|Year : 2017 | Volume
| Issue : 6 | Page : 916-929
Cancer-related fatigue treatment: An overview
Hemanth Mohandas1, Saravana Kumar Jaganathan2, Mohan Prasath Mani3, Manikandan Ayyar4, GV Rohini Thevi1
1 Department of Biomedical Engineering, The University of Texas at Arlington, Arlington 76019, TX, United States of America
2 Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam; Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; IJN-UTM Cardiovascular Engineering Centre, Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia, Skudai 81300, Johor, Malaysia
3 IJN-UTM Cardiovascular Engineering Centre, Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia, Skudai 81300, Johor, Malaysia
4 Department of Chemistry, Bharath Institute of Higher Education and Research, Bharath University, Chennai, Tamil Nadu, India
|Date of Web Publication||13-Dec-2017|
Dr. Saravana Kumar Jaganathan
Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam
Source of Support: None, Conflict of Interest: None
Cancer-related fatigue is a symptom of cancer where most patients or the general practitioners tend to misinterpret due to the insufficient understanding or knowledge of cancer-related fatigue (CRF). This paper will provide a better perspective for the patients and the health professionals on how to manage and handle CRF for both mild and severe fatigue patients. Articles were selected from the searches of PubMed database that had the terms “randomized controlled trials,” “cancer,” “fatigue,” “pharmacologic treatment,” and “nonpharmacologic treatment” using both Mesh terms and keywords. The authors have reviewed the current hypothesis and evidence of the detailed etiology of the CRF present in the literature for healthier management, directives, and strategies to improve the treatment of cancer-related fatigue. An algorithm has been blueprinted on screening, and management, of the CRF, and various kinds of effective treatments and assessment tools have been briefly studied and explained. Although many strategies seemed promising, the quality of randomized controlled trials is generally quite low in studies, making it difficult to draw conclusions about the effectiveness of each self-care strategies. Therefore, future studies require better design and reporting of methodological issues to ensure evidence-based self-care recommendations for people receiving cancer treatment.
Keywords: Cancer-related fatigue, complementary and alternative medicine, erythropoietin-stimulating agents, management of cancer-related fatigue, Modafinil, nonpharmacologic treatment, pharmacologic treatments, psychostimulants, randomized controlled trials
|How to cite this article:|
Mohandas H, Jaganathan SK, Mani MP, Ayyar M, Rohini Thevi G V. Cancer-related fatigue treatment: An overview. J Can Res Ther 2017;13:916-29
| > Introduction|| |
Cancer-related fatigue (CRF) is one of the most commonly found problems among the cancer survivors which affect all aspects of quality of life (QOL), but it is a treatable problem. CRF is the highly prevalent and debilitating symptom experienced by most of the cancer patients at diagnosis, which increase during therapy and often seen for considerable period of time (months and years) after well-structured cancer diagnosis. Globally, around 50%–90% of the cancer patients experiences the difficulties of cancer-related fatigue, the latter number resemble to the patients subjected to active anticancer chemotherapy and radiotherapy. CRF has been well-defined as per the guiding principle of the National Comprehensive Cancer Network (NCCN) as “a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.” Although a lot of evidence and research findings on CRF have been provided within the last two decades, CRF is still underreported, underdiagnosed, and undertreated.
The pathogenesis of cancer-related fatigue is ambiguous, and a variety of mechanisms may contribute to its development. These contain effects of cancer and its treatment on neuropsychological impairment, muscle metabolism dysregulation, circadian rhythms disruption, mediators of inflammation and stress, immune activation, and hormonal changes related to effects on the hypothalamic-pituitary axis, premature menopause in women, or androgen deprivation in men.,,,, As shown in [Figure 1], the most common symptoms of cancer-related fatigue include physical fatigue (inactivity, idleness, and stress) and mental fatigue (reduced capacity of attention, concentration, learning, and short-term memory loss) along with pain and nausea and vomiting (which are mostly due to the cancer and its treatments). Patients aged greater than 60 years are expected to have fewer symptoms than younger patients; female patients are expected to have more side effects than male patients.
|Figure 1: Representing the most common symptoms of cancer-related fatigue|
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Fortunately, with the notable progress of biological-psychological-social medical model, extension of the overall survival time, and much more confirmed pursuit toward higher QOL, CRF has provoked stronger concern among the medical personnel, patients, and corresponding relatives. Regretfully, faced with the absence of any detailed official guidelines on how to manage CRF, it is essential to study and explore present screening, assessment, and both pharmacologic and nonpharmacologic therapies. The articles have been selected for their significance from the searches of the PubMed database that combined the terms “randomized controlled trials,” “cancer,” “fatigue,” “pharmacologic treatment,” and “nonpharmacologic treatment” using both Mesh terms and keywords, with wide range of data (21st century). The authors have reviewed the current hypothesis and evidence of the detailed etiology of the CRF present in the literature for healthier management, directives, and strategies to improve the treatment of cancer-related fatigue.
| > Screening, Evaluation, and Management of Cancer-Related Fatigue|| |
Effective management of CRF is important for patients and challenging for clinicians. Most of the outcomes from cancer and its treatment have been reasonably characterized very well, but less is known on how the patients interact and respond with these fatigues during and after the treatment. General practitioners may have insufficient understanding of fatigue and its effects or may misinterpret the impact of it on the QOL of the patient. On the other hand, the patient may consider it as inevitable and irrevocable side effect and fear on reporting it may perhaps incite a change toward less aggressive cancer treatment. Numerous valuation scales have been developed for screening, but there are no consensuses on the best available assessment scale. There are two types of fatigue assessment tools: unidimensional tools and multidimensional tools. The simplest of these tools are unidimensional tools which are single-item measures of CRF, such as visual analog scale (VAS), brief fatigue inventory (BFS), MD Anderson Symptom Inventory, and Cancer-related Fatigue Distress Scale. Multidimensional Fatigue Inventory, Functional Assessment of Cancer Therapy-Fatigue (FACT-F) Subscale Instrument, Multidimensional Fatigue Symptom Inventory, Piper Fatigue Scale, Fatigue Symptom Inventory, and Cancer Fatigue Scale are the multidimensional tools, which consider more than a single-item measure of CRF. It is more detailed with questionnaires, hence mainly used in clinical research.
According to NCCN, evaluation and treatment of cancer fatigue is based on four phases: screening, primary evaluation, intervention, and re-evaluation. Screening is done by quantitative or semi-quantitative assessment tools such as BFS, VAS, or FACT-F and is documented. Diagnosis of CRF excludes reversible treatable contributing factors such as pain, hypothyroidism, climacterium, emotional distress, electrolyte or metabolism disturbances, or organ dysfunctions such as heart failure, myopathy, or pulmonary fibrosis. Primary evaluation includes the study of patient's history and physical examination and evaluation of undergoing cancer treatment. Later, the cancer-associated fatigue treatment or intervention is planned for the patient as per the assessment of fatigue and primary evaluation, along with re-evaluation at regular intervals of undergoing treatment. Those with moderate or severe fatigue may benefit with both pharmacologic and nonpharmacologic interventions, while mild fatigue that does not interfere with QOL can be treated with nonpharmacologic interventions. A schematic algorithm for the CRF screening and treatment is presented in [Figure 2] for the patients and clinician perusal. The various nonpharmacologic and pharmacologic treatments are explained in detail [Figure 3].
|Figure 2: Representing the algorithm of diagnosis and treatment of cancer-related fatigue, respectively|
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|Figure 3: Denoting the different types of treatment for cancer-related fatigue|
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| > Nonpharmacologic (Self-Care Strategies) Treatment|| |
Patients with mild CRF can be related with nonpharmacologic treatment and patients with severe fatigue should be related with both pharmacologic and nonpharmacologic treatments. The preliminary treatment for any CRF necessitates an inclusive valuation on patient life, education and cancer treatment plan, and development of a systematic fatigue treatment according to the overall patient study. Exemptions should to be addressed and practical goals have to be established.
| > Cognitive-Behavioral Interventions|| |
Cognitive-behavioral therapy (CBT) is “problem focused” and “action oriented,” which includes group therapy, stress reduction, relaxation training, fatigue-related psychoeducational, and other supportive interventions.,,, A number of pilot and randomized controlled trials (RCTs) on CBT along with other interventions resulted in clinically relevant effect in reducing fatigue, pain, and sleep disturbance.,,, CBT and Hypnosis (CBTH) is noninvasive, has no adverse effects, and its beneficial effects persist long after the last intervention session, but does not have any neuropsychological test performance. Assessment of epithelial ovarian cancer patients with exercise-CBT intervention was associated with significant increase in aerobic fitness.
A review containing 27 studies of moderate quality on effectiveness of psychosocial interventions on patients suffering from cancer fatigue showed that interventions specific for fatigue was significantly higher (80%) compared to interventions not specific for fatigue (14%). A modest gain was seen in CRF treatment group where 396 fatigued cancer patients beginning with chemotherapy or radiotherapy were randomly allotted to spend similar nursing orientation time focused on either diet and nutrition or strategies to preserve energy and monitor the association of different activities with level of fatigue. These interventions help the individuals to educate themselves and be strong mentally and physically and get emotionally strong to find against the illness. The interventions help in getting along with the peer groups undergoing the same difficulties and provide support for each other. This intervention combined with other nonpharmacologic interventions can yield good results for CRF treatments.
| > Exercise|| |
Physical activity is one of the most supporting evidence of effectiveness in fatigue management. Several studies specified that the role of exercises has positive effects that decrease rates of fatigue, enrich physical performance, and advance QOL.,, A recent study on home-based exercise program was capable of improving the mobility, fatigue, and sleep quality of patients with Stage IV lung and colorectal cancer. Regular physical exercises increase the functional capacity, thereby reducing the effort to carry on daily activities. Regular exercise improves the health condition of patients who have experienced multiple chemotherapy and radiation therapy in breast cancer, prostate cancer, and lymphoma cancer patients. Exercise also helps in improving the cardiovascular fitness of the patient. Allowing the patients to choose their exercise regimen  and providing printed information and motivating materials such as step pedometer  improves the outcome. According to us, this intervention is being very effective in treating the CRF. Regular physical exercise means very mild exercises such as walking and moving the body parts, which helps the person to be more active. The combination of this intervention with CBTH can help provide better results.
| > Rest and Sleep|| |
Review articles have established that fatigue is associated with poor sleep. Randomized clinical trials have reported positive effects on both sleep and fatigue after 4–5 weekly behavioral sleep sessions in breast and mixed-diagnosis cancer survivors with insomnia years after receiving chemotherapy. A BT sleep intervention studies reported that fatigue was mild before cancer treatment, moderate but decreasing during treatment, and mild 1 year after treatment.,, Total sleep time and sleep percent were normal, but number and duration of night awakenings were elevated. Most individuals suffering from cancer and CRF will have trouble in a good night sleep or rest. Anything which can provide the patient with good sleep and rest will help them improve their treatment conditions.
| > Nutrition|| |
Undernutrition is a major source of morbidity and mortality in individuals with cancer. Evidence from a study counting 205 consecutive patients with head and neck, gastroesophageal, colon, and rectum cancer revealed that a proper and systematic diet combined with essential nutritional supplements will optimize the QOL for patients. A study on nutritional supplements on 111 colorectal cancer patients showed that the nutritional supplements and diet followed by the patients had made a significant contribution to improving the nutritional deficiencies that resultant from anorexia, diarrhea, and nausea and vomiting. The prevalence of malnutrition in a radiation oncology study was 39.2%. The results of this study served a basis for the implementation of nutrition intervention to patients being treated with radiation therapy. A healthy diet and the intake of the right amount of vitamins, minerals, proteins, and carbohydrates can help the patient gain energy and fight the disease and its fatigue.
| > Complementary and Alternative Medicine|| |
The World Health Organization defines complementary and alternative medicine (CAM) as including diverse health practices, approaches, knowledge and beliefs incorporating plant, animal, and/or mineral based medicines, spiritual therapies, manual techniques, and exercises applied singularly or in combination to maintain well-being, as well as to treat, diagnose or prevent illness. CAM is also described as a comprehensive term used to refer to both traditional medical systems such as traditional Chinese medicine, Indian Ayurveda, Arabic Unani medicine, and to various forms of indigenous medicine. Acupuncture is the most common treatment seen in CAM. Acupuncture and moxibustion appeared an efficacious auxiliary therapeutic method for CRF. A significant improvement was seen in 37 patients treated with six to eight sessions of acupuncture, who had undergone chemotherapy treatment for an average of 2 years. Another study of 47 fatigued cancer patients randomly assigned to acupuncture, acupressure, and sham acupressure showed that acupuncture had significant benefit over acupressure and sham acupressure.
Intravenous (IV) Vitamin C treatment has been gaining popularity in CRF treatment in the past few years showing improvement in a number of cancer and chemotherapy-related symptoms, such as fatigue, insomnia, loss of appetite, nausea, and pain. Evidence has been gathered from the past studies which point out that IV vitamin C may improve the QOL of cancer patients, both in the presence and absence of adjuvant chemo- and radiotherapy.,, Other treatments include herbalism, aromatherapy and reflexology, yoga  and much more, but the effectiveness of these treatments are not researched on solid evidence. The CAM treatments prove to be very effective for cancer-related fatigue. A number of CAM procedures have been practiced around the globe and very few of them are been published. A number of treatments discussed above should be tested on RCTs on a number of patients to find the best treatment for cancer-related fatigue.
| > Pharmacologic Treatment|| |
Pharmacological treatments were not seen until the late 1980s due to the misperception of CRF as an inevitable and omnipresent consequences of cancer and its treatment. Later on, awareness of prevalence and impact of CRF increased and so did the concern on its original pathophysiology. Owing to the greater awareness, research began focusing on identifying the therapeutic interventions starting initially from pharmacologic treatment and later leading on with nonpharmacologic treatments. Erythropoietin-stimulating agents (ESAs) and psychostimulants are the two most popular nonpharmacologic treatments studied and will be discussed in the forthcoming paragraphs along with Modafinil, L-carnitine, and other recent pharmacologic treatments.
| > Hematopoietics (OR) Erythropoietin-Stimulating Agents|| |
One of the most reversible causes of CRF is anemia and it has a significant impact on a patient's level of fatigue and QOL. In the presence of anemia, efforts should be taken in order to identify correctable causes such as iron deficiency, B12 or folate deficiency, blood loss or hemolysis. In case no issues are found or the condition persists despite of the correctable treatment, ESAs and blood transfusions may be considered, according to the guidelines on the use of ESA published by the American society of Hematology in 2002 and updated in 2007. Erythropoiesis-stimulating agents have shown a steady increase in hemoglobin levels, a reduced need for blood transfusions, and improvement in overall QOL. The two erythropoietin found in the literature for cancer fatigue treatments are Epoetin (alfa/beta) and Darbepoetin.,,,,, Comparisons made between Epoetin alfa and Darbepoetin from a recently published real-world clinical trial resultant in increased hemoglobin level and no reports of serious drug-related adverse events. Rendering to a systematic study, there was no clinically important difference between the two types of erythropoietin, and both drugs can be safely and effectively used for treating chemotherapy-induced anemia, leading to improved fatigue levels.
Patients achieved significant improvement in energy level, activity level, the overall QOL, and a decrease in fatigue., ESA therapy has been effective in producing a hemopoietin response and shown a positive response to a wide variety of tumor types including solid and nonmyeloid hematologic malignancies. On the contrary, some of the recent studies show the development of venous thrombosis in ESA-treated patients., Furthermore, there has been a concern on ESA studies stating ESA increases the mortality rates in some patients. A study reported that the ESA treatment increased the mortality by 17% and worsened overall survival by 6%. A fresh study on investigative and retrospective analysis pronounced increased dose, dose frequency, and dosing duration of erythrocyte sedimentation rate in addition to high hematocrit (HCT) contributed to mortality and thrombosis. In order to further prove the relationship between the factors, the incidence of toxicities was compared in rats and the outcomes displayed that the ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration of ESA, and not solely dependent on a high HCT. In a nutshell, risks of ESAs must be balanced against benefits of ESA, depending on the clinical circumstances of individual patient during clinical practices.
| > Methylphenidate/Dexmethylphenidate (Psychostimulants)|| |
Among traditional psychostimulants, methylphenidate (MPH) has been studied the most, and it is effective and well tolerated among patients with cancer despite common side effects. MPH, a psychostimulant, is one of most researched drugs and most widely administered drug for the pharmacological management of attention deficit hyperactivity disorder patients. Five RCTs experimenting MPH for CRF were found from the literature.,,,, A randomized clinical trial on the efficacy of dex MPH for patients with fatigue after chemotherapy showed significant improvement in fatigue and clinical global impression severity scores (P = 0.02), without clinically relevant changes in hemoglobin levels, but with a higher rate of drug-related adverse events such as headache, nausea, and dry mouth. A different study showed MPH is effective in treating fatigue in men with prostate cancer.
A RCT was carried out to check the effectiveness of MPH compared to placebo in cancer patients with fatigue, and the result revealed that both treatments yield significant symptom improvement. The previous study was further elaborated as a palliative care intervention with the role of daily telephone calls from a research nurse to check the patient's fatigue level, but MPH and nursing telephonic intervention combined were not superior to placebo in improving fatigue. A recent systematic review and meta-analysis study done on the above discussed RCTs ,,, showed that efficacy of MPH on CRF is getting better with prolonging treatment duration, with a MD of − 3.70 (95% confidence interval [CI] −7.03–−0.37, P= 0.03) for long-time group and a MD of − 2.49 (95% CI − 6.01–1.03, P= 0.17) for short-time group. In general, there was no impact of MPH on depression and cognition associated with CRF. Adverse events were similar between MPH and placebo groups except that more patients reported vertigo, anxiety, anorexia, and nausea in MPH group compared to placebo group.
| > Modafinil|| |
Modafinil is a novel central nervous system stimulant used for the treatment of excessive sleepiness and has been administrated by the US Food and Drug Administration for the treatment of narcolepsy, obstructive sleep anemia, and shift-work sleep disorder. A phase 3 randomized, placebo-controlled, double-blind, clinical trials supported the above open-label studies concluding that Modafinil was indeed useful in controlling fatigue in patients with severe fatigue. However, a recently published RCT consisting of adults with advanced nonsmall-cell lung cancer, who were not treated with chemotherapy or radiotherapy within last 4 weeks, randomly assigned to daily Modafinil showed no effect on CRF treatment. Conclusions cannot be met from the very few studies made on Modafinil. More RCTs should be carried out in order arrive at a better conclusion on this treatment and make it available for the patient treatments.
| > L-Carnitine|| |
The main physiological function of Carnitine (β-hydroxyl-γ-N-trimethylaminobutyric acid) is that it acts as a carrier for the translocation of long-chain fatty acid from the cytoplasmic compartment into mitochondria, where beta-oxidation enzymes are located for energy production. One of the reasons of high mortality rate is cancer cachexia, defined as an unintended weight loss of more than 10% in 6 months, which is present in more than 80% of pancreatic cancer patients, and it is the main underlying cause is the deficiency of L-carnitine. The investigation on the effects of L-carnitine on gene expression and liver lipid metabolism-related proteins was carried out in cachectic tumor-bearing rats. The data showed L-carnitine preserves hepatic lipid metabolism in tumor-bearing animals, resulting in the effectiveness of L-carnitine in reversing the cachexia-associated disruption. Further, in vitro studies of L-carnitine on human tumor cells yield positive effects regarding the inhibition of apoptosis and DNA-damage. Various RCT were also gathered on L-carnitine supplements effect on cancer fatigue treatment.,, Two RCTs showed positive results, one for treating pancreatic cancer  and the other for combined treatment of carnitine, celecoxib, and megestrol acetate for cancer-related cachexia syndrome. Unfortunately, L-carnitine cannot be used for the treatment of all types of cancer. A recent mixed cancer RCT study showed that 4 weeks of 2 g of L-carnitine supplementation did not improve fatigue in patients with invasive malignancies. Furthermore, the scope of L-carnitine is yet to be researched on various other cancers to know its complete efficiency to use against cancer-related fatigue.
| > Other Pharmacologic Management|| |
Fresh RCTs was carried out on dexamethasone (high dose corticosteroids) in a total of 84 patients which reported more effective treatment for CRF. However, the study does not allow us to be certain of the efficacy or safety of dexamethasone beyond 14 days, thus limiting its applicability to routine clinical practice in the supportive care setting. American ginseng (Panax quinquefolius) is an herbaceous perennial plant used as Chinese or herbal medicine, and recently two RCTs studies were carried out on American ginseng to be used as a treatment for CRF., Both the results exemplified positive results for improved fatigue treatment for cancer patients. In one study, the benefit of American ginseng on CRF over an 8-week period was seen and no discernible toxicities were associated with the treatment, whereas in the second study, some activity and tolerable toxicity at 1000–2000 mg/day doses of American ginseng with regard to CRF. Studies of numerous further pharmacological treatments were examined for CRF and no significant results were accounted. The effectiveness of donepezil was evaluated alongside placebo in cancer patients with fatigue, but donepezil was not found superior to placebo in the treatment of CRF. Depression-specific treatment such as antidepressant was not sufficient to treat CRF.
| > Conclusion|| |
CRF should be regarded as a serious problem alongside cancer and its treatment. More than 60% of the individuals with cancer experiences fatigue, depression and anxiety, sleeping problems, nausea, stress, and anemia. Guidelines suggest that the patients should screen for fatigue in the initial visits, identify the fatigue cause and treatable factors, start its treatment along with the cancer treatment, and continue after cancer treatment is done. Unidimensional scales for fatigue assessment is appropriate during the initial scoring of fatigue severity. VAS and BFI are two simplest and most commonly used tools during the initial stages of fatigue analysis. However, multidimensional analysis yields more accurate and better results during and after the cancer treatment as an additional number of factors contributes to the fatigue conditions of a neoplasm treating the patient. One of the best multi-dimensional tool and most commonly studied tool is FACT-F. Fatigue treatment also includes taking into account the patient's medical history and psychological study of the patient.
All the RCT used to study both pharmacologic and nonpharmacologic treatments are shown in [Table 1] (RCTs used for Pharmacologic treatment studies) and [Table 2] (RCTs used for nonpharmacologic treatments studies). Moderate and severe fatigue can be treated with both pharmacologic and nonpharmacologic treatments, whereas mild fatigue can be treated with nonpharmacologic treatment. The initial approach to any fatigue treatment is education and counseling for both patient and their family. Education, determination of individualized treatment plan, self-confidence, and stress management can be important and crucial factors affecting the treatment of CRF of the patients. Furthermore, an individualized treatment plan should essentially include nutrition, exercise, sleep, and stress management tactics to help patient gain confidence in the treatment plan. Nonpharmacologic treatments have provided promising results in exercise, sleep therapy, and cognitive-behavioral interventions. CAM also provided great results, but the field of acupuncture, IV Vitamin C, and other CAM treatments such as yoga, reflexology, and herbalism should gain popularity and more studies should be carried out in these areas to yield more promising results. Pharmacologic treatments are an essential tool for severe fatigue treatment of patients. Treatments such as ESAs, MPH, dexmethylphenidate, Modafinil, L-carnitine, and American ginseng have provided tremendous results for cancer fatigue treatment. Care should be taken in handling these pharmacologic treatments, and it should be dispensed in required and appropriate amount, or they may turn out to have harmful side effects. Certain pharmacologic treatments seem to target a specific cancer fatigue, for example, ESA tends to improve Anemia, L-carnitine treats human cachexia, and antidepressants fight depression. Therefore, a fatigue treatment plan should study each fatigue contributing factor, and treatment should be planned out to eradicate each fatigue contributing factor. It is very difficult to tailor therapy according to cancer types, stage, or phase based on the literature. In the trials and observational studies reviewed above, there is a clear tendency to study patients actively undergoing, or immediately following anticancer treatment. This is the case especially among the pharmacologic interventions, and many of the studies do not restrict enrollment to a specific stage or phase of treatment. Finally, although many strategies seemed promising, the quality of RCTs is generally quite low in the studies, making it difficult to draw conclusions about the effectiveness of each self-care strategies. Future studies require better design and reporting of methodological issues to ensure evidence-based self-care recommendations for people receiving cancer treatment.
|Table 1: Randomized controlled trails data collected for nonpharmacologic treatments|
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|Table 2: Randomized controlled trails data collected for pharmacologic treatments|
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Financial support and sponsorship
This work was supported by the Ministry of Higher Education Malaysia with the Grant no.Q.J130000.2545.14H59.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]