Vijayaratnam N; Gagnon L; Kwan R; Leguerrier
B; Huang F; Fairchild A

Special Article - Palliative Care

J Fam Med. 2016; 3(1): 1047.

An Evidence-Based Summary of Recommendations for the use of Dexamethasone in the Management of Brain Metastases

Vijayaratnam N¹, Gagnon L², Kwan R², Leguerrier B³, Huang F³ and Fairchild A^1,3*

¹Faculty of Medicine, University of Alberta, Canada

²Department of Pharmacy, Cross Cancer Institute, Canada

³Palliative Radiation Oncology Program, Department of Radiation Oncology, Cross Cancer Institute, Canada

*Corresponding author: Fairchild A, Department of Radiation Oncology, Cross Cancer Institute, 11560 University Ave, Canada

Received: December 03, 2015; Accepted: January 11, 2016; Published: January 13, 2016

Abstract

Intracranial edema associated with brain metastases commonly contributes to symptoms of headache, nausea or emesis. Corticosteroids are the pharmacologic agent of choice for many patients, to temporize symptoms until definitive antineoplastic therapy can be initiated. However, careful management is required to minimize related side effects which may compromise a patient’s quality of life. The literature on dosing, appropriate duration of therapy and tapering will be reviewed, along with practical guidelines on the initiation of dexamethasone, appropriate prophylaxis, and secondary screening for adverse events.

Keywords: Brain metastases; Dexamethasone; Steroid; Taper; Radiotherapy; Palliative

Abbreviations

AVN: Avascular Necrosis; BID: Twice Daily; BBB: Blood- Brain Barrier; CT: Computed Tomography; CVA: Cerebrovascular Accident; DM: Diabetes Mellitus; DXM: Dexamethasone; GERD: Gastroesophageal Reflux Disease; GI: Gastrointestinal; ICP: Intracranial Pressure; MRI: Magnetic Resonance Imaging; NR: Not Reported; nSAID: non-Steroidal Anti-Inflammatory; OD: Daily; PCP: Pneumocystis Carinii Pneumonia; PE: Pulmonary Embolus; PJP: Pneumocystis Jurovecii Pneumonia; QID: Four Times Daily; RCC: Renal Cell Carcinoma; RCT: Randomized Controlled Trial; RT: Radiotherapy; TB: Tuberculosis; VTE: Venous Thromboembolism; WBRT: Whole Brain Radiotherapy

Introduction

Almost 10% of all patients with cancer will develop brain metastases, which are most commonly diagnosed in lung, renal, breast, and colorectal cancers, and melanoma [1,2]. The edema commonly associated with brain metastases is typically due to increased vascular permeability. This is secondary to blood-brain barrier (BBB) disruption around the lesion(s), and is termed vasogenic edema. BBB disruption is caused by vascular endothelial growth factor overexpression and secretion by metastatic lesions. BBB disruption allows passage of plasma and proteins from the vascular compartment into brain parenchyma, resulting in edema and therefore increased interstitial pressure within and around the tumor. The resulting increase in intracranial pressure (ICP) leads to the classic symptoms of headache, nausea and vomiting [3].

Corticosteroids appear to have a mechanism of action specific to vasogenic edema, as they are relatively ineffective in cytotoxic or intracellular edema. Studies using gadolinium-enhanced magnetic resonance imaging (MRI) in primary and secondary brain tumours suggest that the anti-edema effect of corticosteroids is related to decreasing BBB permeability [4]. After seven days of treatment, a reduction in radiologically-apparent cerebral edema is seen which correlates with a reduction in blood-tumour-barrier transport [4].

Dexamethasone

Dexamethasone (DXM) is the corticosteroid of choice for treating edema associated with brain metastases because of its biological properties, including half-life and potency [3,5-6]. It has the least mineralocorticoid activity of the agents in this class, which results in a lower rate of peripheral fluid retention [7]. The biological half-life is 36-54 hours, such that frequent dosing is not necessary, and the potency is six times that of methylprednisolone, reducing tablet burden [7,8]. There are also multiple available routes of administration. However, the long half-life may increase the risk of adrenal suppression with long term use. It is also more difficult to taper slowly when sub-physiological dosing is required, due to lack of availability of very low strength formulations [9].

Side Effects

Side effects of DXM are common (Table 1), and they increase in frequency and severity with increased dose and duration of therapy [3].

Table 1: Commonly reported dexamethasone adverse effects. Incidence varies based on total daily dose.




  
    Adverse Effect 
    Incidence Range 
    Example References 
  
  
    Hyperglycemia
    5-72%
    [3,14,18,21,25]
  
  
    Cushing’s syndrome
    4-65%
    [21,25]
  
  
    Psychiatric disorder*^
    10-62%
    [3,14,21,25]
  
  
    Insomnia^
    22-62%
    [3,14]
  
  
    Hypertension
    12-45%
    [3,21]
  
  
    Muscular weakness /    proximal myopathy
    4-38%
    [3,14,21,25]
  
  
    Peripheral edema
    5-26%
    [18,21,25]
  
  
    GI symptoms**^
    3-24%
    [14,21,25]
  
  
    Increased appetite^
    22%
    [14]
  
  
    Infection including    PCP, PJP
    6-9%
    [3,14,21]
  
  
    Oropharyngeal +/-    esophageal candida^
    5-7%
    [14,18,25]
  
  
    PE / VTE
    2%
    [25]
  
  
    Other (seizures,    CVA, weight gain^, hiccups^, osteoporosis, acne^, AVN)
    NR
    [3,14]



Table 1:  Commonly reported dexamethasone adverse effects. Incidence varies based on total daily dose.

In a review of the literature encompassing 93 cases (14 previously unpublished) and 29 clinical studies, the overall incidence of mild to moderate psychiatric symptoms such as anxiety, irritability, and insomnia was 27% (range 13-62%), while severe manifestations (mania, depression, psychosis) were limited to approximately 5% (range 1.6-50%) [10].

The relative risk of gastrointestinal toxicity while on corticosteroids has been reported by two meta-analyses: Messer et al evaluated 71 controlled clinical trials and described a 2.3 greater incidence of peptic ulcers during steroid therapy [11]. Conn et al ’s meta-analysis included 93 double-blind randomized controlled trials (RCT) of more than 8700 patients, reporting an estimated annual peptic ulcer incidence of 1.7% in the control group and 2.1% in the steroid group (RR 1.2) [12]. The relative risks of GI hemorrhage cited by the same papers were 1.5 and 1.2, respectively [11,12]. In a nested case-control study of 1415 patients hospitalized for gastric or duodenal ulcer or upper GI hemorrhage of unknown cause (versus 7063 controls), those receiving concurrent non-steroidal anti-inflammatory medication had a risk of peptic ulcer disease 15-foldhigher than non-users of either drug [13].

Comorbidities such as pre-existing gastro esophageal reflux disease (GERD) and diabetes mellitus (DM) are likely to increase the risk of clinically significant DXM-related toxicity [14]. Likewise, poor nutrition resulting in hypoalbuminemia (<25g/L) increases the risk of toxicity because the percentage of unbound steroid increases [15]. DXM is metabolized by the cytochrome p450 3A4 pathway shared by many other drugs, increasing the potential for interaction with other medications, including the risk of rapid catabolism of DXM [3].

Methods to minimize known DXM side effects should be instituted especially in patients at increased risk (Table 2). This may be in the form of adjustments in DXM dosing, addition of prophylactic agents, or proactive management of side effects. Patients and caregivers should be informed of pertinent signs and symptoms to report.

Table 2: Prophylaxis of and methods to minimize dexamethasone side effects.




  
    Adverse Effect 
    Approach 
    Population 
    Intervention 
    Example References 
  
  
    Oropharyngeal    candida
    Prophylactic
    All patients
    Nystatin 500 000U (5mL)    poswish& swallow QID x7 days*
    ]28,31]
  
  
    Gastric irritation
    Prophylactic
    All patients but especially    those with a history of gastric ulcer or hiatus hernia
    Pantoprazole 40mg po OD - BID
    [28]
  
  
    Gastric irritation
    Prophylactic
    Discontinue nSAID use during    dexamethasone
    Consider replacing with a weak    opioid
    [13]
  
  
    Pneumocystis    jirovecii Pneumonia

    Prophylaxis
    Anticipated dose equivalent:    prednisone 20mg daily for one month or more
    Trimethoprim-sulfamethoxazole�    DS three times weekly until completion of taper^
    [31-33]
  
  
    Avascular necrosis
    Secondary screening
    Patients who develop groin, hip    or femur pain
    Perform plain x-rays of    bilateral hips
    [34]
  
  
    Hyperglycemia
    Secondary screening
    Patients with DM; patients with    or without DM who develop symptoms
    Blood glucose monitoring BID -    QID
    [3] 
  
  
    Reactivation    Hepatitis B
    Secondary screening
    Anticipated dose equivalent:    prednisone 7.5mg daily for one month or more
    Hepatitis B serology (surface    antigen or core antibody)
    [36] 
  
  
    Reactivation    Tuberculosis
    Secondary screening
    Anticipated dose equivalent:    prednisone 15mg daily for one month or more
    TB screening especially in    those who are at high risk of latent TB
    [35,36] 
  
  
    StrongyloidesHyperinfection    Syndrome**
    Secondary screening
    Any corticosteroid dose and    duration in a patient who has lived in or travelled to an endemic area at any    time
    Strongyloidesstercoralis    screening
    [36]
  
  
    Proximal Myopathy
    Treatment
    Symptomatic proximal myopathy
    Switch from DXM to prednisolone
    [7]
  
  
    *Or for    2 days after improvement. **Mortality    approaches 100%. �Sulfamethaxazole 800mg +    trimethoprim 160mg. ^Decreases the risk of    infection by 91% in HIV-negative individuals. Abbreviation: BID: Twice Per Day;    DM: Diabetes Mellitus; DXM: Dexamethasone; nSAID: non-Steroidal Anti-Inflammatory;    OD: Daily; QID: Four Times Daily; TB: Tuberculosis.



Table :  Prophylaxis of and methods to minimize dexamethasone side effects.

The Dexamethasone Symptom Questionnaire [16] is an example of a validated instrument used to systematically measure DXM toxicity. It includes 13 symptoms reflective of DXM toxicity (Table 1), and has been recently used in a RCT assessing relative risks and benefits of DXM in radiation treatment of bone metastases [17]. Each item is scored independently (not at all/a little/quite a bit/ very much), with a higher total score indicative of worse symptom severity [16].

Literature Summary: Initial Dose

The optimal DXM starting dose that confers maximal benefit at minimal toxicity for patients with brain metastases is not known [7]. In a survey of 34 oncologists and palliative care specialists involved in managing patients with lung, breast, renal cell, gastrointestinal cancers and melanoma, 45% prescribed DXM at a fixed dose of 16mg daily. The presence or absence of symptoms, types of symptoms, neurologic deficits, and the degree of edema on imaging were factors cited by respondents as impacting the choice of starting dose [14] (Table 3). This dose schedule of 4mg QID has been reported in small prospective trials [18-19]. In a systematic review of twenty one RCTs of whole brain radiotherapy (WBRT) used in the setting of multiple brain metastases, 18 studies documented steroid use, but only five provided details on the specific agent and dose [20]. DXM was the most commonly used at total daily doses ranging from 8mg to 16mg [20]. In a pooled analysis of two sequential RCTs involving 89 evaluable patients with brain metastases, Vecht et al compared quality of life, Karnofsky performance status (100 point scale) and side effects of 4mg or 8mg versus 16mg daily doses of DXM. More side effects were reported at 28 days by the patients treated with 16mg (p<0.03), with no significant improvement in performance status (PS) in comparison to those receiving lower doses [21]. At 7 days, the 4-mg group had improved by 6.7 points (SD 11.3) versus 9.1 (SD 12.4) in the 16-mg group. In the 8-mg group, at the same time point, PS had improved by a mean of 8 points (SD 10.1) compared to 7.3 (SD 14.2) in the 16-mg group [21]. On balance, the literature favors treating mildly or moderately symptomatic patients with a starting daily dose of 4-8 mg, and those with severe symptoms with 16mg, divided into two doses [6,21-23] (Table 3). Anecdotally, patients may experience less insomnia if their two daily doses are delivered with breakfast and lunch, rather than on a strictly BID schedule.

Table 3: Summary of factors to consider before starting corticosteroids in brain metastases.




  
    Factor 
    If Yes� 
    If No� 
    Example References 
  
  
    Mild to moderate    baseline neurologic signs +/- symptoms or symptoms of increased ICP?
    Start DXM 4-8mg daily
    Do not start steroids
    [6,25,27,28-29]
  
  
    Severe baseline    neurologic signs +/- symptoms or symptoms of increased ICP?
    Start DXM 16mg daily
      Consider mannitol
    Do not start steroids
    [23,25,29]
  
  
    Asymptomatic but    undergoing brain RT
    Consider starting DXM 4mg daily
    ^Do not start steroids
    [21,27]
  
  
    Asymptomatic but    undergoing brain RT with vasogenic edema apparent on baseline imaging
    Consider starting DXM 4mg daily
    Do not start steroids
    [21]
  
  
    Patient currently    receiving targeted biological agent or small molecule therapy
    Discuss with Medical Oncologist    prior to starting steroids
    [27]
  
  
    Has the patient had    all age-appropriate vaccines/boosters?
    Start steroids
    Immunize, then start steroids
    [36]
  
  
    ^If no    immediate radiotherapy planned. Abbreviations: DXM: Dexamethasone; ICP: Intracranial    Pressure; RT: Radiotherapy.



Table 3:  Summary of factors to consider before starting corticosteroids in brain metastases.

Literature Summary: Duration

Patients should remain on DXM for the minimum necessary duration [7]. The first 10 days of corticosteroid therapy should be looked upon as a ‘dose-finding’ period, in which the DXM schedule is adjusted according to degree of symptomatic benefit, antineoplastic treatment modality instituted, and side effects [7]. There are presently many options for the definitive treatment of brain metastases, depending on the number of lesions, their size and location, the patient’s PS, extracranial disease and preferences [24]. Many receive radiotherapy (RT), either stereotactic or WBRT. Some patients experience progressive neurological symptoms during RT as a result of the treatment itself, due to transient increases in edema. If that occurs, DXM dose should be increased for a short period of time, such as from 4mg to 8-16mg daily for three days, then decreased back to the baseline schedule [18]. A retrospective single-institution review of 91 patients with brain metastases (1992-1997), all of whom received whole brain RT and DXM initiated at diagnosis, demonstrated a mean duration of DXM treatment of 6.9 weeks (range 1-50.5 weeks), with 17.6% requiring DXM until death [25].

The total dose and duration of DXM must be anticipated in order to institute appropriate prophylaxis and secondary screening measures (Table 2). Recommendations for prophylaxis in relation to the expected immunosuppressive effect of DXM are often described in terms of prednisone equivalent dose per day; 5mg of prednisone is equivalent to 0.75mg of DXM [7]. As an example of the importance of preventative measures, in a retrospective review of 10 729 patients receiving chemotherapy at a comprehensive cancer centre (2004- 2007), 151 had either a positive hepatitis B surface antigen or core antibody; of those, patients who received hepatitis B prophylaxis had a significantly lower all-cause mortality compared to those who either did not receive antiretroviral therapy, or who were treated after reactivation, respectively (22% vs. 71% vs. 72%; p<0.05) [26].

Literature Summary: Tapering

Published evidence and specific recommendations about the optimal tapering schedule vary [14]. Some authors report a taper to be unnecessary if a patient is asymptomatic at baseline and received 4mg per day or less, over 28 days or fewer [21]. However, the general consensus in the literature, as reflected by the review of Aulakh et al, is that significant adrenal suppression may occur after as little as two weeks of corticosteroids [9]. Early tapering is the only means of identifying need, and is critical to the minimization of side effects [7]. Anticipation of the re-emergence of symptoms should not deter attempts at tapering, which should be made in all patients [7]. DXM tapering should be instituted as soon as symptomatic benefit is seen, especially if on 16mg per day or if minimally symptomatic initially, in order to find the lowest effective dose quickly [7,27-28].

In general, tapering schedules most commonly reported involve a gradual decrease in dose and/or interval over a period of 2-4 weeks, with longer periods for patients who were symptomatic at baseline [14,20-22,29] (Table 4). Patients who were minimally symptomatic at baseline may tolerate a faster taper, over a few days [27]. Patients should be given a written schedule for tapering, preferably on a calendar, with information as to who to call should rebound symptoms of increased ICP emerge. Patients should be monitored regularly during a taper for this reason. Steroid withdrawal syndrome is seen in approximately 5% [18]. If such symptoms occur, DXM should be increased back to the previous dose on which the patient felt well. Some patients may require a switch from DXM to prednisolone to facilitate a slow withdrawal in the physiological dose range [7]. Additionally, it is good practice to warn patients and their caregivers that the ‘beneficial’ side effects of increased appetite and energy will also wane with the dose taper, and not to consider these constitutional signs of progressive disease.

The rate of tapering will be dictated in part by the patient’s tolerance and response to disease-modifying therapy, such as radiotherapy [7]. Some clinicians institute a taper within one week of starting RT (before it has finished) [6,18,29], while some wait until the course of treatment has been completed to start decreasing the dose [14]. In a pilot study of 20 patients evaluating a novel schedule of DXM administration during palliative RT, DXM was tapered during radiation and discontinued on the last day of RT as planned, in 70% (14/20), with 93% (13/14) of those symptom-free off steroids at 30 days post-RT [18]. DXM taper should be safe to institute once any RT-related edema has resolved, although it is often difficult in practice to pinpoint that time in the treatment trajectory, since short follow-up CT scans of the brain are not usually performed [14].

After previous unsuccessful attempts at tapering, and in the terminal phase, the ratio of benefit to burden of continuing DXM differs than at baseline [7]. It is necessary to regularly review the pros and cons of continuing corticosteroids, and to ensure any appropriate prophylaxis and secondary screening have been instituted [7].

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Citation:Vijayaratnam N, Gagnon L, Kwan R, Leguerrier B, Huang F and Fairchild A. An Evidence-Based Summary of Recommendations for the use of Dexamethasone in the Management of Brain Metastases. J Fam Med. 2016; 3(1): 1047. ISSN : 2380-0658

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Week 1	4mg po BID	7 days
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