Recurrence patterns after maximal surgical resection and postoperative radiotherapy in anaplastic gliomas according to the new 2016 WHO classification

Authors: Jung Ho Im, Je Beom Hong, Se Hoon Kim, Junjeong Choi, Jong Hee Chang, Jaeho Cho, Chang-Ok Suh

Scientific Reports, 2018, Volume 8, Issue 1

Why is this paper so important?

However, recurrence patterns according to the histological subtypes have not been well studied. Most studies on recurrence patterns were mainly conducted before 1995

This is the reason why this paper is important because it focuses on the type III tumours (which hasn’t been explored in contemporary literature) and the first article to address this.

I am more interested to see how the molecular landscape varies across the different histologies. As you can see from the ensuing table, majority of them were MGMT methylated with IDH1 mutation and some gratifyingly 1p19q co-deleted (for the Anaplastic Oligodendroglioma) (which are known to have a good prognosis, anyway).

The recurrence patterns are more instructive. The following is a representational image of how they took the planning volumes (but more importantly, the way recurrent tumours were defined- they were “outside” the planning volumes.

Let’s talk about the vital survival curves; there’s not much difference between the PFS and OS (which anyway is a known factor for the Grade III tumours). There is nothing earth-shattering about this, in the first instance.

But look carefully at the following table which provides the low down of the molecular abnormalities in the tumours which were identified in the cohort.

Survival outcomes as per the molecular findings; of course, this confirms our biases 🙂 As always, the gross total resection offers the best results along with the mutated IDH and co-del tumours. Again, there’s nothing much to bleat about here because these are known “good prognosis factors”.

Median PFS and OS were 130 (range, 56–204 months) and 158 months, respectively. 5- and 10-year PFS rates were 60.4% and 56.3%, respectively, and 5- and 10-year OS rates were 65.4% and 56.6%, respectively

The authors had used the antibody to test for the IDH presence; although reasonably robust but I ALWAYS prefer to get the sequencing done to identify the mutation if any.

Antibody used was anti-human IDH1 R132H mouse monoclonal antibody (Clone H09L, 1:80 dilution; Dianova, Hamburg, Germany). When the cytoplasmic expression of IDH1 R132H was identifed in glioma cells, we considered the case as “mutant”/“positive.”

They had a pretty robust way to identify the 1p/19q status as well (as per the 2016 guidelines for identification of FISH criteria).

The table is demonstrating break up of the mutations in the cohort (which I feel is the most important table in the entire paper).













Patterns of recurrence according to the 2016 WHO classification and extent of resection. Column 2 represents the number of patients in each subgroup with recurrence and their percentages are indicated in parentheses. GTV, Gross Tumor Volume; CTV, Clinical Target Volume; CSF, Cerebrospinal Fluid; WHO, World Health Organization; AO, Anaplastic Oligodendroglioma; IDH, isocitrate dehydrogenase gene; GTR, Gross Total Resection; STR, Subtotal Resection; PR, Partial Resection; Bx, Biopsy; AA, Anaplastic Astrocytoma.

If you look carefully, the ones that had the maximum out of field recurrences were IDH wild type. Is it possible that they had some pro-migratory characteristics right from the start? Are we missing something?

Recurrence rates for GTR or STR were similar but much lower than those for those who underwent partial resections or biopsy. In patients with GTR, most recurrences (12/13) occurred in the patients with AA, IDH-wildtype. 

The authors had followed the standard protocol.

We prescribed 46–50 Gy to CTV. Therefore, a higher radiation dose to CTV can be considered for AA, IDH-wildtype

I would concur with the above statement.

The Achilles heel of the paper? They had chosen the patients selectively for getting chemotherapy. Not everyone got the adjuvant TMZ.  I prefer to give TMZ to all patients irrespective of the mutational status; however, the bigger question is whether it ought to be for 6 months, 12 months or even up to 24 months. I think, in part, it depends on the performance scale of the patients as well as the MRI perfusion scans. If the perfusion value is less, I’d prefer to keep at it. But these are only anecdotal observations; not backed by the trial outcomes. Which gives me an idea for a study as well.

The role of TMZ has been assessed in a large international trial, CATNON. Interim analysis showed that adjuvant TMZ CTx was associated with significant survival benefits in patients with newly diagnosed 1p/19q non-co-deleted anaplastic glioma.

The authors have proposed increasing the size of the planning target volume. They do mention the newer 2HG MR spectroscopy which detects the abnormality over a wider area.

Metabolic imaging with MR spectroscopy to image the 2-hydroxyglutarate signal in the brain to detect oncogenic IDH1 mutations has been recently developed. It showed that the 2-hydroxyglutarate volume was larger than the FLAIR volume in approximately half of the IDH-mutant glioma patients

But the big question: How much normal brain can you really irradiate?

These are the broader issues that need to be debated.

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