Research in radiation oncology: Break the logjam

I came across this on Twitter (where else!) Despite the “weirdness” (pun intended), it was apparent that it raised substantial issues. I had responded to it, but it merited a blog post.

There has been an institutional push to observe and record in western countries. Higher disposable incomes with specific segments of society helped them to get a better education and as a result, better opportunities. It is not getting into a nuanced debate about the racial differences or affirmative action. Inequalities have always played a part but so is the ability to capitalise on opportunities that present itself.

A lot of research happens because of institutionalised mechanisms. The children have exposure to ideas from the school and paid internships, scholarships and grant opportunities. In India, the approach is entirely insular and works in silos. Medical science has grown incredibly complicated, and it is beyond the purview of anyone to grasp nuances of differentials.

As a result of those initiatives, a few developed economies have led and broken ground in “research” (whether it is transformational or applicable to real-world solutions is immaterial). It has spurred on the likes of China (an aspirational economy) to ape the same system led by the US, but rigid hierarchies stymie them. It is indeed laughable when Government of India decides to set up a “scientific officer for innovation” because it cannot happen in silos. Throwing money at central “research institutes” isn’t going to help because lack of real-world application has hardly moved the needle in any meaningful direction. Likewise, the research is mostly divorced from socio-cultural contexts.

We can only break the log-jam if we first identify the cause of the problem. Outsourced research to understand molecular pathways and then to apply developmental molecules for “blocking them” only perpetuates, what I call a scientific fraud of “monumental proportions” because of perverse incentives associated with “pharmaceuticals”.

(Radiation Therapy needs love- not in delivery methods but radiobiology and fractionation). It is sad that radiation oncologists have more faith and belief in “combination regimes”- altered fractionation schemes have been beneficial too. But progress is excruciatingly slow here.

It would be difficult to think beyond patent protections and intellectual property if someone else controls the purse strings.

Quality of life in brain tumours

This issue is very thorny one in the neuro-oncology community. How do you measure the quality of life objectively?

A RANO working group has defined that outline and is aware of it. We, as radiation oncologists, aren’t oblivious to the fact that radiation therapy offers one single shot to give the maximum chance of cure. I am not discussing the issue of re-irradiation here, but the idea is to minimise the impact of existing delivery mechanisms.

Beyond the tumour volumes (2-3 cm for high-grade gliomas), this is both empirical and observational. They observed that bulk of failures happened in the high dose region. It brings us to two important questions here.

1) If we know that it is going to happen in the 95% isodose, why don’t we focus on intentional dose heterogeneity, at the expense of conformity? We could explore mathematical formulations for it- how best to predict which dose fractionation would be best suitable for the likely outcomes, where the failure is expected to take place and escalate the dose to that region.

2) Some tumours usually fail elsewhere, outside the treatment area. If this is the case, why not “lower” the dose to the treatment area (so-called “de-escalation”)?

Do you see the immediate impact?

Lower the total dose to the normal brain!

Now, that leads us to two more questions.

1) Why don’t we lower the dose to 55+Gy for Grade III tumours, because they have a better outcome?

2) Does Temozolomide also act as a radiation sensitiser?

The problems with these very broad-based assumptions are that we do not have a robust criterion for pre-operative or even intra-operative validation of tumour subsets by use of MR spectroscopy or perfusion (or use of any other metabolites, for that matter). Likewise, after intense scrutiny and numerous workshops, we have just been able to define the glioblastomas/grade III astrocytomas along with the molecular data (or even other variants) objectively. Previously, palisading necrosis was all that we had from my pathology colleagues. Now, we are wading in molecular soup, and no one has the complete picture of how things can be nailed!

However, use of these molecular methods isn’t widespread.

One way out is to sequence the tumours completely, follow up patients standard course fractionation and prospectively identify patterns of failure.

It would be akin to a very preliminary “precision medicine” and not the hype cycle that seeks to identify the “molecular targets”.

No, we don’t need more “research” on something that is being duplicated across the labs. But we need to be able to channelise something that we have learned.

Who is going to bell the cat?

I think, currently, we are just trying to identify who the cat is.