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

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Eligibility criteria

Study arms

• Active comparator
  Arm 1 (IFRT)

  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 CT or PET/CT during screening and MRI as well as LP throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study.

  Procedure: Biospecimen Collection · Procedure: Computed Tomography · Radiation: Involved-Field Radiation Therapy · Procedure: Lumbar Puncture · Procedure: Magnetic Resonance Imaging · Procedure: Positron Emission Tomography · Other: Quality-of-Life Assessment

• Experimental
  Arm 2 (pCSI)

  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.

  Procedure: Biospecimen Collection · Procedure: Computed Tomography · Procedure: Lumbar Puncture · Procedure: Magnetic Resonance Imaging · Procedure: Positron Emission Tomography · Radiation: Proton Beam Craniospinal Irradiation · Other: Quality-of-Life Assessment

Interventions

• ProcedureBiospecimen Collection

  Undergo blood and CSF sample collection

  Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

• ProcedureComputed Tomography

  Undergo CT or PET/CT

  Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

• RadiationInvolved-Field Radiation Therapy

  Undergo IFRT

  Also known as: IFRT, Involved field radiotherapy

• ProcedureLumbar Puncture

  Undergo LP

  Also known as: LP, Spinal Tap

• ProcedureMagnetic Resonance Imaging

  Undergo MRI

  Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

• ProcedurePositron Emission Tomography

  Undergo PET/CT

  Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT

• RadiationProton Beam Craniospinal Irradiation

  Undergo pCSI

  Also known as: Craniospinal Proton Beam Radiation Therapy, p-CSI, Proton Craniospinal Irradiation, Proton Craniospinal Radiation Therapy

• OtherQuality-of-Life Assessment

  Ancillary studies

  Also known as: Quality of Life Assessment

Primary outcomes

1. 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

1. 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

2. 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

3. 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

4. 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

5. 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

Other outcomes

1. Estimates of the primary outcome treatment effect by sex

   Will estimate the primary outcome treatment effect and the corresponding 95% confidence intervals (CIs) by sex.

   Time frame: Up to 3 years

2. Estimates of the primary outcome treatment effect by race

   Will estimate the primary outcome treatment effect and the corresponding 95% CIs by race.

   Time frame: Up to 3 years

3. Estimates of the primary outcome treatment effect by ethnicity

   Will estimate the primary outcome treatment effect and the corresponding 95% CIs by ethnicity.

   Time frame: Up to 3 years

Individual participant data

Plan to share: Yes — NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.