The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

Given the extremely limited number of studies which satisfied the conditions of our search criteria, an additional discussion of published literature on the subject of corticosteroids in metastatic brain disease is provided to offer a larger context for this topic. While the following studies were not part of the body of evidence considered in formulating treatment recommendations in our evidence-based guidelines, they do highlight areas of interest where clinical trials are still required to answer important steroid-related questions.

A review of the outcomes in the Radiation Therapy Oncology Group (RTOG) studies examining various radiotherapeutic regimens for patients with metastatic brain disease demonstrated a dramatic early improvement in patients treated concurrently with steroids during the early phases of the trials [10]. However, as the authors note, the administration of steroids was not well controlled in these studies and was not a primary point of interest so, although these observations contributed to the overall clinical impression that steroids were of benefit in the adjuvant treatment of brain metastases, it is difficult to extrapolate treatment recommendations from these studies. In Borgelt et al., this is shown by the fact that symptomatic patients receiving steroids had a significant improvement in neurological function as opposed to those who did not receive steroids. None of these studies suggested that the use of steroids halted time to progression.

Gaspar et al. [7] published an American College of Radiology (ACR) Committee on Appropriateness Criteria consensus report following an expert panel review on the pre-irradiation evaluation and management of brain metastases. The authors cite six articles to support the generation of their expert opinions [5, 6, 10‐13]. They initially note that although clinical experience has established the effectiveness of corticosteroids in reducing symptoms and radiographic peritumoral edema, controversy remains on the specific indications and dosage used. They point out that the earliest studies to support steroid use prior to radiotherapy used radiation dosing schemes that are presently atypical and that there was evidence that steroids were only indicated when there was a concern about raised intracranial pressure [10‐12]. In one study, 27% of patients who received 10 Gy of single fraction whole brain radiotherapy (WBRT) experienced signs of increased intracranial pressure [12]. They also note evidence from one trial indicating that patients who were moderately symptomatic who received steroid therapy during radiation experienced a more rapid improvement in their clinical symptoms, although there was no impact on progression-free or overall survival. This review went onto outline several papers addressing the acute and chronic side effects and the studies that address dosing and toxicity [5, 6, 13].

This consensus review summarizes the authors’ views on steroid use for metastatic brain disease by indicating that the patient who shows evidence of elevated intracranial pressure, but who does not require immediate surgical attention for either hydrocephalus or impending herniation, should receive 4–6 mg/day of dexamethasone in divided doses and that the routine use of corticosteroids in patients without neurological symptoms is not necessary.

In 1982, Hatam et al. [14] prospectively studied the effect of dexamethasone therapy on peritumoral edema based on computed tomography (CT) describing specifically three cases of metastatic intracranial disease in which a linear decrease in edema volume was observed, reducing the measured volume of edema to one-fourth of the initial volume after 2 weeks of treatment starting with 4 mg four times daily and tapered to 1 mg/day. The exact time course for the metastatic patients was not reported separately but the authors did report a substantial clinical improvement in these patients they felt was associated with the use of dexamethasone.

Andersen et al. [11] published a subsequent report in 1994 that quantified the effect of steroid therapy over time on peritumoral brain edema in vivo using a magnetic imaging based technique. Magnetic resonance based assessments of peritumoral edema were undertaken on 23 brain tumor patients including 13 with brain metastases at baseline and at Days 1, 3 and 7 after starting steroid therapy. Intravenous dexamethasone was used at dose of 0.26–0.64 mg/kg (for a 70 kg patient this range is 20–45 mg/day). After 7 days of steroid treatment the total edema area was reduced by 10.3% in the metastatic patients, with an average reduction in mean volume of 4.6% after 24 h of treatment and 13.5% after 7 days. This effect was observed for up to 63 days and it was demonstrated that after 40–63 days (6–9 weeks) of steroid therapy the peritumoral water content was close to the upper normal range for white matter. The authors concluded that steroids significantly reduce the volume of peritumoral edema in patients with metastatic brain disease even after a few days of treatment. They postulate a mechanism of steroid-induced reduction in edema below the level of absorption and commented that they thought they may have obtained the same effects with a dose-reduction to minimize potential side effects.

Minamikawa et al. [15] studied the effect of glucocorticoid treatment (methylprednisolone, dose not specified) on the apparent diffusion coefficient (ADC) imaging in a series of 13 patient including four with metastatic brain disease. Although it is not possible to examine the effects on the metastatic patients separately, the authors suggested that ADC imaging was a more sensitive technique than conventional MRI imaging for studying the effects of steroids on peritumoral edema, even in the absence of detectable MRI changes.

Hempen et al. [13] retrospectively reviewed 138 consecutive patients to evaluate the impact of dosage and duration of dexamethasone administration during radiation therapy for patients with both primary and metastatic brain tumors (n = 91). The dosage of dexamethasone was gradually reduced from an initial median dose of 7–12 mg/day to a median of 1–6 mg/day with an average duration of 7 weeks for the metastatic group. The authors reported a period of initial clinical improvement with relatively few side effects. Specifically, 33% of patients reported improvement in symptoms with steroid use prior to radiotherapy, 44% during radiotherapy and 11% following radiotherapy. However, as dexamethasone was continued, this trend reversed and less symptom relief was observed with increasing toxicity. Life-threatening complications were rare. Side effects attributed to steroid use included: hyperglycemia (47%), peripheral edema (11%), psychiatric disorder (10%), candidiasis (7%), Cushing’s syndrome (4%), muscular weakness (4%) and pulmonary embolus (2%). Of a cohort of 13 clinically asymptomatic patients who received no dexamethasone during radiotherapy, 12 (92%) showed no sign of worsening neurological problems. The patient with worsened symptoms had brain stem involvement. The authors conclude that dexamethasone effectively minimizes neurological symptoms and radiation therapy related side effects in patients with both primary and secondary brain tumors. The toxicity of dexamethasone was noted to increase over time and therefore a patient-specific dosing pattern and taper was recommended. The authors suggested that a prospective study specifically addressing the relative balance of symptom relief versus toxicity would be of benefit and that there is little evidence to support the use of steroids in the asymptomatic patient.

In 1999, Lagerwaard et al. [8] published an extensive retrospective review of 1,292 patients with metastatic brain disease referred to a single institution to identify prognostic (risk) factors. The majority of patients were treated with WBRT (n = 1,079, 84%); 118 (9%) were treated with steroids only and 95 (7%) with surgery and radiotherapy. Data obtained included: age, sex, performance status, number and distribution of brain metastases, site of primary tumor, histology, interval between primary tumor and brain metastases, systemic tumor activity, serum lactate dehydrogenase, response to steroid treatment, and treatment modality. Dexamethasone was used in a dose range of 4–16 mg/day (mean dosage 14.6 mg/day), which was “tapered slowly and discontinued in the weeks following therapy” (specific details not stated).

Multivariate analysis confirmed the previously reported observation that the impact of treatment modality on survival in patients with brain metastases was the most significant single factor in predicting survival. However, response to steroid treatment, performance status, systemic tumor activity and serum lactate dehydrogenase levels were also all independent prognostic factors on survival, second only to treatment modality in level of significance. Site of primary tumor, age, and number of brain metastases were also identified as prognostic factors.

The authors concluded that the strongest prognostic (risk) factors were choice of treatment modality, response to steroids, performance status, and evidence of systemic disease and they proposed using these classifiers in identifying favorable and unfavorable subgroups of patients with brain metastases for future studies.

Millar et al. [9] attempted to assess the impact of steroid therapy in the management of brain metastases by undertaking a systematic review of published randomized trials on WBRT for multiple cerebral metastases. In this extensive review published in 2004, the authors identified 21 full manuscripts of published randomized controlled trials involving WBRT in the treatment of multiple brain metastases from 1971 to 2003. They attempted to extract details on the use and type of steroid, timing of steroids relative to radiotherapy, response assessment and contribution of steroids to overall outcome. They reported that 18 of the 21 trials reviewed documented steroid use. Overall survival was an outcome assessed in all studies. Thirteen studies assessed neurological response and ten assessed a radiographic endpoint. Ten of the studies (48%) suggested a positive effect of steroid use on the outcome assessed. Only one study—in the palliative setting—provided a fixed steroid dose.

The authors concluded that the reporting of steroid use in previously published randomized trials assessing treatment for patients with brain metastases is “non-uniform and not sufficiently detailed” making it difficult to assess the treatment effect. They call for a more standard approach to steroid dose in future studies or at a minimum better reporting of dosages used to better determine symptom response and durability of response. They also note that side effects of steroid use and the ability to taper off steroids after treatment intervention are additional outcomes of interest in the planning of future studies.

Weissman et al. [16] published their experience with a treatment regimen designed to reduce steroid toxicity in 20 patients with newly diagnosed brain metastases. All patients received dexamethasone starting at 8 mg twice daily for 4 days then 4 mg twice daily for 4 days followed by 2 mg twice daily until the last day of radiation therapy. Radiation dose and schedules ranged from 20 Gy in five fractions to 58 Gy in 29 fractions. Fourteen patients (70%) received dexamethasone for a minimum of 24 h before their first radiation treatment and seven of those patients (50%) experienced improvement in neurologic symptoms and signs before radiotherapy. Fourteen patients (70%) completed the entire course of radiation and dexamethasone as planned. One patient required reinstitution of dexamethasone within 30 days of finishing radiation for neurological decline. The authors felt that the twice-daily dose was well tolerated. Steroid related toxicity included hyperglycemia (5%), candida esophagitis (5%), steroid pseudorheumatism (10%), peripheral edema (5%) and steroid withdrawal syndrome (5%).

In 2006, the results of a series of systematic reviews with the stated purpose “to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases” was published by Soffietti et al. [1]. This was conducted by a multi-disciplinary task force of the European Federation of Neurological Societies and includes a review of data obtained from the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. Under the section on supportive care and steroids only one original article is cited and reviewed, and that is the publication by Vecht [5], which also met the eligibility criteria for this guideline paper and is discussed extensively in the scientific foundation section. This paper was used to support the recommendation that, in most cases, initial dexamethasone doses should not exceed 4–8 mg/day. However, in patients with more severe symptoms related to increased intracranial pressure doses of 16 mg/day or higher should be considered (Level of Evidence B) [17]. The remainder of the recommendations were based on uniform consensus of the task force (referred to as a “Good Practice Point”) and are summarized below. Dexamethasone was noted as the corticosteroid of choice and twice daily dosing was thought to be sufficient (Good Practice Point). Tapering of steroid dosing within 1 week of starting therapy and discontinuation within 2 weeks if possible was encouraged (Good Practice Point). Finally, patients who do not have signs or symptoms of increased intracranial pressure do not have to be treated with steroids (Good Practice Point).

Given the very limited number of studies that met the inclusion criteria for the systematic literature review on the role of steroids in metastatic brain disease, we are unable to propose specific guidelines on many of the issues of central interest to the treating physician.

In summarizing the Discussion section above we are able to offer the following observations: first, Overall the literature favors the position that corticosteroids are of benefit in providing temporary symptomatic relief of CNS symptoms related to increased intracranial pressure and edema secondary to brain metastases [1, 7‐10, 13]. Secondly, dexamethasone is the steroid most often used, with the rationale that it has limited mineralocorticoid effects. Other steroids have been used with similar reported clinical responses. Dosing has been recommended to be sufficient at twice daily although more frequent dosing has been suggested with increasing concern for raised intracranial pressure and impending herniation [1, 7, 8, 11, 14]. Finally, based primarily on the asymptomatic patients in the study by Hempen et al., it is the opinion offered in the available studies that asymptomatic patients do not require steroids [1, 7, 13]. Numerous authors cite concerns for the toxicity of steroid therapy and due to the lack of a uniform recommendation on dosing and the apparent complexity of the response in individual patients it has been recommended that dose reduction be considered within 1 week of initiation of treatment. The dose reduction appears to often require alteration in individual patients due to the diversity of response [1, 7, 9, 13, 16].

An interesting observation in the review of the literature on this subject is the number of authors who appear to assume that steroids are a mainstay of treatment for the patient with metastatic brain disease despite the relative lack of detailed information available to guide specific therapy. In general, the evidence for specific dosages and regimens of steroids are poorly detailed. On the other hand, there is very little information provided in the literature that suggests that steroids are of no benefit in this patient population with the exception of the asymptomatic patient.

Given the general consensus in the literature that steroids are of benefit in selected patients with metastatic brain disease and the frequent observation that dosing needs to be specifically tailored to the individual, it appears unlikely that in depth studies specifically addressing this issue will be forthcoming. However, the need for additional recommendations for dosing and duration of therapy may result in an increased awareness of this concern and potentially an alteration of clinical trials designed to address comparisons.