Use of Pulsed Low-dose Rate Re-irradiation for Recurrent Glioma (PULSAR)

Study Overview
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Brief Summary
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Re-irradiation in gliomas is a therapeutic option at recurrence before of 2nd-line chemotherapy. The dose of re-irradiation with conventional fractionation is unfortunately limited by the risk of symptomatic radionecrosis that is significant for cumulative doses above 100 Gy. The use of unconventional low dose rate pulsed radiotherapy (pLDRT) can reduce the risk of radiotoxicity while taking advantage of the cellular hyper-radiosensitivity that occurs at low dose-rates. The present study therefore aims at evaluating whether the use of pLDRT in the re-irradiation of recurrences of gliomas allows maintaining a low risk of symptomatic radionecrosis even for cumulative doses greater than 100 Gy.

Official Title
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A Phase-2 Trial to Investigate the Use of Pulsed Low-dose Rate Re-irradiation for Recurrent Glioma (PULSAR)

Conditions
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Glioma

Intervention / Treatment
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* Radiation: Pulsed low dose-rate radiotherapy (pLDRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years; Ability to express appropriate informed consent to treatment; Diagnosis of cerebral glioma; Histological/radiological confirmation of disease recurrence/relapse; Previous brain-level radiation therapy completed a minimum of 6 months; Performance status: ECOG=0-2. Exclusion Criteria: Refusal to radiation treatment (i.e., absence of informed consent signed); Concomitant chemotherapy; Leptomeningeal spread of disease and localization in both cerebral hemispheres; Current pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pulsed low dose-rate radiotherapy (pLDRT)<br> | Radiation: Pulsed low dose-rate radiotherapy (pLDRT)<br>* Radiation treatment will be carried out with high-energy photons (6MV) using intensity modulated radiation therapy (IMRT) or volumetric arc radiation therapy (VMAT). The daily dose is 2 Gy, divided into 10 subfractions of 0.2 Gy spaced by 3 minutes. The cumulative dose will be individualized for each patient and can range from a minimum of 40 Gy to a maximum of 60 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence of brain radionecrosis in patients undergoing re-irradiation of brain tumors with pulsed low-dose-rate schedule | Incidence of grade >=2 brain radionecrosis in patients undergoing re-irradiation of brain tumors with pulsed low-dose-rate schedule, defined according to CTCAE v5.0 scale | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the median time to local disease progression | Assessment of median disease progression-free survival. PFS will be defined as the time from study enrollment until progression or death for any cause, whichever comes first. Disease progression defined according to RANO criteria. | up to 5 years | 
| To assess the median survival time | Assessment of median survival time. Survival will be defined as the time from study enrollment until death for any cause | up to 5 years | 
| To assess the incidence of toxicities other than radionecrosis | Assessment of incidence of other neurological toxicities graded with the scale CTCAE v 5.0 | up to 5 years | 
| To assess the presence of biomarkers associated with the actinic toxicity | Frequency of selected circulating biomarkers in patients with actinic toxicity | up to 5 years | 
| To assess the presence of biomarkers associated with response to therapy | Difference in progression free survival (PFS) probability between groups of patients with or without selected circulating biomarkers. PFS will be defined as the time from study enrollment until progression or death for any cause, whichever comes first. Median survival for each biomarker will be calculated | up to 5 years | 
| To assess the presence of biomarkers associated with overall survival (OS) | Difference in OS probability between groups of patients with or without selected circulating biomarkers. OS will be defined as the time from study enrollment until death for any cause | up to 5 years | 
| To evaluate the immunomodulation induced by the pulsed schedule in comparison with the conventional schedule | Difference in the frequency of immunotherapeuthic markers between pulsed and conventional radiotherapy schedules | up to 5 years |