Health-related quality of life and cognition in long-term oligodendroglioma survivors: A landmark study

In this edition of the journal, Florien Boele et al present a multicenter cross-sectional study on patient-reported outcome and neurocognitive functioning in patients diagnosed with oligodendroglioma more than 5 years earlier.¹ This paper presents a landmark paper on a highly relevant clinical topic. With the more stringent definitions of IDH mutant tumors in the WHO Central Nervous System classification, it has become increasingly clear that many patients with an oligodendroglioma, IDH mutant, and 1p/19q co-deleted may achieve long-term survival. This holds true even in anaplastic oligodendroglioma patients, the prospective EORTC and RTOG trials on the addition of PCV chemotherapy to radiotherapy reported no less than 30% progression-free survival at 20 years after radiotherapy with PCV chemotherapy in these patients.² Still, objective neurocognitive assessment in one of these studies revealed that many long-term survivors suffered from cognitive impairment, interfering with independent living in 20% of patients.³ These observations underscore the relevance of quality of survival in this disease: many of these patients are in the middle of their lives, planning families, and making job careers. And our treatments should aim to help them achieve their goals in life. An old concern is, however, that treatment, even if resulting in tumor control, may actively contribute to functional impairments.⁴

Assessing the cause of functional impairment and impairment in HRQOL In individual glioma patient is difficult and may be attributed to the surgery, delayed effects of radiotherapy, fatigue related to chemotherapy, seizures and anti-seizure medication, and the impact of a growing tumor on the brain. The study by Boele et al primarily enrolled oligodendroglioma patients diagnosed at least more than 5 years ago, without limitation on prior treatments or the development of a tumor recurrence. The study conducted within the EORTC network enrolled 237 patients from 9 different countries and 33 centers. Study measures included assessment of quality of life using the EORTC questionnaires, the 6 item Medical Outcomes Study cognitive function scale (MOS), and a screening cognitive test battery consisting of the Hopkins Verbal Learning Test-revised, the Trail Making Test and the Controlled Oral Word Association Test (COWAT). With that, the study offers an in-depth view of the functional outcome of more long-term surviving oligodendroglioma patients. The study confirms the everyday experience when treating these patients. Clinically relevant HRQOL impairments were noted in over 40% of patients. Objective test scores showed impaired test scores in 18%-46% of patients. The heterogeneous patient population allowed exploration of associations between outcome and clinical factors. Not surprisingly, age, radiotherapy, active disease, and the use of antidepressant medication were associated with worse HRQOL outcomes. As one would expect, no such relation was found with prior chemotherapy. Measured cognitive functioning showed impaired functioning at the group level compared to norms, with associations with older age at diagnosis, ever having had radiotherapy, and longer periods since treatment and since diagnosis. This meets the clinical experience of patient over time functioning worse even in the absence of tumor progression. Interestingly, the dose of radiotherapy did not seem to matter.

How representative is this set of patients for the overall outcome of oligodendroglioma patients? It is a large multicenter study, but the study does not present a well-circumscribed cohort of patients. Patients were selected by the participating institutions, which may have introduced all sorts of bias. Nonetheless, those involved in the treatment of these patients will recognize the overall picture of patients developing functional impairment over time. The study also presents a snapshot and does not inform of the changes individual patients develop over time: it is a study at the group level. The association with clinical factors is of an exploratory nature, which can be confounded by the disease course as well. As an example, any oligodendroglioma patient that, after 5 years from the first surgery, still does not need further treatment belongs to a selected patient group with presumably a more indolent course of the tumor.

What can we do to improve functional outcomes in our patients? A longstanding issue is on the timing of and indications for postoperative adjuvant treatment. Some series have suggested better functional outcomes in patients not undergoing further treatments after surgery, but invariably series that report outcomes related to no versus post-operative adjuvant treatment are biased towards a more conservative approach in patients with more favorable prognostic characteristics.^5-7 Surgery alone has been associated with good functional outcomes, but studies that report on cognitive outcomes after surgery are usually of a limited follow-up.⁸ This paper suggests that many functional impairments become overt only after a longer period of follow-up. Importantly, most low-grade IDHmt glioma patients will require, at some point in time, additional treatments beyond surgery. The study presented here supports the argument to wait as long as safely possible. We lack though clear guidance on when to best start radiotherapy and chemotherapy, which is a highly relevant question in these favorable prognosis patients. A historical trial conducted in histological grade 2 glioma showed that postponing radiotherapy as opposed to radiotherapy at progression did not affect overall outcome.⁹ The EORTC IWOT study (NCT03763422) aimed to compare direct and more contemporain postoperative combined treatment versus delayed treatment given at the time of progression in IDHmt astrocytoma, but this trial failed for accrual reasons.

Given the association observed again between impairment and radiotherapy, can we leave radiotherapy out of the initial management of patients requiring postoperative adjuvant treatment? Two studies (NCT05331521, NCT04702581) randomizing oligodendroglioma patients between primary chemotherapy only and radiotherapy followed by PCV chemotherapy with cognitive and/or quality of life deterioration as the primary endpoint are investigating whether functional outcome is improved by that strategy. However, in view of the large studies showing survival benefit after combined radiotherapy and chemotherapy, the trade-off of initial less intensive treatment here may well be worse overall survival.

The new kid on this block is the IDH inhibitor vorasidenib. This targeted agent has been shown to improve progression-free survival in grade 2 IDHmt glioma patients following surgery, although the follow-up duration of the pivotal trial is still limited.¹⁰ Collecting data on long-term functional outcomes in initially vorasidenib-treated patients with IDHmt glioma will be key to understand to long term clinical benefit of vorasidenib, beyond progression-free survival alone. The study by Boele et al sets the standard for the type of effort that will be needed to establish whether indeed early use of an IDH inhibitor will improve functioning of patients with IDHmt glioma over time.

Funding

None declared.

Conflict of interest statement

MJvdB reports consulting fees from Alexion, Servier, Nuvation, Boehringer Ingelheim, and Servier, research support from Boehringer Ingelheim, and participation to the DSMB of Genenta, Incyte, and Fore Biotherapeutics.