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CHAPTER 17
Prostate cancer
Judd W. Moul, MD, FACS, Kenneth J. Pienta, MD, Brent K. Hollenbeck, MD,
and Michael E. Ray, MD, PhD
Prostate cancer is the most common cancer in American men. Despite the factthat this cancer will be diagnosed in an estimated 232,090 American men inthe year 2005 and will lead to the death of approximately 30,350 men, there isno universally agreed-upon strategic plan for its diagnosis and management.
Epidemiology
Age The risk of developing prostate cancer begins to increase at age 50 years
in white men who have no family history of the disease and at age 40 years in
black men and those who have a first-degree relative (father, brother) with
prostate cancer. Risk increases with age, but, unlike other cancers, prostate
cancer has no “peak” age or modal distribution. There has been a downward
“age migration” in the PSA (prostate-specific antigen) era such that the median
age of diagnosis is now approximately 60 years old.
Race The highest incidence of prostate cancer in the world is found in Ameri-
can black men, who have approximately a 9.8% lifetime risk of developing this
cancer. This rate is slightly higher than the 8% lifetime risk for American white
men. Black men have an incidence of prostate cancer that is 1.6 times that of
whites.
The Japanese and mainland Chinese populations have the lowest rates of pros-tate cancer. Interestingly, although Japanese immigrants to the United Stateshave a higher incidence of prostate cancer than Japanese people living in Ja-pan, their rate is still about half that of American whites.
Socioeconomic status appears to be unrelated to the risk of prostate cancer,and the explanation for racial variability is unknown. However, an interplay ofdiet, hormonal factors, and genetics likely acounts for the variability.
Geography The incidence of prostate cancer is highest in Scandinavian coun-
tries (22 cases per 100,000 population) and lowest in Asia (5 per 100,000). Risk
may be inversely related to ultraviolet light exposure, as the incidence increases
the farther one lives from the equator. However, recent studies show extremely
high rates in populations of African heritage, such as Jamaicans.
Etiology and risk factors
Family history Men who have a first-degree relative with prostate cancer have
approximately a twofold increased risk of developing prostate cancer during
their lifetime. An individual who has two first-degree relatives with prostate
cancer has a ninefold increase in lifetime risk.
Sexual activity has beenhypothesized as a possible risk True hereditary prostate cancer occurs in a small number of men and tends to develop at Leitzmann et al may finally providean answer to this question. In the Dietary fat Studies have suggested that di-
etary fat may increase the risk of prostate can- cer. However, no definitive proof of its role their history of ejaculationfrequency by filling out serial Vasectomy Several large epidemiologic stud-
ies suggest that vasectomy may increase the relative risk of prostate cancer by as much as incidence of prostate cancer inthe group. Overall, most 1.85. However, these same studies do not re- port an increased risk of dying from prostate cancer associated with vasectomy but do in- dicate a statistically increased risk of dying ejaculation frequency (greaterthan 21 ejaculations per month) from lung cancer. These findings argue against an association between vasectomy and pros- tate cancer. Currently, this association is un- proven and does not constitute grounds for fundamental changes in the use of vasectomy.
MJ, et al: JAMA 291:1578-1586,2004). Sexual activity/sexually transmitted
disease There is limited association between
sexual activity in a man or sexually transmitted diseases and the incidence ofprostate cancer.
Signs and symptoms
Early-stage disease Men with organ-confined prostate cancer often are
completely asymptomatic. Men with a large component of benign prostatic
hyperplasia often present with bladder outlet obstruction unrelated to their
prostate cancer.
Locally advanced disease Bladder outlet obstruction is the most common
sign of locally advanced prostate cancer. A few men with locally advanced
disease present with hematuria, urinary tract infections, and irritative voiding
symptoms secondary to bladder outlet obstruction.
Advanced disease Rarely, men with bulky lymph node metastasis may pre-
sent with bilateral lower extremity edema. Men with bony metastasis often
present with bone pain and, uncommonly, with lower extremity weakness or
paralysis from spinal cord compression.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH Screening and diagnosis
The optimal threshold torecommend prostate biopsy has Prostate cancer screening with PSA and digi- tal rectal examination (DRE) has resulted in not only an increase in prostate cancer detec- tion but also a stage shift. More cancers are cancer status is to some degreebased upon the result of his PSA now being detected at earlier stages, when they are potentially curable. Prior to screening ef- tool is subject to verification bias.
forts, most prostate cancers were detected when they produced local symptoms or dis- tant metastases, at which point treatment for prostate cancer screening cohortand found that a 4.1 ng/mL Digital rectal examination Prostate biopsy
82% of cancers in men < age 60and 65% of cancers in older men.
prompted by abnormal findings on DRE, such as nodularity or induration of the prostate, leads to a diagnosis of prostate cancer in only 15%-25% of cases. This rate compares with a D’Amico AV, Catalona WJ, et al: N prostate cancer prevalence of < 5% among Engl J Med 349:335-342, 2003).
men of similar age without an abnormal DRE.
Although neither accurate nor sensitive for prostate cancer detection, abnor-mal DRE is associated with a fivefold increased risk of cancer present at thetime of screening.
PSA has revolutionized prostate cancer screening. PSA is a serine protease
produced by the prostatic epithelium and secreted in the seminal fluid in large
quantities. Prostatic disease changes the cellular barriers that normally keep
PSA within the ductal system of the prostate and thereby alters serum levels.
The level of PSA in serum is increased by inflammation of the prostate, urinary
retention, prostatic infection, benign prostatic hyperplasia, prostate cancer, and
prostatic manipulation. Although PSA has good sensitivity, it is not an ideal
test because an elevated PSA level is neither specific to prostate cancer nor
does it distinguish aggressive prostate cancers
from those that are biologically benign. Of
those patients with a PSA level of > 4.0 ng/ tion Trial, among 2,950 men whomL, approximately 15%-25% will have a di- never had a PSA level > 4 ng/mLor an abnormal rectal examina- Current screening recommendations The
cancer at the time of biopsy,although only 67 (2%) had a that the PSA test and the DRE should be of- fered annually beginning at age 50 to men who have a life expectancy of at least 10 years.
prompting subsequent evaluation/biopsy; however, the clinical those with a first-degree relative diagnosed with prostate cancer), screening should be of- fered at an earlier age (40-45 years old). Prior Pauler DK, Goodman PJ, et al: N EnglJ Med 350:2239-2246, 2004).
to testing, physicians should discuss with their patients the potential benefits of early pros- tate cancer detection and its implications in the need for subsequent treatment so that pa- was to describe the prevalenceof histologically proven prostate tients can make an informed decision about to receive daily finasteride(a 5-alpha-reductase inhibitor that There are currently two ongoing major pros- tate cancer screening trials: The Prostate, Lung, Colorectal, and Ovarian (PLCO) trial in the United States funded by the National Cancer Institute and the European Organiza- reduction in the prevalence ofprostate cancer among men tion for Research and Treatment of Cancer it either prevents or delays theappearance of prostate cancer.
Biopsy When indicated, prostate biopsy usu-
ally is performed as an office procedure by transrectal ultrasonographic guidance using an automated 18-gauge biopsy gun. The proce- dure is performed with, at most, local anes- (Thompson IM, Goodman PJ, TangenCM, et al: N Engl J Med 349:215- thesia and carries a risk of significant infec- tion of only 1 in 200 cases. Additional sideeffects of hematuria and hematochezia are common for 2-3 days following the biopsy. Hematospermia may last for up to2-3 weeks. Since about the year 2000, prostate biopsy includes laterally di-rected extended core protocols employing 8—12 biopsy cores per procedure.
Multiple studies have demonstrated that the addition of the lateral cores im-proves the accuracy of biopsies.
If the biopsy result is negative, these men are typically followed conservativelywith serial PSA levels and DRE repeated annually. Repeat biopsy is performedonly when PSA levels rise at abnormal rates (> 0.8 ng/mL/year) or if DREfindings show new nodularity or induration. Men in whom high-grade pros-tatic intraepithelial neoplasia is found on biopsy usually will be recommendedto undergo repeat biopsy, since one-third to one-half will be found to haveprostate cancer.
One caveat to PSA screening is its lack of specificity when the value lies be-tween 4 and 10 ng/mL, since many men with benign prostatic hyperplasiahave PSA levels in this range. There have been several attempts to increasetesting specificity, including the development of age-specific ranges, trends inPSA increase over time (PSA velocity), and calculations of the PSA densitybased on the volume of the prostate gland. A commonly employed test to in-crease testing specificity in this “indeterminate zone” is the percent-free PSA.
Currently, biopsy is generally recommended in men whose percent-free PSA(ratio of free to total PSA) is < 10%, whereas biopsy is not necessary whenpercent-free PSA is > 25%. Complexed PSA (cPSA) can also be measured andis now a US Food and Drug Administration (FDA)-approved screening test. Itis essentially the “non-free” component of PSA in the circulation and may pro-vide a slight improvement in sensitivity and specificity.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH Pathology
Adenocarcinomas make up the vast majority of prostate carcinomas. A total
of 70% of prostate adenocarcinomas occur in the peripheral zone, 20% in the
transitional zone, and approximately 10% in the central zone.
Other tumor types are relatively rare and include ductal adenocarcinoma,
which occurs in the major ducts and often projects into the urethra; and mu-
cinous adenocarcinoma, which secretes abundant mucin and does not arise
from the major ducts. Transitional carcinoma of the prostate occurs within
the ducts and, to a lesser extent, in the prostatic acini. Typically, primary
transitional carcinomas are aggressive cancers that have a poor prognosis.
Similarly, neuroendocrine (small-cell) tumors are rare and aggressive, have a
poor prognosis, and typically require aggressive surgical management.
Histologic grade The grading system developed by Gleason from data accu-
mulated by the Veterans Administration Cooperative Urologic Research Group
appears to provide the best prognostic information in addition to clinical stage
and is the predominant grading system in widespread use.
Metastatic spread Adenocarcinoma of the prostate may spread locally through
direct extension into periprostatic fat or via the ejaculatory ducts into seminal
vesicles; lymphatically to regional lymph nodes, including the hypogastric and
obturator lymph nodes; and hematogeneously to bone. The most common
sites of bony metastases are the lumbosacral spine (probably related to venous
drainage of the prostate through Baston’s plexus) and the axial skeleton, but
any bone, including the skull and ribs, can be involved. Rare sites of metastatic
spread include the liver and lungs.
Staging systems The most widely used and universally accepted staging sys-
tem for prostate cancer is the TNM system (Table 1). In the TNM system, T1
and T2 tumors are confined to the gland, whereas T3 and T4 tumors have local
extension.
Risk-adapted staging The development of
the “Partin Tables” in 1993 ushered in a new era of combining clinical stage, Gleason score, and PSA level to predict pathologic stage af- ter radical prostatectomy. More recently, this has led to the D’Amico et al risk groupings progression-free, metastasis-free,and prostate-specific survivals for newly diagnosed men with clinically lo- calized disease (Table 2). Patients are divided into three risk groups (low, intermediate, or high) of occult micrometastases and relapse after initial local therapy. Although not per- mortality rates increased from15/1,000/year to 44/1,000/year fect, this system is currently in widespread use and allows a framework for multimodal and multidisciplinary treatment strategies based on expectancy > 15 years (JohanssonJE, Andren O, Andersson SO, et al:JAMA 291:2713-2719, 2004). TABLE 1: Staging of prostate cancer
TNM system
Localized disease
T1a Tumor incidental histologic finding in ≤ 5% of resected tissue; not palpable T1b Tumor incidental histologic finding in > 5% of resected tissue T1c Tumor identified by needle biopsy (eg, because of elevated PSA level) T2a Tumor involves one-half of one lobe or less T2b Tumor involves more than one-half of one lobe but not both lobes Local extension
T3a Extracapsular extension (unilateral or bilateral) Bladder invasion, fixed to pelvic side wall, or invasion of adjacent structures Metastatic disease
a Adapted from Greene FI, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th ed. New TABLE 2: D’Amico et al risk stratification for clinically
localized prostate cancer
Diagnostic PSA < 10.0 ng/mL andHighest biopsy Gleason score < 6 andClinical stage T1c or T2a Diagnostic PSA > 10 but < 20 ng/mL orHighest biopsy Gleason score = 7 orClinical stage T2b Diagnostic PSA > 20 ng/mL or Highest biopsy Gleason score < 8 or Clinical stage T2c/T3 In 2003, D’Amico et al combined a number of national datasets to report 10-year cancer-specific mortality for men undergoing radical prostatectomy orexternal-beam radiotherapy by this risk grouping and age at diagnosis. These10-year mortality graphs are useful to counsel contemporary-era men contem-plating surgery or radiation therapy.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH TABLE 3: Risk of dying from clinically localized prostate
cancer without definitive locoregional therapy*
Gleason score
Adapted from Albertsen PC, Hanley JA, Gleason DF, et al: JAMA 280:975–980, 1998.
* Gleason score 7 is now divided between 3 + 4 = 7 (better prognosis) and Gleason score 4 + 3 = 7(worse prognosis), but the data as in this table are not available for these subgroups at this time.
Prognosis and natural history
Prognosis of untreated prostate cancer Survival depends on patient age at
diagnosis, overall health, and tumor grade and stage at diagnosis. The natural
history of prostate cancer is becoming increasingly better understood as long-
term data become available.
Among untreated patients with clinically localized prostate cancer, those witha low Gleason score (2-4) have a very small risk of dying of their cancer within15 years (4%-7%), regardless of their age at diagnosis. Those with poorly differ-entiated tumors (Gleason score 8-10) have a greater risk of dying from prostatecancer than from any other cause, even when the cancer is diagnosed in theeighth decade of life. Indeed, a 55- to 59-year-old man diagnosed with a clini-cally localized, Gleason score 8-10 prostate cancer has an 87% risk of succumb-ing to the disease within 15 years if untreated (Table 3).
Treatment
Treatment needs to be individualized. Decisions regarding treatment optionsare often based on the disease stage and grade, pretreatment PSA level, andrate of PSA level rise, as well as the patient’s age and life expectancy. Mostrecently, prostate biopsy quantification is also an important factor. Specifically,counting the number of involved needle biopsy cores or the percentage of eachcore involved with cancer is a key prognostic factor. In particular, physiologicage (ie, the presence or absence of other significant medical problems) is ofgreater importance than chronologic age, and patients with short life expect-ancy (eg, < 10 years) may well be observed if they have early prostate cancer.
TREATMENT OF CLINICALLY LOCALIZED DISEASE (T1, T2)
Radical prostatectomy
Radical prostatectomy can be performed retropubically through a lower midlineincision⎯an approach that may include pelvic lymph node dissection. Alter-natively, some urologists prefer the perineal approach. With the latter approach,a separate incision is required if lymph node removal is desired. Compared withpatients managed with watchful waiting, those treated with radical prostatectomyhave a lower risk of distant metastases and improved disease-specific survival,although no benefit in overall survival as yet been demonstrated.
Although the morbidity of radical prostatectomy was a major concern in thepast, improvements were made during the 1980s. The hazards of anesthesia,risk of blood loss, and hospital stay have all been minimized. Nationwide, Medi-care data suggest that surgical outcomes are significantly better at those centersperforming > 40 prostatectomies per year than at other hospitals with lowersurgical volume.
Transfusion is usually unnecessary, and treatment-related mortality is < 0.05%at leading prostate cancer centers. The average hospital stay of a man undergo-ing radical prostatectomy is now approximately 2 to 3 days at leading referralcenters in the United States; several institutions routinely discharge patientswithin 24 hours. Although urinary incontinence is common in the first fewmonths after prostatectomy, most men recover urinary control; at some lead-ing centers, 90%-98% of men report few or no long-term urinary problems.
Nerve-sparing radical prostatectomy is appropriate for men with small-vol-
ume disease. It offers those men with good potency prior to surgery the probabil-
ity of recovering that function following the operation. By permitting better
visualization of Santorini’s dorsal venous plexus, the apical prostate, the urethra, and the striated urethral sphincter, the nerve-spar- ing technique also reduces blood loss and im- proves recovery of urinary continence. In ap- from the Cleveland Clinic.
Specifically, 174 of 470 men (37%) propriately selected individuals, a nerve- sparing procedure confers no greater risk of prostate cancer recurrence after considering other relevant clinical information (PSA, sildenafil. The response rate wasstrongly associated with use of Gleason score, margin status, seminal vesicle sparing group; 53.5% in theunilateral nerve-sparing group; Referral centers have reported that 50%-90% of patients who are fully potent prior to sur- gery recover erections following a nerve- sparing procedure, but the quality of these age (younger than 65) werestrong predictors of efficacy of the oral therapy (Raina R, Lakin M, compared with preoperative erections. Erec- Agarwal A, et al: Urology 63:960-966, tion recovery rates can be higher than 50% in patients < 60 years of age and lower in CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH from 2-24 months following surgery. Regard- less of potency, sensation of the penis is not changed after this procedure, and men still mL in this study) were at greaterrisk of death from prostate promise cancer control outcomes in well-se- lected men with early-stage disease. Also, a recent study has suggested that early post- operative use of sildenafil (Viagra) may fa- predicting the aggressiveness ofthe disease (D’Amico AV, Chen MH, cilitate the return of natural erections more Laparoscopic radical prostatectomy
Laparoscopic prostatectomy was initially described by Schuessler in 1997 butwas abandoned because of its technical difficulty and long operative time withlittle apparent benefit to the patient over the conventional technique. A recentresurgence in the technique was prompted by improved instrumentation andrefinements in the procedure itself, although the laparoscopically naive urolo-gist must endure a substantial learning curve (with attendant perioperative mor-bidity realized by the patient) prior to meeting the outcome standards set bythe open technique.
The robotic assisted prostatectomy was developed to overcome some of thedifficulties of the standard laparoscopic prostatectomy (eg, intracorporeal su-turing). The robotic technique allows for three-dimensional visualization of theoperative field and provides for a significantly wider range of movementsintracorporeally than do standard laparoscopic instruments. This advance hasprompted the assimilation of the technique into the armamentarium of manyurologists.
Current evidence suggests that in experienced hands, the laparoscopic and ro-botic techniques have similar oncologic efficacy to that of the open procedure.
However, the length of follow-up (usually < 12 months) in these studies is lim-ited, suggesting that a measure of caution be taken when interpreting the re-sults. Importantly, long-term effects of these modalities on sexual and urinaryhealth (as measured by a psychometrically valid survey) have not been reported,and such data are critical in the context of the prostatectomy patient whenevaluating technical results. Though it is a promising advance in the treatmentof prostate cancer, published data suggest further research in this area is war-ranted.
Pelvic lymph node dissection Studies now indicate that regional pelvic lymph
node dissection may not be necessary for patients with stage T1c disease if the
total Gleason score is < 7 and the PSA level is < 10.0 ng/mL, ie, low-risk indi-
viduals. Selected intermediate-risk men may also not require this staging pro-
cedure, but in high-risk men, it is still considered imperative.
Neoadjuvant hormonal therapy
Recently, Stephenson et alreported the outcome of 501 radical prostatectomy for clinical stage T2 prostate cancer will be found to have patho- logic T3 disease following surgery. This find- at five US academic institutions.
Although preradiotherapy PSA ing led some investigators to evaluate the ef- ficacy of neoadjuvant androgen deprivation therapy in prospective clinical trials. Early neoadjuvant hormonal therapy led to a re- adverse risk factors (a Gleasonscore of 8 or higher, duction in positive surgical margins. How- ever, these findings need to be considered in a technical context: Androgen deprivation therapy causes artifactual changes in prostate and seminal vesicle invasion)achieved a 77% rate of undetect- morphology that cause difficulties for the pathologic identification of prostate cancer lower when adverse featureswere present. These data suggest Indeed, more recent data from prospective studies have shown no benefit of neoadjuvant therapy with regard to disease progression- as low as possible (Stephenson AJ, free survival. At present, therefore, it appears Shariat SF, Zelefsky MJ, et al: JAMA291:1325-1332, 2004).
that neoadjuvant hormonal therapy does notimprove the curative potential of radical pros-tatectomy but instead is associated with morphologic alterations that complicate the prognostic utility of standard pa-thology. Consequently, neoadjuvant hormonal therapy should be reserved forevaluation as an experimental modality in the context of clinical trials.
Adjuvant therapy post prostatectomy
The potential indications for adjuvant therapy following radical prostatectomyin patients with clinical T1 or T2 malignancy include pathologic evidence ofT3 disease, positive nodes, a rising PSA level, and positive surgical margins,among others. Possible adjunct treatments include radiation therapy and an-drogen deprivation with or without radiation therapy. Best available evidencesuggests that early salvage radiotherapy (eg, postprostatectomy PSA level < 0.1ng/mL) affords the best results in terms of subsequent biochemical recurrence.
Radiation therapy Men with pathologic T3 disease following radical pros-
tatectomy are candidates for adjuvant therapy. However, to date, no prospec-
tive randomized trials have demonstrated a survival benefit from adjuvant ra-
diotherapy in patients with pathologic T3 adenocarcinoma of the prostate. At
the ASCO 2004 meeting, Bolla et al presented preliminary data from a Euro-
pean trial, randomized between observation and external beam radiation therapy
(EBRT) to the prostate bed for pT3 disease after surgery. At a median follow-
up of approximately 4 to 5 years, the men randomized to receive EBRT showed
a clinical disease-free benefit, but no disease-specific or overall survival differ-
ence was evident.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH Hormonal therapy Significant controversy
exists within the academic community as to the timing of initiating androgen deprivation following radical prostatectomy. Clinical trials have documented a benefit only for those pa- prostatectomy was authored byMoul et al. Using the Center forProstate Disease Research Treatment recommendations for
postprostatectomy recurrence
authors studied 1,352 men whohad PSA recurrence Following radical prostatectomy, it is expected that serial PSA levels will become undetectable.
Any detectable PSA level (> 0.2 ng/mL) fol- who were observed. For menlowing surgery indicates possible recurrent dis- with high-risk disease, including aPSA doubling time of < 12 ease and the need for restaging and discussion of possible salvage therapies with the patient, including radiation or hormonal therapy, ex- perimental protocols, or observation. However, some patients can develop low levels of detect- delayed clinical metastases.
Although this is the first study to able PSA after prostatectomy without devel- oping a cancer recurrence, even if no additional treatment is administered. Although there is concern for recurrence when the PSA level is is needed (Moul J, Wu H, Sun L, et al: 0.2 ng/mL, most clinicians will wait until a PSA threshold > 0.4 ng/mL is reached to as-sume that the rise in PSA level represents real recurrence.
Definitive radiation therapy
External-beam treatment Traditional EBRT is designed to encompass the
prostate and, for those at high risk of regional metastasis, the pelvic lymph
nodes. A four-field axial box arrangement with customized shielding of normal
structures is commonly used. A recently pre- sented study suggests that treatment of re- gional lymphatics may be beneficial in patients radiotherapy and the timing ofandrogen deprivation in the at risk for harboring lymph node metastases.
Conformal EBRT creates three-dimensional
representations of target structures (ie, the prostate) and designs highly tailored treatment [Gleason score ≥ 6 and > cT2c]cancers). At a median follow-up of portals using unconventional treatment direc- tions to create a volume of high radiation dose that conforms to the target shape. The anat- omic information used to define the target is among those receiving wholepelvic radiotherapy in conjunction generally derived from CT images obtained while the patient is placed in the precise treat- Early results using conformal therapy showed Roach III M, DeSilvio M, Lawton C, etal: J Clin Oncol 21:1904-1911, 2003). a reduction in acute and early morbidity. Also, conformal therapy has permitted the use of doses far above traditional levels without test the utility of long-term (24months) androgen blockade significant increases in serious morbidity.
Patients with relatively low-risk disease (ie, PSA level ≤ 10 ng/mL and Gleason score ≤ 6) generally have a 5-year rate of freedom from cancer (T2c-T4). Among allrandomized subjects, there was disease progression of ~85% when treated with Intensity-modulated radiotherapy (IMRT)
blockade. A secondary analysisdemonstrated that a subset of is becoming widely used for prostate cancer therapy employs highly nonuniform beam in- tensity profiles to create more conformal dose vs 71% survival at 5 years, P = .04;Hanks GE, Pajak TF, Porter A, et al: J distributions. Although it is likely that IMRT Clin Oncol 21:3972-3978, 2004).
will have a greater benefit in the treatment ofnonprostate neoplasms (ie, head and neck cancers), there is emerging evidence that prostate cancer therapy is also anappropriate site for IMRT treatment.
EBRT dose The current standard radiotherapy dose is 70 Gy given over 7-8
weeks; however, trials examining the value of dose escalation now support
higher doses in selected patients. A randomized trial of EBRT dose compared
70 Gy given conventionally with 78 Gy given with a conformal therapy boost.
It showed an advantage in freedom from failure for the higher dose arm that
appeared to be limited to those patients with a pretreatment PSA level > 10 ng/
mL, whereas no benefit was detected for those with a PSA level < 10 ng/mL.
Toxicity was modest but somewhat higher in the higher dose arm. A large trial
being conducted by the RTOG (P0126) will accrue 1,520 cases and provide the
definitive information regarding any beneficial effect on mortality with higher
radiotherapy doses.
Interstitial radiotherapy In the 1970s, the use of permanently placed ra-
dioactive iodine implants produced initial results as good as other available
radiotherapy techniques and posed a small risk of impotence and other morbidity
when compared with conventional EBRT and radical prostatectomy. How-
ever, ultimate control rates were unacceptable. The technique used (freehand
placement during laparotomy) was found to distribute the radioactive seeds
unevenly throughout the gland, and, thus, cold regions may have contributed
to the relatively poor outcome.
The use of transrectal ultrasonography to guide seed placement from a transperi-neal approach has corrected the problem of poor seed placement when per-formed in experienced hands. Also, radioactive palladium seeds have beendeveloped to increase the dose rate. (Palladium has a shorter half-life than io-dine.) Currently, both iodine and palladium implants are used, sometimes inconjunction with EBRT.
Long-term results with improved implant techniques are becoming available,and early results are encouraging for a select population. A large multi-institu- CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH tion trial compared the results of radical pros- tatectomy, radiation therapy, and interstitial radiotherapy in men with low-, intermedi- ate-, and high-risk prostate cancer.
Brachytherapy was equivalent to the two tra- cancer. However, emergingevidence suggests that some of ditional modalities in terms of PSA recur- rence rates for low-risk patients. However, the rates of recurrence were significantly higher in those men with intermediate- and high-risk cancers (specifically, men with a consecutive series of 177 patients,44% of those treated with Gleason score ≥ 7 or a PSA level > 10 ng/ mL). A typical dose used for interstitial iodine therapy is 145 Gy delivered to the periphery of the prostate. The dose is lower for pal- resection of the prostate (15%),colonoscopy (36%), fecal diversion ladium implants due to the higher dose rate.
High-dose—rate (HDR) devices Besides perma- nent implants, which deliver low-dose—rate relatively common in selectedpatients (Sarosdy MF: Cancer (LDR) radiotherapy, brachytherapy for pros- tate cancer has been delivered using tem-porary high-dose—rate devices, usually inpatients with locally advanced disease. In this technique, a high dose (mini-mum, approximately 5 Gy) is delivered to the prostate over ≤ 1 hour by re-motely inserting a highly radioactive source into catheters placed into the pros-tate under ultrasonographic guidance while the patient is under anesthesia.
Several treatments are given on separate occasions, and EBRT is used for ap-proximately 5 weeks as well.
More reports are accumulating on the application of HDR brachytherapy toprostate cancer. Various dose-fractionation combinations of HDR with or with-out combined pelvic EBRT have been employed, with a dose-response rela-tionship apparent in biochemical control. Although the follow-up is short andno prospective randomized trials evaluating this approach have yet been pub-lished, it appears that HDR prostate brachytherapy in combination with pelvicEBRT may be effective. The long-term consequences for normal tissue of de-livering large doses per fraction using this technique are unclear.
For low-risk men, most experts favor brachytherapy alone to balance the effi-cacy and side effects of treatment. Specifically, potency rates are generally con-sidered better with brachytherapy alone. However, some centers recommendcombined brachytherapy plus EBRT for low-risk men as an assurance of can-cer control, but side effects will be greater. At most centers, intermediate-riskand high-risk men are generally offered brachytherapy plus EBRT.
MEDICATIONS AND DEVICES TO MANAGE IMPOTENCE
AFTER PROSTATECTOMY, EBRT, OR BRACHYTHERAPY
Treatments for postprostatectomy impotence Treatment for postprostatectomy impo-tence includes the phosphodiesterase inhibitors sildenafil, vardenafil (Levitra),and tadalafil (Cialis); prostaglandin E , administered as a urethral suppository (Muse); intercavernosal injection (Caverject, Edex); or vacuum-pump erection aids that are association between post-treatment PSA doubling time useful for improving erections in men who have poor erectile function after prostatec- tomy, radiation therapy, or brachytherapy.
These therapies are effective in 15%-40% of radiotherapy and found asignificant association with erectile dysfunction. Insertion of a penile prosthesis is typically offered to patients only after unsuccessful trials with the previously develop distant metastasis and dieof prostate cancer. The authors mentioned, less invasive interventions.
propose that post-treatment PSA-DT may be an acceptable DETECTION AND TREATMENT OF
RECURRENCE
cancer-specific mortality in futureclinical trial designs (D’Amico AV,Moul JW, Carroll PR, et al: J Natl Significance and definition of a rising
Cancer Inst 95:1376-1383, 2003).
PSA level post irradiation
The use of PSA levels following definitivetherapy (either radiotherapy or radical pros- tatectomy) can detect early recurrences that may be amenable to salvage treat-ment. A rising PSA profile following radiotherapy is unequivocal evidence ofthe presence of a residual prostatic neoplasm. However, the definition of arising PSA level after radiation therapy varies in the literature. A 1996 con-sensus conference recommended that PSA failure be considered to have oc-curred after three consecutive PSA level rises, with the rate of failure defined ashalfway between the first rise and the previous PSA level.
Moreover, patients with a rising PSA level after irradiation may be a heteroge-neous group, including patients with truly localized failure as well as those withmetastatic disease. Also, certain patients will have a slowly rising PSA levelafter irradiation and may not require additional treatment. In patients who donot receive androgen ablation, the 5-year actuarial risk of distant metastasisfrom the time that the PSA level begins to rise is ~50%. A rapidly emergingkey concept in rising PSA levels is PSA velocity, or more specifically PSAdoubling time (PSA-DT). Multiple recent studies have found that a PSA-DT < 10-12 months predicts early clinical relapse if biochemical recurrence is un-treated.
Treatment recommendations for recurrence
post irradiation
In general, men who have clear evidence of a rising PSA level 2 years afterdefinitive radiotherapy for localized prostate cancer should be advised aboutthe options of hormonal therapy (see section on “Treatment of locally advanceddisease [T3, T4]”), salvage surgery, salvage cryotherapy, observation, or ex-perimental therapy.
If patients have minimal comorbidity, good life expectancy, and only local evi- CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH dence of disease recurrence, salvage surgery is an option but should be precededby a bone scan, CT scan, cystoscopy, and extensive counseling because urinarydifficulties after salvage prostatectomy are substantial and highly prevalent.
TREATMENT OF LOCALLY ADVANCED DISEASE (T3, T4)
The treatment of patients with locally advanced prostate cancer is centered ona multimodality and multidisciplinary approach, including radiation therapy(EBRT with or without HDR interstitial therapy), androgen ablation plus EBRT,or radical prostatectomy with or without androgen deprivation.
EBRT with and without HDR interstitial therapy For patients with locally exten-
sive prostate cancer, local failure remains a potential problem after EBRT. This prob-
lem has prompted investigations into alternative means to intensify therapy.
One strategy has been to deliver large fractions of radiotherapy using HDRinterstitial techniques in combination with EBRT. The large interstitial frac-tions, which may be on the order of 5 Gy, deliver a high dose to the prostatebut spare normal tissues, due to the rapid dose falloff outside the implantedvolume. Early experience with this strategy is encouraging, but long-term dataon outcome, particularly in patients with locally extensive disease, and onmorbidity are awaited.
Patients with locally advanced prostate cancer probably are not good candidatesfor permanent prostate implants. Patients with stage T3-T4 tumors are at high riskof gross extraprostatic involvement, and thislocalized therapy may not offer adequate do- simetric coverage of extraprostatic disease.
suppression therapy (AST) forintermediate-risk prostate Androgen ablation with EBRT Recently,
cancers have been uncertain. Arecent single-institution, two potential benefits of the use of transient androgen ablation prior to EBRT have been identified. First, there may be some synergy between the apoptotic response induced by androgen deprivation and radiotherapy that extraprostatic disease to receiveEBRT (70 Gy) alone or the same EBRT with 6 months of AST. Aftera median follow-up of 4.5 years, Second, androgen deprivation results in an average 20% decrease in prostate volume.
This volume reduction not only may reduce the number of target cells, and thereby im- prove tumor control, but also may shrink the cancer-specific survival (P = .02),and overall survival (P = .04).
prostate and, thus, diminish the volume of rectum and bladder irradiated during con- ade can be achieved with the luteinizing hor- advanced cases, this new trial inmen with more localized disease leuprolide (Lupron) or goserelin (Zoladex) (D’Amico AV, Manola J, Loffredo M, et (Casodex), or nilutamide (Nilandron).
In addition, since distant metastases are the first manifestation of disease recur-rence in many patients with prostate cancer, the use of early androgen depriva-tion may possibly delay, or even prevent, the development of metastatic disease.
The current body of evidence (RTOG [Radiation Therapy Oncology Group]8610, RTOG 9202, EORTC [European Organization for Research on the Treat-ment of Cancer]/Bolla) suggests that androgen deprivation in conjunction withEBRT improves survival among men with locally advanced prostate cancerwhen compared with radiotherapy alone. Ongoing (eg, RTOG 9413) and fu-ture studies will address questions regarding the timing of androgen depriva-tion and the applicability of androgen deprivation in localized prostate cancerswith favorable prognostic features.
Radical prostatectomy with or without adjuvant therapy
Surgical monotherapy can be considered a reasonable option for patients withlocally advanced prostate cancer. Stage T3 disease can be successfully treatedwith low morbidity and significant reductions in risk of local recurrence, withclinical overstaging (up to 26%) reported by Yamada et al. Well- and moder-ately differentiated cancers have cancer-specific survival rates of 76% at 10 years,comparable to those of other treatment modalities.
The Mayo Clinic has one of the largest radical prostatectomy series for T3disease, consisting of more than 1,000 patients. In this population, of whom34% received adjuvant therapy, 15-year cancer-specific survival and local re-currence rates were 77% and 21%, respectively. Ninety-eight men who werefound to have nodal metastases following radical prostatectomy and pelvic lym-phadenectomy were randomized to receive immediate androgen deprivationor be followed until clinical disease progression. At a median follow-up of 7years, 18 of 51 men in the observation group had died, compared with only 4of 47 in the treatment group (P = .02). Treatment of node-positive disease
Until recently, the standard of care had been to perform frozen-section patho-logic analysis on pelvic lymph nodes at the time of radical prostatectomy, priorto removal of the prostate. If this analysis revealed micrometastases, radicalprostatectomy was thought to be contraindicated. Although retrospective innature, recent data from several American centers, including one large studyfrom the Mayo Clinic, have reported a survival benefit in men who undergoradical prostatectomy despite the presence of micrometastases to regional pel-vic lymph nodes. These men tend to do better and survive longer when startedon early hormonal therapy, either with orchiectomy or an LHRH agonist.
Radiation therapy Whether any local treatment adds to the overall survival
duration in patients with known nodal involvement is debatable. Some data
from M. D. Anderson Cancer Center indicate a benefit from pelvic and pros-
tate radiotherapy plus androgen ablation compared with androgen ablation
alone. This matter deserves further study. However, the addition of radiotherapy
may be indicated in many situations, especially in young men.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH TABLE 4: Hormonal approaches to the treatment
of metastatic prostate cancer
Mechanism of action
Side effects
LHRH = luteinizing hormone-releasing hormone TREATMENT OF ADVANCED SYSTEMIC DISEASE
First-line therapies for advanced disease
The medical treatment of prostate cancer begins when a patient has either notresponded to local treatment efforts or presents with advanced disease thatcannot be treated effectively with surgery or radiation therapy.
First-line therapy for advanced disease is surgical or medical castration.
Bilateral orchiectomy The testes normally produce approximately 95% of
the testosterone in human males, and bilateral orchiectomy reduces plasma
testosterone levels by approximately 93%. Although there are other ways be-
sides castration to lower serum testosterone levels (primarily through the estro-
gen action of LHRH analogs), bilateral orchiectomy has distinct advantages.
They include the lack of compliance problems or the need to adjust the dose to
the patient’s metabolic state and the absence of the potentially fatal cardiovas-
cular complications that are often seen with high-dose estrogen therapy (Table
4). Medical treatment also must be maintained for life and can be very costly.
The psychological impact of castration is severe, however, and many men opt
for medical therapy if given a choice.
LHRH analogs LHRH agonists, such as leuprolide (in 1- 3-, and 4-month de-
pot formulations and in a 12-month implant) and goserelin (in a 1- and 3-month
depot implant), regulate the release of LH and thereby produce chemical cas-
tration. These agents spare the patient the psychological trauma of an orchiec-
tomy and also are devoid of the cardiovascular side effects associated with es-
trogen treatment (Table 4).
Because LHRH analogs can cause a transient increase in testosterone levelsand induce a “flare” response, an antiandrogen, such as flutamide, bicalutamide,or nilutamide, is utilized during the first month of LHRH therapy.
[Plenaxis]) has been approved by the FDA.
practice pattern trends inandrogen deprivation for localized Its main advantage is the lack of an LHRH surge or flare, and it is indicated in men with impending spinal cord compression or other flare could be harmful. However, this drug of androgen deprivation between1989 and 2001 both as primary must be administered every 2 weeks in the first month and monthly thereafter. Also, it can rarely be associated with an anaphylac- rose from 4.6% to 14.2% for low-risk patients and from 32.8% to Antiandrogens block the effects of andro-
gens at the prostate tissue level. These com- pounds appear to interfere with the binding for these increases, includingfinancial incentives, consumer- of the active metabolite of testosterone, dihydrotestosterone, to its receptor within the treat the cancer (Cooperberg MR,Grossfeld GD, Lubeck DP, et al: J Natl used antiandrogens are flutamide,bicalutamide, and nilutamide. Ketoconazole(Nizoral), an antifungal agent, is also used.
As previously mentioned, antiandrogens are added to LHRH analogs to blockany transient stimulation of testosterone by these agents or to directly blockany remaining androgens that may affect the prostate.
Combined androgen blockade Surgical or medical castration decreases cir-
culating testosterone levels by 90%-95%. It has been demonstrated that the
remaining androgens result from peripheral conversion of adrenal steroids.
Several investigators have suggested that complete androgen blockade (CAB)
or total androgen blockade (TAB), achieved by adding flutamide (250 mg PO
tid), bicalutamide (50 mg PO daily), or nilutamide (150 mg PO daily) to castra-
tion, results in better disease control.
Although controversial, CAB is most likely beneficial only in patients with mini-mal symptoms and minimal disease on bone scan. Patients who present withwidespread advanced disease and/or poor performance status do not appear tobenefit from this approach. A recent meta-analysis showed a modest but statis-tically significant survival benefit in patients with stage M1 (D2) disease.
Diethylstilbestrol (DES) Estrogen administration, in the form of DES, also
produces chemical castration. DES inhibits prostate growth, primarily through
the inhibition of the hypothalamic-pituitary-gonadal axis, which blocks testicu-
lar synthesis of testosterone and thus lowers plasma testosterone levels. Since
doses higher than 3 mg/d cause significant cardiovascular mortality, DES has
fallen out of favor as a first-line therapy to induce castration.
Treatment recommendations A patient who presents with advanced pros-
tate cancer requires medical or surgical castration. Although this option has not
definitely been demonstrated to increase the patient’s life span, the quality-of-
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH TABLE 5: The incidence of complications from advanced
prostate cancer with immediate vs deferred androgen
deprivation
Complication
Immediate
Deferred
life benefits gained from disease control are unquestioned. Controversy existsover whether to start treatment early, when a patient is still asymptomatic, orwhether to wait until symptoms develop. However, it is generally accepted thattreatment should begin early. The primary goal of early androgen deprivationshould be prolongation of survival or prevention of catastrophic consequencesof advanced disease (Table 5).
In patients with minimal bone involvement (usually defined as fewer than fivelesions) and minimal symptoms, CAB is the treatment of choice. It can beaccomplished by orchiectomy or the use of depot injections of leuprolide(7.5 mg SC monthly) or goserelin (3.6 mg SC monthly). Further androgen block-ade is accomplished by the addition of an antiandrogen, such as flutamide (250mg PO tid), bicalutamide (50 mg PO daily), or nilutamide (150 mg PO daily).
Patients presenting with widespread bone or soft-tissue disease can be treatedwith surgical castration alone. If medical castration therapy is used, treatmentwith an antiandrogen for 1 month after the initiation of castration therapy isrecommended. This can be accomplished with flutamide, bicalutamide,nilutamide, or ketoconazole (400 mg PO tid). For men with advanced diseasesuch as spinal cord compression, where a flare could be clinically detrimental,the pure LHRH agonist aberelix is appropriate.
Recently, the efficacy of bicalutamide monotherapy (150 mg/d) compared withflutamide plus goserelin was tested in a randomized study of patients with his-tologically proven C or D disease. Fewer patients in the bicalutamide groupexperienced loss of libido (P = .01) and erectile dysfunction (P = .002). Signifi-cant trends also were noted in the bicalutamide-treated patients with respect totheir quality of life and social functioning, vitality, emotional well-being, andphysical capacity. Bicalutamide monotherapy was as effective as traditionalandrogen deprivation therapy for patients with nonmetastatic disease at a me-dian follow-up of about 7 years. However, in patients with stage D (M1) dis-ease, bicalutamide monotherapy provided a slight survival disadvantage (me-dian 45 days shorter survival) than traditional androgen deprivation therapy.
Bicalutamide (150 mg) monotherapy has also been tested as adjuvant therapyafter radical prostatectomy and EBRT and with watchful waiting A clinical disease-free benefit has been observed, but a survival benefit has not yet beendemonstrated.
Second-line hormonal therapies
Initial hormone ablation controls symptoms for 2 to 5 years in the averagecontemporary patient wtih minimal metastatic disease. In the past, patientstypically presented with new urinary symptoms or new bone pain while receiv-ing castration treatment, but with the advent of PSA determinations, most ofthese patients can be identified by a rising PSA level prior to symptom onset. Itis unclear whether these patients should be treated immediately or whethertherapy should be delayed until the onset of symptoms.
Several strategies have been employed as secondary hormonal treatments. Ingeneral, responses are seen in about 20% of patients and usually last ap-proximately 6 months.
Addition or subtraction of an antiandrogen If a patient has been receiving
monotherapy, an antiandrogen is typically added, but responses are seen in
only about 10% of patients. In patients who have been treated with CAB, omit-
ting the antiandrogen from the regimen can cause a paradoxical shrinkage of
measurable disease, a decrease in serum PSA level, and/or a lessening of symp-
toms in 10%-25% of patients. Thus, the addition or subtraction of the
antiandrogen has become the next step for patients in whom initial hormone
TABLE 6: Chemotherapy regimens for prostate cancer
Drug/combination
Dose and schedule
Mitoxantrone/prednisone
Tannock IF, Osoba D, Stockler MR, et al: J Clin Oncol 14:1756–1764, 1996.
Docetaxel/estramustine
280 mg orally on days 1 to 5 every 21 days 60 mg orally given as a premedication before docetaxel Petrylak DP, Tangen CM, Hussain MHA, et al: N Engl J Med 351:1513–1520, 2004.
Docetaxel/prednisone
Note: Standard docetaxel premedication should be given prior to the administration ofdocetaxel Tannock IF, de Wit R, Berry WR, et al: N Engl J Med 351:1502–1512, 2004.
CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH therapy is ineffective. If this measure fails, an- other second-line agent is often employed.
Aminoglutethimide (Cytadren) and hy-
(SWOG) reported on 770 menwith Hormone-refractory drocortisone have been widely used.
Aminoglutethimide is started at a dose of 125 mg PO qid and increased to 250 mg PO qid.
It is associated with significant side effects, in- cluding lethargy, weakness, rash, and fever.
(Taxotere) plus estramustine(Emcyt) plus dexamethasone. The Hydrocortisone (20 mg PO bid) alone affords significant pain relief, as well as occasional survival by a median of 2 months,showing for the first time that a Ketoconazole, with or without hydrocorti-
sone, is also used. Ketoconazole is started at a by Eisenberger et al showed asimilar survival benefit of dose of 200 mg PO tid and then escalated to a total dose of 400 mg tid. The 1,200-mg daily dose is associated with nausea and vomiting, (Petrylak D, Tangen C, Hussain M, et however, and can result in severe liver injury.
al: N Engl J Med 351:1513-1520,2004).
Patients receiving high-dose ketoconazoleneed to be monitored carefully for signs andsymptoms of liver damage, and the drug should be stopped immediately ifliver enzyme levels become elevated.
Chemotherapy for hormone-refractory disease
Despite the effectiveness of initial hormonal therapy, metastatic prostate can-cer is an incurable disease, with patients surviving a median of 16 months.
One recent advance is the acceptance of PSA levels as a surrogate marker forresponse in hormone-refractory prostate cancer. Currently, a PSA level declineof < 50% from pretreatment baseline that persists for at least 4 weeks is consid-ered a partial response in clinical trials. Although not proven in a phase IIIsetting, utilization of PSA levels has helped identify new, potentially active che-motherapy regimens for use in patients with advanced androgen-independentdisease (Table 6).
Mitoxantrone (Novantrone) plus prednisone The combination of mitoxantrone
and prednisone has been approved for use in patients with hormone-refractory
prostate cancer who are experiencing pain. Mitoxantrone (12 mg/m2 IV) is ad-
ministered every 3 weeks. Prednisone is given as a 10-mg oral daily dose (5 mg
bid). Toxicities of the combination include leukopenia and thinning of the hair.
Bisphosphonates for advanced prostate cancer
Bisphosphonates inhibit osteoclast activation. In a recent study, it was demon-strated that zoledronic acid (Zometa) significantly decreased pain associated withbone metastases as well as fractures in patients undergoing chemotherapy forhormone-refractory prostate cancer. Zoledronic acid has been approved by theFDA for use in patients with skeletal metastases and hormone-refractory prostatecancer.
Radiation therapy for palliating bone metastasis
Radiotherapy is effective in controlling local pain associated with skeletal prostate me-tastasis. In general, a treatment regimen of 30 Gy over 10 treatments results in rapidand durable local symptom control and a reduced dependence on analgesics.
For patients with more extensive bone involvement causing pain that may bedifficult to address with localized EBRT, alternatives include wide-field irradia-tion (ie, hemibody irradiation) or systemic administration of radioactive bone-seeking isotopes that can deliver therapeutic doses to skeletal metastatic dis-ease. Radioactive isotopes used in this fashion include strontium-89 chloride(Metastron) and samarium SM 153 lexidronam (Quadramet). A more detaileddiscussion of these approaches can be found in chapter 37.
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CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH Thompson IM, Pauler DK, Goodman PJ, et al: Prevalence of prostate cancer among
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CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

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