A Randomized Trial of Delayed Radiotherapy in Patients Low-grade Oligodendrogliomas Requiring a Treatment Other Than Surgery

Study Overview
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Brief Summary
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Because of their prolonged survival, patients with 1p/19q-codeleted low-grade oligodendrogliomas treated with RT + PCV are at risk of neurocognitive deterioration. We make the hypothesis that withholding radiotherapy until tumor progression could reduce the risk of neurocognitive deterioration without impairing overall survival.

Official Title
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A Randomized Trial of Delayed Radiotherapy in Patients 1p/19q Codeleted Low-grade Oligodendrogliomas Requiring a Treatment Other Than Surgery

Conditions
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Oligodendroglioma, Low-grade Oligodendroglioma, 1p19q Codeletion

Intervention / Treatment
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* Drug: PCV chemotherapy
* Drug: Radiotherapy and PCV chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tumor is co-deleted for 1p and 19q based and IDH-mutant (IDH1 or IDH2) according to local diagnosis Histological confirmation of low-grade oligodendroglioma by central pathological review according to WHO 2016 classification Age ≥ 18 years Patients with one or several prior surgical procedure for a low-grade oligodendroglioma and who undergo a resurgery are eligible if they have not received prior radiotheray or chemotherapy and if the last histological diagnosis is a low-grade oligodendroglioma prior use of specific HDI prohibitions is permitted Patients who undergo an initial follow-up after surgery or re-surgery are eligible if there is no evidence of anaplastic transformation on MRI (no new contrast enhancement, no obvious modification of the growth rate) Patients requiring an oncological treatment other than surgery because of one or more of the following characteristics: Progressive disease defined as documented growth prior to inclusion Symptomatic disease defined as the presence of neurological or cognitive symptoms or refractory seizures defined as having both persistent seizures interfering with everyday life activities other than driving a car and three lines of anti-epileptic drug regimen had not worked, including at least one combination regimen. Age ≥ 40 and any surgical therapy Age < 40 with prior and subtotal resection or biopsy (i.e., anything less than gross total resection) Willing and able to complete neurocognitive examination and the QOL Karnofsky performance status ≥ 60 Laboratory values obtained between 21 days before inclusion andrandomization, respecting the following criteria: Absolute neutrophil count (ANC) ≥1500 /mm3 Platelet count ≥100,000 / mm3 Hemoglobin > 9.0 g/dL Total bilirubin ≤ 1.5 x upper limit of normal (ULN) SGOT (AST) ≤ 3 x ULN Negative serum or urine pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only. Provide informed written consent Exclusion Criteria: Pregnant and nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception for up to 6 months following the completion of PCV. Received any prior radiation therapy or chemotherapy for any CNS neoplasm. Co-morbid systemic illnesses or other severe concurrent disease which would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Concomitant serious immunocompromised status (other than that related to concomitant steroids). Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm (except specific inhibitors of IDH) Other active malignancy within 5 years of registration. Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. Contra-indication to CCNU: hypersensitivity to CCNU, wheat allergy, association to yellow fever vaccin Contra-indication to Procarbazine: severe renal failure, severe hepatic failure, hypersensitivity to procarbazine, association to yellow fever vaccin Contra-indication to Vincristine: hypersensitivity to vincristine, neuromuscular disorder (for example demyelinating Charcot-Mary Tooth neuropathy), severe renal failure, severe hepatic failure. Not depending from the french system of health assurance

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCV alone<br>Administration of 6 cycles of PCV chemotherapy alone. | Drug: PCV chemotherapy<br>* cycle of PCV chemotherapy is given as: Day 1: CCNU 110 mg/m2 orally; Days 8 and 29: Vincristine 1.4 mg/m2 IV; Days 8 to 21: Procarbazine 60 mg/m2 orally 6 cycles are given.<br>|
| Active Comparator: RT + PCV<br>Radiotherapy followed by administration of PCV chemotherapy. | Drug: Radiotherapy and PCV chemotherapy<br>* Radiotherapy will deliver 50.4 Gy in 28 fractions of 1.8 Gy using IMRT technique. Followed by 6 cycles of PCV chemotherapy 1 cycle of PCV is given as: Day 1: CCNU 110 mg/m2 orally; Days 8 and 29: Vincristine 1.4 mg/m2 IV; Days 8 to 21: Procarbazine 60 mg/m2 orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival without neurocognitive deterioration | Survival without neurocognitive deterioration (whatever the cause of deterioration, i.e toxicity or tumor progression) defined as the time from study randomization to failure in any of the 6 cognitive domains that will be explored (i.e memory, working memory, language, visuo-spatial ability, cognitive executive functions, behavioral executive functions) or death due to any cause, whichever occurs first. | During 9 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time from study randomization to the time of progression of the tumor | During 9 years | 
| Overall survival | Time from study randomization to the time of death | During 9 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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low-grade oligodendroglioma, radiotherapy, PCV, neurocognitive deterioration