Size does matter

The size of clinical trials has now become a raging issue. I came across it on Twitter, and I’d like to put in my perspective to it.

The Wall Street Journal article presents a reasonably nuanced view about the need for trials. What it leaves out in the process is that some diseases like those involving brain, because of their relative rarity, would always need a clinical trial. Likewise, for common cancers arising in breast and prostate, the opinion for long-term clinical trials is divided because it is a significant public health problem.

The treatment protocols for brain tumours like gliomas hasn’t changed much in the past 15+ years. For even rarer diseases like CNS lymphomas, the role of chemotherapy has expanded manifold. Patients present to different facilities with varying standard of care. Not everyone has access to the “research facilities”, and especially in developing countries, that conceptual framework is non-existent. The treatment protocols are often the trial and error in what “fits” in with the Indian subset of patients. It is true primarily because out of pocket expenditure is a significant public health issue.

Now comes the emerging role of “personalised medicine” where the opinion for big or small trials is even more sharply divided. What everyone secretly agrees but never speaks out in the open? It is more important to understand the need to publish negative trials. The focus of the oncological community is towards the big bang positive studies; especially for the “blockbuster” drugs. These are often intricately linked to prevailing stock prices. There are perverse incentives as well, not to take the financial risks. It is the pharma companies that decide on “treatment protocols” and the “standard of care” where conflicts of interest are given short shrift in the protocols. That is the reason why I insist on public funding of trials where a leeway has to be made to fail. Previously, I have also argued that “personalised medicine” is way too much in its infancy. We are only nibbling at the outliers and nowhere near the core of the problem.

It is also incredibly naive to assume that if a company is offering an “unrestricted educational grant”, it has no say in the outcomes. It gets them a seat on the board to be able to influence the reports indirectly.

So does size matter? More extensive trials, are time honed but require immense resources. I strongly feel that hair-splitting in current treatment options offers no means to an end. Instead of a clear focus on the outliers (like the drugs), protocols need to include radiation therapy as an inherent component of treatment.

Translational medicine needs to become the centre-stage, and public funding should avoid a substantial scale duplication of work. It comes with its caveats.

Whole Brain Radiotherapy: Is it valid?

The debate between whole brain radiation therapy and stereotactic radiation is spurious. One thumb rule that determines the “success” of stereotactic radiotherapy is the presence of extracranial disease. If it is still present, whatever lesions are being treated, are all likely to recur.

I strongly feel that motivation for stereotactic came in from higher billable for this modality. It isn’t valid and practical for most scenarios across the world. I am not going in for all defence of whole brain radiation which does have its drawbacks, like affecting the quality of life- but any robust psychometric testing hasn’t reliably quantified this. Likewise, the advantages touted for stereotactic don’t always hold water.

The “researchers” have pushed for statistical mumbo-jumbo with the “expert” committees that jump in to “bring order” to the mess of “confusion”. There is no uniform consensus, still, but it is slowly becoming the norm to push for stereotactic XRT (even for multiple mets) when a whole brain radiation therapy may suffice. I believe that the well was poisoned earlier on by papers pushing for many lesions to be treated via Gamma Knife. Cyberknife has only made things worse.

To top it all, multiple “universities” have overactive public relations department to push for “cutting edge treatment”. I was appalled to note that someone was pushing VMAT, for head and neck, as the “standard”. No Sir. Modulation is still not established on substantial evidence but is being only used for its perceived benefits.

This post was triggered because I had a lengthy discussion with a patient’s family about the use of stereotactic radiation for a solitary lesion versus the whole brain, even though she has an extensive extra-cranial disease. She was arguing from half-baked knowledge because she was concerned about the quality of life. Someone told her that the patient might not be able to do mental calculations. Well, is this reason valid in the socio-cultural context? Nope. Only if people are keen to promote “hippocampal sparing” (which adds to unnecessary complexity to treatment), which ultimately, in my opinion, offers no robust advantage. Likewise, scalp sparing again is fancy vanity metric which I call as intellectual masturbation. Good for the conferences to blow your trumpets but the poor practical application or impacting outcomes.

No, whole brain radiation isn’t out of “fashion”. It has more utility in the face of progressive extracranial disease. Stereotactic radiotherapy may be kept in reserve for recurrence or local failure. Whole brain with concomitant boost might serve the same purpose. I prefer SIB, to be honest, which for me, hasn’t shown any sign of failure.

Always keep some steroids handy, taper them down and patients do well to go to receive definitive chemotherapy. I believe, whole brain XRT will hold more importance in the setting of oligometastatic disease that is likely to impact survival. It is an anecdotal observation- liver Mets have a profound impact on survival. Lung Mets or bone Mets end up with a relatively prolonged course.

Brain tumour advocacy:What is the role?

The Role of Brain Tumor Advocacy Groups

This is an excellent paper which I came across, and I find it is very pertinent. I have highlighted the most important aspects here. The full article is behind the paywall (another blog post coming up soon for this!). However, nevertheless, despite the repetitiveness, these are the essential highlights.

Brain tumor patients, caregivers, and loved ones realized that research is underfunded, which catalyzed the creation of nonprofit patient advocacy groups to bridge the gaps that the for-profit sector and the government have not addressed.

I agree here. Rare tumours are “rarely” the focus of researchers. Sadly, I have a strong feeling that bulk of current research in these tumours is dressed up to impress the charities. Because when the push comes to the shove, we hardly have moved the needle.

The challenges that brain tumor advocacy groups and organizations face and the role that they must play are reflective of the nature of their patient population. Individual efforts to combat the deadly disease are driven by a shared sense of urgency.

It is precisely my motivation to set up exclusive Telegram group and a public broadcast channel. It helps to gather all the information in one place with vetted links so that patients or their caregivers do not have to wade through the toxic Google searches.

As recently as fall of 2013, patient advocacy organizations were defined as providing “patient- and caregiver-oriented education,advocacy, and support services”

It is difficult to “define” them (advocacy groups), Definition, by its very nature, limits its scope. I would prefer to call them formal or informal support groups but more on that later.

This role may be sufficient in disease areas where there are effective treatments, but for brain tumors, where treatment options are limited and often ineffective, the community requires proactive research programs, as well as a host of advocacy and patient support services

Exactly. The issues are stark in developed economies while in most of other health care systems where research is either fledgeling or non-existent, brain tumours are likely to be axed. Breast cancer or even head and neck cancer are public health issues, and the bulk of biological research has been directed towards it. The idea is to define “targets” and spin it off to pharmaceutical companies. It does de-risk it but with it comes the high price of failure for other disease sites. Not every research leads to a breakthrough; like for example, in the case of Temozolomide. What next? Electric fields?

The goals of public policy advocacy include improving treatment options and access for brain tumor patients, supporting research funding and innovation, and optimizing conditions for drug development and approval.

As above. It is essential to raise the voice and create awareness. When this was published, using Twitter by patient advocates was not mainstream. However, in light of recent developments, it is essential that physicians also join in patient advocacy. Here’s the shocker. Very few oncologists pursue brain tumours as a career pathway. It is either because of limited treatment options (which is a fact) or restricted interest in putting efforts for what is a uniformly fatal disease. More importantly, it is likely to lead to high burnout rates. However, most of them do agree- it is intensely academically and emotionally challenging.

Owing to the nature of the disease and its treatment(s), the burden on caregivers is often very high, both emotionally and financially. Patients and their caregivers benefit from a variety of support services.

It is true.

Brain tumor treatment is expensive. Brain surgery, radiation therapy, chemotherapy, and targeted drugs all add up to a steep medical bill

Moreover, this leads to financial toxicity. It is true for most of the healthcare systems across the world.

Beyond its steep financial cost, brain tumor treatment is incredibly complicated. Coordinating care requires managing appointments, connecting with the right physicians, and finding the appropriate care services. This burden often falls on the caregiver because of the impact that the disease and treatment have on the brain tumor patient

This is what I dread the most. It is because advocacy groups are far and few in-between. Most general practitioners have a low threshold for diagnosis (which is also okay because these are rare tumours with a low index for suspicion). By the time it is understood in its context, it is usually too late. This issue is more pronounced for childhood cancers (and that breaks me entirely).

By funding research and changing the research system, advocacy groups today strive to identify a cure and transform a deadly disease into a manageable, treatable condition.

More importantly, funding the caregiver system because that is the urgent need. Basic biological research in gliomagenesis will take a long time to mature. I propose that advocacy groups should work with policymakers to push for public funding (because of a high risk of failure/difficulty in reproducing ideal lab conditions to in-vitro conditions) and at the same time, invest in support infrastructure to provide succour to affected families.

Today, the median survival for patients with GBM is approximately 15 months, with a 5-year-survival rate of less than 5% In spite of the money poured into research and although some targets and pathways have been identified, brain tumors such as these are still poorly understood in terms of causal and maintenance mechanisms. If this is a war against brain tumors, few (if any) would say that we are winning.

This is the most realistic statement. (emphasis mine)

Is this paucity of treatment options a question of a broken brain tumor drug discovery and development pipeline?
Is this a question of the research environment generally being inadequate?
What are the real barriers to advance research to treatments?
And which stakeholders are responsible for addressing these barriers? The true role of the advocacy group is to address the issues that the government and for-profit sectors cannot, or will not.

I agree, and these are the set of questions that advocacy groups should ask. (emphasis mine)

Instead, as patient groups have become more sophisticated, there has been a shift from funding research that increases scientific knowledge of the disease to targeting funding to specific points along the drug discovery and development pipeline that will provide incentives for others (such as pharmaceutical and biotechnology companies) to invest in the field.

This is one aspect. I still hold that advocacy groups should push for basic public funded research and invest in support groups on the other. It is a collaborative effort. Individual patients don’t have a voice. However, groups can collectively raise their voice- in mainstream media, social network and align with research charities.

Finally, it gets me to define the patient advocacy groups as a bridge between the policymakers to push for funding and caregivers to provide resources or access to them.

This area has not yet been fully explored by brain tumor advocacy groups, but advances in citizen science and computational platforms have opened the door to leveraging new communities of researchers. Interdisciplinary efforts in systems and computational biology have the potential to translate “big data” into meaningful analyses that further translate into clinical impact

The big data (machine learning/artificial intelligence) is still a way far off, and despite being the catchword of press releases, it is still very much in its infancy. Indeed, I get riled up because of the hype factor built in “tailored research” (which is dressing up done to squeeze in more funding). (Personalised medicine remains an elusive goal).