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.

Social media: Caveat emptor!

The debate about doctors being on social media hasn’t ended. Most people, I have spoken to, have very negative connotations about it. They feel, very strongly feel, that Twitter is nothing but an echo chamber of bigotry, lies and cussedness. It “might” be true but then technology is what you make it out to be!

Facebook is another different beast. Their claimed usage is about 2 billion users, but no has independently verified these numbers. They have been able to grow this because of powerful network effects. Most users feel comfortable here because it allows them to interact with “friends and family”. It also means that most users are reckless about it.

Facebook is a global surveillance system that gives dopamine fuelled high to be voyeuristic or exhibitionist. Their terms of service point towards collecting the data and being able to share it with “third party affiliates”. I often chuckle when people get horrified that the service they depend on its utility, for administrators, for psychological manipulation. What would it take to learn the lessons?

Social media is as good as we make it out to be. The best ideas for the blog post appear in my Twitter timeline. I get ideas, dwell on them and then write. One way out could be to learn from different specialities, see how they are using it and adapt it yours. The ideas take their shape and pretty soon, a rich interactive web form that enriches it even further.

(I prefer Telegram app).

Financial Disclosure: Much more than meets the eye

I have always wondered what the disclosures mean. Financial disclosure, to my understanding, means that no sums of money are involved in the publishing of the manuscript.

If a funding organisation has offered grants to a researcher that leads to publication, is the researcher acting as an “agent” of that organisation by researching what the agency wants?

There’s always an agenda.

Conflicts of interest sound more fanciful. It is a philosophical argument that seems like more of an afterthought and a subtle print as a footnote. I believe that most readers have turned a blind eye to this relative obscurity. I am also surprised that people in conferences often highlight this, but I digress. It is a matter of personal preference.

I think that the time has now come to be more comprehensive about the research agendas as well as identify motivation behind publications. This post was triggered by an innocuous write up in one “prestigious journal” where the lead author had pushed for a particular technological breakthrough in the healthcare system (Disclosure: I don’t want to highlight it for fear of reprisals!). One of the names that caught my eye was a company I had previously aliased. I was keen to bring in the same technology in India and report it’s suitability for Indian conditions. The executives decided not to implement it (and that’s another story!)

But how many people aware that the company in disclosure has precisely the same division working to popularise the health care intervention listed in the article? I have my genuine doubts because it is very niche.

Hint: Most users are unaware of who manufactures the innards of mobile devices.

I think it is time to explain these disclosures comprehensively in the context of the article.

Apple health: The new age digital colonialism

Mobile ecosystems have now boiled down mostly to a duopoly- Android and iOS. Android portrays itself to be an open source but now increasingly locked down by Google with incremental updates. Apple promotes its iOS operating system- increasingly popular with the physicians and lay people in developed and developing economies.

I am not delving into technical nuances, but perceived benefits of Apple are its flawed privacy stance based on its marketing spin called “differential privacy”. Apple hasn’t shown any inclination towards having any independent advertisement networks, and this division doesn’t get any mention. It gets it’s revenues from superior hardware and locked in services (these revenues are never repatriated back to the country of origin). Apple also has controversial policies concerning foreign workers in China, and the manufactured debate about the privacy (it fought FBI) was frivolous. It did divide the tech community. Interestingly, it’s foray in China is opposite of what it does in the US. It has handed over the encryption keys to Chinese government citing the local laws (paywall).

Personally, I find that their stance on privacy as a PR stunt. When I read or hear about their foray into healthcare, I recoil with horror. My privacy stance will not be enough to oppose them, but I was alerted to a write up in Harvard Business Review, which in my opinion, was a plug for Apple.

I can only surmise that interoperability within the electronic health records is a significant pain point. I know this because, at some point in time, I had been privy to getting one for my department. At the same time, my employer was keen to move towards it. (It did not materialise- but that’s another story). The question about the data portability came in, and it was apparent that it relied on some obscure protocol which didn’t have any open source equivalent. It meant that once the company goes belly up, all data, even if exported out, would only disappear into thin air. Or become useless.

Now you can foresee similar issues with the current tech companies. They would push for their proprietary protocols because big money lies in locking up users in their ecosystems. While the initial enthusiasm is understandable (a familiar user interface to work with like messaging applications) but it’s cheerleaders are ignoring the longer and more sinister implications of this move.

When the authors dream up instances of voice assistants detailing health information, I can only roll up my eyes. Either it is naïveté or stupidity or a mixture of both. These ancilliary companies are circling in anticipation of emerging technology, to feed on spoils from the ecosystem.

Is it suitable for the patients? Let’s examine that.

Healthcare data is most valuable commodity in dark web. Primarily, it has been used to impersonate individuals to gain access to medications (further sold in black markets). More importantly, healthcare data is of paramount importance- patterns of diseases, required interventions etc. should strictly be the purview of the governments and not private companies. None of which can be made accountable. The authors have explicitly mentioned about access to the third party companies where individual users are signing away the rights. The same consumers have been signing off the terms of services for Facebook, for example, and are shocked and horrified if they realise that their data is being used for psychological manipulation. People don’t recognise the importance of “caveat emptor”. Most users are technologically averse with very little understanding of the nuances involved.

Therefore, giving up data to these companies is a bad idea. I also see thought leaders and influencers pushing this line on the social media, but then, they have a lot to gain. I guess, no one reads the financial disclosures or stakes in the companies that stand to benefit from this push.

Healthcare and technology are getting more intertwined and complex. Let the likes of Apple and Amazon be excluded from this.

Or else, this would be the new wave of digital colonialism.

Glioma research: Asking right questions

There is an arms race to find the next molecular target. The potential spin-offs are enormous. Royalty payments. Insurance payouts.

Despite insane profits, big pharma has lost its drive to push forward for drug discovery. The easy way is to buy out the biotechnology companies (startups) or chase the clinical conditions which have healthy fat margins (like hypertension). Rare diseases like brain tumours haven’t seen any incremental investments over the past few years because of poor outcomes. Tumour treating field is the only “breakthrough” in recent times for recurrent tumours.

Therefore, the onus lies on informal networks of universities and individual researchers for pushing this narrative forward. Despite the wasted research dollars, there is a lot of promise for translational research.

My proposal has the following (very broad/generic) outline here.

The problem, at the outset, is the cost of sequencing. But it is a necessary evil. Unless we know what type of a tumour we are dealing with or its genetic signature, we cannot hope for proper characterisation. This information needs to be mated to clinical follow up with standard protocols.

Is there any scope for in-vivo monitoring? If yes, what is going to be its timeline? How frequently are we going to see for the mutations? What is the rate of mutations? What is its timescale? When should we intervene?

Another favourite pet theory is the class distinction for stem cells. Do they exist? If yes, why can’t they be reliably identified? What are their niches and what is the best way to target them?

Each sequencing would reveal a wealth of clinical data (both genomics as well as radio-genomics) and spur on more deep dive into the molecular ontology. Yes, that might fulfil the wet dream for molecular targets as well. However, as a radiation oncologist, I am only keen to know whether I can reduce my tumour volumes, how we can reduce the dose to normal structures (brain) and combine efforts with patient-related outcomes.

Bring it on! Let us do it! (Have some laughs!!)

Research and biotech: Asking right questions

The Ken is a wonderful resource for myriad issues.The staff at The Ken is constantly churning out some of the highest quality journalistic write ups in India. Their focus is mostly on start ups, biotech and increasingly now on security of digital assets. The reason why I recommend it is to broad-base your reading sources and think laterally beyond our narrow confines. Financial crunching may not be everyone’s cup of tea but it has spurred me on to understand more about it’s complexity. In the end, it is a deep dive learning experience to write effectively. In the sea of otherwise hopeless mediocrity that Indian journalism has seeped itself, The Ken (and to some extent, Business Standard) redeem themselves.

Today’s post was motivated by an excellent coverage of biotech sector and this prodded me on to think about what the research goals ought to be. Biotech companies are chasing the end of the rainbow for the pot of gold. The reason why US remains the “gold standard” for these companies is because of a perverse incentive that pharmaceutical companies and hospital corporations have to milk the consumer. That’s where the big money is. And these companies are pushing themselves to crack the market in order to get the first mover advantage.

I will not name a few companies that I have worked with (due to non-disclosure agreements with them and that included not calling them names publicly). There were some great individuals, that I had the good fortune to learn from, as well. This aside, they are mostly floundering pushing their luck. In proverbial terms, trying to see what sticks to the wall.

In one presentation, they presented a “case scenario” which showed how the medical oncologist based his decision on genomic details for lung cancer. In another, they were keen to show for cool-rectal cancer. All laudable but with one significant omission. They did not have any follow up for outcomes! Not only this, none for any clinical trial, suitability for a vast majority or how the specific gene sets were chosen to be marketed.

Its stupidity compounded by idiocy. Over and over again.

Sadly, the translational science hasn’t made specific progress and now we have the buzz words like “precision medicine”. Pray, what is precision medicine?

Hype fuels another set of hype cycles. It is a good thing that all of this looks great on dossiers or fanning our collective egos in fancy conferences but they remain a collective effort for intellectual masturbation. We need hard core data sets and equally hard nosed questions before we thrust all of this in front of hapless patients.

The company mentioned in The Ken write up hasn’t specifically mentioned as to how they will find out the difference in the genetic mutations (from primary index lesion) to the current state. I had earlier explored this concept in an editorial arguing for liquid core biopsies as means to monitor the course of treatment in lung cancers because of the range of molecular mutations.

Rest assured, I have a healthy disdain for pharma company sponsored trials with results that appear too good to be true. When it is translated into actual clinical practise, it doesn’t live up to it’s hype. Remember the Cetuximab “landmark trial”? Or even for that matter, Bevacizumab?

Lets pause. Think.

There ought to be healthy skepticism. A side note to fellow radoncs- there is a lot that can be achieved in Radiation Therapy. We need to explore different fractionation schedules or even radiation sensitisers. Combination therapies do-not always work out. That is the subject for another blog post.

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.