1
THREE DISCIPLINE COLLABORATIVE RADIATION THERAPY (3DCRT) DEBATE
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.1, 2 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 first 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.
2
INTRODUCTION
The energy deposition characteristics of protons are substantially different from
those of conventional radiotherapy beams of photons or electrons. As a result, the
use of proton beams for radiotherapy offers the potential for significant improvements
in achievable dose distributions.3, 4 These differences may result in significant
improvements in the efficacy or toxicity profiles of radiotherapy for certain types
of cancer. However, such improvements have yet to be demonstrated for many treatment
sites. In addition, proton therapy is substantially more expensive than conventional
radiotherapy. As such, an important question becomes “How many proton therapy facilities
are necessary in the United States?” There are currently 75 operational proton therapy
facilities worldwide, with 30 of these in the US alone,5 and additional proton therapy
facilities are currently both under construction and under consideration. How many
such facilities do the science and the economics support?
Arguing for the proposition will be Drs. Steve Braunstein, Li Wang, and Wayne Newhauser.
Dr. Braunstein is an academic radiation oncologist at the University of San Francisco
– California specializing in the treatment of pediatric and adult primary and metastatic
brain and spine tumors. His research focus includes examination of late toxicity in
patients undergoing radiotherapy using advanced imaging and clinical analytics toward
identification of predictors and mitigation of cognitive impairment and secondary
malignancies.
Dr. Wang, is an Assistant Professor at the University of Texas MD Anderson Cancer
Center. Her research focuses on radiobiology and radio‐sensitization of tumors of
the upper aero‐digestive tract, and assessing the preclinical effects of targeted
combination treatments both in vitro and in vivo. Her recent emphasis includes the
biological effects of proton vs photon radiotherapy, including relative biological
effectiveness, gene expressions, and cell death mechanisms.
Dr. Newhauser, is Professor and Director of the Medical Physics Program at Louisiana
State University and Mary Bird Perkins Cancer Center. His research focus is to improve
long‐term health outcomes of patients with good prospects for survival of a primary
cancer. In particular, his research projects include modeling and measurements of
radiation exposures. He researches risk projection, visualization, and optimization,
and develops methods and prototype systems to translate these technologies into clinical
tools.
Arguing against the proposition will be Drs. Todd Tenenholz, Yi Rong, and Albert van
der Kogel. Dr. Tenenholz is currently the Director of Residency Training at the West
Virginia University Department of Radiation Oncology. He previously served as the
principal pediatric radiation oncologist at Vanderbilt University for 10 yr, and is
a member of the Children's Oncology Group.
Dr. Rong earned her PhD in Medical Physics at the University of Wisconsin Madison
in 2008. She has been working as a faculty medical physicist for 10 yr and is currently
an associate professor in the Radiation Oncology department at University of California
– Davis. She has also been serving as a reviewer and Associate Editor for JACMP for
more than 8 yr.
Dr. van der Kogel is professor of clinical radiobiology at the University of Wisconsin,
Madison. His research has focused on effects of radiation on normal tissues and in
particular the spinal cord, as well as on radiation resistance mechanisms related
to the tumor microenvironment. He is the recipient of the ESTRO Gold medal and Lifetime
Achievement Award, and the ICRU Gray Medal. He is co‐editor of the textbook “Basic
Clinical Radiobiology”.
3
OPENING STATEMENTS
3.A
Steve Braunstein, MD, PhD; Li Wang, PhD; Wayne Newhauser, PhD
Photon beam radiotherapy, including x‐rays and γ‐rays, is the most widely used type
of ionizing radiation in cancer‐directed treatment. Proton beam therapy has emerged
over the past several decades as a potentially significantly improved technological
advancement for radiotherapy clinical application. Our community of scientists and
evidence‐based practitioners in the United States should build additional proton therapy
facilities in order to responsibly develop, carefully study, and properly implement
this emerging technology such that it may deliver on the promise of improved patient
care.
Based upon its advantageous physical features, proton‐based radiotherapy can offer
improved dose‐sparing of regional normal tissues while simultaneously allowing for
dose‐escalation to the tumor target.4 This dosimetric advantage is elegantly achieved
by the shape of the Bragg peak; beyond the end of which the dose falls off very quickly.5
As a result, the exit dose is but a small fraction of that from photon beam therapies.
When this basic physical advantage of finite proton range is utilized with algorithmically
optimized treatment planning methods, then delivered with range and fluence modulation,
it leads to dosimetrically superior treatment plans, particularly in regions of proximity
to uninvolved normal anatomy. Numerous computational studies have predicted lower
risks of second cancers and other radiogenic late effects in long‐term survivors who
receive proton therapy compared with photon therapy.6, 7, 8, 9, 10, 11 More generally,
there is increasing impetus to reduce radiogenic toxicities in normal tissues,12 a
challenging task common to all types of external beam radiotherapy. Decreased off‐target
dose may also engender increased preservation of the immune compartment leading to
improved tumor control.13
Notably, the technology to deliver proton therapy is significantly distinct from photon‐based
delivery and historically has been resource‐intensive, limiting widespread manufacture
and deployment of proton delivery facilities. Currently, there are 30 proton centers
in operation, 10 centers are under construction or in development, and two centers
are expanding in the United States.3 Unfortunately, many of these centers are geographically
clustered, limiting access to large segments of the population.14 Most of the contention
regarding further expansion of proton therapy has centered on considerations of absolute
cost, cost effectiveness, and related economic considerations. Currently, proton therapy
units are the most expensive medical device regulated by the US FDA. Furthermore,
the long‐term finances of the US health care system are tenuous and the aging of the
population suggest the potential of increased utilization. Thus, cost of care is a
very legitimate concern. But to neglect the other costs of cancer in this calculation
would be wrong. We have made tremendous advances in cancer treatment outcomes with
more than 60% of adults and 80% of children surviving their primary cancer for 5 yr
or more (this represents a good surrogate for long‐term disease‐specific survival).
Approximately two‐thirds of the cost of cancer to society is attributed to disease‐
and treatment‐related morbidity and mortality. Only about one‐third of the cost goes
to direct medical care. Stated in terms of aspirational goals, if we could completely
eliminate the morbidity and mortality of cancer, the savings in avoided morbidity
and mortality would allow a tripling of the direct medical care expenditures. As decades
of medical research progress has shown, an expensive cure is cheaper than an ineffective
treatment. With the continued advancement in proton delivery technology, leading to
decreased capital and operational costs, the capacity to increase the number of facilities
can be realized. Moreover, the greater dissemination of proton facilities enables
more investigation leading to refinements in treatment planning, delivery techniques
including image‐guidance, and ultimately improved outcomes for select patients. A
similar precedent was observed with the widespread deployment and subsequent evolution
of intensity‐modulated and volumetric arc based photon therapy, which ultimately emerged
as the most advanced iterations of photon technology. The pace of proton therapy development
can only be improved with investment in disseminating the technology to more centers.
Based on the above facts, select patients may potentially benefit more from proton
vs photon therapy in the respects of normal tissue protection and superior tumor control.
Large‐scale collaborative clinical trials and epidemiology studies are needed to determine
the role of proton therapy, particularly for children,15 and additional treatment
capacity is needed to accelerate the accrual of outcome data. The preponderance of
available evidence indicates proton therapy is as good as or better than photon therapy
for many, but not all, patients. To generate a more complete base of outcomes evidence,
more proton therapy centers will be needed to conduct multi‐institutional clinical
trials and long‐term epidemiology studies that compare the outcomes of patients who
receive proton vs photon treatments. In the end, expanding proton therapy capacity
involves risk and uncertainty; there is no guarantee that the centers will cooperate
and generate much needed evidence. Conversely, based on more than 6 decades of clinical
experience, the desired evidence may never arrive if proton treatment capacity remains
at current levels. Therefore, the United States should build additional proton therapy
facilities in more states to deliver on the promise of improved patient care.
3.B
Todd Tenenholz, MD, PhD; Yi Rong, PhD; Albert van der Kogel, PhD
Over the past 12 yr, the United States has seen a dramatic increase in the number
of proton therapy centers available to treat patients. In 2006, only four proton centers
operated general‐purpose gantries, but since then, an additional 26 facilities have
opened, with 10 more centers under construction or in planning. This remarkable growth
has occurred in a mixture of settings, with some facilities entirely operated by research‐oriented
institutions, while others operate as partnerships with for‐profit entities. At least
nine of these centers operate as private‐practice entities with no or minimal ties
to an academic research institution. Due to the decentralized nature of the US medical
system, all of these centers have developed based on local interest, funding, and
philanthropy. With no attempt to build a network of centers that would conduct systematic,
nationwide investigation into the potential benefits, possible pitfalls, and knowledge
of the infrastructure (both physical and intellectual) needed to utilize this new
technology appropriately, much of the data we now have about proton therapy is based
on limited, single institution investigations. Few of these studies have direct comparisons
between contemporary groups of patients treated with proton vs. photon therapy. This
environment has led to a rapid expansion of proton therapy with very limited evaluation
of efficacy, and in some cases, with limited evaluation of even the safety of these
approaches. Such rapid growth has come at the expense of some “growing pains”.
In 2016, the National Cancer Institute (NCI) convened a national panel to investigate
growing concerns about the incidence of brainstem injury in pediatric patients treated
with proton therapy.16 The growing use of proton therapy as a near mandatory consideration
in children with medulloblastoma,17 despite the lack of clinical data,18 had led to
unexpected cases of severe, even fatal brainstem damage. Although first reported in
2014,19 the pediatric oncology community had been aware of this problem for several
years prior to this initial admission of clinical problems with proton therapy. In
comparing the treatment approaches of the three proton centers with the largest pediatric
experience, there was a wide range of approaches to treatment planning even among
academic institutions, but all of them had calculated effective doses using a fixed
relative biological effectiveness (RBE) value of 1.1 for protons. However, the concern
that proton RBE for the central nervous system might be higher than 1.1 has recently
been confirmed in a comprehensive study in the rat spinal cord.20 In this study, the
rat cord was irradiated at different positions of the Bragg peak, showing the RBE
to increase to 1.2–1.3 at the distal edge. This finding fundamentally disproved the
previous assumption of a fixed and uniform RBE, which suggested potential varying
degrees of impact on patients that had been or will be planned with a fixed RBE value
of 1.1.
As an interim measure, the guidelines of ACNS0831 were modified, essentially allowing
dose de‐escalation for patients treated with protons. Subsequent literature 21, 22
has suggested that a more nuanced (and far more complicated) approach to the problem
of RBE value in proton therapy planning will be required for clinically accurate modeling
of the effect of proton beam therapy on normal tissues.
What lessons can we glean from this experience? The early problems seen in proton
treatment of the posterior fossa in children only became widely discussed and acknowledged
many years after the first cohort of patients were treated. If these patients had
been treated on prospective, dose‐escalation trials, the unanticipated toxicity of
the treatment might well have been detected earlier, but would likely have significantly
slowed the adoption of proton therapy. By the time these issues came to light, an
additional 20 proton facilities had opened, all treating patients with varying techniques.
A comprehensive report of the toxicities encountered in this time frame has not been
published, and general consensus on the solution to the problem of RBE in proton therapy
does not yet exist, much less has been tested widely and made commercially available
to private‐practice centers. Is it ethical to continue the expansion of proton therapy
when fundamental problems such as the ability to predict toxicity remain unresolved?
From a hospital's sustainability aspect, proton therapy centers are still struggling
financially. The Scripps Health Proton Cancer Therapy Center in San Diego opened in
2014, but filed for bankruptcy protection in 2017.23 The hope of recouping the initial
$220 million investment by treating 2000 patients per year in the San Diego metropolitan
area was never achieved. Instead, only about 1400 patients a year have been treated
since 2014 according to Scripps.24 Most of these patients were treated for prostate
cancer. Even such a large volume of relatively simple cases could not keep the center
operating on “a break‐even basis”. Based on the 2017 American College of Radiation
Oncology Billing and Coding Guide,25 25 fractions of proton radiotherapy can only
be billed at the same amount as 44 fractions of intensity modulated photon therapy
(IMRT), yet the initial investment for protons is more than ten times higher than
photon therapy. This is due to the lack of evidence that would demonstrate to insurers
and policy experts that protons have higher effectiveness and better outcome when
compared with conventional photon therapy.
From a physics point of view, we are all aware that the proton's famous “Bragg Peak”
is a double‐edged sword. It provides sharp dose fall off distal from the Bragg Peak,
yet at the same time, it is too sensitive to tumor mobility and patient setup accuracy.
Even with stationary tumors and precise patient setup, proton therapy at its early
phase (scanning or scattered beam) has not been proven superior to conventional IMRT.26
While the more advanced intensity modulated proton therapy technique may be associated
with reduced toxicity compared to IMRT,27 most reported studies were done in a retrospective
fashion, and there is still a dearth of prospective multicenter randomized trials
to validate those reported benefits.
One may argue that we need more proton centers to start and participate in those prospective
trials. However, there are already two dozen operating proton therapy centers in the
United States, while the enrolled patient numbers on the proton arm of numerous prospective
trials are still very low. While there may be other issues that are limiting the accrual
of patients into prospective trials of proton therapy, the number of proton facilities
does not seem to be the problem, and, adding more proton facilities is unlikely to
improve accrual.
Overall, we would argue that the unchecked growth in proton treatment facilities is
outstripping the radiation oncology community's ability to properly study, analyze,
and use this treatment modality. A limited number of proton centers, with a primary
mission of research, clinical development, and training would be better able to define
the appropriate role and scope for proton therapy. Shortly after the publication of
the NCI consensus opinion, the question of expanding proton therapy centers was compared
to the development of autonomous vehicles28: research and development was not being
halted because of “early crashes and technical set‐backs”. Shortly thereafter, such
vehicles were placed into “real‐world” use, and then promptly withdrawn after they
proved unsafe in this setting. Proton therapy is a powerful tool, but it is clear
that we don't fully understand it. It's time to put on the brakes.
4
REBUTTAL
4.A
Steve Braunstein, MD, PhD; Li Wang, PhD; Wayne Newhauser, PhD
We appreciate our colleagues’ thoughtful position against building additional proton
radiotherapy facilities. However, while it is true that upfront capital costs of proton
facilities are significant in comparison to photon‐based technologies, that cost is
decreasing, albeit slowly, with an increasing number of vendors supporting cost‐cutting
technological developments in proton therapy.29 In addition, though several of the
initial proton centers were funded with high profit‐margin expectations, current health
care economics have led to adjusted expectations such that future proton facilities
are being developed thoughtfully for the current climate, including design of smaller
facilities and with community partnerships to ensure sustainability. Importantly,
comparisons of true cost‐effectiveness should consider not only the cost of treatment
of the primary cancer, but also the actual or estimated costs of late toxicities,
which are lower with advanced radiotherapy technologies like proton therapy.30, 31
Thus, the economic gain of proton therapy will be realized with long‐term follow‐up.
It has taken decades to rigorously study the appropriate parameters for optimum photon‐based
radiotherapy delivery, with many clinical, biological, and technical issues still
unresolved. The challenges of assessing value with deployment of advanced technologies
in radiation oncology, such as protons, are well‐recognized and require a concerted
effort of the community to properly study.32 Once value is recognized, broader insurance
coverage may follow. Such a herculean effort is only afforded by large‐scale cooperative
registries and networks of treatment centers of study, demonstrated by the NRG, Alliance,
SWOG, and ECOG groups. Large cooperative group studies with focus on proton therapy
are emerging but ultimately require more centers to achieve the needed accrual rates.
As noted in the opposition statement, the recent effort of an NCI working group addressing
the uncertainties in proton therapy RBE and subsequent structured recommendations
to minimize radionecrosis risk justify the additional centers to participate in these
and other collaborative efforts.
Ultimately, we must acknowledge radiation as an empirical science. After decades of
implementation, we are ready to move beyond early phase limited study for proton therapy.
No one can deny that the physics and biology of proton therapy can afford more conformal
radiotherapy treatment with superior avoidance of normal tissue and thus significantly
mitigated toxicity. We are ready to move on to large scale phase III studies, requiring
additional proton centers for enrollment to exhaustively examine the parameters for
maximum benefit of proton over photon‐based radiotherapy as well as identify new opportunities
for improved outcomes. The upfront costs will be readily offset by gains in reduced
costs of managing late toxicities. The benefits of proton therapy are established;
we do not need to put on the brakes, but rather move forward in a scientific, methodical,
and cooperative manner to continue to improve patient outcomes. We owe our patients
these efforts and resources.
4.B
Todd Tenenholz, MD, PhD; Yi Rong, PhD; Albert van der Kogel, PhD
Our colleagues have argued that expanding the number of US proton therapy centers
will lead to increased patient access and effectiveness research, and that the direct
costs of such expansion are small related to the overall costs of patient care. Unfortunately,
while the US has led the world in the adoption of expensive treatment technologies
and paradigms, the return on this investment in terms of actual health outcomes has
been disappointing relative to other industrialized, English‐speaking countries.33
In fact, a great deal of this cost has been transferred to our patients, with over
half of US patients diagnosed with a serious medical condition reporting severe financial
hardship as a result.34 Even if we accept the premise that “an expensive cure is cheaper
than an ineffective treatment”, there is little evidence, or even theoretical speculation,
that protons will be more effective than photons from a cancer control perspective.
While our colleagues may argue that the decrease in late effects promised by protons
may justify their cost, the current rapid expansion of proton therapy has not resulted
in increased research to establish this argument. As an example, despite enrollment
of 437 proton therapy eligible patients in ACNS 0831, only 135 of these patients have
been enrolled in the ALET07C1 companion study of neuropsychological outcomes.35 This
is not a failure of patient access, it is a failure of the treating physicians to
prioritize outcomes research.
While there are important arguments to be made regarding the reduction of second primary
cancers in the pediatric population, such patients constitute a small minority of
patients treated with radiotherapy in the US. While the population of adult 5 yr cancer
survivors is growing, these are predominantly patients treated for prostate and breast
cancer. The incidence of secondary malignancy in such patients appears to be low in
the former,36 and has likely been overestimated in the latter.37, 38 Such arguments
hardly justify recent reports of proton therapy for treating small cell lung, pancreatic,
and esophageal cancers.39, 40, 41 In fact, the dose limiting toxicities for many adult
malignancies relate to tissues in close proximity to the target volume, a situation
in which protons may have little dosimetric advantage compared to other treatments,
due to high dosimetric sensitivity to internal tumor/organ motion and anatomy change.42
In addition to this theoretical advantage of a reduced risk of secondary malignancies,
the key argument for the use of protons has been the steep dose fall off beyond the
Bragg peak, thus conferring an advantage when treating tumors close to critical normal
tissues. As we mentioned in the opening statement, the generally accepted RBE of 1.1
for proton dose delivered in normal tissues has been challenged by the recent rat
spinal cord study with a 10% or more increase at the distal edge of the Bragg peak.
These uncertainties emphasize the need for (pre)clinical studies of normal tissue
tolerance that so far have been lacking. Therefore, the combined impact of dosimetric
and radiobiological uncertainties may diminish the claimed benefits of critical organ
sparing by proton therapy for various cancer sites.
Our colleagues further offered IMRT and VMAT as an analogy to proton therapy and argued
that as more centers adopt this technology, its value will become obvious. However,
the well‐established improvement in dosimetric conformity of IMRT over conventional
3D‐CRT planning came at a relatively modest financial cost in the range of 1 million
dollars per gantry. VMAT offers a significant, practical advantage of shortened treatment
delivery time at even less cost in upgrading the software and hardware. For these
reasons, both practitioners and insurers were willing to adopt these evolutions of
existing technology based on predicted dosimetric improvements. The dosimetric improvement
and potential impact on outcome promised by proton therapy is mostly applicable to
a limited population of patients, but the cost of building a proton center is in the
range of $100–$200 million dollars.
The current geographic clustering of proton therapy centers is driven by the same
market‐driven factors that have led the cost of US healthcare to vastly outpace its
improvement in outcomes. The closure of the Indiana University and Scripps proton
centers due to financial infeasibility, despite their locations in areas that should
have improved accessibility for large populations, highlights the burden that the
extreme cost of proton therapy places on the healthcare system and patients. The problem
is not access, it is cost. For about $1 million, a cohort of 120 patients eligible
for clinical investigation of proton therapy could be given transportation and lodging
for the duration of their radiation treatment. This would be far more effective in
terms of accomplishing actual clinical research, and orders of magnitude less costly
than the construction of a single additional proton facility. Adopting a more “St
Jude's” like model for conducting proton therapy research would help to identify the
patients who would truly benefit from this new modality, and would likely do so with
higher quality data and much lower overall cost than construction of additional proton
centers.
CONFLICT OF INTEREST
No conflicts of interest.