Background

Fatigue is one of the most common complaints in cancer patients. It can be due to cancer per se or because of treatment modalities like chemotherapy, radiotherapy or surgery. Fatigue is an important cause of decreased quality of life and suffering in patients with cancer and is frequently overlooked and unaddressed. Many patients continue to have severe fatigue and it interferes with activities of daily living (ADLs).(1) Physicians have insufficient knowledge about fatigue.(1) There are many studies which have reported on the prevalence and effect of fatigue, however, there is a paucity of studies in literature looking at the pharmacological and psychological treatment of chemotherapy-associated fatigue. Steroids have been known to have a positive effect on metabolism and sense of general well-being. Studies have been done in which only a short course of steroids was used to assess the improvement in symptoms. However, no studies have been done so far looking at improvement in fatigue over long-term. If fatigue can be controlled in these patients, it will be an important achievement in palliative care. The current study aims to look at the benefit of long-term use of steroids in controlling cancer associated fatigue in patients receiving chemotherapy.

Review of literature

Cancer related fatigue

Fatigue is one of the most common and treatable problems in cancer patients. It is difficult to define and is multidimensional. It may be perceived as physical tiredness, need for reduced activity and decreased motivation. Fatigue also has psychological dimensions like mental fatigue which includes reduced capacity for attention, concentration, and learning, and disturbance in short-term memory. (2) The International Classification of Diseases-10 (ICD-10) criteria for cancer-related fatigue require ‘significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level’ to be present every day or nearly every day during the same 2-week period in the past month, as well as the presence of additional symptom including generalised weakness, diminished concentration, insomnia or hypersomnia and unrestorative sleep.(3)

Many patients report fatigue as very important and distressing symptom. (1) National Comprehensive Cancer Network (NCCN) Cancer-Related Fatigue Panel describes fatigue as universal symptom in cancer patients. (4) The overall prevalence of fatigue in cancer ranges from 50 to 90 percent depending on patient sample and estimation method with the prevalence being more in patients actively undergoing treatment for cancer. (1) In a study by Glaus et al, more than 75 percent of patients reported tiredness and more than usual need for rest, 20 to 50 percent of patients reported lack of motivation, sadness and anxiety and 25 percent reported inability to concentrate and difficulty in thinking.(5) Cancer related fatigue can present as tiredness, weakness, and lack of energy and is not relieved by rest or sleep.  Fatigue can be an early symptom of malignancy and is reported in around 40% of patients at diagnosis.  In one-third of the patients, it can persist for months to years following completion of treatment. It significantly affects patient’s quality of life and functioning. (6)

Two studies looked at the prevalence of fatigue in patients on chemotherapy. In a study done by Curt et al, 76% patients reported fatigue on at least few days during the chemotherapy and 30% reported fatigue every day. 91% of patients reported that fatigue prevented their normal life. (7) In another study, among 379 individuals receiving chemotherapy with or without RT, 37 per cent reported fatigue for at least 2 weeks in the prior month.(8)

Many scales are used to assess fatigue in cancer patients. One systematic review of scales used to assess cancer related fatigue found that the Functional Assessment of Cancer Therapy Fatigue (FACT F), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) (fatigue subscale) and the Fatigue Questionnaire (FQ) were most commonly used and validated.(9) Most of these scales are developed in western population and in a country like India with multiple languages and also illiteracy, visual analogue scale of assessment is needed. Symbolic Assessment of Fatigue Extent (SAFE) has been developed at Cancer Institute and has been validated. It correlated significantly with measures of quality of life, anxiety, depression, and sleep. The tool was able to distinguish between cancer patients, survivors, and healthy controls. (10)

Many mechanisms have been described to explain the fatigue in cancer. One is increased serotonin levels in brain or upregulation of serotonin receptors. Systemic cytokines like interleukin (IL)-1b, interferon (IFN)-a, IFN-g, and TNF-α alter the serotonin metabolism in the brain and play a role in development of fatigue. Another mechanism is disturbance in hypothalamic-pituitary-adrenal (HPA) axis. Many patients with chronic fatigue syndrome have low levels of circulating cortisol. It has been shown that patients with active cancer have blunted response of cortisol to various stressors. It has also been shown that women who are survivors of breast cancer have significantly lower cortisol levels and there was significant difference between women who experience fatigue and those who do not. Women with more fatigue had lesser early morning cortisol. (2) Sleep related disorders and disturbance in circadian rhythm are other mechanisms proposed. Cytokines, in addition to alteration in serotonin metabolism, play very significant role in many symptoms of cancer like fever, night sweats, cachexia, anemia, depression and susceptibility to infections. (11) Steroids are known to supress production of cytokines.

Treatment of cancer related fatigue includes non-pharmacological interventions like cognitive behavioral therapy, exercise and sleep therapy. Pharmacological agents that have been tried include CNS stimulants like methylphenidate, modafinil, anabolic agents like erythropoietin. Methyphenidate and modafinil had benefit in patients with severe fatigue and use of erythropoietin had increased risk of thromboembolic events and higher mortality. Other agents like dextroamphetamine, multivitamins and antidepressants have not been shown to have benefit. (1)

Steroids in cancer related fatigue

Corticosteroids are one of the important drugs used in palliative care setting with a frequency ranging from 32 to 80%. (12) These have anti-inflammatory effects and modulatory effects on proinflammatory cytokines interleukin 6, interleukin 1b, tumor necrosis factor α, and prostaglandin E2 and dopamine, which have been associated with a number of distressing symptoms related to cancer and their treatment. They also impact hypothalamic-pituitary-adrenal axis function and also tumor mass, function, and tumor by-products.

Moertel et al (13) studied the effects of dexamethasone in patients with preterminal gastrointestinal cancers. They performed a randomised controlled trial where patients (N=116) received dexamethasone 0.75 mg or 1.5 mg four times a day or placebo. At the end of 4 weeks, patients on dexamethasone had significant improvement in appetite (p<0.05) and strength (p=0.07) compared to placebo and there was no difference between low and high dose dexamethasone. No difference in survival was found. One patient had gastrointestinal haemorrhage and 36% had edema compared to 30% in placebo.

In a randomized placebo-controlled study by Paulsen et al (14), 50 adult patients with cancer receiving opiods and pain score of >4,  were randomly assigned to methylprednisolone 16 mg twice daily versus placebo for 7 days. AT the end of study, statistically significant improvement was found in terms of fatigue (p=0.003) and loss of appetite (p=0.003) as measured by European Organisation for Research and Treatment of Cancer–Quality of Life Questionnaire and patient satisfaction (p=0.001). There was no difference in the number of adverse events though patients on steroids reported more restlessness and sleeplessness.

Bruera et al (15) in 1985, conducted a randomized, double-blind crossover trial comparing 14 day course of oral methylprednisolone against placebo for the relief of pain and other symptoms in 40 terminally ill cancer patients. After the 14-day, double-blind phase was completed and all patients were given methylprednisolone for 20 days. The daily dose of methylprednisolone was 32 mg. There was a significant benefit regards to pain (p<0.01) and 77 percent patients reported improved appetite and 68 percent reported improved activity. 71 percent reported decrease in depression. Methylprednisolone was chosen over placebo by 71 percent of patients. No serious toxicity was observed.

Della Cuna et al (16) in 1989, did a randomised double-blind, placebo-controlled study in which 403 patients were randomised to receive 125 mg/ day of intravenous methylprednisolone versus placebo for 8 weeks. There was improvement in quality of life as judged by the changes from baseline in the Nurses’ Observational Scale for Inpatient Evaluation (NOSIE), the Linear Analog Self-Assessment Scale (LASA)scores (P<0.05) and by the Physicians’ Global Evaluation (P <0.001).

Yennurajalingam et al (17) conducted a placebo-controlled RCT in patients with advanced cancer using dexamethasone (N = 84). It was found that a dose of 4 mg orally twice a day was able to significantly improve cancer related fatigue as measured by the Functional Assessment of Chronic Illness–Fatigue (FACIT-F) scale (effect size 5.9 points) at day 8 (P =0.005) and day 15 (P = 0.008). Subset analysis suggested a significant improvement in the physical domains of quality of life and distress scores, with no significant effects on psychological domains. No significant differences in the number of adverse events of grade 3 or greater between dexamethasone versus placebo group (P = 0.27) were found. The efficacy or safety of dexamethasone beyond 14 days was not established.

Study Rationale

Steroids have been shown to improve cancer related fatigue over a short term period. However, no studies have been done so far looking at the usefulness and safety of steroids over long term. Corticosteroids, being cheap and easily available, will be of great benefit to patients if proven useful for fatigue in the long term. The results on safety of steroids can be used to develop measures to ameliorate the same. Majority of adverse effects of steroids like osteoporosis and peptic ulceration can be medically managed or prevented. The present study will try to fill the lacuna in the literature on long term use of steroids for cancer related fatigue.

Hypothesis

In patients with advanced cancer on chemotherapy, use of dexamethasone plus standard treatment reduces cancer related fatigue compared to standard treatment alone.

Aim of Study

To assess the safety and efficiency of dexamethasone in reducing cancer related fatigue in patients with advanced cancer on chemotherapy.

Setting:

Patients on palliative chemotherapy will be enrolled from day care and medical oncology wards.

Placebo arm:

Patients shall receive palliative chemotherapy according to the institute protocol and physician choice. Patients shall receive empty capsules as placebo. The capsules cannot be opened and made from vegetable material.

Dexamethasone arm:

In this group, patients will receive palliative chemotherapy and additionally receive 4 mg of dexamethasone per day (equivalent to a prednisolone dose of 20 mg/day).  The antiemetic doses of dexamethasone (8 mg) will be delivered along with chemotherapy as indicated and the study dose of 4 mg/day will be started a day after the anti-emetic dose of dexamethasone is administered. Dexamethasone will be taken in the morning at 8 am after consumption of breakfast.

Patients in the dexamethasone arm will also receive H2 blockers (Tab Ranitidine 150 mg B) and pneumocytis carinii prophylaxis with tablet cotrimoxazole (80mg/400 mg) 2 tablets BD twice a week on Monday and Thursday. Ranitidine and cotrimoxazole will be continued for 2 weeks after stopping dexamethasone.  Our institute data on long term use of steroids as part of oral metronomic chemotherapy in 149 patients with a median duration of treatment 6.1 months did not show any serious adverse effects of 20 mg Prednisolone per day in an intermittent schedule. Thus, we justify use of steroids for 12 weeks.

Laboratory monitoring

Complete blood count and biochemical investigations including serum creatinine, SGOT, SGPT, bilirubin, random blood sugar and albumin will be performed at baseline and monitored prior to each cycle of chemotherapy. Monitoring of white blood cell (WBC) count in between chemotherapy cycles will be according to the recommendations followed for the specific chemotherapy protocol.  Random blood sugar and blood pressure will be assessed every week in the patients receiving dexamethasone. Patients who develop diabetes or hypertension while on dexamethasone will be medically managed according to the current guidelines.

Study Period

Patients will start dexamethasone on the first day of first cycle of chemotherapy and receive it for a total duration on 12 weeks (3 months). Dexamethasone will be tapered and stopped over 1 week after completion of 12 weeks. Dexamethasone will be stopped before 12 weeks if the patient is not planned for chemotherapy due to various reasons like disease progression or chemotherapy related toxicity. Dexamethasone will also be stopped for patients who develop grade 3 or 4 toxicity related to its administration.  Patients having grade 2 toxicity due to dexamethasone will receive the drug on alternate days till the toxicity resolves.

Evaluation of Toxicity

Toxicity due to dexamethasone and chemotherapy will be monitored using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 grading system.

Evaluation of Fatigue:

Symbolic Assessment of Fatigue Extent (SAFE) scale will be used to calculate magnitude and extent of fatigue. The SAFE scale will be administered before the initiation of chemotherapy and at the end of 6 and 12 weeks of chemotherapy. The SAFE scale will be administered by the investigators or staff from the psycho-oncology department. NCI CTCAE V4.0 grading of fatigue will also be done.

SAFE Scale

SAFE (Symbolic Assessment of Fatigue Extent) scale (Annexure A) is a visual analogue scale useful in multi-lingual and multi-literate populations. It has 4 questions about fatigue extent, each scored from 0 to 4. If the answer is 0, the scoring is not carried out further. The minimum score is 0 and maximum score is 16. Then, there are 8 questions about the impact of fatigue on patient, with each having responses from 0 to 4. Minimum score is 0 and maximum is 32.

EORTCQLQ c30 FATIGUE SCALE(18)

EORTC QLQ c30 scale (Annexure B) is used to assess quality of life in cancer patients. It has 30 questions with 28 questions having response from 1 to 4 and 2 questions from 1 to 7. There is a subscale for fatigue in cancer patients which needs to be co-administered along with QOL c30 scale which is called EORTC QLQ FA-12 scale (Annexure C). It has 12 questions and the responses are from 1 to 4.

NCI CTCAE V4.0 FATIGUE GRADING

Fatigue is defined as state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities. The grading is as follows-

Grade 1 – fatigue relieved by rest

Grade 2 – Fatigue not relieved by rest. Limiting instrumental ADLs. (Instrumental ADLs include preparing meals, shopping, using the telephone, managing money. Self-care ADLs include bathing, dressing, using the toilet, taking medications.)

Grade 3- Fatigue not relieved by rest, limiting self-care ADLs.

End points

Patients will be censored in the trial at the following instances

1.      Death.

2.     Patient withdraws from the trial.

3.     Completion of 12 weeks of dexamethasone

4.     Discontinuation of dexamethasone before 12 weeks of planned treatment due to stopping of chemotherapy by the treating physician because of disease progression or toxicity.

Serious Adverse Events (SAE)

The following will be considered as SAE and will be reported to ethics committee and data safety monitoring board (DSMB).

·       Mortality directly attributable to dexamethasone

·       Grade 3 or 4 toxicity attributable to dexamethasone including gastrointestinal bleeding, diabetes mellitus (RBS>300 mg%), fractures, psychosis and hypertension.

References

1.         Campos MPO, Hassan BJ, Riechelmann R, Del Giglio A. Cancer-related fatigue: a practical review. Ann Oncol. 2011 Jun 1;22(6):1273–9.

2.         Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow GR. Mechanisms of Cancer-Related Fatigue. The Oncologist. 2007 May 1;12(Supplement 1):22–34.

3.         Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W. Progress toward guidelines for the management of fatigue. Oncol Williston Park N. 1998 Nov;12(11A):369–77.

4.         Mock V, Atkinson A, Barsevick A, Cella D, Cimprich B, Cleeland C, et al. NCCN Practice Guidelines for Cancer-Related Fatigue. Oncol Williston Park N. 2000 Nov;14(11A):151–61.

5.         Glaus A, Crow R, Hammond S. A qualitative study to explore the concept of fatigue/tiredness in cancer patients and in healthy individuals. Eur J Cancer Care (Engl). 1996 Jun;5(2 Suppl):8–23.

6.         Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-Related Fatigue: The Scale of the Problem. The Oncologist. 2007 May 1;12(Supplement 1):4–10.

7.         Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. The Oncologist. 2000;5(5):353–60.

8.         Cella D, Davis K, Breitbart W, Curt G, Fatigue Coalition. Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol Off J Am Soc Clin Oncol. 2001 Jul 15;19(14):3385–91.

9.         Minton O, Stone P. A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol. 2009 Jan 1;20(1):17–25.

10.       Jeyaram S, Veeraiah S, Elangovan V. Validation of the symbolic assessment of fatigue extent (SAFE)—a cancer fatigue tool with visual response formats. Support Care Cancer. 2017 Apr 1;25(4):1111–9.

11.       Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer. 2001 Sep 15;92(S6):1684–8.

12.       Yennurajalingam S, Bruera E. Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids. Cancer J Sudbury Mass. 2014 Oct;20(5):319–24.

13.       Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer. 1974 Jun;33(6):1607–9.

14.       Paulsen Ø, Klepstad P, Rosland JH, Aass N, Albert E, Fayers P, et al. Efficacy of Methylprednisolone on Pain, Fatigue, and Appetite Loss in Patients With Advanced Cancer Using Opioids: A Randomized, Placebo-Controlled, Double-Blind Trial. J Clin Oncol. 2014 Oct 10;32(29):3221–8.

15.       Bruera E, Roca E, Cedaro L, Carraro S, Chacon R. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep. 1985 Aug;69(7–8):751–4.

16.       Della Cuna GR, Pellegrini A, Piazzi M. Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: a placebo-controlled, multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol. 1989 Dec;25(12):1817–21.

17.       Yennurajalingam S, Frisbee-Hume S, Palmer JL, Delgado-Guay MO, Bull J, Phan AT, et al. Reduction of Cancer-Related Fatigue With Dexamethasone: A Double-Blind, Randomized, Placebo-Controlled Trial in Patients With Advanced Cancer. J Clin Oncol. 2013 Sep 1;31(25):3076–82.

18.       Scott NW, Fayers P, Aaronson NK, Bottomley A, Graeff A de, Groenvold M, et al. EORTC QLQ-C30 Reference Values Manual. 2008 Jul [cited 2018 Mar 25]; Available from: https://abdn.pure.elsevier.com/en/publications/eortc-qlq-c30-reference-values-manual