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Locoregional Therapies for Early-Stage Prostate Cancer

Locoregional Therapies for Early-Stage Prostate Cancer

ABSTRACT: Widespread use of prostate-specific antigen (PSA) as a screening tool has led to an increased incidence of biopsy-proven prostate cancer, as well as a shift toward more cases with clinically confined disease (stage T1 to T2). The two traditional therapeutic modalities, radical prostatectomy and external-beam radiation therapy, have undergone technical refinements. Other modalities, such as brachytherapy and cryosurgery, are also being used to treat early-stage disease. Comparisons between treatment results are difficult. Biochemical failure, based on PSA findings, is currently used to measure treatment efficacy, but the precise definition and clinical relevance of biochemical failure have yet to be established. The author presents current analyses of biochemical failure, cause-specific survival, distant metastasis, and morbidity rates following various treatment modalities. [ONCOLOGY 9(9):803-816, 1995]

Introduction

Use of prostate-specific antigen (PSA) as a screening tool has
increased the incidence of biopsy-proven prostate cancer, as well
as shifted the stage of presentation increasingly to early-stage
disease. Of the estimated 244,00 patients with newly diagnosed
prostate cancer in 1995 [1], approximately 75% will have disease
clinically confined to the prostate gland (stage T1 to T2). The
treatment of these patients with early-stage prostate cancer is
highly controversial. The controversy centers around two general
issues: (1) Which patients require treatment for their prostate
cancer and which only need to be observed? (2) Once the decision
for treatment has been made, which therapeutic modality is optimal?

Traditionally, the two modalities used to treat early-stage prostate
cancer have been radical prostatectomy and external-beam radiation
therapy. Recent technical advances in both modalities have led
to decreased morbidity with the promise of improved results. In
addition, new treatment approaches, such as brachytherapy and
cryosurgery, are now being used for early-stage prostate cancer.

This review describes the various treatment options for early-stage
prostate cancer and their technical refinements. It also analyzes
treatment end points, compares results, and explores treatment-related
morbidity.

Treatment Modalities

Radical Prostatectomy

Radical prostatectomy is the standard surgical treatment for prostate
cancer. Using a retropubic or perineal approach, the prostate
and seminal vesicles are removed and the bladder is reanastomosed
with the urethra. In addition, a bilateral pelvic lymph node dissection
is usually performed to identify patients who have lymph node
metastases.

In 1982, Walsh and Donker introduced a modification of the standard
retropubic prostatectomy, the nerve-sparing radical prostatectomy
[2]. The major change came from a more precise anatomic identification
of the prostate gland, which permitted excision of the prostate
without injuring the neurovascular bundles containing the cavernous
nerves and vessels that preserve sexual potency. In addition,
Walsh demonstrated that, in patients with extracapsular tumor
extension, these bundles could be sacrificed to obtain wider margins
than are usually achieved with a standard retropubic or perineal
prostatectomy [3].

External-Beam Radiation Therapy

Beginning in the 1970s, external-beam radiation techniques for
treating prostate cancer were refined. These refinements included
irradiation of the pelvis to treat the prostate, seminal vesicles,
and primary draining lymph nodes, accomplished with the use of
a four-field pelvic box technique. Following pelvic irradiation,
a radiation boost to the prostate alone or prostate and seminal
vesicles was delivered via a four-field technique or arcing beams.

Over time, the concept of treating the whole pelvis for early-stage
prostate cancer fell out of favor. A Radiation Therapy Oncology
Group (RTOG) randomized trial failed to show any benefit of irradiation
of the whole pelvis plus prostate over irradiation of the prostate
alone for stages A and B disease [4]. In addition, data from surgical
series helped distinguish patients at low risk for pelvic lymph
node metastases from those at high risk [5]. High-risk patients
could then be selected for less invasive surgical procedures,
such as laparoscopic pelvic lymph node dissection, to identify
those with negative nodes for curative therapy.

These findings supported the concept of radiation treatment of
the prostate and seminal vesicles alone. With advances in CT imaging
and computer programming technology, three-dimensional conformal
external-beam therapy was developed [6]. This new technique enables
the prostate and seminal vesicles to be treated with a high degree
of accuracy while greatly decreasing the dose delivered to surrounding
normal structures, such as the bladder and rectum.

Brachytherapy

The use of brachytherapy with permanent radioactive seed implants
to treat early-stage prostate cancer gained popularity in the
1970s and '80s. Based on work done by Whitemore and Hilaris, an
open laparotomy exposed the prostate gland, calipers measured
the prostate volume, and freehand placement of needles guided
seed placement into the gland [7]. Improved dosimetric evaluation
and long-term follow-up often revealed a poor distribution of
seeds with a corresponding inadequate radiation dose coverage.
Also, patients with inadequate im- plants had high local recurrence
rates based on digital rectal examination [8]. Due to these findings,
brachytherapy fell out of favor as a treatment for prostate cancer.

Recent refinements in ultrasound and CT imaging led to the development
of a transperineal implantation technique and spurred a renewed
interest in this procedure [9-11]. The new technique achieves
accurate seed placement within the gland and improved dose coverage.

Cryosurgery

Cryosurgery was pioneered as a treatment for prostate cancer in
the early 1960s but was abandoned due to a high rate of complications
stemming from an inability to adequately control the freezing
technique [12]. Transrectal ultrasound and percutaneous tissue
accessing techniques subsequently enabled the accurate placement
of cryoprobes and, thus, an enhanced ability to control freezing.

Radical cryosurgical ablation is currently defined as the freezing
of the entire prostate gland, periprostatic tissue, neurovascular
pedicles, and proximal seminal vesicles [13]. Current cryosurgery
involves a transperineal technique with placement of cryoprobes
into the gland under ultrasound guidance. A urethral warming device
is used to prevent freezing of the urethra, and formation of an
ice ball is monitored by ultrasound imaging.

Comparing Treatment Results

It is difficult to compare results of the two most common treatment
modalities, external-beam radiation therapy and radical prostatectomy.
In a randomized trial comparing the two modalities conducted by
the Uro-Oncology Research Group [14], radical prostatectomy was
superior in terms of time to treatment failure, but the trial
was faulty in many respects, including small numbers of patients
and inherent methodologic problems. In addition, outcomes in the
radiation therapy arm were inferior to results reported in other
large single- and multi-institutional radiation oncology studies
for T1 to T2 cancers, and were more consistent with results for
stage T3 to T4 cancers reported by the same group [15]. Further
attempts to run a comparison trial failed due to poor patient
accrual [16].

Selection Bias

Difficulties in comparing the results of radical prostatectomy
and radiotherapy stem, in part, from biases in selecting patients
for the two modalities. In general, patients with higher PSA levels,
grade, and stage are referred for radiation therapy. Emerging
data suggest that pretreatment PSA is one of the most important
determinants of outcome [17-19].

Recent radiation oncology series from both Massachusetts General
Hospital and the Mayo Clinic show the typical PSA ranges of patients
referred for radiation therapy. In the series by Zeitman et al,
53% of patients had PSA levels 10 ng/mL or less[19]. The series
by Pisansky et al revealed that 50% of patients receiving radiation
therapy had PSA levels < 13 ng/mL [20]. Of the patients selected
for radical prostatectomy by Catalona and Smith [21] and Partin
et al [22], 67% and 75%, respectively, had PSA levels 10 ng/mL
or less. Within one institution, a selection bias has been demonstrated,
with a larger percentage of patients with advanced-stage and higher
PSA being selected for radiation therapy than for surgery [19].

In addition, patients with positive pelvic lymph nodes are thought
by many to be destined to develop distant metastases [23,24].Radical
prostatectomy is often abandoned if positive nodes are found,
and therefore, prostatectomy series often do not include node-positive
patients in treatment reports. In contrast, since patients receiving
radiation do not benefit from surgical staging of their lymph
nodes, radiation therapy series more often include node-positive
patients. In a Stanford study, patients undergoing radiation therapy
were staged surgically; 19% of patients with T1 or T2 disease
had positive nodes [25].

Different End Points

Another obstacle to comparing studies stems from the different
end points used to define outcome. There are methodologic differences
in the detection of local recurrence following radiation therapy
and radical prostatectomy. Some reports require biopsy-proven
recurrence to signify local failure, whereas others use only the
digital rectal examination.

Historically, most radiation therapy series have reported local
failure based on digital rectal findings, which can be unreliable,
rather than the more accurate method of post-treatment ultrasound-guided
prostate biopsies. Post-treatment prostate biopsies have only
recently been used routinely to assess local control [26].

In addition, local failure following radical prostatectomy is
often difficult to detect by digital rectal examination, and prostate
bed biopsies are not routinely performed. In a series by Lightner
et al, 42% of patients with an elevated PSA and a normal digital
rectal examination had biopsy-proven local recurrence at the site
of anastomosis [27].For this reason, disease-free survival, which
is also affected by local recurrence, is not the optimal end point
for use in comparing treatment modalities.

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