NO ICREASED RISK OF TOXICITY WITH COMBINATION OF TKIs AND RADIOSURGEY

CHICAGO — The addition of first-line tyrosine kinase inhibitors (TKIs) to spine stereotactic radiosurgery (STS) safely improves outcomes in the treatment of metastatic renal cell carcinoma with little risk for toxicity, a new study shows.

"Our results show that concurrent TKIs appear to be safe with SRS," said first author and presenter Jacob A. Miller, a medical student with the Cleveland Clinic in Ohio.

"Spine SRS should be considered alongside first-line TKIs in the oligometastatic setting."

The results were presented here at the American Association of Neurological Surgeons (AANS) 84th Annual Meeting.

With bone representing the second most common site of metastases in renal cell carcinoma, antiangiogenic TKIs (vascular endothelial growth factor) have emerged as significantly improving systemic control of the disease, with some studies suggesting a synergistic relationship between the drugs and STS in which TKIs boost the response to radiation, Miller explained.

However, the risks for potential increased toxicity with the combination have remained unclear, he said.

For the study, Miller and colleagues conducted an institutional retrospective review of patients undergoing spine SRS for metastatic renal cell carcinoma, dividing them according to type of treatment, including patients treated concurrently with first-line TKIs and SRS, patients treated with SRS alone, patients treated with first-line TKIs alone as a negative cohort, and patients whose cancers had progressed during treatment with a first-line TKI (considered TKI-resistant) and were treated with SRS, with or without current TKI treatment.

The results showed that among 100 patients and 151 consecutive treatments, the primary outcome of 12-month cumulative incidence of local radiographic treatment failure was lowest in patients treated with concurrent first-line TKIs and SRS (5%) compared with treatment failure rates in patients receiving first-line TKIs alone (57%).

In the other treatment groups, the local failure incidence rates ranged from 19% to 27%.

The unadjusted results remained consistent after adjustment for characteristics such as demographics and comorbidities, Miller said.

After the multivariate adjustment, patients treated with concurrent first-line TKIs also showed less rapid failure compared with the patients in the other groups (hazard ratio, 0.16; P < .01).

Importantly, in looking at toxicity rates, there were no significant increases among patients receiving concurrent TKI and SRS therapy compared with the other groups, including rates of pain flare and vertebral fracture, which ranged from 15% to 27%.

There were no cases of grade 3 or higher toxicity in the concurrent first-line TKI and SRS or SRS alone groups and two cases (2%) in the TKI-resistant and SRS group.

"These findings suggest the efficacy of concurrent therapy is superior and toxicity is not significantly increased," Miller said.

He noted that the prevalence of ogliometastatic disease was particularly high among the patients — representing approximately 75% of patients on first-line TKI therapy and concurrent SRS — and that those patients could benefit most from the concurrent treatment approach.

"Maximizing local control is most important among patients with ogliometastatic disease because you could offer a systemic progression-free survival benefit or perhaps delay the time to second-line systemic therapies," Miller said.

Commenting on the paper, Mark H. Bilsky, MD, from Memorial Sloan-Kettering Cancer Center in New York, New York, noted that the dose of radiation, 16 Gy, in the treatments in Miller's study can be significant.

"Studies have shown high-dose SRS (24 Gy) provides 95% durable control in renal cell carcinoma, but is constrained by toxicity to OARs [organs at risk]," he said.

"A prospective trial will be needed to determine whether TKIs and lower-dose SRS (16 Gy) provide equivalent control and reduced toxicity."

However, the study "appears to provide clinical evidence that TKIs are radiosensitizers when combined with SRS," he said.

"The authors are to be congratulated on this superb, thought-provoking and impactful paper."

The authors have disclosed no relevant financial relationships. Dr Bilsky has a consulting relationship with Globus and Depuy Spine.