Could Dexamethasone Dose Affect Glioblastoma Survival?

Alexander M. Castellino, PhD

July 23, 2015

Dexamethasone is commonly used in the clinical management of the neurologic effects of glioblastoma, such as brain edema. Although it has been associated adverse effects, until now, it was not clear that dexamethasone influences the clinical outcomes of glioblastoma treatment.

For the first time, investigators report that high-dose dexamethasone given to patients with recurrent glioblastoma might be associated with decreased survival, perhaps through a suppression of immune effector functions. The conclusion comes from a retrospective analysis — which the authors call a 'unique' study — published online June 30 in the British Journal of Cancer.

"Our analysis strongly suggests that dexamethasone used at doses greater than 4.1 mg per day may influence clinical outcomes for patients," Kenneth D. Swanson, MD, one of the two principal investigators, told Medscape Medical News.

"Indeed, it may be prudent to re-evaluate the doses at which dexamethasone are used," coprincipal investigator Eric  T. Wong, MD, told Medscape Medical News.

Both authors are from the Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.

However, two experts not involved in the study raised questions about this conclusion. "That high-dose dexamethasone impacts survival is an interesting hypothesis," Mark Gilbert, MD, senior investigator and chief of neuro-oncology at the National Cancer Institute in Bethesda, Maryland, told Medscape Medical News.

However, he added, "there is a concern that the investigators did not perform a multivariate analysis to account for other prognostic factors that may have been reasons that necessitated the use of high-dose dexamethasone. In the clinical management of glioblastoma, the dose of dexamethasone used is based on physicians' choice and practice patterns, and is not controlled by clinical trial protocols.

Howard A. Fine, MD, from the Weill Cornell Medical College and the New York Presbyterian Hospital in New York City, agreed. "These observations must be interpreted carefully within the context of how patients with glioblastoma are clinically managed," he told Medscape Medical News. "This analysis is limited and does not take into account the primary reason for dexamethasone use in these patients," he added.

Dr Fine is Feil Professor of Medicine, director of the Weill Cornell Brain Tumor Center, and associate director of translational research at the Meyer Cancer Center of Weill Cornell Medical College.

Study Uniquely Poised to Evaluate Dexamethasone

Dr Wong and colleagues chose to study the effects of dexamethasone on glioblastoma by analyzing data from patients who took part in the phase 3 registration trial of a device that delivers alternating electric fields, or tumor treating fields (TTFields), to the tumor and its surroundings.

The device, NovoTTF-100A, has since been approved for the treatment of glioblastoma. It is thought to work by perturbing the mitotic division of proliferating cells; the alternating electric fields generate "mitotic catastrophe" leading to cell death.

In the registration trial, patients were treated with this device or with chemotherapy. This study therefore provides "a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy," the authors explain.

In addition, Dr Swanson noted that "the responders in the trial that evaluated the efficacy of the NovoTTF-100A device for the treatment of recurrent glioblastoma had a unifying feature: they all had low dexamethasone usage."

The registration study had initially shown that responses were higher, although not significantly so, with the NovoTTF-100A device than with the best physician's choice of chemotherapy in the treatment of recurrent glioblastoma (Eur J Cancer. 2012;48:2192-2202).

A further post hoc analysis revealed that dexamethasone and low-grade histology were predictors of response (Cancer Med. 2014;3:592-602).

Retrospective Analysis of Effects of Dexamethasone

These observations led the investigators to the current study, which was a retrospective analysis of the phase 3 study that assessed survival by stratifying patients according to dexamethasone use. The investigators established that a cutoff of 4.1 mg/day would provide the best statistical difference in median survival.

In the analysis of the NovoTTF-100A cohort, the 64 patients who received high-dose dexamethasone (>4.1 mg/day) had a significantly shorter median survival than the 56 patients who received low-dose dexamethasone (≤4.1 mg/day) (4.8 vs 11.0 months; < .0001).

A similar but less robust effect was seen in the chemotherapy cohort. The 54 patients who received high-dose dexamethasone had a significantly shorter median survival than the 63 patients who received low-dose dexamethasone (6.0 vs 8.9 months).

Given the increasing preclinical evidence that chemotherapeutic agents also require immune effector function, the effects of dexamethasone in the chemotherapy cohort were understandable. This might provide guidance on its use in patients receiving chemotherapy, Drs Swanson and Wong indicate.

"These results suggest that doses of dexamethasone in excess of 4.1 mg per day mitigate the effectiveness of both TTFields and chemotherapy," Dr Swanson said.

The investigators validated these conclusions with an analysis of survival data for patients who received TTField therapy at their own institution on the basis of dexamethasone dose. In this single-institution validation cohort, median survival was 3.2 months for patients who received high-dose dexamethasone and 8.7 months for patients who received low-dose dexamethasone.

Survival Influenced by Patient Immune Characteristics

Dexamethasone is used as an immunosuppressant in several diseases. Preclinical data suggest that dexamethasone exerts its effects by suppressing immune effector function, limiting a patient's ability to mount an effective immune response.

In separate experiments, the investigators showed that CD3+, CD4+, and CD8+ counts also affect median survival. For patients with glioblastoma who were undergoing TTFields-based treatment, survival was longer for patients with CD3+ counts above 382 cells/mm³ than for those with counts below that level (7.6 vs 2.0 months), for patients with CD4+ counts above 236 cells/mm³ than for those with counts below that level (8.0 vs 2.7 months), and for patients with CD8+ counts above 144 cells/mm³ than for those with counts below that level (6.8 vs 2.0 months).

Taken together, these observations suggest that dexamethasone exerts its effects by mitigating immune effector functions, the investigators note. Drs Swanson and Wong indicate that preclinical research is underway to determine exactly how dexamethasone influences immune effector functions.

Explanation for the Effects of High-Dose Dexamethasone

What is the explanation for the reduced survival seen with high-dose dexamethasone? Does it influence a clinical outcome or is there another explanation?

Dr Gilbert noted that high-dose dexamethasone is used in patients with larger, more aggressive tumors, and the most common reasons for its use are tumor size, mass effect, and peritumoral edema.

However, in this study, the investigators showed that tumor size was similar for patients receiving low-dose and high-dose dexamethasone.

Hence, Dr Gilbert raised a concern regarding the incongruity of high dexamethasone use without larger tumor size.

"Looking at patients receiving low-dose dexamethasone vs high-dose dexamethasone may be just another way of looking at less sick vs sicker patients, who typically have worse clinical outcomes," Dr Fine told Medscape Medical News.

"The analysis overlooks an important observation of 30 years — that sicker patients get high-dose dexamethasone as palliative treatment. These patients inherently have worse outcomes from harboring worse tumors," he added.

"Indeed, high-dose dexamethasone may be a surrogate marker for sicker patients," Dr Fine said.

Additionally, Dr Gilbert pointed to data from two recent phase 3 studies investigating the use of bevacizumab (Avastin) in glioblastoma: the RTOG 0825 and AVAglio studies. In both studies, there was no difference in survival benefit between the bevacizumab and placebo groups, even though the use of bevacizumab allowed for lower doses of dexamethasone.

However, these two bevacizumab studies were conducted in patients with newly diagnosed glioblastoma, whereas the TTFields study was conducted in patients with recurrent glioblastoma, and it is not clear whether disease stage has an influence on the effects of dexamethasone.

Will This Change Clinical Practice?

Will these observations have an impact on clinical practice? Medscape Medical News wanted to know.

In standard clinical practice, dexamethasone is given as a bolus of 10 mg followed by 4 mg every 6 hours. In the management of patients with cancer, the dexamethasone dose is often influenced by physician judgment or by customary practice pattern and preference, Dr Wong told Medscape Medical News.

"Our study suggests that physicians should re-examine the doses of dexamethasone they prescribe for their patients," Dr Wong said.

Dr Gilbert told Medscape Medical News that "although these observations on high-dose dexamethasone may raise concern, they will not change the management of glioblastoma until there is a suitable substitute for corticosteroids."

"However, it does reinforce the general principle to use low doses of dexamethasone. In patients with glioblastoma, managing the edema associated with the disease is of paramount importance, and this sometimes requires high-dose dexamethasone," he said.

Dr Fine agreed, emphasizing that the goal of clinical management is always to give dexamethasone at the lowest possible dose. "Because of the side effects of long-term use of steroids — such as myopathy, infections, emotional lability, and hyperglycemia — in clinical practice, steroids are used at the lowest possible dose; when possible, patients are even weaned off steroids," he told Medscape Medical News.

In the future, exclusion criteria in clinical trial protocols for glioblastoma may set a limit on the dose of dexamethasone when enrolling patients, Dr Wong suggested.

Dr Gilbert agreed that the most convincing proof of the effect of dexamethasone would be to conduct trials with stringent criteria for the use of dexamethasone and not leave it to physician discretion.

Dr Fine indicated that limiting the dose of dexamethasone when evaluating typical agents such as chemotherapy will be difficult because each patient will require an individualized dose of dexamethasone, according to clinical symptoms and sensitivity to the drug.

"Understanding the overall effects of dexamethasone in patients with glioblastoma may ultimately be most important for the increasing number of clinical trials evaluating immunotherapy, such as PD-1 inhibitors," Dr Fine told Medscape Medical News.

"Trying to determine if dexamethasone attenuates the very immune response that these new therapeutic agents are trying to invoke will be critical for evaluating their overall effectiveness and how best to use them in patients with brain tumors," he said.

The investigators report receiving research funding from industry. Dr Gilbert and Dr Fine have disclosed no relevant financial relationships.

Br J Cancer. Published online June 30, 2015. Abstract

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