Drug therapy for the management of cancer related fatigue
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1) To evaluate the effectiveness and adverse events related to drugs used in the treatment of CRF at all stages of cancer treatment (including palliative care) compared with a standard care or non‐pharmacological intervention.
2) To establish optimal dose and duration of drug therapy(s).
Background
Cancer‐related Fatigue (CRF) is one of the most common symptoms experienced by cancer patients (Morrow 2002). It can be problematic at the time of diagnosis, during and after treatment and in patients with advanced disease (Morrow 2002). Most studies have reported prevalence figures in excess of 60% (Stone 2002). The subjective sensations attributed to CRF are characterised by a pervasive and persistent sense of tiredness not relieved by sleep or rest. These can adversely affect a person's emotional, physical and mental well‐being (Morrow 2005). CRF can also affect patients' abilities to function in terms of their usual social activities and their ability to carry on with their normal working lives. Fatigue is not only a problem in cancer patients:
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it is a recognised condition within the general population (Lawrie 1997; Bultmann 2002);
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it is a feature of other chronic illnesses such as multiple sclerosis (Krupp 1988) and chronic obstructive pulmonary disease (Trendall 2001);
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it can also be a separate diagnosis in its own right in the case of chronic fatigue syndrome (CFS) (Sharpe 1992).
While CRF in some groups may have similarities with CFS there are important differences in particular in relation to concerns about its relationship to disease progression and toxicity of treatment (Servaes 2002). It has therefore been suggested that CRF should be considered to represent a diagnostic entity in its own right (Cella 2001; Sadler 2002). CRF is a complex condition with many physical and psychological components potentially predisposing to it. These same factors may also exacerbate and perpetuate established CRF. The complex nature of the condition makes it difficult to identify a clear underlying mechanism. Indeed, it is more than likely that no such single mechanism exists (Andrews 2004). Nevertheless, CRF is a disabling and distressing condition which is often under‐recognised by cancer physicians (Stone 2000).
Previous reviews (Stone 2002; Mock 2004; Morrow 2005) and clinical guidelines (NCCN 2006) have attempted to summarise existing evidence for both pharmacological and non‐pharmacological treatments for CRF. The main focus of one of these reviews (Mock 2004) was on non‐pharmacological measures where there have been a number of studies investigating exercise interventions and the role of support groups. The authors of the review concluded that:
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exercise had a direct effect on reducing fatigue;
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there was some evidence that correction of anaemia improved quality of life and energy.
A separate group focused their review on pharmacological interventions (Morrow 2005). They considered the evidence in support of a number of treatment options:
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on the basis of one study (Breitbart 1995) anti‐depressants were suggested as a possible treatment for fatigue associated with advanced disease or uncontrolled symptoms, or both. However, the review authors did not recommend the routine use of antidepressants in the absence of concurrent depression. This opinion was based in part on the results of a large randomised controlled trial (RCT) conducted with paroxetine which improved mood but found no effect on fatigue in ambulatory cancer patients (Morrow 2003);
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erythropoietin was recommended because it has been studied as a treatment for anaemia in cancer patients receiving chemotherapy and some studies have reported improvements in fatigue in those patients with the correction of anaemia (Glaspy 1997; Demetri 1998);
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the review authors concluded that corticosteroids may produce modest improvements in quality of life including fatigue in patients with metastatic cancer but are limited by side effects (Bruera 1985).
The National Comprehensive Cancer Network's (NCCN 2006) clinical guidelines also provide further options for CRF management. These suggest initially treating any underlying reversible causes of fatigue (e.g. anaemia, poor nutrition or depression) and attending to general supportive measures and psychosocial support. The most common specific recommendation for an intervention targeted at fatigue is the use of an exercise programme which is the subject of a seperate cochrane review currently in progress (Cramp 2006). The main drug treatment the NCCN guidelines recommend is the use of methylphenidate in selected cases of cancer‐related fatigue after other non‐pharmacological approaches have been tried. However, most of the evidence for this suggestion is from a trial in HIV patients (Breitbart 2001). A recent RCT in cancer patients failed to find any significant superiority over placebo (Bruera 2006).
The previous literature reviews have made suggestions for the use of different drugs based on varying amounts and quality of evidence. No previous review has collated all of the relevant literature concerning pharmacological interventions for cancer‐related fatigue in a systematic way. A cochrane systematic review is therefore needed in order to evaluate all of the available evidence for the effectiveness of pharmacological interventions for CRF. Treatment of fatigue in palliative care will be the subject of another cochrane review prepared by Radbruch et al. currently in press (Radbruch 2007). Close collaboration between the two review groups will ensure a maximum coverage and minimum overlap of the two reviews.
Objectives
1) To evaluate the effectiveness and adverse events related to drugs used in the treatment of CRF at all stages of cancer treatment (including palliative care) compared with a standard care or non‐pharmacological intervention.
2) To establish optimal dose and duration of drug therapy(s).
Methods
Criteria for considering studies for this review
Types of studies
Only RCTs of a particular drug therapy will be included. Studies that are single blind or open label will be allowed.
Types of participants
The review will include studies that evaluate drug therapy for CRF in adults and with a clinical diagnosis of cancer. We intend to include studies which have recruited participants at any point of the cancer treatment spectrum, including those undergoing curative treatment, those with advanced disease receiving palliative care, and disease‐free survivors
Types of interventions
Included studies will compare drug therapy with placebo, standard care or an alternative non‐pharmacological treatment for CRF including studies that include nutritional status or mood. Only those studies that investigate drug interventions to improve fatigue as a prior identified aim will be included.
Studies comparing different types of cancer‐modifying treatment (e.g. chemotherapy regimens or radiotherapy) and their effect on prognosis and quality of life will be excluded.
Types of outcome measures
1) Differences in fatigue between intervention group and controls using patient self‐reported measures or valid assessment tools, or both.
2) Adverse events
Search methods for identification of studies
The following search strategy will be utilised for this review using text and keyword and MESH terms in each database, with an RCT filter applied.
Search strategy format for CENTRAL:
#1 Exp NEOPLASMS
#2 BONE MARROW TRANSPLANTATION
#3 neoplasm* or cancer* or carcinoma* or tumour* or adenocarcinoma* or leukeni* or leukaemi* or lymphoma* or tumor* or tumor* or malignan* (title, abstract & keywords)
#4 neutropeni* or neutropaeni* (title, abstract & keywords)
#5 Exp RADIOTHERAPY
#6 radioth* or radiat* or irradiat* or radiochemo* or chemotherap* (title, abstract & keywords)
#7 "bone marrow" NEAR transplant*
#8 "bone‐marow" NEAR transplant*
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 FATIGUE (drug therapy)
#11 fatigue* (title, abstract & keywords)
#12 tired* or weary or weariness or exhaustion or exhausted or lacklustre or astheni* or asthenia*
#13 lack* NEAR/2 energy
#14 lack* NEAR/2 vigour
#15 lack* NEAR/2 vigor
#16 loss NEAR/2 energy
#17 loss NEAR/2 vigour
#18 loss NEAR/2 vigor
#19 lost NEAR/2 energy
#20 lost NEAR/2 vigour
#21 lost NEAR/2 vigor
#22 apathy or apathetic or lassitude or letharg* or "feeling drained" or "feeling sleepy" or "feeling sluggish" or "feeling weak*"
#23 #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22
#24 #9 AND #23
This strategy will be adapted for the following databases ‐ for the different terms that are used in these please refer to Additional Table 1; Table 2; Table 3.
| No. | search term |
| 1 | Exp NEOPLASMS |
| 2 | Exp BONE MARROW TRANSPLANTATION/ |
| 3 | neoplasm$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| no. | search terms |
| 1 | Exp NEOPLASM |
| 2 | BONE MARROW TRANSPLANTATION/ |
| 3 | neoplas$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| 15 | 8 AND 14 |
| no. | search terms |
| 1 | Exp NEOPLASM |
| 2 | BONE MARROW TRANSPLANTATION/ |
| 3 | neoplas$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | CANCER FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| 15 | 8 AND 14 |
The following databases will be used to obtain relevant studies for this review. There will be no language restriction.
‐ The PaPaS group specialized register.
‐ The Cochrane Central Register of Controlled Trials (CENTRAL)
‐ MEDLINE (1966 to present)
‐ EMBASE (1980 to present)
‐ CINAHL (1982 to present)
‐ Dissertation Abstracts International (1861 to present)
‐ Meta register of controlled trials (mRCT)
The following journals will be hand searched:
British Journal of Cancer, Journal of Clinical Oncology, Journal of Pain and Symptom Management and Palliative Medicine.
Reference lists of all articles obtained will be checked for additional studies.
Experts in the field of CRF will be contacted in order to identify any research that may not have been published.
Published abstracts will also be obtained through searches of conference proceedings and full trial data obtained where possible. We will attempt to communicate with the study authors to secure information not presented in the paper or conference abstract if not subsequently published as a full article.
Data collection and analysis
Eligibility of the retrieved articles will be assessed from the title and abstract. Where there is insufficient information for assessment, the full article will be scrutinised by the review authors (OM and PS). All RCTs will be assessed independently by two review authors (OM and PS). For a trial to be included it must include fatigue as part of a primary outcome measure and one treatment arm must be a drug therapy. Disagreement will be resolved by consensus with other members of the review group (MS, AR, MH).
Each trial will be assessed for potential bias on the basis of allocation and concealment as described in the Cochrane Reviewers' Handbook (Higgins 2006)
A ‐ adequate; B ‐ unclear; C ‐ clearly inadequate; D ‐ allocation concealment not used. The methodological quality of each study will also be assessed using the Oxford Quality Score scale (Jadad 1996) which is concerned with the presence and adequacy of randomisation; the presence and adequacy of blinding and the description of participant withdrawals. All studies will also have an assessment of efforts made to match groups in terms of prognostic factors. Study quality will be further assessed based on an intention‐to‐treat analysis, standardization and blinding of outcome assessment and percentage loss to follow‐up. This information will be used to determine an overall risk of bias from a study ‐ those studies felt to be at an unacceptably high risk of bias will be excluded from the review. Study quality will not be scored on an additive basis. Impact of study quality will be determined by sensitivity analysis.
Data management
Data will be organised using RevMan (version 4.2.10). Data extraction forms will be developed a priori and will include information regarding methods, participant details, dose and frequency of drug administration, attrition and outcome measures. Data will be extracted by two independent review authors (OM and PS) and disagreements will be resolved by consensus with the other members of the group.
Heterogeneity assessment
Homogeneity of the results of the various endpoints of interest will be explored using L'Abbe's visual plot and through formal statistical testing (L'Abbe 1987). Heterogeneity in the results is expected as a result of many potential factors (postulated a priori) and efforts will be made to identify sub groups where the results are homogenous. If these are sufficiently homogenous then meta‐analysis will be undertaken. We will look for heterogeneity using Chi‐squared or I‐squared tests and if significant we will use a random effects model for analysis.
Potential sources of heterogeneity:
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quality of studies,
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medication dose and frequency,
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duration of treatment,
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duration of follow up,
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rate of attrition,
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outcome measures used,
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case mix/stage of disease accessed.
Statistical considerations
Quantitative outcomes for dichotomous and continuous data will be evaluated using RevMan 4.2.10 using random effect models. Analysis based on intention‐to‐treat will be used. Outcomes of interest will be compared between treatment and control arms using an odds ratio (OR) with 95% confidence.
The Number Needed to Treat (NNT) will be calculated to identify the magnitude of any effect, if identified. Assessment of publication bias (funnel plot ‐ Light 1984) will be performed to evaluate the likelihood of bias in this topic. A judgement on how to combine outcome measures will be made depending on how this information is collected. If it is not possible to do a quantitative analysis then a qualitative review and synthesis of study results will be undertaken.
| No. | search term |
| 1 | Exp NEOPLASMS |
| 2 | Exp BONE MARROW TRANSPLANTATION/ |
| 3 | neoplasm$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| no. | search terms |
| 1 | Exp NEOPLASM |
| 2 | BONE MARROW TRANSPLANTATION/ |
| 3 | neoplas$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| 15 | 8 AND 14 |
| no. | search terms |
| 1 | Exp NEOPLASM |
| 2 | BONE MARROW TRANSPLANTATION/ |
| 3 | neoplas$ or cancer$ or carcinoma$ or tumour$ or adenocarcinoma$ or leukeni$ or leukaemi$ or lymphoma$ or tumor$ or tumor$ or malignan$ (title, abstract & keywords) |
| 4 | neutropeni$ or neutropaeni$ (title, abstract & keywords) |
| 5 | Exp RADIOTHERAPY |
| 6 | radioth$ or radiat$ or irradiat$ or radiochemo$ or chemotherapy$ (title, abstract & keywords) |
| 7 | (("bone marrow" adj4 transplant$) or ("bone‐marow" NEAR transplant$)) |
| 8 | OR/1‐7 |
| 9 | CANCER FATIGUE/ (drug therapy) |
| 10 | fatigue$ (title, abstract & keywords) |
| 11 | tired$ or weary or weariness or exhaustion or exhausted or lacklustre or astheni$ or asthenia$ |
| 12 | ((lack$ or loss or lost) adj2 (energy or vigour or vigor) |
| 13 | (apathy or apathetic or lassitude or letharg$ or (feeling adj3 (drained or sleepy or sluggish or weak$))) |
| 14 | OR/9‐13 |
| 15 | 8 AND 14 |
