Three discipline collaborative radiation therapy (3DCRT) special debate: Equipment development is stifling innovation in radiation oncology

Radiation Oncology is a highly multidisciplinary medical specialty, drawing significantly from three scientific disciplines — medicine, physics, and biology. As a result, discussion of controversies or changes in practice within radiation oncology involves input from all three disciplines. For this reason, significant effort has been expended recently to foster collaborative multidisciplinary research in radiation oncology, with substantial demonstrated benefit. In light of these results, we endeavor here to adopt this “team‐science” approach to the traditional debates featured in this journal. This article represents the fifth in a series of special debates entitled “three discipline collaborative radiation therapy (3DCRT)” in which each debate team will include a radiation oncologist, medical physicist, and radiobiologist. We hope that this format will not only be engaging for the readership but will also foster further collaboration in the science and clinical practice of radiation oncology.


| INTRODUCTION
The field of radiation oncology has recently experienced a period of remarkable transformation of our technical capabilities. These technical and computational advancements have resulted in a tremendous improvement in our ability to precisely and accurately deliver radiation dose. However, this increased emphasis on technical capabilities may be inadvertently diverting attention and funding from scientific developments in other areas, even at a time when exciting new advances are occurring in cancer biology. Much of our recent technical development has been promoted and subsidized by the manufacturers of radiation oncology equipment. The question now becomes "who will encourage and subsidize the research needed to bring our recent biological advances to clinical fruition?" In a recent commentary which inspired this debate, Brown and Adler suggest that we "…are in a golden age of radiation and cancer biology" and that "…the industry's current focus on equipment development alone is undermining significant potential clinical advances in radiation oncology." 3 This is the subject of this month's 3DCRT debate.
Arguing for the proposition will be Drs. Leonard Kim Radiation oncology is a science, and good science balances theory and experiment: the questions we seek to answer and the means to answer them. Without balance, progress and innovation can stall. For example, a "crisis" in high-energy particle physics has been in the news lately, in which current technology does not or cannot validate theory. 4 In radiation oncology, we have arguably the opposite imbalance.
Equipment development is giving us answers to questions that perhaps should not be our top priority, questions such as "how good is my dose delivery now?" Certainly, continued improvement in delivery accuracy have contributed to the reduction in planning target volume (PTV) margins. But the clinical impact of further improvements to something that is already at submillimeter levels in some cases is certainly questionable given that, for example, the most sizable and uncertain margin today is probably the clinical target volume (CTV), which must be attacked through a better understanding of the biology underlying each cancer scenario rather than setup accuracy.
More insidiously, equipment development can influence the questions researchers choose to ask. This influence can take several forms. One is availability: though protons have been used clinically for decades, does it surprise anyone that there have been as many publications on proton radiotherapy in the past 5 years as in the 15 years previous to that? Characterizing newly available technology and its usage, even when it is not truly novel, is a comparatively easy path to the research productivity required for professional advancement in our field. It is a path additionally laden with incen- For example, a meta-analysis of radiation therapy (RT) techniques for the treatment of medically inoperable early-stage non-small cell lung cancer (NSCLC) reported a 2-year overall survival estimate of 53% for conventional RT. 5 Improvements in radiation dose delivery and hypofractionation using stereotactic body radiation therapy (SBRT) improved 2-year survival to 70%. 6 Despite these improvements, distant disease recurrence develops in approximately 20% of patients following SBRT. 6,7 This is an example where clinical evidence suggests that despite technology-based improvements in treatment delivery, there is an unmet need to address the systemic reduction of disease. Another example is the treatment of cervical cancer, where improved local control through advances in radiotherapy delivery such as image guidance for brachytherapy have not translated into improved cancer-specific mortality, which for cervical cancer has not improved over the last several decades. 8 Unpredictable systemic effects of radiation have not been adequately characterized or addressed. Both pro-metastatic behavior as well as systemic reduction (known as the abscopal effect) have been observed in tumors treated with radiation. [9][10][11][12][13][14][15][16][17] Radiation therapy and the technological drive toward conformality capitalize on the wellcharacterized cytotoxic effect of radiation, but we need a better understanding of the dynamics between radiation and the complex biological system we are treating. This understanding in turn could lead to significant advances and even paradigm shifts in the way radiation is used to treat cancer. The use of immune modulation in combination with radiation therapy, 18-21 the characterization of microscopic disease that compose the CTV, 22 the effects of tumor microenvironment, 23 and genomic heterogeneity leading to potential differences in radioresistance 24,25 are all other important areas of research that have the potential to drastically change radiation oncology. By investing research efforts into a more fundamental understanding of the biological basis of our targets, we can potentially improve patient outcomes and better utilize the equipment that is already developed.
In the US, government funding accounts for much of the funding for radiation oncology research. While there appears to be an emphasis on cancer biology amongst National Institutes of Health (NIH) funded grants, the total funding for a treatment modality (radiation) which is applied to two-thirds of all cancer patients is a mere 1.6% of NIH funding for cancer research. 26 Additionally, radiation oncology vendors should be motivated to invest in better understanding of cancer biology and specifically radiation biology, particularly in the setting of newer techniques such as SBRT and the implementation of increasing numbers of targeted agents. Not only could the efficacy of traditional radiation therapy be maximized with this approach, but novel indications for radiation as discussed above could greatly expand the use of radiotherapy and thus existing radiotherapy equipment. New inquiry should also include the effect of different radiation modalities on "normal tissues" affected by other pathologies such as seizure disorder, cardiovascular disease, and cardiac conductivity disorders to name only a few.
In conclusion, the field of radiation oncology must prioritize over- Only a moderately increased radiation dose (6-9 Gy per fraction) was found to be necessary to stimulate immune activity, a dose already achievable by current clinical instrumentation. 43 Rather than further equipment development, the key problem and limitation for any clinical implementation of the ideas proposed in the study (as well as the gene-expression profiling study cited by our opponents (Ref. [ 39 ]) is biological validation and understanding, without which further funding approval, clinical trial initiation, and adoption by clinicians will be limited.
In the end, the conclusion to which our opponents arrive is our own exact point. The innovations in our field most likely to make a significant impact on patient care and outcomes will only be achieved through better understanding the biology of our therapies and how radiation treatment may be best applied in a biological context. Investing in these areasand not equipment developmentis exactly what our field should be doing starting no later than now. Advances in molecular techniques such as gene-expression profiling have been needed to further insights in general cancer biology.
These in turn have opened new areas of investigation for radiation biology. [44][45][46] While submillimeter accuracy may not be needed to treat all tumors, radiation therapy is used to treat a variety of tumor types that require different levels of accuracy and precision. One example of the huge clinical impact of submillimeter accuracy is during brain tumor radiation therapy, especially in children. Dose delivery in such cases is limited by the tolerance of normal tissues surrounding the target. 47,48 Even with the current precision, nearly all children undergoing brain tumor radiation therapy develop a certain level of cognitive deficits long-term. The physical basis for the damage to the nontargeted brain cortex from MV x-rays or Co-60 gamma rays is the spatial distribution of the radiation they produce in the brain.
Specifically, the doses produced to the brain tissue located proximal and distal to the target are excessive. 49 Better accuracy translates to less normal brain cortex damage. Furthermore, without a reliable and safe way of accurately delivering radiation in the clinic, even the most detailed radiobiologic understanding would have limited translation into real patient care.
As for the concern regarding funding, we are in complete agreement that not enough NIH research dollars are allocated to the study of basic radiobiology and radiation oncology in general. However, until this can be changed, any additional funding to help move our field forward should be not be discounted. There are examples of equipment development based on evidence where private developers work in conjunction with the NIH to generate relevant clinical data. A good example is the emerging data for rectal sparing in prostate cancer. We know risk of rectal toxicity depends on the volume of the rectum that receives a high-radiation dose. In a large prospective series, the percentage of rectum receiving > 70 Gy (V70) correlated with the occurrence of chronic rectal toxicity. 50 Based on this information, in vitro work was supported by NIH grants and cadaveric studies funded by an equipment developing company to analyze risks, benefits, and dosimetric effects of prostate-rectum separation using polyethylene-glycol (PEG)-based hydrogels. 51 Evaluation in a prospective multicenter randomized controlled trial showed a significant reduction in late (3-15 months) rectal toxicity severity. 52 Finally, our colleagues make the argument that we may have plateaued on accuracy due to CTV accounting for uncertain margins.
Thus far SBRT ablative doses are delivered without a CTV, therefore, little to no room for uncertainty. As we head toward immune modulation in combination with radiation therapy and tumor microenvironment modulation with radiation, as predicted by our colleagues, we will likely need even more accuracy in radiation treatment delivery.
Overall, in order to deliver innovative radiation oncology treatments in the clinic, we will continue to require equipment development. Therefore, while it will be essential to answer cancer and radiation biology questions, equipment development will continue to be an integral part innovation in radiation oncology.

ACKNOWLEDG MENTS
SM is supported by NIH K08 CA237822. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. PARALLEL OPPOSED EDITORIAL