Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer.

Abstract

We report on the long-term results and late toxicity outcomes of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer.
Between 1996 and 2000 a total of 561 patients with clinically localized prostate cancer were treated with intensity modulated radiation therapy. All patients were treated to a dose of 81 Gy prescribed to the planning target volume. Prostate specific antigen relapse was defined according to the American Society for Therapeutic Radiology and Oncology consensus and Houston definitions (absolute nadir plus 2 ng/ml dated at the call). Median followup was 7 years (range 5 to 9).
The 8-year actuarial PSA relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the American Society for Therapeutic Radiology and Oncology definition were 85%, 76% and 72%, respectively (p <0.025). The 8-year actuarial prostate specific antigen relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the Houston definition were 89%, 78% and 67%, respectively (p = 0.0004). The 8-year actuarial likelihood of grade 2 rectal bleeding was 1.6%. Three patients (0.1%) experienced grade 3 rectal toxicity requiring either 1 or more transfusions or a laser cauterization procedure. No grade 4 rectal complications have been observed. The 8-year likelihood of late grade 2 and 3 (urethral strictures) urinary toxicities were 9% and 3%, respectively. Among patients who were potent before intensity modulated radiation therapy, erectile dysfunction developed in 49%. The cause specific survival outcomes for favorable, intermediate and unfavorable risk cases were 100%, 96% and 84%, respectively.
These long-term results confirm our previous observations regarding the safety of high dose intensity modulated radiation therapy for clinically localized prostate cancer. Despite the application of high radiation doses, the incidence of rectal bleeding at 8 years was less than 2%. Despite the increased conformality of the dose distribution associated with intensity modulated radiation therapy, excellent long-term tumor control outcomes were achieved.

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Long-Term Outcome of High Dose
Intensity Modulated Radiation Therapy
for Patients With Clinically Localized Prostate Cancer
Michael J. Zelefsky,*,† Heather Chan,† Margie Hunt,† Yoshiya Yamada,‡ Alison M. Shippy† and
Howard Amols†
From the Departments of Radiation Oncology (MJZ, HC, YY) and Medical Physics (MH, HA), Memorial Sloan-Kettering Cancer Center,
New York, New York
Purpose: We report on the long-term results and late toxicity outcomes of high dose intensity modulated radiation therapy
for patients with clinically localized prostate cancer.
Materials and Methods: Between 1996 and 2000 a total of 561 patients with clinically localized prostate cancer were
treated with intensity modulated radiation therapy. All patients were treated to a dose of 81 Gy prescribed to the planning
target volume. Prostate specific antigen relapse was defined according to the American Society for Therapeutic Radiology and
Oncology consensus and Houston definitions (absolute nadir plus 2 ng/ml dated at the call). Median followup was 7 years
(range 5 to 9).
Results: The 8-year actuarial PSA relapse-free survival rates for patients in favorable, intermediate and unfavorable risk
groups according to the American Society for Therapeutic Radiology and Oncology definition were 85%, 76% and 72%,
respectively (p ?0.025). The 8-year actuarial prostate specific antigen relapse-free survival rates for patients in favorable,
intermediate and unfavorable risk groups according to the Houston definition were 89%, 78% and 67%, respectively
(p ? 0.0004). The 8-year actuarial likelihood of grade 2 rectal bleeding was 1.6%. Three patients (0.1%) experienced grade 3
rectal toxicity requiring either 1 or more transfusions or a laser cauterization procedure. No grade 4 rectal complications have
been observed. The 8-year likelihood of late grade 2 and 3 (urethral strictures) urinary toxicities were 9% and 3%,
respectively. Among patients who were potent before intensity modulated radiation therapy, erectile dysfunction developed
in 49%. The cause specific survival outcomes for favorable, intermediate and unfavorable risk cases were 100%, 96% and 84%,
respectively.
Conclusions: These long-term results confirm our previous observations regarding the safety of high dose intensity
modulated radiation therapy for clinically localized prostate cancer. Despite the application of high radiation doses, the
incidence of rectal bleeding at 8 years was less than 2%. Despite the increased conformality of the dose distribution associated
with intensity modulated radiation therapy, excellent long-term tumor control outcomes were achieved.
Key Words: radiotherapy, intensity-modulated; prostatic neoplasms; toxicity
E
clinically localized prostate cancer. These studies have pro-
vided convincing evidence for improved tumor control out-
comes with the application of higher radiation dose levels.1–9
Based on published reports it appears that dose levels of at
least 78 Gy, and likely even higher, are necessary to achieve
optimal tumor control outcomes. One of the significant lim-
itations of high dose radiotherapy delivery has been the
potential for an increased risk of long-term morbidity. Sev-
eral studies have confirmed increased risks of urinary and
rectal toxicities with the use of higher radiation doses.10–12
nhanced methods of delivering external beam radia-
tion doses in a highly precise fashion have paved the
way for dose escalation trials in the treatment of
In a report of the outcomes of the phase III randomized trial
from MD Anderson Hospital, among those patients who
received the 78 Gy dose, the 5-year incidence of grade 2 to 3
rectal toxicity was 25%. In addition, chronic proctitis was
more likely when an increased volume of the rectum was
exposed to these higher dose levels.11
We introduced intensity modulated radiation therapy in
1996 at our institution to facilitate dose escalation therapy
by further enhancing the conformality of the dose distribu-
tion around the tumor target, and reducing the volume of
rectum and bladder exposed to high doses of radiotherapy.
In our initial experience we observed substantially lower
rectal dose levels when IMRT treatment planning was used
compared to 3D-conformal treatment planning. With 2-year
followup observations we noted a significant reduction in the
Submitted for publication November 10, 2005.
* Correspondence and requests for reprints: Department of Radi-
ation Oncology, Memorial Sloan-Kettering Cancer Center, 1275
York Ave., New York, New York 10021 (telephone: 212-639-6802;
FAX: 212-639-8876; e-mail: zelefskm@mskcc.org).
† Nothing to disclose.
‡ Financial interest and/or other relationship with Varian Medi-
cal.
Editor’s Note: This article is the third of 5 published in
this issue for which category 1 CME credits can be
earned. Instructions for obtaining credits are given
with the questions on pages 1690 and 1691.
0022-5347/06/1764-1415/0
THE JOURNAL OF UROLOGY®
Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 176, 1415-1419, October 2006
Printed in U.S.A.
DOI:10.1016/j.juro.2006.06.002
1415

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rectal bleeding rates among patients receiving IMRT treated
to 81 Gy compared to a similar cohort treated to the same
dose level with 3D-CRT.13,14
The current report represents to our knowledge the first
description of long-term biochemical outcome and tolerance
of high dose radiotherapy using IMRT for localized prostate
cancer. Our results demonstrate that this highly conformal
form of radiotherapy delivery continues to be associated
with excellent long-term tolerance outcomes and biochemi-
cal control rates. These data indicate that IMRT is the
optimal form of external beam treatment delivery when high
dose radiotherapy is required.
METHODS AND MATERIALS
Between April 1996 and January 2000, 561 patients with
clinically localized prostate cancer were treated with IMRT.
Their median age was 68 years (range 46 to 86). Pretreatment
diagnostic evaluations were performed as previously de-
scribed.14The clinical characteristics are shown in table 1.
Simulation and immobilization in the prone position were
performed as previously described.3A 1.0 cm margin was
contoured around the computerized tomography identifiable
prostate tissue, extending from the apex of the prostate to
the superior aspects of the seminal vesicles, except posteri-
orly of the interface with the reaction, where a 0.6 cm mar-
gin was used.
The techniques for treatment planning, delivery and
quality assurance for IMRT have been described in detail
elsewhere.3,14In general an isocentric 5-field technique was
used and treatments were planned with an inverse optimi-
zation algorithm. Parameters used for optimization included
the specified dose to the PTV, the dose limits for each of the
critical normal tissue structures, and the respective penal-
ties for deviation from these criteria. The treatment plan-
ning goals defining an acceptable dose distribution included
dose homogeneity within 10% (100% to 110% of the prescrip-
tion) for all regions of the PTV excluding the prostate-rectal
overlap and a maximum dose to the rectal wall of approxi-
mately 81 to 82 Gy. The rectal wall volume exceeding 75.6
Gy and 47 Gy was limited to 30% and 53%, respectively.
Similar constraints were applied to the bladder wall. Inten-
sity profiles of the 5 IMRT beams generated by the treat-
ment planning system were used for calculation of the dose
distribution. The desired beam intensity profiles were deliv-
ered by DMLC using the sliding window technique.
Treatment was delivered with 15 MV x-rays in daily
fractions of 1.8 Gy. All patients were treated to a dose of 81
Gy prescribed to the planning target volume. In general, less
than 5% of the PTV received less than 81 Gy (77 to 81 Gy),
and this lower dose area was confined to the prostate-rectal
overlap region where a tighter dose constraint was applied.
In general, less than 5% of the PTV received less than 81 Gy
(77 to 81) and this lower dose area was confined to the
prostate-rectal overlap region where a tighter dose con-
straint was applied. Typically 85% (75% to 99%) of the
prescription dose was delivered to 99% of the complete PTV
volume (including the overlap region).
Portions of the target including the isocenter (Interna-
tional Commission of Radiation Units prescription point)
received up to 10% higher than the 81 Gy prescription dose
level. Before IMRT a total of 296 patients (53%) were treated
with short course (3-month) androgen deprivation therapy
to decrease the size of the prostate. In general ADT was
given to those patients with large volume prostate glands for
pretreatment volume reduction or those with high risk pre-
treatment prognostic features including patients with Glea-
son 8 disease (table 1). ADT was discontinued at the com-
pletion of radiotherapy.
Followup evaluations after treatment were performed at
intervals of 3 to 6 months for 5 years. The median followup
time was 7 years (range 5 to 9). Late toxicity was scored
according to the National Cancer Institute Common Ter-
minology Criteria for Adverse Events toxicity scale. Dis-
ease status was determined as of the time of analysis in
September 2005. A PSA relapse was defined according to
the ASTRO consensus definition (3 successive PSA increases
after a post-treatment nadir was achieved)15and according
to the Houston definition (absolute nadir plus 2 ng/ml dated
at the call).16None of the patients received post-irradiation
androgen deprivation or other anti-cancer therapy before
documentation of a PSA relapse.
Patients were classified into prognostic risk groups ac-
cording to the National Comprehensive Cancer Network
guidelines recurrence risk groups (www.nccn.org). Patients
were classified as having favorable risk with clinical stages
T1 to T2a, a Gleason score of 6 or less, and a pretreatment
PSA less than 10 ng/ml. Patients with the presence of clin-
ical stage T2b or T2c, a Gleason score of 7, or a pretreatment
PSA of 10 to 20 ng/ml were classified as having intermediate
risk disease. If patients had clinical stage T3a or higher, a
Gleason score 8 or greater, or a pretreatment PSA more than
20 ng/ml they were classified as having unfavorable risk
disease. Distributions of PSA relapse-free survival times
were calculated according to the product limit (Kaplan-
Meier) method. Differences between time adjusted incidence
TABLE 1. Patient characteristics
No. (%)
Age:
60 or Younger
Older than 60
T stage:
T1c-T2a
T2b-c
T3a-T3c
Gleason score:
6 or Less
7
8 or Greater
Prognostic risk group:
Low
Intermediate
High
Pretreatment ng/ml PSA:*
0–4
4–10
10–20
Greater than 20
NAAD in all pts:
No
Yes
NAAD in low recurrence risk group:
No
Yes
NAAD in intermediate recurrence risk group:
No
Yes
NAAD in high recurrence risk group:
No
Yes
74 (13)
487 (87)
425 (76)
101 (18)
35 (6)
301 (54)
208 (37)
52 (9)
203 (36)
255 (46)
103 (18)
62 (11)
338 (60)
116 (21)
45 (8)
265 (47)
296 (53)
133 (66.5)
67 (33.5)
124 (48)
136 (52)
8 (8)
93 (92)
* Median PSA 7.5 ng/ml.
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rates were evaluated using the Mantel log rank test for
censored data.
RESULTS
Biochemical Control
PSA relapse-free survival rates according to NCCN recur-
rence risk groups are shown in figure 1. Using the ASTRO
definition for biochemical relapse, the 8-year actuarial PSA
relapse-free survival outcomes for favorable, intermediate
and unfavorable risk group patients were 85%, 76% and
72%, respectively. When using our previously published risk
group classification system (Memorial Sloan-Kettering Can-
cer Center),3biochemical control rates were similar to the
rates observed using the NCCN classification. The 8-year
actuarial PSA relapse-free survival outcomes for favorable,
intermediate and unfavorable groups were 85%, 76% and
69%, respectively. Using the Houston definition for biochem-
ical relapse, the 8-year actuarial PSA relapse-free survival
outcomes for favorable, intermediate and unfavorable risk
group patients were 89%, 78% and 67%, respectively. When
using the Memorial Sloan-Kettering Cancer Center classifi-
cation system, biochemical control rates were comparable to
the biochemical control rates by NCCN classification. The
8-year actuarial PSA relapse-free survival for favorable, in-
termediate and unfavorable risk groups were 90%, 79% and
61%, respectively. In a Cox regression analysis the clinical
stage (stage less than T3 vs T3 or greater, p ?0.001) and the
pretreatment PSA (less than 10 ng/ml vs more than 10
ng/ml, p ? 0.02) were significant predictors for improved
long-term biochemical outcome. The Gleason score and the
use of short course ADT had no impact on the long-term
biochemical outcome in this cohort of patients (table 2).
Distant Metastases and Overall Survival Outcomes
Distant metastases developed in 17 (3%) patients. The
8-year actuarial likelihood of distant metastases develop-
ment for NCCN defined favorable, intermediate and unfa-
vorable risk patients were 1%, 5% and 4%, respectively
(favorable vs intermediate risk p ? 0.03; intermediate vs
unfavorable risk p ? 0.86). The cause specific survival out-
comes for favorable, intermediate and unfavorable risk pa-
tients were 100%, 96% and 84% (p ? 0.17), respectively.
Toxicity
Grade 2 rectal bleeding developed in 7 patients (1.5%) at a
median of 13 months after completion of IMRT. Grade 3
rectal toxicity developed in 3 patients (less than 1%) who
were treated with 1 or more transfusions or a laser cauter-
ization procedure. No grade 4 rectal complications have been
observed. The 8-year actuarial likelihood of late grade 2 or
greater rectal toxicity was 1.6% (fig. 2). Late grade 2 chronic
urethritis requiring medication for symptom control devel-
oped in 50 patients (9%) at a median of 14 months after
completion of IMRT. Urethral stricture requiring dilation
(grade 3) developed in 18 patients (3%). The 8-year actuarial
likelihood of late grade 2 or greater urinary toxicities was
15% (fig. 2).
Before the initiation of therapy 403 (72%) patients re-
ported the ability to maintain an erection sufficient for sex-
ual intercourse. In this group of patients ED developed in
49%. The addition of short-term ADT significantly increased
the risk of ED in these patients. The incidence of ED among
FIG. 1. A, ASTRO definition PSA relapse-free survival by NCCN
recurrence risk group. B, Houston definition PSA relapse-free sur-
vival by NCCN recurrence risk group.
FIG. 2. Actuarial likelihood of late grade 2 or greater rectal toxici-
ties and late grade 2 or greater urinary toxicities.
TABLE 2. Multivariate analysis on PSA relapse
Houston PSA RelapseASTRO PSA Relapse
Relative Riskp ValueRelative Risk p Value
T stage (greater than T2c vs T2c or less)
Gleason (8 vs less than 8)
Neoadjuvant hormonal therapy? (yes vs no)
Pre-radiotherapy PSA (greater than 10 vs 10 or less)
4.181976
Not significant
Not significant
2.183251
?0.0001
0.9634
0.8336
0.029
2.188387
Not significant
Not significant
Not significant
0.0286
0.4536
0.1289
0.2385
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patients treated with short-term ADT and IMRT was 57%
compared to 43% for those patients treated with IMRT alone
(p ? 0.006). Secondary cancer development was not observed
in these patients.
DISCUSSION
The long-term results in these patients further corroborate
the efficacy of high dose IMRT for patients with localized
prostate cancer and confirm this form of treatment delivery
to be associated with a superior tolerance profile compared
to what has been reported when using high dose radiother-
apy with first generation 3-dimensional conformal tech-
niques. Our long-term rectal bleeding rates of 1.5% are con-
sistent with IMRT achieving a high degree of conformality
with concomitant reduction of volume of normal tissues ex-
posed to higher radiation dose levels.
While there are currently no randomized trials compar-
ing IMRT to 3D-CRT or to other more conventional forms of
therapy, we believe the long-term data demonstrating effi-
cacy and safety in this report substantiate the role of IMRT
as a standard treatment intervention for patients with lo-
calized prostate cancer. IMRT is an enhanced form of 3D-
CRT and should not be considered a new or experimental
mode of radiotherapy delivery. The characteristics of the
IMRT beam are identical in physical and radiobiological
aspects to conventional megavoltage radiotherapy. Taking
advantage of enhanced technologies including DMLC and
inverse planning treatment software, IMRT allows the beam
to be targeted more precisely to the prostate with the ability
to expose less of the rectum and bladder to the higher doses
of radiation. Our study also dispels the notion that given the
tight dose distributions associated with IMRT, tumor under-
dose is potentially more likely a significant clinical consid-
eration. Despite the enhanced conformality of IMRT, our
results are consistent with excellent long-term biochemical
outcomes comparable to the best outcomes published with
3D-CRT for patients with similar recurrence risk character-
istics with less long-term morbidity.
Some have raised concerns that IMRT may be associated
with a higher incidence of secondary cancer development
due to the longer beam on times compared to what is used
for conventional external beam radiotherapy. Conservative
maximal estimates of induced fatal malignancies after
IMRT have been estimated by Kry et al to be 2 to 5 times
that of conventional treatment.17According to their study
IMRT treatment using 15 MV x-rays from a Varian acceler-
ator, as done at our institution, conferred an overall risk of
fatal second malignancy roughly twice that of conventional
treatment with 18 MV x-rays. This risk estimate is based on
measured and calculated photon and neutron out-of-field
dose equivalents, explicitly excluding sarcomas, rectal or
bladder malignancies occurring within the treated volume.
However, preliminary calculations for our typical 5-field 15
MV 81 Gy prostate IMRT portal arrangement have demon-
strated that the improved dose conformality can lead to
integral doses within the irradiated volume that are compa-
rable to a 4-field 75.6 Gy conventional external beam ar-
rangement and significantly lower than a 75.6 Gy 6-field
3D-CRT arrangement.18The commensurate decrease in rec-
tal, bladder and bone doses should translate, in fact, to a
lower risk of induced malignancies in these organs. To date
we have not observed secondary cancer development in this
patient population; however, longer followup beyond 10
years will be necessary to confirm these findings and estab-
lish the presence or absence of any deleterious effect of the
increased neutron dose.
IMRT with the increased labor intensity necessary for
quality assurance and treatment verification for implemen-
tation and treatment delivery has been associated with ex-
cellent long-term biochemical outcomes and minimal long-
term toxicities. With emerging studies continuing to
demonstrate improved outcomes with higher radiation
doses, IMRT would represent the modality of choice for
external beam high dose radiotherapy delivery.
CONCLUSIONS
These long-term results indicate that high dose IMRT is
associated with minimal long-term toxicities and excellent
biochemical outcomes. As studies have continued to demon-
strate significant improvement in tumor control outcomes
for favorable, intermediate and unfavorable risk prostate
cancer using higher radiation doses, IMRT represents the
safest way of delivering high dose external beam radiother-
apy. However, with a highly conformal dose distribution, the
implications of prostate motion take on greater importance
and issues of tumor under-dose must be considered. Based
on the acceptable biochemical outcomes we have observed in
these patients, it would appear that the margins of normal
tissue we routinely use are sufficient to encompass the clin-
ical target volume and the potential for motion. New image
guided cone beam online imaging techniques, which we have
adopted into clinical practice, will likely enhance our target
precision further and facilitate reduction of the clinical tar-
get volume margins currently in practice. Such approaches
will likely pave the way for implementation of hypofraction-
ated short course treatment regimens which may be equally
effective and as safe as the current protracted 9 to 10-week
treatment regimens currently administered to patients with
prostate cancer.
Abbreviations and Acronyms
?
androgen deprivation therapy
?
American Society for Therapeutic
Radiology and Oncology
?
3-dimensional conformal radiation
therapy
?
dynamic multi-leaf collimation
?
erectile dysfunction
?
International Commission of Radiation
Unit
?
intensity modulated radiation therapy
?
neoadjuvant androgen deprivation
?
National Comprehensive Cancer
Network
?
prostate specific antigen
?
primary target volume
ADT
ASTRO
3D-CRT
DMLC
ED
ICRU
IMRT
NAAD
NCCN
PSA
PTV
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