Prevalence of fatigue among cancer patients receiving various anticancer therapies and its impact on Quality of Life: A cross-sectional study
Background: Fatigue is disabling and continuous phenomenon in cancer patients during and after various anticancer treatments which can continue for many years after treatment and definitely it has profound effect on Quality of Life (QOL). However, determining its severity is still underestimated among the cancer patients and also very few studies in the literature exist reporting on Cancer-Related Fatigue (CRF) among Indian population.
Keywords: Anticancer therapy-related fatigue, Brief fatigue inventory, Cancer-related fatigue, Concurrent chemo-radiotherapy, FACT-G, Quality of life
Cancer-Related Fatigue (CRF) is one of the most prevalent symptoms of patients with cancer ,, experience, both during and after treatment. It is prevalent condition among patients with cancer and survivors of cancer ,, that occur across all ages, genders, cancer diagnoses, stages of disease, and treatment regimens.  Fatigue associated with cancer or its treatment is distinct from the typical fatigue that most people experience as a result of normal daily life. Unlike typical fatigue, CRF is disproportionate to exertion level and is not relieved by rest or sleep.  Overall 50-90% of cancer patients experience fatigue the latter number corresponding with those undergoing active anticancer chemotherapy or radiotherapy. ,,,,
Fatigue can have an immensely negative impact on patients' Quality of Life (QOL) and daily activities. Research reports that cancer-specific QOL is related to all stages of this disease.  The amount of symptoms distress experienced by an individual has been related to QOL in a number of people with cancer. QOL is increasingly being used as a primary outcome measure in studies to evaluate the effectiveness of treatment. 
Previous studies had clearly defined CRF as disabling and continuous phenomenon in patients during and after treatment  which can continue for many years after treatment and definitely it have profound effect on the life quality.  Until recently, fatigue in patients with cancer was under recognized and under-treated because attention has been focused on other common symptoms, such as nausea and pain. 
The pathogenesis of CRF is not well understood, and a variety of mechanisms may contribute to its development.  These involve effects of cancer or its treatment on the central nervous system, muscle energy metabolism, sleep, or circadian rhythms,  mediators of inflammation and stress,  immune activation, , and so on. CRF may occur due to various treatment therapies such as radiotherapy, chemotherapy, or concurrent chemo-radiation, which is one of the most common, ongoing symptom reported by the patient. , Fatigue is also common in patients undergoing radiation therapy  and in nearly all patients receiving the biologic modifiers interferon or interleukin-2.  Moreover, researchers estimated that about 70% of cancer patients experience fatigue during radiotherapy and chemotherapy. 
Severe fatigue leads not only to physical restrictions but also to serious impairment in QOL, social activities and the ability to go to work. , The incidence and severity of CRF appear to be influenced by characteristics of the patient,  primary malignancy, and type/intensity of treatment.  Therefore, CRF evaluation and classification should be the first step in the clinical assessment of cancer patients for the implementation of an appropriate treatment strategy. The diagnosis of CRF is usually achieved after the exclusion of reversible or treatable causes of fatigue, , and once these potential contributing factors are evaluated, the patients must be investigated through a brief and self-explanatory questionnaire such as Visual Analogue Scale (VAS) or Brief Fatigue Inventory (BFI). ,
Despite its high prevalence and potential negative effect on patients' activities and emotional well-being, research in fatigue is still underdeveloped and there are only very few studies in the literature reporting on CRF among Indian population. Estimating the prevalence of CRF and its association with QOL will enable healthcare providers the adequate, accurate information regarding CRF. Also, it will help the physiotherapist to prescribe appropriate exercises and reduce the impact of fatigue, and improve QOL among cancer survivors. , Furthermore, till now the prevalence has been reported previously for either of two therapies combination or for single therapy and there are no studies in literature reporting the combined comparative prevalence of fatigue among all the three therapies. So the purpose of this study is to measure the proportion of fatigue among cancer patients receiving radiotherapy, chemotherapy, and concurrent chemo-radiotherapy and to assess its relative impact on QOL.
Cancer patients receiving chemotherapy, radiotherapy, and concurrent chemo-radiotherapy of this cross-sectional study were collected by adapting purposive sampling method from the SAIMS Medical College, Head and Oncology Centre, and from MY Government Hospital, Madhya Pradesh, India. Permission with the ethical clearance was obtained from the ethical committee of Srinivas College of Physiotherapy and Research Center and from the ethical committee of those hospitals. This study was approved by the ethical committee of Srinivas College of Physiotherapy and Research Center and was registered with Rajiv Gandhi University of Health Sciences, Bangalore, India.
A total 121 number of cancer subjects were selected for the study using purposive sampling. The sample consisted of patients receiving radiotherapy (20), chemotherapy (59), and concurrent chemo-radiation (42) who were included based on the following criteria. Patients with the age more than 15 years and with the Karnofsky Performance Scale (KPS) score at least 50 were included for the study. Any patient with known history of psychiatric disorders, neurological impairments, cognitive, and perceptual impairments were excluded from participation. The data was collected during the months of July, August, and November 2011.
Brief fatigue inventory
The BFI  is used as screening tool for fatigue which measures severity of fatigue over the previous 24 hours (Alfa = 0.82 to 0.97). The BFI has only nine items, with the items measured on 0-10 numeric rating scales (Annexure 1). [Additional file 4] Three items ask patients to rate the severity of their fatigue at its "worst," "usual," and "now" during normal waking hours, with 0 being "no fatigue" and 10 being "fatigue as bad as you can imagine." Six items assess the amount that fatigue has interfered with different aspects of the patient's life during the past 24 hours. The interference items include general activity, mood, walking ability, normal work (includes both work outside the home and housework), relations with other people, and enjoyment of life. The interference items are measured on a 0-10 scale, with 0 being "does not interfere" and 10 being "completely interferes. Fatigue was categorized using the BFI as either severe (score 7-10) or no severe (score 0-6), with the latter further subcategorized into moderate (score 4-6) and mild (score 0-3). 
The functional assessment of cancer therapy-general (FACT-G) scale
FACT-G  is widely used to measure health-related Quality Of Life (HRQOL) in cancer patients. The latest version 4 consists of a total of 27 Likert-type items formulated into separate subscales: Physical (seven items), emotional (six items), social/family (seven items), and functional (seven items) well-being (Annexure 2). [Additional file 5] Subjects are asked to respond to each item with a score of 0-4, where 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much. A higher score indicates a better quality of life. 
Participants who met the inclusion criteria were clearly explained about the study and written consent was taken from them stating their voluntary participation. Ethical committee approval was obtained from the hospitals where the patients were approached. Pre-participation data was taken for each subject prior to study which included name, age, sex, literacy level, concurrent disease, socioeconomic status, type of cancer, type of therapy received, and type of cancer. Along with this KPS score was also taken where, the lower the score, the worse the survival for most serious illnesses. The cut-off score was 50.
Survey was conducted in the months of July, August, and November 2011. Various types of cancer sufferers participated while they were receiving three different therapies in the hospital as in-patients. Subjects were asked to fill the questionnaire to measure their level of fatigue and quality of life by using Brief Fatigue Inventory and FACT-G respectively. The participants, who did not know to read and write, were explained about the questions in their mother tongue by the researcher and response was noted on the interview basis.
The data collected was tabulated using Microsoft Excel work sheet and the data was analyzed using SPSS 11.0 version. Prevalence rate is measured on the basis of number of patients under the category of mild, moderate and severe and their percentage is calculated from the total number of patient in each of three groups, i.e., radiotherapy, chemotherapy, and concurrent chemo-radiation using the descriptive statistics. Pearson product moment correlation was used to find out the association between the CRF and QOL in the all three groups.
The details regarding KPS score, education, age group, concurrent disease, and sex ratio of various cancer patients receiving anticancer treatment is given in [Table 1]. Almost 95/121 subjects were between the age group of 35-65 years in this study and 60/121 patients only having primary school education. Among the 121 patients, 49 subjects were having one another concurrent diseases at that time. The detail of various type of cancer patients participated while they were receiving three different therapies is given in [Table 2].
[Table 3] describes the prevalence of fatigue (fatigue distribution) among the patients receiving the various therapies such as radiotherapy, chemotherapy and concurrent chemo-radiation. Out of 20 patients who received radiotherapy, 10% (2) reported mild fatigue, 45% (9) reported moderate, and 45% (9) reported severe fatigue. Among patients who received chemotherapy only 1 patient (1.69%) reported moderate fatigue, while rest all the patients (49) reported severe fatigue 98.30%. Among patients who received concurrent chemo-radiation, 4 patients reported (9.52%) mild fatigue and 5 patients reported moderate fatigue (11.90%) and 33 patients experienced severe fatigue (78.57%).
The mean and standard deviation for the level of present fatigue (fq1), usual level of fatigue in past 24 hours (fq2), and the worst level of fatigue in past 24 hours (fq3) in radiotherapy group were 6.15 ± 1.814, 5.6 ± 1.875, and 5.65 ± 1.954, respectively. The minimum and maximum values are given in [Table 4]. The mean and standard deviation for the level of present fatigue (fq1), usual level of fatigue in past 24 hours (fq2) and the worst level of fatigue in past 24 hours (fq3) in chemotherapy group were 8.37 ± 0.998, 8.37 ± 1.097, and 8.42 ± 0.914, respectively. The mean and standard deviation for the level of Present fatigue (fq1), usual level of fatigue in past 24 hours (fq2) and the worst level of fatigue in past 24 hours (fq3) in chemotherapy group were 7.14 ± 2.203, 7.02 ± 2.158, and 7.07 ± 2.168, respectively.
Correlation analysis of CRF and QOL reveals negative correlation. The correlation can be interpreted as any increase in severity of the level of fatigue, worst the QOL. The correlation was interpreted separately for fatigue occurring due to radiotherapy, chemotherapy, and concurrent chemo-radiation with quality of life domains. There is moderate correlation (r = -0.71 at 0.01 significance) between fatigue due to radiotherapy and QOL shown in [Table 5] and Graph 1. [Additional file 1]
Correlation between fatigue due to chemotherapy and QOL reveals weak correlation (r = -0.361 at 0.01 significance) shown in Graph 2. [Additional file 2] Correlation between fatigue due to concurrent chemo-radiation and QOL reveals negative and weak correlation (r = -0.453 at 0.01 significance) shown in Graph 3. [Additional file 3]
CRF is the most prevalent phenomena in individuals with cancer who receive radiation therapy, cytotoxic chemotherapy, or biological response modifiers.  It is a multi-factorial, multidimensional phenomenon, which consists of physical, psychological, social, cognitive, and behavioral aspects.  Almost every patient suffers from fatigue during cancer treatment and in the scientific literature reported prevalence rates of fatigue are up to 99%.  In spite of growing evidence regarding the fatigue occurring due to various anticancer treatments and how CRF affect patient's quality of life, still determining its severity is underestimated among the cancer patients those who are suffering with this distressing symptom. The current study is focused on measuring the prevalence rate of fatigue (severity of fatigue) among the cancer patients receiving the various anticancer treatment, and how it impacts the QOL.
In our study, total 121 cancer subjects were selected. The type of cancer was already diagnosed with the help of histo-pathological reports, mammography, CT etc., FACT-G was used to measure HRQOL in our patients. Both the scales were applied while the patients were receiving the respective treatment regimen while admitted in the in-patient department.
CRF is present in majority of the patients at the start of the treatment.  Our results revealed that among 20 patients received radiotherapy, 10% had mild fatigue, and 45% patients perceived moderate and severe level of fatigue. Even other studies also found increased fatigue levels initially and then plateau of fatigue levels at Week 4 in a radiotherapy regimen that lasted 6 to 9 weeks. ,
Radiotherapy causes transient increase in the fatigue which accumulates over weeks and reaches to the pretreatment level at one month after completion of treatment.  Pain can occur secondary to surgery or radiation therapy  and may lead to fatigue through its effects on mood, activity level, and/or sleep. Fatigue during radiotherapy is unique as the treatment is protracted over many weeks and the patient needs to travel all the way everyday to receive the treatment. Even in this study the patients were receiving for the duration of several weeks and the fatigue was measured between 14 th and 15 th session of radiotherapy treatment. It is also associated with significant acute radiation side effects which may alter the patient's nutrition, blood parameters leading to aggravation of the fatigue.  Furthermore, it was observed that the fatigue starts increasing from second week onwards and this coincides with the beginning of radiation reactions. This may explain the reason for lesser level of fatigue in this study as the fatigue measurement was taken only once, that too during early days while the patients were receiving the radiotherapy.
Fatigue is one of the most prevalent side effects during chemotherapy, usually persisting for more than two weeks; also, it has been shown to have the greatest and most long-lasting impact after chemotherapy.  It had been observed that during the first 24 to 48 hours of chemotherapy, there is a spiked rise in fatigue levels. , Fatigue level was measured here when the patients were receiving the second or third session of chemotherapy treatment. In this study, among 59 patients who were receiving chemotherapy, only one patient had moderate level of fatigue, while rest all patients experienced severe level of fatigue 98.30%. So the magnitude of fatigue after chemotherapy is more than that of radiotherapy treatment. A study by Donovan et al.  provides the first evidence that among women with early stage breast cancer, chemotherapy is associated with more severe fatigue than radiotherapy, which is similar to our results. They also found that women who received chemotherapy as their initial type of treatment for early stage breast cancer would report greater fatigue during the active treatment period than women who received radiotherapy as their initial treatment. In this study, the fatigue measurement was done only once that is while they were receiving the treatment and the population was not specific to one type of cancer, while Donovan et al. measured only in breast cancer patients. Still, 15 out of 59 patients in chemotherapy group were treated for breast cancer.
It was found that patients receiving a combination of chemotherapy and radiotherapy have reported higher levels of fatigue compared to those receiving a single therapy. , In patients receiving multiple forms of treatment for cancer, a "response shift" during the initial treatment may influence perceptions of fatigue during the second treatment, as patients become accustomed to their fatigue. Response shift is defined as a re-conceptualization of the quality of life brought about by a change in health status.  In this study, among the 42 patients receiving concurrent chemo-radiation in this study, 9.52% reported mild fatigue, 11.90% documented moderate level of fatigue, and 78.57% reported severe level of fatigue. So the magnitude of fatigue resulted after the concurrent chemo-radiation is more than that of radiotherapy alone and little lesser than that of chemotherapy alone in this study. This explains that patient felt more fatigued when they receive the chemotherapy than any other treatment.
Schmidt et al.  also found that fatigue level substantially increased during chemotherapy and radiotherapy and among the patients who received both therapies it was 61.4% higher, 30% same, and 8.6% lower fatigue level during chemotherapy. This study also documented that the severity of fatigue was more in patient receiving concurrent chemo-radiation and chemotherapy as compare to those who receiving the radiotherapy alone. Another study  also proved that even before the start of their initial treatment, women in the CT + RT group reported significantly more fatigue, both in terms of severity and disruptiveness, than women in the radiotherapy group.
That is, patients who received chemotherapy as their initial treatment were expected to report greater fatigue severity and disruptiveness than patients who received radiotherapy as their initial treatment. They also found that that fatigue increased during radiotherapy only among women not pre-treated with chemotherapy is consistent with research suggesting a response shift in perceptions of fatigue as a consequence of cancer treatment.  That means, reports of fatigue severity during subsequent radiotherapy may have been influenced by the perception that it was "not as bad" or "no greater" than the fatigue experienced during chemotherapy. At the same time, women not pre-treated with chemotherapy experienced increased fatigue over the course of radiotherapy, whereas women pre-treated with chemotherapy did not.  With respect to this result, previous findings  also found that fatigue would increase during radiotherapy only among patients who had not been treated previously with chemotherapy.
Two other studies reported higher levels of fatigue among former chemotherapy patients compared with those treated with radiation therapy alone. , By this at least one alternative explanation can be ruled out. The cause of CRF is not only the anticancer treatment, which is received by cancer patients; it is also reported before the initiation of treatment which is described by Goedendorp et al.  As per their statement, the reported factors that contributed to severe fatigue at this stage were physical activity, depressive mood, impaired sleep and rest, and fatigue 1 year before diagnosis. Meanwhile, another study found that the strongest fatigue predictor was poor mental health. In this study we have not considered any of these factors.
Fatigue was by far the predominant determinant of overall QOL, showing a univariate correlation with overall QOL of 0.76. As the previous studies had reported that CRF affects the QOL, correlation analyses of our study suggest that there is moderate correlation (r = -0.71 at 0.01 significance) between fatigue due to radiotherapy and QOL. At the same time, correlation between the fatigue due to chemotherapy and concurrent chemo-radiation and QOL reveals weak correlation (r = -0.361 at 0.01 significance, r = -0.453 at 0.001 significance, respectively). But the severity of fatigue was found more in concurrent chemo-radiation and chemotherapy group as compare to the radiotherapy group. Dagnelie et al.  found in their study that the fatigue showed by far the strongest univariate correlation with overall QOL (r = -0.76, P < 0.001).
Overall on observation, chemotherapy receiving patients had significantly more problems especially with smell aversion. Activity level inside and outside the home, anxiousness and depressive symptoms were similar in both groups. It is well argued that though there is significant strong correlation between CRF and QOL, this relationship could not be well established in our study due to number of samples in each group (as "r"value and P value sensitive to sample size). Janaki et al.  found the physical, role, cognitive and social functions were reduced during radiation therapy treatment and returns to baseline at one month follow up. Even, the length of time since diagnosis and treatment was associated with fatigue levels in only one study, which found a positive correlation between time since treatment and a one-item measure of fatigue.  We have not measured and correlated that factor also in this study as we took the fatigue evaluation only once. Moreover, this study has measured prevalence rate of fatigue among the Indian population for cancer patient receiving the radiotherapy, chemotherapy, and concurrent chemo-radiation, which is reported in only few literature.
Assessing fatigue will help the health care practitioner to diagnose and plan the treatment for reducing fatigue and helps the cancer patient improving their QOL. However, to understand the fatigue mechanism and to gain knowledge regarding the why severity of fatigue is more in chemotherapy and concurrent chemo-radiation longitudinal studies are required. In addition, CRF should be assessed before and after the initiation of anticancer treatments.
The finding of this study cannot fully justify the relationship between CRF due to various anticancer therapies and QOL. Though the previous studies have clearly documented that CRF have profound effect on quality of life, occurrence of CRF due to various anticancer treatment is not a single predictor for affecting QOL. There are many other variables which can affect QOL among cancer patients such as cancer type and stage, as some types of cancer do not present any symptoms until they are in advanced stages, time since diagnosis, patient acceptance, intensity of the disease, and the level of psychological distress experienced by caregivers.  These variables along with other confounders such as age, gender, tumor stage, and type of cancer should also be well documented and correlated with further upcoming studies, So that better treatment can be provided to improve patient QOL and reduced fatigue.
Though our study examined fatigue that is contributed by radiotherapy, chemotherapy, and combined chemo-radiation therapy, we have not assessed in specific cancer patients. Further studies should be conducted to assess the fatigue with respect to primary site, volume of irradiation, and other altered fractionation regimes. It becomes more imperative to study fatigue, and QOL by considering causative elements and co-morbid factors during various anti-cancer therapies as that is the standard care in most of the cancers. So, further research should be focused on specific type of cancer and cancer stages with respect to primary site. This might give better insight into the magnitude and management of fatigue in cancer patients undergoing more intensive treatment. In another aspect, because the type and duration of chemotherapy were not assessed in this report, it is unclear whether the intensity of chemotherapy received had any impact on fatigue levels. So it is possible that those who received more intensive chemotherapy regimens may have experienced more fatigue.
This study had certain other limitations in terms of sample size as it was relatively smaller and unequal between the groups. Nevertheless, the fact we did not examine potential correctable etiologies for patients' fatigue is a limitation of this study. Whether our findings generalize to a more diverse population of women with any particular type or stage of cancer is not known. To precisely know fatigue distribution, how long its impact remains longitudinal, further studies should be done.
CRF occurs due to various anticancer therapies such as radiotherapy, chemotherapy, and concurrent chemo-radiation but the prevalence rate varies widely among all the therapies received by cancer patients. Severity of fatigue was more in chemotherapy and concurrent chemo-radiation group as compare to radiotherapy. CRF was found to be moderately correlated to QOL among the patients receiving radiotherapy and weakly correlated with chemotherapy and concurrent chemo-radiation groups. Therefore, assessment of CRF should begin once the patient diagnosed with cancer and before the patient began the anticancer treatment. Further, evaluating CRF before and after treatment will help healthcare practitioner in preventing and treating this severe distress symptom. Thus, it can be useful in clinical settings and for further research work.
We would like to acknowledge Dr.Vinod Bhandari (HOD, Oncology, SAIMS Medical College), Dr. Vandana (HOD, Head and Neck Oncology Department, RAU), and Dr. Tehsin, Dr.Abha Kaliya for their unswerving help and support during data collection. Furthermore, we are deeply indebted to Mr. Satpal Singh, who had helped in statistical analysis. In addition without fail, we gratefully acknowledge the Authority members, and clinical staff of SAIMS Medical College Indore, Head and Neck Oncology Center MAHU and MY Government Hospital Indore. Our thanks are expressed to all the participants of this study.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]