First Phase 3 Results for SRS vs WBRT for Brain Metastases

It's Cognition vs Control

Nick Mulcahy

September 26, 2016

Despite being widely used after surgery for brain metastases in cancer patients, stereotactic radiosurgery (SRS) has not been proven to be effective in medicine's most important testing ground: a phase 3 randomized clinical trial.

Now, that milestone has been reached.

"Many centers around the world are using radiosurgery [in this setting]," said lead study author Paul D. Brown, MD, a radiation oncologist at the Mayo Clinic in Rochester, Minnesota. "But there's no trial comparing whole-brain radiotherapy [WBRT], the current standard of care, to radiosurgery."

The randomized trial, known as N107C, was conducted at 48 North American centers. It is the first such trial to clearly demonstrate the efficacy of SRS in comparison with WBRT in a postoperative setting, he said.

Dr Brown spoke at a press briefing here at the American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting.

SRS was as effective as WBRT in terms of overall survival, he reported.

Furthermore, SRS, which is a much more precise technology than the older whole-brain approach, was more effective in other ways — in the trial, it reduced cognitive decline and provided better quality of life (QOL).

The trial would have been nothing but good news for SRS if a secondary outcome had not been disappointing.

The new trial showed that SRS has an important shortcoming for use after surgery: it is not as good for local control.

Local control is important, because without it, paralysis, headache, speech difficulties, seizures, and other symptoms related to the presence of brain tumors may emerge.

The virtues of the two treatment technologies with respect to resected brain metastases are a matter of "control vs cognition," summarized Vinai Gondi, MD, of the Northwestern Medicine Cancer Center in Warrenville, Illinois, who acted as study discussant at the oral presentation.

"Sterotactic radiosurgery is a ― but not the ― standard of care" following resection for brain metastases, he told a large audience.

The N107C trial was conducted in 194 patients with various cancers (59% lung cancer) who had one to four brain metastases. Patients were randomly allocated to receive either SRS or WBRT after surgical resection at cancer centers in the United States and Canada from 2011 to 2015.

Median overall survival (OS) was similar for the treatment groups: 11.5 months for SRS, and 11.8 months for WBRT (P = .65).

In the SRS group, however, there was statistically significantly longer cognitive decline–free survival (CDFS): median CDFS was 3.2 months for SRS and 2.8 months for WBRT (hazard ratio, 2.0; P < .0001).

CDFS was defined as a decline greater than 1 standard deviation from the patient's baseline score in any of six cognitive tests. OS and CDFS were the primary endpoints of the trial, which had a median follow-up of 15.6 months.

The negative consequences of WBRT on cognition continued 6 months following treatment. The rate of cognitive deterioration at 6 months was 85.7% for the WBRT group, compared to 53.8% after SRS (P = .0006). Also, a greater proportion of WBRT patients experienced worse immediate recall, memory, and attention in comparison with SRS patients.

However, SRS was not the superior approach for all measures in the trial.

WBRT provided higher overall intracranial tumor control than SRS at 6 months (90.0% vs 74%) and 12 months (78.6% and 54.7%); these differences were statistically significant (P < .0001).

WBRT also showed better control vs SRS with regard to surgical bed relapse-free survival, even though there was no clinically meaningful difference between treatment arms (7.7 months vs 7.5 months; P = .04).

The mixed results caused Dr Gondi to reflect on the sum of the findings.

SRS provided patients with better cognitive outcomes, but WBRT was superior for the local control of the brain metatsatses, he summarized. The latter is an especially important outcome, because patients with a limited number of resected brain metastases, such as was the case in the current trial, have a "long" overall survival (the median OS in the trial was nearly 1 year).

Among the local control findings was the fact that, at 12 months, there was a 44% risk for surgical bed relapse after resection among the patients treated with SRS vs only a 21.8% risk among the WBRT group, pointed out Dr Gondi. That 44% risk was almost as high as that for patients in other clinical trials who were treated with resection alone and who had a minimal number of brain metastases, he pointed out.

Dr Gondi also described the SRS cognitive benefit in N107C as "modest," which was a factor in his concluding that SRS has not replaced WBRT but is only another option in this setting.

More Study Details

The majority of patients (77%) had a single brain metastasis. Lung tumors were the primary site for most patients (59%). The median patient age was 61 years, and study arms were balanced in terms of patient and tumor characteristics.

QOL was better with SRS treatment. At 3 months following treatment, declines in QOL and physical well-being were significantly less pronounced after SRS than after WBRT (mean QOL change from baseline: -1.5 vs -7.0, P = 0.03; mean well-being change from baseline: -6.4 vs -20.2, P = .002).

At 6 months, physical well-being remained significantly better for SRS patients than for WBRT patients (decline of -3.2 vs -15.1; P = .016).

"There is no significant difference in survival whether a patient receives postoperative radiosurgery or WBRT, and radiosurgery avoids the well-known toxicities of WBRT. Furthermore, due to less time commitment and a quicker recovery after SRS, patients can restart systemic therapies more rapidly. Radiosurgery to the surgical cavity after resection of brain metastases should be considered a standard of care," concluded Dr Brown in a meeting press statement.

The presenters disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting. Abstract LBA-1. Presented September 25, 2016.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

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