Low Grade, High Impact

First, an understatement: oncology is a vast area. Nowhere is this more apparent than at the ASCO annual meeting, where multiple simultaneous sessions compete for attention at any point in time, despite the conference spanning 4.5 days. Inevitably, this leads to having to make some hard choices about which sessions to attend and which ones to skip.

I decided in advance that I wanted to attend as many sessions related to central nervous system tumours as possible. The reason for this is partly professional, as several of our clients are involved in developing new GBM treatments, and partly personal, as someone very close to me is a brain tumour patient. Given her specific diagnosis - a diffuse astrocytoma - my main area of focus was on new developments in low grade gliomas (LGGs). Hence, in addition to poring over all LGG-related posters on day 3, I made sure to head to the day 4 session entitled Management for Different Glioma Subtype: Are All Low Grade Gliomas Created Equal?

The approach to LGG management underwent somewhat of a revolution a few years back, when the WHO came out with the 2016 Classification of CNS Tumors, which completely overhauled the 2007 system. Instead of classifying these gliomas purely based on grade and cell type (morphological features, based on microscopy), they were now defined based on the presence or absence of certain molecular markers, more specifically IDH mutations and 1p19q co-deletions. Whereas the 2007 system classified grade II gliomas into diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas, the 2016 system recognises that the clinical course and prognosis of these tumours is strongly linked to their molecular characteristics, and hence requires classification into:

• diffuse astrocytoma, IDH mutant
• diffuse astrocytoma, IDH wild type
• diffuse astrocytoma, NOS (not otherwise specified)
• oligodendroglioma, IDH mutant and 1p19q co-deleted
• oligodendroglioma, NOS
• oligoastrocytoma, NOS

Note that, in this system, the molecular (genotypic) information trumps the morphological (phenotypic) information. For example, a diffuse glioma that appears morphologically astrocytic, but has an IDH mutation and a 1p19q co-deletion, would be classified as an oligodendroglioma. While all of this may appear needlessly technical and just a matter of convoluted nomenclature, the key principle in this revised classification is that the molecular information provides a more accurate - and more objective - measure of the true nature and clinical behaviour of a tumour.

In fact, in Monday's presentation entitled Integration of Molecular Methods (WHO 2016) into Surgical Management of Low Grade Gliomas, Daniel P. Cahill (Massachusetts General Hospital) noted that the new classification method has had a significant impact on how patients are approached clinically. The previous system had noteable "reproducibility issues", for example different physicians classifying the same tumour as either grade II or grade III; the new system has resulted in a much more unified and consistent approach. Importantly, the best surgical approach differs based on the molecular subtype.

IDH wild type astrocytomas are essentially seen as "GBM-like", and have a significantly worse prognosis than IDH mutant astrocytomas. However, as Jennifer S. Yu (Cleveland Clinic) showed in her talk To Radiate or Not to Radiate: Nuances of Radiation Therapy for Low-Grade Gliomas, it appears that IDH mutants (without 1p19q co-deletions) can be further subdivided into IDH mutant, G-CIMP high, and IDH mutant, G-CIMP low. The latter essentially appear to also act as GBM-like tumours, with a poorer prognosis despite the presence of an IDH mutation. As the speaker noted, we still have a lot more to learn about molecular features, and how to integrate these into our treatment patterns.

Clearly the use of molecular markers in the classification of LGGs is a great step forward for physicians and patients alike: as the various presentations in Monday's session demonstrated, the molecular subtypes are now a key factor in deciding on the best approach for surgery, radiotherapy and/or chemotherapy (the latter being the subject of Mayo Clinic's Jan C. Buckners's presentation To Chemo or Not to Chemo: The Question for High-Risk, Low-Grade Gliomas). All of this, however, reinforced in my mind a key question that I had been struggling with for a while. I therefore went ahead and submitted this question to the speakers, worded as follows:

For patients who were diagnosed and resected prior to 2016 and did not get tested for IDH (and were classified as grade II based on the old criteria), would you recommend restrospective IDH testing? Would you need to rebiopsy?

As I noted above, the patient close to me was diagnosed with a diffuse astrocytoma, but this was back in 2013, before the new guidelines came into force. Hence, her IDH status was unknown to us, and has never come up in discussions with her neurosurgeon.

To my relief, my question was addressed during the panel question and answer session. Dr Cahill, agreeing that this was a good question, said that a key consideration here is that all evidence points to the fact that IDH mutation status does not really change over time. Hence, he said that any sample that was taken during the clinical course could in theory be used to test IDH status retrospectively. Dr Buckner added that "if I were a patient, I think I'd want to know this." I am grateful indeed for this advice, and for this opportunity to interact directly with the leading international experts in this complicated field.

(Edit: as it turns out, an IDH test was conducted at the time of her initial biopsy, but this information had not been clearly communicated at the time; this again highlights the importance of making sure patients and caregivers are not kept in the dark about biomarker testing pertaining to their diagnosis, although one could argue that the importance of IDH status was not fully understood back then.)

Another patient-centric aspect that often gets overlooked in the discussions related to PFS and OS in the context of LGGs is that, despite their often very slow progression and hence long median survival times (relative to other malignancies), they can have a huge impact on patients' lives even in the absence of any progression (as defined by imaging techniques). It was therefore encouraging to see that the final presentation in the session was entitled When the Tumor is Not the Target: Long-term Care of Patients with LGG. In this presentation, Jorg Dietrich (Massachusetts General Hospital) used a number of case studies to illustrate that LGG survivors often have to cope with cognitive decline, mood disorders, fatigue, weakness, breakthrough seizures, and a host of other symptoms that impact quality of life. Often, it is challenging to determine whether these symptoms are a result of the tumour itself, or therapeutic intervention such as surgery, radiation and chemotherapy.

I've witnessed all too clearly how debilitating these symptoms can be, and how hard seizures can be to keep under control. Too often, these concerns get dismissed as being of secondary importance to what's happening to the tumour; neurosurgeons sometimes do take the attitude that if they can't see any changes on the MRIs, then everything is fine. It was therefore heartening to hear the speaker say that the field is now being more attentive to issues like cognitive decline in previously treated patients. Several trials are in fact investigating the best approach to slow down cognitive decline in this patient population, true to this year's conference's theme of Caring for Every Patient, Learning from Every Patient.

Lastly, it was also good to see a reference in this presentation to the fact that caring for patients with a LGG - despite, or maybe because of, their slow progression - requires a very extensive multi-disciplinary approach, potentially involving neuro-oncology, medical oncology, imaging/radiology, radiation oncology, neurosurgery, neuropsychology, psychiatry, neuro-rehabilitation, nutrition, palliative care, and physical/occupational therapy. All of these specialties do indeed have an important role to play in making sure that every LGG patient is cared for, and that we continue to all learn from them.

References

1. D. N. Louis et al. The 2016 World Health Organization Classification ofTumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Feb 9;DOI 10.1007/s00401-016-1545-1
2. A. Gupta et al. A Simplified Overview of World Health Organization Classification Update of Central Nervous System Tumors 2016. J Neurosci Rural Pract. 2017 Oct-Dec; 8(4): 629–641
3. Jennifer S. Yu (chair). Education Session: Management for Different Glioma Subtypes Are All Low-Grade Gliomas Created Equal? Monday June 03, 2019, 09:45 AM - 11:00 AM, ASCO 2019 Annual Meeting