Radiotherapy innovations to optimize brain metastases control

Radiotherapeutic management of brain metastases has improved considerably over the past decade with several practice-changing advances. Technologic improvements in the stereotactic non-invasive delivery of focal high-dose radiotherapy to multiple macrometastases have provided efficient approaches to providing durable long-term local control and preventing symptomatic progression. Incorporation of neuroprotective approaches of hippocampal avoidance¹ and prophylactic memantine² has led to safer delivery of whole-brain radiotherapy (WBRT) to control micrometastatic disease in the brain. The judicious and complementary utilization of these radiotherapy innovations yields the most optimal intracranial control available to brain metastasis patients irrespective of underlying histology, as illustrated in the manuscript by Westover et al.³

The authors report on a single-arm phase II trial, which treated 50 brain metastasis patients with hippocampal-avoidant (HA) WBRT to 20 Gy in 10 fractions with simultaneous integrated boost (SIB) to macrometastatic disease to 40 Gy in 10 fractions. They report intracranial control comparable to modern series of sequential WBRT plus stereotactic radiosurgery (SRS), better neurocognitive outcomes compared with historical trials of conventional WBRT, and an acceptable toxicity profile.

Specifically, HA-WBRT + SIB led to one-year rates of 91% local control of boosted macrometastatic disease and 87.5% distant brain control. These are dramatic and durable intracranial control rates, not achieved with either radiosurgery alone or whole brain radiotherapy alone. Table 1 demonstrates the comparability of these outcomes with prior prospective trials of combined WBRT and SRS. Interestingly, the high distant brain control rate comparable to historical series of WBRT was achieved in spite of an approximate 40% reduction in biologically equivalent dose for the HA-WBRT component. In fact, the dose of 20 Gy in 10 fractions represents a 23% reduction in biologically equivalent dose relative to doses commonly employed for prophylactic cranial irradiation. Thus, the results of this phase II trial suggest that a lower radiotherapy dose may be sufficient to durably sterilize micrometastatic brain disease.

Table 1.

Summary of intracranial control following WBRT + SRS or SIB

Study	Treatment	1-Year Outcomes
		Local Control	Distant Brain Control
RTOG 95–084	WBRT	71%	67%
	WBRT + SRS	82%	73%
EORTC 229525	SRS	70%	56%
	WBRT + SRS	87%	72%
MDACC6	SRS	67%	45%
	WBRT + SRS	100%	73%
JROSG-99–17	SRS	76%	37%
	WBRT + SRS	90%	58%
Alliance N05748	SRS	73%	70%
	WBRT + SRS	90%	92%
Summary of WBRT + SRS Arms		82–100%	58–92%
Popp et al9	HA-WBRT 30 Gy/12 fx + SIB 51Gy/42Gy/12 fx for metastases/resection cavities	98%	69%
Westover et al3	HA-WBRT 20 Gy/10 fx + SIB 40 Gy/10 fx for metastases	91%	87%

Popp et al⁹ reported similar results in a recently published single-institution feasibility trial of HA-WBRT + SIB: HA-WBRT 30 Gy in 12 fractions, SIB 51 Gy/42 Gy in 12 fractions for macrometastases/surgical cavities. The neurocognitive function component of this approach is being evaluated further in HIPPORAD,¹⁰ a randomized phase II trial of HA-WBRT + SIB versus WBRT + SIB for patients with at least 4 brain macrometastases (but not more than 10) and at least 1 macrometastasis ≥5 mm (none within 7 mm of the hippocampus).

One of the limitations of the phase II trial reported by Westover et al³ is that the historical comparator employed conventional WBRT to 30 Gy in 10 fractions as opposed to the 20 Gy in 10 fractions HA-WBRT. This confounds the historical comparison of neurocognitive results. However, the practice-changing neurocognitive and patient-reported symptom benefits of hippocampal avoidance added to WBRT plus memantine have already been established by the phase III trial NRG Oncology CC001.¹

Another important consideration of the phase II trial reported by Westover et al³ is the eligibility limit of a maximum number of 8 brain metastases. In our experience, limiting the hippocampal dose in HA-WBRT with SIB techniques is highly dependent on the number, size, and location of macrometastases, as well as the technical details of treatment planning. Therefore, broad generalizability of these results cannot be assumed, and sequential HA-WBRT and SRS could be considered as an alternative.

As advances in systemic therapy improve the survival of brain metastases patients, the question of when to use HA-WBRT in combination with SIB or SRS to provide optimal brain metastasis control becomes even more salient. This question will be addressed by NRG Oncology BN009, a phase III trial of salvage SRS versus salvage HA-WBRT plus SRS for first or second distant brain relapse after upfront SRS with brain metastasis velocity (BMV) of 4 or more brain metastases per year.

This trial is based on prior data from a cohort of 737 brain metastasis patients reported by Farris et al¹¹ who observed that BMV at first or second distant brain relapse after upfront SRS predicted overall survival. In a larger validation dataset of >2000 brain metastasis patients from 9 institutions, BMV remained prognostic with nearly identical median survival outcomes. Specifically, patients who had a BMV ≥4 brain metastases/year had a 7-month shortening in median survival as compared with patients with BMV <4 brain metastases/year (P < 0.0001). BMV at first distant brain relapse was also predictive of BMV at second distant brain relapse, highlighting the ability of BMV to serve as a surrogate marker for intracranial control. The prognostic value of BMV has since been validated in 2 additional published series.^12,13

Further, BMV at first or second distant brain relapse after upfront SRS predicted for neurologic death following salvage SRS.¹¹ Patients with BMV ≥4 brain metastases/year were nearly 2-fold more likely to suffer neurologic death than patients with BMV <4 brain metastases/year. A recent analysis of brain metastasis patients treated with SRS in the immunotherapy era confirmed that BMV remained prognostic for both overall survival and neurologic death, with >7-fold increased risk of neurologic death in patients with BMV ≥4 brain metastases/year (P = 0.005).¹⁴

The summation of these findings underscores the capacity of BMV following upfront SRS to distinguish a subset of patients (BMV ≥4 brain metastases/y) for whom optimizing intracranial control with combined HA-WBRT plus SRS may prevent neurologic death from being a primary contributor to survival. NRG Oncology BN009, scheduled to activate in winter 2020, will test this hypothesis.

The reimbursement landscape for Medicare patients is anticipated to change to a fixed payment model for an “episode of care,” which amounts to an almost 4-month period of time during which only one predefined amount for all care would be provided. Whether such a change on the reimbursement landscape motivates providers to shift from a “treat/image/re-treat” approach as seen with SRS followed by repeat SRS, to broader utilization of HA-WBRT plus SIB or SRS remains to be seen.

In summary, the phase II trial results reported by Westover et al are an important contribution to our understanding of how recent radiotherapy innovations, when combined together, provide a safe and effective approach to optimizing brain metastases control.