The management of patients with locally
advanced prostate cancer remains a significant therapeutic
challenge.[1-13] Although radiation therapy has been the traditional
curative treatment option for these patients for the past 2 decades,
the ability of standard doses of external-beam radiation alone to
cure patients has recently been questioned. Prior to the use of post-radiation
prostate-specific antigen (PSA) testing, most studies of radiation
therapy for locally advanced prostate cancer reported clinical local
control rates in the range of 75% at 10 years. However, recent
studies employing PSA monitoring, ultrasound-guided follow-up
biopsies, and longer follow-up have made it clear that only 10% to
20% of patients treated with external-beam radiation doses of 65 to
70 Gy are free of recurrence at 5 years.[15,16]
Multiple factors are responsible for the suboptimal control rates
reported in the past for locally advanced prostate cancer, but two
factors are most important. First, locally advanced cancers are
generally bulky tumors that have a statistically lower likelihood for
cure with conventional doses of radiation. This is clearly
exemplified by studies employing post-treatment biopsies, in which
75% to 80% of patients with increasing PSA levels had persistent
disease in their prostate. The inability to cure all of these
cancers with conventional external-beam radiation therapy may be
related, in part, to regions of hypoxia in these higher-grade,
bulkier tumors or, possibly, their inherent radioresistance.
Second, although patients with locally advanced prostate cancer may
be judged, both clinically and radiographically to have only
locoregional disease, the probability that occult micrometastatic
disease exists at the time of diagnosis has been clearly shown in
multiple studies.[18,19] As a result, several ongoing trials are
investigating whether some of these patients should be treated with
systemic therapy (in the form of androgen deprivation) in combination
with local treatment.[16,20-25] Already, substantial preliminary data
suggest that combined-modality therapy may provide significant
improvements not only in local, regional, and biochemical control but
also in disease-free and overall survival (Table
Irrespective of the impact androgen deprivation may have on improving
various outcome measures, local disease control within the gland
still remains a fundamental therapeutic goal. Data from the
experience with iodine-125 implants at Memorial Sloan-Kettering
Cancer Center indicates that persistent local cancer can lead to
dissemination or death in patients whose disease would otherwise have
been controlled.[26-28] In recognition of this fact, a series of
clinical trials employing several radiotherapeutic techniques have
been initiated to address this issue (see below). Central to all of
these strategies is the premise that there is a direct relationship
between the delivered radiation dose and the probability of tumor
control. Both older and more recent data clearly support this concept.
Recent investigations of conformal external-beam radiation
therapy,[12,29-34] high-energy neutrons, [7,35,36] hyperfractionated
radiation therapy, particle beam therapy,[38,39] and interstitial
implants[28,40,41] have all suggested a dose-response relationship of
radiation in this malignancy. The challenge facing todays
clinicians is to determine which of these strategies is most
applicable when efficacy, cost, convenience, and quality of life are
taken into consideration. This review will focus on the various
brachytherapy boost approaches that have been developed to treat
patients with locally advanced prostate cancer in an attempt to
clarify their role in the overall management of this malignancy.
Central to any discussion of the treatment of locally advanced
prostate cancer is the issue of what constitutes advanced disease.
Unfortunately, no consistent definition has yet been adopted in the
literature. This stems, in part, from the recognition that there
are multiple critical prognostic factors. In the past, only patients
with stage T3 or T4 disease were considered to have locally advanced
cancer. Currently, patients with Gleason scores of 7 or
higher,[42,43] perineural invasion, or those with serum PSA levels
> 10 to 15 ng/mL have also been included in the locally advanced category.
Although less frequently discussed, larger tumor volume (as
represented by the number or percentage of biopsy cores with tumor
involvement or the number of hypoechoic nodules on ultrasonography)
also appears to be a factor that may need to be included in the
locally advanced category . All of these factors are considered
to be part of the locally advanced spectrum due to poorer outcomes of
standard treatment in patients with any of these findings.
Brachytherapy boost techniques can be broadly divided into two
categories. The first is the open retropubic technique, which
literally involves placing either radioactive sources or afterloading
devices into the prostate gland via an open lower abdominal incision
under direct visualization. The second technique consists of placing
the same sources or afterloading devices transperineally under
ultrasound guidance. Regardless of the technique used, sources can
either be implanted permanently or temporarily at low- or high-dose rates.
Open Retropubic Technique
The concept that tumor control probability increases with the
delivered dose has long been central to the practice of both older
and modern brachytherapy techniques. To this end, the open retropubic
placement of radioactive seeds was developed with the goal of
significantly increasing the central prostatic dose while sparing
adjacent normal tissues.
As unimodality therapy, the open retropublic approach did not prove
to be highly successful. This was mainly due to the technical
shortcomings inherent to the technique, which resulted in the
inability to deliver a homogeneous dose of radiation therapy to the
gland. However, in combination with external-beam radiation
therapy to a larger prostate field, the open retropubic approach has
resulted in biochemical control rates that appear to be as good as or
better than other forms of therapy in similarly staged patients.
Permanent ImplantThe traditional retropubic implant
technique pioneered by Whitmore and colleagues at Memorial
Sloan-Kettering Cancer Center consisted of a formal retropubic
exploration through an extraperitoneal lower abdominal incision,
pelvic lymph node sampling, opening of the endopelvic fascia, and
mobilization of the prostate from surrounding tissues to allow for
easy access of large-gauge trocars. In order to produce a proper
dose distribution of radiation, the trocars were placed as parallel
as possible throughout the implanted volume so that the sources
(radioactive seeds) were homogeneously distributed throughout the
prostate gland. Radioactive seeds were then deposited into the
trocars using a number of devices specifically designed for this function.
The freehand nature of this retropubic implant technique, as well as
the rich venous plexus of Santorini, led to imprecise, irregular
source placement. The desired target dose was obtained by measuring
the prostate intraoperatively and then determining the appropriate
spacing of the sources and trocars by the use of a nomogram. Dose was
calculated based on the concept of the matched peripheral dose, which
is the dose delivered to an ellipsoid volume with the same average
dimensions as the prostate. Unfortunately, this concept was
inaccurate, since it did not account for the location of the prostate
volume relative to the delivered dose. Although the open retropubic
approach had relatively low morbidity, poor local control and
disease-free survival rates diminished enthusiasm for the technique
as unimodality therapy.
Several researchers have continued to use the open retropubic
approach, but they combine it with external-beam radiation therapy
and employ lower doses (Table 2).[48-54]
The impetus to continue this technique was the belief that even
though the implant might produce an inhomogeneous dose throughout the
prostate, it still was capable of delivering a highly
conformal boost dose to most of the gland. By adding
external-beam radiation therapy to the implant, periprostatic and
intraprostatic doses were increased homogeneously.
Unfortunately, many institutions abandoned these procedures due to
morbidity and disappointing clinical results. Although recent
publications by Critz et al have shown significantly better outcomes,
the technique is only in use at a few centers across the country.[40,48]
Temporary Implant BoostA modification of the open
retropubic technique has been used by several groups (Table
2).[55-58] In this modified approach, afterloading guides are
implanted into the gland via a transperineal approach (with a
template) while the gland is directly visualized and palpated through
the abdominal incision. The implant is designed to cover the entire
gland, along with any local disease extension.
After appropriate dosimetric treatment planning (generally using
computed tomographic (CT) scans), low- dose-rate (LDR) radiation is
delivered as a boost to the gland. This is followed by external-beam
radiation therapy. Initially high morbidity and the subsequent
introduction of ultrasound guidance have led most centers to abandon
this technique in favor of the TRUS-guided approaches discussed below.
Ultrasound-Guided Transperineal Technique
Major improvements in the efficacy of prostate brachytherapy occurred
as a direct result of technologic advances in TRUS imaging. This
technique allows the physician to visualize needle and source
placement during surgery. This real-time visualization not only
improves accuracy but also enables the operator to identify and
correct for potential sources of error. The improved imaging and a
shift to the perineal route for needle placement eliminated the need
for a laparotomy (with its associated surgical morbidity) and
permitted the procedure to be performed on a cost-effective
Permanent Implant BoostAlthough combined with
external-beam radiation therapy, the basic TRUS-guided transperineal
permanent implant is performed in a manner analogous to its use as
unimodality therapy. Before the implant is performed, prostate
ultrasound images are obtained from the base to apex of the prostate
at 0.5-cm increments, and the adjacent rectum, urethra, and bladder
neck are identified. Following imaging, the appropriate distribution
of needles and sources is determined using computerized treatment
planning software, so that the desired dose of radiation is delivered
to the prostate while ensuring that neither the urethra nor rectum
receive an excessive dose. Seeds are then deposited into the gland
during a separate procedure according to the idealized preplan. (The
technique can also be performed using intraoperative, real-time
dosimetric calculations for optimal seed placement).
It should be noted that different institutions have significantly
different philosophies regarding radiation source and dose
distribution. A comprehensive discussion of this topic is beyond the
scope of this review. Common to all techniques and philosophies,
however, is the conformal calculation of implant dosimetry based on
the actual anatomy of the individual prostate.
Implant doses in this setting have ranged from 80 to 160 Gy,
depending on the isotope used and the dose of external-beam radiation
therapy planned (Table 3).[40,46,60-63]
Although the implant is believed to provide a more effective
radiobiological dose if given prior to external-beam radiation
therapy, the sequencing of implantation and external-beam radiation
therapy has varied from institution to institution.
Technical problems with the TRUS boost technique are similar to those
experienced when implants are used as unimodality therapy. These
include incomplete information on the impact of edema on the
dosimetric quality of the implant, problems stemming from seed
placement error, nonstandardized methods of assessing dosimetry
and reporting implant quality, and substantially different
philosophies on optimal seed and dose distribution patterns.
Temporary Implant BoostA second TRUS-guided technique in
current use is the placement of temporary afterloading needles into
the prostate for LDR or HDR brachytherapy. Although technically
similar to their permanent seed implant counterparts, these temporary
implants take advantage of the improved dosimetric coverage of the
gland that HDR brachytherapy offers.
Basically, afterloading needles or catheters are placed into the
gland under TRUS guidance in a pattern predetermined either by
computerized planning or physician preference. Depending on the
institution where the implant is performed, the relationship of these
needles to the gland, rectum, and urethra is recorded, and a
dosimetric plan is developed.[67-74] A remote afterloading unit then
transfers a single high-activity radioactive source into each needle
at predetermined points.
Since the single source can be kept at a desired position along the
needle for a specified amount of time (dwell time), the radiation
dose can be optimized to conform to the gland and to avoid excessive
overdosage or underdosage to adjacent normal tissues. An additional
advantage of this temporary implant system is that the prostate is
essentially immobilized by the needles during the 8- to 12-minute
treatment delivery time, thereby reducing the risk of a marginal miss.
Although the temporary HDR implant systems in current use permit a
more homogeneous dose to be delivered to the gland (due to
optimization after needle placement), further improvement in implant
quality is limited since needles cannot be adjusted once in position.
However, Martinez et al have developed a novel, intraoperative,
real-time implant procedure that continuously updates the physician
on the dosimetric quality of the implant being performed. Not only
does the software program provide the physician with ideal needle
positions to construct an optimal implant, it also gives the
physician the ability to adjust needles intraoperatively as needed to
achieve the desired coverage. In effect, since real-time
adjustments of the implant can be performed, a truly
conformal dose of radiation can be delivered to the gland.
Recent data by Kini et al clearly demonstrate this point. Using
three-dimensional radiation therapy evaluation tools, the authors
showed that their real-time interactive HDR system resulted in
excellent coverage of the gland in 20 randomly selected implants from
their institution. On average, 92% of the target volume received the
prescribed dose (range, 75% to 99%) with a mean homogeneity index of
0.8. These results compare quite favorably with both permanent
implants (an average of 85% of the target volume receives the
prescribed dose) and three-dimensional conformal radiation therapy.
Doses used in this setting have been quite variable due to the
inherent problems encountered in determining the radiobiological
equivalence of LDR and HDR radiation. In addition, some of the
studies in Table 4 are
dose-escalating studies.[67-74] Regardless of the institution,
efficacy appears to be quite good. This approach is among those that
have evoked great interest.
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