Background
Cancer-related fatigue (CRF) is the most common cancer-related symptom and is defined as a “distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”1 CRF is more frequent, persistent, and severe in patients with advanced cancer than in those with early cancer or in posttreatment survivors.2,3 In patients with advanced cancer, CRF negatively affects quality of life, interferes with daily activity, has potentially devastating social and economic consequences, and affects the patient’s ability to receive palliative cancer therapy.2,4–7 Although the population of patients with advanced cancer continues to increase, effective treatments for CRF in these patients remain elusive.3,8,9 Established therapies for CRF, such as physical activity (PA), have demonstrated only modest efficacy,10–14 and results from pharmaceutical agents for CRF have been mixed.13,15,16 Recent studies suggest that the most efficient strategies may involve combining existing treatments—both pharmacologic and nonpharmacologic—that have shown promise in order to target the multifactorial causes of CRF in patients with advanced cancer. Previous studies from our group16,17 and others,17–23 as well as recently updated ASCO,24 NCCN,25 and ESMO guidelines,13 suggest that corticosteroids can improve CRF and related symptoms in patients with advanced cancer. NCCN and ESMO advise short-term use of corticosteroids for CRF in patients with advanced cancer.13 Prior research by our team found that dexamethasone (Dex) was safe and efficacious in patients with advanced cancer26 but, like PA, it had only small to modest effects, largely due to the multifactorial nature of fatigue.13,14,26–28 In a recent pilot study, we found that the combination of PA with Dex was feasible, and appeared to be effective for the treatment of CRF.29 The improvement in CRF may be related to the synergistic effect due to the augmentation of the CRF-alleviating effects of PA by Dex. This may be through improvements in inflammation, fitness, and psychological distress,30–34 or may be due to the effects Dex has on different factors that contribute to CRF, such as cancer symptoms like anorexia, nausea, pain, and mood changes.35,36 Further studies are needed to characterize the mechanism through which this combination therapy improves CRF. Therefore, in this phase II study, we aimed to determine the feasibility (adherence, safety, and satisfaction) of PA+Dex and PA+PBO (placebo) for CRF, and to explore the effects of PA+Dex and PA+PBO on CRF as assessed by change in Functional Assessment of Chronic Illness Therapy–fatigue (FACIT-F) score; fatigue dimensions and quality of life at days 8 and 29 using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF); Patient-Reported Outcomes Measurement Information System-Fatigue Short Form 7a (PROMIS-Fatigue SF-7a); Edmonton Symptom Assessment Scale (ESAS) and its symptom distress scores; Hospital Anxiety and Depression Scale (HADS); Pittsburgh Sleep Quality Index (PSQI); Godin Leisure-Time Exercise Questionnaire (GLTEQ); and Functional Assessment of Cancer Therapy-General (FACT-G).
Patients and Methods
The MD Anderson Cancer Center (MDACC) Institutional Review Board approved the study protocol, and all participants signed an informed consent (see Appendix in the supplemental materials, available online with this article). The study was activated for patient accrual on June 29, 2018, and was closed to new patient accrual on January 4, 2023. We reported study findings using the EQUATOR Reporting guidelines.
Participants
Patients were enrolled from the outpatient oncology and supportive care clinics at MDACC. Eligibility criteria included (1) diagnosis of advanced cancer with average intensity of fatigue of ≥4 on the ESAS fatigue item (ESAS-Fatigue; scale, 0–10)37 in the previous 24 hours, (2) presence of fatigue for at least 2 weeks, (3) normal cognition as assessed by a Memorial Delirium Assessment Scale (MDAS) score of ≤13 (range, 0–30),38 (4) no evidence of significant anxiety or depression as determined by a HADS39 total score of <21, (5) hemoglobin level ≥8 g/L within 1 week of enrollment, (6) life expectancy of at least 4 months, (7) no severe cardiac disease (New York Heart Association functional class III or IV), (8) no regular participation in moderate- or vigorous-intensity physical activity for ≥30 minutes at least 5 times a week or in strength training for ≥2 days, (9) no history of falls in the past 30 days, (10) no infections and absolute neutrophil count ≥1,000 cells/mm3 within 1 week of enrollment in the study, and/or (11) no uncontrolled diabetes mellitus or surgery within 2 weeks prior to study enrollment.
Interventions
A total of 92 eligible patients were randomized equally between the 2 treatment arms. All patients enrolled in the study received standardized PA intervention for 4 weeks and were randomly assigned to receive either 4 mg of oral Dex or matching PBO twice a day, administered at 8 am and 2 pm every day for the first 7 days. Patients and all members of the research team except the investigational pharmacist and statistician were blinded to the study medication assignment throughout the study.
We used the same PA regimen as in our previous study of PA+Dex,29 which showed that PA was safe and feasible. The PA prescription included a graded resistance exercise program and a walking regimen. We used resistance tubes as our mode of providing resistance exercises. These tubes were color-coded to indicate their specific resistance level (light, moderate, or hard). Prescribed resistance exercises targeted major muscle groups: squats (modified to sit-to-stand if needed), chest press, biceps curls, seated back row, seated leg extension using body weight, standing leg extension using body weight, and standing hip extension. The prescription was to complete 2 sets of 12 repetitions of all exercises. The resistance exercise sessions were to be completed 3 days per week, allowing at least 48 hours between each session. Participants also engaged in a walking program in which they were asked to walk a minimum of 5 days a week for at least 30 minutes.
At the first study visit, the research nurse met with each participant to evaluate their current strength and aerobic fitness level and supervised the assigned exercises. The resistance exercise sessions were designed so that the participants began with a lighter resistance and progressed to heavier resistance once a level had been mastered. Likewise, because the level of aerobic fitness varied among participants, the intensity and duration of the walking program was established based on the initial assessment of the participant’s current aerobic fitness level using a 6-minute walk test. Patients were given pedometers to self-monitor adherence to the walking prescription. Participants received a weekly check-in call from the trained research nurse to assess their progress, address barriers, and adjust the difficulty of the resistance exercises and walking program. The assessment included the percentage of completion of the prescribed resistance exercise, specific resistance level (light, moderate, hard), and completion of prescribed walking exercise and duration.
We assessed satisfaction with the combination treatment program (resistance and walking exercise with study medication) using a single-item, 5-point, fully word-anchored balanced bipolar scale. The options to assess satisfaction were “completely dissatisfied,” somewhat dissatisfied,” “neither satisfied nor dissatisfied,” “somewhat satisfied,” and “satisfied.” Tolerability to the study interventions was assessed through monitoring adverse events (AEs), in accordance with NCI’s CTCAE version 4.03 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_4.03.xlsx).
Outcome Measures
Patients’ demographic data, including age, sex, race/ethnicity, cancer diagnosis, and treatment history were recorded at the time of randomization. A research nurse supervised the patients’ completion of the FACT-G and its fatigue scale (FACIT-F),40 ESAS,41 PROMIS-Fatigue SF-7a,42,43 MFSI-SF,44 HADS, PSQI, and GLTEQ at baseline, day 8, day 29, and 1 month post study.
The FACT-G is a well-validated quality-of-life instrument widely used for the assessment of CRF in clinical trials. It consists of 27 general quality-of-life questions divided into 4 domains (physical, social, emotional, and functional), with scores based on a scale of 0 (not at all) to 4 (very much).
Our primary outcome measure was the FACIT-F subscale, a highly validated tool that our team and others have used in multiple fatigue treatment trials.45–49 In addition, our goal in this study was to determine the sensitivity to change in fatigue-related symptoms using the MFSI-SF, PROMIS-Fatigue SF-7a, and ESAS fatigue item that might be of interest for future CRF research.
The FACIT-F is a 13-item subscale of the FACT-G that allows patients to rate the intensity of their fatigue and its related symptoms.50 The calculated scoring varies from 0 to 52, with a lower score indicating a more severe fatigue level. Test-retest reliability coefficients for the fatigue subscale are 0.84 to 0.90. This scale has also demonstrated strong internal consistency (α = 0.93–0.95). In previous studies, a 3-point improvement in FACIT-F scores was considered a minimally important clinical difference.40,41
PROMIS-Fatigue SF-7a was used to measure both the experience of fatigue and its interference in patients’ daily activities over the past week. This questionnaire consists of 7 items with response options on a 5-point Likert scale, ranging from 1 (never) to 5 (always).42,43 A higher score indicates greater fatigue. A 3- to 5-point improvement is considered a minimally important clinical difference.33
The MFSI-SF is a 30-item scale used to assess the multidimensional nature of fatigue.44 The MFSI-SF is validated with a Cronbach α of 0.83 to 0.92.51 Responses are selected using 5-point scale, ranging from 0 (not at all) to 4 (extremely). The MFSI-SF total score is calculated by summing the general, emotional, physical, and mental fatigue subscales scores and subtracting the vigor subscale score. A higher score indicates a higher level of fatigue.
The ESAS is validated scale ranging from 0 to 10 used to assess 10 symptoms commonly experienced by patients with cancer during the previous 24 hours: pain, fatigue, nausea, depression, anxiety, drowsiness, dyspnea, anorexia, sleep, and feelings of well-being.41,37,52,53 For the purpose of post hoc analysis,37,54,55 we categorized the ESAS as follows: ESAS physical distress score—sum of pain, shortness of breath, appetite, nausea, fatigue, and drowsiness scores; and ESAS psychological distress score—sum of anxiety and depression scores. The ESAS total is the sum of all ESAS items.
The HADS is a 14-item questionnaire used to measure anxiety and depression. The HADS has been validated and is widely used in medically ill patients.56
The PSQI is a 19-item validated questionnaire that was to measure sleep quality over the past month.21,22 For this study, the PSQI was assessed as a measure of tolerability.
The GLTEQ was used to measure frequency and intensity of exercise over the past week. The questionnaire evaluates the number of times one engages in mild, moderate, or strenuous leisure time physical activities of at least 15 minutes in a week.
Statistical Analysis
Descriptive summary statistics were provided using median and IQRs for continuous variables and frequency and percentages for categorical variables. Feasibility was assessed based on satisfaction with, adherence to, and tolerability of study interventions. We estimated the proportion of patients completing the intervention, the adherence rate, and the proportion of patients with a satisfaction rating of “somewhat satisfied” or “completely satisfied.” Adherence was defined as reported consumption of 75% of pills prescribed; 65% of walking exercise prescribed; and 65% of resistance exercise prescribed. PA+Dex was deemed feasible if the adherence rate to its daily use during the 4-week intervention was ≥75% and if >75% of patients reported being “somewhat satisfied” or “completely satisfied” with PA+Dex. The chi-square test was used to compare patient characteristics and the Wilcoxon rank sum test was used to assess change from baseline in FACIT-F, PROMIS-Fatigue SF-7a, FACT-G, ESAS-Fatigue item, MFSI-SF, ESAS Total, ESAS Physical Distress, ESAS Psychological Distress, HADS, PSQI, and GLTEQ scores. Exploratory linear mixed models were conducted to test whether there was a treatment effect on fatigue outcomes.
Sample Size Calculation
Our prior data16 showed that oral Dex at 4 mg twice daily resulted in clinically relevant or robust improvement of CRF (FACIT-F scores) in 33% of patients. In the present study, a change in FACIT-F scores was assessed in the PA+Dex and PA+PBO arms. To obtain a reliable estimate of clinically relevant improvement at day 8, we estimated that 35 subjects were needed in each group, with a total sample size of 70. If the robust response proportions were 0.33 or 0.60, the half-widths of the 95% confidence intervals would be 0.16. Due to the preliminary nature of this study, no intent-to-treat analysis was conducted, and multiple testing was not considered. AEs were described descriptively, with frequencies by relation and grade. Fisher exact tests were used to compare maximum grade and severe AEs (SAEs; defined as grade ≥3) reported between groups. A P value of ≤.05 was considered statistically significant. All statistical analyses were performed using Stata/MP, version 17.0 (StataCorp LLC).
Results
Figure 1 shows the details of patient enrollment, follow-up, and analysis. Of the 92 randomized patients, 72 received the study intervention, and 64 (89%) of these were evaluable. Reasons for not receiving study interventions after randomization included withdrawal of consent (n=12), ineligibility (n=6), and loss to follow-up (n=2). Of the 72 evaluable patients, 8 were lost in follow-up after the start of intervention for the following reasons: failure to complete the study assessments (n=4), loss to follow-up (n=2), withdrawal of consent (n=1), and withdrawal from the study by the principal investigator for nonadherence to protocol (n=1).
CONSORT diagram.
Abbreviations: Dex, dexamethasone; PA, physical activity; PBO, placebo; PI, principal investigator.
Citation: Journal of the National Comprehensive Cancer Network 23, 1; 10.6004/jnccn.2024.7071
We found no significant differences in baseline characteristics between patients who were randomized and completed the study intervention and those who did not complete the study (see Table S1). Table 1 shows patient demographics and clinical characteristics at baseline. There was no difference in baseline characteristics between patients in the PA+Dex and PA+PBO arms except for race/ethnicity and FACT-G physical well-being scores.
Patient Demographics and Clinical Characteristics at Baseline
PA+Dex Arm (n=47) |
PA+PBO Arm (n=45) |
P Valuea | |
---|---|---|---|
Characteristic | n (%) | n (%) | |
Age, median (range), y | 56 (31–77) | 59 (25–87) | .94 |
Sex | .55 | ||
Female | 32 (68.09) | 28 (62.22) | |
Male | 15 (31.91) | 17 (37.78) | |
Race/Ethnicity | .02 | ||
White | 35 (78) | 19 (62) | |
Hispanic | 4 (9) | 15 (10) | |
Black | 4 (9) | 9 (7) | |
Asian/Other | 2 (4.4) | 0 (0) | |
Cancer diagnosis | .37 | ||
Breast | 18 (40) | 9 (21) | |
Lung | 5 (11) | 5 (11.6) | |
Gastrointestinal | 16 (36) | 21 (49) | |
Genitourinary | 4 (8.9) | 2 (4.7) | |
Gynecologic | 1 (2) | 2 (5) | |
Cancer treatmentb | .44 | ||
Chemotherapy | 31 (66) | 30 (66.7) | |
Radiation | 8 (17) | 12 (26.7) | |
Hormone therapy | 7 (14.9) | 4 (8.9) | |
Targeted therapy | 17 (25.5) | 14 (31.1) | |
Assessment | Median (IQR) | Median (IQR) | |
FACIT-F | 29 (23–39) | 26 (19–28.5) | .07 |
FACT-G | 75.5 (61–86.3) | 75.33 (65–90) | .80 |
FACT-G SWB | 20.5 (17.5–26) | 24.5 (20–28) | .45 |
FACT-G PWB | 20.5 (16–22) | 16.5 (11–22) | .005 |
FACT-G EWB | 18 (15–20) | 19 (15–22) | .63 |
FACT-G FWB | 17.5 (14–20) | 18 (12–23) | .94 |
HADS Anxiety | 5 (3–11) | 4 (2–6) | .42 |
HADS Depression | 5 (2–8) | 4.5 (2.5–7.5) | .99 |
ESAS Fatigue | 6 (3–6) | 5 (4–8) | .86 |
ESAS Physical Distress | 15 (10–22) | 21 (15–26) | .11 |
ESAS Psychological Distress | 4 (2–10) | 2 (0–5) | .50 |
PSQI total | 10 (6–13) | 10.5 (5.5–13) | .39 |
PROMIS-Fatigue SF-7a | 20.5 (18–24) | 21.5 (19–25) | .45 |
MFSI-SF total | 22.5 (7.5–30.5) | 18 (3–29) | .38 |
Abbreviations: Dex, dexamethasone; ESAS, Edmonton Symptom Assessment Scale; EWB, Emotional Well-Being; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FACT-G, Functional Assessment of Cancer Therapy-General; FWB, Functional Well-Being; HADS, Hospital Anxiety and Depression Scale; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form; PA, physical activity; PBO, placebo; PROMIS-Fatigue SF-7a, Patient-Reported Outcomes Measurement Information System-Fatigue Short Form 7a; PSQI, Pittsburgh Sleep Quality Index; PWB, Physical Well-Being; SWB, Social Well-Being.
P value estimated using chi-square/Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Bold indicates statistically significant values (P≤.05).
Patients received >1 treatment.
A total of 91% and 92% of patients in the PA+Dex and PA+PBO arms, respectively, were adherent to study medication (P=.15). Patients in the PA+Dex and PA+PBO arms completed 83% and 70.6% of prescribed resistance exercises, respectively (P=.35), and 82.9% and 78.3% of prescribed aerobic exercises, respectively (P=.73). The satisfaction rate for combination treatment was 98% in the PA+Dex arm and 79% in the PA+PBO arm.
Table 2 shows the changes from baseline in fatigue scores at days 8 and 29 in the PA+Dex and PA+PBO arms. The median (IQR) change for FACIT-F, as well as effect size (ES) and P value, at day 8 and day 29 was 9 (2 to 16; ES, −3.49; P<.001) and 5.75 (0 to 12.5; ES, −2.43; P=.015), respectively, in the PA+Dex arm, and 3.5 (−2.1 to 10; ES, −1.93; P=.054) and 6.5 (2.5 to 15.5; ES, −2.72; P=.006), respectively, in the PA+PBO arm.
Changes in Fatigue Scores at Days 8 and 29 From Baselinea
Main Outcome | PA+Dex Arm | PA+PBO Arm | ||||||
---|---|---|---|---|---|---|---|---|
Day 8 From Baseline | Baseline Median (IQR) | Day 8 Median (IQR) | Change Score Median (IQR) | P Valueb | Baseline Median (IQR) | Day 8 Median (IQR) | Change Score Median (IQR) | P Valueb |
FACIT-F | 29 (23 to 39) | 43 (27 to 47) | 9 (2 to 16) | <.001 | 26 (19 to 28.5) | 28.5 (21.9 to 37.5) | 3.5 (−2.1 to 10) | .054 |
ESAS Fatigue | 6 (3 to 6) | 3 (1 to 5) | −2 (−3 to 0) | .001 | 5 (4 to 8) | 5 (3 to 7) | 0 (−2 to 1) | .23 |
PROMIS-Fatigue SF-7a | 56.4 (53.7 to 62) | 50 (43.9 to 55.1) | −7.9 (−12 to 0) | .003 | 58.5 (55.1 to 63.4) | 56.4 (50.8 to 62) | −1.4 (−8.3 to 4.2) | .09 |
MFSI-SF total | 22.5 (7.5 to 30.5) | 6 (−4 to 19) | −8 (−16 to 1) | .023 | 18 (3 to 29) | 15 (1 to 27) | −3.5 (−9 to 3) | .26 |
Main Outcome | PA+Dex Arm | PA+PBO Arm | ||||||
---|---|---|---|---|---|---|---|---|
Day 29 From Baseline | Baseline Median (IQR) | Day 29 Median (IQR) | Change Score Median (IQR) | P Valueb | Baseline Median (IQR) | Day 29 Median (IQR) | Change Score Median (IQR) | P Valueb |
FACIT-F | 29 (23 to 39) | 39.5 (29.5 to 45.5) | 5.75 (0 to 12.5) | .015 | 26 (19 to 28.5) | 34 (26 to 42) | 6.5 (2.5 to 15.5) | .006 |
ESAS Fatigue | 6 (3 to 6) | 4 (2 to 6) | −1 (−2 to 0) | .015 | 5 (4 to 8) | 4.5 (2 to 6.5) | 0 (−4 to 1) | .07 |
PROMIS-Fatigue SF-7a | 56.4 (53.7 to 62) | 51.45 (45.8 to 56.4) | −5.45 (−8.8 to 0) | .005 | 58.5 (55.1 to 63.4) | 54.4 (48.4 to 62) | −4.25 (−9.8 to 1.7) | .14 |
MFSI-SF total | 22.5 (7.5 to 30.5) | 7.5 (−3 to 16.5) | −11 (−21 to 4) | .007 | 18 (3 to 29) | 13 (−2 to 34) | −7.5 (−16 to 3) | .094 |
Abbreviations: Dex, dexamethasone; ESAS, Edmonton Symptom Assessment Scale; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form; PA, physical activity; PBO, placebo; PROMIS-Fatigue SF-7a, Patient-Reported Outcomes Measurement Information System-Fatigue Short Form 7a.
Number of patients included in this analysis differs from the total study patients analyzed (Figure 1) due to differences in questionnaire completion.
Wilcoxon rank sum test was used to estimate P value. Bold indicates statistically significant P value (P≤.05).
Exploratory linear mixed model (LMM) analysis showed significant treatment effect of the PA+Dex arm, with treatment showing an improvement of 5.63 units (95% CI, 1.74 to 9.52; P=.005) for FACIT-F scores and −4.09 units (95% CI, −7.04 to −1.15; P=.006) for PROMIS-Fatigue SF-7a.
Table 3 shows changes from baseline in fatigue-related symptom scores at days 8 and 29 in both arms.
Changes in Fatigue-Related Symptoms at Days 8 and 29 From Baselinea
PA+Dex Arm | PA+PBO Arm | |||||||
---|---|---|---|---|---|---|---|---|
Day 8 From Baseline | Baseline Median (IQR) | Day 8 Median (IQR) | Change Score Median (IQR) | P Valueb | Baseline Median (IQR) | Day 8 Median (IQR) | Change Score Median (IQR) | P Valueb |
FACT-G | 75.5 (61 to 86.3) | 82.5 (68 to 92) | 5.5 (−0.8 to 12) | .017 | 75.33 (65 to 90) | 83 (68 to 88) | 2.17 (−3.83 to 10) | .14 |
FACT-G PWB | 20.5 (16 to 22) | 23.7 (21 to 25.7) | 3 (0 to 5) | .001 | 16.5 (11 to 22) | 16 (14 to 23) | 2 (−1 to 3) | .049 |
FACT-G SWB | 20.5 (17.5 to 26) | 23.2 (19.8 to 27) | 1.08 (−1 to 3.3) | .085 | 24.5 (20 to 28) | 25 (22.2 to 27) | 0 (−1 to 2.3) | .42 |
FACT-G EWB | 18 (15 to 20) | 19 (14 to 21) | 0 (−1 to 3) | .298 | 19 (15 to 22) | 20 (18 to 22) | 0 (−1 to 2) | .33 |
FACT-G FWB | 17.5 (14 to 20) | 19 (14 to 22) | 0.5 (−3 to 4) | .32 | 18 (12 to 23) | 18 (13 to 21) | 0 (−4 to 3) | .66 |
Total ESAS | 30 (19 to 42) | 20 (15 to 32) | −7 (−14 to 0) | .007 | 34.5 (26 to 40) | 28.5 (19 to 36) | −2 (−10 to 0) | .034 |
ESAS Physical Distress | 15 (10 to 22) | 9 (7 to 16) | −5 (−9 to 3) | .004 | 21 (15 to 26) | 17.5 (11.5 to 27) | −0.5 (7 to 3) | .38 |
ESAS Psychological Distress | 4 (2 to 10) | 3 (0 to 6) | 0 (−3 to 0) | .025 | 2 (0 to 5) | 1.5 (0 to 4) | 0 (−2 to 0) | .085 |
MFSI-SF General | 12 (8 to 15) | 6 (4 to 11) | −3 (−6 to −1) | .002 | 12 (10 to 15) | 11 (7 to 14) | −2 (−5 to 2) | .044 |
MFSI-SF Physical | 5 (3 to 9) | 2 (0 to 8) | −1.5 (−4 to 1.5) | .098 | 5 (3 to 10) | 6 (3 to 10) | 0 (−2 to 2) | .96 |
MFSI-SF Emotional | 6 (2 to 9) | 4 (1 to 9) | 0 (−3.5 to 2) | .66 | 3 (1 to 7) | 3 (1.5 to 6) | −1 (−2 to 2) | .39 |
MFSI-SF Mental | 4 (2 to 10) | 3 (1 to 6) | −1 (−2 to 0) | .10 | 4 (2 to 9) | 4 (3 to 9) | 0 (−1 to 1) | .43 |
MFSI-SF Vigor | 10 (6.5 to 13) | 12 (6 to 16) | 1 (−1 to 5) | .16 | 11 (8 to 15) | 10 (−3 to 14.5) | −1 (−3 to 3) | .79 |
HADS Anxiety | 5 (3 to 11) | 4 (2 to 9) | 0 (−3 to 1) | .36 | 4 (2 to 6) | 4 (1 to 6.5) | −1 (−2 to 1) | .29 |
HADS Depression | 5 (2 to 8) | 4 (2 to 8) | 0 (−2 to 2) | .65 | 4.5 (2.5 to 7.5) | 5 (3 to 8) | 0 (−1 to 1.5) | .5 |
GLTEQ | 20 (3 to 29) | 34 (12 to 62) | 3 (0 to 32) | .01 | 15 (6 to 24) | 26 (12 to 46) | 10 (0 to 28) | .002 |
PA+Dex Arm | PA+PBO Arm | |||||||
---|---|---|---|---|---|---|---|---|
Day 29 From Baseline | Baseline Median (IQR) | Day 29 Median (IQR) | Change Score Median (IQR) | P Valueb | Baseline Median (IQR) | Day 29 Median (IQR) | Change Score Median (IQR) | P Valueb |
FACT-G | 75.5 (61 to 86.3) | 83 (78 to 8,91) | 6.97 (3 to 10.5) | .001 | 75.33 (65 to 90) | 78 (73 to 89) | 3.09 (−3.75 to 10) | .094 |
FACT-G PWB | 20.5 (16 to 22) | 24 (20 to 25) | 2 (1 to 4) | .002 | 16.5 (11 to 22) | 19 (14 to 23) | 0 (−1 to 3) | .15 |
FACT-G SWB | 20.5 (17.5 to 26) | 23.8 (20 to 26) | 1.2 (−1 to 3) | .19 | 24.5 (20 to 28) | 26 (22 to 28) | 0 (0 to 1.6) | .045 |
FACT-G EWB | 18 (15 to 20) | 18 (15 to 23) | 1 (0 to 3) | .021 | 19 (15 to 22) | 19 (16 to 22) | 0 (−1.5 to 1) | .94 |
FACT-G FWB | 17.5 (14 to 20) | 18 (15 to 23) | 2 (0 to 3) | .012 | 18 (12 to 23) | 19 (13 to 21) | −0.5 (−3.25 to 3.5) | .83 |
ESAS Total | 30 (19 to 42) | 22 (13 to 28) | −4 (−14 to 0) | .049 | 34.5 (26 to 40) | 24 (10 to 39.5) | −6 (−22 to 4) | .015 |
ESAS Physical Distress | 15 (10 to 22) | 11 (6 to 18) | −2.5 (−5 to 1) | .063 | 21 (15 to 26) | 16 (5.5 to 24) | −1 (−15 to 3) | .071 |
ESAS Psychological Distress | 4 (2 to 10) | 2.5 (0 to 5) | −1 (−4 to 0) | .005 | 2 (0 to 5) | 1 (0 to 4.5) | 0 (−3 to 0) | .083 |
MFSI-SF General | 12 (8 to 15) | 6.5 (4 to 9) | −3.00 (−4.5 to −0.5) | .009 | 12 (10 to 15) | 12 (10 to 15) | −4 (−7 to 0) | .007 |
MFSI-SF Physical | 5 (3 to 9) | 3 (1 to 6) | −2 (−3 to 0.5) | .015 | 5 (3 to 10) | 6 (3 to 9) | 0 (−2 to 1) | .49 |
MFSI-SF Emotional | 6 (2 to 9) | 4 (1 to 5) | −2 (−5 to 1) | .045 | 3 (1 to 7) | 5 (1 to 7) | 0 (−3 to 2) | .72 |
MFSI-SF Mental | 4 (2 to 10) | 4 (2 to 7) | −1 (−4 to 0) | .12 | 4 (2 to 9) | 5 (2 to 8) | −1 (−3 to 1) | .18 |
MFSI-SF Vigor | 10 (6.5 to 13) | 12 (9 to 17) | 2 (−1 to 4) | .082 | 11 (8 to 15) | 12 (8 to 16) | 0 (−3 to 3) | .87 |
PSQI Total | 10 (6 to 13) | 8 (5.5 to 11) | −1 (−3 to 1) | .15 | 10.5 (5.5 to 13) | 8 (5 to 10.5) | −1 (−4 to 1) | .11 |
HADS Anxiety | 5 (3 to 11) | 4.5 (2 to 7) | −2 (−3 to 1) | .024 | 4 (2 to 6) | 4 (2 to 8) | 0 (−1 to 1) | .71 |
HADS Depression | 5 (2 to 8) | 4 (2 to 8) | −0.5 (−2 to 0) | .13 | 4.5 (2.5 to 7.5) | 3 (2 to 7) | 0 (−1.5 to 0.5) | .12 |
GLTEQ | 20 (3 to 29) | 31 (0 to 56) | 7 (−5 to 25) | .083 | 15 (6 to 24) | 26 (6 to 47) | 7.5 (−6 to 30) | .028 |
Abbreviations: Dex, dexamethasone; ESAS, Edmonton Symptom Assessment Scale; EWB, Emotional Well-Being; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FACT-G, Functional Assessment of Cancer Therapy-General; FWB, Functional Well-Being; GLTEQ, Godin Leisure-Time Exercise Questionnaire; HADS, Hospital Anxiety and Depression Scale; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form; PA, physical activity; PBO, placebo; PSQI, Pittsburgh Sleep Quality Index; PWB, Physical Well-Being; SWB, Social Well-Being.
Number of patients included in this analysis differs from the total study patients analyzed (Figure 1) due to differences in questionnaire completion.
Wilcoxon rank sum test was used to estimate P value. Bold indicates statistically significant P value (P≤.05).
Table 4 shows the frequency of SAEs in the PA+Dex and PA+PBO arms. There was no significant difference in SAEs between the 2 arms (P=.36). All SAEs were unrelated to study treatment except for one that was possibly related to the PA+Dex arm (insomnia, grade 3).
Serious Adverse Events
SAEa,b | Total (n=13) |
PA+Dex Arm (n=6) |
PA+PBO Arm (n=7) |
---|---|---|---|
Abdominal pain | 1 | 1 | 0 |
Dizziness | 1 | 1 | 0 |
Fatigue | 2 | 1 | 1 |
Insomnia | 3 | 1 | 2 |
Depression | 1 | 1 | 0 |
Shortness of breath | 1 | 1 | 0 |
Confusion | 1 | 0 | 1 |
Death, NOS | 1 | 0 | 1 |
Hypoglycemia | 1 | 0 | 1 |
Hyponatremia | 1 | 0 | 1 |
Abbreviations: Dex, dexamethasone; NOS, not otherwise specified; PA, physical activity; PBO, placebo; SAE, serious adverse event.
Fisher exact test. Adverse events were graded based on NCI’s CTCAE version 4.03. SAEs were defined as grade ≥3 adverse events.
No significant difference in SAEs was reported between groups (P=.36).
Discussion
In this study, we found that combined therapy with PA+Dex or PA+PBO was associated with high satisfaction rates, adherence to study medications, and tolerability. Combination PA+Dex resulted in a clinically meaningful improvement in CRF (>3 points on FACIT-F). We observed a sustained improvement in CRF and fatigue-related outcomes for up to 3 weeks compared with baseline after discontinuation of Dex, suggesting that possible priming effects of Dex helped sustain PA. We found a significant treatment effect of combination PA+Dex in the improvement of CRF scores.
In addition to improvement of fatigue, we observed an overall improvement in quality of life (FACT-G) in the PA+Dex arm, and it appeared this may have been driven by an improvement of the physical dimension of FACT-G without significant effects on the other dimensions of FACT-G. These results were similar to those of our previous studies using Dex and PA+Dex.26,29 Furthermore, these results may suggest a possible impact of combination PA+Dex more on the peripheral rather than the central causes,57 such as reduction of inflammatory components of CRF.58,59 However, more research is necessary.26
The overall symptom burden as assessed by ESAS improved significantly in the PA+Dex arm by day 8 and remained improved by day 29 (Table 3).16 Dex has been known to significantly improve several cancer-related symptoms, including anorexia, nausea, and pain, as well as overall feelings of well-being, that contribute to the symptom distress.16 In our study, the improvement in symptom distress may be attributed to improvement of cancer-related symptoms, such as anorexia, fatigue, nausea, and pain.
In our previous study using 2 different doses (8 mg/d and 16 mg/d) of Dex in combination with PA,29 we found significant improvement of CRF scores at days 8 and 29 in both arms. However, there was no difference in improvement of CRF between the 2 different doses of Dex in this study. Therefore, in this study we chose a lower dose for safety reasons and decided to randomize patients to either Dex with PA or PBO with PA. Results of our study demonstrated high satisfaction rates and rates of adherence to study medication and PA that were comparable to those of our previous study.29 Our results also suggest that the higher dose of Dex did not appear to have any impact on adherence. In comparison with studies of PA alone in advanced cancer,60,61 the addition of Dex seems to have a potentially beneficial effect on adherence, and additional research is warranted. In prior studies by our group, we found that PBO has a beneficial effect in improving CRF, and this might have helped adherence to PA in the PA+PBO arm of our study.62,63 We found a significant treatment effect of PA+Dex in the improvement of CRF. This result was not surprising, as we found similar benefit using a similar dose of Dex with PA in our prior study using combination therapy.29 These results are consistent with prior fatigue treatment trials using medication or PA interventions.8,64,65 These findings justify a well-powered multicenter phase III comparative study using a factorial design to ascertain whether the improvement was due to the combination or to the individual intervention, and also whether treatment with Dex impacted adherence to PA intervention and whether levels of adherence were associated with CRF outcomes.
There are challenges with the use of corticosteroids and PA for managing CRF in patients with advanced cancer, including the AEs associated with corticosteroids, especially long-term use, and the need to avoid their use during immunotherapy.8,35 There are also challenges with adherence to exercise in patients with advanced cancer. Our current study, which used a short course of dexamethasone with a standardized exercise regimen, provided preliminary data on adherence, efficacy, and safety. We also found that sleep quality (PSQI) scores were not significantly different between groups (Table 3). Further studies are needed to assess whether the levels of adherence to study interventions are associated with change in the study outcomes.
Our study has several limitations. Due to the COVID-19 pandemic, we were unable to reach the expected sample size of 70 evaluable patients (only 64 patients were evaluable), and therefore results of the primary outcome should be interpreted cautiously. Results of the secondary outcomes should also be interpreted cautiously, because the study was not powered to detect the differences between the 2 arms regarding secondary outcomes, and further well-powered studies using a randomized controlled design are needed. In this study, we did not document the barriers associated with the interventions during the weekly check-in calls by the study nurse, and further studies are needed to assess potential barriers to adherence and whether adherence was associated with outcomes in patients using the combination therapy. Unlike in our previous study of combination PA+Dex, objective evidence of adherence to PA could not be assessed.29 Further studies are needed to investigate the optimal methods for remote self-monitoring of resistance and walking exercise when using the combination therapy of PA+Dex to improve CRF outcomes. However, our study found high satisfaction rates, adherence to study medications, and tolerability. Similar to the findings in our prior studies using Dex, we also found no worsening of poor sleep quality scores due to the use of Dex intervention (Table 3).26,29 Another potential limitation of the study is the presence of a PBO in the PA+PBO arm, given that we now have data suggesting that PBO per se can result in improvement of CRF, which would therefore impact the comparison between treatment arms; this should be addressed in future studies.62,63 In previous studies, our group found significant symptomatic improvement, including CRF reduction, using Dex as well as PBO,8,62 and therefore it is not clear whether the benefits of Dex may have had an impact on the ability of the participants to recognize that they were on an active treatment arm; this should be investigated in future research studies. Lastly, in this study we were unable to assess the differences in satisfaction rates for PA+Dex versus PA+PBO (98% vs 79%) attributable to specific intervention components, and therefore further studies are needed.
Conclusions
Our study found that the use of combination therapies with PA+Dex and PA+PBO for CRF were associated with high rates of satisfaction; adherence to study medication, resistance exercise, and aerobic (walking) exercise; and tolerability. Results of the secondary outcomes of this study suggest that the CRF improvement with PA+Dex was clinically significant at days 8 and 29, and the improvement was sustained 3 weeks after discontinuation of Dex. Further larger studies are justified.
Acknowledgments
The authors sincerely thank the National Institutes of Health for grant support and Debra L. Barton, Penny Stanton, Carolina Diaz Hernandez, Irma Lopez-Quinones, Hilda P. Torres, Paul Chavez, Melissa Gaffney, Jennifer C. Ellefson, Zhanni Lu, Premjit Roy, Aline Rozman Moraes, and Janet L. Williams for patient accrual and data support.
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