Combating Cancer-Related Fatigue: Yoga, Bupropion, Exercise Plus Methylphenidate

CHICAGO — A month-long structured yoga program helped patients with cancer improve mood disturbance, anxiety, and fatigue, contributing to a reduction in insomnia, a large multicenter randomized trial showed.

Scores on tests for mood disturbance, fatigue, and anxiety all improved significantly (P<0.05 to P<0.001). The results added to previous research showing that the yoga program helped improve insomnia in patients with cancer, and the new data showed that improvement in mood disturbance and fatigue explained a substantial portion of the improvement in insomnia.

The program had good adherence, and only one adverse event occurred, which was unrelated to the program, reported Yuri Choi, RN, PhD, of the University of Rochester Medical Center and Wilmot Cancer Institute in New York, at the American Society of Clinical Oncology (ASCO) meeting.

“Our yoga intervention, YOCAS [Yoga for Cancer Survivors], is effective for treating mood disturbance, anxiety, fatigue, and insomnia among cancer survivors,” said Choi. “Part of the reason YOCAS may improve insomnia may be because it reduces mood disturbance and fatigue. Accordingly, clinicians should recommend gentle Hatha and restorative yoga for survivors experiencing mood disturbance, anxiety, fatigue, or insomnia.”

As many as 95% of cancer survivors report mood disturbance, anxiety, fatigue, or insomnia at some point during their cancer experience, she added. More than half of survivors report that the side effects occur together. The effects can significantly increase morbidity and interfere with daily activities, ultimately reducing quality of life.

Another randomized study reported at the ASCO meeting showed significant improvement in fatigue scores in cancer survivors taking the atypical antidepressant bupropion. Prespecified subgroup analyses showed improvement in women but not men, said Luke Peppone, PhD, MPH, also of the University of Rochester. Patients who had ever smoked also derived significant benefit, he added, noting bupropion’s use as a smoking-cessation aid.

A third randomized trial showed no improvement in objectively measured fatigue in men with prostate cancer and fatigue randomized to exercise and the psychostimulant methylphenidate. All four study groups had improvement in cancer-related fatigue, suggesting a strong placebo effect, said Sriram Yennu, MD, of the University of Texas MD Anderson Cancer Center in Houston. Additionally, methylphenidate groups had significant improvement in fatigue as compared with placebo groups.

Choi reported updated findings from a randomized trial of YOCAS; an earlier report showed the program significantly improved sleep quality in cancer survivors. The new analysis centered on the program’s impact on mood disturbance, anxiety, and fatigue, and whether improvement in those side effects contributed to improved sleep quality.

The 4-week YOCAS program consisted of twice-weekly 75-minute yoga sessions led by practitioners who received training in working with cancer survivors. The sessions included 18 yoga postures, breathing exercises, and meditation. Participants also received a mat, booklet, and access to videos for practicing yoga at home.

Participants in the randomized trial had completed treatment for cancer and reported persistent moderate/severe sleep disturbance. The study excluded patients with sleep apnea or metastatic cancer and those who had practiced yoga regularly within the previous 3 months.

Investigators at multiple sites in 12 U.S. cities enrolled and randomized patients to standard follow-up care with or without YOCAS. The primary endpoint was the change in score on objective measures of mood disturbance, anxiety, and fatigue, which were assessed by means of the Profile of Mood States, and insomnia by the Insomnia Severity Index.

Data analysis included 410 randomized participants who had a median age of 54, and white women accounted for more than 90% of the participants. Three-fourths of the patients had breast cancer, and half were on hormonal therapy. On average, participants attended 6.5 of the eight prescribed YOCAS sessions.

A comparison of results between the two groups showed a mean difference in mood disturbance of 5.08 (P<0.001), in anxiety of 0.72 (P<0.05), and in fatigue of 1.49 (P<0.001).

To examine the contributions of the cancer-related side effects to improvement in insomnia, investigators performed causal mediation analysis. The total improvement in insomnia score was 2.6. Causal mediation analysis showed a direct effect of YOCAS accounted for 75% (1.95) of the improvement in insomnia and the effect on mood disturbance for 25% (0.65). The analysis showed the same results for the YOCAS effect on insomnia and fatigue.

“Our findings suggest that our YOCAS intervention is an effective integrative medicine intervention to improve mood disturbance, anxiety, fatigue, and insomnia among cancer survivors,” said Choi. “The findings further suggest that part of the reason you improve insomnia is because it reduces mood disturbance and fatigue. Clinicians should consider recommending gentle Hatha and restorative yoga for cancer survivors who experience these side effects.”

Bupropion

The rationale for bupropion to treat cancer-related fatigue includes the agent’s anti-inflammatory effects, inhibiting tumor necrosis factor-alpha and NF-kappaB signaling, which are linked to fatigue, said Peppone. Additionally, bupropion boosts norepinephrine to restore disrupted cortisol rhythms in fatigued patients. The drug is generically available and has a favorable safety profile. Two small open-label pilot studies suggested a beneficial effect on cancer-related fatigue.

Investigators in the University of Rochester Cancer Center NCI Community Oncology Research Program conducted a randomized, phase III trial involving adults with any type or stage of cancer, fatigue score ≥4 out of 10 within the past week, and treatment completed at least 2 months previously. Patients were randomized to bupropion or placebo and followed for 12 weeks. The primary endpoints were change in the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) subscale at 12 weeks and tolerability.

Data analysis included 428 randomized patients, who had a mean age of 61-62, and women accounted for 81-85% of the study population. Three-fourths of the patients had breast cancer, which was stage 0-1 in 70% of cases. About two-thirds of the patients had received chemotherapy and radiation therapy. Baseline fatigue was similar between the two groups.

At week 12, the adjusted mean FACIT-F score was 36.1 in the bupropion group and 34.1 in the placebo group, a difference that achieved statistical significance (P=0.03). The proportion of patients who achieved the co-primary endpoint of at least a 3-point improvement did not differ significantly between the two groups (79% vs 75%, P=0.39).

The prespecified moderator analysis by sex showed that men did not benefit from bupropion (-2.72 vs the placebo group), whereas women obtained a significant benefit (+2.83 vs placebo, P=0.006). Patients with a history of smoking, another prespecified moderator, also benefited from bupropion (+4.24 vs placebo, P=0.005), whereas never-smokers did not benefit (+0.58, P=0.63). Bupropion did not work better in patients who had higher baseline depressive symptomatology, said Peppone.

Adverse events occurred in a similar proportion of patients in the two groups.

Peppone said laboratory analysis is ongoing to investigate relationships between study outcomes and different biological parameters.

Exercise and Methylphenidate

The rationale for evaluating exercise and methylphenidate comes from studies showing that each intervention has a modest impact on fatigue, said Yennu. A pilot study provided preliminary evidence of a beneficial effect.

Eligible patients had prostate cancer treated with androgen deprivation therapy and/or radiation therapy, fatigue within the prior 2 weeks, no recent history of regular moderate or vigorous physical activity, no evidence of cognitive failure, and hemoglobin level ≥10 g/dL. Patients were randomized to four intervention groups: exercise plus methylphenidate or placebo and stretching plus methylphenidate or placebo.

Patients randomized to exercise groups participated in a standardized regimen for 12 weeks, consisting of aerobic exercise and resistance training. Patients in the stretching control groups engaged in passive static stretching exercises 4 days a week.

The primary endpoint was the change in FACIT-F score from baseline to 12 weeks. The study population consisted of 161 men: 65 randomized to exercise and methylphenidate, 34 to exercise and placebo, 30 to stretching and methylphenidate, and 32 to stretching and placebo.

The study was powered to detect a standardized effect size of 0.392 using a linear mixed-effects model that included treatment, time, and interaction. Investigators assumed a 10-point difference in FACIT-F change from baseline.

Comparison of the change in FACIT-F between exercise plus methylphenidate or placebo groups did not achieve statistical significance (P=0.097). The only between-group difference that did reach statistical significance was exercise-methylphenidate versus stretching-placebo (P=0.019). Comparison of methylphenidate-containing arms versus placebo-containing arms also achieved statistical significance (P=0.008). Comparisons of exercise versus stretching did not achieve statistical significance.