.85; p<0.001). Between SMI150 and muscle strength parameters significant low to moderate positive correlations (r = 0.39–0.68, p<0.01) were observed.

MA100 and SMI100 showed a moderate to high positive correlation with the muscle strength parameters (MA100 r = 0.51–0.72; p<0.001; SMI100 r = 0.41–0.55; p<0.01).

For muscle density (MD150 and MD100) and intramuscular fat (IMFA), no correlation was observed with the muscle strength parameters (r = -0.2–0.23; p>0.05).

Survival analysis

The survival analysis for the baseline values was performed with all n = 53 patients included. Table 5 presents the univariate cox regressions with the parameters at T0.

Table 5

Univariate survival analysis with baseline parameters.

Parameter T0	HR	95% CI lower	upper	p-value
BMI	0.958	0.857	1.071	0.451
TFA	0.999	0.996	1.002	0.572
VFA	1.000	0.995	1.005	0.933
SFA	0.997	0.992	1.002	0.288
IMFA	0.978	0.907	1.055	0.563
VFR	2.084	1.163	3.732	0.014*
MA150	0.992	0.978	1.006	0.273
MD150	1.019	0.962	1.078	0.528
SMI150	0.982	0.933	1.034	0.492
MA100	0.996	0.980	1.013	0.662
MD100	1.095	0.964	1.244	0.162
SMI100	0.996	0.942	1.052	0.883

Cox regressions and calculations hazard-ratios (HR), n = 53. CI: confidence interval; * = significant.

At baseline, VFR showed a significant influence on the overall survival (HR = 2.084; p = 0.014). Hereby a high VFR indicated a higher risk of death. The other adipose and muscle tissue parameters showed no significant influence on overall survival. Fig 2 shows the Kaplan-Meier-curve comparing patients with high VFR (≥1.3; n = 8) showing a lower median overall survival of 14.6 months with patients with lower VFR (<1.3; n = 45) having a higher median overall survival of 45.3 months (p = 0.012).

Fig 2

Kaplan-Meier-curve for VFR at T0.

Log-rank-test, n = 53. Patients with high VFR (≥1.3; n = 8; continuous line) show a lower median overall survival of 14.6 months than patients with low VFR (<1.3; n = 45; dotted line) with a median overall survival of 45.3 months (p = 0.012).

The survival analysis for the change of parameters between T0 and T2 was performed with n = 28 patients. Table 6 presents the time-dependent Cox regressions with the differences of parameters between T0 and T2. There was no significant influence of the changes of the adipose and muscle tissue parameters on overall survival. For the change of BMI from T0 to T2 a significant influence on the overall survival was observed. Fig 3 shows the Kaplan-Meier-curve comparing patients with loss of muscle mass (SMI150-difference < 0cm2/m2) with patients that gained muscle mass (SMI150-difference ≥ 0 cm2/m2). Patients with muscle loss showed a lower overall survival than patients with muscle gain (24.6 months vs. 50.8 months, p = 0.049).

Table 6

Bivariate survival analysis with difference of parameters from T0 to T2.

Parameter T2-T0	HR	95% CI lower	upper	p-value
BMI (n = 24)	0.815	0.671	0.990	0.040 *
TFA	0.998	0.994	1.003	0.432
VFA	0.998	0.988	1.007	0.624
SFA	0.996	0.989	1.004	0.328
IMFA	1.035	0.905	1.182	0.618
VFR	1.041	0.324	3.340	0.947
MA150	0.986	0.967	1.006	0.174
MD150	0.959	0.875	1.051	0.371
SMI150	0.940	0.878	1.018	0.143
MA100	0.983	0.962	1.005	0.137
MD100	1.000	0.821	1.219	0.997
SMI100	0.943	0.876	1.014	0.113

Cox regressions (adjusted for time as dependent variable and intervention group as fixed factor) and calculation of hazard-ratios (HR), n = 28. CI: confidence interval

* = significant.

Fig 3

Kaplan-Meier-curve for difference in SMI150 from T0 to T2.

Log-rank-test, n = 28. Patients with loss of muscle mass (SMI150-difference < 0 cm/m; n = 12, continuous line) show a median overall survival of 24.6 months vs. patients with gain of muscle mass (SMI150-difference ≥ 0 cm/m, n = 16; dotted line) and a median survival of 50.8 months (p = 0.049).

Discussion

The explorative analysis presented here investigated the effects of progressive resistance training on muscle and adipose tissue compartments in pancreatic cancer patients. Our primary aim was to investigate, if RT shows a better course of body composition with a higher increase in muscle mass. After the 6-month intervention period, there were no significant differences of resistance training on muscle and adipose tissue parameters between RT and CON. At the same time, the data show no depletion of muscle mass in all patients. On the contrary, there was a very slight increase in muscle mass, although it was greater in CON than in RT. Therefore, we couldn’t confirm our primary hypothesis in this study. In addition, we observed a good correlation between muscle strength and muscle mass. Our secondary aim was to identify prognostic parameters for overall survival. Both a high visceral to subcutaneous fat ratio and loss of muscle mass turned out to be predictors of poor overall survival.

It is frequently reported that patients with pancreatic cancer show sarcopenia and a decrease of muscle mass, which has been associated with negative effects and a poor prognosis [24-26]. The question emerged if it is possible to counter these catabolic effects with an exercise training program. In our study population we could show, that there is an anabolic potential in patients with pancreatic cancer. Patients in RT maintained their muscle mass with a very slight increase during the intervention period (MA150 +0.3cm; SMI150 +0.1 cm2/m2; see Table 3). Therefore, resistance training might have a positive impact on maintaining muscle mass in pancreatic cancer patients. However, patients in CON on average even gained fair amounts of muscle mass (MA150 +5.7 cm; SMI150 +1.9 cm2/m2; see Table 3) although they were not part of a training program. We cannot really explain the fact that CON showed a higher increase in muscle mass than RT and our explanations for this topic are speculative. One possible explanation could be that hormones, that play a role in anabolism and catabolism, such as insulin produced in the pancreas, are disrupted through surgery and training effects and thus have an altered effect on the overall metabolism. The patients with pancreatic cancer underwent pancreatic surgery in varying extent with changes and disruption of production of insulin in the pancreas. Patients adapt differently and individually to these changes. Insulin is an anabolic hormone and plays a big role in protein synthesis and muscle metabolism [27]. Therefore the changes in insulin production may be an influencing factor on the change in muscle mass. Another possible, albeit very speculative explanation could be a contamination of the control group, e.g. the adoption of the intervention by themselves [28, 29]. It can be assumed that most patients taking part in an exercise intervention study are highly motivated to participate in the intervention and have generally a positive attitude towards exercise. Patients of CON could catch up information of the exercise program through other patients, medical staff or literature/media. Consequently, they could become motivated to do some exercises themselves. However, CON would have had to do the same training load as the RT or even more in order to achieve a significant effect compared to the RT, which seems unlikely.

There was a decrease of adipose tissue across all quantified compartments in control and resistance training group during the intervention period. One reason for this loss of adipose tissue could be cachexia with catabolic processes due to the malignant disease. Further, treatment of the patients with chemotherapy and surgery might have negative effects on body composition, which might be another probable explanation for the loss of adipose tissue. In addition, both groups showed no significant change in BMI over this time. This indicates that some changes in body composition are not detected by the anthropometric measurements like weight or BMI alone. Those changes may occur before they are detected by those measurement tools and thus this possible sign of cachexia might be registered earlier by imaging [30].

To our knowledge, there is currently no directly comparable exercise intervention study available with patients with pancreatic cancer and CT quantified body compartments. Dieli-Conwright et al. analysed the effect of a 16-week combined aerobic and resistance exercise program on breast cancer survivors [31]. They found a decrease in body weight and an increase in lean body mass and appendicular skeletal muscle index [31]. Another study investigated the effects of a 12-week resistance training on body composition in prostate cancer patients [32]. They also found increases in lean body mass and reduced sarcopenia [32]. In both studies muscle mass was quantified by dual-energy X-ray absorptiometry (DXA). Despite the different method and different cancer types this agrees with our finding, that there is anabolic potential in cancer patients and that an exercise intervention program may increase muscle mass. These findings may be less distinctive in patients with pancreatic cancer, because of the higher malignant potential of pancreatic cancer and a larger surgical procedure.

Our results showed a strong correlation between muscle strength and muscle mass (Table 4). Patients with more muscle mass tended to show a higher strength. Especially the MA150 including also the fatty infiltrated muscle parts revealed a strong correlation with the elbow flexors (r = 0.85; Table 4) and the knee extensors (r = 0.73). MA100 also showed a good but lower correlation with the muscle strength parameters than MA150. MA100 was quantified with tighter threshold values (in HU), which excluded the fatty infiltrated muscle parts, which had a lower HU attenuation because of the partial volume effect. Therefore, the fatty infiltrated muscle parts seem to contribute to the muscle strength which could explain the higher correlation coefficients. Also for the skeletal muscle index (SMI150, SMI100) and muscle strength a good positive correlation was observed. The muscle density parameters (MD150 and MD100) and the IMFA showed no significant correlation with muscle strength. This indicates that muscle density as well as fat tissue between the various muscle parts (IMFA) are not the primary factors for muscle strength. Our results are partially consistent with a study by MacDonald et al. [33], which measured the correlation between CT quantified L3 SMI and lower limb muscle strength and measures of complex function. Although they did not see a correlation between lower limb muscle strength and L3 SMI but only between complex functions and SMI, they also found a correlation between muscle mass and lower limb muscle strength (MRI quantified mass of M. quadriceps femoris). Although these findings don’t match completely with our results, they point in a similar direction. SMI150 at lumbar L3/4 level therefore may represent a surrogate for general muscle strength and function.

At baseline, patients with a high VFR tended to have a poorer survival than patients with a lower VFR (median survival 14.6 vs. 45.3 months; p = 0.012; Fig 2). A high VFR represents a high amount of intraabdominal fat tissue (VFA) in relation to the subcutaneous fat tissue (SFA). This finding of a prognostic impact of high VFR aligns with other studies conducted with pancreatic cancer patients [34, 35] or lung cancer patients [9], where a high VFR turned out to be a predictor of poor prognosis. This prognostic impact seems to be consistent across several cancer entities. Visceral fat tissue seems to have a different risk profile than subcutaneous fat tissue [36]. Additionally, it was previously reported that patients with a high amount of visceral fat tissue also have a higher cardiovascular mortality [36].

Muscle mass (MA150) at baseline didn’t show a statistically significant impact on overall survival in our study population. Low muscle mass has previously been reported to be predictive of poor overall survival in resectable and advanced pancreatic cancer [24–26, 37, 38]. Several other studies couldn’t show a predictive impact of muscle mass at a single time point with pancreatic cancer and lung cancer [9, 39]. Nevertheless, a high absolute amount of muscle mass still seems advantageous. Muscle density (MD150) at baseline also didn’t turn out to be a predictor of overall survival in our study population. Lower mean muscle density (in HU-values) of muscle tissue is presumably caused by fatty infiltration of muscle tissue and may be a sign of muscle wasting. Some studies showed an impact of muscle density on overall survival [21, 40], while others showed no impact [9]. It may be due to small sample size in our study population that there was no statistically significant effect on prognosis. Patients with a loss of muscle mass over time (mean 7.3 months) showed a poorer overall survival than patients without muscle loss (median survival 24.6 vs. 50.8 months; p = 0.049; see Fig 3). Loss of muscle mass is a central element of the cachectic syndrome [5] and was previously reported to predict poorer survival in patients with pancreatic cancer [24, 41] as well as with lung cancer [9].

This was a explorative sub-analysis of CT quantified muscle and adipose tissue compartments within the randomized controlled SUPPORT-study. Patients performed progressive resistance training, muscle strength parameters as well as muscle and adipose tissue compartments were assessed using criterion-standard assessments and intention-to-treat analysis was performed. However, our study had also some limitations. First, the small sample size of 53 patients with eligible CT scans in total, respectively, 28 patients with eligible CT scans who completed the 6-month intervention period, resulting in a reduced generalizability. The SUPPORT-study was stopped due to recruitment difficulties, thus, before the planned sample size of 150 evaluable patients had been reached. The drop-out rate was as expected and similar in the 3 groups. Further, the unbalanced group size of RT and CON could be an influencing factor. Due to the allocation of patients to either of the two resistance training groups, supervised or home-based, or to CON according to the living distance of the patients and the fact that more distant living patients were included, unbalanced group sizes occurred. In addition, for the presented analyses both resistance training groups were combined to one resistance training group due to the small number of patients, so the results should be interpreted carefully. Another limitation was that muscle strength was measured by muscle groups of the upper and lower extremities and muscle tissue parameters at the lumbar level L3/4 of the body trunk. Thus, the respective muscle parameters recorded did not match. In addition, a small number of patients (21.4%) had surgery performed in between CT scans as a possible influencing factor on muscle and adipose tissue compartments (see S1 and S2 Tables).

In conclusion, we couldn’t confirm our primary hypothesis in this study that RT shows a greater increase in muscle mass than CON, due to an increase in muscle mass in CON. But the results of our study support the assumption that there is an anabolic potential in patients with pancreatic cancer. RT sustained muscle mass and CON gained a small amount of muscle mass. Progressive resistance training may be a promising modality to support pancreatic cancer patients to maintain their muscle mass and avoid muscle depletion. The parameters used in this study could also help identify patients, who may profit from progressive resistance training, and monitor the progress during the training period. Furthermore, muscle mass quantified at L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. For our secondary aim, to identify prognostic parameters, we found that a high loss of muscle mass and a high visceral to subcutaneous fat ratio at baseline turned out to be predictors of poor overall survival. Therefore, the CT-quantified parameters could help with risk stratification of patients. Corresponding training programs could help to avoid or weaken these signs of cachexia in pancreatic cancer patients. Further randomized controlled exercise intervention studies with higher numbers of patients and bigger control groups should be conducted to verify possible benefits of maintaining muscle mass. Additional randomized and controlled studies are also needed to determine the optimal intensity and quantity of training programs to achieve possible positive effects for patients with pancreatic cancer.

(DOC)

Click here for additional data file.

CT quantified body compartments with a baseline CT after surgery.

n = 22. TFA = total fat area, VFA = visceral fat area, SFA = subcutaneous fat area, VFR = visceral fat ratio, MA = muscle area, IMFA = inter-muscular-fat area, SMI = skeletal muscle index, MD = muscle density (in HU); paired t-test; * = significant.

(DOCX)

Click here for additional data file.

CT quantified body compartments with a Baseline CT before surgery.

n = 6. TFA = total fat area, VFA = visceral fat area, SFA = subcutaneous fat area, VFR = visceral fat ratio, MA = muscle area, IMFA = inter-muscular-fat area, SMI = skeletal muscle index, MD = muscle density (in HU); paired t-test; * = significant.

(DOCX)

Click here for additional data file.

Study protocol SUPPORT-study.

(PDF)

Click here for additional data file.

1 Jul 2020

PONE-D-20-06946

Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients

PLOS ONE

Dear Dr. Steindorf,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

While I find the study well-written and organized, some major concerns were raised by the reviewers and by me. Please, consider replying carefully all questions.

Please, send the dataset to specific supplementary material server managed by the library service of the German Cancer Research Center.

Abstract, line 29: which hypothesis was tested? (please state it).

Abstract, lines 29-31: Please put the primary outcome first to indicate the hierarchy. Please also clearly state what was the primary outcome.

Abstract, results: Please add effect sizes and not just p-values. Focus on group contrasts in the reporting (please see the PREPARE Trial guide for guidance). And, consider including ES and p-values in the non-differences found.

Abstract, end: Please add clinical-trial registration-info at the end of the abstract. Because it seems as if the trial was retrospectively registered (registration after inclusion of the first participant) add “retrospectively registered” after the trial registration number. Please state clearly in the manuscript if the primary outcome was pre-defined (defined before inclusion of the first participant).

Hypotheses

Consider including objective hypotheses, not just diff or not, but y higher than x condition style.

Was it possible to account for confounding factors across groups, such as the effect of pharmacological doses?

Please remove statistical tests for baseline differences. CONSORT advise against this. Please see http://www.consort-statement.org/Media/Default/Downloads/CONSORT%202010%20Explanation%20and%20Elaboration%20Document-BMJ.pdf  page 17.

Results and Stats: please report 95CI of all variables and effect sizes.

Results: Consider improving the readability of this section. Consider respecting the stats hierarchy , first main and interactions effects, if has significant interaction, post hocs, if don’t, just the main effects.

As an example, your paragraph is (at least to primary and secondary outcomes):

"The TFA was affected by time (main effect: P < ..., EF = …) and group (main effect: P < ..., EF = …). Further, a significant interaction was observed (main effect time x group: P < ..., EF = …). In both groups, TFA increased as a function of time. Finally, significant differences between groups were observed at pretest (P < ..., EF = …) and posttest (P < ...) (Figure table xxxx)".

Discussion: first paragraph, please consider rewritten this paragraph in basis on primary and secondary outcomes (defined in the final of introduction). And after you re-analyze the results, persisting these negative results, please state clearly that (in terms of muscle mass, the RT precludes a gain on it, in comparison to control).

Discussion: One para addressing some potential applications of your findings can be useful for patients and health professionals.

Line 341 – were not

Lines 339-343 – Here, I see a huge problem of this experiment due to weak control of physical activity levels to both groups. Please, consider carefully discuss on possible deleterious effect of strength training. We know that any disruption to hormones related to catabolism and anabolism, like insulin produced in the pancreas, may also affect these processes and the overall metabolism. And, make clear that this rationale is speculative (as such your hypothesis of higher physical activity in which is less probable, because if it was true, the control group needed to do a very high training load to impact significantly in comparison to RT group)

Conclusion: as in previous parts, consider rewritten concluding strictly what you found, and considering future better controlled RCT’s to confirm these findings, and particularly, trying to find the optimal exposure-response of RT for individuals with pancreatic cancer.

Line 356 – occurs instead of happens

==============================

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

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Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: The paper entitled "Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients" wirtten by Wochner and colleagues aims to investigate the effectsof progressive resistance training onmuscle and adipose tissue compartments and the effect of body composition on overall survival. to this purpose 65 patients with pancreatic cancer were recruited and randomly assigned to either a training intervention or a control group. The 6-month intervention consisted of resistance training 3 times a weekwhile control group underwent usual care. Beforeand after the 6 months muscle strenght and CT scans were assessed. CT scans evaluated total-fat area, visceral fatarea, subcutaneous fat area, intramuscolar fat ares, and visceral tu subcutaneous fat ratio, muscle area, muscle density and skeletal musle index. Auhtors did not find any significant effec of the resistance training on muscle and adipose tissue compartments. However significant correlations were found between muscle mass and strenght parameters. Auhtors concluded that there is an anabolic potential with pancreatic cancer and progressive resistance training may be a promising tool that helps pancreatic cancer patients to maintain theri muscle mass and avoid muscle depletion.

Although the article is well and clearly written I personally have some concer:

1) How authors ensure the execution of the home-based training program? How the activity of the home-based group was monitored and recorded? Are authors sure that individuals included int he study attendend all the scheduled training sessions?

2) Many individuals were lost in the post-intervention assessment, resulting in 19 subjects in the intervention group and only 9 subjects in the control group. Don't you think that the lack of sttistical significant might be due to the great difference in the sample size of the two groups?

3) Have you thought to add a whitin group analysis?

4) Did you try to split the intervention group in RT1 and RT2 and check for possible differences?

5) How the intensity of the exercise was monitored in the home-based group? Is the RPE the right method to use to set the intensity of a resistance trainng intervention?

6) With an intervention of 2 times a week was the minimum amount of physical activity suggested by ACSM's guidelines for cancer patients achieved?

7) Authors decided to include in the resistance training major muscles for upper and lower estremities. Do authors have measured muscle mass of lower and upper limbs too? As far as I understood authors measured adipose tissue and muscle mass for:M. erector spinae, M. psoas major, M. rectus abdominis, M. obliquus internusabdominis, M. obliquus externus abdominis, M. transversus abdominis, M. quadratus, lumborum, M. latissimus dorsi, were those muscles directly involved in the resistance training?

8) Did authors performed some measure of muscle mass and adipose tissue in the trained limbs?

Reviewer #2: GENERAL COMMENTS:

This is a fine paper examining an important topic related to the effects of progressive resistance training on muscle and adipose tissue compartments and the effect of body composition on overall survival in pancreatic cancer patients. The topic of the study is original, and both the study design and the results presentation are sound. However, basic editing is needed and some basic questions require clarification. I have listed below specific comments to the authors for reference.

SPECIFIC COMMENTS:

Title:

I suggest the authors to include in the title the type of the study (i.e., Randomized Clinical Trial.

Abstract:

I suggest the authors to describe in the purpose that the exercise group was compared with usual care or control group.

Methods:

Which block size was used in the randomization process?

Results:

RT1 and RT2 presented similar baseline values for all outcomes? Is a limitation of the study pool the RT1 and RT2 data? Please, explain in more details.

Only intention-to-treat analysis was performed? Per protocol was analyzed? How the missing values were imputed in the analysis?

Is it possible to present the effect size for all outcomes?

The authors sharing the data in a public repository?

Reviewer #3: The manuscript entitled ‘Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients’ with the aim to investigate whether the intervention group showed a different course of body composition than the control group and to investigate whether there are any predictive factors in body composition that influence the survival of patients with pancreatic cancer.

The manuscript can be further improved based on the following comments.

Materials and Methods

Study population

Page 5 Line 111, the person who prepared the randomization block with allocation list and concealment to be stated. Likewise personnel involved in the recruitment and assessment. The impossible of blinding to be stated.

The exclusion criteria to be stated.

Statistical analysis

Page 9 Line 201=202, intent to treat basis not clear. Was there separate analysis for this? More information to be provided.

Page 9 Line 204-205, t-tests to be written as t-test (singular).

Page 9 Line 213, 1 or 2 tailed test to be stated in the sample size calculation.

Page 9 Line 215, the outcome variable to be clearly stated.

Results

The usage of n or N to be standardized throughout the manuscript.

Page 9 Line 224-225, sd to be stated apart from mean.

Page 11 Table 1, for ‘All patients, smoking (non smoker 83,0)’ the figure to be replaced with 75.5. Title is too short.

Page 13 & 14 Table 2 & 3, the word mean to be added to the adjusted difference. 95CI to be written as 95% CI. The word diff to be omitted and to be replaced with symbol * and denoted. Statistical test ANCOVA to be denoted in the table footnote.

Page 15 Line 283, correlation range values to be stated.

Page 16 Table 4, decimal point for the correlation value to be reduced (see also Line 277-283). Likewise with the p values and to be standardized.

Table 5 & 6. the lower and upper 95% CI to be presented in the following format

95% CI

Lower Upper

S1 Table 7 and S1 Table 8, summary findings to be stated in the results section.

Effect size could be presented.

Discussion

Page 28 Line 440, 'supplementary materials' to be replaced with S1 Table 7 and S1 Table 8.

Apart from the limitation discussed, what was the post hoc study power based on the final sample size (although it may be controversial to discuss) including the statistical analysis.

The source of funding for the study to be stated in the manuscript.

**********

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Reviewer #1: No

Reviewer #2: Yes: Stephanie Santana Pinto

Reviewer #3: No

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15 Sep 2020

PONE-D-20-06946

Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients

PLOS ONE

Thank you for carefully reviewing our manuscript and providing us with very helpful and constructive comments. We revised the manuscript accordingly.

Academic editor:

Please, send the dataset to specific supplementary material server managed by the library service of the German Cancer Research Center.

REPLY: We sent the minimal data set to the supplementary material server of the library service of the German Cancer Research Center. The patients’ informed consent did not include public data sharing. Due to protection of private data, the data set is intended only for the review process for the editors and reviewers and needs to be handled confidentially.

Below the link to the data set:

http://suppl.dkfz.de/KS/Support_minimal_Data_set_24_07_2020.xlsx

Thank you for your confidentiality.

Abstract, line 29: which hypothesis was tested? (please state it).

REPLY: We rephrased the sentence to make it clearer which was our primary aim within this explorative analysis.

Abstract, lines 29-31: Please put the primary outcome first to indicate the hierarchy. Please also clearly state what was the primary outcome.

REPLY: We added the hierarchy of the analyses. As all analyses presented in this manuscript were based on secondary endpoints of the randomized SUPPORT-trial, we prefer not to use the term primary outcome. We defined a primary and secondary aim for the analyses presented here and revised and standardized the terminology throughout the manuscript.

Abstract, results: Please add effect sizes and not just p-values. Focus on group contrasts in the reporting (please see the PREPARE Trial guide for guidance). And, consider including ES and p-values in the non-differences found.

REPLY: Thank you for the indication. We added also effect sizes.

Abstract, end: Please add clinical-trial registration-info at the end of the abstract. Because it seems as if the trial was retrospectively registered (registration after inclusion of the first participant) add “retrospectively registered” after the trial registration number. Please state clearly in the manuscript if the primary outcome was pre-defined (defined before inclusion of the first participant).

REPLY: We added the clinical-trial registration info at the end of the abstract. The study record was submitted on October 30th 2013 and the recruitment of the study started in December 2013.

Secondary outcomes defined before the start of the study included body weight and body composition with mentioning the routinely performed CT scans as information source in the study protocol.

Hypotheses: Consider including objective hypotheses, not just diff or not, but y higher than x condition style.

REPLY: We rephrased the sentence and added a specific hypothesis on page 4.

Was it possible to account for confounding factors across groups, such as the effect of pharmacological doses?

REPLY: Unfortunately, we were not able to assess data on pharmacological doses or chemotherapy completion rates within our study. Not all patients received their chemotherapy treatment at the National Center for Tumor Diseases in Heidelberg. Patients who lived further away received their treatment at an oncologist close to their homes.

Please remove statistical tests for baseline differences. CONSORT advise against this. Please see http://www.consort-statement.org/Media/Default/Downloads/CONSORT%202010%20Explanation%20and%20Elaboration%20Document-BMJ.pdf page 17.

REPLY: Thank you for the indication. We removed the statistical tests for baseline differences.

Results and Stats: please report 95CI of all variables and effect sizes.

REPLY: We added 95CI of all variables and effect sizes. We used partial omega squared instead of eta squared due to correcting the bias and removing sampling error influences and due to small sample size.

Results: Consider improving the readability of this section. Consider respecting the stats hierarchy, first main and interactions effects, if has significant interaction, post hocs, if don’t, just the main effects.

As an example, your paragraph is (at least to primary and secondary outcomes):

"The TFA was affected by time (main effect: P < ..., EF = …) and group (main effect: P < ..., EF = …). Further, a significant interaction was observed (main effect time x group: P < ..., EF = …). In both groups, TFA increased as a function of time. Finally, significant differences between groups were observed at pretest (P < ..., EF = …) and posttest (P < ...) (Figure table xxxx)".

REPLY: Since we performed analyses of covariance to assess the differences in body composition between the groups from pre- to post-intervention we didn’t obtain the main effect results (as analyzed in the mixed model analyses). Therefore, we could not report the main effects of time and group.

Discussion: first paragraph, please consider rewritten this paragraph in basis on primary and secondary outcomes (defined in the final of introduction). And after you re-analyze the results, persisting these negative results, please state clearly that (in terms of muscle mass, the RT precludes a gain on it, in comparison to control).

REPLY: Thank you for the indication. We rephrased the first paragraph of the discussion on page 21 to be in line with the definition of the hypothesis in the introduction and stated, that we couldn’t confirm the hypothesis (primary aim) in this study.

Discussion: One para addressing some potential applications of your findings can be useful for patients and health professionals.

REPLY: We added potential applications in the conclusion part of the discussion on page 26: Identify patients, who could profit from training, monitoring of training and also risk stratification of patients.

Line 341 – were not

REPLY: Thank you for the indication. We corrected the terminology.

Lines 339-343 – Here, I see a huge problem of this experiment due to weak control of physical activity levels to both groups. Please, consider carefully discuss on possible deleterious effect of strength training. We know that any disruption to hormones related to catabolism and anabolism, like insulin produced in the pancreas, may also affect these processes and the overall metabolism. And, make clear that this rationale is speculative (as such your hypothesis of higher physical activity in which is less probable, because if it was true, the control group needed to do a very high training load to impact significantly in comparison to RT group)

REPLY: We agree that the weak control of physical activity levels is a huge limitation of this study. Due to small sample size individuals could have a huge impact and we don’t have a verifiable explanation for the increase in muscle mass in CON. We emphasized that our explanations are speculative and added changes to anabolic hormones such as insulin as possible explanation on page 21 and 22.

Conclusion: as in previous parts, consider rewritten concluding strictly what you found, and considering future better controlled RCT’s to confirm these findings, and particularly, trying to find the optimal exposure-response of RT for individuals with pancreatic cancer.

REPLY: We rephrased the conclusion on page 25 and 26 to be more in line with the hypothesis introduced in the introduction.

Line 356 – occurs instead of happens

REPLY: Thank you for the indication. We corrected the terminology.

Reviewers' comments to the Author:

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper entitled "Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients" written by Wochner and colleagues aims to investigate the effects of progressive resistance training on muscle and adipose tissue compartments and the effect of body composition on overall survival. to this purpose 65 patients with pancreatic cancer were recruited and randomly assigned to either a training intervention or a control group. The 6-month intervention consisted of resistance training 3 times a week while control group underwent usual care. Before and after the 6 months muscle strength and CT scans were assessed. CT scans evaluated total-fat area, visceral fat area, subcutaneous fat area, intramuscular fat areas, and visceral to subcutaneous fat ratio, muscle area, muscle density and skeletal muscle index. Authors did not find any significant effect of the resistance training on muscle and adipose tissue compartments. However significant correlations were found between muscle mass and strength parameters. Authors concluded that there is an anabolic potential with pancreatic cancer and progressive resistance training may be a promising tool that helps pancreatic cancer patients to maintain their muscle mass and avoid muscle depletion.

Although the article is well and clearly written I personally have some concerns:

1) How authors ensure the execution of the home-based training program? How the activity of the home-based group was monitored and recorded? Are authors sure that individuals included in the study attended all the scheduled training sessions?

REPLY: We included further information in the methods section on page 6 about recording the training. The monitoring of the home-based group was done by weekly phone calls of the exercise therapist.

Further, we also included information on the training adherence rate of the patients in the intervention group in the results section on page 11, as this information was previously missing. Thank you for the good indication.

2) Many individuals were lost in the post-intervention assessment, resulting in 19 subjects in the intervention group and only 9 subjects in the control group. Don't you think that the lack of statistical significance might be due to the great difference in the sample size of the two groups?

REPLY: We agree with your statement. The unbalanced group size of the intervention group and the control group could be an influencing factor. We stated this already in our limitations on page 25. Due to ionizing radiation of CT no additional CT scans were performed and only CT scans of clinical routine indication were used. Therefore, we needed to exclude patients who didn’t have an eligible CT-scan.

3) Have you thought to add a within group analysis?

REPLY: In addition to the ANCOVA (main analysis) we also performed paired t-test for the changes from T0 to T2 for each group. The results are also presented in Table 2 and 3.

4) Did you try to split the intervention group in RT1 and RT2 and check for possible differences?

REPLY: As there were only n= 4 patients in the supervised resistance training group (RT1) and n= 15 patients in the home-based resistance training group (RT2) with no differences between the groups, we decided to combine both training groups to a pooled resistance training group (RT) for the analysis.

5) How the intensity of the exercise was monitored in the home-based group? Is the RPE the right method to use to set the intensity of a resistance training intervention?

REPLY: The intensity in the home-based group was monitored with the Borg Scale of Perceived Exertion by weekly phone calls. We agree that monitoring the intensity with guidelines of, for example, 60-80% 1RM under supervision is better than training at home with intensities monitored with the RPE. However, we believe that prior to the fact that patients exercise alone at home during chemotherapy, monitoring intensity with the RPE is feasible and justifiable.

6) With an intervention of 2 times a week was the minimum amount of physical activity suggested by ACSM's guidelines for cancer patients achieved?

REPLY: The updated ACSM guidelines for exercise for cancer patients from 2019 recommend to perform resistance training 2 times a week with 2 sets with 8-15 repetitions with 60% of the one repetition maximum for the major muscle groups. Based on this suggestion, we meet the requirements to generate a positive effect on the quality of life, fatigue and physical function. At present, pancreatic cancer patients follow the general ACSM recommendations for exercise for cancer patients.

7) Authors decided to include in the resistance training major muscles for upper and lower extremities. Do authors have measured muscle mass of lower and upper limbs too? As far as I understood authors measured adipose tissue and muscle mass for: M. erector spinae, M. psoas major, M. rectus abdominis, M. obliquus internus abdominis, M. obliquus externus abdominis, M. transversus abdominis, M. quadratus, lumborum, M. latissimus dorsi, were those muscles directly involved in the resistance training?

REPLY: Unfortunately, we didn’t assess muscle mass of the upper and lower limbs. The above stated muscles were not directly targeted in the resistance training, but were partially involved as overall stabilizing muscles during the exercise. For example, squats were used as exercise, at which the core muscles like M. erector spinae are used as stabilizing muscles.

There is evidence, that measurement of muscle tissue on a single slice image on vertebra L3 level shows a high correlation with whole body muscle mass:

Shen, W., M. Punyanitya, Z. Wang, D. Gallagher, M. P. St-Onge, J. Albu, S. B. Heymsfield, and S. Heshka. 2004. 'Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image', J Appl Physiol (1985), 97: 2333-8

Therefore, we took the L3 SMI as a surrogate parameter for whole body muscle mass.

8) Did authors perform some measure of muscle mass and adipose tissue in the trained limbs?

REPLY: Unfortunately, we didn’t. We had already mentioned this as a limiting factor in the discussion on page 25. Imaging of extremities (arms and legs) is very rare in routine clinical context with patients with pancreatic cancer and not frequently performed. Therefore, no routine imaging of those body regions was available and we weren’t able to measure the muscle mass of the limbs directly.

Please see also the answer above.

Reviewer #2: GENERAL COMMENTS:

This is a fine paper examining an important topic related to the effects of progressive resistance training on muscle and adipose tissue compartments and the effect of body composition on overall survival in pancreatic cancer patients. The topic of the study is original, and both the study design and the results presentation are sound. However, basic editing is needed and some basic questions require clarification. I have listed below specific comments to the authors for reference.

SPECIFIC COMMENTS:

Title: I suggest the authors to include in the title the type of the study (i.e., Randomized Clinical Trial.

REPLY: The analyses presented focus on secondary endpoints of a prospective randomized controlled trial. Thus, we tend to not mention the study type (randomized controlled trial) in the title.

Abstract: I suggest the authors to describe in the purpose that the exercise group was compared with usual care or control group.

REPLY: This concern was addressed in the methods section of the abstract on page 2 line 33,34. Due to the limiting word count we did not add the information also in the purpose.

Methods: Which block size was used in the randomization process?

REPLY: A 2:1 block randomization with varying block sizes of 3 and 6 was used. We added the varying block sizes to the method section on page 6.

Results: RT1 and RT2 presented similar baseline values for all outcomes? Is a limitation of the study pool the RT1 and RT2 data? Please, explain in more details.

REPLY: As there were only n= 4 patients in the supervised resistance training group (RT1) and n= 15 patients in the home-based training group (RT2) with no differences between the groups, we decided to combine both training groups to a pooled resistance training group (RT) for the analysis.

We agree that the pooling could be a limitation, as we mentioned in the discussion of the manuscript on page 25.

Only intention-to-treat analysis was performed? Per protocol was analyzed? How the missing values were imputed in the analysis?

REPLY: The presented subsequent analysis on routine CT scans was intention-to-treat. There were no missing values imputed in the analysis, as missing values most likely occurred due to patients’ death or disease progression or due to non-existent CT scans or not evaluable, not suitable CT scans.

Is it possible to present the effect size for all outcomes?

REPLY: Thank you for the indication. We added also effect sizes. We used partial omega squared instead of eta squared due to correcting the bias and removing sampling error influences and due to small sample size.

The authors sharing the data in a public repository?

REPLY: Yes, the minimal dataset was sent to specific supplementary material server managed by the library service of the German Cancer Research Center. However, due to the data protection regulations applicable here in the context of the study (the patients’ informed consent did not include public data sharing), the data will only be available for the review process for the editor and the reviewers and needs to be handled confidentially. See also answer to first comment of the editor.

Reviewer #3: The manuscript entitled ‘Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients’ with the aim to investigate whether the intervention group showed a different course of body composition than the control group and to investigate whether there are any predictive factors in body composition that influence the survival of patients with pancreatic cancer.

The manuscript can be further improved based on the following comments.

Materials and Methods

Study population

Page 5 Line 111, the person who prepared the randomization block with allocation list and concealment to be stated. Likewise personnel involved in the recruitment and assessment. The impossible of blinding to be stated.

REPLY: We added a sentence about blinding within the SUPPORT-study on page 6. The Randomization of a patient was done by an independent biometrician.

The exclusion criteria to be stated.

REPLY: We added the exclusion criteria to the paragraph of the study population within the Materials & Methods section on page 5.

Statistical analysis

Page 9 Line 201=202, intent to treat basis not clear. Was there separate analysis for this? More information to be provided.

REPLY: We added further information and rephrased the sentence on page 9 to make it more clear.

Page 9 Line 204-205, t-tests to be written as t-test (singular).

REPLY: We corrected the terminology as you recommended.

Page 9 Line 213, 1 or 2 tailed test to be stated in the sample size calculation.

REPLY: We used the 2-sided test. We have slightly reworded the sentence. But since this is an explorative analysis of CT scan data, we decided to delete this sentence with the sample size calculation. Please, see also the answer below.

Page 9 Line 215, the outcome variable to be clearly stated.

REPLY: The outcome variable of the sample size calculation for the SUPPORT study was the physical functioning subscale of the quality of Life questionnaire (EORTC-QLQ-C30). No further power calculation was performed for the explorative sub-analysis presented here. Therefore, we decided to delete the part with the description of the sample size calculation on page 9 and added the following sentence instead: “For the presented explorative analysis on routine CT scans no further power calculation was performed.”

Results

The usage of n or N to be standardized throughout the manuscript.

REPLY: Thank you for the indication. We have standardized the use of “n” in the manuscript.

Page 9 Line 224-225, sd to be stated apart from mean.

REPLY: Thank you for the indication. We added the SD.

Page 11 Table 1, for ‘All patients, smoking (non smoker 83,0)’ the figure to be replaced with 75.5. Title is too short.

REPLY: Thank you very much for the indication. We have corrected the mistake. Further, we extended the title of Table 1 with more information.

Page 13 & 14 Table 2 & 3, the word mean to be added to the adjusted difference. 95CI to be written as 95% CI. The word diff to be omitted and to be replaced with symbol * and denoted. Statistical test ANCOVA to be denoted in the table footnote.

REPLY: Thank you for the indication. We adjusted the tables 2 and 3 on page 14 and 15.

Page 15 Line 283, correlation range values to be stated.

REPLY: We added the correlation range values.

Page 16 Table 4, decimal point for the correlation value to be reduced (see also Line 277-283). Likewise with the p values and to be standardized.

REPLY: We reduced the decimal point for the correlation coefficient to 2 and p-values were standardized to 3 decimal points in Table 4.

Table 5 & 6. the lower and upper 95% CI to be presented in the following format

95% CI

Lower Upper

REPLY: Thank you for the indication. We adjusted the tables 5 and 6.

S1 Table 7 and S1 Table 8, summary findings to be stated in the results section.

REPLY: A paragraph about S1 and S2 was added in the results section on page 16.

Effect size could be presented.

REPLY: We added effect sizes. We used partial omega squared instead of eta squared due to correcting the bias and removing sampling error influences and due to small sample size.

Discussion

Page 28 Line 440, 'supplementary materials' to be replaced with S1 Table 7 and S1 Table 8.

REPLY: Thank you for the indication. We adjusted the wording.

Apart from the limitation discussed, what was the post hoc study power based on the final sample size (although it may be controversial to discuss) including the statistical analysis.

REPLY: Since this is an explorative analysis of CT scan data, no further power calculation was performed.

The source of funding for the study to be stated in the manuscript.

REPLY: We followed this comment by adding the source of funding for the study at the end of the manuscript on page 27.

Submitted filename: Response to Reviewers.docx

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10 Nov 2020

Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients

PONE-D-20-06946R1

Dear Dr. Steindorf,

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Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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Reviewer #1: Yes

Reviewer #3: Partly

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Reviewer #1: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #3: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Authors have addressed all the comments of this reviewer.

This reviewer does not have any other suggestion.

Reviewer #3: The authors have put in effort to address the comments.

Minor comment.

Please ensure the partial omega squared symbol is correctly inserted/copied into the manuscript and comments by academic editor on statistical presentation are addressed.

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Reviewer #1: No

Reviewer #3: No

16 Nov 2020

PONE-D-20-06946R1

Impact of progressive resistance training on CT quantified muscle and adipose tissue compartments in pancreatic cancer patients

Dear Dr. Steindorf:

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