Effect of Adapted Physical Activity in Patients With Advanced Pancreatic Cancer: The APACaP GERCOR Randomized Trial

Authors:
Cindy Neuzillet GERCOR, Paris, France
Department of Medical Oncology, Institut Curie – Site Saint Cloud, Versailles Saint-Quentin University, Paris Saclay University, Saint-Cloud, France

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Olivier Bouché Department of Digestive Oncology, Université de Reims Champagne-Ardenne, CHU Reims, Reims, France

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Christophe Tournigand Department of Medical Oncology, Assistance Publique–Hôpitaux de Paris, Hôpital Henri-Mondor, University Paris Est Créteil, Créteil, France

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Benoist Chibaudel Department of Medical Oncology, Hôpital Franco-Britannique – Fondation Cognacq-Jay, Levallois Perret, France

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Lucile Bauguion Department of Hepato-Gastroenterology, Hospital Center Departmental Vendée, La Roche-sur-Yon, France

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Leïla Bengrine-Lefevre Department of Medical Oncology, Georges-François Leclerc Cancer Center, UNICANCER, Dijon, France

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Daniel Lopez-Trabada Ataz Department of Medical Oncology, Saint-Antoine Hospital, Paris, France

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May Mabro Department of Medical Oncology, Foch Hospital, Suresnes, France

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Jean-Philippe Metges Cancerology and Hematology Institute, University Hospital, Brest, France

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Denis Péré-Vergé Department of Hepato-Gastroenterology, Centre Hospitalier Saint-Joseph Saint-Luc, Lyon, France

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Thierry Conroy Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy, France
Université de Lorraine, APEMAC, équipe MICS, Nancy, France

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Astrid Lièvre Department of Gastroenterology, Rennes University Hospital, Rennes 1 University, Rennes, France

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Morgan Andre Department of Gastroenterology, Centre Hospitalier Intercommunal Mont-de-Marsan-Pays des Sources, Mont de Marsan, France

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Françoise Desseigne Department of Medical Oncology, Centre Léon Bérard, Lyon, France

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François Goldwasser Department of Medical Oncology, CARPEM, Cochin University Hospital, Assistance Publique–Hôpitaux de Paris, Paris Cité University, Paris, France

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Julie Henriques Unit of Methodology and Quality of Life in Oncology, Besançon University Hospital, Besançon, France
Bourgogne Franche-Comté University, INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France

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Amélie Anota Unit of Methodology and Quality of Life in Oncology, Besançon University Hospital, Besançon, France
Department of Clinical Research and Innovation & Human and Social Sciences Department, Centre Léon Bérard, Lyon, France

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Pascal Hammel GERCOR, Paris, France
Department of Medical and Digestive Oncology, Hôpital Beaujon, Assistance Publique–Hôpitaux de Paris, Clichy, France
Department of Digestive and Medical Oncology, Hôpital Paul Brousse, Assistance Publique–Hôpitaux de Paris, Paris Saclay University, Villejuif, France

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Background: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. Patients and Methods: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. Results: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were −0.98 (SD, 23.9; P=.39), −2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non–statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. Conclusions: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

Abstract

Background: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. Patients and Methods: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. Results: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were −0.98 (SD, 23.9; P=.39), −2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non–statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. Conclusions: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

Background

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer-related death in the United States and Europe by 2030.1,2 Patients with PDAC have a poor prognosis, partially due to a late diagnosis resulting from lack of specific symptoms and early metastatic dissemination.3

Advanced PDAC (aPDAC) is managed with chemotherapy (5-FU/folinic acid, irinotecan, and oxaliplatin combination [FOLFIRINOX] or gemcitabine-based), with limited efficacy (median overall survival [OS] of 6–12 months).46 Targeted therapies and immunotherapies have not been found to be effective, except in rare forms with druggable genetic alterations.7

Pancreatic cancer is a systemic disease with a significant impact on patients’ general and nutritional status, especially at an advanced stage, and a high symptom burden (including fatigue, pain, and anxiety/depression), affecting health-related quality of life (HRQoL) and ultimately survival.8 Therefore, supportive care is crucial to improve HRQoL and tolerance of treatment. Adapted physical activity (APA) may be beneficial for patients with cancer by reducing disease- or treatment-related symptoms and improving physical fitness and muscle mass/strength.911 Physical exercise has been shown to be feasible and safe in patients with various advanced stage cancers.1215 Studies on the effects of APA on HRQoL in aPDAC are scarce. In this setting, the APACaP trial was designed to determine whether an APA intervention may improve HRQoL in patients with aPDAC receiving first-line chemotherapy.16

Patients and Methods

Study Design

This study is a national, prospective, multicenter, open-label, randomized, controlled phase III trial. The study protocol and amendments (supplemental eAppendix 1, available with this article at JNCCN.org) were submitted for formal approval to the French health authorities and an independent ethics committee. All patients provided written informed consent before inclusion.

Eligible patients were randomized via a central computer-assisted procedure centralized at the GERCOR data center in a 1:1 ratio to receive either standard care alone (standard arm) or standard care plus the APA program (APA arm). The randomization was performed using a minimization technique and was stratified for treatment center, cancer stage (locally advanced vs metastatic), chemotherapy (weekly vs biweekly regimen), ECOG performance status (PS; 0–1 vs 2), baseline physical activity level (very active, moderately active, or inactive according to the Global Physical Activity Questionnaire [GPAQ]).

Patients

Eligible patients were aged ≥18 years; had histologically confirmed, previously untreated, locally advanced, or metastatic PDAC, measurable according to the RECIST version 1.1 criteria17; were fit for chemotherapy; had an ECOG PS of 0 to 2 and an identified APA partner (more details provided in the following section); and were registered in a national health care system. Patients were excluded if they had any medical condition (cardiovascular, respiratory, psychiatric, musculoskeletal, or neurologic) that contraindicated exercise.

Procedures

In both study arms, patients received first-line chemotherapy of the investigator’s choice, nutritional support (according to national guidelines), and routine tumor evaluation. Patients in the standard arm received usual information and counseling by their caregivers about physical activity, according to the center’s routine practice and available scientific evidence.

The 16-week APA program was developed according to national and international guidelines.16 Two types of exercises were combined (supplemental eAppendix 1): (1) aerobic training according to the patient’s preferences (walking, Nordic walking, or cycling) and (2) resistance workout with elastic bands. Patient fitness before treatment (GPAQ) and a baseline physical evaluation (6-minute walk test and maximal strength test) were considered.

The exercises were performed at home in addition to daily life activities, with weekly remote supervision by an APA professional trainer (from Mooven adapted physical activity services) and unsupervised sessions with a physical activity partner (ie, healthy family relative/friend volunteer chosen by the patient to attend the exercise session at least once per week).

Exercise tolerance was assessed during a weekly follow-up video call with the APA professional trainer. A remotely supervised session was also performed during this video call. If exercises were well tolerated, their duration was increased, followed by the frequency, and finally the intensity (supplemental eFigure 1).

Objectives and Assessments

The primary aim of the study was to evaluate the effect of APA on HRQoL at week 16 according to the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) with 3 targeted dimensions: global health status, physical function, and fatigue. The secondary aims were to assess other dimensions of EORTC QLQ-C30, HRQoL longitudinal analysis, nutritional status, insulin resistance, chemotherapy toxicity, progression-free survival (PFS), OS, and adherence to the APA program.

The EORTC QLQ-C30 questionnaire was administered before randomization (until 14 days after randomization) and then every month until week 16, at month 6, then every 3 months thereafter up to 24 months. Tumor evaluation with CT of the thorax, abdomen, and pelvis and CA 19-9 serum measurements were performed every 8 weeks. Tumor response was classified according to RECIST version 1.1.17 Patients were seen in follow-up for survival until death or study closure. Toxicities were graded according to CTCAE version 4.0.

Statistical Analysis

The trial was designed to detect a difference of means between the study arms with a Z test for the 3 targeted HRQoL dimensions of the EORTC QLQ-C30 at week 16, with a minimal clinically important difference (MCID) of 5 points, an expected standard deviation of 10 points, a statistical power of 80%, and a one-sided α-level of 0.017 for each dimension (global α of 0.05 with Bonferroni adjustment). Two interim analyses for efficacy and futility were planned using the α-spending function with the O’Brien-Fleming boundaries at 30% and 65% of the information fraction (after enrollment of 45 and 100 evaluable patients). Based on these hypotheses, a total of 154 patients with both baseline and week 16 HRQoL questionnaires were required.

Seven amendments were made to the protocol during the study (supplemental eAppendix 1), leading to the current version of the document. Clinical and biologic characteristics as well as baseline HRQoL scores were described in the overall, modified intention-to-treat [mITT] populations (mITT1: patients with available baseline and week 16 scores for the 3 targeted dimensions of the EORTC QLQ-C30 questionnaire; mITT2: patients who completed a baseline and at least one follow-up questionnaire) and between arms using mean, standard deviation, median, and range values for continuous variables and percentages for categorical variables.

The primary HRQoL analysis was performed in the mITT1 population. The study was considered positive if a statistically significant difference in mean scores of ≥5 points was observed using a Z test in at least one of the targeted HRQoL dimensions at week 16 showing a benefit to the APA program, with no statistically significant deterioration of the 2 other dimensions. To address an imbalance in baseline HRQoL between arms, the mean differences in targeted dimensions between baseline and week 16 were compared using Student’s t test. Subgroup analyses for the primary endpoint were performed for variables used for randomization stratification.

The mean scores of nontargeted dimensions of the EORTC QLQ-C30 questionnaire at week 16 and the mean difference between baseline and week 16 were compared between arms using Student’s t test. Secondary longitudinal analyses of changes in the HRQoL were performed with the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods (supplemental eAppendix 1) in the mITT1 and mITT2 populations, including all measurement times up to 24 months. Differences of ≥5 points in HRQoL scores were considered to be clinically significant (MCID) for all analyses. To explore the impact of population selection in the mITT2 group, a conservative sensitivity analysis for the TUDD method was performed in all randomized patients by considering that patients not eligible for mITT2 had deteriorating HRQoL the day after randomization. Adjusted mean differences between treatment arms and the corresponding 95% confidence intervals were presented.

For time-to-event endpoints (DATECAN consensus),18 OS was defined as the time from the date of randomization to the date of death of any cause. Patients who were still alive at the date cutoff were censored. PFS was defined as the time from the date of randomization to the date of tumor progression or death. Patients who were alive without progression at the date cutoff were censored.

TUDD, OS, and PFS were presented as medians and 95% confidence intervals using the Kaplan-Meier method and compared in the treatment arms with the log-rank test. The association between treatment arms and the time-to-event endpoints was assessed with Cox proportional hazards models. Median follow-up was estimated with the reverse Kaplan-Meier method.

A P value of .017 was considered statistically significant for each dimension of the primary endpoint and assessed with a unilateral test (Bonferroni adjustment with a global α of 0.05). Bilateral tests at the threshold of 5% for secondary endpoints were provided for exploratory purposes. All analyses were performed using SAS version 9.4 (SAS Institute Inc) and R version 4.1.1 (R Core Team).

Results

Patient Characteristics

A total of 313 patients were included in the study between November 2014 and October 2020; 157 were randomly assigned to the standard arm and 156 to the APA arm (Figure 1). Median patient age was 64 years (range, 29–87 years), and most were male (55%), had an ECOG PS of 0 or 1 (93%), had metastatic disease (77%), and received FOLFIRINOX (78%) (supplemental eTable 1). The patient distribution according to GPAQ groups was homogeneous.

Figure 1.
Figure 1.

Study flow diagram.

Abbreviations: APA, adapted physical activity; HRQoL, health-related quality of life; mITT1, modified intention-to-treat population 1; mITT2, modified intention-to-treat population 2; W16, week 16.

Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7065

Patient characteristics and survival in the overall, mITT1 (n=172), and mITT2 (n=259) populations are presented in supplemental eTables 2 and 3. Patient characteristics between the standard and APA arms were well balanced in the overall population (supplemental eTable 1) as well as in the mITT1 and mITT2 populations (Table 1).

Table 1.

Baseline Patient Characteristics

Table 1.

Median follow-up was 24.4 months (95% CI, 23.8–25.1), 25.1 months (95% CI, 24.1–29.0), and 24.6 months (95% CI, 23.9–25.8) in the overall, mITT1, and mITT2 populations, respectively. The median PFS and OS values were similar in all populations. Prognosis in the patients in the mITT1 and mITT2 populations was significantly better than in excluded patients (median OS, 15.8 vs 10.4 months and 15.3 vs 7.3 months, respectively; supplemental eFigures 2 and 3).

Delivery and Safety of Intervention

The mean [SD] ratios of sessions performed during the weekly videocall compared with planned sessions in the mITT1, mITT2, and overall populations were 80% [33.0], 74% [35.6], and 69% [38.2], respectively (supplemental eTable 4). The percentages of patients who stopped the APA program prematurely were 4.6% and 14.2% in the mITT1 and mITT2 populations, respectively (supplemental eFigure 4). No APA-related adverse events were observed in the mITT1 population. One patient in the mITT2 population experienced grade 3 fatigue with documented concomitant tumor progression.

HRQoL Compliance

The median number of HRQoL questionnaires available was 5.7 (IQR, 3–8) in the overall population (standard arm, 5.0 [IQR, 3–8]; APA arm, 6.0 [IQR, 2.5–8]) and 6.0 (IQR, 4–8) in the mITT2 population (standard arm, 6.0 [IQR, 4–8]; APA arm, 7.0 [IQR, 3.5–8.5]). Similar completion rates were observed between arms in both the overall and mITT2 populations at each time point (supplemental eTable 5).

Efficacy

Primary Analysis

The Z test showed no statistically significant difference at the α-threshold of 0.017 for global health status, physical function, and fatigue (Table 2). There was a difference of ≥5 points (MCID) between the APA and standard arms for physical function at week 16 (−5.8; SD, 18.9; P=.02, not statistically significant). After taking into consideration the mean change between baseline and week 16 scores, the adjusted difference between arms was reduced to −2.1 points.

Table 2.

Mean Differences in 3 HRQoL Targeted Dimensions From Baseline to Week 16 in mITT1 (N=172)

Table 2.

Secondary Analyses

Subgroup Analyses

On one hand, there was no differential effect of the intervention in the subgroup analyses for stage, ECOG PS, or chemotherapy regimen (supplemental eFigure 5). On the other hand, a mean difference of ≥5 points in the baseline-to-week 16 score comparison between arms was observed in the very active GPAQ group for global health status, physical function, and fatigue, showing a benefit in the APA arm but not in the less active GPAQ groups.

Other HRQoL Dimensions at Week 16 in the mITT1 Population

Transversal analysis of other HRQoL dimensions of the EORTC QLQ-C30 questionnaire in the mITT1 population showed a mean difference adjusted from baseline ≥5 points between arms for role and social functioning scores as well as for pain, insomnia, and appetite loss in favor of the APA arm (Figure 2).

Figure 2.
Figure 2.

Analysis of changes from baseline to week 16 in EORTC QLQ-C30 scale scores between study arms (APA vs standard). (A) Mean differences of changes in the mITT1 population. (B) Mean differences of changes with an MMRM analysis in the mITT2 population. (C) HRs of changes with TUDD analysis in the mITT2 population. Results of baseline to week 16 analysis and MMRM analysis have been reversed, respectively, for symptomatic scales and for functional scales on the graph, so a negative change was in favor of the APA arm for all scales.

Abbreviations: APA, adapted physical activity; EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30; HR, hazard ratio; mITT1, modified intention-to-treat population 1; mITT2, modified intention-to-treat population 2; MMRM, mixed model for repeated measures; TUDD, time until definitive deterioration.

Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7065

Longitudinal Analyses of HRQoL

The MMRM analysis of 15 HRQoL dimensions of the EORTC QLQ-C30 questionnaire in the mITT2 population showed a statistically significant difference in favor of APA for global health status; physical, cognitive, and social functioning scores; and appetite loss. The TUDD analysis showed a statistically significant benefit with APA for global health status; cognitive, emotional, and social functioning scores; and pain, insomnia, constipation, and financial difficulties (Figure 2, supplemental eFigure 6 and eFigure 7). Similar results were observed in the sensitivity analyses in the mITT1 (supplemental eFigure 7) and overall (supplemental eFigures 8–10) populations.

Secondary Objectives

In the mITT2 population, OS (hazard ratio [HR], 0.83; 95% CI, 0.62–1.11) and PFS (HR, 0.86; 95% CI, 0.66–1.11) were longer in the APA arm than in the standard arm (Figure 3), although these results were not statistically significant. There was also a trend toward an increased objective response rate (complete response plus partial response) in the APA group (41.7% vs 30.6%; P=.27; supplemental eTable 6 and eFigure 7). There was no statistically significant difference for the delay of chemotherapy treatment or the rate of grade 3/4 toxicities across arms (supplemental eFigure 8). The median number of chemotherapy cycles was similar between arms.

Figure 3.
Figure 3.

Kaplan-Meier curves of (A) OS and (B) PFS in the mITT2 population according to study arm.

Abbreviations: APA, adapted physical activity; mITT2, modified intention-to-treat population 2; OS, overall survival; PFS, progression-free survival.

Citation: Journal of the National Comprehensive Cancer Network 21, 12; 10.6004/jnccn.2023.7065

Discussion

This pivotal, open-label, randomized clinical trial is the largest reported study to date on APA in patients with aPDAC. This study confirms that the APA program is feasible and safe in this challenging patient population with a poor prognosis and a high symptom burden.12,13 The primary endpoint was not found to be statistically significant. In particular, the standard deviation of the HRQoL dimensions was higher than expected for the sample size calculation (20 vs 10), which reduced the statistical power to detect statistically significant differences among arms in the primary transversal analysis. In fact, we did not expect to find such extensive HRQoL heterogeneity in patients with aPDAC. Moreover, longitudinal analysis (eg, TUDD) may have been more informative than time point transversal analysis in evaluating HRQoL heterogeneity and determining a benefit to HRQoL. However, the TUDD approach originated in the past decade and was a relatively new method when this study was designed, and the data to generate statistical hypotheses for sample size calculation were not available. Finally, several definitions of TUDD have been proposed,18,19 and a consensus was only reached in 2020.20

Nevertheless, the trend toward improvement in HRQoL in the 3 targeted parameters was always positive with APA, although not significant with the MCID established at 5 points. In addition, APA resulted in statistically and clinically significant improvement in several HRQoL dimensions (function and specific symptoms, including pain, insomnia, appetite loss, and constipation) in longitudinal analyses, including a 3-month improvement in median time until deterioration in general health (12.1 vs 9.0 months; HR, 0.69; 95% CI, 0.52–0.92), with no deterioration of any HRQoL scores. In addition, there was a trend toward improved efficacy outcomes (OS, PFS, objective response rate) with APA. Overall, the risk/benefit balance of APA in aPDAC appears to be favorable.

APA has already been found to be beneficial for HRQoL in other cancers, particularly breast cancer.2123 However, the data are limited in patients with PDAC. In the only other available randomized trial, Steindorf et al24 assessed the efficacy of a 6-month resistance training program on physical function (using the EORTC QLQ-C30) in a single center in Germany. Of the 304 patients who were approached, 239 declined to participate, mainly due to a long driving distance to the hospital or because they were overwhelmed by the diagnosis. A total of 65 patients were assigned to home-based training, supervised training, or standard care control groups. The study mainly enrolled patients with stage I–II PDAC, and there was only 1 patient with metastatic disease. The global tests did not indicate an overall between-group difference for physical function or secondary outcomes at 6 months. In addition, there was a continuous decline in the adherence rate during the intervention period, which was lower in the supervised hospital-based group than in the home-based group.

The original design of the APACaP (Adapted Physical Activity in Advanced Pancreatic Cancer Patients) trial considered the specificities of PDAC.16 In particular, although APA group sessions have been found to be suitable to maintain motivation and adherence, such as in breast cancer in the adjuvant setting,25 we anticipated that this could be psychologically detrimental in the aPDAC setting due to the risk of clinical deterioration of participants. In addition, hospital-based group sessions could impair the feasibility of the trial through logistic constraints (eg, need for additional travel to hospital, coordination of patients and APA professional schedules, room availability). Thus, we proposed a home-based, remotely supervised APA intervention and introduced the notion of an “APA partner,” chosen by the patient, to attend the exercise sessions and keep the patient motivated. Moreover, although certain experimental APA programs might be difficult to implement outside the hospital because they require complex measurements (eg, maximum oxygen consumption [Vo2 max]) or specific material for exercises, we designed an easy-to-implement intervention requiring only basic sports gear (elastics).

Because this was an initial study, we decided not to select a specific category of patients based on their initial physical condition but to stratify randomization according to GPAQ. Indeed, we hypothesized that whatever the patient’s initial level, chemotherapy could reduce their level of physical activity, and thus APA could play a role in either increasing (low/moderately active) or maintaining (very active patients) a sufficient level of physical activity. Patients were well distributed among the GPAQ categories, and a greater benefit of APA was observed in more active patients. Because the intensity of the APA program was tailored to the patient’s initial physical condition, this could suggest that exercise has a potential dose effect. Nevertheless, the GPAQ remains an imperfect tool because it is declarative.

Our trial raises statistical questions for future studies. Methodologically, our results highlight the need to consider a larger standard deviation for means in transversal analysis and to favor, when possible, a longitudinal approach (eg, TUDD) as a primary endpoint rather than single time point. Therefore, more systematic HRQoL reporting, including TUDD analysis, should be encouraged in randomized controlled trials whenever possible. One trial investigated TUDD in patients with metastatic PDAC receiving either FOLFIRINOX or gemcitabine.26 In that study, HRQoL differed with these treatments and was better with FOLFIRINOX. It should be noted that in our study, randomization was stratified by chemotherapy regimen, and the distribution of patients receiving FOLFIRINOX between arms was balanced. Moreover, similar results were found for several HRQoL dimensions in the overall, mITT1, and mITT2 populations showing a benefit with APA in our study with the use of both the MMRM and TUDD approaches, further confirming the robustness of our results.

Conclusions

This large, randomized trial confirms the feasibility and favorable risk/benefit balance of APA in patients with aPDAC receiving first-line chemotherapy. The home-based, remotely supervised APA program did not require any complex material or measurements and resulted in clinically relevant improvement in several HRQoL dimensions, with no adverse events or deterioration in any HRQoL scores. APA should be considered in routine practice in patients with aPDAC who have no contraindication to exercise. Our results support the rationale of providing physical activity during cancer treatment.10,11

Acknowledgments

The authors thank the patients and physical activity partners who participated in this study and their families, the investigators and their site staff, the GERCOR team, Mooven adapted physical activity services, and the ARCAD foundation. Editorial support was provided by Magdalena Benetkiewicz, ScD. This article is dedicated to the memory of Prof. Franck Bonnetain.

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    Neuzillet C, Anota A, Foucaut AM, et al. Nutrition and physical activity: French intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC, SFP-APA, SFNCM, AFSOS). BMJ Support Palliat Care 2021;11:381395.

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    Ligibel JA, Bohlke K, May AM, et al. Exercise, diet, and weight management during cancer treatment: ASCO guideline. J Clin Oncol 2022;40:24912507.

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    Muscaritoli M, Arends J, Bachmann P, et al. ESPEN practical guideline: clinical nutrition in cancer. Clin Nutr 2021;40:28982913.

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    Solheim TS, Laird BJA, Balstad TR, et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J Cachexia Sarcopenia Muscle 2017;8:778788.

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    Naito T, Mitsunaga S, Miura S, et al. Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-small-cell lung cancer. J Cachexia Sarcopenia Muscle 2019;10:7383.

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    Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO clinical practice guidelines. ESMO Open 2021;6:100092.

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    Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol 2020;38:24382453.

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    Neuzillet C, Vergnault M, Bonnetain F, et al. Rationale and design of the Adapted Physical Activity in Advanced Pancreatic Cancer Patients (APACaP) GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) trial: study protocol for a randomized controlled trial. Trials 2015;16:454.

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    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.

    • PubMed
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    Bonnetain F, Bonsing B, Conroy T, et al. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (definition for the assessment of time-to-event end-points in cancer trials). Eur J Cancer 2014;50:29832993.

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  • 19.

    Anota A, Hamidou Z, Paget-Bailly S, et al. Time to health-related quality of life score deterioration as a modality of longitudinal analysis for health-related quality of life studies in oncology: do we need RECIST for quality of life to achieve standardization? Qual Life Res 2015;24:518.

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    Coens C, Pe M, Dueck AC, et al. International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium. Lancet Oncol 2020;21:e8396.

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    Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol 2007;25:43964404.

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    van Waart H, Stuiver MM, van Harten WH, et al. Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial. J Clin Oncol 2015;33:19181927.

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    Dieli-Conwright CM, Courneya KS, Demark-Wahnefried W, et al. Effects of aerobic and resistance exercise on metabolic syndrome, sarcopenic obesity, and circulating biomarkers in overweight or obese survivors of breast cancer: a randomized controlled trial. J Clin Oncol 2018;36:875883.

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    Steindorf K, Clauss D, Tjaden C, et al. Quality of life, fatigue, and sleep problems in pancreatic cancer patients—a randomized trial on the effects of exercise. Dtsch Arztebl Int 2019;116:471478.

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    Husebø AM, Karlsen B, Allan H, et al. Factors perceived to influence exercise adherence in women with breast cancer participating in an exercise programme during adjuvant chemotherapy: a focus group study. J Clin Nurs 2015;24:500510.

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  • 26.

    Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013;31:2329.

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Submitted May 24, 2023; final revision received July 22, 2023; accepted for publication July 27, 2023.

Author contributions: Concept and design: Neuzillet, Hammel, Anota. Data acquisition, analysis, or interpretation: All authors. Statistical analysis: Anota, Henriques. Administrative, technical, or material support: Neuzillet, Bouché, Tournigand, Chibaudel, Bauguion, Bengrine-Lefevre, Lopez-Trabada Ataz, Mabro, Metges, Péré-Vergé, Conroy, Lièvre, Andre, Desseigne, Goldwasser, Hammel. Supervision: Neuzillet, Hammel. Writing—original draft: Neuzillet, Hammel, Anota, Henriques. Writing—review & editing: All authors.

Disclosures: Dr. Neuzillet has disclosed receiving honoraria from and serving as a consultant for Amgen, AstraZeneca, Baxter, Bristol Myers Squibb, Fresenius Kabi, Incyte, Merck & Co., MSD, Mundipharma, Novartis, Nutricia, Pierre Fabre, Roche, Sanofi, Servier, and Viatris; and receiving grant/research support from AstraZeneca, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, and Viatris. Dr. Bouché has disclosed serving on the speaker’s bureau or as a consultant for Merck KGaA, Apmonia Therapeutics, Bayer, Grünenthal, MSD, Amgen, Servier, and Pierre Fabre. Dr. Chibaudel has disclosed serving on the speaker’s bureau or as a consultant for Amgen, Bayer, BeiGene, Biocartis, Bristol Myers Squibb, Eli Lilly & Co., Merck & Co., MSD, Pfizer, Pierre Fabre, Roche, Sanofi, SeqOne, Servier, and Takeda. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by GERCOR (C. Neuzillet) and ARCAD Foundation (C. Neuzillet).

Correspondence: Cindy Neuzillet, MD, Department of Medical Oncology, Institut Curie – Site Saint Cloud, 35 Rue Dailly, 92210 Saint Cloud, France. Email: cindy.neuzillet@curie.fr

View associated content

Supplementary Materials

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  • Figure 1.

    Study flow diagram.

    Abbreviations: APA, adapted physical activity; HRQoL, health-related quality of life; mITT1, modified intention-to-treat population 1; mITT2, modified intention-to-treat population 2; W16, week 16.

  • Figure 2.

    Analysis of changes from baseline to week 16 in EORTC QLQ-C30 scale scores between study arms (APA vs standard). (A) Mean differences of changes in the mITT1 population. (B) Mean differences of changes with an MMRM analysis in the mITT2 population. (C) HRs of changes with TUDD analysis in the mITT2 population. Results of baseline to week 16 analysis and MMRM analysis have been reversed, respectively, for symptomatic scales and for functional scales on the graph, so a negative change was in favor of the APA arm for all scales.

    Abbreviations: APA, adapted physical activity; EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30; HR, hazard ratio; mITT1, modified intention-to-treat population 1; mITT2, modified intention-to-treat population 2; MMRM, mixed model for repeated measures; TUDD, time until definitive deterioration.

  • Figure 3.

    Kaplan-Meier curves of (A) OS and (B) PFS in the mITT2 population according to study arm.

    Abbreviations: APA, adapted physical activity; mITT2, modified intention-to-treat population 2; OS, overall survival; PFS, progression-free survival.

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    • Export Citation
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    Ligibel JA, Bohlke K, May AM, et al. Exercise, diet, and weight management during cancer treatment: ASCO guideline. J Clin Oncol 2022;40:24912507.

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    Muscaritoli M, Arends J, Bachmann P, et al. ESPEN practical guideline: clinical nutrition in cancer. Clin Nutr 2021;40:28982913.

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    Solheim TS, Laird BJA, Balstad TR, et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J Cachexia Sarcopenia Muscle 2017;8:778788.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Naito T, Mitsunaga S, Miura S, et al. Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-small-cell lung cancer. J Cachexia Sarcopenia Muscle 2019;10:7383.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO clinical practice guidelines. ESMO Open 2021;6:100092.

  • 15.

    Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol 2020;38:24382453.

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    Neuzillet C, Vergnault M, Bonnetain F, et al. Rationale and design of the Adapted Physical Activity in Advanced Pancreatic Cancer Patients (APACaP) GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) trial: study protocol for a randomized controlled trial. Trials 2015;16:454.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Bonnetain F, Bonsing B, Conroy T, et al. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (definition for the assessment of time-to-event end-points in cancer trials). Eur J Cancer 2014;50:29832993.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Anota A, Hamidou Z, Paget-Bailly S, et al. Time to health-related quality of life score deterioration as a modality of longitudinal analysis for health-related quality of life studies in oncology: do we need RECIST for quality of life to achieve standardization? Qual Life Res 2015;24:518.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Coens C, Pe M, Dueck AC, et al. International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium. Lancet Oncol 2020;21:e8396.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol 2007;25:43964404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    van Waart H, Stuiver MM, van Harten WH, et al. Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial. J Clin Oncol 2015;33:19181927.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Dieli-Conwright CM, Courneya KS, Demark-Wahnefried W, et al. Effects of aerobic and resistance exercise on metabolic syndrome, sarcopenic obesity, and circulating biomarkers in overweight or obese survivors of breast cancer: a randomized controlled trial. J Clin Oncol 2018;36:875883.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Steindorf K, Clauss D, Tjaden C, et al. Quality of life, fatigue, and sleep problems in pancreatic cancer patients—a randomized trial on the effects of exercise. Dtsch Arztebl Int 2019;116:471478.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Husebø AM, Karlsen B, Allan H, et al. Factors perceived to influence exercise adherence in women with breast cancer participating in an exercise programme during adjuvant chemotherapy: a focus group study. J Clin Nurs 2015;24:500510.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013;31:2329.

    • PubMed
    • Search Google Scholar
    • Export Citation

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