BPH and Prostate Cancer (FL INITIAL Autonomous Practice- Pharmacology)

Multiple risk factors are linked to BPH, and age is the best predictive risk factor. Research suggests that men in their fourth decade have an eight percent prevalence of BPH, which increases to 80% for men in their eighties (Wei et al., 2005). In older men, the prostate volume grows 2 to 2.5% yearly (Lim, 2017).

BPH is genetic, and research proposes inheritance demonstrates an autosomal dominant pattern(Na et al., 2017). Individuals who require surgery for BPH at a younger age are more likely to have a genetic form of the disease (Lim, 2017). Genetic BPH is associated with larger prostate size and diagnosis at an earlier age than sporadic BPH (McVary, 2021a).

Race is not highly linked to BPH, and research tends to be variable, but no strong pattern has been demonstrated. Some research suggests that BPH is less common in Asian men compared to white men (Sanda et al., 1997). One study showed that moderate to severe LUTS is more prevalent in black men when compared to white men (McVary, 2021a).

Many lifestyle factors, including diet, exercise, and alcohol use, are linked to BPH (Lin, 2017). Dietary factors associated with an increased risk of BPH include excessive calories, a fatty diet, red meat, milk, dairy products, and a high-protein diet. Dietary factors associated with a reduced risk of BPH include vitamin D, fruits, vegetables, polyunsaturated fats, and linoleic acid. Blood concentrations of lycopene, selenium, vitamin E, and carotene are inversely linked to BPH.

Exercise and physical activity are associated with reduced BPH risk, with higher degrees of physical activity linked to a greater protective effect (Lim, 2017). Interestingly, alcohol may reduce the risk of BPH with a 35 percent reduction in the chances of BPH in men who drink daily (Negri, 2005).

Features of metabolic syndrome are associated with BPH. Obesity and waist circumference is associated with an increased risk for BPH (Lim, 2017). Increased fat levels, body mass index, and waist circumference are associated with increased prostate volume (Calogero et al., 2019). Obesity not only increases the risk of BPH but increases the risk of urinary symptom progression and BPH surgery (Lim, 2017). Diabetes, elevated insulin, and glucose levels are linked to increased prostate size and BPH (Calogero et al., 2019).

Other factors linked to BPH (Maserejian et al., 2013; Lim, 2017; Andriole, 2022):

• Erectile dysfunction.
• A family history of bladder cancer.
• Increased coffee and caffeine intake increases the risk of BPH progression.
• Citrus juice intake was associated with 50% lower odds of LUTS/BPH progression.
• High levels of alcohol may lower the risk of BPH due to reduced androgen levels.
• Inflammation is linked to BPH. Inflammation is often seen on prostate biopsies in those with BPH. In addition, inflammatory cytokines are overexpressed in BPH tissues. Potential causes of prostatic inflammation include an autoimmune response, obesity-related inflammation, and tissue infection.

BPH affects 14 million people in the United States and is more common in the older population. About one in three men in their fifties have BPH symptoms, while about 90% of men at age 85 suffer from some degree of BPH (Deters, 2021). Certain medical conditions are associated with BPH, including cardiovascular disease and cardiovascular risk factors like hypertension. Alpha-adrenergic fibers and receptors are associated with symptoms of BPH and hypertension, and autonomic hyperactivity is linked to the development of LUTS. Those with heart failure may have increased urine production due to B-type natriuretic peptide production and fluid overload, which may exacerbate urinary symptoms (McVary, 2021a).

Neurological disease can affect urinary function. Individuals with Parkinson's disease, multiple sclerosis, and cerebral vascular accidents can all be affected by voiding dysfunction. Diabetes can also worsen LUTS for multiple reasons, including polyuria, decreased bladder sensation, incomplete bladder emptying, and reduced detrusor contractility (McVary 2021a).

The pathophysiology of BPH is not entirely understood, and multiple factors are likely associated with the disease. Inflammation and metabolic factors are contributory to BPH. Histologically, BPH forms mainly in the periurethral or transitional zone of the prostate (the area around the urethra). Hormones, including testosterone, dihydrotestosterone (DHT), and estrogen, are likely involved in developing BPH. Enlargement of the prostate gland can result in prostatic obstruction and lead to urethral resistance via increased smooth muscle tone, leading to detrusor instability and an overactive bladder.

Image 1: BPH

Androgens are involved in prostatic cell proliferation. Inflammation is linked to LUTS/BPH, and inflammation may occur due to chronic infections, obesity-related inflammation, or an autoimmune process (McVary, 2021a). Obesity is associated with increased inflammatory cytokines, and dietary fats lead to prostatic inflammation. Alpha-1-adrenergic receptors are present in the smooth muscle around the prostate and bladder neck. When these receptors are stimulated, smooth muscle contracts leading to symptoms of BPH (Deters, 2021).

The lumen of the prostatic urethra eventually narrows as the increased prostatic volume pushes on the urethra and may lead to urinary obstruction. Bladder distention results from increased pressure, which may progress to bladder detrusor hypertrophy, diverticula, and trabeculation (thickened bladder wall with a reduced ability to contract). Urinary retention may lead to urinary stasis, infection, bladder stones, hydronephrosis, and impaired renal function.

Signs and symptoms of BPH can be variable. Some patients are asymptomatic, but others develop severe symptoms and severe LUTS with bladder neck obstruction. Common symptoms of BPH can be classified as obstructive or irritative (See Table 1). Obstructive symptoms include urinary hesitancy, straining to void, slow stream, splitting of the stream, terminal dribbling, and intermittent urinary stream. Irritative symptoms include urgency, urinary incontinence, urinary frequency, and nocturia. Symptoms vary over time, and the size of the prostate does not correlate with the severity of the symptoms. Typically, the obstructive symptoms are more troublesome than irritative symptoms. Symptoms are graded on severity; typically, those with more severe diseases are more likely to seek treatment.

The physical exam includes a complete exam. The abdomen should be examined for abdominal distention, costal vertebral angle tenderness, suprapubic distention, or tenderness. The neurological exam should assess for any sensory or motor deficits.

The exam should also include a digital rectal exam (DRE) to evaluate the size of the prostate and check for any nodules that may be suggestive of malignancy. The prostate size is often reported as how many fingerbreadths wide; each fingerbreadth correlates to about 15-20 grams. The typical size is about 7 to 16 grams, and the gland should be firm and non-tender. Abnormal findings include a tender prostate (suggestive of prostatitis), asymmetry or nodules (cancer), decreased sphincter tone, or reduced perineal sensation (neurological disease). The prostate size is not correlated with symptom severity.

The disease progresses slowly over the years, but some patients may notice spontaneous improvement. About one in four patients progress to severe LUTS over six years (Platz et al., 2013). BPH can lead to complications. Acute urinary retention is a significant complication of BPH. Chronic urinary retention can increase the risk of urinary tract infection, bladder diverticula, bladder stones, and kidney damage. BPH does not increase the risk of prostate cancer. Prostate cancer mainly develops in the peripheral region of the gland, whereas BPH occurs in the central or transitional zone of the prostate.

Patients who present with LUTS may have conditions that should be considered before jumping directly to BPH. Urological conditions can lead to signs and symptoms similar to BPH, including urinary tract infection, prostatitis, prostate cancer, and bladder cancer. When obstruction is the primary symptom, diagnoses to consider include prostate cancer (will be discussed later), urethral stricture, and bladder neck contracture. Bladder tumors may present with irritative symptoms.

Conditions not related to the urinary tract, including neurological diseases such as Parkinson's disease, Multiple Sclerosis, and cerebrovascular accidents, can present with voiding dysfunction. Individuals afflicted with edema, such as in heart failure, may present with symptoms similar to BPH when fluid shifts lead to diuresis. Poorly controlled diabetes can mimic symptoms of BPH, as elevated glucose levels lead to osmotic diuresis. In addition, complications of long-standing diabetes are associated with reduced bladder sensation, reduced detrusor contractility, and incomplete bladder emptying. Some medications can lead to symptoms suggestive of BPH, including diuretics, antihistamines, and decongestants.

As discussed above, the history should differentiate between irritative and obstructive symptoms. The workup of a patient who has signs and symptoms suggestive of BPH includes a history-focused physical exam (as discussed above) and targeted diagnostic tests. Patients not impacted significantly by disease symptoms should not have intensive workup, and targeted laboratory tests are used to rule out other causes. The clinician should evaluate for hematuria, urinary retention, or incontinence, which, if present, are referred to urology.

The clinician should evaluate other features of the history. Patients with a history of cigarette smoking are at increased risk for bladder cancer. Hematuria is suggestive of bladder cancer or stones in the bladder. Hematuria may be present with BPH, but anyone with hematuria should be worked up for cancer after an infection has been ruled out. Urethral stricture may be present if the patient complains of a history of urethral trauma or urethritis.

Other key features of the history include the presence of neurological disease, which could suggest a neurogenic bladder. A complete medication history is important, as certain medications may lead to LUTS. Diuretics increase urinary output and may mimic BPH. Anticholinergic medications and decongestants have the potential to cause urinary retention.

A voiding diary is a helpful tool to help assess the disease. It offers information regarding the total volume of urine, frequency of urination, nocturnal fracture of urine voided, fluid intake, and incontinence. This tool will help the patient see patterns and help the patient manage lifestyle choices to optimize symptom control. Nocturnal polyuria occurs when greater than one-third of urine output is expelled at night. If present, other causes, such as congestive heart failure, should be investigated.

Patients who present with LUTS should have focused laboratory tests. A urinalysis looks for any abnormalities which may suggest diseases other than BPH. A urinalysis may point the clinician toward infection or diabetes. Hematuria present on the urinalysis should raise suspicion of cancer. A urine culture should be performed if an infection is suspected based on symptoms and urinalysis (the presence of hematuria, pyuria, or bacteria).

Blood work may include a test for renal function and a prostate-specific antigen (PSA). Testing for the glomerular filtration rate (GFR) is typically unnecessary unless there is a concern for kidney damage due to increased post-void residual (PVR). A reduced GFR should be followed by a renal ultrasound to assess for any degree of upper tract hydronephrosis.

A PSA can be used for two primary reasons. The first is screening for prostate cancer (discussed later). Second, it assesses prostate volume. A prostate volume above 35 grams correlates with a PSA greater than 1.5 ng/dL (McVary, 2021b). The use of 5 alpha-reductase inhibitors tends to lower PSA levels and can affect the use of the PSA for cancer screening.

The International Prostate Symptoms Score (IPSS) is a commonly used scale to quantify the severity of LUTS and monitor response to therapy or disease progression. It is a series of seven questions, each scored from 0 to 5, and the scores are totaled, and the final score is given. A total sum score of:

• 0-7 = Mild
• 8-19 = Moderate
• 20-35 = Severe

Post-void residual should be assessed in all patients with LUTS or BPH symptoms. The two most popular methods to assess PVR include using a bladder scanner or performing a straight catheterization after a spontaneous void. Bladder palpation cannot accurately measure the degree of urinary retention. Worsening PVR suggests treatment is ineffective and has an increased likelihood of needing a surgical intervention to control symptoms. A high baseline PVR is associated with more severe disease.

Treatment of BPH/LUTS includes lifestyle changes, medications, and surgical options. All patients should be taught lifestyle changes that may improve symptoms of BPH/LUTS. Patients who do not get adequate relief from lifestyle changes should be considered for medical therapy. Those who do not experience symptom control or develop a red flag should be referred to a urologist to consider invasive therapy, including surgical options, to manage symptoms.

The patient and clinician should engage in shared decision-making when discussing therapy options. The patient should be educated regarding the risks and benefits of all treatment options. All BPH patients should engage in lifestyle changes. For those on medical therapy, regular follow-up should ensure adequate control of symptoms and monitoring for side effects.

Routine follow-up should include monitoring for any changes in treatments for other diseases. Patients with BPH are often older and are treated for other comorbid conditions. Many treatments for other disease states result in side effects that may worsen BPH symptoms. Medications contributing to worsening LUTS symptoms include diuretics, anticholinergics, antidepressants, bronchodilators, and sympathomimetics.

Steve is a 62-year-old male who presents to his primary care physician with the chief complaint of having difficulty starting his urination stream and urinating 4-5 times per night. Upon further questioning, Steve was found to have a weak urination stream, needing to urinate every hour, and staining his pants with urine as he leaks after urinating. The patient denies any history of a sexually transmitted disease and denies previous endoscopy or surgery on the urinary tract. His past medical history is significant for hypertension, for which he takes hydrochlorothiazide; hyperlipidemia, for which he takes atorvastatin; and depression/anxiety, for which he takes sertraline.

On exam, Steve is a man who appears of stated age with no significant abnormality noted on the physical exam, including a normal abdominal exam, no costovertebral tenderness, normal anal sphincter tone, normal perianal sensation, and no signs of congestive heart failure. The digital rectal exam demonstrates an enlarged firm prostate without nodules. The physician orders a urinalysis and some basic blood work, including glycated hemoglobin, a basic metabolic panel, and a prostate-specific antigen. The physician performs the IPSS, which shows a score of 15, equating to moderate symptoms.

The physician recommends that the patient reduce caffeine intake, reduce fluid intake within three hours of bedtime, changes his hydrochlorothiazide to lisinopril, and schedules a follow-up appointment in three weeks to review the effectiveness of the interventions and review the blood work. Upon return exam, the patient reports that his symptoms are somewhat improved. The IPSS score is 12, which is improved but still considered a moderate degree of symptoms. The urinalysis is negative for any white or red blood cells. The blood work shows normal serum creatinine (to help assure there is no obstructive uropathy) and a prostate-specific antigen of 4.2 ng/dL. The patient is started on tamsulosin (Flomax) at 0.4 mg daily. After two months, his IPSS remains elevated at ten, and he is referred to a urologist due to persistent symptoms and an elevated PSA.

The urologist discusses the possibility of performing a prostate biopsy but, instead, opts to check the PSA in six months to see if there is any significant increase. The urologist performs urodynamic testing, including uroflowmetry, to assess the severity of BPH and determines the patient has a ten milliliters per second flow rate. The patient was evaluated for post-void residual volume, and it was determined that he had 150 milliliters of urine in the bladder after a complete void.

The urologist increases the dose of tamsulosin to 0.8 mg daily, adds finasteride, and schedules a follow-up in three months. At the three-month follow-up, there is some improvement, but the patient continues to be plagued by nocturia, urinary frequency, and hesitancy. Steve asks the urologist about the possibility of a surgical intervention to help with symptoms and decides to undergo a transurethral resection of the prostate (TURP). After the procedure, his symptoms dramatically improved.

Risk factors for prostate cancer include age, genetics, ethnicity, and dietary factors. Age is highly correlated to prostate cancer. The incidence of prostate cancer is highest between the ages of 65 and 74, and occult prostate cancer is common. Researchers who looked at autopsy studies demonstrated that autopsy-proven prostate cancer significantly increased with age, with up to 46% of people in their 50s and 70% in their 70s, and up to 83% in their 80s having prostate cancer on autopsy (Delongchamps, 2006). The prevalence of prostate cancer is higher in older men, but younger men are at higher risk of having severe disease. Bleyer et al. (2020) showed that men less than 40 with prostate cancer suffered higher death rates than older men.

Ethnicity is linked to prostate cancer. Black men are at the highest risk for prostate cancer, and Asian Americans have the lowest risk (see table 4). In addition, black men tend to have an earlier onset of disease when compared to white men. Also, when diagnosed, black men tend to have higher PSA scores, worse Gleason scores, more advanced diseases, and receive less guideline-concordant treatment (Sartor, 2022).

(Adapted from Sartor, 2022)

Prostate cancer runs in families. According to Sartor (2022), those with a family member diagnosed with prostate cancer before age 65 are at increased risk. In addition, other risks of prostate cancer include a family history of early-onset breast cancer, male breast cancer, pancreatic cancer, melanoma, colorectal cancer, and ovarian cancer. The genetic risk for prostate cancer results from genetic variants, single-nucleotide polymorphisms (SNPs), or mutations (American Cancer Society [ACS], 2020; Sartor, 2022).

Certain dietary factors affect the risk of prostate cancer. High levels of animal fat, especially high intake of alpha-linolenic acid, are associated with prostate cancer risk (Harvard School of Public Health, 2019; Orlich et al., 2022; Sartor, 2022). Lycopene, found in tomato-based products, is associated with a lower risk of prostate cancer (Zu et al., 2014.). Other foods that may lower prostate cancer risk include broccoli, cauliflower, soy, tomatoes, and salmon (Harvard School of Public Health, 2019). Consumable products associated with an increased risk of prostate cancer include red meat, processed meat, fish oil, and dairy intake (Harvard School of Public Health, 2019; Orlich et al., 2022; Sartor, 2022).

Other factors that influence prostate cancer risk (Sartor, 2022; Wilson et al., 2011; Murphy et al., 2013; Pernar, 2018; Xu et al., 2021; Olivas & Price, 2021):

• Consumable products associated with mixed results on the risk of prostate cancer include alcohol, multivitamin use, calcium, and vitamin D.
• Coffee has been shown to reduce the risk of prostate cancer. In a study over twenty years, the reduction in lethal prostate cancer correlated with increased coffee consumption in those who drank six or more cups per day.
• The effect of cigarette smoking on prostate cancer is somewhat conflicting, and most research finds an increased risk of prostate cancer and more severe disease at diagnosis in smokers. Research does suggest that smoking raises risks in African Americans much more than in white Americans. Smoking at the time of diagnosis is associated with higher death rates and higher rates of metastasis.
• 5-alpha reductase inhibitors lower PSA levels and may delay diagnosis, increasing the risk of more advanced prostate cancer.
• A slightly increased risk of prostate cancer and advanced prostate cancer is associated with vasectomy, but no increase in prostate cancer mortality.
• Obesity is associated with an increased risk of prostate cancer, a risk of recurrent disease, and prostate cancer mortality.
• The effect of physical activity on reducing the risk of prostate cancer is uncertain, but older men who engaged in vigorous exercise had a lower risk of fatal or advanced disease.
• Prostatitis possibly increases the risk of prostate cancer, but data is of low quality. However, prostatitis increases PSA and may lead to more biopsies and, thereby, more diagnoses of prostate cancers, even though many of these cancers may have never become clinically apparent.
• Radiation to the pelvis may increase the risk of prostate cancer.

The most common presentation of prostate cancer is an asymptomatic patient who underwent a screening test. Most screen-detected prostate cancer cases are asymptomatic and never progress to clinical significance. Occasionally, patients with symptoms are diagnosed with prostate cancer. Symptoms are non-specific and may include:

• Urinary frequency
• Urinary urgency
• Hematuria
• Hemospermia

Although, most presentation of non-specific lower urinary tract symptoms is associated with a condition other than prostate cancer (Kang et al., 2021). Prostate cancer grows slowly and typically disseminates in a predictable pattern, starting in the prostate, moving to the pelvic lymph nodes, and then to the bones of the pelvis and spine.

At the time of prostate cancer diagnosis, 73% of men have localized cancer, 14% spread to a lymph node, 7% have metastasized, and 6% of cases are unknown (NCI, 2022). Those with metastatic prostate cancer may present with:

• Bone pain
• Weight loss
• Pathological fractures
• Urinary retention
• Hematuria
• Lower extremity weakness secondary to spinal cord compression
• Fatigue

When patients present with LUTS, prostate cancer should be considered. Still, LUTS is commonly caused by other diagnoses, including BPH, urinary tract infection, interstitial cystitis, prostatitis, bladder outlet obstruction, or chronic pelvic pain syndrome.

Physical exam findings of prostate cancer are typically confined to an abnormal prostate on a digital rectal exam, and findings may include prostate asymmetry, nodules, or induration. A prostate that is symmetrical and firm is more suggestive of BPH. The DRE can only assess the prostate's posterior and lateral aspects, so the DRE may miss cases of prostate cancer. DRE is not sensitive to detecting small tumors and will not detect tumors in other prostate regions. DRE is less successful at detecting prostate cancer when compared to a PSA but helps detect cancer in those with normal PSA levels.

Prostate-specific antigen (PSA) testing can detect prostate cancer along with the DRE. The higher the PSA, the more likely prostate cancer is present. Other conditions can elevate PSA readings, including BPH, prostatitis, and perineal trauma. A normal PSA does not rule out prostate cancer. Most prostate cancers are detected with slightly elevated PSA readings (typically less than 10.0 ng/dL).

Multiple measures can be used to differentiate prostate cancers from other findings. The PSA may be compared to typical ranges for the patient's age, and the PSA typically increases as someone ages. Some clinicians consider further evaluation for prostate cancer for any PSA above 4.0 ng/dL. The rate at which the PSA rises, the percentage of free PSA, the PSA density, and the Prostate Health Index (PHI) test can help predict prostate cancer's likelihood.

A repeat PSA should be done a few weeks after an initial high reading to verify the reading. Certain factors discussed above may elevate the PSA that are not prostate cancer and, if present, should be addressed before repeating the PSA (for example, antibiotics for an infection). If the repeat PSA is normal, no nodule, induration, or asymmetry is felt on DRE, and it has not significantly increased over the last year, an intensive workup is likely not indicated.

Screening slightly reduces prostate cancer death rates, but screening is associated with risks (Ilic et al., 2018). Shared decision-making with PSA should be done with all patients at risk, and screening should be more strongly considered in patients with risk factors. In 2018, the United States Preventative Services Task Force (USPSTF) (2018) recommended that prostate cancer screening be offered with PSA based on patient preference and patient judgment in men between 55 and 69 (United States Preventative Services Task Force, 2018). It is not recommended for patients over the age of 70.

Most with elevated PSA readings do not have prostate cancer, but what do we do with an elevated PSA reading? The diagnostic evaluation of an elevated PSA includes a good history and physical; it is essential to determine if any other factors contribute to the elevated PSA (for example, UTI or prostatitis). A DRE is an essential part of the evaluation of an elevated PSA. A repeated PSA often normalizes, so this should be done before moving to a prostate biopsy.

When clinical findings are equivocal, prostate imaging or other diagnostic tests may help determine if a prostate biopsy is warranted. The PSA density is the ratio of PSA to ultrasound-measured prostate volume. Those with a small prostate and a high PSA are more problematic than a large prostate with a relatively lower PSA. Another PSA test that can be used is free to total PSA ratio. Patients with prostate cancer more often have a lower percentage of free PSA. When readings are less than 10 to 15%, prostate cancer is more likely, and readings above 25% are more likely due to BPH. The free-to-total ratio is often used when a repeat biopsy is considered in those who had a previous negative biopsy.

Based on clinical evaluation, a prostate biopsy is performed in those suspected of prostate cancer. The biopsy takes multiple tissue samples but may miss the cancerous tissue. Adenocarcinoma accounts for 99% of prostate malignancies, although lymphomas, sarcomas, and small-cell neuroendocrine tumors may cause prostate cancer. Prostate biopsy is associated with infection, blood in the urine, blood in the semen, urinary retention, and rectal bleeding. Due to the side effects and the pain associated with the procedure, it may not be desired by all patients.

After discussion with the patient, a prostate biopsy may ensue if life expectancy is at least five to ten years and clinical factors suggest prostate cancer (elevated PSA, a rapid increase of PSA, or an abnormality of the DRE). A biopsy may not be indicated for patients with short life expectancies and severe medical comorbidities. After the initial biopsy, a repeat biopsy may be indicated if PSA increases or DRE abnormalities change significantly.

Magnetic resonance imaging (MRI) has become essential to evaluating an elevated PSA. An MRI helps visualize prostatic tumors and helps clinicians better determine who needs a prostate biopsy. A normal MRI is associated with a low risk of invasive prostate cancer, and an abnormal MRI can detect tumors and improve the prostate biopsy's accuracy. The MRI helps clinicians stage the tumor and evaluate the response to treatment. In addition to imaging, newer diagnostic tests (IsoPSA, miR Sentinel tests, and polygenic single-nucleotide panels) are currently being studied to determine who will most likely benefit from a prostate biopsy (Chang et al., 2021).

The biopsy can be done in two ways: transrectal or transperineal. Transrectal biopsy uses a probe in the rectum; the biopsy needle enters the rectum to access the prostate after the anesthetic. Typically, ten to twelve cores are taken to look for cancer. The transperineal technique involves placing a needle in the perineum. This is a cleaner area associated with lower infection rates but is often associated with more pain and requires more sedation. This procedure has similar efficacy to the transrectal biopsy in detecting prostate cancer (Lo et al., 2019). Both techniques use imaging with ultrasound or MRI or both to help assure a safe and accurate procedure. An MRI-guided biopsy is associated with a higher cancer detection rate when compared to an ultrasound-guided biopsy (Das et al., 2020).

The Gleason score and Grade Group are determined after prostate biopsy. The Gleason score is an older system that offers scores based on primary and secondary biopsy grades and is scored on a range from 6-10. The International Society of Urological Pathology revised the grading system into a Grade Group in 2014 (Epstein et al., 2016). The grading system grades cancer from one to five, constructed on primary and secondary Gleason patterns.

The Gleason score and grade are used to classify the severity of the disease. The Gleason grade is based on the features of the prostate cancer cells, and a higher score is associated with an increased risk of severe disease:

• Grade Group 1 – Gleason score of 6
• Grade Group 2 – Gleason score 3+4=7
• Grade Group 3 – Gleason score 4+3=7
• Grade Group 4 – Gleason score of 8
• Grade Group 5 – Gleason score of 9 or 10

Increased Grade Group is associated with an increased hazard ratio for death. When compared to Grade Group 1, Grade Group 2 is associated with a hazard ratio for death of 2.8, Grade Group 3 is associated with a hazard ratio of 6.0, Grade Group 4 has a hazard ratio of 7.1, and Grade Group 5 has a hazard ratio of 12.7 (Ham et al., 2017). Five-year recurrence-free survival is 95% for Grade Group 1, 83% for Grade Group 2, 65% for Grade Group 3, 63% for Grade Group 4, and 35% for Grade Group 5 (Carter et al., 2012).

Imaging studies are used selectively in the workup of prostate cancer. Common tests include ultrasound, MRI, computed tomography (CT), and bone scan. These studies evaluate the prostate and look for metastatic disease and regional adenopathy. Generally, imaging is not used for very low and low-risk patients, but MRI is sometimes used in very-low and low-risk disease to ensure high-grade disease is not present. Multiparametric MRI can improve the yield of prostate biopsy. The use of bone scans and pelvic imaging are used when the risk is intermediate or higher (Wong et al., 2019).

Prostate MRI is sometimes used to help make decisions regarding the necessity of a prostate biopsy. A patient with an elevated PSA and no suspicious findings on MRI could be considered to forgo a biopsy, especially in an older patient. Transrectal ultrasound can also be considered to evaluate an abnormal DRE. Still, transrectal ultrasound often misses prostate tumors, and even a normal ultrasound in the face of other concerning finding warrants a biopsy (Taplin & Smith, 2022). A biopsy can be performed using a transrectal biopsy with imaging guidance. Transrectal ultrasound or MRI can be used. An MRI-targeted biopsy is more expensive but likely more accurate (Taplin & Smith, 2022).

Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is a more accurate test and can show local disease in the prostate. PSMA-PET demonstrates moderate sensitivity of 68% and a specificity of 94% to detect local prostate cancer (Woo et al., 2020).

Before treatment of prostate cancer, it is essential to fully understand the patient's characteristics, including age, medical comorbidities, overall health, the extent of the disease, the PSA score, the histological grade, and the tumor's molecular characteristics. When these facts are known, the clinician and patient should engage in a conversation to determine optimal treatment options. The clinician should discuss the following:

• Treatment options
• The probable outcome of each treatment
• Complications of each treatment

Patients are risk-stratified using categories created by the National Comprehensive Cancer Network (NCCN). Patients are risk classified as very low, low, favorable, unfavorable, high, and very high (National Comprehensive Cancer Network, 2022):

• Very-low-risk disease is associated with a PSA less than 10 ng/mL, PSA density less than 0.15 ng/mL/g, T1c, Grade Group 1, and less than three biopsy cores being positive.
• Low-risk disease entails a PSA of less than 10 ng/mL, T1 to T2a, and Grade Group 1.
• Favorable intermediate-risk disease includes no high-risk features, no more than one intermediate risk factor - PSA 10-20 ng/mL, T2b to T2c, Grade Group 2-3, and less than 50% positive core biopsies.
• Unfavorable intermediate-risk disease includes no high-risk features, two or more of the following - PSA 10-20 ng/mL, T2b to T2c, Grade Group 2-3, and Grade Group 3 and/or more than 50% positive core biopsies.
• The high-risk group includes PSA over 20 ng/mL, T3a, or Grade Group 4 or 5.
• The very high-risk group includes T3b to T4, more than four cores with Grade Group four or five, or primary Gleason pattern 5.

Localized prostate cancer can be treated in multiple ways. In some cases, it does not need to be treated. More people with localized disease die with prostate cancer rather than of prostate cancer. Low-risk disease is not associated with a survival benefit from treatment, and treatment is likely not beneficial for those with less than a ten-year life expectancy (Klein, 2022).

Expectant management includes watchful waiting and active surveillance. Active surveillance involves actively looking for progression and treating cancer before progression. All low-risk patients should be considered for active surveillance.Young patients who do not want to experience the potential complications of interventions could be considered for this option. If disease progression is noted in this population, then re-evaluating treatment options need to be considered. Expectant management can also be used in those with Gleason 7. Watchful waiting involves watching for symptoms and palliating symptoms if they occur. Watchful waiting is appropriate for those with significant co-morbidities or older adults.

Localized disease can be treated with radiation or surgery. All patients are candidates for both treatments, so each treatment needs to be considered for all patients. Radiation is less invasive, well tolerated, with lower incontinence rates, and requires less recovery time (Klien, 2022). Surgery offers better pathological staging and more salvage options, and follow-up with recurrence is easier. Surgery following radiation is complex, but radiation following surgery is easier and often done. In addition, when significant LUTS are present, surgery can help relieve the symptoms.

Radical prostatectomy and radiation are not effective definitive treatments for metastatic disease. There are two types of metastatic disease, castrate-sensitive and castrate-resistant. These terms discuss the responsiveness of cancer to hormone therapy.

Castrate-sensitive disease (or hormone-sensitive disease) is controlled by maintaining low androgen levels. Prostate cancer is dependent on androgens, and in castrate-sensitive disease, androgen deprivation will control the disease. Reducing androgens can be accomplished by orchiectomy or taking an LHRH antagonist or agonist. Castrate-sensitive metastatic prostate cancer is often treated with agents co-administered with ADT. Popular combination therapies include docetaxel (chemotherapy) with hormone therapy, abiraterone/prednisone/hormone therapy, apalutamide/hormone therapy, and enzalutamide/hormone therapy (Cancer.net, 2021).

Castrate-resistant disease is where cancer progresses even when androgens are suppressed (a serum testosterone level less than 50 ng/dL). Treatments include hormone therapy, abiraterone, or a newer anti-androgen. Other treatment options for prostate cancer include chemotherapy, targeted treatment, and immunotherapy. Chemotherapy can be used in metastatic disease, especially in castrate-resistant disease. It can be given when hormone therapy is ineffective and sometimes may be given along with hormone therapy. Chemotherapeutic agents used to treat prostate cancer include cabazitaxel, mitoxantrone, docetaxel, and estramustine. Targeted treatment includes olaparib (Lynparza®) and rucaparib (Rubraca®), which are classified as PARP inhibitors, and are used for metastatic castrate-resistant prostate cancer.

Immunotherapy uses medication to enhance the immune response to treat cancer cells. A cancer vaccine, individually made for each person, called sipuleucel-T, can be used to treat advanced prostate cancer. While not a cure, it can extend life expectancy.

Immune checkpoint inhibitors are used to help manage advanced prostate cancer. "Checkpoints" are proteins that reside on immune cells that behave like switches to start an immune response. Cancer cells utilize checkpoints to protect themselves from the immune system. These medications are utilized in metastatic disease, recurrent disease, or after chemotherapy. Pembrolizumab (Keytruda®) is a medication given intravenously every two to three weeks, and it targets the PD-1 checkpoint to boost the immune system's fight against prostate cancer. This medication removes the breaks from the immune system and may lead to certain autoimmune diseases.

John is a 58-year-old male diagnosed with Gleason 6 prostate cancer five years ago and treated with radical prostatectomy. He has his annual checkups with his urologist, who performs regular PSA tests. His PSA was undetectable for the first two years, and then the levels rose to 0.6 ng/dL in the third year and 1.3 ng/dL in the fourth year.

In the fifth year, he neglects to return for his follow-up exam. He had recently retired and was enjoying traveling with his wife. In the sixth year after his prostate surgery, he started to feel fatigued. Over the next month, he reported having increased back pain and had a 10-pound weight loss. One evening his back pain became severe, and he presented to the emergency department. The workup in the emergency department showed that the patient had anemia, an elevated creatinine level, and elevated alkaline phosphatase. Further workup showed a PSA of 103 ng/dL.

A lumbar spine x-ray is negative, but a bone scan shows scattered metastatic lesions in the spine. The oncologist decides to treat with androgen deprivation therapy and docetaxel. Over the next few months, the patient does well, resulting in a PSA reduction to 22.0 ng/dL.

The patient's prostate cancer is controlled over three years with a stable PSA while on ADT. Eventually, the PSA increases, and the patient is referred back to the oncologist to assess treatment options.