Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.
Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.
These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.
The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.
However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.
“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
Preclinical and clinical results
Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.
Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.
At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.
A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.
The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.
In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.
After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.
In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.