Background
Cancer-related fatigue (CRF) in patients with advanced cancer is more frequent and severe than in those with early cancer or in cancer survivors.1 In patients with advanced cancer, moderate to severe fatigue is associated with poor quality of life (QoL) outcomes, poor performance status scores, frailty, and lower overall survival.1–3 Limited studies have been conducted to determine whether established therapies for CRF such as physical activity (PA) are effective in patients with advanced cancer.4–6 In patients with early cancer and cancer survivors, the overall clinical effectiveness of PA has been reported as low to moderate (effect size ∼0.28–0.30).7,8 In patients with advanced cancer, another barrier to PA is adherence to exercise programs.4–6 In addition, prior pharmacologic studies for CRF in patients with advanced cancer have shown mixed results.9,10 An earlier study found that dexamethasone (Dex) at 8 mg/d was safe and had efficacy at the end of 1 and 2 weeks.11 Prior research also found that an improvement of ≥10 points in the Functional Assessment of Cancer Illness Therapy-Fatigue (FACIT-F) subscale score was associated with a clinically relevant improvement of fatigue in patients with advanced cancer.12 Only 33% of patients who received Dex at 8 mg/d in this prior study were found to have clinically relevant improvement of fatigue.11 Therefore, there is a need for a study to evaluate treatments or combination therapies that result in clinically relevant improvement of CRF for more than a few weeks.
We hypothesized that the combination therapy of PA for 4 weeks with Dex for 1 week is feasible and is associated with clinically relevant improvement of CRF. Therefore, in this phase II randomized controlled trial, our objective was to examine the feasibility and preliminary results of the combination therapy on CRF as assessed by the FACIT-F subscale (primary outcome), the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), and the Patient-Reported Outcomes Measurement Information System-Fatigue (PROMIS-F). We also explored the change in symptom distress score using the Edmonton Symptom Assessment Scale (ESAS), sleep quality (using the Pittsburgh Sleep Quality Index [PSQI]), a myopathy questionnaire, and fasting blood glucose (FBG) levels after study treatments.
Methods
The University of Texas MD Anderson Cancer Center (MDACC) Institutional Review Board approved this protocol, and all participants provided informed consent as a condition of enrollment to the trial. The study was activated for patient accrual on August 21, 2015, and was closed to new patient accrual on March 25, 2019. We reported study findings using the EQUATOR Reporting guidelines (ClinicalTrials.gov identifier: NCT02491632).
Participants
Patients were enrolled from the outpatient clinics for supportive care and oncology at MDACC. Patients’ eligibility criteria included the following: (1) diagnosis of advanced cancer with average intensity of fatigue of ≥4/10 on the ESAS13 in the previous 24 hours; (2) presence of fatigue for at least 2 weeks; (3) normal cognition; (4) no evidence of significant anxiety or depression as determined by a total score of <21 on the Hospital Anxiety and Depression Scale14; (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 PA for ≥30 minutes at least 5 times a week and strength training for ≥2 days per week; (9) no falls in the past 30 days; (10) no infections/absolute neutrophil count ≥1,000 cells/mm3 within 1 week of enrollment in the study; and (11) no uncontrolled diabetes mellitus or surgery in the 2 weeks prior to study enrollment. To ensure the safety of enrolled patients, those with a history of falls within the past 30 days were excluded.
Interventions
Seventy-six patients were randomized equally between the 2 treatment arms. All patients enrolled in the study received a standardized PA intervention for 4 weeks and were randomly assigned to receive either 4 mg (LoDex) or 8 mg (HiDex) of Dex orally, twice daily, administered at 8 am and 2 pm every day for 7 days. All patients and members of the research team except the investigational pharmacist and statistician were blinded to the study medication assignment throughout the study.
We used a combination of a supervised and home-based PA regimen. The research nurse, who was blinded to the study medication, also supervised the PA interventions. The weekly regimen included a graded resistance exercise program and a walking regimen. Resistance tubes, color-coded to indicate their specific resistance level (light, moderate, or hard), were used as the mode of resistance. The resistance exercise sessions were completed 3 days a week, allowing at least 48 hours between each session. Individuals also engaged in a walking program. Because the level of aerobic fitness varied among participants, the intensity and duration of the walking program was established based on the initial evaluation of the participant’s current aerobic fitness level assessed using a 6-minute walk test. The participants were asked to walk a minimum of 5 days a week. At the first study visit, the research nurse met with each participant to evaluate current strength and aerobic fitness levels and supervise the assigned exercises. Patients then received weekly phone calls from the research nurse to assess their progress and to help them identify and overcome any barriers to completing the exercise program.
Adherence to the Dex intervention was calculated by the proportion of prescribed pills taken during the 7-day intervention and was defined as a patient taking at least 10 of the prescribed 14 study medication pills. Adherence to the PA intervention was calculated by the percentage completion of total prescribed resistance exercises and walking minutes for 4 weeks. Adherence to the walking exercise was defined as walking at least 90 minutes every week, and adherence to resistance exercise was defined as performing at least 2 sets of exercises every week. Satisfaction was assessed using a 5-point, fully word-anchored balanced bipolar scale. Tolerability was assessed using adverse events monitoring, in accordance with the NCI’s CTCAE, version 3.0 (https://ctep.cancer.gov/protocoldevelop ment/electronic_applications/ctc.htm).
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 Functional Assessment of Cancer Therapy-General (FACT-G) and its fatigue subscale (FACIT-F),15 the ESAS,16 the PROMIS-F,17,18 the MFSI-SF,19 the PSQI, and the myopathy questionnaire.
The FACT-G is a well-validated QoL instrument widely used for the assessment of CRF in clinical trials. It consists of 27 general QoL questions divided into 4 domains (physical, social, emotional, and functional). The FACIT-F subscale is a 13-item subscale of the FACT-G20 that allows patients to rate the intensity of their fatigue and its related symptoms on a scale of 0 (not at all) to 4 (very much). The calculated scoring varies from 0 to 52, with a lower score indicating a more severe fatigue level. FACIT-F has a sensitivity of 0.92 and a specificity of 0.69.15
The ESAS is a 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.13,16,21,22 For the purpose of post hoc analysis,13,23,24 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 PROMIS-F short form was used to measure both the experience of fatigue and the interference of fatigue in patients’ daily activities over the past week. It consists of 7 items with response options on a 5-point Likert scale, ranging from 1 (never) to 5 (always).17,18
The MFSI-SF is a 30-item scale used to assess the multidimensional nature of fatigue.19 Responses are selected using a 5-point scale, ranging from 0 (not at all) to 4 (extremely). The MFSI-SF total scale and subscales are validated with a Cronbach α of 0.83 to 0.92.25 The MFSI-SF consists of 5 subscales: general, physical, emotional, mental and vigor. The MSFI-SF total score is the sum of the general, physical, emotional and mental subscale scores and subtracting vigor subscale score.
Our primary outcome was the FACIT-F subscale, a highly validated tool previously used in multiple fatigue treatment trials.26–30 In addition, our goal in this study was to determine the sensitivity to change and patient adherence to a number of tools (MFSI-SF, PROMIS-F, and ESAS fatigue item) that might be of interest for future fatigue research.
The PSQI is a 19-item questionnaire that was used to measure the quality and patterns of sleep.31 Numerous studies using the PSQI have supported its validity and reliability.32
FBG was measured using a glucometer, and a patient-reported myopathy questionnaire was used to assess weakness in the past 1 week due to myopathy. This myopathy questionnaire (0–5 scale) assessed 3 domains of the perception of weakness, including the ability to walk up and down stairs, stand from a seated position, and button or unbutton, sew, or pick up coins. The PSQI, FBG, and myopathy questionnaire were assessed as measures of tolerability.
Statistical Analysis
Descriptive summary statistics were provided using median and interquartile ranges for continuous variables and frequency and percentages for categorical variables. Feasibility was assessed using adherence to and satisfaction with study interventions, along with tolerability. To compare patient characteristics, we used the chi-square and the Wilcoxon signed rank tests for the FACIT-F (primary outcome), ESAS fatigue item, PROMIS-F, MFSI-SF, ESAS physical distress score, ESAS psychological distress score, PSQI, FBG, and myopathy questionnaire scores. Using a mixed-model analysis, we analyzed the time × treatment effects of the 2 arms on the FACIT-F, FACT physical well-being, and MFSI-SF scores. A prior study11 showed that Dex at 4 mg twice daily resulted in clinically relevant improvement (≥10 points change in the FACIT-F score) in 33% of patients. To obtain a reliable estimate of clinically relevant improvement in this noncomparative trial, we estimated 35 in each arm with a total sample size of 70. If the response proportions were 0.60, then the half-widths of the 95% confidence intervals were estimated to be 0.16. Because of the preliminary nature of the study, no intent-to-treat analysis was conducted, and multiple testing was not considered. A significance of ≤.05 was considered statistically significant. All computations were performed using SAS, version 9.4 (SAS Institute Inc.).
Results
Figure 1 shows the details of patient enrollment, follow-up, and analysis. A total of 67 of the 76 randomized patients received the study intervention; 9 did not receive study interventions after randomization because 4 withdrew consent and 5 withdrew due to disease progression. Of the 67 patients, 7 were lost to follow-up after the start of the study interventions: 4 withdrew due to disease progression, 2 due to hospitalization, and 1 due to an adverse event unrelated to the study treatment.
CONSORT flow diagram.
Abbreviations: LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
CONSORT flow diagram.
Abbreviations: LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
CONSORT flow diagram.
Abbreviations: LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
Table 1 shows the demographic and baseline clinical characteristics. We found that 51.7% of the study population was female, the median age was 60 years, and the baseline fatigue severity (FACIT-F) score was 21. All patients were adherent to study medication. Results showed that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The satisfaction rate for the PA and Dex combination therapy was 85%, with median (interquartile range) scores of 5 (4–5).
Patient Demographics and Clinical Characteristics at Baseline
Table 2 shows that the FACIT-F effect size in patients in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and that the effect size in patients in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. Similar results were seen in the PROMIS-F, ESAS fatigue, MFSI-SF general, and MFSI-SF total scores at days 8 and 29 in patients in the LoDex and HiDex arms.
Changes in Fatigue Levels at Day 8 and Day 29 From Baseline
Mixed-model analysis showed significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F (P=.86), FACT physical well-being (P=.11), and MFSI-SF physical (P=.53) scores were not significantly different between patients in the 2 arms.
Results showed that 64.5% and 69% of patients in the LoDex arm and 79.2% and 81.8% of patients in the HiDex arm had minimal clinically important improvement in FACIT-F scores (≥3.5 points) at days 8 and 29, respectively. Additionally, we found that 45.2% and 37.9% of patients in the LoDex arm and 50.0% and 72.7% of patients in the HiDex arm had clinically relevant improvement in FACIT-F scores (≥10 points) at days 8 and 29, respectively (Figure 2).
The percentages of patients with FACIT-F scores improved by at least 10 points at day 8 and day 29 from baseline between the PA + LoDex arm and the PA + HiDex arm. The y axis represents the percentage of patients with FACIT-F scores improved by 10 points.
Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HiDex, 8 mg of dexamethasone; LoDex, 4 mg of dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
The percentages of patients with FACIT-F scores improved by at least 10 points at day 8 and day 29 from baseline between the PA + LoDex arm and the PA + HiDex arm. The y axis represents the percentage of patients with FACIT-F scores improved by 10 points.
Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HiDex, 8 mg of dexamethasone; LoDex, 4 mg of dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
The percentages of patients with FACIT-F scores improved by at least 10 points at day 8 and day 29 from baseline between the PA + LoDex arm and the PA + HiDex arm. The y axis represents the percentage of patients with FACIT-F scores improved by 10 points.
Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HiDex, 8 mg of dexamethasone; LoDex, 4 mg of dexamethasone; PA, physical activity.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7066
Table 3 shows significant changes in the FACT physical well-being, ESAS physical distress, and MFSI-SF physical subscale scores at days 8 and 29 in patients in the LoDex and HiDex arms.
Changes in Fatigue-Related Symptoms at Day 8 and Day 29 From Baseline
No significant differences were found between the LoDex and HiDex arms in the percentages of patients with poor sleep scores (PSQI scores ≥5 points) at baseline (P=.28), day 8 (P=.69), and day 29 (P=.71). We also found no significant differences in FBG levels between the LoDex and HiDex arms at baseline (P=.90), day 3 (P=.56), and day 8 (P=.51). Additionally, no significant differences were found between patients in the LoDex and HiDex arms in the myopathy questionnaire scores for walking up and down stairs, standing from a seated position, and buttoning/unbuttoning, sewing, or picking up coins.
There were a total of 10 reported grade 3 to 5 adverse events in patients in the LoDex and HiDex arms. Except for one possible related adverse event (insomnia) in the LoDex arm, all of the grade 3–5 adverse events in the LoDex (n=5) and HiDex arms (n=5) were unrelated to the study intervention (supplemental eTable 1, available with this article at JNCCN.org). There was no significant difference in grade ≥3 adverse events between patients in the 2 arms (P=.44).
Discussion
Results of this preliminary phase II randomized, double-blind, controlled study suggested that the combined therapy was feasible and resulted in a significant reduction in CRF. Patients were adherent to the combined therapy and had no significant adverse events. We observed a sustained improvement in CRF and fatigue-related outcomes for up to 3 weeks after discontinuation of Dex, suggesting that the possible priming effects of Dex helped sustain PA. There was no significant improvement in CRF scores between patients in the 2 arms. We found improvement in QoL and physical fatigue subscale scores in both arms. Sleep quality and myopathy questionnaire scores along with FBG levels after combination therapy use in both arms did not worsen.
Results from prior PA studies in advanced cancer settings were mixed in terms of fatigue outcomes.4–6,33 Prior meta-analysis by Buffart et al34 and Nadler et al5 suggested a nonlinear relationship in the benefit of PA on fatigue, with the greatest benefit in improvement of fatigue seen among patients with the most severe fatigue. In our study, the adjuvant use of a short course of Dex with the 4 weeks of PA may have provided an immediate improvement in fatigue levels. Positive adherence to exercise resulting in an improvement of fatigue over 4 weeks may have been because of the selection of patients with moderate to severe fatigue scores in our study. In addition, the results of our study were encouraging in that we found approximately 40% and 61% clinically relevant improvement in CRF at days 8 and 29, respectively.11
Our study found no significant difference in the myopathy, FBG levels, and sleep quality scores between patients in the 2 arms. These findings are consistent with the findings of a previous study in patients with advanced cancer using Dex alone.11 They are also different from prior literature concerning the negative effects of steroids on myopathy, FBG levels, and sleep quality scores.35–38 The possible reason may be the short-term use of the Dex in our study and also the proinflammatory response in patients with advanced cancer that the combination therapy used in our study was able to antagonize. Further studies are needed to validate these findings.
Our study found that combined therapy improves physical fatigue, perhaps suggesting its possible mechanism of action for alleviating CRF, and its effects may be more peripheral than central via anti-inflammatory cytokine and adrenergic pathways.39 In addition, we found an improvement in physical QoL indices but not corresponding improvements in emotional or social QoL indices, as might be expected if patients were able to pursue more activities because of improved fatigue. This finding may result from the effects of Dex. Similar results were found in a prior trial using Dex alone for CRF.11
We found no significant difference in CRF between patients in the LoDex versus HiDex arms. This result was not surprising because our study was not powered to compare the 2 different dosages. Both arms had excellent adherence rates and these adherence rates were consistent with results from prior fatigue treatment trials using medication or PA interventions.40–42 These findings justify a well-powered multicenter phase III comparative study using a factorial design to ascertain whether the improvement resulted from the combination or from the individual intervention and also whether Dex treatment impacted adherence to PA intervention, because CRF is a barrier to PA engagement.
There are challenges with the use of corticosteroids for CRF, including the risk of hyperglycemia, myopathy, and insomnia, and avoidance of their use in patients receiving immunotherapy. However, there are potentially significant advantages that need to be explored, including the use of a short course of Dex in combination with PA for CRF. Our current study shows preliminary data regarding efficacy and safety. However, further studies are needed.
Our study has several limitations. In our study, 67 of the 76 randomized patients received the study intervention, and 60 of these patients were evaluable. It is reassuring that although many patients who were randomized did not get to begin the actual study, the vast majority (90%) of patients who started the intervention were evaluable. Future studies should explore ways to reduce nonparticipation. Another minor limitation of this study was that exploratory physical performance outcomes (eg, 6-minute walk, muscle strength) were not assessed. However, these assessments should be considered in future studies because they can be used to guide the exercise prescribed.
Conclusions
Our findings suggest that combination therapy of PA and Dex was feasible and resulted in improvement in CRF. The improvement was observed for up to 3 weeks after discontinuation of Dex, suggesting possible priming effects of Dex to sustain PA. Further larger studies are justified.
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