Introduction
Cancer-related fatigue (CRF) is defined by the NCCN (National Cancer Comprehensive Network) and ASCO (American Society of Clinical Oncology) as a “distressing, persistent subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [1]. Differently from what happens in healthy people, CRF is not completely relieved by sleep and rest.”
Among the symptoms referred by cancer patients, CRF is one of the most frequent: almost 65% of patients experienced CRF, often not only during cancer treatment. CRF is reported by 40% of patients at diagnosis, by 70–100% of patients submitted to active oncological treatments and by 20–50% of patients after the end of therapy [1, 2].
Advertisement
CRF is a very disabling and distressing symptom with a relevant impact on quality of life. Over two thirds of patients report CRF as severe for at least 6 months and one third report CRF as persistent even post-treatment [3, 4]. CRF, involving physical, psychological, and cognitive aspects, is a multi-dimensional symptom often with multiple determinants: the cancer itself and its complications (i.e., anemia, renal, hepatic, and cardiac failure), cancer’s physical symptoms, and/or its treatment (pain, dyspnea), comorbidities (diabetes mellitus, heart failure), psychological and behavioral symptoms (anxiety, depression), iatrogenic factors (chemotherapy, targeted therapies, radiotherapy), and adverse events of other drugs (opioids, psychiatric drugs) [1, 5].
In conclusion, CRF is a very complex symptom; moreover, fatigue is not specific for cancer and can be associated with many diseases. The diagnosis of CRF therefore requires well-defined diagnostic criteria [6].
According to the NCCN and ASCO guidelines [1, 2], all cancer patients should be screened for the presence of CRF at their first oncological visit and subsequently re-evaluated during and at the end of therapy.
An objective evaluation and measurement of CRF is very important but also potentially complicated due to many methodological problems concerning measurement CRF [7‐9].
Advertisement
Several scales are available: linear numeric scales, uni-dimensional scales, uni-dimensional multi-item scales (i.e., the Brief Fatigue Inventory [BFI], the Visual Analogue Fatigue Scale [VAFS], the EORTC QLQ-C30 Fatigue Scale, the Functional Assessment of Cancer Therapy-Fatigue Scale [FACT-F]), and multi-dimensional scales (i.e., the Multidimensional Fatigue Inventory [MFI] and the Piper Fatigue Scale [PFS]). One of the most used is the BFI because it is complete and simple and thus easily used in daily clinical practice.
If patients report fatigue, the determinants should be removed or treated if possible. Fatigue which persists despite treatment should be investigated.
The treatment of CRF is not standardized and the efficacy of several therapies has been evaluated: complementary therapies (yoga, acupuncture, ginseng), behavioral therapies (physical exercise), psychosocial interventions, and/or pharmacological therapies (methylphenidate, dexamethasone) [10‐14].
In recent years, knowledge of CRF has rapidly increased and four international guidelines are now available [1, 2, 15, 16] together with many published studies regarding treatment.
CRF characteristics in Italian patients have not yet been well defined. Moreover, the attitude of medical oncologists to assess and treat CRF in hospitals and in the National Cancer Institutes is little or completely unknown.
Therefore, the NICSO (Italian Network for Supportive Care in Cancer) promoted an observational cross-sectional study to evaluate the presence and intensity of CRF in Italian cancer patients who are attending each participating cancer center for any reason.
In this study, patients presenting any grade of fatigue were submitted to a fatigue measurement instrument (Brief Fatigue Inventory, BFI) to measure its impact on quality of life; they were then evaluated to assess and possibly remove its potential determinants. Finally, treatment for CRF was registered.
Patients and methods
Patients
All cancer patients in any phase of the disease and its treatment, > 18 years old, who attended the participating cancer centers for any reason (i.e., chemotherapy, radiotherapy, adverse events, follow-up control, supportive care, inpatients) in two non-consecutive days previously defined, were accrued to the study after giving informed consent. Patients with cognitive alterations who were unable to adequately comply with the study were excluded.
Advertisement
Methods
Initially, all patients were asked about the presence of fatigue (yes–no) during the previous week. If the answer to this question was no, the second question was: “Did you receive any treatment for fatigue during the previous week?”
If the patient’s answer was negative for both questions, the study was concluded and patients were invited to respond to a questionnaire (yes–no) regarding the presence of possible determinants of fatigue (anemia, electrolyte abnormalities, dehydration, anorexia/cachexia, hepatic, renal, heart failure and adrenal insufficiencies, hypoxia, fever, pain, dyspnea, dysphagia, anxiety, depression, insomnia, neurological deficits, and reduced physical activity).
If the answer was positive to at least one of the two questions, the intensity as well as the duration of fatigue was evaluated with the BFI (Italian validated version). The questionnaire was filled out by the patient himself, sometimes with the help of a relative or an oncological operator if necessary (nurse, data manager, or psychologist). The BFI evaluated fatigue features and their impact on quality of life using numeric rating scales. The oncologist then reported his own opinion of each patient regarding the most important (probable or almost sure) determinants of fatigue.
For all enrolled patients, demographic characteristics (age, sex) and clinical history (ECOG Performance Status, type of neoplasm, time to diagnosis); state of disease (no evidence of disease, localized cancer, locally advanced cancer, metastatic cancer); reason for going to the oncological center; all surgical, medical, and radiotherapy treatments received; and drugs different from oncological treatment were registered.
Advertisement
Any intervention, pharmacological or other, used to control the CRF was registered. Lastly, each patient was asked to indicate what, in his/her opinion, could be the cause of his/her CRF.
Statistical analysis
The usual descriptive statistics were used to analyze the study population. Chi-square tests were calculated for comparing two proportions as well as to test the null hypothesis of independence. Sample size was not calculated because the study design was concerned with patients attending for any reason each center in two pre-specified non-consecutive days.
Results
From October, 2014, to May, 2015, a total of 1394 patients, attending for any reason the 24 participating centers, were enrolled in the study.
Patient characteristics are reported in Table 1.
Table 1
Patient characteristics
No. (%) | ||
|---|---|---|
Total | 1394 (100) | |
Gender | Male | 581 (41.7) |
Female | 813 (58.3) | |
Age | < 50 | 263 (18.9) |
50–69 | 709 (50.9) | |
≥ 70 | 422 (30.2) | |
Mean (SD) | 62.21 (12.1) | |
Median (min–max) | 64 (19–93) | |
ECOG PS | 0 | 878 (63.0) |
1 | 407 (29.2) | |
2–3 | 109 (7.8) | |
Diagnosis | Breast | 474 (34.0) |
Colorectal | 167 (12.0) | |
Lung | 121 (8.7) | |
Prostate | 73 (5.2) | |
Other | 559 (40.1) | |
Stage | NED | 417 (29.9) |
Localized | 132 (9.5) | |
Locally advanced | 170 (12.2) | |
Metastatic | 674 (48.4) | |
Reasons for attending the oncological center | Follow-up | 314 (22.6) |
Supportive care | 154 (11.0) | |
Chemotherapy | 683 (49.0) | |
Target therapy | 148 (10.6) | |
Radiotherapy | 95 (6.8) | |
Time from cancer diagnosis | > 1 year | 615 (44.1) |
≤ 1 year | 779 (55.9) | |
Mean (SD), years | 3.07 (4.2) | |
Median (min–max), years | 1.29 (0–37.4) | |
Surgery | Yes | 984 (70.7) |
No | 410 (29.3) | |
Radiotherapy | Yes | 485 (34.8) |
No | 909 (65.2) | |
Chemotherapy | Yes | 1076 (77.2) |
No | 318 (22.8) | |
Advertisement
Median time from the diagnosis of cancer was 1.3 years; median time from the last cancer treatment was 1.3 months from surgery, 1.0 months from radiotherapy, and 0.5 months from last chemotherapy.
CRF was referred by 866 patients (62.1%); its duration was > 4 months in 441 patients (50.9%), and ≤ 4 months in 425 patients (49.1%). Based on answers to BFI, fatigue intensity was reported as moderate (score 4–6)/severe (score 7–10) by 43%/29.2% of patients while usual fatigue during the last 24 h was reported by 45%/33.1% of patients, and the worst fatigue in the last 24 h was reported by 33%/54.8% of patients, respectively.
Table 2 shows the presence of each possible determinant of CRF in all patients, as well as the percentages of patients with fatigue with respect to the presence/absence of its different possible determinants (i.e., 54.3% of patients had fatigue without anemia versus 85.3% of anemic patients). These percentages should be evaluated considering that in the whole study population, 62.1% of patients suffered from fatigue. The differences in the presence of fatigue between patients who had or did not have each possible determinant are all significant at p < 0.001.
Table 2
Association between presence of fatigue and health problems (no. and % of patients suffering from fatigue in each group)
No. (%) | No. (%) of patients with fatigue§ | ||
|---|---|---|---|
Anemia | No | 1041 (74.7) | 565 (54.3) |
Yes | 353 (25.3) | 301 (85.3) | |
Electrolyte abnormalities | No | 1330 (95.4) | 805 (60.2) |
Yes | 64 (4.6) | 61 (95.3) | |
Dehydration | No | 1316 (94.4) | 790 (60.0) |
Yes | 78 (5.6) | 76 (97.4) | |
Anorexia | No | 1243 (89.2) | 724 (58.2) |
Yes | 151 (10.8) | 142 (94.0) | |
Hepatic failure | No | 1350 (96.8) | 826 (61.2) |
Yes | 44 (3.2) | 40 (90.9) | |
Renal failure | No | 1342 (96.3) | 822 (61.3) |
Yes | 52 (3.73) | 44 (84.6) | |
Heart failure | No | 1366 (98.0) | 841 (61.6) |
Yes | 28 (2.0) | 25 (89.3) | |
Hypoxia | No | 1367 (98.1) | 839 (61.4) |
Yes | 27 (1.9) | 27 (100) | |
Adrenal insufficiencies | No | 1382 (99.1) | 854 (61.8) |
Yes | 12 (0.9) | 25 (89.3) | |
Fever | No | 1339 (96.1) | 813 (60.7) |
Yes | 75 (3.9) | 53 (96.4) | |
Neurologic failure | No | 1307 (93.8) | 785 (60.0) |
Yes | 87 (6.2) | 81 (93.1) | |
Pain | No | 1090 (78.2) | 603 (55.3) |
Yes | 304 (21.8) | 263 (86.5) | |
Dyspnea | No | 1244 (89.2) | 721 (58.0) |
Yes | 150 (10.8) | 145 (96.7) | |
Difficulty swallowing | No | 1310 (94.0) | 791 (60.4) |
Yes | 84 (6.0) | 75 (89.3) | |
Anxiety | No | 1005 (72.1) | 519 (51.6) |
Yes | 389 (27.9) | 347 (89.2) | |
Depression | No | 1101 (79.0) | 597 (54.2) |
Yes | 293 (21.0) | 269 (91.8) | |
Insomnia | No | 1042 (74.7) | 552 (53.0) |
Yes | 352 (25.3) | 314 (89.2) | |
Decreased physical activity | No | 845 (60.6) | 357 (42.2) |
Yes | 549 (39.4) | 509 (92.7) |
In the investigators’ opinion, the most important (probable or almost sure) determinants of fatigue were reduced physical activity (271 patients), anxiety (149), pain (131), insomnia (125), anemia (123), and depression (123).
Concerning concomitant drugs used (another possible determinant of fatigue), opioids, benzodiazepines, and psychiatric drugs were associated with fatigue (81.2%, 86.6%, and 83.1% of patients, respectively); these results should be interpreted considering that the overall percentage of patients reporting fatigue was 62.1%. Even patients submitted to corticosteroids reported fatigue more often than the average (72.6%). However, in this case, the patients probably had received corticosteroids just to control CRF.
Considering the reasons of the visit to the oncological centers, patients in follow-up reported fatigue less frequently (49.7%), while patients receiving supportive care reported CRF more frequently (81.2%) than those submitted to chemotherapy (62.1%), targeted therapy (66.9%), and radiotherapy (65.3%). Interestingly, the patients receiving an active oncological therapy reported CRF with a similar frequency, regardless of the specific type of treatment.
Table 3 shows that 50.6% of patients without evidence of neoplastic disease reported fatigue, while in patients with localized, locally advanced, and metastatic disease the percentage was 67.0% (p < 0.001).
Table 3
Fatigue and disease extension
Fatigue | Disease extension [no. (%)] | |||
|---|---|---|---|---|
No evidence of disease | Localized | Locally advanced | Metastatic | |
Yes | 211 (50.6) | 80 (60.6) | 124 (72.9) | 450 (66.8) |
No | 206 (49.4) | 52 (39.4) | 46 (27.1) | 224 (33.2) |
Total | 417 (100) | 132 (100) | 170 (100) | 674 (100) |
Considering the ECOG Performance Status (Table 4), the prevalence of CRF significantly increased from ECOG 0 to ECOG 1 and ECOG 2–3 (p < 0.001).
Table 4
Fatigue and ECOG PS [no. (%)]
Fatigue | ECOG PS | ||
|---|---|---|---|
0 | 1 | 2–3 | |
Yes | 467 (53.2) | 304 (74.7) | 95 (87.2) |
No | 411 (46.8) | 103 (25.3) | 14 (12.8) |
Total | 878 (100) | 407 (100) | 109 (100) |
Fatigue was also slightly more referred by female (529/813, 65.1%) than male patients (337/581, 58.0%).
Furthermore, the prevalence of fatigue seems unrelated to patient age (62.7% in those < 50 years old, 61.5% in 50–69 years old, and 62.8% in ≥ 70 years old).
Concerning the impact of CRF on quality of life, fatigue interfered moderately/severely with general activity in 30.8%/38.6% of patients, with mood in 26.1%/32.8%, with the ability to work in 27.9%/35.6%, with normal work in 26.7%/38.9%, with relationships with other people in 21%/23.4% and with the ability to amuse oneself in 22.2%/33.1%.
In the patients’ opinion, the most important determinant of fatigue was (alone/together with other causes) the following: chemotherapy (33.7%/18.9%, total 52.6%), cancer (15.3%/13.3%; total 28.6%), adverse events of therapy and/or uncontrolled symptoms (8.9%/5.8%; total 14.7%), anxiety and emotional tension (3.8%/3.1%; total 6.9%), surgical intervention (2.5%/2.2%; total 4.7%), other causes (radiotherapy, drugs, age, social difficulties, low physical activity, etc. 13.5%).
Only 117/866 (13.5%) patients suffering from CRF received pharmacological treatment for fatigue that was a corticosteroid in 101 patients (86.3%). Other drugs (megestrol, carnitine, antidepressants, homeopathic drugs) were used in the remaining 13.7% of patients. Moreover, 188 patients (21.7%) received a non-pharmacological treatment such as physical exercise or yoga (122 patients, 65%) and various alimentary supplements in the remaining 27.6% of patients: ginseng (9 patients), food supplements (52 patients), mix (propolis, artemisia, vegan diet, and pollen; 32 patients).
From the patients’ point of view, of 305 patients receiving treatment for fatigue (pharmacological 117 or non-pharmacological 188), 159 (52.1%) patients achieved benefit from it.
At the end of the interview, the oncologists suggested other treatments (alone/together with other advice) to 229/673 (34%) of patients referring fatigue: drugs (28%/6.9%; total 34.9%), physical activity (17.9%/14.4%; total 32.3%), psychological support (6.5%/8.3%; total 14.8%), food supplements (7.8%/7.4%; total 15.2%), ginseng (3.4%/3.9%; total 7.3%), lifestyle changes (3.9%/2.6%; total 6.5%), other (socialization, yoga, diet, and vitamins to 10% of patients).
Discussion
CRF is frequently reported by oncological patients: 62% in about 1400 patients enrolled in 24 Italian oncological centers in our study. This value is similar to the literature data, with a prevalence of about 65% of CRF in oncological patients (range 15–90%) and the true incidence very difficult to ascertain [17‐19].
CRF may arise at any time in oncological patients: in our study by 49.7% of patients survivors, by 81.2% of patients receiving supportive care, and by about 62.1–66.9% of patients in active treatment. Two American surveys [20, 21] showed similar results many years ago: in the first survey, 74% of patients reported fatigue at some point during the course of illness, with 32% reporting daily fatigue; in the second, 76% and 30%, respectively.
Notably, the proportion of patients experiencing fatigue is over 50% among those without evidence of disease as well as among those with 0 ECOG Performance Status.
The intensity of CRF was moderate/severe in 43%/29% of patients, and the duration was more than 4 months in 51% of patients. Moderate/severe intensity of CRF usually may interfere with daily activities. As regards the intensity of CRF, literature data are very heterogeneous because of the interaction of many variables that are also time-dependent. For example, for patients receiving chemotherapy, CRF is commonly cyclic; in contrast, the intensity of CRF in patients submitted to RT typically peaks toward the end of therapy. Concerning CRF duration, the available data suggest that up to one third of patients will have persistent fatigue even for a number of post-treatment years [22, 23].
A relevant impact of CRF on different aspects of quality of life, such as general activity, ability to work, mood, and relationship with other people, was reported: 21–31% of patients referred a moderate impact and 23–39% severe impact. Moreover, the majority of patients presented CRF interfering with quality of life.
At present, there is no standard, specific, useful pharmacological treatment for CRF. Many studies evaluating psychostimulants (such as methylphenidate) or other drugs (steroids), nutraceutical treatments (ginseng), have shown them to be negative, while physical exercise and psycho-behavioral interventions have been demonstrated efficacious [14].
In our study, only 13% of patients received a pharmacological treatment, most often represented by a corticosteroid (86% among those who were treated). Due to the lack of efficacious pharmacological treatment for CRF, many patients received non-pharmacological treatments (physical exercise in about 65% of patients) or various alimentary supplements.
This observational study presents some limitations. Firstly, it was carried out in 24 Italian medical oncology centers; therefore, the prevalence of CRF could be different in patients receiving palliative care in a hospice or at home. Similarly, CRF intensity, duration, and impact on quality of life could be different. Another limitation is that, despite the high number of patients evaluated, there was a wide heterogeneity of conditions even if our sample presents the characteristics of patients referred to medical oncology departments. For these reasons, our results must be considered an indication of prevalence of fatigue among cancer patients.
Nevertheless, this study is important in order to animate the interest of oncologists regarding the important problem of CRF, often under-reported by our patients, but too often under-evaluated by clinicians. In American surveys [20, 21], only 50% of patients had discussed fatigue with their clinician, and in only one fourth of cases was any intervention proposed. Moreover, patients and oncologists often disagreed on the importance of CRF. The Italian situation in the year 2017 is very similar.
In conclusion, oncologists in the immediate future should start evaluating fatigue and its characteristics in all patients admitted to the oncological center as outpatients. At the same time, the oncologists should make a greater effort to identify new and more effective treatments to improve CRF, through improving the quality of research on this topic.
Acknowledgements
Other investigators are the following: Andrea Sbrana, Gianna Musettini, Azzurra Farnesi, Francesco Spina, Paola Matteucci, Paolo Bossi, Elisa Minenza, Camilla Di Nunzio, Elena Orlandi, Claudia Biasini, Alessandro Inno, Monica Turazza, Fabiana Marchetti, Domenica Pellegrini, Simona Gasparro, Daniele Alesini, Rossana De Feudis, Teresa Gasparre, Michele Altieri, Elisabetta Cretella, Alessandro Marabese, Maurizio Valeriani, Claudia Scaringi, Salvatore Artale, Lucia Barbarini, Eleonora Capovilla, Silvia Tessarin, Giovanni Battista Ivaldi, Ilaria Meaglia, Evaristo Maiello, Chiara Parati, Saverio Cinieri, Luigi Coltelli, Angela S. Ribecco, Emanuela Romagnoli, Antonio Ardizzoia, Paolo Tralongo, Amalia Falzetta, Elena Bandieri, Marco Danova.
Compliance with ethical standards
Conflict of interest
Fausto Roila declares no conflict of interest. Fausto Roila declares to have full control of all primary data and he agrees to allow the journal to review the data if requested.