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Management of Locally Advanced Prostate Cancer

Management of Locally Advanced Prostate Cancer

ABSTRACT: The staging and treatment of prostate cancer are complex, particularly in patients with clinical disease that has advanced locally beyond the confines of the gland. Management choices are made more difficult by a paucity of quality randomized and controlled studies. Staging has traditionally relied on digital rectal examination, which is now being augmented by improved noninvasive radiologic studies. Radiation is the most common form of treatment today, and newer techniques are being examined and compared to external-beam therapy. Surgical intervention as monotherapy has failed to show a survival advantage. Current approaches treatment appear to be evolving toward combination therapies, potentially incorporating hormonal manipulation. Patients with locally advanced disease should be encouraged to enter prospective clinical trials. [ONCOLOGY 10(9):1289-1300, 1996]


Prostate cancer has overtaken lung cancer as the most prevalent
malignancy in males, and is now the second most common cause of
cancer death in men. As the proportion of elderly males in the
population has grown, so too has the incidence of prostate cancer.
Improved screening programs, utilization of the prostate-specific
antigen (PSA) blood assay, and a greater awareness of prostate
cancer as a disease entity have resulted in a dramatically increased
overall detection rate, particularly for organ-confined tumors.

Up to two-thirds of newly diagnosed cases of prostate cancer are
clinically confined to the gland at presentation. Therapeutic
intervention, including surgery or radiation, will be recommended
for many of these patients. Those men with distant metastatic
disease at initial diagnosis will likely receive hormonal therapy.
Finally, a subset of patients will present with locally advanced
disease. Therapeutic alternatives for this last group of patients
are quite varied, and there is no clear consensus as to which
alternative is most appropriate.

Natural History

The choice among the different management options for prostate
cancer patients, particularly those with locally advanced lesions,
is made more difficult by the complex natural history of the disease.
Similar to other malignancies, progression of prostate cancer
is related to both disease stage and tumor grade at the time of
diagnosis. The rate and severity of progression, however, often
are much slower with prostate cancer than normally seen with other
common tumors.

In a study by Johansson et al, patients who presented with low-stage
prostate cancers did not receive treatment until the time of disease
progression. Only 8.5% of these patients ultimately succumbed
to prostate carcinoma, and the 10-year disease-free survival rate
was 86.8%. The same study emphasized the importance of tumor grade.
Patients initially diagnosed with grade 3 (poorly differentiated)
tumors had a relative risk of dying from their prostate cancer
58.4 times that of patients with grade 1 (well-differentiated)

Research by Stamey et al demonstrated the effect of prostate cancer
volume on disease progression. Most tumors with volumes moer than
12 cm³ are associated with adverse pathologic features, including
nodal disease and seminal vesicle invasion. Larger tumors, therefore,
are more likely to metastasize,[2] while prostate cancer lesions
with volumes less than 4 cm³ rarely spread.[3]

Prostatic capsular penetration by tumor cells, also has prognostic
significance, particularly important are the location and amount
of capsular violation. Epstein et al reported a higher rate of
tumor progression in the presence of established penetration of
the capsule, as compared with focal involvement.[4]


Prostate cancer has traditionally been staged according to the
American Urological Association (AUA) classification as stage
A, B, C, or D; more recently, the tumor, node, metastasis (TNM)
system has gained popularity (Table 1). The term "clinically
locally advanced prostate cancer" refers to lesions defined
as clinical stage C or T3-T4, N0 disease. These cancers have penetrated
through the prostatic capsule, often invading the seminal vesicles.

Clinical staging of prostate cancer can be imprecise. In a review
of 703 men with clinically localized prostate cancer, Partin et
al found that as many as 38% had established capsular penetration
during pathologic examination following radical prostatectomy.[5]
Nodal metastasis varies in frequency according to tumor grade
and stage, and is seen more often in the setting of seminal vesicle
involvement than gross capsular penetration.[6]

Staging Modalities

Digital rectal examination (DRE) is the oldest staging
modality, but is limited in its inability to give precise estimates
of tumor volume and in the differentiation of stage B from early
stage C lesions.[7] Phillips and Thompson found that only 39%
of their clinical B1 patients had pathologically confined tumors
at the time of prostatectomy.[8] Digital rectal examination is
unlikely to overstage, however, and patients with evidence of
locally advanced disease on physical examination will usually
have extraprostatic tumor extension on pathologic evaluation.

Prostate-specific antigen has gained widespread use in
the detection and monitoring of prostate carcinoma. Although PSA
levels can be suggestive of tumor volume and stage, categorical
values for determining various stages do not exist currently.

Transrectal ultrasound (TRUS) is an imaging tool utilized
primarily to guide needle biopsy of the prostate. Estimates of
TRUS staging accuracy vary, with a sensitivity of 35% to 85% for
extracapsular extension.[9-16] Tranrectal ultrasound-guided needle
biopsy of suspicious periprostatic regions can confirm the presence
of non-organ-confined disease.

Tranrectal ultrasound has been shown to be a more accurate staging
tool than DRE. In one study, TRUS correctly predicted the local
extent of disease in 84% of patients, whereas DRE understaged
64% of patients.[17]

Computed Tomography (CT) has been insufficiently accurate
for preoperative staging of prostate cancer and fails to demonstrate
the needed precision to evaluate for local extent of this disease.[18-22]

Magnetic Resonance Imaging (MRI)--The staging efficacy
of MRI has improved with the introduction of endorectal coil techniques;
sensitivity ranges from 37% to 80% for body coil MRI vs 63% to
91% for endorectal coil MRI).[13,23-29] Studies comparing the
staging efficacy of TRUS and MRI have shown a sensitivity for
advanced disease from 35% to 66% for TRUS, 47% to 76% for body
coil MRI, and 91% for endorectal coil MRI.[13,14,16]

Relative to body coil imaging, endorectal coil MRI provides higher
contrast and better spatial resolution when imaging the prostate,
capsule, and perioprostatic tissues, including the neurovascular
bundles and seminal vesicles (Figures 1 and 2).[30-33] Fast-spin
echo-pulse sequences, as well as the use of glucagon, can further
improve image quality while decreasing examination time and motion
artifact.[28,34] The multicoil array technique offers more uniform
signal-to-noise ratios and better image resolution for the evaluation
of extracapsular disease and visualization of the anterior aspect
of the gland.[20,27,32,34] Post-biopsy hemorrhage can be misinterpreted
as extracapsular tumor extension, and staging accuracy improves
significantly when MRI of the prostate is deferred for at least
21 days after biopsy.[35]

D'Amico et al recently demonstrated that endorectal coil MRI improved
the detection of clinically unsuspected seminal vesicle involvement
and extracapsular extension in a heterogeneous subgroup of patients
with moderately elevated PSA (more than 10 to 20 ng/mL) and a
Gleason score of 5 to 7.[36] A limiting factor with present imaging
techniques is the inability to detect microscopic capsular penetration.
However, endorectal coil MRI is the standard to which all imaging
is compared for staging efficacy analysis.[27,36] It is the imaging
modality of choice when assistance with clinical staging is required.


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