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.
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
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, while prostate cancer lesions
with volumes less than 4 cm³ rarely spread.
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.
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.
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.
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. Phillips and Thompson found that only 39%
of their clinical B1 patients had pathologically confined tumors
at the time of prostatectomy. 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.
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.
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. 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.
1. Johansson JE, Adami HO, Andersson SO, et al: High 10-year survival
rate in patients with early, untreated prostatic cancer. JAMA
2. Stamey TA, Villers AA, McNeal JE, et al: Positive surgical
margins at radical prostatectomy-importance of apical dissection.
J Urol 143:1166-1173, 1990.
3. McNeal JE, Bostwick DG, Kindrachuk RA, et al: Patterns of progression
in prostate cancer. Lancet 1:60-63, 1986.
4. Epstein JI, Carmichael MJ, Pizov G, et al: Influence of capsular
penetration on progression following radical prostatectomy: a
study of 196 cases with long-term follow-up. J Urol 150:135-141,
5. Partin AW, Yoo J, Carter HB, et al: The use of prostate specific
antigen. clinical stage, and Gleason score to predict pathologic
stage in men with localized prostate cancer. J Urol 150:110, 1993.
6. Lange PH, Naravan P: Understaging and undergrading of prostate
cancer: argument for postoperative radiation as adjuvant therapy.
Urology 21:112-118, 1983.
7. Palken M, Cobb OE, Warren BH, et al: Prostate cancer: Correlation
of digital rectal examination, transrectal ultrasound and prostate
specific antigen levels with tumor volume in radical prostatectomy
specimens. J Urol 143:1155-1162, 1990.
8. Phillips TH, Thompson IM: Digital rectal examination and carcinoma
of the prostate. Urol Clin North Am 18:459-465, 1991.
9. Pontes JE, Eisenkraft S, Watanabe H, et al: Preoperative evaluation
of localized prostatic carcinoma by transrectal ultrasound. J
Urol 134:289, 1985.
10. Salo JO, Kivisaari L, Rannikko S, et al: Computerized tomography
and transrectal ultrasound in the assessment of local extension
of prostatic cancer before radical retropubic prostatectomy. J
Urol 137:435, 1987.
11. Andriole GL, Coplen DE, Mikkelsen DJ, et al: Sonographic and
pathological staging of patients with clinically localized prostate
cancer. J Urol 142:1259, 1989.
12. Hardeman SW, Causey JQ, Hickey DP, et al: Transrectal ultrasound
for staging prior to radical prostatectomy. Urology 34:175, 1989.
13. Rifkin MD, Zerhouni EA, Gatsonis CA, et al: Comparison of
magnetic resonance imaging and ultrasonography in staging early
prostate cancer: Results of a multi-institutional cooperative
trial. N Engl J Med 323:621, 1990.
14. Schiebler ML, McSherry S, Keefe B, et al: Comparison of the
digital rectal examination endorectal ultrasound and body coil
magnetic resonance imaging in the staging of adenocarcinoma of
the prostate. Urol Radiol 13:110, 1991.
15. Rorvik J, Halvorsen OJ, Servoll E, et al: Transrectal ultrasonography
to assess local extent of prostatic cancer before radical prostatectomy.
Br J Urol 73:65, 1994.
16. Presti JC. Hricak H, Narayan PA, et al: Local staging of prostatic
carcinoma: Comparison of transrectal sonography and endorectal
MR imaging. Am J Roentgenol 166:103, 1996.
17. Perrapato SD, Carothers GC, Maatman TJ, et al: Comparing clinical
staging plus transrectal ultrasound and prostate specific antigen
levels with tumour volumes in radical prostatectomy specimens.
Urology 33:103-105, 1989.
18. Golimbu M, Morales P, Al-Askari S, et al: CAT scanning in
staging of prostatic cancer. Urology 13:305, 1981.
19. Platt JF, Bree RL, Schwab RE: The accuracy of CT in staging
of carcinoma of the prostate. Am J Roentgenol 149:315, 1987.
20. Hricak H, Dooms GC, Jeffrey RB, et al: Prostatic carcinoma:
Staging by clinical assessment, CT, and MR imaging. Radiology
21. Engeler CE, Wasserman NF, Zhang G: Preoperative assessment
of prostatic carcinoma by computerized tomography. Weaknesses
and new perspectives. Urology 40:346, 1992.
22. Rorvik J, Halvorsen OJ, Espeland A, et al: Inability of refined
CT to assess local extent of prostatic cancer. Acta Radiol 34:39,
23. Biondetti PR, Lee JKT, Ling D: Clinical stage B prostate carcinoma:
Staging with MR imaging. Radiology 162:325, 1987.
24. Bezzi M, Kressel HY, Allen KS, et al: Prostatic carcinoma:
Staging with MR imaging at 1.5 T. Radiology 169-339, 1988.
25. Kahn T, Burrig K, Schmitz-Drager B: Prostatic carcinoma and
benign prostatic hyperperplasia: MR imaging with histopathological
correlation. Radiology 173:847, 1989.
26. Schnall MD, Imai Y, Tomaszewski J, et al: Prostate cancer:
Local staging with endorectal surface coil MR imaging. Radiology
27. Schiebler ML, Schnall MD, Pollack HM, et al: Current role
of MR imaging in the staging of adenocarcinoma of the prostate.
Radiology 189:339, 1993.
28. Cheung LP, Schnall MD, Chelsky MJ, et al: Current clinical
utility of endorectal surface coil MR imaging of the prostate
gland. Radiology 185:275, 1992.
29. Krebs TL, Silverman JM: Clinical utility of endorectal surface
coil MR imaging for local staging of prostate cancer. J Urol 150:391,
30. Martin JF, Hajek P, Baker L, et al: Inflatable surface coil
for MR imaging of the prostate. Radiology 167:268, 1988.
31. Schnall MD, Lenkinski RE, Pollack HM, et al: Prostate: MR
imaging with an endorectal surface coil. Radiology 172:570, 1989.
32. Schnall MD, Connick T, Hayes CE, et al: MR imaging of the
pelvis with an endorectal-external multicoil array. J MRI 2:229,
33. Chelsky MJ, Schnall MD, Seidmon EJ, et al: Use of endorectal
surface coil magnetic resonance imaging for local staging of prostate
cancer. J Urol 150:391, 1993.
34. Quinn SF, Franzini DA, Demlow TA, et al: MR imaging of prostate
cancer with an endorectal surface coil technique: Correlation
with whole-mount specimens. Radiology 190:323, 1994.
35. White S, Hricak H, Forstner R, et al: Prostate cancer: Effect
of postbiopsy hemorrhage on interpretation of MR images. Radiology
36. D'Amico AV, Whittington R, Schnall M, et al: The impact of
the inclusion of endorectal coil magnetic resonance imaging in
a multivariate analysis to predict clinically unsuspected extraprostatic
cancer. CA Cancer J Clin 75:2368, 1995.
37. Boxer RJ, Kaufman J, Goodwin W: Radical prostatectomy for
carcinoma of the prostate: 1951-1976: A review of 329 patients.
J Urol 117:208-213, 1977.
38. Villers A, McNeal JE, Redwine EA, et al: The role of perineural
space invasion in the local spread of prostatic adenocarcinoma.
J Urol 142:763-768, 1989.
39. Zincke H, Utz DC, Taylor WF: Bilateral pelvic lymphadenectomy
and radical prostatectomy for clinical stage C prostatic cancer:
Role of adjuvant treatment for residual cancer and in disease
progression. J Urol 135:1199-1205, 1986.
40. Bosch RJ, Kurth KH, Schroeder FH: Surgical treatment of locally
advanced (T3) prostatic carcinoma: Early results. J Urol 138:816-822,
41. Van Den Ouden D, Davidson PJT, Hop W, et al: Radical prostatectomy
as a monotherapy for locally advanced (stage T3) prostate cancer.
J Urol 151:646-651, 1994.
42. Epstein JI, Walsh PC, Brendler CB: Radical prostatectomy for
impalpable prostate cancer: the Johns Hopkins experience with
tumors found on transurethral resection (stages TIA and TIB) and
on needle biopsy (stage TIC). J Urol 154:1721-1729, 1994.
43. Huggins C, Hodges CV: Studies on prostate cancer: Effect of
castration, estrogen and of androgen injection on serum phosphatases
in metastatic carcinoma of the prostate. Cancer Res 1:293-297,
44. Schulman CC, Sassine AM: Neoadjuvant hormonal treatment of
locally advanced prostate cancer: Does it make sense? Curr Opin
Urol 39:394, 1993.
45. Andros EA, Danesghari F, Crawford ED: Neoadjuvant hormonal
therapy in stage C adenocarcinoma of the prostate. Clin Invest
Med 16:510-515, 1993.
46. Aprikian AG, Fair WR, Reuter VE, et al: Experience with neoadjuvant
diethvlstilbestrol and radical prostatectomy in patients with
locally advanced prostate cancer. Br J Urol 74:630-636, 1994.
47. Cher ML, Shinohara K, Breslin S, et al: High failure rate
associated with long-term follow-up of neoadjuvant androgen deprivation
followed by radical prostatectomy for stage C prostatic cancer.
Br J Urol 75:771-777, 1995.
48. Oesterling JE, Andrews PE, Suman VJ, et al: Preoperative androgen
deprivation therapy: Artifical lowering of serum PSA without downstaging
the tumor. J Urol 149:779-782, 1993.
49. Van Poppel H, De Ridder D, Elgamal AA, et al: Neoadjuvant
hormonal therapy before radical prostatectomy decreases the number
of positive surgical margins in stage T2 prostate cancer: Interim
results of a prospective randomized trial. J Urol 154:429-434,
50. Yamada AH, Lieskovsky G, Petrovich Z, et al: Results of radical
prostatectomy and adjuvant therapy in the management of locally
advanced, clinical stage TC, prostate cancer. Am J Clin Oncol
51. Kuban DA, El-Mahdi AM, Schellhammer PF: I-125 interstitial
implantation for prostate cancer: What have we learned 10 years
later? Cancer 63:2415, 1989.
52. Schellhammer PF, El-Mahdi AM: Local failure and related complications
after definitive treatment of carcinoma of the prostate by irradiation
or surgery. Urol Clin North Am 17:835-841, 1990.
53. Holzman M, Carlton CE Jr, Scardino PT: The frequency and morbidity
of local tumor recurrence after definitive radiotherapy. J Urol
54. Rogers E, Ohori M, Kassabian VS, et al: Salvage radical prostatectomy:
Outcome measured by serum prostate-specific antigen levels. J
Urol 153:104-109, 1995.
55. Fuks Z, Whitmore WF, Leibel S, et al: Local control is associated
with decreased distant failure in early stage carcinoma of the
prostate. Int J Radiat Oncol Biol Phys 17:121, 1989.
56. Fuks Z, Leibel SA, Wallner KE, et al: The effect of local
control on metastatic dissemination in carcinoma of the prostate:
Long-term results in patients treated with I-125 implantation.
Int J Radiat Oncol Biol Phys 21:37-547, 1991.
57. Zagars GK, Voneschenbach AC, Johnson DE, et al: Stage C adenocarcinoma
of the prostate: An analysis of 51 patients treated with external
beam radiation. Cancer 60:1489-1499, 1987.
58. Bagshaw MA, Cox RS, Ray GR: Status of radiation treatment
of prostate cancer at Stanford University. Natl Cancer Inst Monogr
59. Pilepich MV, Krall JM, Al-Sarraf M, et al: Androgen deprivation
with radiation therapy compared to radiation therapy alone for
locally advanced prostatic carcinoma-A randomized comparative
trial of the Radiation Therapy Oncology Group. Urology 45:616-623,
60. Corn BW, Hanks GE, Schultheiss TE, et al: Conformal treatment
of prostate cancer with improved targeting: Superior prostate-specific
antigen response compared to standard treatment. Int J Radiat
Oncol Biol Phys 32:325-330, 1995.
61. Leibel SA, Heimann R, Kutcher GJ, et al: Three-dimensional
conformal radiation therapy in locally advanced carcinoma of the
prostate: Preliminary results of a phase I dose-escalation study.
Int J Radiation Oncol Biol Phys 28:55-65, 1993.
62. Sandler HM, McShan DL, Lichter AS: Potential improvements
in the results of irradiation for prostate carcinoma using improved
dose distribution. Int J Radiat Oncol Biol Phys 22:361-367, 1992.
63. Stromberg J, Martinez A, Gonzalez J, et al: Ultrasound-guided
high dose rate conformal brachytherapy boost in prostate cancer:
Treatment description and preliminary results of a phase I/II
clinical trial. Int J Radiat Oncol Biol Phys 33:161-171, 1995.
64. Brindle JS, Martinez A, Schray M, et al: Pelvic lymphadenectomy
and transperineal interstitial implantation of IR 192 combined
with external beam radiotherapy for bulky stage C prostatic carcinoma.
Int J Radiat Oncol Biol Phys 17:1063-1066, 1989.
65. Stromberg J, Martinez A, Ben R, et al: Improved local control
and survival for surgically staged patients with locally advanced
prostate cancer treated with upfront low dose rate Iridium-192
prostate implantation and external beam irradiation. Int J Radiat
Oncol Biol Phys 28:67-75, 1993.
66. Martinez A, Gonzalez J, Stromberg J, et al: Conformal prostate
brachytherapy: Initial experience of a Phase I/II dose-escalating
trial. Int J Radiat Oncol Biol Phys 33:1019-1027, 1995.
67. Whittington R, Malkowicz B, Barnes MM, et al: Combined hormonal
and radiation therapy for lymph node positive prostate cancer.
Urology 46:213-219, 1995.
68. Krieger JN, Krall JM, Laramore GE, et al: Fast neutron radiotherapy
for locally advanced prostate cancer: Update of a past trial and
future research directions. Urology 34:1-9, 1989.
69. Russell KJ, Caplan RJ, Laramore GE, et al: Photon vs. Fast
neutron external beam radiotherapy in the treatment of locally
advanced prostate cancer: Results of a randomized prospective
trial. Int J Radiat Oncol Biol Phys 28:47-54, 1993.
70. Haraf DJ, Rubin SJ, Sweeney P, et al: Photon neutron mixed-beam
radiotherapy of locally advanced prostate cancer. Int J Radiat
Oncol Biol Phys 33:3-14, 1995.
71. Pickles T, Bowen J, Dixon P, et al: Pions: The potential for
therapeutic gain in locally advanced prostate cancer: Dose escalation
and toxicity studies. Int J Radiat Oncol Biol Phys 21:1005-1011,
72. Fowler JF, Ritter MA: A rationale for fractionation for slowly
proliferating tumors such as prostatic adenocarcinoma. Int J Radiat
Oncol Biol Phys 32:521-529, 1995.
73. Byar DP, Corle DK: Hormone therapy for prostate cancer: Results
of the Veterans Administration Cooperative Urological Research
Group Studies. NCI Monographs 7:165-170, 1988.
74. Fellow GJ, Clark PB, Beynon LL, et al: Treatment of advanced
localised prostatic cancer by orchiectomy, radiotherapy, or combined
treatment. Br J Urol 70:304-309, 1992.
75. Pavone-Macaluso M, De Voogt HJ, Vigiano G, et al: Comparison
of diethylstilbestrol, cyproterone acetate and medroxyprogesterone
acetate in the treatment of advanced prostatic cancer: Final analysis
of a randomized phase III trial of the European Organization for
Research on Treatment of Cancer urological group. J Urol 136:624-631,
76. Miller RJ, Cohen JK, Merlotti LA: Percutaneous transperineal
cryosurgical ablation of the prostate for the primary treatment
of clinical stage C adenocarcinoma of the prostate. Urology 44:170-184,
77. Schmidt JD: Cooperative clinical trials of the National Prostatic
Cancer Project: Protocol 900. The Prostate 5:387-399, 1984.
78. Fleischman JD, Catalona WJ: Endocrine therapy for bladder
outlet obstruction from carcinoma of the prostate. J Urol 134:498,
79. Hanks GE, Leibel S, Kramer S: The dissemination of cancer
by transurethral resection of locally advanced prostate cancer.
J Urol 129:309-311, 1983.
80. Paulson DF, Cox EB: Does transurethral resection of the prostate
promote metastatic disease? Urology 33:103-105, 1987.