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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. Intracranial tumor control were compared with patients underwent WBRT by PSM (propensity score matching analysis). 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.
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Introduction 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[1-4]. 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[5]. 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[7].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[8]. But WBRT comes with neurotoxic effects, notably cognitive impairment affecting memory and learning[9, 10]. This cognitive decline is mainly attributed to hippocampal damage, a crucial region for learning and memory[11]. 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[12, 13]. Furthermore, considering the tolerated dose of normal brain tissue, the dose of WBRT was low (30Gy/10F) with only 60% intracranial local control rate[14]. The landmark RTOG9508 trial has demonstrated that WBRT in combination with boosted metastases can improve local intracranial control[15-19].
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[20]. 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.
Method Patient population This is a prospective, single-center, and single-arm phase II clinical study, which has received the Ethical Committee approval of Nanjing Medical University Affiliated Cancer Hospital (Jiangsu Cancer Hospital) and performed following the principles of the Helsinki Declaration. Informed consent was obtained from each participant before study initiation.
The prospective cohort consisted ofpatients who underwent HA-WBRT + SIB at the Department of Radiation Oncology, Jiangsu Cancer Hospital. Eligible patients were 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. Ineligible participants had a history of conditions affecting cognitive function (including mental illness, brain trauma, and Alzheimer's disease), other primary malignant tumors, uncontrolled systemic disease, uncontrolled extracranial sites of gross disease,and suitable for targeted therapy.
The control group (the retrospective WBRT cohort): Firstly, a total of 741 individuals of brain metastases who had received radiotherapy were identified. 688 unsuitable patients were then excluded. As a consequence, 53 patients who received conventional WBRT were retrospectively selected between January 2017 and December 2020, meeting the inclusion and exclusion criteria of the prospective HA-WBRT+SIB cohort (Figure1 Flow chart).
Clinicopathologic data collected included age, sex, number and longest diameters of brain metastases, pathological type, extracranial metastases status, KPS score, prior brain metastases treatment and prior targeted therapy.
Radiation Treatment Planning of HA-WBRT+SIB Patients scanned planning CT (computed tomography) of the whole brain region with a thickness of 1 mm by thermoplastic mask immobilization. To delineate hippocampal contouring based on RTOG0933, 3.0T brain MRI with T1 contrast was carried out two days before planning CT and coregistered with CT scans rigidly (Supplementary Figure 1). The GTVbrain metastases (Gross tumor volume of metastases) encompassed intracranial tumor lesions visible on MRI. To identify the PTVbrain metastases (Planned target volume of metastases), GTVbrain metastases was subsequently followed by a uniform 1 mm expansion. A 5-mm three-dimensional border around the hippocampus served as the HAR (Hippocampal avoidance region). Patients with multiple brain metastases of NSCLC received HA-WBRT (30Gy in 12 fractions, Dmax of thehippocampal volume ≤ 17 Gy, Dmean of the hippocampal volume ≤ 12Gy) and a SIB with 48Gy in 12 fractions. The prescribed dose covered 95% isodose. Eclipse v15.5 software (Varian, USA) facilitated treatment plan calculations. Twenty-three patients (100%) in the HA-WBRT+SIB cohort were treated with non-coplanar IMRT (intensity-modulated radiation therapy) designed with nine homogeneous fields. The radiotherapy techniques used in the WBRT cohort include traditional 2-dimensional planning (6.5%) and 3-dimensional planning based on CT (93.5%). Treatment was administered using a TureBeam linear accelerator (Varian, USA) in 6-MV FFF X-ray mode. Hausdorffdistance between PTVbrain metastases and bilateral hippocampi was measured using Velocity (Varian, USA).
Follow-Up and Study endpoint The prospective HA-WBRT+SIB cohort underwent 3.0T MRI scans to be evaluated following RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria. Regular follow-up visits occurred every 3 months post-radiotherapy, involving physical examinations, chest and abdomen CT scans, brain MRI, laboratory tests, and other examinations and toxicity assessments via CTCAE5.0 (Common Terminology Criteria for Adverse Events 5.0). Cognitive endpoints were assessed using the HVLT-R DR score at the baseline and then at 2 and 4 month post-HA-WBRT+SIB.
Follow-up visits for the WBRT retrospective cohort were approximately every three months (according to clinical practice), including physical examination, chest and abdomen CT scans, brain MRI, and laboratory tests.
Primary endpoint: Intracranial local progression-free survival time (iLPFS)was determined as the time from HA-WBRT+SIB initiation to death, existing intracranial metastases progression, or last follow-up. Intracranial progression-free survival time (iPFS) was measured from HA-WBRT+SIB initiation to existing or new metastases intracranial progression, death, or last follow-up. Cognitive function was measured by the relative change in HVLT-R DR score from the start of HA-WBRT+SIB to 4 months after the start of HA-WBRT+SIB. Secondary endpoint: OS (Overall survival) was described as the time from initiation of radiation to the last follow-up or death. The cumulative incidence of local intracranial failure was measured as the progression of existing intracranial metastases. Cumulative incidence of intracranial failure was described as the progression of existing or new intracerebral metastases.
Statistical analysis R software (version 4.1.0; The R Foundation for Statistical Computing, Vienna, Austria) was utilized for all statistical analyses. Propensity score matching (PSM) (1:2; HA-WBRT+SIB: WBRT = 23:46), with a caliper size of 0.01, adjusted for variables like age, sex, KPS scores, number and longest diameters of brain metastases, extracranial metastases status, prior brain metastases treatment and prior targeted therapy. The Kaplan-Meier method was used to draw the survival curve of iLPFS and iPFS. And HA-WBRT+SIB cohort and WBRT cohort were compared by log-rank test. Cumulative incidence of local intracranial failure and intracranial failure were estimated for cumulative incidences by the Aalen-Johansen estimator, considering death as a competing risk. Statistical significance was set at P < 0.05.
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