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06-07-2018 | Corticosteroids | Article

Side effects of corticosteroids in patients with advanced cancer: a systematic review

Journal:
Supportive Care in Cancer

Authors: Yutaka Hatano, Hiromichi Matsuoka, Lawrence Lam, David C. Currow

Publisher: Springer Berlin Heidelberg

Abstract

Corticosteroids are commonly used in palliative care settings, but are associated with several side effects. Although adverse events (AEs) are highly distressing for patients, few data are available from prospective studies to look at incidence or predictors of such harms. The aim of this study is to identify AE reporting among studies of patients with advanced cancer receiving corticosteroids for any reason.
A systematic review was conducted using the following data sources: PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL. Randomized controlled trials (RCTs) with patients with advanced cancer assessing the effect of corticosteroids were included. Consecutive cohort observational studies of corticosteroid toxicities in cancer patients were also included.
Twenty-seven RCTs and 12 consecutive cohort observational studies were identified. The most frequently reported primary outcome of RCTs was nausea and vomiting (8/27). Dexamethasone was prescribed in almost half of RCTs (13/27). In consecutive cohort studies, the primary outcomes were a wide variety of symptoms. Dexamethasone was also the most common glucocorticoid used (7/12). In terms of quality of AE reporting, two RCTs and one consecutive cohort study used a validated AE assessment tool in their studies.
Side effects of corticosteroids in advanced cancer patients were poorly reported with few data using validated tools. Researchers should be aware of the guideline of AE reporting to provide the best evidence of risk-benefit balance. Developing specific consensus guidelines about AE reporting in studies of glucocorticoids in studies of people with advanced cancer would be useful.

Introduction

Corticosteroids are used in the treatment of a wide variety of diseases. In the field of palliative care, corticosteroids are frequently prescribed to alleviate distressing symptoms in patients with advanced cancer, including anorexia, fatigue, and pain [ 13]. However, corticosteroids are associated with several side effects: susceptibility to infection, hyperglycemia, insulin resistance, proximal myopathy and catabolic effects, skin changes, and adrenal insufficiency [ 4]. Patients with advanced cancer are particularly vulnerable to adverse events (AEs) associated with corticosteroid use. Treatment decisions should be decided based on a risk-benefit balance. It is therefore important to assess both effectiveness and AEs associated with corticosteroid use in people with advanced cancer.
Randomized controlled trials and consecutive cohort studies are both study designs that collect data prospectively and can contribute data to the incidence of an event because they have clear numerators and denominators. Given that randomized controlled trials (RCTs) and consecutive cohort studies report AEs, both can provide useful data [ 5, 6]. Equally, both may suffer from varying quality of AE reporting [ 7].
In order to manage symptoms without harms, it is important to know the risk-benefit balance of corticosteroid use for patients with advanced cancer. However, no systematic review of AE reporting in clinical studies of corticosteroids in patients with advanced cancer has been reported to date. The purpose of this systematic review was to identify the AE reporting in RCTs and consecutive cohort studies of corticosteroids in patients with advanced cancer.

Methods

We conducted a systematic review of the literatures using online databases.
Inclusion criteria: (1) patients with life-limiting advanced cancer; (2) corticosteroids prescribed for symptom control (such as pain, fatigue, anorexia, nausea, well-being, and headache attributed to metastases); (3) adult participants; (4) randomized controlled trial (placebo-controlled or comparison with other drugs) or a consecutive, prospective cohort study; (5) use of any of the following corticosteroids: dexamethasone, methylprednisolone, prednisone, prednisolone, or betamethasone; (6) oral or intravenous (systemic) administration route; (7) written in English language.
Exclusion criteria: (1) corticosteroid administration by inhalation; (2) other chronic progressive diseases for which corticosteroid therapy is indicated, including ulcerative colitis and rheumatoid arthritis; (3) cancer patients undergoing chemotherapy and receiving steroids only for chemotherapy-related nausea; (4) steroids prescribed as chemotherapy (for example, in leukemia); (5) reviews or summary studies; (6) child and adolescent cancer patients; (7) case reports and retrospective studies; and (8) studies with no corticosteroid administration.
The relevant literature was extracted from PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL online databases. Search filters were created by the authors with the assistance of an experienced librarian. The details of the search filters are shown in Supplementary Material 1. Following PRISMA guidelines, two review authors (Y.H. and H.M.) independently selected studies that met the criteria. Disagreements were resolved by discussion with all authors. The systematic review protocol was registered on PROSPERO (CRD42015025813) and is available [ 8]. Selected studies were assessed for reporting of AEs based on CONSORT extension for harms [ 9]. Risk biases of RCTs were also assessed according to Cochrane guidelines [ 10].

Results

Studies

A total of 15,048 initial titles and abstracts were retrieved. Following the removal of duplicates, two authors (Y.H. and H.M.) conducted an initial screening. Among 9360 titles and abstracts, 54 full-text articles were assessed for eligibility. Fifteen studies were excluded for the following reasons: conference abstract (4), primary outcome was overall survival (3), corticosteroid use was not systemic (3), protocol-only manuscript (1), written in a language other than English (4). Finally, 27 RCTs and 12 consecutive cohort studies were selected for analysis (see the CONSORT diagram, Fig.  1). The listing of the included reports and their characteristics are shown in Supplementary Material 2 and 3, respectively.

Study characteristics

All participants in the selected RCTs were patients with advanced cancer. The most frequently reported primary outcome was nausea and vomiting (8), followed by pain (5), loss of appetite (3), quality of life (3), and fatigue (2). Types of corticosteroids included dexamethasone (13), methylprednisolone (9), and prednisolone (4), and one study included no information on the types of corticosteroids used. Doses of corticosteroids varied widely, and duration of corticosteroid exposure ranged from 1 to 250 days.
In the included 12 consecutive cohort studies, (Supplementary Material 3), primary outcomes included pain (3), anorexia (1), fatigue (1), spinal compression (1), and bowel obstruction (2). In four studies, the priorities of outcomes were not specific, and participants were taking corticosteroids to relieve several symptoms. Dexamethasone was the most commonly used corticosteroid in the consecutive cohort studies (7), followed by methylprednisolone (1). Four studies included participants who were taking different types of corticosteroids. Doses of corticosteroids and the length of the study period differed widely across the selected studies.

AE assessment

For reporting AEs of corticosteroids, among 27 RCTs, three did not report any harm or toxic effects associated with corticosteroids and six RCTs reported that there were no AEs. Sixteen RCTs did not include any information on AE assessment methods. AEs were reported by grade in four RCTs. Of these, two RCTs used the Common Terminology Criteria for Adverse Events (CTCAE) [ 11], while the other two used original Likert scales. Fifteen RCTs did not describe the timing of AE assessment. Sixteen RCTs discussed AEs in their reports.
Among the 12 consecutive cohort studies, seven studies did not include a statement on AE assessment methods. One consecutive cohort study used the CTCAE. Other methods to assess AEs included Likert scales (1), original checklists (1), and clinical impression (1). Three studies assessed AEs by grade.
Seven consecutive cohort studies discussed about AEs in their reports. Three studies did not mention any about AEs. Three of these studies reported the timing of AE assessment.

Risk of bias (RCTs)

Figure 2 shows the risk of bias among the 27 RCTs. According to the Cochrane review guidelines, we assessed the risk of bias and found that approximately 30% of RCTs were rated as having a high risk of AE reporting bias. Many studies reported only severe AEs such as Cushing syndrome, severe infection, or gastrointestinal bleeding, while others reported only a few types of AE symptoms. The assessment of AEs without validated tools was also related to a high risk of reporting bias. Although seven open-label or single-blinded studies were included in this review, the RCTs mostly adequately described the random allocation of patients and blinding condition.

Discussion

Among the studies included in this review, many failed to report sufficient information about AEs associated with corticosteroid. An extension of the CONSORT checklist is available to report AEs in RCTs [ 9] and was developed following calls to improve the quality of AE reporting among RCTs [ 5, 6]. In this review, two RCTs and one consecutive cohort study in which a validated AEs assessment tool was used were published after developing CONSORT extension. However, the remaining studies used no validated tools to assess AEs. As previous reviews have been suggested, [ 7, 12, 13] more promotion to improve quality of AE reporting in clinical should be needed.
Corticosteroids are commonly used in clinical practice to treat a variety of conditions. Clinicians should therefore be aware of both the benefits and harms of corticosteroid. Patients of deteriorating condition may be more susceptible to toxicities arising from pharmacological intervention. To avoid the occurrence of harmful events by the proper use of pharmaceutical products, clinical researchers should be more aware of the importance of reporting AEs.
Sixteen RCTs (59%) and seven consecutive cohort studies (58%) did not report the method used for assessing AEs. Assessment of the side effects of corticosteroids without specific measurements may lead to under-estimation of the actual harm caused by corticosteroids, which can present with a wide variety of symptoms. Furthermore, the use of different measurement tools may limit the ability to analyze differences in AEs between studies. PRO-CTCAE [ 14], developed to assess cancer patients’ subjective side effects, should be considered as a standardized tool for assessment and minimizing the risk of under-estimation of AEs of corticosteroids.
Nevertheless, there was no significant difference in the proportion of AEs between corticosteroid and placebo groups in recent RCTs in which validated AE assessment tools were used [ 15, 16]. This may be explained by low statistical power related to small numbers of participants and short study periods. Restrictive inclusion/exclusion criteria may also be related to the low rates of AEs observed in the RCTs. In terms of the timing of AE assessment, 15 RCTs (56%) and 11 consecutive cohort studies (92%) did not report the timing of AE assessment. Corticosteroids present not only acute side effects but also long-term side effects [ 17]. It is important that consecutive cohort studies of larger numbers of participants taking corticosteroids for longer periods of time with high-quality AE assessment are reported.
RCTs provide the highest level of evidence of treatment effectiveness. However, most RCTs are designed to assess benefit, capturing AEs or harms collaterally [ 18]. While measuring effectiveness of treatment is essential, assessing harms is also important. The CONSORT extension for harms was developed in 2004 [ 9]. This guideline provides lists of recommendations for AE reporting in clinical trials. However, recent reviews show that the quality of reporting has not improved since the publication of the CONSORT extension for harms in 2004 [ 7, 12, 13]. Authors insist more effort is needed to improve AE reporting in clinical trials.
The outcomes of consecutive cohort studies, in which the criteria of participants were less restrictive, may better reflect clinical practice than the RCTs. However, it is often difficult to differentiate delirium due to corticosteroid from the natural disease progression in patients with terminal cancer [ 19]. For example, delirium may be caused by several factors such as opioids, infectious diseases, cerebral metastases, and organ failure, as well as by corticosteroids. The vulnerable populations included in the studies may be less likely to show resolution of risk factors for delirium. Nevertheless, a previous cohort study showed that approximately 50% of delirium symptoms might be reversible, even in patients with advanced cancer [ 20]. The cause of AEs in advanced cancer patients receiving corticosteroids should therefore be carefully assessed with validated tools.

Limitations

This study did not include studies written in languages other than English, and this may potentially have contributed to selection bias. Secondly, we analyzed only published studies. Thirdly, the population in this review was limited to studies of people with advanced cancer, with limited data on specific glucocorticoids, dose, duration, or survival. The lack of these factors limits the interpretation that can be made, even in the RCTs.

Clinical implications

Our systematic review shows that side effects of corticosteroid use are poorly reported. Treatment decisions need the evidence of both treatment effectiveness and harms. Researchers should be aware of the guideline of AE reporting to provide high-quality data of both benefit and AEs. Short study durations and (relatively) small sample sizes of RCTs may not be sufficient to detect longer term AEs. A long-term consecutive cohort study with same standard as RCTs for reporting AEs may more closely reflect real world practice. A consensus guideline of AE reporting in studies of people taking glucocorticoids in the setting of advanced cancer may be of benefit.

Acknowledgements

We thank Mikaela Lawrence, a librarian who assisted us in the search filtering.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.
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