Proton Versus Intensity-Modulated Radiotherapy for Prostate Cancer: Patterns of Care and Early Toxicity
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Proton Versus intensity-Modulated r adiotherapy for Prostate c ancer: Patterns of c are and early t oxicity
James B. Yu
Pamela R. Soulos
Laura D. Cramer
Arnold L. Potosky
Kenneth B. Roberts
Cary P. Gross
Proton radiotherapy (PRT) is an emerging treatment for prostate cancer despite limited knowledge of clinical benefit or potential harms compared with other types of radiotherapy. We therefore compared patterns of PRT use, cost, and early toxicity among Medicare beneficiaries with prostate cancer with those of intensity-modulated radiotherapy (IMRT). We performed a retrospective study of all Medicare beneficiaries aged greater than or equal to 66 years who received PRT or IMRT for prostate cancer during 2008 and/or 2009. We used multivariable logistic regression to identify factors associated with receipt of PRT. To assess toxicity, each PRT patient was matched with two IMRT patients with similar clinical and sociodemographic characteristics. The main outcome measures were receipt of PRT or IMRT, Medicare reimbursement for each treatment, and early genitourinary, gastrointestinal, and other toxicity. All statistical tests were two-sided. We identified 27,647 men; 553 (2%) received PRT and 27,094 (98%) received IMRT. Patients receiving PRT were younger, healthier, and from more affluent areas than patients receiving IMRT. Median Medicare reimbursement was $32,428 for PRT and $18,575 for IMRT. Although PRT was associated with a statistically significant reduction in genitourinary toxicity at 6 months compared with IMRT (5.9% vs 9.5%; odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38 to 0.96, P = .03), at 12 months post-treatment there was no difference in genitourinary toxicity (18.8% vs 17.5%; OR = 1.08, 95% CI = 0.76 to 1.54, P = .66). There was no statistically significant difference in gastrointestinal or other toxicity at 6 months or 12 months post-treatment. Although PRT is substantially more costly than IMRT, there was no difference in toxicity in a comprehensive cohort of Medicare beneficiaries with prostate cancer at 12 months post-treatment.
Over the past decade, intensity modulated radiotherapy (IMRT)
has become the standard form of radiotherapy for the treatment of
prostate cancer, accounting for more than 80% of all radiotherapy
). Even as IMRT has been widely adopted, other radiotherapy
modalities have come to market, most notably proton radiotherapy
(PRT). Although PRT predates IMRT, dissemination of PRT has
been increasing rapidly in recent years. In part because of its high
capital cost, Medicare is reported to reimburse PRT at a rate 1.4 to
2.5 times that of IMRT (
), despite many unexplored questions.
First, there is a lack of data regarding national patterns of use
and the true cost of PRT among Medicare beneficiaries. Currently,
there are only nine PRT centers in operation in the United States
), and this relatively low treatment capacity limits costs. However,
eight other centers are in development (
), along with smaller and
more affordable proton machines (
), conceivably opening the
door to more widespread adoption of PRT across the country.
Second, the Institute for Clinical and Economic Review
concluded unanimously that the state of current knowledge of
comparative clinical effectiveness was “insufficient” (
differences in cancer cure rates and survival from prostate cancer
treatment often take many years to become evident, it has been
suggested that initial study of prostate cancer treatments should
focus on treatment-related toxicity (8). Proponents of PRT argue
that the physical properties of protons may decrease the most
common side effects associated with prostate radiotherapy—
gastrointestinal and genitourinary toxicity (
). Early outcomes
from single-arm, prospective trials investigating PRT are
forthcoming, indicating low levels of radiation-induced toxicity
with early follow-up (
). However, IMRT itself has a robust
literature describing excellent efficacy and low toxicity in the
treatment of prostate cancer (12). Therefore, it is unclear that PRT
offers a statistically significant benefit beyond IMRT. Prior studies
investigating PRT in Medicare beneficiaries using the Surveillance,
Epidemiology, and End Results–Medicare database have been
single-institution studies (
) and, therefore, are not of the
whole country. These studies (
) noted a statistically significant
reduction of gastrointestinal toxicity for patients undergoing
IMRT compared with PRT. A comprehensive comparison of PRT
with IMRT requires examination of the entire country for the most
recent years available.
As more PRT centers become operational, it will be crucial for
patients, providers, and policy makers to understand the cost and
national pattern of adoption of PRT and the incidence of
treatmentrelated toxicity compared with IMRT. Therefore, we used a national
sample of Medicare beneficiaries with prostate cancer to investigate
the patterns and cost of PRT delivery, as well as the early
treatmentrelated toxicity associated with PRT compared with IMRT.
Data Source and Study Sample
Our data source was the Chronic Condition Warehouse, a
comprehensive national database of 100% of Medicare fee-for-service
claims for patients with specific chronic conditions (
system characteristics at the level of hospital referral region (HRR)
were obtained from the Dartmouth Atlas of Healthcare (
HRRs are geographical units representing regional healthcare
markets. The Yale Human Investigation Committee determined
that this study did not constitute human subjects research.
Using Medicare claims from 2008 and 2009, we identified a
sample of early-stage, treated prostate cancer patients aged 66 to
94 years using a multistep algorithm (Supplementary Figure 1,
available online). Only patients who received IMRT or PRT as
primary treatment were included. Treatment date was assigned as
the date of first radiation treatment. We excluded patients who did
not have Medicare Parts A and B fee-for-service coverage from
9 months prior through 3 months after treatment date to ensure
completeness of claims.
For the analysis of treatment selection, we included all patients.
For the analysis of 6-month toxicity and costs, we included only
patients who initiated radiotherapy prior to July 1, 2009, and had
Medicare Parts A and B fee-for-service coverage for 6 months
posttreatment. For the analysis of 12-month toxicity, we included only
patients who initiated radiotherapy prior to January 1, 2009, and
had coverage for 12 months post-treatment.
Construction of Variables
We used Healthcare Common Procedure Coding System codes to
identify the type of radiotherapy received. Patients were assigned to
the PRT group if there were any codes for PRT delivery; patients
were assigned to the IMRT group if there were four or more codes
for IMRT treatment delivery or if they had the IMRT treatment
planning code (77301) in addition to four or more generic external
beam treatment delivery codes.
The cost of IMRT or PRT treatment was calculated for each
patient using the sum of Medicare reimbursements for all
outpatient and physician claims with Healthcare Common Procedure
Coding System codes indicative of radiotherapy, including
treatment planning, management, and delivery in the 3 months
following initiation of radiotherapy.
Using insights from prior studies investigating Medicare
claims for prostate cancer treatment-related toxicity (
rigorously compiled a list of potential treatment-related toxicity
(Supplementary Table 1, available online), specifically excluding
codes that were thought to be due to surgical complications. We
searched claims for Healthcare Common Procedure Coding
System or International Classification of Diseases, 9th revision
diagnosis or procedure codes associated with the following
categories of toxicity, which were constructed a priori: genitourinary
(infection, upper urinary tract dysfunction, urethral stricture/
obstruction, incontinence, erectile dysfunction); gastrointestinal
(fistula, rectal repair, stenosis, bowel resection, other); and other
toxicity (local musculoskeletal damage, red blood cell transfusion,
systemic derangements, infection, nerve injury, and fractures).
Some codes may be indicative of preexisting conditions and be
unrelated to treatment; if a patient had one of these codes after
treatment but also had evidence of the code in the 9 months prior
to treatment, we did not count it as a complication. Our outcome
was whether a patient had a complication between 0 and 6 months
or 0 and 12 months after start of treatment.
Patient characteristics included age, race, year of treatment,
residence in a metropolitan county, median household income at the
zip code level, and distance to the nearest proton center. Because
access to primary care may be an important factor in the
development and reporting of toxicity, receipt of an influenza
vaccination or visit to a primary care provider in the 9 months prior to
treatment was recorded. The use of androgen deprivation therapy
(ADT) was assessed by adapting algorithms used in prior
studies (Supplementary Table 2, available online) (
). We identified
comorbidities by searching inpatient, outpatient, and physician
claims billed between 9 months and 1 month prior to treatment
date for specific International Classification of Diseases, 9th
revision diagnosis codes that appeared on at least one inpatient claim or
two or more outpatient/physician claims billed more than 30 days
apart. Using the comorbidity categories outlined by Elixhauser
et al. (
), we looked for conditions that we had previously found
were statistically significantly associated with survival in a sample
of noncancer patients.
Each patient was assigned to a HRR based on their zip code.
HRRlevel variables included the number of discharges for ambulatory
care sensitive conditions, number of available acute care beds, and
density of primary care providers and radiation oncologists. We
created a variable indicating whether each patient resided in a state
that required a certificate of need prior to expansion or creation of
new radiation facilities, used by some states to restrict unnecessary
or redundant increases in healthcare services and facilities.
We used χ2 tests to assess bivariate associations between the
independent variables and receipt of PRT. We used random effects
logistic regression with clustering by HRR to investigate the unadjusted
and adjusted associations between covariates and use of PRT versus
IMRT. To illustrate the travel patterns of patients receiving PRT, we
created a map with lines going from the centroid of patients’ home
states to the PRT center at which treatment was administered. We
only included lines representing two or more patients.
Usual techniques to account for treatment selection bias,
such as instrumental variables and propensity score matching,
were computationally problematic because of the small
number of PRT patients. To adjust for treatment selection bias from
known confounders in our analyses of cost and toxicity outcomes,
we used Mahalanobis matching (
). Matching was based on the
Mahalanobis distance calculated using age, race, residence in a
metropolitan county, comorbidity, receipt of ADT, prior
influenza vaccination or prior visit to a primary care physician (both
as proxies for access to care), and income. Matches were assigned
by choosing the two best IMRT patient matches for each PRT
patient; when two or more PRT patients matched the same control
(that is, had Mahalanobis distance minimized by the same control),
one was randomly selected as a match, with this process reiterated
until all PRT patients had two matched controls. Matching was
done separately for patients with 6-month and 12-month
followup. We assessed the validity of the matching by comparing risk
factors between the PRT and IMRT groups using χ2 tests.
To compare the relative cost of PRT and IMRT, we calculated
the median and interquartile range (IQR) of Medicare
reimbursement for patients in the matched 6-month complication sample.
To estimate the effect of PRT on outcomes, we estimated a
conditional logit model for the 6- and 12-month complication samples,
including an indicator for whether the patient was treated with
PRT or IMRT. Because Mahalonobis matching takes into account
all known variables simultaneously to match appropriate IMRT
patients with PRT patients, there were slight imbalances between
individual variables after the matching. Therefore each model was
conditioned on the matched grouping and adjusted for factors that
were not perfectly balanced between groups (age, race,
comorbidity, and use of ADT).
All analyses were performed using SAS version 9.2 (SAS
Institute Inc., Cary, NC), Stata version 12.1 (StataCorp, College
Station, TX), and ArcMap version 10 (ESRI, Redlands, CA).
Patterns of Care and Costs
We identified 27,647 patients who received either IMRT
(n = 27,094; 98.0%) or PRT (n = 553; 2.0%) during the study period
(Table 1). Patients who were aged 66 to 69 years were three times as
likely to receive PRT than those aged 85 to 94 years (3.3% vs 1.0%;
P < .001). White patients were more likely to receive PRT than black
patients (2.2% vs 0.5%; P < .001). Patients with no comorbidity
were statistically significantly more likely to receive PRT than those
with three or more comorbidities (2.6% vs 0.8%; P < .001). Patients
who received ADT were less likely to have received PRT than those
who did not receive ADT (1.0% vs 2.9%; P < .001).
In the adjusted analysis, patients who were younger, white, and
had less comorbidity were more likely to receive PRT (Table 2)
than others. Geographically, patients from more affluent areas and
from states not requiring a certificate of need were more likely to
receive PRT. No HRR-level characteristics were associated with
receipt of PRT. Patients who received an influenza vaccination in
the 9 months prior to treatment were also less likely to receive PRT
than those who did not receive an influenza vaccination (odds ratio
[OR] = 0.63, 95% confidence interval [CI] = 0.52 to 0.78).
Patients living closest to (<75 miles) and furthest from (>500
miles) a PRT center were more likely to receive PRT than those
living 75 to 500 miles from a center (4.9% and 4.2%, respectively,
compared with 1.5% for 75–500 miles; P < .001). Patients traveled
substantial distances to undergo PRT treatment (Figure 1).
Approximately 25% of patients undergoing PRT traveled less than
75 miles and 15% traveled more than 500 miles for treatment.
The median amount reimbursed by Medicare was $32,428
(IQR = $31,265–$34,189) for PRT patients and $18,575 (IQR =
$14,911–$23,022) for the matched group of IMRT patients.
Comparison of Toxicity
There were 421 PRT patients matched with 842 IMRT controls
for the analysis of 6-month toxicity and 314 PRT patients matched
with 628 IMRT controls for the analysis of 12-month toxicity.
The samples were well matched for sociodemographic
characteristics, comorbidities, and ADT use, with the bivariate P value for
independence for each variable ranging from .86 to 1.00 (Table 1;
results shown for the 12-month toxicity sample only, results were
consistent for the 6-month sample). The rate of cumulative
genitourinary toxicity at 6 months was 9.5% for IMRT vs 5.9% for
PRT, a statistically significant difference (Table 3) (OR = 0.60, 95%
CI = 0.38 to 0.96; P = .03). However, at 12 months post-treatment,
cumulative genitourinary toxicity was no longer statistically
significantly different between treatment groups (IMRT = 17.5%
vs PRT = 18.8%; OR = 1.08, 95% CI = 0.76 to 1.54; P = .66).
Gastrointestinal toxicity at 6 months was 3.6% vs 2.9% for IMRT
vs PRT (OR = 0.84, 95% CI = 0.42 to 1.66; P = .61) and 10.2% vs
9.9% at 12 months (OR = 0.97, 95% CI = 0.61 to 1.53; P = .89).
Other toxicity was 2.5% vs less than 2.6% for IMRT vs PRT at
6 months (OR = 0.69, 95% CI = 0.29 to 1.66; P = .41) and 5.6%
vs 4.5% at 12 months (OR = 0.78, 95% CI = 0.41 to 1.50; P = .46).
A more-precise estimate of the rate of 6-month other toxicity
for PRT is not reportable because the Centers for Medicare and
Medicare Services prohibits the description of groups of less than
11 patients. This prohibition also prevents us from describing
complication rates for individual complication codes.
Although prostate cancer treatment with PRT was roughly 70%
more expensive than IMRT, we found only a modest associated
reduction in genitourinary toxicity for patients undergoing PRT
compared with IMRT at 6 months post-treatment and no
difference at 12 months. Gastrointestinal and other toxicity were not
statistically significantly different for PRT compared with IMRT
at either 6 or 12 months post-treatment.
We found that many patients traveled substantial distances to
undergo PRT. In fact, some patients traveled past one PRT center,
sometimes in their home state, to receive treatment at a more
distant PRT center. Because PRT treatment involves 7 to 9 weeks
of daily treatment, such travel often involves relocating for the
duration of the treatment, so patients may incur substantial
outof-pocket costs. This is perhaps an extreme example of an indirect
cost associated with cancer care (
). Thus, the adoption pattern
of PRT reflects a tiered system of access to cancer care; one level
involving most Americans who travel locally for cancer care, and
another level where a select group of patients can afford to travel
nationally to obtain the treatments that are perceived to be “best.”
The long distances traveled by some patients highlight the
importance of examining a national sample. The Chronic Condition
† P value calculated using χ2 test. All P values are two-sided.
Year of treatment
Residence in metro county
Median household income
Distance to nearest proton center, miles
Receipt of androgen deprivation therapy
Flu shot (9 months prior to start of radiation)
Visit to primary care physician (9 months prior
to start of radiation)
Health system characteristics
State certificate of need for radiation facility
Discharges for ambulatory care sensitive
conditions per 1000 Medicare enrollees
Acute care hospital beds per 1000 residents
Primary care providers per 100,000 residents
Radiation oncologists per 100,000 residents
* All odds ratios restricted to patients with known hospital referral region and metro status. CI = confidence interval; — = no 95% CI for referent values.
† Wald P value. All P values are two-sided.
Warehouse includes comprehensive Medicare claims for all
enrollees nationwide with prostate cancer. Therefore, in contrast with
prior studies (
), we were able to include six treatment facilities
rather than a single center.
Regarding toxicity, it is plausible that differences between PRT
and IMRT would be limited to early genitourinary side effects. In
prior studies, the only improvement in radiation dose distribution
for PRT compared with IMRT was a reduction in the amount of
bladder exposed to low and intermediate levels of radiation (
Because the amount of bladder exposed to low doses of radiation
predicts early toxicity (
), the reduction of radiation to the
bladder may be responsible for the transient improvement in 6-month
toxicity associated with PRT.
Our findings on toxicity should be considered in conjunction
with our findings on cost. We found that Medicare’s
reimbursement per patient for PRT was 1.7 times that of IMRT. The relative
reimbursement of new medical technologies needs to be
considered carefully so that physicians and hospitals do not have a
financial incentive to adopt a technology before supporting evidence is
There were several limitations to our study, including the lack
of some treatment-related information and patient-reported
outcome data. We do not know radiation dose and field size; it is
possible that IMRT patients may have received a higher dose or nodal
radiotherapy, which could explain the increase in 6-month toxicity.
Furthermore, the grading of toxicity is unreliable using Medicare
claims. Our analysis detected moderate to severe toxicities that
often required direct medical intervention. As a result, our analysis
was relatively specific in its detection of toxicity. Unfortunately, we
were unable to reliably detect milder and more common toxicities
from treatment, such as mild to moderate proctitis or cystitis that
did not require medical intervention. Therefore, it is possible that
PRT may reduce these more mild to moderate toxicities compared
with IMRT. Prospective studies of quality of life based on
patientreported outcomes are also needed in order to fully evaluate whether
the increased expense of new radiation technologies is justified.
Although we excluded patients with a diagnosis of metastatic
disease, other staging data were not available. Only 12 months of
follow-up were available, so further analyses of longer-term
outcomes concerning both toxicity and cancer control are warranted.
In addition, patients were not randomized; however, the large pool
of controls allowed us to match PRT patients very closely with
respect to observed risk factors.
Our study investigated a comprehensive and clinically relevant
set of procedure and diagnosis claims to assess toxicity. Because the
complication rate from IMRT has been reportedly low (
), we felt
that a method of measuring complications that erred on the side of
sensitivity was required to truly assess for any subtle differences in
Although we were unable to adjust for unknown risk factors, any
bias that may not have been accounted for in our analysis is likely to
be in favor of PRT. For example, IMRT sometimes involves
radiation to the entire pelvis, whereas PRT involves only treatment of
the prostate. Thus, the patients in our study who underwent IMRT
were more likely to receive regional radiation, placing them at
increased risk for toxicity (
). Because PRT is performed in only
a few medical centers, there is perhaps more uniform technique,
including the use of prostate and rectal immobilization with an
endorectal balloon. IMRT is widely performed, potentially
increasing the variability of treatment, which may increase the likelihood
for treatment-related toxicity.
Therefore, our finding of a modest and transient benefit to the
use of PRT compared with IMRT for prostate cancer indicates
that the likelihood of a true clinically significant benefit with the
use of PRT is low in this population. Nonetheless, prospective,
randomized trials are needed to confirm our finding of transient
improvement in toxicity with PRT compared with IMRT without
a long-term effect.
This study represents the most robust comparison of early
toxicity for PRT vs IMRT for prostate cancer to date. In a national
sample of Medicare beneficiaries, PRT was rare and expensive and
was associated with only a modest and transient reduction in
genitourinary toxicity. Continued longitudinal study of the
comparative effectiveness of PRT compared with IMRT is needed before
widespread application of PRT for prostate cancer can be justified.
This work was supported by the National Cancer Institute, National Institutes of
Health (R01CA149045). JBY is also supported by CTSA grant KL2 RR024138
from the National Center for Advancing Translational Science (NCATS), a
component of the National Institutes of Health (NIH), and NIH Roadmap for
The study sponsor (NIH) did not play a role in the design of the study; the
collection, analysis, or interpretation of the data; the writing of the manuscript; or
the decision to submit the manuscript for publication. The content is solely the
responsibility of the authors and does not necessarily represent the official views
of the National Institutes of Health.
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