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Contemporary Management of Prostate Cancer With Lethal Potential

Contemporary Management of Prostate Cancer With Lethal Potential

ABSTRACT: Screening for prostate cancer by determining serum prostate-specific antigen (PSA) levels has resulted in a stage migration such that patients with high-risk disease are more likely to be candidates for curative local therapy. By combining serum PSA, clinical stage, and biopsy information-both Gleason score and volume of tumor in the biopsy cores-specimen pathologic stage and patient biochemical disease-free survival can be estimated. This information can help patients and clinicians understand the severity of disease and the need for multimodal therapy, often in the context of a clinical trial. While the mainstays of treatment for local disease control are radical prostatectomy and radiation therapy, systemic therapy must be considered as well. A randomized trial has shown a survival benefit for radical prostatectomy in patients with positive lymph nodes who undergo immediate adjuvant androgen deprivation. Clinical trials are needed to clarify whether adjuvant radiation therapy after surgery confers a survival benefit. PSA is a sensitive marker for follow-up after local treatment and has proven that conventional external-beam irradiation alone is inadequate treatment for high-risk disease. Fortunately, the technology of radiation delivery has been dramatically improved with tools such as three-dimensional conformal radiation, intensity-modulated radiation therapy, and high-dose-rate brachytherapy. The further contributions of pelvic irradiation and neoadjuvant, concurrent, and adjuvant androgen deprivation therapy have been defined in clinical trials. Future management of high-risk prostate cancer may be expanded by clinical trials evaluating neoadjuvant and/or adjuvant chemotherapy in combination with androgen deprivation.

Prostate cancer continues to be
the most common noncutaneous
cancer in men in the United
States and the second leading cause
of cancer-related death.[1] Before
prostate-specific antigen (PSA) measurement
enabled early detection, a
significant number of men presented
with metastatic disease or bulky local
high-grade disease that discouraged
curative local therapy. PSA screening
now identifies a cohort of men with
normal prostate exams who, while at
high risk based on grade and biochemical
data, are candidates for local
therapy. However, local monotherapy
by surgical excision or externalbeam
irradiation has been replaced
by multimodal therapy, often in the
context of clinical trials, as an important
new direction in the management
of such high-risk disease. Newer
modalities for local treatment such as
brachytherapy and cryotherapy are
being applied to all risk groups,
and their role as mono- or combination
therapy is in the early stages of
development.

The most common features of prostate
cancer that identify a patient as
"high risk" are PSA level, Gleason
score, and clinical stage. Notably, the
first two parameters, which are objective
measures, are not included in the
current TNM staging system. We
present a brief review of our current
understanding of risk stratification of
prostate cancer using PSA, Gleason
score, and clinical stage.

Risk-Stratification ParametersProstate-Specific Antigen
PSA is a serine protease enzyme
secreted by prostate epithelial cells.
Large quantities are present in seminal
fluid, and only a fraction escapes
into the bloodstream. PSA elevations
can be secondary to benign prostate
hyperplasia. However, due to the disorganization
of gland and duct structure
associated with cancer, greater
increases are more common. A PSA
> 4.0 ng/mL has been considered the
standard cutpoint in defining an abnormal
PSA level, but as a tumor
marker it lacks specificity; eg, in the
4- to 10-ng/mL range, only 30% of
biopsies will be positive for cancer;
in the 10- to 20-ng/mL range, approximately
50% of biopsies will be positive
for cancer.

If the total PSA elevation had no
prognostic significance, screening of
an enriched population might be an
easier proposition. The urologist could
wait until the PSA level was quite
high, thereby increasing specificity before
advising a biopsy. However, PSA
is prognostic for all treatment modalities,
such that the likelihood of cure
diminishes as pretreatment PSA increases.[
2] For example, Pollack et al
cite a 50% to 80% incidence of
biochemical failure after radiation,
surgery, or androgen deprivation monotherapy
when pretreatment PSA is
> 20 ng/mL.[3]

Gleason Pattern
Albertsen et al published an informative
study from the Connecticut
Surveillance, Epidemiology, and End
Results (SEER) cancer registry.[4]
Men with prostate cancer who elected
not to be treated with curative therapy
were followed for 15 years to determine
the incidence of death from prostate
cancer vs death from any cause.
Not surprisingly, the risk of death from
prostate cancer is closely related to
age at diagnosis and biopsy Gleason
score. For men with a Gleason score
of 6, the prostate cancer death rate at
15 years was 18% to 30%; for a Gleason
score of 7, it was 42% to 70%;
and for a Gleason score of 8 to 10, it
was 60% to 87%. The lower end of
these ranges occurred among men diagnosed
in their 70s, whereas the higher
death rates occurred among men
diagnosed in their 50s. Thus, if not
treated with curative intent, a 50-yearold
man with a Gleason score of 8 to
10 had a very high risk-nearly
90%-of dying from prostate cancer.

Clinical Stage
Clinical stage is determined by the
physician's digital rectal examination.
This designation is highly subject to
interobserver interpretation and is the
least prognostic variable. The incidence
of clinical stage T1c (cT1c)
disease (or nonpalpable lesions) has
markedly increased with PSA screening.
Patients rarely present with bulky
lesions that are clearly extraprostatic
(cT3a) or that invade the seminal vesicle
(cT3b) or the bladder (cT4).

Combination of
Prognostic Factors

Combining prognostic factors to
construct tables was initiated and popularized
by Partin et al.[5] Based on
radical prostatectomy data, they combine
clinical stage, pretreatment PSA
level, and biopsy Gleason score to predict
extracapsular extension, seminal
vesicle invasion, and lymph node involvement.
Men with "low-risk" disease,
ie, PSA < 10 ng/mL, Gleason
score of 3+3, and cT1c disease, have
a 67% chance of organ confinement
and only a 1% risk of lymph node
involvement. On the other hand, a patient
with a Gleason score of 8, PSA of
25 ng/mL, and cT2a disease is predicted
to have an organ-confined rate of
5% and a 24% risk of lymph node
involvement. Overall, high-risk disease
is defined by any of the following features:
PSA > 20 ng/mL, Gleason score
8 to 10, or clinical stage T2c/3 disease.
Approximately 35% of newly diagnosed
cancers, a significant minority,
fall into this category.[6,7]

Although the Partin tables predict
for pathologic stage, it is well known
that some patients with an adverse pathology
after radical prostatectomy
will never experience biochemical failure.[
5] To more accurately predict
5-year PSA recurrence-free survival,
Nelson et al have added the greatest
percentage of cancer on any biopsy
core to Gleason score, PSA level, and
disease stage.[8] The key concept is
that while the presence of a single
high-risk factor is certainly adverse,
additional high-risk factors dramatically
worsen prognosis. For example,
for a PSA > 20 ng/mL, stage cT1c
disease, and no single biopsy core percentage
< 60%, the 5-year recurrencefree
survival rates for Gleason score
8-10 was 19%. PSA survival dropped
to 9% if any biopsy core percentage
was > 60%, and further to 3% if the
clinical stage was advanced to T2.

Looking at the wide range of these
outcomes, it may be reasonable to
consider truly high-risk prostate cancer
as the presence of one high-risk
factor plus a second intermediate- or
high-risk factor. An exact definition
of "high-risk" prostate cancer is therefore
somewhat relative and better
described in gradients rather than
absolutes.

Treatment Options for
High-Risk Prostate Cancer
Radical Prostatectomy
Radical prostatectomy alone can
on occasion be successful in treating
men with high-risk disease.[9,10] In
the Cancer of the Prostate Strategic Urologic
Research Endeavor (CaPSURE)
database, 547 patients with high-risk
disease underwent radical prostatectomy;
with a median follow-up of 3.1
years, 68% maintained an undetectable
PSA. Although PSA level, Gleason
score, and percent positive biopsy
were each significant predictors of
failure, together they increased the
odds of biochemical failure.

Mian et al from M. D. Anderson
Cancer Center recently reported a
PSA-era series of patients who underwent
radical prostatectomy as monotherapy
for Gleason 8-10 disease.[11]
They cite pre-PSA series that reported
a high (70%-100%) incidence of
nodal metastases and poor survival
rates.[12-14] By contrast, in their series
of 188 patients with specimen
Gleason scores of 8 to 10 and no neo-
adjuvant or adjuvant therapy, PSA recurrence-
free survival was 68% at a
median of 5 years follow-up. Pathologic
staging of the series showed organ-
confined and margin-negative
disease in 31%, specimen-confined
disease (pT2/pT3, margin-negative) in
57%, extraprostatic extension with
positive margins in 9%, seminal vesicle
invasion in 21%, and positive
lymph nodes in 6%. A pretreatment
PSA < 10 ng/mL was more likely to
correlate with organ- and specimenconfined
disease than a PSA
> 10 ng/mL. The median time to recurrence
was 36 months. A striking finding
of this study was that the 5-year
biochemical disease-free survival was
similar for 84% of patients with organconfined
disease, with or without positive
margins, and for those with
negative-margin pT3a disease.
However, where disease was both extraprostatic
and margin-positive, biochemical
recurrence-free survival
dropped to 50%. Thus, although rates
of extraprostatic disease were high, as
one would expect with Gleason 8-10
disease, achieving a negative margin resulted
in a significant PSA recurrencefree
survival benefit. In this setting,
surgeons would not risk a positive margin
with a nerve-sparing procedure.

In the Mayo clinic surgical series
of Gleason 8-10 prostate cancer patients
reported by Lau et al, biochemical
progression-free 5- and 10-year
survival rates were 49% and 36%.[10]
Organ-confined disease was seen in
25%, 54% had positive margins, 48%
had positive seminal vesicles, and
27% had positive lymph nodes. Organ-
confined tumors, some with positive
margins, had 5- and 10-year
progression-free survival rates of 53%
and 28%. By comparison, the highrisk
surgical series reported by Tefilli
et al showed a less optimistic 3-year
biochemcial disease-free rate of 33%.
Their series had a higher proportion
of patients with a pretreatment PSA
level > 10 ng/mL and lower proportions
of organ-confined and specimenconfined
disease.[15] In conclusion,
prostate cancer with high-risk features
that is organ confined, or at least specimen
confined, and of low volume on
pathologic examination, may be cured
by surgical monotherapy.

Radical Prostatectomy With
Adjuvant or Neoadjuvant Therapy

If nodal metastases are found at
the time of radical prostatectomy, early
application of adjuvant androgen
deprivation therapy has been shown
to prolong survival in a randomized
trial. Messing et al randomized 98
node-positive patients to immediate
or delayed androgen deprivation therapy
after radical prostatectomy-commencing
only at the time of metastatic
occurrence, ie, not for asymptomatic
rises in PSA.[16] After a median follow-
up of 7.1 years, disease progression
was reduced from 77% to 18%,
and survival increased from 65% to
85%. (The strategy of initiating androgen
deprivation therapy at the onset
of a rising PSA was not tested and
may be as efficacious as initiating therapy
immediately after surgical removal
of the prostate.) This trial did not
reach its accrual goal of 220 patients
due to the decreasing incidence of
nodal metastases with PSA detection.
Nevertheless, a statistically significant
survival benefit was realized in this
small trial. These findings combined
with those of the Medical Research
Council study and the European Organization
for Research and Treatment of
Cancer (EORTC) trials reported by
Bolla provide evidence-based data for
early rather than delayed treatment of
high-risk patients with androgen deprivation
therapy.[17-19]

Although adjuvant androgen deprivation
for node-positive disease has
demonstrated a survival benefit in
clinical trials testing, neoadjuvant androgen
deprivation prior to radical
prostatectomy has not demonstrated
any clinical benefit. Soloway et al reported
extended follow-up of a trial
comparing 3 months of neoadjuvant
androgen deprivation for cT2b, NX,
M0 disease.[20] In the prostatectomy-
only group, positive margins were
detected in 48% with a 5-year biochemical
recurrence-free survival of
68%. In the neoadjuvant hormonal
group, while the positive margins were
reduced to 18%, the 5-year biochemical
recurrence-free survival was a similar
65%. Thus, neoadjuvant androgen
deprivation decreased the recognition
of positive margins but did not affect
recurrence-free survival. Patients with
higher PSA levels and Gleason scores
had higher relapse rates that were unaffected
by neoadjuvant therapy.

The Canadian Uro-Oncology
Group recently reported follow-up of
a trial comparing 3 vs 8 months of
neoadjuvant androgen deprivation followed
by radical prostatectomy.[21]
The investigators postulated that the
8-month schedule would prove more
efficacious, as this regimen was associated
with further declines in PSA
nadir and reduction of positive margins
when compared to the 3-month
schedule. However, with 4-year follow-
up, both arms had a similar PSA
progression-free survival.[21]

Adjuvant irradiation is a common
strategy used after surgery for prostate
cancer with high-risk features. As
reviewed by Syed et al, while improved
local control may be a benefit,[22] no
randomized trial has demonstrated a
survival advantage for adjuvant radiation
in this setting.[23-27] A Southwest
Oncology Group (SWOG) phase III
trial randomized patients with extraprostatic
extension, positive margins,
or seminal vesicle involvement to either
observation or 62-64 Gy of adjuvant
radiation. This trial is designed
to evaluate a survival benefit; the outcome
analysis is still pending.

External-Beam Radiation Therapy
In 1999, we reported our experience
with external-beam irradiation
as monotherapy delivered between
1976 and 1995 at Eastern Virginia
Medical School.[28] Our technique
during that era was described as follows:
"Patients were treated with
4-MV photons in the earliest years
and 10-18 MV photons in the last
10 years of the study period. A minimum
dose of 62-65 Gy was delivered
to the entire prostatic volume, with
40-45 Gy to the lymph node drainage
sites of the pelvis for poorly differentiated
> T2b staged cancers. A typical
four-field technique was used to treat
the whole pelvis and the initial prostatic
fields, while an anterior and two
lateral fields or 120o bilateral arc rotation
was used for the prostate boost."

The sensitivity of PSA as a followup
tool after local treatment made it
clear that this technique was inadequate,
especially for high-risk disease.
In the past decade, radiation oncologists
have radically updated their techniques
to deliver increased doses to
the prostate while sparing the surrounding
bowel and bladder. We will
review these efforts and their surrounding
controversies.

  • Field Size-Considerable controversy
    remains regarding the role of
    elective pelvic lymph node irradiation
    in clinically localized high-risk prostate
    cancer. Retrospective reports support[
    29,30] and refute[31] a benefit for
    elective pelvic radiation therapy in this
    setting. The issue was first prospectively
    evaluated by Radiation Therapy
    Oncology Group (RTOG) protocol
    7706.[32,33] In this study, 445 patients
    with clinical stage A2 or B disease
    (cT1b or cT2) and no clinical or pathologic
    evidence of pelvic lymph node
    involvement were randomized to receive
    either 45 to 50 Gy of pelvic nodal
    irradiation followed by a 20-Gy
    boost to the prostate, or 65 to 72 Gy to
    the prostate only. Elective pelvic irradiation
    failed to improve local control,
    freedom from distant metastases, and
    disease-specific or overall survival.
    However, this trial had several weaknesses:
    The doses used were moderate,
    the field size was small (6 * 6 cm
    to 7 * 7 cm) prior to computed tomography
    (CT) localization of the prostate,
    a "sandwich technique" was
    allowed whereby treatment of the pelvic
    nodes was given in a split-course
    fashion, and the definition of failure
    was clinical (ie, not PSA failure). More
    significantly, the patient population
    analyzed had a low risk of occult
    lymph node involvement.

    Recent randomized data have shed
    new light on this decades-old issue.
    RTOG 9413 evaluated elective pelvic
    nodal irradiation in clinically staged
    patients with greater than a 15% risk
    of lymph node involvement.[34] In
    this study, nearly 1,300 patients were
    randomized to receive either 50.4 Gy
    to the pelvis followed by a 19.8 Gy
    prostate boost (70.2 Gy total to prostate)
    or 70.2 Gy to the prostate alone.
    All patients were also treated with 4
    months of total androgen deprivation
    therapy, which they were randomized
    to receive either 2 months prior to and
    during radiation therapy or 4 months
    following the completion of radiation
    therapy. With a median follow-up of
    5 years, a significant improvement in
    4-year progression-free survival was
    shown (54% vs 47%) when elective
    pelvic irradiation was compared with
    prostate-only irradiation in patients
    also receiving neoadjuvant and concurrent
    total androgen suppression. An
    overall survival benefit has not yet
    been demonstrated, and it will be important
    to follow this critical end point.
    Therefore, pelvic irradiation when given
    in the context of neoadjuvant and
    concurrent androgen deprivation therapy
    may be of benefit for patients at
    high risk for lymph node involvement.

  • Dose Response-A dose response
    in locally advanced prostate cancer
    was recognized with evidence that
    delivery of conventional doses of radiation
    therapy-ie, 65 to 70 Gy-
    results in poor local control, high
    biochemical failure rates, and positive
    postradiation biopsies. A patternof-
    care outcomes survey found that
    patients with stage C (cT3) tumors
    had improved local control with doses
    ≥ 70 Gy.[35] Zietman et al analyzed
    the long-term outcome of over
    1,000 patients with localized prostate
    cancer who received 68.4 Gy to the
    prostate.[36] Using a strict definition
    of biochemical failure, only 20% of
    men with either cT3/4 or cT1/2 disease
    and a Gleason score of 8 to 10
    were disease-free at 10 years. Crook
    et al reported the results of postradiation
    prostate biopsies in 226 patients
    after doses of 65 to 66 Gy to the
    prostate.[37] At 30 months' followup,
    38% of T3 and 83% of T4 patients
    had positive or indeterminate biopsies.
    Despite the realization that higher
    doses were necessary, dose
    escalation above 70 Gy using conventional
    treatment techniques resulted
    in significant rectal and bladder
    toxicity.[38] Fortunately, advances in
    computer technology have made the
    necessary transition to dose escalation
    a reality.
  • 3D CRT and IMRT-Three-dimensional
    conformal radiotherapy
    (3D CRT) starts with acquiring a CT
    scan of the patient in the desired treatment
    position. The resulting two-dimensional
    axial images are stacked
    into a virtual 3D representation of the
    entire treatment area, including the
    prostate and adjacent critical organs.
    These structures can be projected as
    if one were viewing them along the
    path of a radiation beam from any
    angle (beam's-eye view). Each beam
    used during treatment can thus be
    shaped to maximally conform to the
    target while excluding adjacent normal
    tissue. The result is a marked
    improvement in dose conformation
    around the target compared with a
    classic four-field technique.

    Intensity-modulated radiation therapy
    (IMRT) is a further refinement of
    3D CRT. This technique uses computer-
    optimized nonuniform beam intensities
    to conform the dose even
    more closely to the target volume.
    IMRT systems generally utilize inverse
    planning, a plan optimization
    process that first considers the desired
    outcome (adequate dose to the
    target and minimum dose to surrounding
    critical structures) and then designs
    a treatment scheme to achieve
    that outcome. This is in contrast to
    forward planning on most 3D CRT
    systems, in which a trial-and-error
    method of arranging beam combinations
    and blocking must be performed
    to arrive at the desired solution.

    As with all new technology, the
    successful implementation of IMRT
    requires an understanding of its potential
    drawbacks. Increasingly, conformal
    dose delivery means that
    margins around the target become
    smaller and dose gradients around the
    tumor become steeper. Despite strict
    immobilization of the patient, some
    daily variation in both patient position
    and internal prostate motion will
    occur, which needs to be considered
    in treatment planning. In rigidly immobilized
    prostate cancer patients receiving
    conformal radiation therapy,
    Rosenthal found a median patient position
    variability of 4 mm between
    simulation and treatment.[39] Ten
    Haken observed an average prostate
    movement of 5 mm in 50 patients due
    to differential filling of the rectum
    and bladder.[40] Daily localization of
    the prostate with transabdominal
    ultrasound imaging[41] or implanted
    radiopaque seed markers[42] can significantly
    improve the accuracy of
    treatment and should be utilized when
    treating with tight margins.

  • Dose Escalation: Retrospective
    or Nonrandomized Studies
    -Investigators
    at Fox Chase Cancer Center
    described the results in 618 patients
    treated with different doses of 3D CRT
    alone.[43] Patients were grouped by
    pretreatment PSA level (< 10 ng/mL,
    10-19.9 ng/mL, or ≥ 20 ng/mL) and
    further subgrouped by unfavorable
    risk if they had T2b/3 disease, Gleason
    score ≥ 7, or perineural invasion.
    Favorable-risk patients lacked any of
    these features. Among unfavorablerisk
    patients with a PSA < 10 ng/mL,
    any patient with a PSA between 10 and
    19.9 ng/mL, and the favorable PSA
    ≥ 20 ng/mL group, an increase in the
    median dose from approximately 73 to
    77.5 Gy resulted in a 14% to 40% improvement
    in 5-year biochemical freedom
    from failure. Outcome was poor
    in the unfavorable group with PSA
    > 20 ng/mL regardless of dose, suggesting
    that disease is present outside the
    local field and additional therapy such
    as androgen deprivation is necessary.

    Zelefsky and colleagues reported on
    the long-term outcome of 1,100 patients
    with stage T1c-3 disease treated
    with 3D CRT and IMRT.[44] The radiation
    dose was incrementally increased
    from 64.8 to 86.4 Gy. Unfavorablerisk
    patients were defined as having at
    least two of the following factors: PSA
    > 10 ng/mL, stage T3 disease, or a
    Gleason score ≥ 7. For the 416 patients
    with unfavorable risk criteria, 81 Gy
    significantly improved 5-year PSA relapse-
    free survival to 67%, compared
    to 43% for 75.6 Gy and 21% for 64.8-
    70.2 Gy. Posttreatment biopsies were
    obtained at least 2.5 years after treatment
    in 108 of the 416 men. The incidence
    of positive biopsies decreased
    steadily as the radiation dose was escalated
    in increments of 5.4 Gy.

  • Dose Escalation: Randomized
    Studies-Shipley et al randomized
    202 patients with T3/4 tumors to
    67.2 Gy or 75.6 cobalt gray equivalent,
    using a conformal perineal proton
    boost.[45] No patient received
    androgen deprivation therapy. In the
    subset of 57 patients with poorly differentiated
    tumors, local control was
    significantly improved (84% vs 19%)
    with the higher dose. In the M. D.
    Anderson dose escalation trial, over
    300 patients with T1-3 disease were
    randomized to a radiation dose of
    70 or 78 Gy as monotherapy.[3] A
    preliminary analysis revealed that
    among patients with a pretreatment
    PSA > 10 ng/mL, a dose of 78 Gy
    increased 5-year freedom from
    clinical or biochemical failure from
    48% to 75% (P = .011). A subsequent
    analysis at 60 months' median follow-
    up confirmed the benefit for these
    intermediate- to high-risk patients;
    dose escalation significantly improved
    the 6-year freedom from clinical or
    biochemical failure rate from 43%
    to 62%.[46]

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