Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06557187
Status:
COMPLETED
Last Update Posted:
None
First Post:
2024-08-13
Brief Title:
Hippocampus-Avoidance Whole-Brain Radiation Therapy With Simultaneous Integrated Boost for BMs of NSCLC
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Phase II Trial of Hippocampus-Avoidance Whole-Brain Radiation Therapy With Simultaneous Integrated Boost for Multiple Brain Metastases in Non-small Cell Lung Cancer
Status:
COMPLETED
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
WBRT whole-brain radiation therapy exhibits poor tumor control and decreased NCF neurocognitive function Herein we investigated the safety and efficacy of HA-WBRTSIB hippocampus-avoidance whole-brain radiation therapy with simultaneous integrated boost in NSCLC non-small cell lung cancer with multiple brain metastasesWe 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 RecallA-WBRTSIB emerges as a promising and safe therapeutic improving intracranial tumor control and protecting cognitive function in NSCLC with multiple brain metastases
Detailed Description:
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 illness1-4 With advancements in therapies like targeted therapy and immunotherapy the incidence of brain metastases have raised paralleled by a rise in survival rates of NSCLC5 And NSCLC patients with brain metastases only 2 to 3 months of natural survival6 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 therapeutic7Stereotactic 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 optionsWhile 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 months8 But WBRT comes with neurotoxic effects notably cognitive impairment affecting memory and learning9 10 This cognitive decline is mainly attributed to hippocampal damage a crucial region for learning and memory11 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 metastases12 13 Furthermore considering the tolerated dose of normal brain tissue the dose of WBRT was low 30Gy10F with only 60 intracranial local control rate14 The landmark RTOG9508 trial has demonstrated that WBRT in combination with boosted metastases can improve local intracranial control15-19
Prokic et al reported that the simultaneous integrated boost during WBRT WBRTSIB demonstrated superior hippocampal sparing and biological benefits of fractionation over sequential integrated boost20 Advancements in radiotherapy techniqueshave led to the innovative HA-WBRTSIB strategy delivering higher dosages to existing metastases while minimizing radiation exposure to the hippocampus However evidence for the application of HA-WBRTSIB in multiple 4 brain metastases of NSCLC remains insufficient Therefore this study aims to investigate the efficacy and safety of HA-WBRTSIB 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 Alzheimer39s disease other primary malignant tumors uncontrolled systemic disease uncontrolled extracranial sites of gross diseaseand 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-WBRTSIB 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-WBRTSIB 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 30T 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 v155 software Varian USA facilitated treatment plan calculations Twenty-three patients 100 in the HA-WBRTSIB 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 65 and 3-dimensional planning based on CT 935 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-WBRTSIB cohort underwent 30T 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 CTCAE50 Common Terminology Criteria for Adverse Events 50 Cognitive endpoints were assessed using the HVLT-R DR score at the baseline and then at 2 and 4 month post-HA-WBRTSIB
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 iLPFSwas determined as the time from HA-WBRTSIB initiation to death existing intracranial metastases progression or last follow-up Intracranial progression-free survival time iPFS was measured from HA-WBRTSIB 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-WBRTSIB to 4 months after the start of HA-WBRTSIB 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 410 The R Foundation for Statistical Computing Vienna Austria was utilized for all statistical analyses Propensity score matching PSM 12 HA-WBRTSIB WBRT 2346 with a caliper size of 001 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-WBRTSIB 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 lt 005
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 therapeutic7Stereotactic 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 optionsWhile 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 months8 But WBRT comes with neurotoxic effects notably cognitive impairment affecting memory and learning9 10 This cognitive decline is mainly attributed to hippocampal damage a crucial region for learning and memory11 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 metastases12 13 Furthermore considering the tolerated dose of normal brain tissue the dose of WBRT was low 30Gy10F with only 60 intracranial local control rate14 The landmark RTOG9508 trial has demonstrated that WBRT in combination with boosted metastases can improve local intracranial control15-19
Prokic et al reported that the simultaneous integrated boost during WBRT WBRTSIB demonstrated superior hippocampal sparing and biological benefits of fractionation over sequential integrated boost20 Advancements in radiotherapy techniqueshave led to the innovative HA-WBRTSIB strategy delivering higher dosages to existing metastases while minimizing radiation exposure to the hippocampus However evidence for the application of HA-WBRTSIB in multiple 4 brain metastases of NSCLC remains insufficient Therefore this study aims to investigate the efficacy and safety of HA-WBRTSIB 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 Alzheimer39s disease other primary malignant tumors uncontrolled systemic disease uncontrolled extracranial sites of gross diseaseand 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-WBRTSIB 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-WBRTSIB 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 30T 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 v155 software Varian USA facilitated treatment plan calculations Twenty-three patients 100 in the HA-WBRTSIB 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 65 and 3-dimensional planning based on CT 935 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-WBRTSIB cohort underwent 30T 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 CTCAE50 Common Terminology Criteria for Adverse Events 50 Cognitive endpoints were assessed using the HVLT-R DR score at the baseline and then at 2 and 4 month post-HA-WBRTSIB
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 iLPFSwas determined as the time from HA-WBRTSIB initiation to death existing intracranial metastases progression or last follow-up Intracranial progression-free survival time iPFS was measured from HA-WBRTSIB 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-WBRTSIB to 4 months after the start of HA-WBRTSIB 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 410 The R Foundation for Statistical Computing Vienna Austria was utilized for all statistical analyses Propensity score matching PSM 12 HA-WBRTSIB WBRT 2346 with a caliper size of 001 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-WBRTSIB 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 lt 005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None