Research in Radiation Oncology: Unanswered questions

 

Paper identified:

Current and Future Initiatives for Radiation Oncology at the National Cancer Institute in the Era of Precision Medicine

Charles A. Kunos, C. Norman Coleman

International Journal of Radiation Oncology Biology Physics, 2018

I have always wondered about the processes that fuel the current research programs. In fact, its fascinating to understand and learn how the various processes work in a different cultural context. Herein, I present an editorial recently published in the Red Journal (2018) and have highlighted the excerpts of what I feel are the most pertinent issues.

Current NCI Cancer Therapy Evaluation Program (CTEP) initiatives for radiation therapy devote resources and study to novel combination radiation plus agent study. Here, CTEP defines a radiation plus agent study as any-type radiation therapy given in close proximity (same line of treatment [first-, second-,etc]) before, during, or after therapeutic drugs or biologic agents

It is obvious that bulk of funding goes in identification of “targets”. They are important but not the only goal. Therefore, I am seeing bulk of money going in “biological agents”.

By investigating radiation plus agent combinations at the outset, there is an opportunity to broaden clinical utility.

While this sounds good in theory, the problem with the targeted approach is that we have no idea of how the cancer mutagenesis takes place. Radiation Therapy may also alter the tumour micro-environment and the biological agents may or may not be “effective” in this scenario. If you may remember the famously infamous Bonner trial for Cetuximab and XRT; the benefit was most with the conventional radiation using “field-in-field” (almost analogous to the SIB of today) (a type of altered fractionation) and follow up trials haven’t really shown the cetuximab to be “stellar”. I am not getting in the specifics (its a different sub-site altogether) but these issues have also rankled me.

Overview of the XRT combination

Proposed areas of research in radiation oncology

This is an important pertinent issue:

For example, it is suggested that up to 10 logs of tumor cell kill are needed to sterilize a single targeted tumor, which is a level of cytotoxicity possibly attained by radiation therapy alone, but better achieved when an agent is co-administered during radiation therapy

Bulk of what we know is primarily empiricism. The authors have also highlighted this aspect. For example, the XRT combination with Cisplatin, wherein the earlier trials were motivated by see “whatever-sticks-to-the-wall” approach. We as a community have wisened over the years and now it has been proposed that the newer agents “prove” their efficacy in the “cell lines”

CTEP endorses a preclinical approach that analyzes and emphasizes relevant cell lines (at least 2) and then cell-derived or patient derived (preferably) xenografts orgenetically engineered mouse models of cancer

My beef with it is the issue related to “in-vivo” versus the “in-vitro” model. Like really? Nope, the real time conditions faced inside the cellular environment can never be replicated outside in the petri-dish. But the “hope” is it would be safe (in animal models) with proven efficacy in the cell lines. What do we get in return? Progression Free Survival? Is that the end goal for a hopeless scenario? Is that progress and innovation in cancer?

Further, luckily this article does mention pushing for altered fractionation- hypo fractionation here. At least, there’s an awareness that it might be something better than the “conventional” methodology. I strongly feel that these are motivated by primary concerns of “finishing” off radiation therapy than exploring the true benefit of giving large doses per fraction. I am reminded of a beautiful issue of Seminars in Radiation Oncology about the fractionation and whether the venerated LQ model is applicable to giving large doses per fraction. Hopefully, with the trails that are being encouraged to explore the fractionation schedules, we might have a better clarity about the effect of radiation fractionation on tumour micro-enviroment. I remain hopeful about a better understanding on this important pertinent issue.

Reasonable number to initiate clinical trials, although the larger the enhancement the better, especially when considering hypofractionation, because there are few fractions to enhance compared with standard fractionation (2 Gy per day)

A lot of funding is also being made available for immunotherapy and in particular, abscopal effect, if any. This remains an exciting area of research and hopefully, we might have better insight in this. Is XRT having “only-local” effects or does it extend beyond the narrow confines of planning target volume? Interesting!

A proof-of-principle trial utilized local radiation therapy and granulocyte-macrophage colony-stimulating factor to potentially induce an abscopal response among treatment refractory solid tumor cancer patient. A trial evaluating high versus low radiation dose and immunotherapy is underway (NCT02888743) (emphasis mine)

Ah, the heavy particles. This opens another can of worms, isn’t it? Protons/Carbon Ions versus the Photons (traditional). Meta-analysis hasn’t been kind on its use but it probably represents an arms race to push for the lingering effect of higher OER/presumed benefit versus lower rate of side effects. I haven’t been exposed to the working but it remains subject of much interest. The countries listed here are indeed in a technological arms race. My only interest would be in radio-biology; more than the Bragg peak 🙂

The heavier particles, such as carbon ions, already in clinical use in Japan, Germany, Austria, Italy, and China, might offer further radiobiological advantages beyond protons

Radiogenomics offers the best insight. This is closest to the “personalised medicine” that we are talking about and is perhaps the sum combination of what all I have discussed above. I strongly feel that in sensitive patients; i.e. the ones have the driver mutations, there ought to be an “intensification” of treatment with a higher chance of more prolonged remission/local control, rather than the de-escalation of treatment schedules (as is currently in HPV positive oropharyngeal trials). Nope, we want to hit it hard when it matters the most and not otherwise. I think in the entire editorial, this is the most pertinent issue that’s been highlighted.

Single-arm design umbrella trial that aims to test whether patients with a specific tumor mutation, amplification, or translocation of genes in a driver molecular pathway derive clinical benefit if treated by radiation therapy or by radiation-agent combinations specifically targeting the driver molecular pathway. Such a study is akin to the NCI Molecular Analysis for Therapy Choice trial (NCT02465060) (emphasis mine).

Further aside in the ongoing discussion about the “personalised medicine”:

New radiation therapy trials are taking a first step to identify tumor mutation, amplification, or translocation of genes that drive radiation therapy sensitivity or resistance (NCT02888743,NCT01096368) (emphasis mine) 

The bureaucratic nightmare! The process of drug discovery and final clinical trials!

Last but not the least, the authors have not forgotten about the most important subset of patients: kids! It breaks my heart to see them in the hospital but someone has to care for them! Its important though to keep the fundamentals in place here. Delayed developmental milestones are a huge problem because of the human opportunity cost as well as the burden on the healthcare where costs are spiralling out of control. Research, here, would need to identify where paediatric patients need to be treated and how much treatment regimes need to be identified. With a whole different universe of molecular mutations, this area is ripe for disruption.

Whether radiation therapy could be delayed until developmental milestones are reached or whether radiation therapy could be omitted altogether remain important clinical questions for the radiation oncology field. Improving pediatric patient selection for radiation therapy, perhaps through molecular prognostic factors, is a good example of future radiation therapy science better anticipating needs for intensive local therapy or for intensive systemic therapy.

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