Testing Proton Craniospinal Radiation Therapy Versus the Usual Radiation Therapy for Leptomeningeal Metastasis, RADIATE-LM Trial

Phase 3RecruitingNCT06500481

NRG Oncology115 enrolled

Overview

This phase III trial compares proton craniospinal irradiation (pCSI) to involved-field radiation therapy (IFRT) for the treatment of breast or non-small cell lung cancer that has spread from where it first started to the cerebrospinal fluid filled space that surrounds the brain and spinal cord (leptomeningeal metastasis). Patients with leptomeningeal metastasis (LM) may develop multiple areas of nervous system (neurologic) impairment that can be life-threatening. Radiation therapy (RT) effectively relieves local symptoms due to LM. RT uses high energy radiography (x-rays), particles, or radioactive seeds to kill cancer cells and shrink tumors. IFRT is commonly used to treat symptoms of LM. IFRT is radiation treatment that uses x-rays to treat specific areas of LM and to relieve and/or prevent symptoms. pCSI uses protons that can be directed with more accuracy than x-rays which allows treatment of the entire central nervous system space containing the cerebrospinal fluid (CSF), brain, and spinal cord. The pCSI treatment could delay the worsening of LM. Giving pCSI may be better than IFRT in treating LM in patients with breast or non-small cell lung cancer.

PRIMARY OBJECTIVE: I. To compare overall survival (OS) between proton craniospinal irradiation (pCSI) and involved-field radiotherapy (IFRT) in patients with breast cancer or non-small cell lung cancer (NSCLC) leptomeningeal metastasis. SECONDARY OBJECTIVES: I. To compare central nervous system progression-free survival (CNS PFS) between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis. II. To compare time to CNS progression between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis. III. To compare CNS PFS between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis, as evaluated by central review of imaging. IV. To compare the rate of radiation-induced central nervous system necrosis between pCSI versus (vs.) IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis. V. To characterize treatment-related adverse events using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. VI. To compare patient-reported outcomes (symptoms severity subscale per MD Anderson Symptom Inventory for Brain Tumors \[MDASI-BT\] and MD Anderson Symptom Inventory for Spine Tumors \[MDASI-SP\]) in patients with breast cancer or non-small cell lung cancer leptomeningeal metastasis. EXPLORATORY OBJECTIVE: I. To compare patient-reported outcomes (symptoms interference, brain tumor-specific, spine tumor-specific subscales per MDASI-BT and MDASI-SP) in patients with breast cancer or non-small cell lung cancer leptomeningeal metastasis. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients undergo involved-field radiation therapy delivered to specific areas of LM that are causing and/or may cause symptoms 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT during screening and magnetic resonance imaging (MRI) as well as possible lumbar puncture (LP) throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study. ARM 2: Patients undergo pCSI radiation therapy delivered to the entire space containing the CSF, brain, and spinal cord 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT during screening and MRI as well as possible LP throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study. After completion of study treatment, patients are followed every 3 months for 12 months, and then every 6 months for up to 3 years from end of RT.

Interventions

Biospecimen CollectionPROCEDURE

Undergo blood and CSF sample collection

Computed TomographyPROCEDURE

Undergo CT or PET/CT

Involved-Field Radiation TherapyRADIATION

Undergo IFRT

Lumbar PuncturePROCEDURE

Undergo LP

Magnetic Resonance ImagingPROCEDURE

Undergo MRI

Positron Emission TomographyPROCEDURE

Undergo PET/CT

Proton Beam Craniospinal IrradiationRADIATION

Undergo pCSI

Quality-of-Life AssessmentOTHER

Ancillary studies

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * PRIOR TO STEP 1 REGISTRATION * Patients with pathologically (histologically or cytologically) proven diagnosis of breast cancer or NSCLC * Patients must have newly diagnosed leptomeningeal metastasis established through at least one of the following: * Positive CSF cytology for malignancy * CSF cytology with suspicious cells is considered positive; CSF cytology with atypical cells is considered equivocal and not positive * Patients with an equivocal or negative CSF cytology result, or not suitable for CSF sampling, radiographic diagnosis of leptomeningeal metastasis with linear and/or nodular disease and documentation of typical clinical signs (European Association of Neuro-Oncology \[EANO\]-European Society for Medical Oncology \[ESMO\] Diagnostic Criteria Type IIA-IIC) is required * Patients with typical clinical signs of leptomeningeal metastasis may have one or more of the following symptoms and signs: headache, nausea, vomiting, mental status change, gait difficulty, cranial nerve palsy, diplopia, visual change, hearing loss, radicular weakness, radicular sensory change, urinary retention, saddle anesthesia, constipation, neck pain, and back pain * For patients with prior history of immunotherapy or current immunotherapy, CSF sampling rather than just MRI enhancement is strongly recommended to exclude immune-related aseptic meningitis * Patients must be candidates for radiation therapy for the treatment of leptomeningeal metastasis * Age ≥ 18 * PRIOR TO STEP 2 REGISTRATION * Note: Step 2 registration must occur no later than 30 calendar days after step 1 registration * Financial clearance for proton therapy treatment * Patients must have systemic disease evaluation through standard of care imaging for example CT chest/abdomen/pelvis or body PET/CT * Karnofsky performance status ≥ 60 * Not pregnant and not nursing * Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal * Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] ≥ 8.0 g/dl is acceptable) * Absolute neutrophil count (ANC) ≥ 1,000/mm\^3 (Note: the use of granulocyte-colony stimulating factor or other intervention to achieve ANC ≥ 1,000/mm\^3 is acceptable) * Platelets ≥ 100,000/mm\^3 (Note: the use of transfusion or other intervention to achieve platelets ≥ 100,000/mm\^3 is acceptable) * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (patients with known Gilbert disease without other clinically significant liver abnormalities are not excluded) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine transaminase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × ULN * No prior radiation therapy to the spinal cord with equivalent dose in 2 gray (Gy) fractions (EQD2) more than 40Gy or cauda equina with EQD2 more than 50Gy using alpha/beta ratio of 3 * No prior treatment for leptomeningeal metastasis (note: prior CNS treatment for other non-leptomeningeal disease is allowed) * No history of unstable angina requiring hospitalization in the last 3 months * No history of myocardial infarction within the last 3 months * New York Heart Association Functional Classification II or better (New York Heart Association \[NYHA\] Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.) * No active infection currently requiring intravenous (IV) antibiotic management * No active chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy * No CTCAE v5.0 ≥ grade 2 encephalopathy

Outcomes

Primary Outcomes

Overall survival (OS)

Will be event-driven and will be conducted when a total of 88 OS events (from both treatment arms) have been observed. The final analysis (if the trial does not stop early at an interim) is expected to occur roughly 45 months after study activation (including the initial 6-months ramp-up). All analyses (interim or final) will be done on a modified intent-to-treat (ITT) basis such that all randomized patients who have follow-up information will be included in the arm to which they are randomized regardless of what treatment the patients receive. Treatment comparisons will be based on the log-rank test. At the final analysis, if the test has an associated 1-sided p-value of 0.024 or less in favor of proton craniospinal irradiation (pCSI) (equivalently, Z \> 1.98), then the trial will conclude that the pCSI arm results in improved survival over the involved field radiotherapy (IFRT) arm.

Time frame: From randomization until death due to any cause, assessed up to 3 years

Secondary Outcomes

Central nervous system (CNS) progression-free survival (PFS)

Will be based on modified ITT, including all randomized patients who have follow-up information. The analysis will be performed according to the treatment arm to which patients were randomized. Analysis for CNS-PFS will consist of estimation of its distribution for each treatment arm via the Kaplan-Meier method and a log-rank test. Statistical power will depend on the total CNS-PFS events accumulated at trial end. Additional analyses may consist of estimating the treatment hazard ratio via the Cox proportional hazards model accounting for prognostic covariates including randomization stratification factors evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying, and evaluating for potential treatment by prognostic covariate interactions.

Time frame: Randomization until CNS progression or death, whichever occurs first, assessed up to 3 years

Time to CNS progression

Analysis for time to CNS progression will involve comparing the rate of CNS progression in patients who receive pCSI to patients who receive IFRT. The cumulative incidence function (CIF) estimator will be used to estimate the median time to CNS progression in the presence of competing event of deaths in the two arms, separately. The Gray's test will be used to evaluate the difference in the distribution of CNS progression between treatment arms. These results will be interpreted in light of the competing deaths. The comparison of treatment effect on time to CNS progression will involve estimating the cause-specific hazard ratio (CHR) in a Cox proportional hazards model adjusting for patients and disease characteristics (e.g. stratification randomization factors).

Time frame: Randomization until CNS progression, assessed up to 3 years

Time to radiation-induced CNS necrosis (TTRN)

Analysis will involve comparing the rate of radiation necrosis in patients who receive pCSI to patients who receive IFRT. Death will be treated as a competing risk event in this analysis. The cumulative incidence function (CIF) estimator will be used to estimate the median time to radiation-induced CNS necrosis in the presence of competing event of deaths in the two arms, separately. The Gray's test will be used to evaluate the difference in the distribution of TTRN between treatment arms. These results will be interpreted in light of the competing deaths. The comparison of treatment effect on TTRN will involve estimating the CHR in a Cox proportional hazards model adjusting for patients and disease characteristics (e.g. stratification randomization factors).

Time frame: Randomization until radiation necrosis in brain and/or spinal cord, assessed up to 3 years

Incidence of treatment-related adverse events (AEs)

Will be evaluated by comparative frequency summaries for all adverse event types between arms. AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher AE will be compared between treatment arms. Similarly, frequencies for specific potentially treatment related AEs where grade 3 or higher events are noted may be compared. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level 0.05.

Time frame: Baseline to 30 days from end of radiation therapy

Patient reported outcomes (PRO)

Will be assessed using MD Anderson Symptom Inventory for Brain Tumors and MD Anderson Symptom Inventory for Spine Tumors. Data from these four subscales will be analyzed separately. For each subscale, scores from individual questions will be averaged to arrive at a subscale-specific score for each patient. The symptom severity scores, symptom interference scores, and brain tumor-specific and spine tumor-specific scores will be summarized at each assessment timepoint using descriptive statistics and visualized with box plots and series plots. Changes over time will also be assessed visually. The comparison of changes in quality of life between treatment arms will be conducted separately for each of these four subscales using mixed effects models.

Time frame: Baseline to 24 months post-radiation therapy