This document discusses prostate cancer, including:
1. Epidemiology, risk factors, protective factors, prevention, clinical states model, clinical manifestations, screening and diagnosis using PSA tests and prostate biopsies, Gleason grading, staging, and treatment options for clinically localized prostate cancer including radical prostatectomy, radiation therapy, and active surveillance.
2. Radiation therapy can involve external beam radiation therapy using 3D conformal planning or brachytherapy involving radioactive seed implantation directly into the prostate. Treatment related adverse events are a main concern.
3. Active surveillance involves monitoring the illness at fixed intervals with exams and tests rather than immediate treatment, and is an option for some clinically localized prostate cancers.
This document discusses prostate cancer, including:
1. Epidemiology, risk factors, protective factors, prevention, clinical states model, clinical manifestations, screening and diagnosis using PSA tests and prostate biopsies, Gleason grading, staging, and treatment options for clinically localized prostate cancer including radical prostatectomy, radiation therapy, and active surveillance.
2. Radiation therapy can involve external beam radiation therapy using 3D conformal planning or brachytherapy involving radioactive seed implantation directly into the prostate. Treatment related adverse events are a main concern.
3. Active surveillance involves monitoring the illness at fixed intervals with exams and tests rather than immediate treatment, and is an option for some clinically localized prostate cancers.
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PROSTATE CANCER
Dr Alex Mogere Consultant Physician PROSTATE ANATOMY PROSTATE ANATOMY Epidemiology
The risk of being diagnosed with prostate Ca increases by a factor of 2 if one
first-degree relative is affected and by 4 if 2 or more are affected Current estimates are that 40% of early-onset and 5–10% of all prostate Cas are hereditary. Matched for age (in US), African-American males have both a higher incidence of prostate Ca and larger tumors and more worrisome histologic features than white males. Risk factors
Environmental and dietary factors may play a role in prostate Ca growth and progression High consumption of dietary fats, eg α-linoleic acid or the polycyclic aromatic hydrocarbons that form when red meats are cooked, is believed to increase risk. The risk of prostate Ca in Asian men increases when they move to Western environments Lower Vit D levels Obesity prostatitis Protective factors
Protective factors include :
consumption of the isoflavonoid genistein (which inhibits 5α-reductase) found in many legumes, cruciferous vegetables that contain the isothiocyanate sulforaphane, retinoids such as lycopene found in tomatoes, and inhibitors of cholesterol biosynthesis (e.g., statin drugs). (Although statins may have some protective effect, the potential risks outweigh the benefits given the small number of men who die of prostate cancer. ) Prevention
No drugs or dietary supplements are approved by the U.S. FDA for prevention of prostate Ca 5α-reductase inhibitors (5ARI) are the most likely therapy to reduce the future risk of a prostate Ca diagnosis-finasteride, dutasteride The clinical states model
The prostate Ca continuum—from the appearance of a preneoplastic and
invasive lesion localized to the prostate, to a metastatic lesion that results in symptoms and, ultimately, mortality—can span decades. For those with a prostate Ca diagnosis, the clinical states model considers the probability of developing symptoms or dying from prostate Ca. Thus, a patient with localized prostate Ca who has had all Ca removed surgically remains in the state of localized disease as long as the PSA remains undetectable. Cont. The clinical states model
The time within a state becomes a measure of the efficacy of an intervention,
although the effect may not be assessable for years. Cont. The clinical states model CLINICAL MANIFESTATION CONT. CLINICAL MANIFESTATION CONT. CLINICAL MANIFESTATION Screening and Diagnosis: P/E
The need to pursue a diagnosis of prostate cancer is based on;
symptoms, an abnormal DRE, or, more typically, a change in or an elevated serum PSA The urologic history should focus on symptoms of outlet obstruction, continence, potency, or change in ejaculatory pattern. Many cancers occur in the peripheral zone and may be palpated on DRE. Carcinomas are characteristically hard, nodular, and irregular, while induration may also be due to benign prostatic hypertrophy (BPH) or calculi Overall, 20–25% of men with an abnormal DRE have cancer. Screening and Diagnosis: PSA
PSA is produced by both nonmalignant and malignant epithelial cells and, as
such, is prostate-specific, not prostate cancer–specific. Serum levels may also increase from prostatitis and BPH Serum levels are not significantly affected by DRE, but the performance of a prostate biopsy can increase PSA levels up to tenfold for 8–10 weeks PSA testing was approved by the U.S. FDA in 1994 for early detection of prostate Ca The level of PSA in blood is strongly associated with the risk and outcome of prostate Ca. Cont. Screening and Diagnosis: PSA
The PSA criteria used to recommend a diagnostic prostate biopsy have
evolved over time. Based on the commonly used cut point for prostate biopsy (a total PSA ≥4 ng/mL), most men with a PSA elevation do not have histologic evidence of prostate cancer at biopsy In addition, many men with PSA levels below this cut point harbor cancer cells in their prostate Thus, the PSA level establishes the likelihood that a man will harbor cancer if he undergoes a prostate biopsy Cont. Screening and Diagnosis: PSA
Generally the goal is 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. Patients with symptomatic prostatitis should have a course of antibiotics before biopsy(However, the routine use of antibiotics in an asymptomatic man with an elevated PSA level is strongly discouraged. ) Screening and Diagnosis :Prostate Biopsy
A diagnosis of cancer is established by an image guided needle biopsy
Direct visualization by transrectal ultrasound (TRUS) or MRI assures that all areas of the gland are sampled Extended pattern 12-core biopsy that includes sampling from the peripheral zone as well as a lesion-directed palpable nodule or suspicious image guided sampling. If abnormal PSA and negative biopsy - advised to undergo a repeat biopsy. Cont. Screening and Diagnosis :Prostate Biopsy Each core of the biopsy is examined for the presence of cancer, and the amount of cancer is quantified based on the length of the cancer within the core and the percentage of the core involved. Of the cancers identified: >95% are adenocarcinomas; the rest are squamous or transitional cell tumors or, rarely, carcinosarcomas Mets to the prostate are rare, but in some cases colon Cas or transitional cell tumors of the bladder invade the gland by direct extension. GLEASON PATTERN GLEASON’S SCORE GRADES Prostate Ca Staging/TNM Role of imaging on staging
TRUS is the imaging technique most frequently used to assess the primary tumor, but its chief use is directing prostate biopsies, not staging. CT lacks sensitivity and specificity to detect extraprostatic extension and is inferior to MRI in visualization of LNs In general, MRI performed with an endorectal coil is superior to CT to detect cancer in the prostate and to assess local disease extent. Radionuclide bone scans (bone scintigraphy) are used to evaluate spread to osseous sites. Tx of Prostate Ca
Depends on the clinical state
Clinically localized prostate Ca
radical prostatectomy, radiation therapy, or active surveillance After radical surgery to remove all prostate tissue, PSA should become undetectable in the blood within 6 weeks. If PSA remains or becomes detectable after radical prostatectomy, the patient is considered to have persistent disease After radiation therapy, in contrast, PSA does not become undetectable because the remaining nonmalignant elements of the gland continue to produce PSA even if all cancer cells have been eliminated Cont. Clinically localized prostate Ca
The more advanced the disease, the lower the probability of local control and the higher the probability of systemic relapse. Normograms
To better assess risk and guide TX selection, many groups have developed prognostic models or nomograms that use a combination of the initial clinical T stage, biopsy Gleason score, and baseline PSA. Some use discrete cut points (PSA <10 or ≥10 ng/mL; Gleason score of ≤6, 7, or ≥8); others employ nomograms that use PSA and Gleason score as continuous variables Tx related Adverse events
Following radical prostatectomy, incontinence rates range from 2–47% and
impotence rates range from 25–89%. After surgery, impotence is immediate but may reverse over time, while with radiation therapy impotence is not immediate but may develop over time. Of greatest concern to patients are the effects on continence, sexual potency, and bowel function. Overall, with the availability of drugs such as phosphodiesterase-5 (PDE5) inhibitors, intraurethral inserts of alprostadil, and intracavernosal injections of vasodilators, many patients recover satisfactory sexual function. Radiation TX
Radiation therapy is given by external beam(EBT), by radioactive sources
implanted into the gland, or by a combination of the two techniques. Radiotx Tx; EBT
Contemporary EBRT requires 3-dimensional conformal TX plans to max the
dose to the prostate and to min. the exposure of the surrounding normal tissue Cancer control after radiation therapy has been defined by : a decline in PSA to <0.5 or 1 ng/mL, “nonrising” PSA values, and a negative biopsy of the prostate 2 years after completion of Tx The current std definition of biochemical failure (the Phoenix definition) is a rise in PSA by ≥2 ng/mL higher than the lowest PSA achieved. Radiation dose is critical to the eradication of prostate cancer Cont. Radiotx; EBT
Overall, radiation therapy is associated with a higher frequency of bowel
complications (mainly diarrhea and proctitis) than surgery The frequency relates directly to the volume of the anterior rectal wall receiving full-dose treatment Brachytherapy
Brachytherapy is the direct implantation of radioactive sources (seeds) into
the prostate The goal is to deliver intensive irradiation to the prostate, minimizing the exposure of the surrounding tissues The implantation is performed transperineally as an outpatient procedure with real-time imaging. Brachytherapy is well tolerated, although most patients experience urinary frequency and urgency that can persist for several months. Active surveillance
Active surveillance is the policy of monitoring the illness at fixed intervals
with DREs, PSA measurements, and repeat prostate biopsies as indicated until histopathologic or serologic changes correlative of progression warrant treatment with curative intent Concerns about active surveillance include the ltd ability to predict pathologic findings by needle biopsy even when multiple cores are obtained, the recognized multifocality of the disease, and the possibility of a missed opportunity to cure the disease. RISING PSA AFTER DEFINITIVE LOCAL THERAPY
This term is applied to a group of patients in whom the sole manifestation of
disease is a rising PSA after surgery and/or radiation therapy. By definition, there is no evidence of disease on an imaging study. the central issue is whether the rise in PSA results from persistent disease in the primary site, systemic disease, or both. The decision to recommend radiation therapy after prostatectomy is guided by the pathologic findings at surgery, because imaging studies such as CT and bone scan are typically uninformative Salvage radiation Tx
Factors that predict for response to salvage radiation therapy are:
a positive surgical margin, lower Gleason score in the radical prostatectomy specimen, long interval from surgery to PSA failure, slow PSA doubling time, absence of disease in the lymph nodes, and a low (<0.5–1 ng/mL) PSA value at the time of radiation treatment Radiation therapy is generally not recommended if the PSA was persistently elevated after surgery, which usually indicates that the disease has spread outside of the area of the prostate bed and is unlikely to be controlled with radiation therapy Cont. rising PSA after definitive local therapy PSA doubling times are also prognostic for survival Most physicians advise treatment if the PSA doubling time is 12 months or less Metastatic disease : Non castrate
The state of noncastrate metastatic prostate Ca includes men with mets
visible on an imaging study and noncastrate levels of testosterone (>150 ng/dL) The patient may be newly diagnosed or have a recurrence after treatment for localized disease Std Tx is to deplete/lower androgens by medical or surgical means and/or to block androgen binding to the AR with antiandrogens. More than 90% of male hormones originate in the testes; <10% are synthesized in the adrenal gland Metastatic disease : non castrate
Surgical orchiectomy is the “gold standard” but is rarely used due to the availability of effective medical therapies and the more widespread use of hormones on an intermittent Testosterone lowering agents
Of these, GnRH analogues such as leuprolide acetate and goserelin acetate
initially produce a rise in LH and FSH, followed by a downregulation of receptors in the pituitary gland, which effects a chemical castration The initial rise in testosterone may result in a clinical flare of the disease As such, these agents are relatively contraindicated in men with significant obstructive symptoms, cancer-related pain, or spinal cord compromise Cont. Testosterone lowering agents
GnRH antagonists such as degarelix achieve castrate levels of testosterone
within 48 h without the initial rise in serum testosterone and do not cause a flare in the disease. Estrogens such as DES are rarely used due to the risk of vascular complications such as fluid retention, phlebitis, embolic events, and stroke. Progestational agents alone are less efficacious Associated with androgen depletion syndrome (hot flushes, weakness, fatigue, loss of libido, impotence, sarcopenia, anemia, change in personality, and depression). Cont. Testosterone lowering agents
Changes in lipids, obesity, and insulin resistance, along with an increased risk of diabetes and cardiovascular disease, can also occur, mimicking the metabolic syndrome A decrease in bone density may also result that worsens over time and results in an increased risk of clinical fractures Anti androgens
1st-generation nonsteroidal antiandrogens e.g flutamide, bicalutamide, and
nilutamide block ligand binding to the AR and were initially approved to block the disease flare that may occur with the rise in serum testosterone associated with GnRH agonist therapy When antiandrogens are given alone, testosterone levels typically increase above baseline, but relative to testosteronelowering therapies, they cause fewer hot flushes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss Gynecomastia remains a significant problem but can be alleviated in part by tamoxifen Sites of action of different hormone therapies Combined androgen blockade, the administration of an antiandrogen plus a GnRH analogue or surgical orchiectomy, and triple androgen blockade, which includes the addition of a 5ARI, have not been shown to be superior to androgen depletion monotherapies and are no longer recommended Intermittent androgen deprivation therapy The hypothesis is that by allowing endogenous testosterone levels to rise, the cells that survive androgen depletion will induce a normal differentiation pathway. It is postulated that by allowing the surviving cells to proliferate in the presence of androgen, sensitivity to subsequent androgen depletion will be retained and the chance of developing a castration-resistant state will be reduced Metastatic disease: Castrate
Castration-resistant prostate cancer (CRPC) is defined as disease that
progresses despite androgen suppression by medical or surgical therapies where the measured levels of testosterone are 50 ng/ mL or lower Patients receiving an antiandrogen alone, whose serum testosterone levels are elevated, should be treated first with a GnRH analogue or orchiectomy and observed for response. Pts on an antiandrogen in combination with a GnRH analogue should have the antiandrogen discontinued, because approximately 20% will respond to the selective discontinuation of the antiandrogen. S/Es of Hormonal Therapy Chemotherapy and new agents
docetaxel sipuleucel-T- a biologic Cabazitaxel- a taxane mitoxantrone abiraterone acetate- a CYP17 inhibitor Enzalutamide- next generation antiandrogen Alpharadin - an alpha-emitting bone-seeking radioisotope Other bone-targeted agents: bisphosphonates and the RANK ligand inhibitor denosumab Most men seek to avoid chemotx and are 1st treated with a biologic agent and/or newer hormonal agent approved for this indication Pain mx
Pain largely due to osseous metastatic disease
alpharadin or the beta emitter 153Sm-EDTMP (Quadramet) can be considered in addition to abiraterone acetate, docetaxel, and mitoxantrone, each of which is formally approved for the palliation of pain due to prostate cancer metastases. BPH
Is a pathologic process that contributes to the development of LUTS in men
The symptoms are generally measured using a validated, reproducible index
that is designed to determine disease severity and response to therapy—the AUA’s Symptom Index (AUASI), also adopted as the International Prostate Symptom Score (IPSS) Tx BPH
Asymptomatic patients do not require treatment regardless of the size of the
gland In pts with symptoms, uroflowmetry can identify those with normal flow rates who are unlikely to benefit from treatment, and bladder ultrasound can identify those with high postvoid residuals who may need intervention Cystoscopy is recommended if hematuria is documented and to assess the urinary outflow tract before surgery Alpha-adrenergic receptor antagonists- reduce sympathetic tone of the bladder outlet, thereby decreasing resistance and improving urinary flow 5ARIs are thought to treat the static aspect of BPH by reducing prostate volume Tx BPH
5ARIs---They have also proven to be beneficial in the prevention of BPH
progression, as measured by prostate volume, the risk of developing acute urinary retention, and the risk of having BPHrelated surgery. PDE5 inhibitors anticholinergics—for overactive bladder(coexistd with BPH symptom) Surgical therapy is considered second-line therapy Surgical therapy BPH
Surgical approaches include:
TURP, transurethral incision, or removal of the gland via a retropubic, suprapubic, or perineal approach, transurethral ultrasound-guided laser induced prostatectomy (TULIP), stents, and hyperthermia..) THANK YOU !
