a 5-year survival of 80 to 90% for low-grade lesions. More in-
`W1 we or histologically poorly differentiated tumors are more likely
`vflieaur locally and metastasize. Metastatic disease is treated with the
`loemotherapy used it: bladder cancer, and the outcome is similar to
`[lit of metastatic transitional cell cancer of bladder origin.
`
`fumes moms
`VANCED BLADDER CANCER META—ANALYSIS COLLABORATION: Neoad-
`AD
`J-uvant chemotherapy in invasive bladder cancer: A systematic review and
`meta-analysis. Lancet 36111927, 2003
`
`61 Hyperplastic and Malignant Diseases of the Prostate
`
`543
`
`BORDEN LS JR et al: Bladder cancer. Curr Opin Oncol 15:227. ZOG3
`LINEBAN WM et al: The genetic basis of cancer of the kidney. J Urol 170:
`2163, 2003
`
`MEJEAN A et al: Prognostic factors of renal cell carcinoma. J Urol 1692821,
`2003
`7
`
`WHANG YE, GODLEY PA: Renal cell carcinoma. Curr Opin Oncol 152213
`2003
`
`WINQUIST E et al: Neoadjuvant chemotherapy for transitional cell carcinoma
`of the bladder: A systematic review and meta-analysis. J Urol
`l71:56l,
`2004
`
`IT'S
`S Pm,
`-ntents
`I hilar
`'.l‘O\Ig]-\
`II dis.
`)ass is
`tumor
`[10 de‘
`atiemg
`
`in
`
`HYPERPLASTIC AND it‘lALl5%iA?iT D¥SEASES OF TEE PROSTATE
`
`Howard I. Scher
`
`The frequency of both benign and malignant changes in the prostate
`increase with age. Autopsies of men
`the eighth decade of life show
`hyperplastic changes in >90% and malignant changes in >70% of
`individuals. The high prevalence of these diseases in an elderly pop-
`ulation with competing causes of morbidity and mortality mandates a
`risk-adapted approach to diagnosis and treatment. This can be achieved
`by considering these diseases as a series of states. Each state represents
`a distinct clinical milestone for which intervention(s) may be recom-
`mended based on the presence or risk of developing symptoms or death
`from disease in a given time frame (Fig. 81-1). For benign proliferative
`disorders, symptoms of urinary frequency, infection, and potential for
`obstruction are weighed against the side effects and complications of
`medical or surgical therapy. For prostate malignancies, the risk of de-
`veloping the disease, symptoms, or death from cancer are balanced
`against the morbidities of interventions recommended and preexisting
`comorbid conditions.
`
`In 2004, around 230,000 prostate cancer cases were diagnosed, of
`whom 29,900 succumbed. The absolute number of prostate cancer
`deaths has decreased in the past 5 years; this has been attributed by
`some to the widespread use of detection strategies based on monitoring
`prostate-specific antigen (PSA). However, screening has not been
`proven to improve survival in prospective randomized trials. The
`adox management is that although the disease remains the second
`leading cause of cancer deaths in men, the almost 8:] ratio in incidence
`to prostate cancer—specific mortality shows that the majority of nten
`do not die of their disease.
`
`ANATOMY AND PATHOLOGY
`The prostate is located in the pelvis and is surrounded by the rectum,
`the bladder, the periprostatic and dorsal vein complexes that are re-
`Sponsible for erectile function, and the urinary sphincter that is re-
`sponsible for passive urinary control. The prostate is composed of
`branching tubuloalveolar glands arranged in lobules and surrounded
`by a stroma. The acinal unit includes an epithelial compartment made
`“P 0f epithelial, basal, and neuroendocrine cells and a stromal com-
`partment that includes fibroblasts and smooth-muscle cells. The com-
`partments are separated by a easement membrane. PSA and acid phos-
`Phatase (ACP) are produced in the epithelial cells. Both cell types
`express androgen receptors and depend on androgens for growth. Tes-
`‘°31er0ne, the major circulating androgen, is converted by the enzyme
`fa Teductase to dihydrotestosterone in the gland. Changes in prostate
`s'ze'0CCur during puberty and after the age of 55 in the periurethral
`P0171011 of the gland. Most cancers develop in the peripheral zone,
`Much Can often be palpated by a digital rectal examination (DRE).
`
`Nonmalignant growth occurs predominantly in the transition zone
`around the urethra.
`
`EPIDEMIOLOGY
`
`The development of a prostate cancer involves a multistep process.
`Hyperrnethylatien of the GSTPI gene promoter, leading to a loss of
`function of a gene that detoxifies carcinogens, is one early change.
`Epidemiologic studies show that the risk of being diagnosed with pros-
`tate cancer increases by a factor of 2 if one first-degree relative is
`affected and by 4 if two or more are affected. Current estimates are
`that 40% of early-onset and 5 to 10% of all cancers are hereditary and
`follow a Mendelian inheritance pattern. Prostate cancer affects ethnic
`groups differently. Matched for age, the prostates of African-American
`males have both a greater number of precursor prostatic intraepithelial
`neoplasia (PIN) lesions and larger tumors than white males, possibly
`related to the higher levels of testosterone seen in African-American
`males. These lesions are highly unstable, and typically multifocal.
`Polymorphic variants of the androgen receptor gene, the cytochrome
`P450 C17 gene, and the steroid Sat-reductase type II (SRDSAZ) gene
`have also been implicated in the variations in incidence. The incidence
`of autopsy-detected cancers is similar around the world, while the
`incidence of the clinical disease varies. Thus, environmental factors
`may play a role. High consumption of dietary fats, such as ct-linoleic
`acid, or polycyclic aromatic hydrocarbons that form when red meats
`are cooked is believed to increase risk. Similar to breast cancer in
`Asian women, the risk of prostate cancer in Asian males increases
`when they move to western environments. Protective factors include
`the isoflavinoid genistein (which inhibits 5a-reductase), cruciferous
`vegetables that contain isothiocyanate sulfuraphane, retinoids such as
`lycopene (in pizza and tomatoes), and inhibitors of cholesterol bio-
`synthesis. The antioxidant or-tocopherol (vitamin E) and selenium may
`also reduce risk.
`
`DIAGNOSIS AND TREATMENT BY CLINICAL STATE
`
`The clinical states framework considers the risk of morbidity from an
`enlarging but nonmalignant gland; the probability that a clinically sig-
`nificant cancer is present in an individual with or without urinary
`symptoms: or, for those with a prostate cancer diagnosis; the proba-
`bility of developing symptoms or dying from disease. At any point in
`time, a patient resides in one state and remains there until the disease
`has progressed to the next state. Applying this paradigm, a patient with
`localized prostate cancer who has had all cancer removed surgically
`remains in the state of localized disease as long as the PSA remains
`undetectable. The time within a state becomes a measure of the impact
`of an intervention on the natural history of disease, be it benign or
`malignant in etiology, recognizing that the impact may not be assess-
`able for years. It also allows a distinction between cure—the elimi-
`nation of all cancer cells, the primary therapeutic objective when treat-
`ing most cancers—and cancer control, in which the tempo of the
`illness is modulated and symptoms controlled until the patient dies of
`other causes. It is the concept of cancer control that makes the man-
`
`
`
`enmcany
`
`localized
`disease
`
`
`Fl
`GUM 31-I
`Clinical states of prostate cancer. PSA, prostate-specific antigen.
`
`Clinical
`metastases:
`Noncaetrate
`
`V Clinical
`metastases.
`Caetrate
`
`
`WCK1009
`Page 1
`
`
`
`
`
`WCK1009
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`
`

`
`544
`
`Part V Oncology and Hematology
`
`agement of prostate cancer unique. Ever; when a recurrence is docu-
`mented, immediate therapy is not always necessary. Rather, as at the
`time of diagnosis, the need for intervention is based on the tempo of
`the illness
`it unfolds in the individual, relative to the risk:reward
`ratio of the therapy being considered.
`
`NO CANCER DIAGNOSIS E’ Symptoms The need to pursue a diagnosis of
`prostate cancer is based on symptoms, an abnormal DRE, or an ele-
`vated serum PSA. The urologic history should focus on symptoms of
`outlet obstruction, continence, potency, or a change in ejaculatory pat-
`tern. Benign proliferative disease may produce hesitancy, intermittent
`voiding, a diminished stream,
`incomplete emptying, and postvoid
`leakage. The severity of these symptoms can be quantitated with the
`self-administered American Urological Association (AUA) Symptom
`Index (Table 81-1) recognizing that the degree of symptoms does not
`always relate to gland size. Resistance to urine flow reduces bladder
`compliance, leading to nocturia, urgency, and, ultimately, to retention.
`Infection. tranquilizing drugs, antihistamines, or alcohol can precipi-
`tate urinary retention. Prostatitis often produces pain or induration.
`Symptoms of metastatic disease include pain secondary to osseous
`metastases, although many are asymptomatic despite extensive spread.
`Less common are symptoms related to marrow compromise (mye—
`lophthisis), a coagulopathy, or spinal cord compression.
`
`Physical Exarfiination The DEE focuses on the size, consistency, and
`abnormalities within or beyond the gland. Many cancers occur in the
`peripheral zone and can be palpated on DRE. Carcinomas are char-
`acteristically hard, nodular, and irregular, while induration may be due
`to benign prostatic hypertrophy (BPH) er to calculi or tumor. Overall,
`20 to 25% of men with an abnormal DRE have cancer.
`
`PROSTATE-SPECIFIC ANTlGEN
`
`PSA is a kallii:rein-like serine protease that causes liquefaction of sem-
`inal coagulum. It is produced by both nonmalignant and malignant
`epithelial cells. PSA is prostate specific, not prostate cancer specific,
`and increases may occur from prostatitis, nonmalignant enlargement
`of the gland (BPH), prostate cancer, and prostate biopsies. The level
`is not affected by the performance of a DRE. It circulates in the blood
`as an inactive complex with the protease inhibitors a-,-antichymo-
`trypsin and Bymacroglobulin and has an estimated half-life in the
`serum of 2 to 3 days. Levels should be undetectable if the prostate has
`been removed. PSA immunostaining is used to establish a prostate
`cancer diagnosis.
`PSA testing was approved for early detection in 1994. It is rec-
`ommend on an annual basis along with a DRE for men over age 50
`
`(with an anticipated survival of >10 years; this includes men up to
`age 76 years). For African Americans and men with a family history,
`testing is advised to begin at age 40. The normal range of PSA is
`[0
`4 ng/mL. For values >4, the sensitivity for prostate cancer detection
`is 57 to 79%, the specificity is 59 to 68%, and the positive predictive
`value is 40 to 49%.
`
`The PSA-based criteria used to recommend a diagnostic prostate
`biopsy have evolved over time. PSA values may fluctuate for no ap_
`parent reason; thus, an isolated abnormal value should be confirmed
`before proceeding with further testing. Taese evolving criteria aim to
`increase the sensitivity of the test for younger men more likely to die
`of the disease and to reduce the frequency of detecting cancers of low
`malignant potential in elderly men more likely to die of other causes.
`Age-specific reference ranges apply a lower “upper” limit of normal
`for younger males and higher “upper” limit for older individuals. Dif_
`ferent thresholds alter sensitivity and specificity of detection. The
`threshold for performance of a biopsy is now 2.6 ng/mL for men under
`age 60. Prostate—specific antigen density (PSAD) measurements were
`developed to correct for the contribution of BPH to the total PSA level_
`PSAD is calculated by dividing the serum PSA by the estimated pmS_
`tate weight calculated by transrectal ultrasound (TRUS). Values <0_10
`are consistent with BPH, while those >O.15 suggest cancer. PSA ve_
`locizy is the rate of change in PSA levels over time. It is particularly
`useful for men with values that are rising in the seemingly “normal”
`range. Rates of rise >O.75 ng/mL per year suggest cancer. As an ex.
`ample, an increase from 2.5 to 3.9 in a 1-year period would warram
`further testing. Free and complexed PSA measurements are used when
`levels are between 4 and 10 ng/mL to decide who needs a biopsy. In
`cancer, the level of free PSA is lower. The ratios of free to total,
`complexed to total, and free to complexed PSA have also been used,
`In one series, specificity improved by 20% using a normal range of
`free/total >0.15; complexed/total <0.70; and free/complexed >0_25_
`A diagnostic algorithm based on the DRE and PSA findings is illus-
`trated in Fig. 81-2. In general, a biopsy is recommended if the DRE
`or PSA are abnormal.
`
`Prostate Biopsy A diagnosis of cancer is established by a TRUS-guided
`needle biopsy. Direct visualization assures that all areas of gland are
`sampled. A minimum of six separate cores, three from the right and
`three from the left, are advised, as is a separate biopsy of the transition
`zone, if clinically indicated. Performance of a biopsy is not advised in
`a patient with prostatitis until a course of antibiotics has been admin-
`istered. The positive predictive value of an abnormal DRE is 21%,
`while 25% of men with a PSA > 4
`and an abnormal DRE, and
`17% of men with a PSA of 2.5 to 4.0 ng/mL and normal DRE, leave
`cancer. Those with an abnormal PSA and negative biopsy are advised
`to undergo a repeat biopsy.
`
`nuns 31-1
`
`AUA System Index
`
`Questions to 5e Answered
`
`Over the past month, how ofeen you have had a sensation of not
`emptying your bladder coittpletely after you finislicd urinating‘!
`Over the past month, now often have you had to urinate again less than
`2 h after you linislied urinating?
`Over the past month, how often have you found you stopped and started
`again several times when you uriiiated?
`Over the past month, how often have you found it difficult to postpone
`urination?
`
`Over the past month. how often have you had a weak urinary stream?
`Over the past month, now often have you éiazl to pusl: c-r strain to begin
`urination‘?
`Over the past month. how many times did you most typically get up to
`urinate from the time you went to bet! at niglit until the time you got
`up in the ittoming?
`Sum of 7 circled numbers (AUA Symptom Score):
`
`AUA Symptom Score -fdircle .1 Number on Each line)
`less than 1
`Less than
`About Half
`More than
`Time in 5
`Half the Time
`the Time
`Half the time
`
`Almost
`Alwtlyf _,
`
`Not at All
`
`0
`
`0
`
`0
`
`D
`
`0
`0
`
`l
`
`E
`
`I
`
`l
`
`l
`l
`
`2
`
`2
`
`2
`
`2
`
`2
`2
`
`3
`
`3
`
`3
`
`3
`
`3
`3
`
`4
`
`4
`
`4
`
`4
`
`4
`4
`
`5
`
`5
`
`5
`
`5
`
`5
`5
`
`(None)
`
`(1 time)
`
`(2 times)
`
`(3 times)
`
`(4 times)
`
`(5 tim65)
`
`Nate: AUA. American Urological Association.
`
`Source: Barry M] et al: J Urol l48:l549. 1992. Used with permission.
`
`_
`
`._
`
`_
`
`WCK1009
`Pa e 2
`
`WCK1009
`Page 2
`
`

`
`Men >50 orAfrican Americans >45 or
`
`+ Family history
`
`
`
`
`
`DRE normal
`
`Abnormal PSA Normal
`Positive
`Borderline
`
`
`
`i
`' DHE
`
`.
`and PSA
`
`
`
`Total <4
`PSA velocity <0.75
`
`
`
`
`
`PSA 4-10
`
`+5
`
`Staging
`
`
`
`TRUS guided [ -TT
`(a—--{ Check % free PSA in 5-12 months ]
`...:.-a
`
`l
`
`__.,__"/°F'°*:E_S_'.*._lj271i—' B_i°e~°~ I-*9"-‘"'* .$:'=&9i."9_ I
`
`EUS guided biopsy
`
`t’4:*}—- Staging I
`
`
`
`Consider repeat
`
`TRUS guided biopsy W—_...._.:
`
`_"—'j‘-_:—’i
`.
`
`C-)r—- Repeat annuall
`
`
`
`Total <4
`PSA velocity >0.75
`
`
`
`FIGURE 81-2
`
`Algorithm for diagnostic evaluation of men based on digital rectal examination and prostate-specific antigen levels.
`
`Faiholofiu The noninvasive proliferation of epithelial cells within
`ducts is termed prostzztic imraepitiielial neaplasia. PIN is a precursor
`of cancer, but not all PIN lesions develop into invasive cancers. Of
`the cancers identified, >95% are adenocarcinomas; the remaining are
`squamous, transitional cell tumors, and rarely, carcinosarcomas. Me-
`tastases to the prostate are rare, but in some cases, transitional cell
`tumors of the bladder or colon cancers invade the gland by direct
`extension. Each core of the biopsy is examined for the presence of
`cancer, and the amount of cancer present is quantified. A measure of
`histologic aggressiveness is also assigned using the Gleason grading
`System, in which the dominant and secondary glandular histologic pat-
`terns are scored from 1 (well differentiated) to 5 (undifferentiated) and
`Sllmmed to give a total score of 2 to 10 for each tumor. The most
`P00Tly differentiated area of tumor (i.e., the area with the highest his-
`‘°l08iC grade) often determines biologic behavior. The presence or
`absence of perineural invasion and extracapsular spread are also re-
`corded.
`
`PSA-based detectéon strategies have changed the clinical spectrum
`Pfthe disease. Now, 95 to 99% of newly diagnosed cancers are clin-
`‘Cally localized, 40% are not palpable, and, of these, 70% are patho-
`tielftlically organ-confined. The downside of widespread use is the de-
`thatilfll and treatment of cancers with such a low malignant potential
`um] 9}’ Would not have shortened survival or produced symptoms
`impmge the patient’s lifetime. The side effects of treatment, including
`ese nce, incontinence, and bowel dysfunction, are unacceptable for
`mostafases. Formal clinical trials to assess the value of screening on
`of these Cancer morbidity and mortality areongoing. Until the results
`decisioe Studies are available, men are. advised to make an informed
`1'1 about whether to undergo testing.
`9:
`dgjgpon
`It is difficult to identify individuals who are at risk for
`Vegplng a cancer that is clinically significant. The l’rostate Cancer
`signed :10? Thai IS a double-blinded, randomized multicenter trial. de-
`:0 rev 0 investigate the ability of finasteride, a Sat-reductase inhibitor,
`ml the development of prostate cancer in men age 255 years.
`
`The prostate cancer detection rate was 18.4% (803 of 4364) for finas-
`teride and 24.4% (1 147 of 4692) for placebo-treated men. However,
`more of the cancers detected in the finasteride group were high-grade
`[37% (280 of 757) vs. 22% (237 of 1068 cancers) for the placebo].
`No effect on survival was detected. Vitamin E and selenium (the SE-
`LECT study) are also being tested as preventive agents.
`
`Treatment of Benign Disease Asymptomatic patients do not require treat-
`ment regardless of the size of the gland, while those with an inability
`to urinate, gross hematuria, recurrent infection, or bladder stories may
`require surgery. Typically, obstruction does not occur and the symp-
`toms iemain stable over time. In these cases, uroflowmetry can identify
`patients with normal flow rates who are unlikely to benefit from treat-
`ment and those with high postvoid residuals who may need other in-
`terventions. Psessure—flow studies detect primary bladder dysfunction.
`Cystoscopy is recommended if hematuria is do-Jumerited and to assess
`the urinary outflow tract before surgery. Imaging of the upper tracts is
`advised for patients with hematuria, a history of calculi, or prior uri-
`nary tract problems. Therapies such as finasteride, which blocks the
`conversion of testosterone to dihydrotestosterone. have been shown to
`decrease prostate size, increase urine flow rates, and improve symp-
`toms. They will also lower baseline PSA levels by 50%, an important
`consideration when using PSA to guide biopsy recommendations.
`a-Adrenergic blockers such as terazosin act by relaxing the smooth
`muscle of the bladder neck and increasing peak urinary flow rates. No
`data show that these agents influence the progression of the disease.
`Surgical approaches include a transurethral resection of the prostate
`(TURP), transurethral incision, or removal of the gland via a retro-
`pubic, suprapubic or perineal approach. TULIP (transurethral ultra-
`sound-guided laser-induced prostatectomy), coils, stents, and hyper-
`thermia are also utilized.
`
`PROSTATE CANCER STAGING The TNM staging system includes catego-
`ries for cancers that are palpable on DRE, those identified solely on
`the basis of an abnormal PSA (Tlc), those that are palpable but clin-
`
`WCK1009
`
`
`
`rant
`
`ital
`sed.
`e of
`>25.
`.lus-
`)RE
`
`ided
`l are
`and
`ition
`:d in
`min-
`ll %.
`and
`have
`rised
`
`r5t
`lys
`
`Repeat
`annually
`
`
`
`
`W]--' Repeat biopsy
`in 3-6 months
`
`WCK1009
`Page 3
`
`

`
`546
`
`Part V 0nco¥ugy and Hematology
`
`ically confined to the gland (T2), and those that have extended outside
`of the gland (T3 and T4) (Table 81-2). The assessment of disease
`extent based on DRE alone is inaccurate with respect to the extent of
`the disease within the gland, the presence or absence of capsular in-
`vasion, involvement of seminal vesicles, and extension of disease to
`lymph nodes. This led to a modification of the staging system to in-
`clude the results of imaging studies on the assignment of T stage.
`Unfortunately, no single test has proven to predict the pathologic stage
`accurately, be it the presence of organ-confined disease, se eeinal ves-
`ical involvement, or lymph node spread.
`TRUS is most frequently used to assess the primary tumor. but no
`consistent finding predicts cancer with certainty. TRUS is used pri-
`marily to direct prostate biopsies. Computed tomography (CT) scans
`lack sensitivity and specificity to detect extraprostatic extension and
`are inferior to magnetic resonance imaging (MRI) in visualization of
`lymph nodes. Mi<I specificity is improved with an endorectal coil and
`aids in planning radiation therapy. T1-weighted images demonstrate
`the periprostatic fat, periprostatic venous plexus, perivesicular tissues,
`lymph nodes, and bone marrow. T2-weighted images demonstate the
`internal architecture of the prostate and seminal vesicles. Most cancers
`have a low signal, while the normal peripheral zone has a high signal,
`although the technique lacks sensitivity and specificity.
`Radionuclide bone scans are used to evaluate spread to osseous
`sites. This test is sensitive but relatively nonspecific because areas of
`increased uptake are not always related to metastatic disease. Healing
`fractures, arthritis, Paget’s disease, and other conditions will also show
`abnormal uptake. True-positive bone scan results are rare if the PSA
`<8 ng/mL and uncommon when the PSA < 10 ng/mL unless the
`tumor is high grade. When the PSA <10 ng/mL, a positive bone scan
`is usually falsely positive, which in turn, leads to additional low-yield
`testing.
`
`CLINICALLY LDCALIZED DlSEA§E Localized prostate cancers are clinically
`confined to the prostate. Patients with localized disease are managed
`by radical surgery, radiation therapy, or watchful waiting. Data from
`the literature do not provide clear evidence for the superiority of any
`one treatment. Choice of therapy needs consideration of several fac-
`
`l'ABl.E 81-2 Comparison of Ellnlral 5tage—by the TNM Classification
`System and the Whltmore-Jewett Staging System
`TNM
`Whitmore-Jeweit
`Stage Description
`Stage
`
`Description
`
`Tla Nonpalpable, with 5% or
`less of resccted tissue
`with cancer
`Tlb Nonpajpable. with >5%
`of resected tissue with
`cancer
`
`Tl:
`
`T2a
`
`T2b
`
`T2c
`
`Tia
`
`Nonpalpable, detected
`due to elevated serum
`PSA
`
`Palpable. half of one
`lobe or less
`
`half of one
`Pajpable,
`lobe but not both lohcs
`Falpable. involves both
`lobes
`Palpalele, unilateral
`extracaesulnr extension
`
`A1
`
`A2
`
`BIN
`
`Bl
`
`B2
`
`CI
`
`Well dit”l‘e.renti-ated
`tumor on few chips
`1“ I
`l ‘robe
`Involvement more
`diffuse
`
`Palpirhle, < one
`lobe, stlrrounded
`by normal tissue
`Ffalpnble. 4: one lobe
`
`Fatpablet one entire
`lnhe or both lobes
`Falpable, outside
`capsule, not into
`seminal vesicles
`
`'l'3b
`
`T3c
`
`C2
`
`Palpable, bilateral
`extracapsular extension
`Palpable, seminal
`Tumor invades seminal
`vesicle it'l\ olved
`vesiclets)
`
`Distant meta tases DMl Metastatic disease
`
`
`
`
`
`Source: Adapted from FF Schroder et al: TNM classification of prostate cancer. Prostate
`(Suppl; 4:129, i992; and American Joint Committee on Cancer, 1992.
`
`
`
`tors: the presence of symptoms, the probability that the untreated tu
`mor will adversely affect the patient during his lifetime and um‘
`require treatment, and whether the tumor can be cured by single-m S
`dality therapy directed at the prostate or requires both local and Sys:
`temic therapy to achieve cure. As most of the tumors detected are
`deemed clinically significant, most men undergo treatment.
`Comparing the outcomes of various forms of therapy is limited h
`the lack of prospective trials, referral bias, and differences in the out‘
`comes used. The primary outcomes are cancer control and treatment_
`related morbidities. These benchmarks of success or failure vary h
`modality. Often, PSA relapse-—free survival is used because an effect
`on metastatic progression or survival may not be apparent for years
`Based on a half-life in the blood of 3 days, PSA should be undetectablé
`in the blood 4 weeks after all prostate tissue has been removed by
`radical surgery. If PSA remains detectable, the patient is considered
`to have persistent disease. In contrast, the PSA does not become un‘
`detectable after radiation therapy because the remaining nonmalignant
`elements of the gland continue to produce PSA even if all cancer cells
`have been eliminated. Similarly, there is no adequate cancer C0ntro1
`definition for a patient treated with watchful waiting because PSA
`levels will continue to rise in the absence of therapy. Other outcomes
`are the time to objective progression (local or systemic) and cancer_
`specific and overall survival; however, these outcomes may take years
`to define.
`
`The more advanced the disease, the lower the probability of local
`control and the higher the probability of systemic relapse. More im-
`poitant is that within the categories of T1, T2, and T3 disease are
`tumors with a range of prognoses. Some T3 tumors are curable with
`therapy directed solely at the prostate, and some Tl lesions have a
`high probability of systemic relapse that requires the integration of
`local and systemic therapy to achieve cure. Tlc tumors particularly
`require the use of other factors to predict outcomes and select treat-
`ment. Many groups have developed prognostic models based on a
`combination of the initial T stage, Gleason score, and baseline PSA.
`Some are based on discrete cut points (PSA <10 or 2 10; Gleason
`score of S6, 7, or 28). Others are nomograms that use PSA and
`Gleason score as continuous variables. These algorithms are used to
`predict disease extent: organ confined vs. nonorgart confined, node
`negative or positive, and the probability of success using a PSA-based
`definition of failure specific to the local therapy under consideration.
`lzxactly what cut-off value would lead a patient to accept one form of
`therapy vs. another is an area of active debate. One nomogram to
`predict PSA relapse—free survival following radical surgery is illus-
`trated in Fig. 81-2. Specific nomograms have been developed for rad-
`ical prostatectomy, extemal—beam radiation therapy, and brachyther-
`apy (seed implantation). These are being refined continually t0
`incorporate other clinical parameters and biologic determinants. Sur-
`gical technique, radiation therapy delivery, and criteria for watchful
`waiting continue to be refined and improved; the year treatment was
`given affects outcomes independent of other factors. The improve-
`ments make treatment decisions a dynamic process.
`The frequency of adverse events for the different modalities i5
`highly variable. Of greatest concern to patients are the effects on COR‘
`tinence, sexual potency. and bowel function. Part of the variability
`relates to the definition used for a specific complication and whethef
`the patient or physician is reporting the event. Incontinence figures
`range from 2% to 47% and impotence rates range from 25% to 89%
`following radical prostatectomy. The time of the assessment is 3150
`important. After surgery, impotence is immediate but may reverse 0V6’
`time, while with radiation therapy, impotence is not immediate but
`may develop over time.
`
`Radical Retropuhic Prostatectorag (RR?) The goal of radical prostateC'
`tomy is to excise the cancer completely with a clear margin, to main’
`tain continence by preserving the external sphincter, and to preser‘/5
`potency by sparing the autonomic nerves in the neurovascular bundle-
`RRP is advised for patients with a life expectancy of >10 years and
`is performed using a retropubic, perineal, or laparoscopic approach-
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`Outcomes can be predicted using postoperative nomograms that con-
`ider pretreatment factors and the pathologic findings at surgery. PSA
`imlure is defined as a detectable value of 0.2 or 0.4 ng/mL, although
`the exact definition varies among series. The techniques continue to
`improve as the 30111!)/' to localize the tumor within or beyond the pros-
`we are refined with different biopsy algorithms-and with imaging. The
`resuu is better case selection and surgical planning, which in turn have
`led to more rapid recovery and higher rates of continence and potency.
`Factors associated with incontinence include older age, shorter urethra
`length, surgical technique, preservation of neurovascular bundles, and
`development of an anastomotic stricture. Surgical experience is also a
`factor. In one series, 6% of patients had mild stress urinary inconti-
`Hence (SUI) (requiring 1 pad/day), 2% moderate SUI (>1 pad/day),
`and 0.3% severe SUI (requiring an artificial urinary sphincter). At 1
`Year, 92% were completely continent. In contrast, the results in a Med-
`icare population treated at multiple centers showed that at 3, 12, and
`24 months following surgery, 58, 35, and 42% wore pads in their
`underwear, and 24, 11, and 15% reported “a lot” of urine leakage.
`Factors associated with recovery of erectile function include younger
`age, quality erections before surgery, and the absence of damage to
`the neurovascular bundles. Erectile function returns in a median of 4
`to 6 months if both bundles are preserved. Potency is reduced by half
`if at least one nerve bundle is sacrificed. In cases where cancer control
`requires the removal of both bundles, sural nerve grafts are being ex-
`plored. Overall, with the availability of drugs such as sildenafil, in-
`traurethral inserts of alprostadil, and intracavernosal injections of va-
`sodilators, many patients recover satisfactory sexual function.
`High—risk patients are those with a predicted high probability of
`failure with surgery alone based on pretreatment factors. In these sit-
`uations, nomograms and predictive models can only go so far. Exactly
`what probability of success or failure would lead a physiciah to rec-
`ommend and a patient to seek alternative approaches is controversial.
`For example, it may be appropriate to recommend radical surgery for
`a younger patient with a low probability of cure. To improve the out-
`comes of surgery for high-risk patiehts, neoadjuvant hormonal therapy
`has been explored. The results of several large trials testing 3 or 8
`months of androgen ablation before surgery showed that serum PSA
`levels decreased by 96%, prostate volumes reduced by 34%, and mar-
`gin positivity rates declined from 41 to 17%. Unfortunately, hormones
`did not produce an improvement in PSA relapse—free survival. Thus,
`neoadjuvant hormonal therapy is not recommended.
`
`Radiation Therapy Radiation therapy is given by external beam, the
`implantation of radioactive sources into the gland, or a combination
`Of both. Contemporary external beam radiation techniques now use
`three—dimensional conformal treatment plans to maximize the admin-
`istered dose to the tumor and to minimize the exposure of the sur-
`rounding normal structures. The addition of intensity modulation
`(IMRT) has allowed further shaping of the isodose curves and the
`delivery of higher doses to the tumor and a further reduction in normal
`Ilssue exposure. These advances have allowed the safe administration
`Of doses >80 Gy, higher local control rates, and fewer side effects.
`Overall, radiation therapy is associated with a higher frequency of
`b0Wel complications (mainly diarrhea) than surgery. Measures of can-
`Cel‘ control include the proportion of patients who show a decline in
`PSA t0 <0.5 or 1 ng/mL, the proportion with “nonrising” PSA values,
`“H116 proportion with a negative biopsy of the prostate 2 years after
`°_°f11pletion of treatment. PSA relapse is defined as three consecutive
`“W13 PSA values from the nadir value, with the time to failure as the
`mldpoint between the nadir and first rising value.
`Radiation dose is important. A PSA nadir of <1.0 ng/mL was
`gbsefvecl in 90% of patients receiving 75.6 or 81.0 Gy vs. 76 and 56%
`‘_’Y those receiving 70.2 Gy and 64.8 Gy, respectively. The positive
`‘°PSy rates at 2.5 years were 4% for those treated with 81 Gy, vs. 36
`and 27% for those receiving 70.2 or 75.6 Gy. The frequency of rectal
`fomlflications relates directly to the volume of the anterior rectal wall
`56°31‘/ing full-dose treatment. Grade 3 rectal or urinary toxicities were
`een in 2.1% of cases at a median dose of 75.6 Gy. Grade 3 urethral
`
`81 Hyperplastit and Malignant Diseases of the Prostate
`
`547
`
`strictures requiring dilatation developed in 1% of cases, all of who