Hippocampus-Avoidance Whole-Brain Radiation Therapy With Simultaneous Integrated Boost for BMs of NSCLC

WBRT (whole-brain radiation therapy) exhibits poor tumor control and decreased NCF (neurocognitive function). Herein, we investigated the safety and efficacy of HA-WBRT+SIB (hippocampus-avoidance whole-brain radiation therapy with simultaneous integrated boost) in NSCLC (non-small cell lung cancer) with multiple brain metastases.We conducted a prospective, single-arm phase II trial administering HA-WBRT (30 Gy in 12 fractions, Dmax of the hippocampal volume ≤ 17 Gy, Dmean of the hippocampal volume ≤12 Gy) +SIB (48 Gy in 12 fractions) for multiple brain metastases (≥4) of NSCLC. Cognitive performance was assessed by the HVLT-R DR (Hopkins Verbal LearningTest-Revised delayed Recall).A-WBRT+SIB emerges as a promising and safe therapeutic, improving intracranial tumor control and protecting cognitive function in NSCLC with multiple brain metastases.

Lung cancer has high incidence and mortality rates. NSCLC is the most prevalent form accounting for 85% of all lung cancer cases with approximately 40% of individuals developing brain metastases during the illness. With advancements in therapies like targeted therapy and immunotherapy, the incidence of brain metastases have raised paralleled by a rise in survival rates of NSCLC. And NSCLC patients with brain metastases only 2 to 3 months of natural survival\[6\]. Therefore, it is urgent to improve the prognosis and intracranial control of NSCLC patients with brain metastases.

Brain metastases patients of NSCLC should be treated with local treatment on the basis of systemic treatment. For patients of NSCLC with brain metastases who are not suitable for targeted therapy or with progressing intracranial post targeted therapy, radiotherapy emerges as a significant therapeutic.Stereotactic radiosurgery (SRS) alone should be offered to patients with one to three unresected brain metastases for patients with asymptomatic brain metastases and no systemic therapy options.While the standard treatment for multiple brain metastases (≥4) remains controversial.

WBRT is used to be a common therapy in multiple brain metastases prolonging survival of patients to 6 months. But WBRT comes with neurotoxic effects, notably cognitive impairment affecting memory and learning. This cognitive decline is mainly attributed to hippocampal damage, a crucial region for learning and memory. The RTOG0933 and NRG Oncology CC001 trials have demonstrated that HA-WBRT effectively safeguards cognitive function and enhances the quality of life in patients with brain metastases. Furthermore, considering the tolerated dose of normal brain tissue, the dose of WBRT was low (30Gy/10F) with only 60% intracranial local control rate. The landmark RTOG9508 trial has demonstrated that WBRT in combination with boosted metastases can improve local intracranial control.

Prokic et al. reported that the simultaneous integrated boost during WBRT (WBRT+SIB) demonstrated superior hippocampal sparing and biological benefits of fractionation over sequential integrated boost. Advancements in radiotherapy techniqueshave led to the innovative HA-WBRT+SIB strategy, delivering higher dosages to existing metastases while minimizing radiation exposure to the hippocampus. However, evidence for the application of HA-WBRT+SIB in multiple (≥4) brain metastases of NSCLC remains insufficient. Therefore, this study aims to investigate the efficacy and safety of HA-WBRT+SIB in patients with multiple brain metastases of NSCLC.

Eligibility Criteria:
Inclusion Criteria:

* adults (aged 18-75 years) diagnosed with NSCLC, with a KPS (Karnofsky performance status) ≥70, at least four brain metastases visible on MRI (magnetic resonance imaging) outside a 5-mm margin around the bilateral hippocampi, not suitable for targeted therapy or progressing intracranial post targeted therapy.

Exclusion Criteria:

* Ineligible participants had a history of conditions affecting cognitive function (including mental illness, brain trauma, and Alzheimer\&#39;s disease), other primary malignant tumors, uncontrolled systemic disease, uncontrolled extracranial sites of gross disease, and suitable for targeted therapy.