demonstrate the sensitivity and specificity of claims-based algorithms to detect important radiotherapy outcomes and exposures across disease sites. Second, equipment manufacturers
should develop unique technology identifiers for radiotherapy
devices and image guidance that would facilitate identification
in registries or possibly claims data. For example, the proposed
National Radiation Oncology Registry will ascertain finer details
on radiotherapy delivery quality at a population level through
an integrated electronic infrastructure (8). Third, investigators
should explore novel, prospective CER clinical trial designs.
Randomization is the most appropriate study design to minimize
confounding when investigators hypothesize modest to moderate differences in outcomes between treatment exposures (as with
proton therapy for prostate cancer); large-scale, pragmatic, randomized trials or parallel, randomized and observational cohort
studies can extend the generalizability of traditional randomized
studies (9).
Is a randomized trial of proton therapy vs IMRT worth the
costs? A rough calculation of the incremental health-care expenditures associated with replacing IMRT with proton therapy for
even just one-third of the nearly 28 000 Medicare beneficiaries who
received treatment in 2008 and 2009 would be at least $100 million of excess spending. The costs of a randomized trial that would
compare the two radiation modalities range from $5 to $15 million. For such a scientifically important question in radiotherapy
CER, a randomized trial of proton therapy vs IMRT would appear
to be a good investment for patients and clinicians. The University
of Pennsylvania and the Massachusetts General Hospital have partnered with other centers to conduct this randomized trial. Similar
efforts, combined with important findings from Yu et al. (3), will
continue to build the body of evidence for advanced radiotherapy
technologies.
References
DOI:10.1093/jnci/djs509

© The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
1. Urie M, Goitein M, Wagner M. Compensating for heterogeneities in proton radiation therapy. Phys Med Biol. 1984;29(5):553–566.
2.Emanuel EJ, Fuchs VR, Garber AM. Essential elements of a technology
and outcomes assessment initiative. JAMA. 2007;298(11):1323–1325.
3. Yu JB, Soulos P, Herrin J, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl
Cancer Inst. 2012;105(1):XXX–XXX.
4.Strom BL. Methodologic challenges to studying patient safety and comparative effectiveness. Med Care. 2007;45(10 Suppl 2):S13–S15.
5. Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation
therapy, proton therapy, or conformal radiation therapy and morbidity
and disease control in localized prostate cancer. JAMA. 2012;307(15):
1611–1620.
6. Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following
radiation therapy for prostate cancer. Eur Urol. 2011;60(5):908–916.
7.Bekelman J, Shah A, Hahn S. Implications of comparative effectiveness
research for radiation oncology. Pract Radiat Oncol. 2011;1(2):72–80.
8.Rose CM, Lawton CA, Efstathiou JA, et al. Developing a National
Radiation Oncology Registry (NROR): a Radiation Oncology Institute
(ROI) initiative. Int J Radiat Oncol Biol Phys. 2011;81(2):S693–S694.
9.Britton A, McKee M, Black N, et al. Choosing between randomised
and non-randomised studies: a systematic review. Health Technol Assess.
1998;2(13):i–iv, 1–124.
Funding
JEB is supported by the National Cancer Institute (1K07CA16316-01).
Note
The study sponsors had no role in the writing of the editorial or the decision to
submit it for publication.
Affiliations of authors: Department of Radiation Oncology, Abramson
Cancer Center (JEB, SMH) and Center for Clinical Epidemiology and
Biostatistics, Department of Biostatistics and Epidemiology (JEB), Perelman
School of Medicine, and Leonard Davis Institute of Health Economics (JEB),
University of Pennsylvania, Philadelphia, PA.
Protons for Prostate Cancer: the Dream Versus the Reality
Theodore S. Lawrence, Mary Feng
Correspondence to: Mary Feng, MD, Department of Radiation Oncology, University of Michigan, University Hospital Fl B2C490, 1500 E Medical Center Dr,
SPC 5010, Ann Arbor, MI 48109 (e-mail: [email protected]).
Proton therapy has generated much excitement among physicians
and patients. During the period from 2006 to 2009, the number of
prostate cancer patients treated with protons nearly doubled (1)
and use continues to rise. There are 11 operational proton facilities
in the United States, opening at a rate of more than 1 per year over
the past 6 years. Why is everyone so excited? There are at least
three reasons. Two are clear, and one is complex.
First, protons are a new technology. Although, proton therapy
has been around for more than 20 years, it is viewed as a new or
jnci.oxfordjournals.org
advanced technology. Everyone in the United States wants new; it
sells both breakfast cereal and therapies.
The second reason is reimbursement: The current method
of reimbursement by Centers for Medicare & Medicaid Services
(CMS) is based on cost and not effectiveness. Prostate cancer proton treatment is delivered quickly because it uses just a few beams
(high throughput) and there are many men with prostate cancer
(high volume). High reimbursement per case × High throughput ×
High volume = High profit.
JNCI | Editorials 7
The third—and complex—reason is physics. Protons have
some theoretical advantages over photons. Protons are charged
particles that deposit only a low dose as they enter the body and
deliver most of their energy over the last few millimeters of their
range (the Bragg peak). Essentially no radiation passes this point.
Therefore, protons have the potential to treat a tumor while giving
less radiation to normal tissues, which is the holy grail of radiation
therapy. Unfortunately, some “dragons” may keep the grail from
being reached. First, because the Bragg peak of a single energy is
too focused to treat a tumor, protons of different energies must be
combined to broaden the peak. This increases the entrance dose.
Second, because of uncertainty about how far these protons will
travel, the hig- dose region is typically extended several millimeters
beyond the target. Third, protons are susceptible to changes in tissue density, so slight changes due to respiration or gas motion during a given treatment or tumor shrinkage or rectal filling over the
course of several treatments can allow high doses to escape beyond
the planned region into normal tissues or cause them fail to reach
the far edge of the target. Intensity-modulated (photon) radiotherapy (IMRT), which has become the standard of care, conforms
the high-dose region to the prostate better than current proton
therapy. Thus, although 20 years ago it seemed clear that protons
should be superior to photons, the superiority of current proton
therapy over IMRT photons is no longer certain.
In this issue of the Journal, Yu et al. (2) examine the patterns of
use, cost, and early toxicity of modern proton therapy for prostate
cancer. They performed a retrospective study of all Medicare beneficiaries aged 66 years or older who received proton radiotherapy
or IMRT during 2008 and 2009. They identified factors associated with the receipt of proton radiotherapy and its cost. They also
compared early genitourinary, gastrointestinal, and other toxicities
experienced by patients treated with each modality. Not surprisingly, patients who received proton therapy were younger, healthier, and of higher socioeconomic status than patients who received
IMRT. With few proton centers across the country, patients must
seek them out, often travel long distances, and stay for 7 to 9 weeks
of therapy. Median Medicare reimbursement was $32 428 for proton therapy and $18 575 for IMRT. As alluded to, this differential is
likely a key driver in the spread of proton centers, despite their high
building cost of $125 to $200 million per facility.
So what was the outcome of treatments? Cancer control data
will not be available for many years because of to the relative indolent nature of prostate cancer, but it is unlikely that a difference
will emerge (3,4). Was toxicity decreased? Six months after treatment, men treated with protons had slightly less genitourinary
(GU) toxicity (6% vs 10 %; P =.03), but this difference disappeared
at 12 months. There was no difference in gastrointestinal or other
toxicities at any time point. Proponents of proton therapy may
argue that any reduction in toxicity is worthwhile. However, is
this small transient difference enough to justify a 70% higher cost
per patient? Also consider a recent Surveillance, Epidemiology,
and End Results Medicare analysis of patients treated during the
period from 2000 to 2009 (4), which found a lower rate of gastrointestinal toxicity in patients treated with IMRT than in those
treated with proton therapy.
8 Editorials | JNCI
These studies have weaknesses. It is assumed that one can assess
toxicity by evaluating billing codes, but toxicities are not well
graded, and many could be missed. We have no dosimetric data
evaluating the radiation delivery. These are all problems associated with retrospective, population-based studies, as the authors
are aware. Therefore, a rigorous comparison of protons vs photons
cannot yet be made.
Recently, the emerging technology committee of the American
Society for Radiation Oncology published an evidence-based
review of proton beam therapy, which concluded that, although
proton therapy holds promise, there is insufficient evidence
that it is superior or even comparable to photon radiotherapy in
most cancer sites (5). The National Cancer Institute, Institute of
Medicine, Agency for Healthcare Research and Quality, and Centers
for Medicare and Medicaid Services have called for randomized
studies. We should commit to running and encouraging patients to
participate in randomized trials of photons vs protons because we
are uncertain that protons, as they are delivered in 2012, produce
a superior outcome to IMRT photons. In a recent survey study,
59% of patients stated they would either “definitely” or “probably”
participate in a randomized study comparing IMRT and proton
beam radiotherapy (6). Although it seems unlikely that proton
therapy will be superior to IMRT photons for prostate cancer,
protons may be superior for tumors in which the elimination of
the low-dose regions might decrease normal tissue injury (eg, lung
cancers, when combined with chemotherapy). However, this is
a hypothesis that must be tested. Declaring that proton therapy
is new, awarding it high reimbursements, and stating that it has
theoretical dosimetric advantages over photons is not acceptable.
We need prospective clinical trials directly comparing protons to
IMRT photons.
References
1.Jarosek S, Elliott S, Virnig BA. Proton beam radiotherapy in the U.S.
Medicare population: growth in use between 2006 and 2009. In: Data Points
#10. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
2.Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated
radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl
Cancer Inst. 2012;XX(XX):XXX–XXX.
3.Coen JJ, Zietman AL, Rossi CJ, et al. Comparison of high-dose proton
radiotherapy and brachytherapy in localized prostate cancer: a casematched analysis. Int J Radiat Oncol Biol Phys. 2012;82(1):e25–e31.
4.Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and
morbidity and disease control in localized prostate cancer. JAMA.
2012;307(15):1611–1620.
5. Allen AM, Pawlicki T, Dong L, et al. An evidence based review of proton
beam therapy: the report of ASTRO’s emerging technology committee.
Radiother Oncol. 2012;103(1):8–11.
6.Shah A, Efstathiou JA, Paly JJ, et al. Prospective preference assessment
of patients’ willingness to participate in a randomized controlled trial
of intensity-modulated radiotherapy versus proton therapy for localized
prostate cancer. Int J Radiat Oncol Biol Phys. 2012;83(1):e13–e19.
Note
The authors have no conflicts of interest to declare.
Affiliation of authors: Department of Radiation Oncology, University of
Michigan, Ann Arbor, MI (TSL, MF).
Vol. 105, Issue 1 | January 2, 2013