Can Stereotactic Radiosurgery Be Safely Combined with Systemic Therapy for Brain Mets?

Patients undergoing stereotactic radiosurgery (SRS) for newly diagnosed brain metastases are at no increased risk of radiation necrosis when being treated concurrently with systemic therapies — except for selected targeted agents. So concludes a Cleveland Clinic study — the largest and most comprehensive of its kind — recently published online in the Journal of Neuro-Oncology.

Out of multiple chemotherapies studied — including cytotoxic, hormone, cytokine (interleukins, interferons) and targeted systemic therapies – only VEGFR tyrosine kinase inhibitors (TKIs) and EGFR TKIs were associated with increased radiation toxicity. The investigation also found that combining whole-brain radiation therapy (WBRT) with SRS exacerbated the negative effects.

Abundance of caution stemming from evidence gaps

“Physicians have been reluctant to allow patients to continue their chemotherapy while undergoing stereotactic radiosurgery out of fear of contributing to long-term toxicities,” says Samuel T. Chao, MD, a radiation oncologist in Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center and leader of the study team. “This study provides strong evidence that we can safely continue most therapies while giving radiosurgery.”

SRS (using Gamma Knife®) offers high rates of local control for brain metastases, but it results in radiation necrosis — confirmed by radiographic or pathologic evidence — in 5 to 10 percent of treated lesions. Half of patients with evident radiation necrosis (as in the imaging study above) develop symptomatic neurological deficits, sometimes requiring prolonged treatment with steroids or anti-angiogenic agents.

In the absence of data on whether chemotherapy is safe to give concurrently with SRS, conventional practice has been to withhold drugs for a couple of weeks before and after radiation treatment, Dr. Chao notes. This results in about a month-long gap in chemotherapy. Given the rarity of radiation necrosis and the multitude of chemotherapeutic choices, proving the safety of combining SRS with concurrent chemotherapy has been difficult. Although previous studies have suggested that systemic therapies may be safely delivered with SRS, these investigations have been underpowered to assess the safety of specific agents.

The new study also evaluated the risk of radiation necrosis when adding WBRT to SRS and modern concurrent systemic therapies, an avenue of research not previously explored in the literature.

Study design and findings

Dr. Chao and colleagues retrospectively reviewed 1,650 patients (with 2,843 newly diagnosed brain metastases) who underwent SRS at Cleveland Clinic from 1997 to 2015. Of these, 650 patients (39 percent) also underwent WBRT. Across the overall sample, 445 patients (27 percent) were treated with concurrent systemic therapy at the time of SRS. The primary outcome measure was the incidence of radiation necrosis by radiographic evidence.

Statistical analysis revealed a significantly increased rate of radiation necrosis among patients treated with concurrent targeted therapies (N = 451 lesions), driven primarily by VEGFR and EGFR TKIs. Several previous smaller reports have also implicated targeted therapies with increased radiation necrosis, which may be caused by these drugs’ effects on vascularization, which would enhance radiation effects.

No increased risk was found with cytotoxic chemotherapy (N = 260 lesions), hormone therapy (N = 300 lesions) or cytokine therapy (N = 10 lesions).

Upfront WBRT, combined with SRS and concurrent chemotherapy, more than doubled the risk of radiation necrosis relative to SRS without WBRT (8.7 percent vs. 3.7 percent; P=0.04). The peak period for radiation necrosis after combined SRS, WBRT and systemic treatment occurred sharply at 5 to 9 months; this was in contrast to a very gradual increase in radiation necrosis over two years among patients receiving SRS alone with or without systemic therapy.

Implications for practice

The study provides evidence supporting new standards around SRS therapy for brain metastases. According to Dr. Chao:

• Physicians can feel comfortable allowing patients to continue most chemotherapies without a gap while providing SRS for newly diagnosed brain metastases.
• For patients taking VEGFR TKIs or EGFR TKIs, doctors can feel justified in withholding therapy to avoid radiation toxicity while treating with SRS.
• The study provides growing evidence that WBRT should be omitted for the initial treatment of brain metastases for patients on systemic therapy.

Future directions

Dr. Chao notes that his team plans further research with the goal of refining SRS doses for cancer therapy.

“Different systemic agents — as well as different tumor types — may alter sensitivity to radiation,” he explains. “It would be useful to have evidence in different situations for optimizing efficacy while minimizing toxicities.”