The Role of External-Beam Radiation Therapy in the Treatment of Clinical
Localized Prostate Cancer

Javier F. Torres-Roca, MD

Cancer Control.  2006;13(3):188-193.  ©2006 H. Lee Moffitt Cancer Center and
Research Institute, Inc.
Posted 08/29/2006

Abstract and Introduction

Abstract

Background: The treatment of clinically localized prostate cancer is
controversial. Options include radical prostatectomy, external-beam
radiation therapy (EBRT), brachytherapy, cryotherapy, and watchful waiting.

Methods: The author reviews EBRT as treatment for clinically localized
prostate cancer, with particular emphasis on the technological advances
that have allowed dose escalation and fewer therapy-related side effects.

Results: Technological advances in the last two decades have significantly
improved the delivery of EBRT to the prostate. This has resulted in an
overall increase in the total dose that can be safely delivered to the
prostate, which has led to modest improvements in biochemical outcome. An
alternative approach of combining androgen suppression therapy and EBRT has
also been successful in improving clinical outcomes. However, establishing
the optimal therapy for prostate cancer remains controversial.

Conclusions: Recent progress has led to improvements in clinical outcomes in
patients treated with EBRT for prostate cancer. It is hoped that the next
decades will bring continued advances in the development of biologicals
that will further improve current clinical outcomes.

Introduction

In 2006, approximately 234,460 American men will be diagnosed with prostate
cancer.[1] One of the first challenges they will face is the decision of
how to treat their disease. A number of options are available to the vast
majority of men with newly diagnosed prostate cancer, including surgery,
external-beam radiation therapy (EBRT), brachytherapy (BT), cryotherapy,
androgen suppression therapy (AST), expectant management, or some
combination of these treatments. This review focuses on the role of EBRT in
patients with clinically localized prostate cancer.

Technological Advancements in Radiation Dose Delivery: From Two-Dimensional
Radiotherapy to Image-Guided Radiotherapy

In the last two decades, technological improvements in the delivery of EBRT
have improved the ability of radiation oncologists to target radiation to
the prostate while more efficiently sparing the surrounding normal tissue
[2] These improvements were initially achieved by integrating
three-dimensional (3D) anatomical information into the radiation therapy
planning process. Treatment planning utilizing 3D conformal radiotherapy
(CRT) permitted the 3D visualization of both the target and the normal
tissue, allowing for the planning of treatment techniques that conform the
dose to the target while sparing the normal tissue. The next step came with
the development of intensity-modulated radiation therapy (IMRT).[3] With
IMRT, further sparing of normal tissue is achieved by modulating the
intensity of the beam across the different fields of radiation being
delivered. Prior to IMRT, radiation oncologists chose and designed the
treatment fields to be utilized in the treatment process.[3] This resulted
in a uniformity of the technique used for patients with a particular
disease. For example, patients with prostate cancer were classically
treated with a four-field technique combining four radiation ports that
were delivered from the front, the back, and both sides of the patient. The
development of CRT provided more options in terms of the field arrangements
that would achieve the desired goals. Using CRT, both the target and normal
tissue are contoured, which allows physicians to better customize treatment
fields. However, in IMRT, the concept of inverse-treatment planning was
introduced whereby the physician no longer chooses and designs the
treatment fields. The responsibility of the radiation oncologist lies in
contouring both the radiation therapy target volumes and the normal tissue
that needs to be spared. The radiation oncologist also establishes a set of
dose constraints for each target and normal tissue volume. A computer
algorithm calculates the most effective way to physically deliver the
radiation and achieve the desired goals.[3]

As the ability to conform radiation dose to the prostate improved, many
studies reported the clinical significance of prostate motion in the
setting of 3D CRT.[4] Movement occurs primarily in the anterior-posterior
direction, although it also occurs in the superior-inferior and lateral
directions.[5-7] To address these concerns, a number of daily prostate
localization techniques have been developed. A common technique utilizes a
transabdominal ultrasound to daily localize the prostate during the
delivery of a fractionated course of radiotherapy.[8-10] Other approaches
involve imaging implanted radio-opaque fiducial markers[11,12] and using
daily computed tomography (CT).[13-15] The ability to image the position of
the prostate on a daily basis has allowed the development of image-guided
radiotherapy (IGRT), where imaging has helped to reduce set-up errors
caused by organ motion and thus has improved the overall accuracy of
treatment. The current development and integration of megavoltage cone beam
CT technology into the design of linear accelerators will play a major role
in IGRT.[14-17]

Clinical Benefits of Dose Escalation

Investigators at the M.D.Anderson Cancer Center were among the first to
recognize the potential clinical benefits of increasing the radiation dose
to the prostate. A principal rationale for increasing doses to the prostate
stemmed from postradiation biopsy studies that showed a high incidence of
positive prostate biopsies in patients treated with standard doses (70 Gy
or less) of radiation therapy.[18-24] Pollack et al[25,26] published the
first prospective, randomized trial that supported a role for dose
escalation in patients with clinically localized cancer ( Table 1 ). They
randomized 305 patients to receive either standard dose (70 Gy/35 fx) or
high-dose (78 Gy/39 fx) EBRT. At a median follow-up of 60 months, there was
an absolute benefit of 6% in improvement of 5-year biochemical failure-free
survival. Further evidence supporting the benefits of dose escalation was
provided by a randomized phase III collaborative study[27] between
Massachusetts General Hospital and Loma Linda University. In this study,
protons were used to deliver a portion of the treatment in all patients.
Patients randomized to the standard dose arm received a standard-dose
equivalent to 70.2 Gy, while patients randomized to the experimental arm
received a dose equivalent to 79.2 Gy. At 5.5 years of median follow-up,
the patients who received 79.2 Gy had a superior biochemical failure-free
survival rate (80.4%) compared with patients treated in the standard arm
(61.4%, P < .001). A study by Sathya et al[28] has also shown a modest
improvement in biochemical failure rates by dose escalation. In their
approach, dose escalation was achieved by using a temporary interstitial
iridium implant. In summary, all three studies showed a modest improvement
in biochemical outcomes in clinically localized prostate cancer. However,
none has shown an improvement in overall or disease-specific survival.
Dose Escalation: Is Brachytherapy Superior?

It could be argued that conceptually, brachytherapy (BT) provides the most
"conformal" of all radiation delivery techniques.[29,30] The placement of
radioactive sources either permanently (iodine-125 or palladium- 103 or
temporarily (iridium-192) in the prostate allows the maximal sparing of the
surrounding normal tissue while concentrating the dose on the target. As
with EBRT, modern techniques of BT have been refined in the last 15 years
with the introduction of transrectal ultrasound and template guidance as
well as 3D volumetric treatment planning.[29,31] Although no prospective,
randomized study comparing BT to EBRT has been reported, most retrospective
series suggest similar prostate cancer outcomes for both therapeutic
approaches.[32-35] Others have argued that BT in combination with
supplemental pelvic radiotherapy may be the most effective approach when
using BT. Several retrospective and mature series have been published
showing excellent results for the combination approach.[36-38]

The belief that EBRT and BT have similar clinical outcomes has recently been
questioned. Pickett et al[39] studied the effect of both EBRT and BT on
normal prostate metabolism using magnetic resonance spectroscopy.
Interestingly, these authors reported that patients treated with BT had a
higher rate of complete metabolic atrophy than those treated with EBRT (60%
vs 40%, respectively), suggesting that BT is biologically more efficient in
abolishing normal prostate metabolism. Although their endpoint was not
prostate cancer control, these intriguing observations strongly suggest
that the biological effect of both techniques is different. Whether this
improved efficiency in abolishing metabolism will translate into better
cancer control is currently being studied. However, it is important to note
that in this study patients did not undergo daily prostate localization
during the delivery of EBRT. Therefore, it could be argued that some of
these patients could have been underdosed during EBRT as a consequence of
the natural movement of the prostate. This is not an issue with BT because
these patients underwent postimplant dosimetry to confirm coverage; it
could be argued that low-dose regions in the EBRT patients could account
for the difference in the complete metabolic atrophy rate.

AST in Low- and Intermediate-Risk Clinically Localized Prostate Cancer

For more than 60 years,AST has played a central role in the clinical
management of prostate cancer. Although the role of AST in metastatic
disease, as well as in high-risk patients with clinically localized
disease, is well established,[40-46] its role in patients with intermediate
and low-risk prostate cancer is more controversial. Table 2 presents the
definitions of risk groups. Four prospective, randomized trials, all using
standard doses of 70 Gy or less, have demonstrated that patients with
high-risk clinically localized prostate cancer derive a clear clinical
benefit from the use of long-term AST (at least 2 years) in conjunction
with EBRT ( Table 3 ).[41,42,44-46] Several investigators have studied
whether intermediate- risk prostate cancer patients also derive a benefit
from the combination of AST and EBRT.[47-49] A recent phase III
prospective, randomized study by D'Amico et al[47] showed an improvement in
5-year survival rate in patients treated with complete AST for 6 months
plus standard EBRT (70 Gy) when compared to patients treated with standard
EBRT alone (88% vs 78%, respectively, P = .04). Eligible patients included
patients with a prostate-specific antigen (PSA) of at least 10 ng/mL or a
Gleason score of at least 7. Although the study was designed before the
development of the risk stratification criteria, all of these patients
would have been grouped in either the intermediate- or high-risk stratum.
The only other trial examining EBRT alone vs EBRT plus AST showed an
improvement in biochemical control ( Table 4 ).[48] The other trials in
this risk stratum addressed the length of AST as well as the sequence of
AST and EBRT.[48,50,51] Although the clinical benefit of AST in high-risk
prostate cancer has been previously established, these trials suggest that
AST in conjunction with EBRT may result in therapeutic benefit in
intermediate- risk patients as well.

AST Plus EBRT or Dose Escalation in Intermediate- and Low-Risk Prostate
Cancer

Determining the best therapeutic approach for patients with low-risk and
intermediate-risk prostate cancer remains a subject of great debate among
radiation oncologists. It is likely that no single approach is best for all
patients. The use of AST is associated with an increase in treatment
morbidity, particularly sexual side effects.[40] Therefore, it is important
that AST is used when treatment is more likely to influence cancer
outcomes. Since there is no randomized trial in intermediate- or low-risk
patients that has addressed whether dose escalation is equivalent or
superior to short-term AST plus standard EBRT, this area will continue to
be controversial. However, an analysis of the features of the
dose-escalating trials as well as the D'Amico trial shows that there are
some differences in both eligibility criteria and clinical outcome. In the
trial by D'Amico et al,[47] 59% of patients showed a Gleason score of 7
compared to 33% and 15% in the trials by Pollack et al[25,26] and Zietman
et al,[27] respectively. Furthermore, the D'Amico trial included patients
with a PSA level of up to 40 ng/mL. Therefore, the populations of these
trials represent different overall risk groups in prostate cancer, with the
Zietman and Pollack trials including patients who would have been
classified mainly in the low-risk and intermediate-risk strata and the
D'Amico trial with patients mainly in the intermediate- or high-risk
strata. Furthermore, all dose escalation trials showed modest improvements
in the biochemical control of the disease but no difference in
disease-specific or overall survival. In contrast, the D'Amico trial showed
an improvement in 5-year overall survival with the addition of 6 months of
complete AST. This suggests that the effect of dose escalation and AST may
be different. It could be speculated that dose escalation appears to be
critical in patients with low risk for micrometastatic disease at the time
of treatment. Since most of these patients would not die of prostate cancer
in the first decade after diagnosis, one would not expect any therapeutic
intervention to affect either disease-specific or overall survival. In
contrast, in the D'Amico trial,AST was shown to affect overall survival at
5 years, suggesting that at least part of its effect is in altering the
natural history of micrometastatic disease. Therefore, it could be argued
that since a significant proportion of patients with intermediate-risk
disease are also at risk of micrometastatic disease as well, short-term AST
in conjunction with EBRT should be considered as an important option in
their clinical management.

Conclusions and Future Directions

The previous two decades have brought great technological innovations in the
field of radiation oncology. The development of more precise radiation
planning and delivery methods has improved our ability of targeting
radiation dose to the prostate,which has resulted in significant clinical
benefit. Technological innovations will continue in the near future with
the development of four-dimensional treatment planning systems that will
allow further refinements in radiation delivery and planning techniques.
However, some of the biggest strides in prostate cancer therapeutics will
probably come from biological innovations that will allow more precise
definitions of clinical risk groups through the use of genomics and
proteomics technology. Furthermore, it is hoped that a better understanding
of prostate cancer biology will lead to the development of better imaging
modalities and to the development of biological modifiers of radiation
response.

LINK --> www.medscape.com/viewarticle/542997_print