Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q – IMPROVE CODEL: the NOA-18 trial

Abstract

Background Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. Methods NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. Discussion qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. Trial registration Clinicaltrials.govNCT05331521. EudraCT 2018–005027-16.

Conventional and emerging treatments of astrocytomas and oligodendrogliomas

“…The IMPROVE-CODEL/NOA-18 trial aspires to prove the superiority of lomustine and temozolomide (CETEG) plus RT-PCV at progression over RT-PCV as determined at the level of overall survival without sustained functional deterioration for patients with oligodendroglioma [ 34 ]. The combination of lomustine and temozolomide has been proven to be beneficial over temozolomide in patients with MGMT promotor methylated glioblastoma in the NOA-09/CETEG trial [ 35 ] and is currently evaluated in patients with 1p/19q codeletion.…”

“…WHO grade 4 astrocytomas present a new entity and it is currently unclear whether these tumors should be treated with concomitant temozolomide [ 57 ] or adjuvant temozolomide only [ 27 ]. Besides this, the role of upfront combinatorial chemotherapy without early radiotherapy for chemosensitive oligodendroglioma is currently being answered in the IMPROVE-CODEL trial [ 34 ]. However, these combinatorial treatments are not curative for most patients and progression is likely at some point in time.…”

High costs, low quality of life, reduced survival, and room for improving treatment: an analysis of burden and unmet needs in glioma

“…Challenges include repeated disappointments in the development of new treatment options, particularly immunotherapies and targeted therapies, none of which have so far improved on the available therapies ( 79 , 126 ). For a substantial number of potential treatment choices, evidence is not (yet) available or remains inconsistent, including, for example, uncertainty around managing oligodendrogliomas without initial radiotherapy or the potential interchangeability of PCV and TMZ in these patients ( 196 ). The most recent WHO classification increases the complexity of choosing treatments based on evidence, as newly defined glioma types and subtypes may not map directly to past trials that used prior classifications ( 86 ).…”

Comparison of Low-Grade Gliomas Molecular Features and Survival by 1p/19q Codeletion in The Cancer Genome Atlas

“…The exploration of 1p/19q codeletion is not only helpful for the diagnosis of gliomas, but also helps to clarify the mechanism of the disease and guide clinical treatment [29][30][31]. For example, researchers have observed that 1p/19q codeletion patients are likely to respond well to the temozolomide chemotherapy [32], although the exact reason is unclear. Thanks to the rapid progress of high-throughput sequencing technology, our understanding of transcriptional changes in glioma has improved signi cantly.…”