Precision Exercise Effect on Fatigue and Function in Lung Cancer Surgery

This randomized clinical trial investigates if a perioperative exercise program with remote monitoring can improve physical function and fatigue in patients with lung cancer who are undergoing surgery.

Key Points

Question

Can a personalized, clinic-aligned, perioperative exercise program with remote monitoring improve physical function and fatigue in patients with lung cancer undergoing surgery?

Findings

In this randomized clinical trial, 182 patients were assigned to either a tailored exercise intervention or standard care. The exercise group showed improved physical function and stable fatigue scores, whereas the standard-care group showed decreased physical function and worsened fatigue; statistically significant improvements were noted overall for fatigue and for physical function in women.

Meaning

Results suggest that a personalized exercise program can enhance physical function and reduce fatigue in patients with lung cancer undergoing surgery, particularly benefiting women.

Abstract

Importance

Exercise intervention studies have shown benefits for patients with lung cancer undergoing surgery, yet most interventions to date have been resource intensive and have followed a one-size-fits-all approach.

Objective

To determine whether a personalized, clinic-aligned perioperative exercise program with remote monitoring and instructions can improve physical function and fatigue among patients undergoing surgery for lung cancer.

Design, Setting, and Participants

The Precision-Exercise-Prescription (PEP) randomized clinical trial is a single-center phase 3 trial. Adult patients with primary lung cancer (stages I-IIIa) or oligometastatic disease to the lung (where all disease could be removed) were assessed for eligibility and randomized to either an exercise intervention or standard care. Patients were enrolled between November 2017 and 2021, and the trial continued during the COVID-19 pandemic. Data were analyzed from November 2022 to December 2023.

Interventions

The structured exercise program, personalized based on mobility scores, was a home-based exercise intervention prescribed and monitored remotely by a licensed physical therapist. The program started approximately 2 weeks before surgery and continued after surgery. Standard care included use of incentive spirometer and encouragement to exercise without a formal program.

Main Outcomes and Measures

Physical function (6-minute walk test [6MWT]), the Short Physical Performance Battery, and cancer-related fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue) were assessed at baseline and 2 months after surgery.

Results

A total of 182 patients (92 receiving exercise intervention, 90 receiving standard care) were assessed in the intention-to-treat population. Patients had a mean (SD) age of 62.7 (13.8) years, 108 (59%) were female, and 89 (49%) had low mobility scores (Activity Measure for Post-Acute Care scores, 1-3). Physical function in the exercise group increased at 2 months after surgery (mean [SE] 6MWT at baseline, 467.9 [13.0] m; at 2 months, 482.2 [14.1] m), compared with a decrease in the standard-care group (mean [SE] 6MWT at baseline, 481.4 [11.1] m; at 2 months, 471.5 [14.0] m). Mean (SE) between-group changes in 6MWT distance for intent to treat from baseline to 2 months were 22.7 (12.7) m (P = .08), with greater effect sizes among women (mean [SE], 37.8 [17.3] m; P = .03). Similarly, women showed greater improvements in the Short Physical Performance Battery (mean [SE], 0.9 [0.4]; P = .04). Patients in the exercise group maintained stable fatigue scores at 2 months, whereas participants in the standard-care group deteriorated (mean [SD], 3.7 [1.4]; P = .009), with greater effect sizes among individuals who were younger, from rural areas, had overweight or obesity, and had primary lung cancer.

Conclusions and Relevance

The PEP intervention, a personalized, clinic-aligned, and remotely monitored perioperative exercise program for patients with lung cancer undergoing surgery demonstrated improvements in physical function for women and significant improvements in fatigue scores across all groups.

Trial Registration

ClinicalTrials.gov Identifier: NCT03306992

Introduction

Lung cancer is a significant burden worldwide and the most common cause of death in patients with cancer.¹ Lung resection offers a potential cure among patients with early-stage primary lung cancer and is an effective strategy for oligometastatic disease where all disease can be removed. However, surgical intervention in these patients often can have a major detrimental effect on the health and well-being of patients.^2,3,4

Fatigue is recognized as the most common disease- and cancer treatment–related adverse effect,⁵ is reported by nearly 80% of lung cancer survivors, and has significant impacts on treatment completion, recovery, and quality of life.⁶ In surgical candidates, fatigue can persist for several months after surgery,^3,4 with prevalence up to 75% at 4 months.⁵ Further, physical function predicts lung cancer postsurgical outcomes including quality of life and survival.

Exercise training positively affects patients’ physical functioning, quality of life, physical capacity, and fatigue, irrespective of tumor type.^{7,8,9,10,11,12,13,14,15,16} The American Society for Clinical Oncology recently published guidelines on exercise interventions in patients with cancer undergoing active treatment and recommended perioperative exercise for patients undergoing surgery for lung cancer; yet, the evidence base remains low to moderate.¹⁷

Translation of exercise interventions to the clinic has not been achieved in large part because the interventions tested to date are not aligned with existing clinic workflow and used a one-size-fits-all approach.¹⁸ Continuous adaptation of the exercise prescription is critical in populations with cancer to account for changes in performance status.¹⁸

The purpose of the phase 3 Precision-Exercise-Prescription (PEP) trial¹⁹ was to test the effects of a personalized clinic-aligned perioperative home-based exercise intervention with remote monitoring on physical function and fatigue after 2 months in patients with lung cancer undergoing surgery.

Methods

Trial Design

The PEP study has been approved by the institutional review board of the University of Utah (IRB 00104671). All patients provided written informed consent. An independent data safety monitoring board ensured scientific standards, safety, and integrity in the conduct of the clinical trial. The PEP study design has previously been described (Supplement 1).¹⁹ The trial compared the effectiveness of a personalized exercise intervention based on Activity Measure for Post-Acute Care (AM-PAC) stages outpatient basic-mobility short form with standard care for patients undergoing surgery for primary lung cancer (stages I, II, or IIIa) or patients with oligometastatic disease to the lung, where all disease could be removed (R0 resection). Our team also successfully conducted an intervention-only phase 1/2 pilot study of 40 patients to demonstrate the feasibility of study implementation and protocol in this population. For the clinical trial, surgeons encouraged all patients to exercise as per their usual discussions and stated that an exercise clinical trial was open for enrollment. Once patients showed interest, a different member of the study team described the clinical trial in a standardized manner (pamphlet and informed consent). Patients were recruited at Huntsman Cancer Institute (HCI), University of Utah, Salt Lake City, Utah, between November 2017 and November 2021. Inclusion and exclusion criteria are summarized in eTable 1 in Supplement 2. Eligible patients were randomized into an intervention arm (presurgery and postsurgery PEP interventions) and a control arm (standard care, offering delayed intervention on study completion). Randomization was a uniform 1:1 allocation ratio with block sizes of 8. The random allocation sequence was stratified by preintervention mobility (AM-PAC stage high, 4-5 vs low, 1-3) score and primary/secondary lung cancer diagnosis. Patients self-identified with the following races and ethnicities: American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, not Hispanic or Latino, Native Hawaiian or Other Pacific Islander, White, and not reported. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

Baseline assessments included AM-PAC, the 6-minute walk test (6MWT), the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), and the Short Physical Performance Battery (SPPB). The PEP clinical trial was a pragmatic clinical trial designed to assess the impact of intervention delivered in usual real-world conditions.^19,20 Patients were enrolled at the 2-week preoperative visit, and then followed up at 2 weeks after discharge, 2 months, and 6 months after surgery, to reflect the typical perioperative clinic schedule at HCI for patients undergoing lung resection. The intervention did not impact treatment guidelines for any patients. The primary outcome (and focus of the present assessment) was the difference in 6MWT distance between baseline (presurgery) and 2 months postsurgery.

Exercise Intervention Group

Patients in both groups were issued incentive spirometers at the presurgery clinic visit. The PEP intervention involved home-based exercise,¹⁹ prescribed during clinic visit assessments, and was monitored remotely by a licensed physical therapist (C.A.B.). Methods for exercise prescription have been previously described.²¹ Briefly, exercise mode and dosage were standardized and modified with respect to each patient’s AM-PAC mobility stage (eTable 2 and eFigures 1 and 2 in Supplement 2). Exercise modes included basic transfer and mobility, calisthenics, aerobics, and resistance, performed in various postures (supine, sitting, standing, and walking), and with variable levels of mobility (level walking, bending, inclines, steps, and squatting). Physical therapist evaluations (15-30 minutes) were performed at standard surgical clinic visits (clinically integrated physical therapist): presurgery consult, discharge visit (typically 2 weeks after discharge from the hospital), and 2-month postsurgery follow-up with the surgeon. Exercise mode and dosage were further modified by the study physical therapist in response to physical impairments such as fatigue, muscle weakness, pain, and shortness of breath, to encourage exercise adherence, or to address barriers.

An exercise education manual was used to educate patients on all aspects of starting and maintaining the exercise intervention. The exercise group was given access to resistance bands as needed, a tracking exercise diary/calendar, and an activity tracker (Fitbit Flex II [Google Fitbit]) to support behavior change²² for the home-based exercise program (explained subsequently) at no cost. The physical therapist reviewed (verbally and in writing) individual exercise modes and dosages to be performed at home. For all exercises, bouts were defined by duration ranging from 5 to 30 minutes and intensity ranged from moderate to high intensity. Exercise intensity was determined by perceived exertion,²³ with moderate-high intensity defined as activity that allows the participant to talk but not sing while exercising (eTable 2 and eFigure 1 in Supplement 2).

Throughout the PEP study intervention (before surgery through 2 months after surgery, the primary end point), participant well-being, perceived exertion, pain, fatigue and other responses to exercise were recorded in logs collected during weekly Motivation and Problem-Solving (MAPS) phone calls from clinic/study staff.²⁴ MAPS is an empirically validated, dynamic approach to facilitating behavior change that uses a combined motivational enhancement and problem-solving approach based on motivational interviewing and social cognitive theory.²⁴ MAPS phone calls used semi-structured scripts inquiring about patient well-being, adverse events, requested adjustments to exercise prescription, patient goals and progress, goal setting, barriers and facilitators to patient goals, and problem-solving. Issues with exercise identified during MAPS calls were referred to the study physical therapist for follow-up.

Adherence to the Program

Adherence to the intervention was assessed using quantitative and qualitative information from the regular MAPS phone calls. The investigator team established a 3-tiered scoring system classifying participants into (1) nonadherent, (2) good adherence, and (3) fully adherent (further detail in eTable 3 in Supplement 2). Four investigators (C.H., C.A.B., B.D., V.B.) independently scored a random sample of 15 participants for quality control, which typically involves 5% to 10%. A total of 87% agreement (13 of 15 participants) was achieved, and discrepancies were resolved. An independent investigator (V.B.) with no interaction with PEP study participants scored adherence to the intervention for each participant’s calls from baseline to 2 months. A 2-month adherence score was then computed for each participant using the median score across all scored MAPS calls. This scoring methodology allows for evaluation of alternative forms of physical activity not typically captured by other adherence assessments (eg, swimming, resistance training, occupational activity). This approach to measuring adherence has been further used to examine factors predicting adherence in the study sample.²⁵

Standard-Care Group

Patients randomized into the standard-care group received an incentive spirometer at the presurgery clinic visit and were encouraged to increase walking in the presurgery and postsurgery period without any formalized exercise program. At the end of the study, patients in this group were provided a PEP study intervention session with exercise prescription and received a free activity tracker for their participation.

Primary Outcome

The primary outcome was the difference in 6MWT distance between baseline (presurgery) and 2 months postsurgery. The 6MWT is the most pragmatic, nonlaboratory test to measure physical functioning in individuals with lung cancer.²⁶ 6MWTs were performed in clinic 1A at the HCI at all time points, using consistent testing conditions. After March 2020, patients wore face masks during the test due to the COVID-19 pandemic and mandatory safety protocols (baseline without mask/2 months with mask: n = 13; baseline and 2 months with mask: n = 39).

Secondary Outcomes

Cancer-related fatigue was assessed using the FACIT-F,²⁷ which comprises 13 items measuring self-reported fatigue in people with cancer. It is widely used in clinical studies among people with lung cancer and was applied in our prior exercise intervention studies in this population.^28,29,30 The 5-point Likert-type scale responses were computed into a score from 0 to 52, with higher scores indicating lower fatigue-related symptoms. Physical function was also assessed using the SPPB (scores, 0-12),³¹ which assesses balance, gait speed and chair-rise capacity. This test has been widely used in both general and oncology populations to measure functional status and decline.^32,33,34

Statistical Analyses

Mean values and SDs for continuous variables, as well as frequencies and percentages for categorical variables to describe patient characteristics at baseline and follow-up (surgical outcomes) were computed. Intent-to-treat analyses were conducted (modified to account for final eligibility postsurgery). Missing data on primary and secondary end points were handled using multivariate imputation (100 imputed datasets) by chained equations as implemented in the R package mice (R Project for Statistical Computing).³⁵ Additional information can be found in eTable 4 in Supplement 2. Paired t tests were computed to assess statistical significance of changes in primary and secondary outcomes from baseline to 2 months. Between-group differences in mean changes and SEs for primary and secondary outcomes were evaluated using analysis of covariance (ANCOVA) adjusted for baseline 6MWT. Preplanned stratified analyses investigated differences by gender. Post hoc analyses included stratified models by age at baseline, rural-urban status, body mass index, cancer type, tumor stage, and mobility stage (low [AM-PAC, score 1-3] vs high [AM-PAC score, 4-5]). Supplementary analyses were conducted including only those patients who completed the end point (referred to as patients with completed primary end point). Analyses were performed with R Studio, version 4.2.2 (R Project for Statistical Computing). All P values were 2-sided, and P value <.05 was considered statistically significant.

Power calculations were done for an ANCOVA model with 6MWT at 2 months postsurgery as outcome, treatment group as predictor, and baseline 6MWT as covariate. We hypothesized that the difference in 6MWT distance between the study arms would be greater than 39.95 m. This effect size stems from a meta-analysis, where 4 weeks of pos-surgery exercise training provided a 39.95-m increase in the 6MWT distance in patients with non–small cell lung cancer.³⁶ For our primary end point, with at least 150 evaluable patients (accounting for a 25% dropout rate after randomizing 200 patients) the estimated power was greater than or equal to 80% at 2-sided type I error equal to .05. Data were analyzed from November 2022 to December 2023.

Results

A total of 231 patients were screened for the study, and 200 enrolled, resulting in a recruitment rate of 87% (Figure 1). However, 18 patients (9 in the exercise group; 9 in the standard-care group) were ineligible after informed consent done at initial clinic visit (eg, advanced stage, no surgery, benign pathology), leading to 182 eligible patients (92 exercise intervention; 90 standard care) for the intent-to-treat analyses. Nine patients were classified as dropouts, and 1 died before the primary end point assessment at 2 months after surgery. Main reasons for dropouts included patients being too overwhelmed, lost to follow-up, withdrew, or discontinued care at HCI. A total of 173 patients (86 exercise intervention; 87 standard care) completed visits at baseline and 2 months follow-up, and 165 completed the primary outcome assessment for per-protocol analyses.

Figure 1. Consolidated Standards of Reporting Trials Diagram of the Precision-Exercise-Prescription Trial.

Intent-to-treat analysis included all eligible participants after informed consent (n = 92 exercise, n = 90 standard care, N = 182 total). Per-protocol analysis included those who completed the primary end point (n = 81 exercise, n = 84 standard care, N = 165 total). HCl indicates Huntsman Cancer Institute; 6MWT, 6-minute walk test.

Participants had a mean (SD) age of 62.7 (13.8) years, 108 (59%) were female, 74 (41%) were male, 25 (14%) were rural residents, 143 (79%) had primary lung cancer, and 89 (49%) had low mobility scores (AM-PAC scores, 1-3) (Table 1). Patients self-identified with the following races and ethnicities: 10 Hispanic or Latino (5%), 169 not Hispanic or Latino (93%), 169 White (93%), 3 not reported ethnicity (2%), and 7 not reported race (4%). A total of 166 patients (91%) had good to excellent adherence to the intervention from baseline to 2 months postsurgery. No differences in baseline characteristics were observed across the intervention vs standard-care groups. No severe adverse events (≥grade 3) were reported in association with the intervention. Grade 1 to 2 adverse events related to the intervention are described in eTable 5 in Supplement 2. Surgical outcomes (length of stay, readmission, infections, and other surgical complications) in both groups are described in eTable 6 in Supplement 2. There were no significant differences in surgical outcomes. The following results were derived from intent-to-treat analyses using multiple imputation.

Table 1. Baseline Participant Characteristics.

Characteristic	No. (%)
	All (N = 182)	Exercise (n = 92)	Standard care (n = 90)
Demographics
Age, mean (SD), y	62.7 (13.8)	62.7 (14.7)	62.7 (13.0)
Sex
Female	108 (59)	51 (55)	57 (63)
Male	74 (41)	41 (45)	33 (37)
Race
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Black or African American	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Hispanic or Latino	10 (5)	4 (4)	6 (7)
Not Hispanic or Latino	169 (93)	86 (93)	83 (93)
White	169 (93)	86 (93)	83 (93)
Not reported ethnicity	0	0	0
Not reported race	7 (4)	2 (2)	1 (1)
Ethnicity
Non-Hispanic	169 (93)	86 (93)	83 (92)
Hispanic	10 (5)	4 (4)	6 (7)
Not reported	3 (2)	2 (2)	1 (1)
Rural-urban statusa
Urban	157 (86)	82 (89)	75 (83)
Rural	25 (14)	10 (11)	15 (17)
Health behaviors
BMIb
Mean (SD)	28.9 (5.7)	28.7 (5.7)	29.1 (5.7)
Underweight	2 (1)	1 (1)	1 (1)
Normal weight	44 (24)	22 (24)	22 (24)
Overweight	67 (37)	35 (38)	32 (36)
Obese	69 (38)	34 (37)	35 (39)
Self-reported smoking status at baseline
Current smoker	32 (18)	16 (17)	16 (18)
No	150 (82)	76 (83)	74 (82)
Clinicopathologic characteristics
Cancer type
Primary lung cancer	143 (79)	70 (76)	73 (81)
Secondary lung cancer	39 (21)	22 (24)	17 (19)
Tumor stage
I	95 (52)	50 (54)	45 (50)
II	32 (18)	15 (16)	17 (19)
III	16 (9)	5 (6)	11 (12)
IV (secondary lung cancer)	39 (22)	22 (24)	17 (19)
Treatment in addition to surgery
Adjuvant treatment (yes)	53 (29)	28 (30)	25 (28)
Mobility assessments
AM-PAC score
Low mobility (1-3)	94 (52)	47 (51)	47 (52)
High mobility (4-5)	88 (48)	45 (49)	43 (48)

Abbreviations: AM-PAC, Activity Measure for Post-Acute Care; BMI, body mass index.

^a Rural-urban status based on rural-urban commuting area (RUCA) codes (urban = codes 1-6; rural = code 7-10).

^b BMI is calculated as weight in kilograms divided by height in meters squared. Underweight is defined as <18.5; normal weight as ≥18.5 -<25; overweight as ≥25 -<30; and obese as ≥30.

Changes in 6MWT Distance

At baseline, the mean (SE) 6MWT distance was 467.9 (13.0) m among the exercise group and 481.4 (11.1) m among the standard-care group (P = .43) (Table 2). The mean (SE) 6MWT distance increased among patients in the exercise group (baseline, 467.9 [13.0] m; 2 months, 482.2 [14.1] m), whereas a slight decrease was observed among patients in the standard-care group (baseline, 481.4 [11.1] m; 2 months, 471.5 [14.0] m). The mean (SE) between-group difference in 6MWT distance from baseline to 2 months was 22.7 (12.7) m (P = .08) (Figure 2). Analyses of patients with completed primary end point showed similar results (mean [SE], 23.7 [12.4] m; P = .06). Preplanned stratified analyses showed statistically significant between-group changes in 6MWT distance from baseline to 2-month among women (mean [SE], 37.8 [17.3] m; P = .03) (Table 3). Somewhat greater effect sizes of the intervention on 6MWT distance were observed among older (≥60 years) and urban vs rural patients. Analyses stratified by tumor stage and primary vs secondary cancer showed no significant difference of the exercise intervention effect by subgroups (Table 3).

Table 2. Comparison of 6-Minute Walk Test (6MWT) Distance, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Fatigue Scores, and Short Physical Performance Battery (SPPB) Scores Between Intervention Groups at Baseline and 2-Month Follow-Up Based on Imputed Data^a.

Test type	Baseline		2-mo			Baseline vs 2-mo between-group difference
	No.	Mean (SE)	No.	Mean (SE)	P valueb	Mean (SE)	P valuec
Intent to treat
6MWT, m
Exercise	92	467.9 (13.0)	92	482.2 (14.1)	.43	22.7 (12.7)	.08
Standard care	90	481.4 (11.1)	90	471.5 (14.0)	.28
FACIT-F fatigue score
Exercise	92	36.2 (1.1)	92	38.4 (1.1)	.05	−3.7 (1.4)	.009
Standard care	90	38.3 (1.1)	90	35.9 (1.2)	.03
SPPB score
Exercise	92	11.1 (0.2)	92	10.8 (0.3)	.32	0.1 (0.4)	.75
Standard care	90	10.8 (0.2)	90	10.6 (0.3)	.26
Patients with completed primary end point
6MWT, m
Exercise	81	474.4 (13.3)	81	490.5 (14.2)	.07	23.7 (12.4)	.06
Standard care	84	484.5 (11.5)	84	475.9 (14.1)	.34
FACIT-F fatigue score
Exercise	61	36.9 (1.3)	61	38.9 (1.1)	.08	4.1 (1.4)	.004
Standard care	63	38.7 (1.2)	63	35.9 (1.4)	.01
SPPB score
Exercise	80	11.1 (0.1)		10.8 (0.3)	.21	0.1 (0.4)	.87
Standard care	83	10.8 (0.2)		10.6 (0.3)	.33

^a Lower fatigue scores correspond to worse fatigue symptoms.

^b P value for paired t test comparing changes in the intervention groups from baseline to 2 months after surgery.

^c P values for analysis of covariance analysis comparing changes between the exercise intervention and standard-care group from baseline to 2 months after surgery.

Figure 2. Effects of the Precision-Exercise-Intervention Trial on 6-Minute Walk Distances (6MWT), Short Physical Performance Battery (SPPB) Scores, and Fatigue Scores (Figures G-I) Across Exercise and Standard-Care Groups Overall and Stratified by Gender.

Fatigue scores are shown as 100 − score on Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) testing. A-C, 6MWT results overall, female, and male, respectively. D-F, SPPB scores overall, female, and male, respectively. G-I, Fatigue scores on FACIT-F overall, female, and male, respectively.

Table 3. Changes in 6-Minute Walk Test (6MWT) Distance and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Scores at 2 Months After Surgery in Participants in the Exercise Intervention Group Stratified by Demographics, Health Behaviors, and Clinicopathological Characteristics.

Variable	Mean (SE)								P value, exercisers vs controlsa
	Total No.	Baseline		2 mo		Baseline vs 2 mo
		Exercise	Standard care	Exercise	Standard care	Exercise	Standard care	Between-group difference
6MWT
Demographics
Age at baseline, y
<50	30	514 (39.0)	530 (28.4)	540 (27.2)	536 (24.5)	26.1 (27.8)	6.7 (12.8)	13.0 (23.6)	.58
50-59	27	511 (20.2)	527 (31.3)	540 (23.7)	534 (29.4)	29.5 (19.1)	7.1 (20.7)	18.1 (27.1)	.51
≥60	125	448 (15.0)	459 (12.3)	457 (17.8)	441 (17.5)	8.4 (10.3)	−17.9 (12.4)	26.2 (16.0)	.10
Sex
Female	108	448 (18.7)	465 (13.7)	469 (19.0)	446 (18.4)	20.9 (12.5)	−18.8 (12.4)	37.8 (17.3)	.03
Male	74	492 (16.9)	510 (18.3)	501 (20.1)	514 (19.6)	8.6 (12.4)	4.5 (13.3)	2.04 (18.1)	.91
Rural-urban statusb
Urban	157	478 (12.3)	489 (12.3)	494 (13.9)	475 (16.1)	15.2 (8.7)	−13.6 (10.5)	28.0 (13.4)	.04
Rural	25	381 (53.3)	444 (24.6)	388 (56.6)	452 (24.1)	6.1 (43.2)	8.2 (17.2)	18.7 (40.4)	.65
Health behavior
BMIc
Normal weight	44	505 (25.6)	519 (18.7)	525 (29.8)	507 (26.1)	20.1 (17.6)	−11.5 (19.9)	30.6 (26.3)	.25
Overweight	67	495 (17.6)	492 (18.1)	505 (20.4)	472 (25.7)	9.7 (14.1)	−19.3 (15.6)	29.0 (21.2)	.18
Obese	69	415 (22.2)	448 (18.7)	430 (22.5)	447 (20.9)	15.0 (15.6)	−0.34 (14.1)	8.8 (20.4)	.67
Clinicopathologic characteristics
Cancer type
Primary lung cancer	143	457 (14.6)	476 (12.0)	463 (16.5)	456 (15.6)	5.6 (10.0)	−19.7 (10.5)	24.0 (14.4)	.10
Secondary lung cancer	39	502 (27.1)	505 (29.1)	544 (23.0)	537 (27.3)	41.7 (18.8)	31.9 (15.7)	8.9 (22.7)	.70
Tumor stage
I	89	445 (17.1)	479 (13.6)	466 (19.7)	472 (19.1)	20.8 (11.5)	−7.0 (11.4)	27.9 (16.2)	.09
II	29	466 (29.7)	439 (26.7)	441 (37.9)	422 (34.7)	−24.8 (19.6)	−17.2 (26.9)	6.7 (34.4)	.85
III	16	547 (62.9)	519 (36.3)	492 (47.0)	443 (41.5)	−54.4 (41.0)	−75.2 (26.7)	27.2 (47.5)	.58
Physical function assessments
AM-PAC score
Low mobility (1-3)	94	401 (18.1)	417 (13.3)	418 (20.7)	407 (18.7)	16.7 (15.1)	−10.3 (15.0)	24.2 (21.0)	.25
High mobility (4-5)	88	537 (11.6)	552 (10.5)	549 (13.1)	542 (14.9)	11.7 (9.2)	−9.5 (10.4)	19.9 (13.8)	.16
FACIT-F d
Demographics
Age at baseline, y
<50	30	32.4 (2.6)	38.0 (2.8)	39.7 (2.8)	35.9 (2.6)	7.3 (2.4)	−2.1 (2.3)	7.6 (3.0)	.02
50-59	27	35.7 (3.4)	35.9 (3.8)	39.1 (2.8)	39.0 (3.6)	3.4 (2.6)	3.1 (2.5)	0.2 (3.2)	.95
≥60	125	37.2 (1.4)	39.0 (1.2)	37.8 (1.3)	35.4 (1.5)	0.6 (1.3)	−3.6 (1.3)	3.5 (1.6)	.03
Sex
Female	108	35.4 (1.6)	38.5 (1.5)	38.2 (1.4)	36.4 (1.5)	2.8 (1.4)	−2.1 (1.5)	3.5 (1.8)	.05
Male	74	37.3 (1.6)	38.0 (1.7)	38.7 (1.6)	35.2 (2.0)	1.4 (1.8)	−2.8 (1.4)	4.0 (2.1)	.06
Rural-urban statusb
Urban	157	36.4 (1.2)	39.2 (1.2)	38.5 (1.2)	36.9 (1.3)	2.1 (1.2)	−2.3 (1.1)	3.3 (1.5)	.03
Rural	25	34.9 (3.9)	34.2 (2.6)	37.0 (3.4)	31.5 (2.8)	2.1 (2.7)	−2.7 (2.6)	5.1 (3.5)	.17
Health behavior
BMIc
Normal weight	44	38.0 (2.3)	41.9 (1.6)	37.5 (2.2)	38.5 (2.4)	−0.5 (1.8)	−3.3 (1.9)	2.0 (2.6)	.44
Overweight	67	37.1 (1.6)	40.0 (1.9)	40.5 (1.6)	37.7 (1.8)	3.5 (1.7)	−2.2 (1.6)	4.3 (2.1)	.04
Obese	69	34.1 (2.2)	34.7 (1.8)	36.7 (1.8)	32.8 (2.0)	2.6 (1.9)	−1.9 (1.8)	4.2 (2.2)	.07
Clinicopathologic characteristics
Cancer type
Primary lung cancer	143	36.7 (1.3)	38.6 (1.2)	38.3 (1.2)	35.5 (1.3)	1.6 (1.2)	−3.0 (1.2)	3.8 (1.5)	.01
Secondary lung cancer	39	34.6 (2.5)	37.7 (2.9)	38.6 (2.4)	38.1 (3.0)	4.0 (2.1)	0.4 (1.9)	2.7 (2.5)	.28
Tumor stage
I	89	36.9 (1.6)	38.7 (1.6)	38.6 (1.5)	35.9 (1.6)	1.6 (1.5)	−2.8 (1.6)	3.6 (1.9)	.06
II	29	35.7 (2.5)	39.0 (2.0)	39.0 (2.2)	37.1 (2.6)	3.3 (2.1)	−1.9 (2.3)	4.0 (3.0)	.20
III	16	37.0 (4.6	37.5 (3.5)	32.7 (3.6)	31.6 (3.6)	−4.2 (4.1)	−5.9 (2.9)	1.5 (4.6)	.75
Physical function assessments
AM-PAC score
Low mobility (1-3)	94	32.7 (1.6)	34.7 (1.6)	35.5 (1.5)	33.0 (1.7)	2.8 (1.5)	−1.7 (1.5)	3.6 (1.9)	.06
High mobility (4-5)	88	39.8 (1.4)	42.4 (1.3)	41.3 (1.5)	39.3 (1.6)	1.5 (1.5)	−3.1 (1.4)	3.5 (1.9)	.07

Abbreviations: AM-PAC, Activity Measure for Post-Acute Care; BMI, body mass index.

^a P values for analysis of covariance analysis comparing changes between the exercise intervention and standard-care group from baseline to 2 months after surgery.

^b Rural-urban status based on rural-urban commuting area (RUCA) codes (urban = codes 1-6; rural = code 7-10).

^c BMI is calculated as weight in kilograms divided by height in meters squared. Normal weight is defined as ≥18.5 -<25; overweight as ≥25 -<30; and obese as ≥30.

^d Lower fatigue scores correspond to worse fatigue symptoms.

Changes in Secondary Outcomes

The exercise group maintained fatigue levels from baseline to 2 months postsurgery (mean [SE] FACIT-F scores at baseline, 36.2 [1.1]; at 2 months, 38.4 [1.1]), whereas the standard-care group experienced a statistically and clinically meaningful decline in fatigue scores, corresponding to worse fatigue symptoms (mean [SE] FACIT-F scores at baseline, 38.3 [1.1]; at 2 months, 35.9 [1.2]; between-group comparisons, intent to treat, 3.7 [1.4]; P = .009; patients with completed primary end point, 4.1 [1.4]; P = .004) (Table 2 and Figure 2). Greater effect sizes of the intervention on fatigue were observed among younger (<50 years) individuals, those from rural regions, individuals with overweight/obesity, and those with primary cancer (Table 3).

Both the exercise and the standard-care groups experienced modest declines in SPPB from baseline to 2 months postsurgery, with no statistical difference between groups (mean [SE], 0.1 [0.4]; P = .75) Table 2. SPPB scores improved significantly among female intervention participants (mean [SE], 0.9 [0.4]; P = .04) and those with obesity (mean [SE], 1.1 [0.5]; P = .04) relative to standard of care (eTable 7 in Supplement 2).

Discussion

The PEP intervention for patients with lung cancer undergoing surgery—a clinic-aligned, tailored exercise intervention—led to statistically significant improvements in physical function for women and across all groups in cancer-related fatigue. This was the first study, to our knowledge, testing an exercise intervention tailored and adapted to a patient’s functional mobility (ie, with specific exercise-dosing according to functional status) that is aligned with clinic workflow and spans the perioperative time period (from presurgery to postsurgery recovery).

Surgical treatment for lung cancer has major detrimental effects on the health and well-being of the patients. Surgical patients experience decreased pulmonary function, functional decline, and reduced activity levels after surgery, as well as frequent persistent pain and increased fatigue.^3,4 Exercise intervention studies in small clinical trials have been shown to ameliorate these treatment-related effects.^{17,37,38,39,40,41,42,43} The majority of prior studies have been conducted during either the presurgery or postsurgery period. To date, only 1 study⁴³ combining a presurgery and postsurgery intervention has been completed showing benefits on cardiorespiratory function and reduced length of stay. That study was limited in its sample size (N = 20) and only included patients with chronic obstructive pulmonary disease.⁴³ The PEP intervention, spanning from 2 to 3 weeks before surgery to 2 months after surgery, aimed to improve both the presurgery and postsurgery rehabilitation process. Further, prior interventions followed a one-size-fits-all model introducing potential barriers or limiting the intervention to those fully able to participate in the exercise protocol. PEP is a tailored intervention based on a patient’s physical function, thus allowing patients in all states of presurgical and postsurgical recovery to participate. As a patient’s level of activity changed, prescribed exercises were modified by a physical therapist according to a standardized protocol.

The primary objective of improving 6MWT distance through the PEP intervention was not achieved; however, the between-group difference (22.7 m) is consistent with previously reported minimal clinically important differences for the 6MWT (14-30.5 m).⁴⁴ Among women, the exercise group experienced greater improvements in 6MWT at 2 months postsurgery as compared with the standard-care group (between group difference averaged 37.8 m). This positive intervention effect on physical function among women was consistent with the results of the SPPB assessment (eTable 7 in Supplement 2). In exercise intervention studies performed in patients with lung disease and broader populations with cancer, lower baseline physical function is typically associated with larger postintervention physical function improvements.^45,46 Another possible explanation is reduced sensitivity of functional tests (6MWT, SPPB) for patients with greater fitness levels, as has been previously reported.^47,48 Regardless, with clinically significant changes in 6MWT distance in low- (24.2 m) and high-mobility groups (19.9 m), this trial still meaningfully benefited both patient groups.

One of the study benefits became evident during the COVID-19 pandemic. As the exercise intervention was home-based with remote monitoring, the clinical trial was able to be continued without interruption. Like other remote intervention exercise studies launched during the pandemic,⁴⁹ there were similar trends of continued adherence in the face of pandemic-related stressors. However, patients recruited during the pandemic had to wear masks during performance of the 6MWT at the time of clinic visits in accordance with mandatory safety protocols. Additional effects include potential limitations on exercise ability with reduced access to exercise facilities and outdoor spaces for participants due to stay-at-home orders and other public health measures. Although the study team managed to maintain high compliance and completion rates, these pandemic effects may have impacted our results with respect to the primary outcome.

Our study was conducted at an NCI-designated cancer center, although we designed the intervention as amenable to implementation in lower-resource settings. This included a physical function assessment (AM-PAC) that can be conducted by nonexperts, along with remote delivery and clinic-based scheduling. The intervention was designed to be adapted and readily implemented by community-health workers following training, with or without the oversight of a physical therapist. Our center has well-established clinical pathways and enhanced recovery protocols in the immediate postoperative period and, thus, our results should be considered applicable to similar contexts of care.

The PEP intervention had a statistically and clinically significant impact on fatigue. Patients in the exercise group did not experience changes in fatigue levels from baseline to 2 months postsurgery, whereas the standard-care group declined 5 points on average, which has previously been shown to be clinically relevant.^50,51,52 Fatigue has major impacts on treatment completion, recovery, and quality of life² and can persist for several months after surgery.^5,6 Previous pretreatment- or posttreatment-only exercise interventions in patients with lung cancer have yielded similar results showing improved fatigue among those participating in the intervention.^8,53 Our results show that a tailored intervention spanning the care continuum from presurgery to postsurgery is safe and effective in reducing cancer-related fatigue.

Limitations

This study has some limitations. The potential effects of the COVID-19 pandemic on the primary outcome were mentioned previously. The 2-month attrition rate of the current study was 18%, which falls within the range of successful exercise oncology interventions (mean attrition levels of 12%⁴⁶ and 24%¹²). Our study tested the efficacy of a precision-exercise intervention administered through review of evidence-based MAPS calls. Responsive to a patient’s performance status, the intervention was adapted, rather than following a specific dose, which may not reflect a patient’s ability to exercise. Thus, adherence measures focused on the review of these calls did not include device-measured adherence. This method of assessing adherence captured all physical activity types relevant to the study population that are often missed (ie, occupational activity). Our sample predominantly involved patients who underwent minimally invasive surgery (79.2%) at a high-volume tertiary care center with experienced thoracic surgeons; therefore, our results may not be generalizable to settings with greater prevalence of open surgery.

Conclusions

Results of this randomized clinical trial reveal that in patients undergoing resection of lung cancer, a personalized and clinic-aligned exercise intervention demonstrated improvements in physical function for women and significant improvements in fatigue scores across all subgroups. The exercise intervention involved a clinic-integrated physical therapist model. Assessments were done during the surgical clinic visit and spanned the presurgery to postsurgery period with home-based exercise interventions and remote monitoring. The intervention was personalized, yet standardized, encouraging participants’ autonomy and motivation to adhere while maintaining the rigor of the exercise intervention. The remote design is translatable into different clinical settings and populations, including rural populations, who commonly encounter barriers to health care access. Recruitment rate and adherence to the intervention were high at 87% and 91%, respectively, demonstrating generalizability to the patient population seen at HCI, with good to excellent adherence. Our results support the implementation of tailored exercise interventions and integration of longitudinal physical function monitoring and exercise intervention into the standard of surgical oncologic care to improve fatigue across the cancer continuum. Given its pragmatic, clinic-aligned design, this intervention can be successfully applied to a variety of health care settings and cancer types.

Supplement 1.

Trial Protocol.

Supplement 2.

eTable 1. Exclusion and Inclusion Criteria

eTable 2. Example of AM-PAC Staging With Exercise Intervention Mode and Dosage

eTable 3. Description of Adherence 3-Tiered Scoring System Used to Assess PEP Adherence With Corresponding Qualitative Examples

eTable 4. Imputation Analysis Description

eTable 5. Adverse Events and Participant Counts by Intervention Groups (Grade 1-2) Until 2-Month Primary End Point

eTable 6. Surgical Outcomes by Intervention Group

eTable 7. Changes in Short Physical Performance Battery (SPPB) at 2 Months After Surgery in Exercise Intervention Participants Stratified By Demographics, Health Behaviors, and Clinicopathological Characteristics

eFigure 1. Exercise Mode and Dosage Modified by AM-PAC Mobility Stage

eFigure 2. AM-PAC Mobility Outpatient Short Form

Supplement 3.

Data Sharing Statement.