Recent advances in the radiotherapeutic
management of localized prostate cancer have focused on methods of
improving local control with the use of brachytherapy and conformal
dose escalation. In addition, androgen suppression has been used to
enhance cytoreduction prior to and induce synergistic cell kill
during radiation therapy, as well as to address microscopically
The implications and treatment of regional lymph node metastases in
patients with prostate cancer have not received as much attention.
The optimal treatment approach for these patients remains
controversial. Most patients undergoing radiation therapy are not
surgically staged. Therefore, an important unresolved issue is
whether prophylactic pelvic irradiation is beneficial in patients at
high risk for lymph node involvement. In order to help clarify these
issues, the following questions need to be addressed:
With the trend toward the diagnosis of earlier-stage prostate cancer,
has the incidence of lymph node metastases changed? Also, what is the
current percentage of patients harboring lymph node metastases who
potentially could benefit most from prophylactic pelvic irradiation?
What is the natural history of lymph node-positive prostate cancer,
and is node positivity synonymous with systemic disease ?
Is there a subset of patients with apparently pathologically negative
lymph nodes who have occult nodal disease that could be eradicated by
prophylactic pelvic irradiation?
What do both prospective and retrospective clinical studies examining
the effect of pelvic irradiation on nodepositive prostate cancer
reveal about the behavioral patterns of this disease and the efficacy
of pelvic irradiation?
Does pelvic irradiation improve outcome over prostate-alone
irradiation in comparative series?
The presentation of prostate cancer has shifted to earlier stages
with lower tumor volumes. This shift is due to the widespread use of
prostate-specific antigen (PSA) as a detection tool.
Paralleling the change to earlier-stage disease at presentation has
been a decrease in the incidence of pelvic lymph node metastases. In
a 1959 study by Flocks et al, of 411 patients undergoing pelvic lymph
node dissection, 146 (36%) had lymph node metastases. Reporting on
511 patients who underwent lymph node dissection prior to receiving
radiation therapy from 1966 to 1979, Gervasi et al found that 152
(30%) had lymph node metastases.
In the 1970s, radical prostatectomy series revealed node-positive
disease in approximately 35% of patients.[3-5] A review of
lymphadenectomy series from that time found that, overall, 30% (726/2,458)
of men had lymph node metastases.
Few data were published on this topic in the early to mid-1980s. In
the late 1980s and early 90s, however, data emerged revealing a
lower yield of positive lymph nodes. Reports showed rates of node
positivity ranging from 3.7% to 7.7% in patients undergoing radical
prostatectomy.[7,8] In a series published by Stock et al, 10% of
patients undergoing laparoscopic pelvic lymph node dissection prior
to external-beam irradiation or brachytherapy were found to have
positive lymph nodes.
In a recent series by Partin et al, only 5% of 4,133 patients
undergoing radical prostatectomy had lymph node involvement.
These data demonstrate that, currently, 5% to 10% of patients with
newly diagnosed prostate cancer harbor pathologically positive lymph
node nodes, depending on the risk features of the study population.
The natural history of lymph node-positive disease is difficult to
define. Most of the data on node-positive patients reveal a high
propensity toward the development of metastatic disease.
In a series of 1,078 patients treated with iodine-125 prostate
implants reported by Leibel et al, the rate of freedom from distant
metastases at 15 years ranged from 4% to 8%, depending on the extent
of nodal disease. In this analysis, local control of the primary
tumor had no effect on the development of distant metastases in
patients with node-positive disease. This led the authors to conclude
that distant micrometastatic dissemination already exists at the time
of initial diagnosis in these patients.
Similar conclusions were reached by Gervasi et al, who showed that
the risk of developing distant metastases at 10 years was 83% in
patients with node-positive disease vs 31% in those with node-negative
disease. Other studies have supported the theory that nodal
disease is synonymous with microscopic distant disease.[12-15]
Other investigators suggest the existence of a subset of
node-positive prostate cancer patients who have locoregional disease
without distant dissemination at presentation. This subset of early node-positive
patients includes those with a single lymph node metastasis, low- to
moderate-grade tumors, or diploid tumors.[16-19]
In a study of 42 patients with node-positive prostate cancer treated
with radical prostatectomy, Golimbu et al found that 50% of patients
with only one node involved were alive at 10 years, as compared with
no patient with metastases in more than one node. Davidson et al
examined 61 patients with lymph node metastases who remained
untreated until disease progression. They found that 36% of patients
with grade 1 or 2 disease were free of disease progression at 5
years, as opposed to 0% of those with grade 3 disease (P < .001).
Zincke et al studied 370 patients with stage D1 disease treated with
radical prostatectomy and hormonal therapy. Their analysis revealed
that 72% of patients with diploid tumors were free of systemic
progression at 10 years, as compared with 45% of those with aneuploid
tumors (P < .0001).
A subset of node-positive patients with locoregional, nonmetastatic
disease has also been shown to exist among patients with cervical,
breast, or head and neck cancers.[20-22] With respect to prostate
cancer, it is this subgroup of node-positive patients with
locoregional disease only who could potentially benefit most from
prophylactic pelvic irradiation.
The detection of prostate cancer cells by the expression of
prostate-specific genes at the messenger RNA (mRNA) level has opened
up the possibility of detecting metastases at the molecular
stage.[23,24] Using the reverse transcription-polymerase chain
reaction for PSA (RTPCR-PSA) and prostate-specific membrane antigen
(RTPCR-PSM), we tested whether tumor spread could be detected in the
pelvic lymph nodes of 33 patients with high-risk prostate cancer
undergoing laparoscopic lymph node dissection prior to radiation
therapy. Overall, four patients (12%) had pathologically positive
lymph nodes. Of the 29 patients with pathologically negative nodes,
15 (52%) were positive for RTPCR-PSA.
An update of these data found that patients with high-grade cancers
were at highest risk for having RTPSR-PSA-positive nodes. Of 72
patients, 56 had Gleason scores ³ 7
and 15 had scores £ 6. Nodes were
RTPCR-PSA-positive in 49% of patients with high-grade cancers vs 20%
of those with low-grade cancers (P = .04).
The prognostic significance of lymph node RTPCR-PSA positivity was
suggested by Edelstein et al, who tested archived lymph node
specimens from patients who had undergone radical prostatectomy for
the presence of RTPCR-PSA. In this series, 88% of patients whose
lymph nodes were positive for RTPCR-PSA experienced disease
recurrence, as compared with 33% of patients with RTPCR-PSA-negative nodes.
These studies suggest that there may be a subgroup of pathologic
lymph node-negative patients who harbor occult lymph node disease,
which can be detected by a highly sensitive assay. Furthermore, as
demonstrated by the study of Edelstein et al, these patients may
develop disseminated disease if left untreated. This subset of
patients may benefit from pelvic irradiation.
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