Download Treatment strategies for high-risk locally advanced prostate cancer

yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Prostate-specific antigen wikipedia, lookup

Treatment strategies for high-risk locally
advanced prostate cancer
Seth A. Rosenthal and Howard M. Sandler
Abstract | High-risk prostate cancer can be defined by the assessment of pretreatment prognostic factors
such as clinical stage, Gleason score, and PSA level. High-risk features include PSA >20 ng/ml, Gleason
score 8–10, and stage T3 tumors. Patients with adverse prognostic factors have historically fared poorly
with monotherapeutic approaches. Multimodal treatment utilizing combined androgen suppression and
radiotherapy has improved survival rates for patients with high-risk prostate cancer. In addition, multiple
randomized trials in patients treated with primary radical prostatectomy have demonstrated improved
outcomes with the addition of adjuvant radiotherapy. Improved radiotherapy techniques that allow for dose
escalation, and new systemic therapy approaches such as adjuvant chemotherapy, present promising future
therapeutic alternatives for patients with high-risk prostate cancer.
Rosenthal, S. A. & Sandler, H. M. Nat. Rev. Urol. 7, 31–38 (2010); doi:10.1038/nrurol.2009.237
Continuing Medical Education online
This activity has been planned and implemented in accordance
with the Essential Areas and policies of the Accreditation Council
for Continuing Medical Education through the joint sponsorship of
MedscapeCME and Nature Publishing Group.
MedscapeCME is accredited by the Accreditation Council for
Continuing Medical Education (ACCME) to provide continuing
medical education for physicians.
MedscapeCME designates this educational activity for a maximum
of 0.75 AMA PrA Category 1 CreditsTM. Physicians should only
claim credit commensurate with the extent of their participation
in the activity. All other clinicians completing this activity will
be issued a certificate of participation. To participate in this
journal CME activity: (1) review the learning objectives and author
disclosures; (2) study the education content; (3) take the post-test
and/or complete the evaluation at
journal/nrurol; and (4) view/print certificate.
learning objectives
Upon completion of this activity, participants should be able to:
1 Define high-risk prostate cancer.
2 Identify the efficacy of androgen suppression therapy for
high-risk prostate cancer.
3 Describe research of adjuvant chemotherapy for high-risk
prostate cancer.
4 Compare emerging treatments for high-risk prostate cancer
with standard therapy.
Prostate cancer is a common malignancy, with 192,280
new cases and 27,360 deaths estimated in the us in 2009.
although the mortality rate for prostate cancer declined
significantly during the period between 1990 and 2005, it
Competing interests:
H. M. Sandler declares an association with the following
company: Sanofi-Aventis. See the article online for full details of
the relationship. S. A. Rosenthal, the Journal Editor S. Farley and
the CME questions author C. P. Vega declare no competing
continues to be the most frequently diagnosed cancer in
men, and the second most frequent cause of cancer
death, after lung cancer, in the us.1 although the benefit
of active treatment versus surveillance for men with
low-risk prostate cancer has been controversial, men
with high-risk disease at presentation are acknowledged
to be at higher risk of prostate cancer-related death.2,3
therefore, attempts to further reduce prostate cancer
mortality are directed at the high-risk population.
High-risk prostate cancer has been variously defined,
but the consensus is that a variety of pretreatment prognostic factors can identify patients for whom treatment
is likely to fail. the primary risk factors for prostate
cancer are clinical stage, Psa level, and Gleason score
at presentation. the small proportion of patients who
present with documented metastases are outside the
scope of this review.4 Before concluding that a patient
has localized but high-risk prostate cancer, an assessment
to exclude the presence of gross metastatic disease should
be performed.
Clinical stage is defined according to the american Joint
Committee on Cancer staging system, which notes that
patients with extensive palpable disease (stage t3) have
a poorer prognosis than patients with incidentally noted
(stage t1) or small volume palpable (stage t2) disease.5
However, clinical staging of prostate cancer is subjective
and potentially imprecise. it has long been recognized
that the histological grading of prostate tumors correlates with prognosis. Donald Gleason described a system
for the assessment and communication of primary and
secondary histological grades, which has become known
as the Gleason score. in his initial paper, Gleason noted
that the combination of histological grading and clinical
staging improved prognostic accuracy over that obtained
with either parameter alone.6 subsequently, Gleason score
has been validated as an independent prognostic factor
nature reviews | urology
Radiation Oncology
Centers, Radiological
Associates of
1500 Expo Parkway,
CA 95815, USA
(S. A. rosenthal).
Department of
Radiation Oncology,
Cedars-Sinai Medical
Center, 8700 Beverly
Boulevard, Los Angeles,
CA 90048, USA
(H. M. Sandler).
Correspondence to:
S. A. Rosenthal
[email protected]
volume 7 | JanuarY 2010 | 31
© 2010 Macmillan Publishers Limited. All rights reserved
Key points
■ Risk stratification using prognostic factors such as clinical stage, Gleason
score, and PSA level is essential for determining the appropriate treatment for
patients with prostate cancer
■ High-risk patients include those with Gleason score 8–10, PSA >20 ng/ml, and
clinical stage T3 disease
■ The combination of radiotherapy and long-term androgen suppression improves
disease control and survival, compared with either treatment alone, for patients
with high-risk disease
■ Adjuvant radiotherapy following radical prostatectomy improves disease control
and survival for patients with stage pT3 disease
■ Improved local treatments, such as dose-escalated radiotherapy, adjuvant
radiotherapy following prostatectomy, and novel systemic treatments such
as adjuvant chemotherapy have the potential to improve disease control in
the future
Table 1 | Definitions of high-risk prostate cancer
High-risk criteria
D’Amico et al.18
Stage T2c or greater and either PSA level >20 ng/ml or Gleason
score 8–10
RTOG 99-02
and 05-2160
PSA 20–100 ng/ml, Gleason score ≥7 and any T stage or,
stage T2 or greater, PSA <100 ng/ml and Gleason score 8–10
PSA level >20 mg/l or Gleason score 8–10 or stage T3 or greater
Abbreviations: NCCN, National Comprehensive Cancer Network; RTOG, Radiation Therapy Oncology Group.
in multiple settings. Patients with Gleason score 8–10
tumors are at high risk of recurrence, metastases, and
death from prostate cancer.7–9 Following the development of Psa testing in the late 1980s, pretreatment Psa
level was also noted to be an independent prognostic
factor for recurrence following primary treatment with
radiotherapy or radical prostatectomy.10–12
Historically, patients with poor prognostic factors had
low survival rates after either surgery or external beam
radiotherapy alone. 13,14 it was recognized that these
patients were more likely to develop metastatic disease
and to die from prostate cancer. as such, this group of
men became the focus of efforts to improve therapeutic
approaches. it is worth noting that in the early Psa era
(late 1980s and early 1990s) patients presented with
higher volume disease than in the current Psa screening epoch. in recent years, a number of clinical trials
addressing potential therapeutic strategies for patients
with high-risk prostate cancer have been reported and
many more are either underway or awaiting maturation
of data. Key randomized studies of radiotherapy in conjunction with androgen suppression therapy and trials
of adjuvant radiotherapy following prostatectomy are
discussed below. the potential advantages provided by
dose-escalated radiotherapy and the addition of adjuvant chemotherapy to other primary treatment regimens are also discussed. the wealth of data produced by
these trials can assist clinicians in selecting the optimal
treatment for patients with high-risk prostate cancer.
Risk stratification
the idea that improved prognostic information could
be gleaned from the combined use of clinical staging,
Gleason score, and Psa levels led to the development
of a variety of predictive tools.15–17 in 1998 D’amico
et al.18 suggested a stratification of patients into lowrisk, intermediate-risk, and high-risk groups that is
still commonly used today. according to this classification scheme, high-risk patients are those with clinical
stage t2c or higher, and either Psa >20 ng/ml, or Gleason
score 8–10.18 at present, cooperative research groups
such as the radiation therapy oncology Group (rtoG),
and organizations such as the national Comprehensive
Cancer network, use risk stratification schemes similar
to those of D’amico et al. to identify patients with highrisk prostate cancer. Commonly used criteria include
patients with combinations of Gleason score 8–10, Psa
levels >20 ng/ml, and clinical stage t2c–t4 disease
(table 1). overall, about 15–20% of patients with prostate
cancer have high-risk disease at presentation.19
a number of secondary risk factors have also been
reported to be associated with a high risk of prostate
cancer progression. For example, a prediagnosis Psa
velocity of >2 ng/ml/year has been shown to increase
the likelihood of death from prostate cancer after
either radical prostatectomy or external beam radiation therapy.20,21 Psa doubling time22,23 and the volume
of cancer at initial diagnosis (as assessed by percentage of positive biopsy cores)24,25 have also been associated with recurrence following primary treatment with
radiotherapy or radical prostatectomy.22–25 in addition, a
tertiary Gleason pattern 5 is a significantly adverse prognostic factor in patients with Gleason score 7 cancers.26,27
information about these secondary risk factors has
not always been collected in routine clinical practice,
however, and when noted they are not always reported
consistently. Furthermore, the potential prognostic value
of a number of biomarkers has been studied by rtoG.
though not yet ready for routine clinical use, if preliminary results are confirmed in further patient cohorts,
these biomarkers might add strength to existing predictive models.28 at present, primary risk stratification
schemes rely mainly on clinical stage, initial Psa level,
and Gleason score. the use of secondary prog nostic
factors to select and stratify patients for clinical trials of
high-risk disease should be considered.
Androgen suppression plus radiotherapy
the sensitivity of prostate cancer to hormonal therapy
has been appreciated for many decades, since it was first
observed that prostate tumors respond to orchiectomy.
estrogenic agents, such as diethylstilbesterol, were subsequently tried in adjuvant trials, but the toxicities of these
agents, such as gynecomastia and cardiovascular adverse
effects, prevented their widespread use. the development
of novel agents such as luteinizing hormone-releasing
hormone (lHrH) analogs (for example, goserelin, leuprolide), and nonsteroidal antiandrogens (for example,
flutamide, bicalutamide) for androgen suppression in
the 1980s prompted trials of combined radiotherapy and
androgen suppression. the positive results of these trials
modified clinical practice and improved outcomes for
men with high-risk prostate cancer.
32 | JANUARY 2010 | volUme 7
© 2010 Macmillan Publishers Limited. All rights reserved
During the randomized rtoG 85-31 trial, patients
received radiotherapy followed by either immediate
indefinite adjuvant androgen suppression with an lHrH
analog, or androgen suppression deferred until the
time of relapse. Participants had an ‘unfavorable prognosis’ defined as either positive lymph nodes, nonbulky
tumor, or stage ct3, or stage pt3 disease. 977 patients
were accrued from 1987 to 1992. the initial report of
results highlighted improved local control, freedom from
distant metastasis, and disease-free survival for patients
treated with immediate androgen suppression compared
with those that received deferred treatment. However,
improved overall survival in the immediate group was
noted only for those patients with Gleason score 8–10
tumors. subsequent analysis after longer follow-up
revealed a survival benefit for the study population as a
whole. subset analysis showed that this long-term benefit
was limited to patients with Gleason score 7–10; patients
with Gleason score 2–6 derived no marked advantage
from immediate androgen suppression. 10-year survival
rates for the study cohort as a whole were 49% and 39%
(P = 0.002), and for patients with Gleason score 8–10
were 39% and 25% (P = 0.0046), in those treated with
immediate and deferred androgen suppression therapy,
respectively.29–31 the rtoG 85-31 study was the first
to demonstrate that survival could be significantly
improved by androgen suppression therapy combined
with radiotherapy. the magnitude of the effect was
large and was primarily noted in patients with Gleason
score 8–10 tumors, who experienced a greater than 50%
improvement in overall survival with the use of adjuvant androgen suppression therapy. Despite this benefit,
overall survival rates were disappointing. even in the
study group with the best outcomes 61% of patients with
Gleason score 8–10 tumors had died within 10 years.
the rtoG 86-10 trial comprised 471 patients diagnosed with clinically bulky tumors between 1987 and
1991. Participants were randomized to receive external beam radiotherapy plus 2 months of neoadjuvant
and 2 months of adjuvant androgen suppression, or to
radiotherapy alone. androgen suppression was associated with better outcomes for many intermediate end
points, including freedom from distant metastases,
disease-free survival, and disease-specific mortality, but
there was no statistically significant improvement in
overall survival.32–34
other trials of short-term androgen suppression in
combination with radiotherapy produced conflicting results in terms of overall survival. in a population of intermediate-risk and high-risk patients,
D’amico and colleagues were able to discern a benefit
in overall survival, in addition to improvements in
other disease-control end points, following 6 months of
androgen suppression therapy.35 Conversely, a study
of patients with locally advanced prostate cancer by
the trans-tasman radiation oncology Group failed
to show a positive effect of androgen suppression
on overall survival, despite detecting highly significant improvements in all other end points, including
prostate-cancer-specific survival.36
long-term androgen suppression
the european organization for research and treatment
of Cancer (eortC) conducted two important studies
that helped to define the role of long-term androgen suppression plus radiotherapy in prostate cancer management. the first trial, eortC 22863, was performed
between 1987 and 1995. 415 patients with locally
advanced prostate cancer were randomized to either
3 years of androgen suppression combined with external beam radiotherapy or external beam radiotherapy
alone. outcomes for all end points, including overall survival, were superior in the combination-therapy cohort.
5-year overall survival was 78% in the androgen suppression plus radiotherapy group and 62% for patients who
received radiotherapy alone (P = 0.0002).37–39
the rtoG followed the 85-31 and 86-10 studies with
rtoG 92-02, which involved the randomization of 1,554
intermediate-risk or high-risk patients to radiotherapy
plus 4 months of androgen suppression (2 months before
and 2 months concurrent with radiotherapy) with or
without 2 additional years of androgen suppression following completion of radiotherapy. significant improvements
in all end points of disease progression were observed in
the prolonged hormone therapy group; overall survival
was the exception. Prolongation of androgen suppression extended 10-year disease-specific survival, but not
overall survival. in the subset of 337 patients with Gleason
score 8–10 tumors, the difference between the two treatment arms was more pronounced; there was a significant improvement in 10-year overall survival in patients
who received prolonged androgen suppression (45%)
compared with patients who did not (32%; P = 0.006).40,41
eortC 22961 was a comparison of short-term and
long-term androgen suppression plus radiotherapy in
970 men with locally advanced prostate cancer randomized to radiotherapy with either 6 months or 3 years of
androgen suppression. marked improvement in diseasecontrol outcomes was noted, including significant
enhancement of overall survival, in favor of the cohort
who received prolonged hormone therapy.42
taken together, these studies established prolonged
androgen suppression (of at least 2 years duration) combined with radiotherapy as a standard of care for patients
with high-risk, Gleason score 8–10, prostate cancer. one
criticism of the data supporting the use of long-term
hormone therapy plus radiotherapy in these patients is
that the trials did not include an androgen suppressiononly cohort. this shortcoming was addressed in a recent
scandinavian trial. widmark et al.42,43 studied a group of
875 men with locally advanced prostate cancer randomized to long-term indefinite androgen suppression alone
or long-term androgen suppression plus radiotherapy.
they noted that combination therapy reduced the
number of prostate-cancer-specific deaths by a factor of
two at 10 years (from 24% to 12%; P <0.001) and markedly
improved overall survival.43,44
unresolved issues
although combined radiotherapy and androgen suppression is now a well-accepted treatment for localized
nature reviews | urology
volume 7 | JanuarY 2010 | 33
© 2010 Macmillan Publishers Limited. All rights reserved
high-risk prostate cancer, there remains room for further
improvement. randomized trials to date have utilized
differing regimens. the clinical significance of these
variations has not been determined.45 the definition
of ‘prolonged androgen suppression’ is also a subject of
debate. it is generally accepted that 2–3 years of androgen
suppression results in better outcomes than 4–6 months,
but comparisons between 2 years and 3 years or 2 years
and 1 year have not been made. Crook et al.45 conducted
a trial of 3 months versus 8 months of neoadjuvant
androgen suppression, and noted a slight improvement
in survival in high-risk patients that received 8 months
of therapy but no significant improvement in outcomes
overall.46 recruitment of patients for an rtoG trial with
a similar protocol, rtoG 99-10, is complete but results
have not yet been reported. nevertheless, it is clear that
the benefits of prolonged androgen suppression are most
evident in patients with high-risk disease.
the question of whether elective treatment of the
pelvic lymph nodes provides any benefit in patients
undergoing radiotherapy for high-risk prostate cancer
has not been definitively addressed in clinical trials. men
with high-risk prostate cancer are most likely to develop
lymph node metastasis.47 although it has been customary to treat the lymph nodes in rtoG trials of highrisk prostate cancer, the benefit of pelvic lymph node
treatment has not been unequivocally established.48–50
as such, the role of elective nodal irradiation in these
patients remains controversial. elective irradiation
might become more clinically significant in the current
era of escalating radiotherapy doses; better control of
intraprostatic disease could result in a clinical situation where the treatment of occult nodal disease might
provide further improvement to outcomes.51 elucidation
of the exact role of nodal irradiation awaits further study.
this knowledge will help to optimize the role of androgen suppression therapy, as well as to define the risks
and benefits of androgen suppression in prostate cancer
more precisely.
no treatment is completely free of potential adverse
effects, and there has been concern regarding the
morbidity associated with androgen suppression therapy,
even of short duration. in addition to hot flashes, night
sweats, fatigue, and deterioration of sexual function,
some investigators have noted potential long-term toxicities including loss of bone density,52 gastrointestinal and
genitourinary morbidity, 53 and cardiac morbidity
and mortality.54–56 other investigators, however, have
failed to detect increased cardiac, gastrointestinal or
genitourinary morbidity in patients treated with longterm androgen suppression.42,57 reports of morbidity
should serve as an impetus for the prospective study of
potential adverse effects in randomized trials, as well as
for consideration of mitigation strategies (for example,
targeted therapy for patients with decreased bone
density).58,59 evidence supporting morbidity associated
with long-term androgen suppression indicates that the
risk:benefit ratio will be most favorable for patients with
high-risk disease, for whom the magnitude of treatment
effect is greatest.
Adjuvant chemotherapy
now that combined long-term androgen suppression
and radiotherapy are commonly used to treat highrisk prostate cancer, interest has turned to therapeutic
enhancement. as the vast majority of patients who
die from prostate cancer have widespread metastases,
one possible means of augmenting treatment results
is systemic therapy directed against micrometastatic
disease presumed to be present at the time of diagnosis
of clinically localized high-risk disease. improvements
in chemotherapy led to the hypothesis that cytotoxic
agents administered during initial treatment of men
with high-risk nonmetastatic prostate cancer would
target androgen-insensitive clones earlier in the course
of disease, thereby improving therapeutic outcomes.
the rtoG initiated a trial, rtoG 99-02, to test this
hypothesis. eligible participants were at higher risk of
disease progression than those enrolled in rtoG 92-02,
and included those with any t-stage tumor, Gleason score
≥7 and Psa 20–100 ng/ml, or palpable tumors, Gleason
score ≥8 and any Psa value. the trial comprised a standard therapy arm of radiotherapy with 2 years of androgen suppression, including combined androgen blockade
during the first 4 months and radiotherapy initiated after
2 months, similar to the experimental arm of rtoG 92-02.
Patients were randomized to either standard therapy
alone, or with the addition of four cycles of chemotherapy
with a three-drug regimen of paclitaxel, etoposide, and
estramustine. Chemotherapy was administered after the
initial period of combined androgen blockade and radiotherapy had been completed. 397 patients were accrued
before the trial was terminated prematurely; increased
thromboembolic toxicity (attributed to estramustine)
had been noted in the adjuvant chemotherapy arm.
analysis of initial efficacy has yet to be performed.60
a successor trial, rtoG 05-21, was subsequently initiated. it used the same basic protocol as rtoG 99-02, but
with updated radiotherapy techniques and doses, and a
chemotherapy regimen of docetaxel and prednisone. 60
this regimen had previously been shown to increase
survival in patients with metastatic hormone-refractory
prostate cancer.61 the trial completed accrual of 612
patients in august 2009. results are yet to be published.
the ability to recruit patients to randomized trials that
include chemotherapy for nonmetastatic disease suggests
that patients with prostate cancer will accept and tolerate
chemotherapy as a component of primary therapy.
in Britain, the stamPeDe clinical trial (medical
research Council Pr08) was initiated in 2005. this
study includes men with localized high-risk disease as
well as patients with known metastatic prostate cancer.
Participants are randomized to either long-term androgen suppression therapy alone or long-term androgen
suppression therapy with either docetaxel, zoledronic
acid, or celecoxib. a total of 3,000 patients is anticipated, with 500 patients reported to have been accrued
in 2008.62
trials examining the role of chemotherapy in conjunction with radical prostatectomy are also underway.63 the
Cancer and leukemia Group B has initiated a randomized
34 | JANUARY 2010 | volUme 7
© 2010 Macmillan Publishers Limited. All rights reserved
Table 2 | Phase III randomized trials of adjuvant chemotherapy for high-risk nonmetastatic prostate cancer
year closed
RTOG 99-0260
Long-term androgen suppression plus radiotherapy vs long-term androgen
suppression plus radiotherapy followed by four cycles of adjuvant chemotherapy
with paclitaxel, estramustine, and oral etoposide
CALGB 9020364
Neoadjuvant chemotherapy consisting of six cycles of estramustine and
docetaxel followed by radical prostatectomy versus radical prostatectomy alone
SwOG 99-2165
Radical prostatectomy followed by 2 years of androgen suppression with or
without six cycles of mitoxantrone
RTOG 05-2160
Long-term androgen suppression plus radiotherapy vs long-term androgen
suppression plus radiotherapy followed by six cycles of adjuvant chemotherapy
with docetaxel and prednisone
Abbreviations: CALGB, Cancer and Leukemia Group B; RTOG, Radiation Therapy Oncology Group; SwOG, Southwest Oncology Group.
Table 3 | Postprostatectomy radiotherapy for high-risk prostate cancer
Trial (year)
Progression-free survival
overall survival
rT (%)
alone (%)
P value
rT (%)
alone (%)
P value
German Cancer
Society (2009)82
P = 0.015
SwOG 87-94 (2006)80
P < 0.001
SwOG 87-94 (2009)83
P = 0.023
EORTC 22911 (2005)81
P <0.0001
Adjuvant radiotherapy was 60–64 Gy for stage pT3a or pT3b disease or evidence of positive margins. Abbreviations: EORTC, European Organization for Research
and Treatment of Cancer; NR, not reported; NS, not significant; RT, radiotherapy; SwOG, Southwest Oncology Group.
phase iii trial (90203) to compare therapy with estramustine and docetaxel before radical prostatectomy with
radical prostatectomy alone for patients with high-risk
disease.64 this trial is ongoing. the southwest oncology
Group conducted a study of chemotherapy with mitoxantrone and prednisone following radical prostatectomy.
983 patients were enrolled but the trial was halted owing
to three cases of acute myelogenous leukemia developing in the adjuvant chemotherapy arm.65 randomized
phase iii cooperative group trials of adjuvant chemotherapy for high-risk, but clinically and radiographically
localized, prostate cancer are summarized in table 2.
the toxicity of adjuvant chemotherapy noted in trials of
high-risk prostate cancer to date reinforces the need for
well-controlled multi-institutional randomized studies
that are large enough to detect important but infrequent
adverse effects as well as discern potential improvements
in tumor control associated with novel therapies.
Dose-escalated radiotherapy
local therapy for prostate cancer has been evolving concurrently with systemic treatment. Clinical trials initiated
during the 1980s and 1990s typically utilized radiation
doses of 70 Gy or less. in the past 10 years, development of
new radiotherapy techniques, such as three-dimensional
conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy and proton
therapy, has made delivery of higher doses of external
beam radiation feasible with acceptable morbidity.
randomized trials have demonstrated improved local
control and freedom from recurrence with higher radiation doses.66–71 in the mD anderson trial, doses of 78 Gy
were found to be superior to doses of 70 Gy,66,71 and in a
Dutch multicenter trial, doses of 78 Gy were noted to be
superior to doses of 68 Gy.70 these trials were conducted
primarily in low-risk and intermediate-risk populations,
but interest has developed in extending dose escalation
to high-risk cohorts.
Brachytherapy has long allowed the delivery of high
doses of radiotherapy to the prostate. in the absence of
data from a high number of large multicenter randomized
trials of brachytherapy for high-risk prostate cancer, the
experience of some institutions is noteworthy. researchers
have obtained favorable disease control and long-term
survival rates using high-dose rate brachytherapy in
combination with external beam radiotherapy.72–74 the
use of low-dose rate permanent prostate seed brachytherapy has also produced promising results according
to selected reports. it is generally accepted that androgen suppression does not improve control and survival
rates in patients with low-risk prostate cancer,75 but stock
et al.76,77 have reported favorable outcomes using a combined trimodal approach of external beam radiotherapy,
prostate seed brachytherapy, and 9 months of androgen suppression.76,77 Comparable results have also been
reported by a consortium of six north american centers
using a similar approach.78 approaches such as these utilizing brachytherapy for high-risk prostate cancer merit
further study in clinical trials, and must be validated in a
randomized, multi-institutional, and controlled setting.
Prostatectomy plus radiotherapy
treating patients with radical prostatectomy is advocated
by some urologists, and is considered by the national
nature reviews | urology
volume 7 | JanuarY 2010 | 35
© 2010 Macmillan Publishers Limited. All rights reserved
Comprehensive Cancer network to be an acceptable
primary treatment option for selected patients with lowvolume high-risk prostate cancer and a limited number of
adverse prognostic factors.79 the results of three randomized trials of adjuvant radiotherapy in high-risk patients,
typically categorized as pathologic stage t3n0 by virtue
of extracapsular extension, positive surgical margins,
or seminal vesicle invasion, have been reported. all
detected improvements in biochemical progression-free
survival with acceptable rates of toxicity (table 3).80–82
Furthermore, reports of swoG trial 87-94 noted a
marked improvement in overall survival following adjuvant radiation therapy.83 the magnitude of the improvement was striking, with a 10-year survival rate of 74%
in patients who received adjuvant radiotherapy, compared with 66% in patients who did not. Furthermore,
a 50% reduction in the number of biochemical failures
was noted with the use of adjuvant radiotherapy. more
than 15 years of follow-up were needed for the difference
in biochemical freedom from relapse to translate into
a survival benefit in this study, indicating the need for
long-term follow-up in clinical trials seeking to detect
an absolute survival benefit.
these studies have established a new standard of prostate cancer treatment that must include the concept of
combining surgery and radiotherapy. However, there
have not yet been any randomized trials comparing
radiotherapy plus prolonged androgen suppression with
radical prostatectomy followed by radiotherapy.
substantial progress has been made in reducing prostate cancer mortality over the past 20 years. improved
Jemal, A. et al. Cancer Statistics, 2009. CA
Cancer J. Clin. 59, 225–249 (2009).
Albertsen, P. C., Fryback, D. G., Storer, B. E.,
Kolon, T. F. & Fine, J. Long-term survival among
men with conservatively treated prostate cancer.
JAMA 274, 626–631 (1995).
Albertsen, P. C. A challenge to contemporary
management of prostate cancer. Nat. Clin. Pract.
Urol. 6, 12–13 (2009).
Ryan, C. J., Elkin, E. P., Cowan, J. & Carroll, P. R.
Initial treatment patterns and outcome of
contemporary prostate cancer patients with
bone metastases at initial presentation:
data from CaPSURE. Cancer 110, 81–86 (2007).
American Joint Committee on Cancer. AJCC
Staging Manual, 6th edn (Springer, New York,
Gleason, D. F. & Mellinger, G. T. Prediction of
prognosis for prostatic adenocarcinoma by
combined histological grading and clinical
staging. J. Urol. 111, 58–64 (1974).
Zagars, G. K., Ayala, A. G., von Eschenbach, A. C.
& Pollack, A. The prognostic importance of
Gleason grade in prostatic adenocarcinoma:
a long term-follow-up study of 648 patients
treated with radiation therapy. Int. J. Radiat.
Oncol. Biol. Phys. 31, 237–245 (1995).
Rioux-Leclercq, N. C., Chan, D. Y. & Epstein, J. I.
Prediction of outcome after radical
prostatectomy in men with organ-confined
Gleason score 8–10 adenocarcinoma. Urology
60, 666–669 (2002).
prognostic tools have made it possible to identify highrisk patients, and thus to focus efforts on testing novel
therapeutic approaches in these men. randomized trials
have identified groups of patients treated with primary
external beam radiotherapy who have better outcomes
when also treated with long-term androgen suppression,
and patients treated with radical prostatectomy whose
life is prolonged by adjuvant radiotherapy. Clinical trials
addressing the role of adjuvant chemotherapy have
been completed, and are awaiting maturation of data.
improved outcomes for low-risk and intermediate-risk
patients have been achieved with the incorporation of
higher radiotherapy doses into multimodal treatment
approaches. the use of dose-escalated radiotherapy in
high-risk patients has yet to be studied. other treatments
for high-risk patients, includin g biologic agents, 84,85
novel therapies targeting the hormonal axis, 86,87 and
bone-targeted therapies88,89 are also being investigated.
many therapies are being studied in patients with metastatic disease. agents shown to be effective in this setting
could be utilized in future trials of primary therapy for
men with high-risk prostate cancer.
Review criteria
we searched for original articles focusing on high-risk
prostate cancer in MEDLINE and PubMed published
between 1985 and 2009. The search terms we used
were “prostate cancer”, “high-risk prostate cancer”, “
Gleason score 8–10” and “clinical trials”. All papers
identified were English-language full-text papers. we also
searched the reference lists of identified articles, and
used our personal knowledge of the literature, to find
further papers.
Bastian, P. J. et al. Clinical and pathologic
outcome after radical prostatectomy for prostate
cancer patients with a preoperative Gleason Sum
of 8 to 10. Cancer 107, 1265–1272 (2006).
Zagars, G. K., Pollock, A. & Eschenbach, A. C.
Prognostic factors for clinically localized prostate
carcinoma: analysis of 938 patients irradiated in
the prostate specific antigen era. Cancer 79,
1370–1380 (1997).
Mitchell, R. E. et al. Preoperative serum prostate
specific antigen remains a significant prognostic
variable in predicting biochemical failure after
radical prostatectomy. J. Urol. 175, 1663–1667
Inman, B. A. et al. Long-term outcomes of radical
prostatectomy with multimodal adjuvant therapy
in men with a preoperative serum prostatespecific antigen level of > or = 50 ng/ml. Cancer
113, 1544–1551 (2008).
Pisansky, T. M., Kahn, M. J. & Bostwick, D. G. An
enhanced prognostic system for clinically
localized carcinoma of the prostate. Cancer 79,
2154–2161 (1997).
Soloway, M. & Roach, M. Prostate cancer
progression after therapy of primary curative
intent: a review of data from prostate-specific
antigen era. Cancer 104, 2310–2322 (2005).
Partin, A. w. et al. Combination of prostatespecific antigen, clinical stage, and Gleason
score to predict pathological stage of localized
prostate cancer. A multi-institutional update.
JAMA 277, 1445–1451 (1997).
36 | JANUARY 2010 | volUme 7
16. Kattan, M. w., Eastham, J. A., Stapleton, A. M.,
wheeler, T. M. & Scardino, P. T. A preoperative
nomogram for disease recurrence following
radical prostatectomy for prostate cancer. J. Natl
Cancer Inst. 90, 766–771 (1998).
17. Kattan, M. w. et al. Pretreatment nomogram for
predicting the outcome of three-dimensional
conformal radiotherapy in prostate cancer.
J. Clin. Oncol. 18, 3352–3359 (2000).
18. D’Amico, A. V. et al. Biochemical outcome after
radical prostatectomy, external beam radiation
therapy, or interstitial radiation therapy for
clinically localized prostate cancer. JAMA 280,
969–974 (1998).
19. Greene, K. L. et al. who is the average patient
presenting with prostate cancer? Urology 66,
76–82 (2005).
20. D’Amico, A. V., Chen, M. H., Roehl, K. A. &
Catalona, w. J. Preoperative PSA velocity and the
risk of death from prostate cancer after radical
prostatectomy. N. Engl. J. Med. 351, 125–135
21. D’Amico, A. V., Renshaw, A. A., Sussman, B. &
Chen, M. H. Preoperative PSA velocity and risk of
death from prostate cancer following external
beam radiation therapy. JAMA 294, 440–447
22. Hanks, G. E., Hanlon, A. L., Lee, w. R., Slivjak, A.
& Schultheiss, T. E. Pretreatment prostatespecific antigen doubling times: clinical utility of
this predictor of prostate cancer behavior. Int. J.
Radiat. Oncol. Biol. Phys. 34, 549–553 (1996).
© 2010 Macmillan Publishers Limited. All rights reserved
23. Roberts, S. G., Blute, M. L., Bergstralh, E. J.,
Slezak, J. M. & Zincke, H. PSA doubling time as
a predictor of clinical progression after
biochemical failure following radical
prostatectomy for prostate cancer. Mayo Clin.
Proc. 76, 576–581 (2001).
24. Grossfeld, G. D. et al. Predicting disease
recurrence in intermediate and high-risk patients
undergoing radical prostatectomy using percent
positive biopsies: results from CaPSURE.
Urology 59, 560–565 (2002).
25. Dong, F. et al. Prostate cancer volume at biopsy
predicts clinically significant upgrading. J. Urol.
179, 896–900 (2008).
26. whittemore, D. E. et al. Significance of tertiary
Gleason pattern 5 in Gleason Score 7 radical
prostatectomy specimens. J. Urol. 179,
516–522 (2008).
27. Nanda, A., Chen, M. H., Renshaw, A. A. &
D’Amico, A. V. Gleason pattern 5 prostate
cancer: further stratification of patients with
high-risk disease and implications for future
randomized trials. Int. J. Radiat. Oncol. Biol. Phys.
74, 1419–1423 (2009).
28. Roach, M., waldman, F. & Pollack, A. Predictive
models in external beam radiotherapy for
clinically localized prostate cancer. Cancer 115,
3112–3120 (2009).
29. Pilepich, M. V. et al. Phase III trial of androgen
suppression using goserelin in unfavorableprognosis carcinoma of the prostate treated with
definitive radiotherapy: report of Radiation
Therapy Oncology Group Protocol 85–31. J. Clin.
Oncol. 15, 1013–1021 (1997).
30. Lawton, C. A. et al. Updated results of the
phase III Radiation Therapy Oncology Group
(RTOG) trial 85–31 evaluating the potential
benefit of androgen suppression following
standard radiation therapy for unfavorable
prognosis carcinoma of the prostate. Int. J.
Radiat. Oncol. Biol. Phys. 49, 937–946 (2001).
31. Pilepich, M. V. et al. Androgen suppression
adjuvant to definitive radiotherapy in prostate
adenocarcinoma—long-term results of phase III
RTOG 85–31. Int. J. Radiat. Oncol. Biol. Phys. 61,
1285–1290 (2005).
32. Pilepich, M. V. et al. Androgen deprivation with
radiation therapy compared with radiation
therapy alone for locally advanced prostatic
carcinoma: a randomized comparative trial of
the Radiation Therapy Oncology Group. Urology
45, 616–623 (1995).
33. Pilepich, M. V. et al. Phase III radiation therapy
oncology group (RTOG) trial 86–10 of androgen
deprivation adjuvant to definitive radiotherapy in
locally advanced carcinoma of the prostate. Int.
J. Radiat. Oncol. Biol. Phys. 50, 1243–1252
34. Roach, M. et al. Short-term neoadjuvant
androgen deprivation therapy and external-beam
radiotherapy for locally advanced prostate
cancer: long-term results of RTOG 8610. J. Clin.
Oncol. 26, 585–591 (2008).
35. D’Amico, A. V. et al. 6-month androgen
suppression plus radiation therapy vs radiation
therapy alone for patients with clinically localized
prostate cancer: a randomized controlled trial.
JAMA 292, 821–827 (2004).
36. Denham, J. w. et al. Short-term androgen
deprivation and radiotherapy for locally advanced
prostate cancer: results form the Trans-Tasman
Radiation Oncology group 96.01 randomised
controlled trial. Lancet Oncol. 6, 841–850
37. Bolla, M. et al. Improved survival in patients with
locally advanced prostate cancer treated with
radiotherapy and goserelin. N. Engl. J. Med. 337,
295–300 (1997).
38. Bolla, M. et al. Long-term results with immediate
androgen suppression and external irradiation in
patients with locally advanced prostate cancer
(an EORTC study): a phase III randomised trial.
Lancet 360, 103–106 (2002).
39. Bolla, M., Descotes, J. L., Artignan, X. &
Fourneret, P. Adjuvant treatment to radiation:
combined hormone therapy and external
radiotherapy for locally advanced prostate
cancer. BJU Int. 100, 44–47 (2007).
40. Hanks, G. E. et al. Phase III trial of long-term
adjuvant androgen deprivation after neoadjuvant
hormonal cytoreduction and radiotherapy in
locally advanced carcinoma of the prostate:
the Radiation Therapy Oncology Group Trial
92–02. J. Clin. Oncol. 21, 3972–3978 (2003).
41. Horwitz, E. M. et al. Ten-year follow-up of
radiation therapy oncology group protocol
92–02: a phase III trial of the duration of
elective androgen deprivation in locally
advanced prostate cancer. J. Clin. Oncol. 26,
2497–2504 (2008).
42. Bolla, M. et al. Duration of androgen
suppression in the treatment of prostate cancer.
N. Engl. J. Med. 360, 2516–2527 (2009).
43. widmark, A. et al. Endocrine treatment, with or
without radiotherapy, in locally advanced
prostate cancer (SPCG-7/SFUO-3): an open
randomised phase III trial. Lancet 373, 301–308
44. Rosenthal, S. A. Prostate cancer: local control
and radiotherapy matter in prostate cancer. Nat.
Rev. Urol. 6, 250–251 (2009).
45. Nanda, A. et al. Total androgen blockade versus
a luteinizing hormone-releasing hormone agonist
alone in men with high-risk prostate cancer
treated with radiotherapy. Int. J. Radiat. Oncol.
Biol. Phys. doi:10.1016/j.ijrobp.2009.03.034.
46. Crook, J. et al. Report of a multicenter Canadian
phase III randomized trial of 3 months vs.
8 months neoadjuvant androgen deprivation
before standard-dose radiotherapy for clinically
localized prostate cancer. Int. J. Radiat. Oncol.
Biol. Phys. 60, 15–23 (2004).
47. Roach, M. et al. Predicting the risk lymph node
involvement using the pre-treatment prostate
specific antigen and Gleason score in men with
clinically localized prostate cancer. Int. J. Radiat.
Oncol. Biol. Phys. 28, 33–37 (1994).
48. Roach, M. et al. Phase III trial comparing wholepelvic versus prostate-only radiotherapy and
neoadjuvant versus adjuvant combined
androgen suppression: Radiation Therapy
Oncology Group 9413. J. Clin. Oncol. 21,
1904–1911 (2004).
49. Lawton, C. A. et al. An update of the phase III
trial comparing whole pelvic to prostate only
radiotherapy and neoadjuvant to adjuvant total
androgen suppression: updated analysis of
RTOG 94–13, with emphasis on unexpected
hormone/radiation interactions. Int. J. Radiat.
Oncol. Biol. Phys. 69, 646–655 (2007).
50. Pommier, P. et al. Is there a role for pelvic
irradiation in localized prostate adenocarcinoma?
Preliminary Results of GETUG-01. J. Clin. Oncol.
25, 5366–5373 (2007).
51. Nguyen, P. L. & D’Amico, A. V. Targeting pelvic
lymph nodes in men with intermediate- and highrisk prostate cancer despite two negative
randomized trials. J. Clin. Oncol. 26, 2055–2056
52. Shahinian, V. B., Kuo, Y. F., Freeman, J. L. &
Goodwin, J. S. Risk of fracture after androgen
deprivation for prostate cancer. N. Engl. J. Med.
352, 154–164 (2005).
53. Feigenberg, S. J. et al. Long-term androgen
deprivation increases Grade 2 and higher late
morbidity in prostate cancer patients treated
nature reviews | urology
with three-dimensional conformal radiation
therapy. Int. J. Radiat. Oncol. Biol. Phys. 62,
397–405 (2005).
D’Amico, A. V. et al. Influence of androgen
suppression therapy for prostate cancer on the
frequency and timing of fatal myocardial
infarction. J. Clin. Oncol. 25, 2420–2425 (2007).
Saigal, C. S. et al. Androgen deprivation therapy
increases cardiovascular morbidity in men with
prostate cancer. Cancer 110, 1493–1500
Tsai, H. K., D’Amico, A. V., Sadetsky, N.,
Chen, M. H. & Carroll, P. R. Androgen deprivation
therapy for localized prostate cancer and the risk
of cardiovascular mortality. J. Natl Cancer Inst.
99, 1516–1524 (2007).
Lawton, C. A., Bae, K., Pilepich, M., Hanks, G. &
Shipley, w. Long-term treatment sequelae after
external beam irradiation with or without
hormonal manipulation for adenocarcinoma of
the prostate: analysis of radiation therapy
oncology group studies 85–31, 86–10, and
92–02. Int. J. Radiat. Oncol. Biol. Phys. 70,
437–441 (2008).
Israeli, R. S., Ryan, C. w. & Jung, L. L. Managing
bone loss in men with locally advanced prostate
cancer receiving androgen deprivation therapy.
J. Urol. 179, 414–423 (2008).
Smith, M. R. et al. Denosumab in men receiving
androgen-deprivation therapy for prostate
cancer. N. Engl. J. Med. 361, 745–755 (2009).
Rosenthal, S. A. et al. Phase III multi-institutional
trial of adjuvant chemotherapy with paclitaxel,
estramustine, and oral etoposide combined with
long-term androgen suppression therapy and
radiotherapy versus long-term androgen
suppression plus radiotherapy alone for high-risk
prostate cancer: preliminary toxicity analysis of
RTOG 99–02. Int. J. Radiat. Oncol. Biol. Phys. 73,
672–678 (2009).
Tannock, I. F. et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced
prostate cancer. N. Engl. J. Med. 351,
1502–1512 (2004).
James, N. D. et al. Systemic therapy for
advancing or metastatic prostate cancer
(STAMPEDE): a multi-arm, multistage
randomized controlled trial. BJU Int. 103,
464–469 (2008).
Oh, w. K. An overview of chemotherapy trials in
localized and recurrent nonmetastatic prostate
cancer. J. Urol. 172, S34–S37 (2004).
Eastham, J. A., Kelly, w. K., Grossfeld, G. D. &
Small, E. J. Cancer and Leukemia Group B
(CALGB) 90203: a randomized phase 3 study of
radical prostatectomy alone versus
estramustine and docetaxel before radical
prostatectomy for patients with high-risk
localized disease. Urology 62, 55–62 (2003).
Flaig, T. w. et al. Randomization reveals
unexpected acute leukemias in Southwest
Oncology Group prostate cancer trial. J. Clin.
Oncol. 26, 1532–1536 (2008).
Pollack, A. et al. Prostate cancer radiation dose
response: results of the M. D. Anderson
phase III randomized trial. Int. J. Radiat. Oncol.
Biol. Phys. 53, 1097–1105 (2002).
Dearnaley, D. P. et al. Phase III pilot study of dose
escalation using conformal radiotherapy in
prostate cancer: PSA control and side effects.
Br. J. Cancer 92, 488–498 (2005).
Zeitman, A. L. et al. Comparison of conventionaldose vs high-dose conformal radiation therapy in
clinically localized adenocarcinoma of the
prostate: a randomized controlled trial. JAMA
294, 1233–1239 (2005).
Dearnaley, D. P. et al. Escalated-dose versus
standard-dose conformal radiotherapy in
volume 7 | JanuarY 2010 | 37
© 2010 Macmillan Publishers Limited. All rights reserved
prostate cancer: first results from the MRC
RT01 randomised controlled trial. Lancet Oncol.
8, 475–487 (2007).
Al-Mamgani, A. et al. Update of Dutch multicenter
dose-escalation trial of radiotherapy for localized
prostate cancer. Int. J. Radiat. Oncol. Biol. Phys.
72, 980–988 (2008).
Kuban, D. A. et al. Long-term results of the M. D.
Anderson randomized dose-escalation trial for
prostate cancer. Int. J. Radiat. Oncol. Biol. Phys.
70, 67–74 (2008).
Martinez, A. A. et al. Dose escalation using
conformal high-dose-rate brachytherapy
improves outcome in unfavorable prostate
cancer. Int. J. Radiat. Oncol. Biol. Phys. 53,
316–327 (2002).
Vicini, F. A., Vargas, C., Edmunson, G., Kestin, L.
& Martinez, A. The role of high-dose rate
brachytherapy in locally advanced prostate
cancer. Semin. Radiat. Oncol. 13, 98–108
Demanes, D. J., Rodriguez, R. R., Schour, L.,
Brandt, D. & Altieri, G. High-dose-rate intensitymodulated brachytherapy with external beam
radiotherapy for prostate cancer: California
endocurietherapy’s 10-year results. Int. J. Radiat.
Oncol. Biol. Phys. 61, 1306–1316 (2005).
Lee, w. R. The role of androgen deprivation
therapy combined with prostate brachytherapy.
Urology 60, 39–44 (2002).
Stock, R. G., Ho, A., Cesaretti, J. A. &
Stone, N. N. Changing the patterns of failure for
high-risk prostate cancer patients by optimizing
local control. Int. J. Radiat. Oncol. Biol. Phys. 66,
389–394 (2006).
77. Stock, R. G., Cesaretti, J. A., Hall, S. J. &
Stone, N. N. Outcomes for patients with highgrade prostate cancer treated with a
combination of brachytherapy, external beam
radiotherapy and hormonal therapy. BJU Int.
104, 1631–1636 (2009).
78. Stone, N. N. et al. Multicenter analysis of
effect of high biologic effective dose on
biochemical failure and survival outcomes in
patients with Gleason score 7–10 prostate
cancer treated with permanent prostate
brachytherapy. Int. J. Radiat. Oncol. Biol. Phys.
73, 341–346 (2009).
79. Mohler, J. L. Updating the prostate cancer
guidelines. J. Natl Compr. Canc. Netw. 5,
647–648 (2007).
80. Thompson, I. M. et al. Adjuvant radiotherapy for
pathologically advanced prostate cancer:
a randomized clinical trial. JAMA 296,
2329–2335 (2006).
81. Bolla, M. et al. Postoperative radiotherapy after
radical prostatectomy: a randomized controlled
trial (EORTC trial 22911). Lancet 366,
572–576 (2005).
82. weigel, T. et al. Phase III postoperative
adjuvant radiotherapy after radical
prostatectomy compared with radical
prostatectomy alone in pT3 prostate cancer
with postoperative undetectable prostatespecific antigen: ARO 96–02/AUO AP 09/95.
J. Clin. Oncol. 27, 2924–2930 (2009).
83. Thompson, I. M. et al. Adjuvant radiotherapy for
pathological T3N0M0 prostate cancer
significantly reduces risk of metastases and
improves survival: long-term followup of a
38 | JANUARY 2010 | volUme 7
randomized clinical trial. J. Urol. 181, 956–962
Aragon-Ching, J. B. & Dahut, w. L. The role of
angiogenesis inhibitors in prostate cancer.
Cancer J. 14, 20–25 (2008).
Aragon-Ching, J. B. & Dahut, w. L. VEGF
inhibitors and prostate cancer therapy. Curr. Mol.
Pharmacol. 2, 161–168 (2009).
Attard, G. et al. Phase I clinical trial of a selective
inhibitor of CYP17, abiraterone acetate, confirms
that castration-resistant prostate cancer
commonly remains hormone driven. J. Clin.
Oncol. 26, 4563–4571 (2008).
Tran, C. et al. Development of a secondgeneration antiandrogen for treatment of
advanced prostate cancer. Science 324,
787–790 (2009).
Nilsson, S. et al. Bone-targeted radium-223 in
symptomatic, hormone-refractory prostate
cancer: a randomised, multicentre, placebocontrolled phase II study. Lancet Oncol. 8,
587–594 (2007).
Tu, S. M. & Lin, S. H. Current trials using bonetargeting agents in prostate cancer. Cancer J. 14,
35–39 (2008).
The authors would like to thank Heidi Mortensen,
Medical Librarian, for her great help in assembling the
Charles P. Vega, University of California, Irvine, CA is
the author of and is solely responsible for the content
of the learning objectives, questions and answers of
the MedscapeCME-accredited continuing medical
education activity associated with this article.
© 2010 Macmillan Publishers Limited. All rights reserved