Prostate Cancer

Introduction

Prostate cancer is the most common solid tumor malignancy in American men and, with a median age at diagnosis in the early 60s, is mainly a disease of the elderly. Following lung cancer, prostate cancer is the second leading cause of cancer deaths in men, resulting in over 35,000 annual deaths in the United States. Earlier detection and diagnosis with the widespread use of Prostate-Specific Antigen (PSA) screening and ultrasound-guided biopsy techniques resulted in a steep increase in incidence in the late 20^th century. Although the number of newly diagnosed cases has stabilized over the past few years, it is estimated that as many as two-thirds of men over the age of 80 have asymptomatic or latent prostate cancer at autopsy.

Epidemiology and Etiology

• Incidence of nearly 300,000 new cases annually in the United States is down from a peak of 341,000 cases in 1991. Incidence is highest in African Americans and lowest in Asians and Native Americans. Internationally, the highest recorded cases are found in the Scandinavian countries and the United States.
• Mortality of approximately 35,000 deaths in the United States per year [1, 2].
• Etiology is incompletely understood, but racial, genetic, and dietary factors have been suspected.
• Hereditary mutations in prostate cancer susceptibility genes, such as the hereditary prostate cancer locus (HPC1), BRCA1, and BRCA2, account for approximately 9% of cases.
• Risk factors include African-American race; one or more first-degree affected relatives; a PSA level above the age-specific reference; age > 60, with about a 12-fold greater risk in 70-year-old males as compared to 50-year-old males; elevated serum testosterone concentrations; diet high in animal fat [3].

Screening Recommendations

• The American Cancer Society recommends the following:
  • Screening may involve digital rectal examination and/or prostate-specific antigen (PSA) blood testing, and the frequency varies depending on factors such as risk and patient preference based on shared decision making [4].
  • Testing should begin at age 50 in men who have a life expectancy of at least 10 years.
  • Men at high risk (African-American, strong family history) should begin annual testing between the ages of 40 and 45.
  • Information should be provided to all men explaining what is known (and what is uncertain) about the benefits and limitations of early detection and treatment of prostate cancer. This way, patients can make an informed decision about testing.
  • Men who ask their doctor to decide on their behalf should be tested. Not offering or discouraging testing is inappropriate [5].
• Although routinely performed in the United States, and despite the subsequent earlier detection of disease, prostate cancer screening has never been demonstrated to save lives in studies of large populations.

Clinical Presentation

• History: Usually asymptomatic at presentation. Although more commonly seen with benign prostatic hyperplasia (BPH), symptomatic patients may experience urinary obstruction symptoms, such as hesitancy, urgency, dysuria, nocturia, incomplete voiding, weakness of stream, post-void dribbling, new-onset erectile dysfunction, and rarely, hematuria or hematospermia. Bilateral lower extremity edema (from lymph node involvement), bone pain, pancytopenia, and lower extremity numbness (from cord compression) can be seen in advanced and metastatic disease.
• Physical exam: Normal in the majority of patients; an irregular, firm mass may be palpated on digital rectal exam (DRE) of the prostate. DRE is most sensitive for tumors in the posterior and lateral aspects of the prostate gland, where malignancies most often form.
• Lab studies: Prostate-specific antigen level (reference value is dependent on age); percent-free PSA (ratio of free to total PSA <7% is highly suspicious for malignancy); urinalysis; serum acid phosphatase, with elevation suggesting extracapsular spread; CBC, variable depending on the extent of disease; serum alkaline phosphatase, with elevation indicating bony metastatic disease.
  • DRE and ejaculation do not affect PSA levels, while prostate biopsies and transurethral resection of the prostate (TURP) can cause elevations in PSA levels that take several weeks to normalize.
• Radiologic studies: A multiparametric MRI is obtained to characterize prostate cancer, including extraprostatic extension, seminal vesicle invasion or pelvic lymph nodes. Increasingly, PSMA PET CT scans are obtained to detect metastatic disease in those with high-risk disease. Bone imaging can also be obtained via bone scan.
• Diagnostic studies: Transrectal biopsies using spring-loaded devices and transrectal ultrasonography (TRUS) for visual guidance. Typically, six to 14 biopsies are obtained.
  • MRI-guided biopsies are also being used more often as the sensitivity for detecting prostate cancers is higher than that of TRUS-guided biopsies.

Natural Course and Pathology

• Staging: The American Joint Committee on Cancer (TNM) system has replaced the American Urological Association (AUA) system as the most widely used and universally accepted pathologic staging system for prostate cancer.
  • The number of lobes involved, degree of capsular invasion, presence of regional or distant metastases, tumor grade, and PSA level are all considered. [6].
  • Survival is stage dependent, with 10-year survival from prostate cancer ranging from 100% with Stage I disease to only 18.5-32.3% with Stage IV disease [7, 8].
• Greater than 95% of cases are adenocarcinoma on histologic study.
  • Approximately 65-70% of adenocarcinomas arise from peripherally located glands within the prostate, while 20% arise from the transitional zone and 10% from the central zone. In contrast, benign prostatic hyperplasia (BPH), a nonmalignant condition, typically arises from the transitional zone, periurethral prostate gland tissue.
  • High yield: unlike many instances of hyperplasia, BPH does NOT progress to neoplasia, and those with BPH are not at an increased risk of prostate cancer.
• Prognostic factors: the most important predictors of outcome are the stage and Gleason score, a numerical score ranging from two to ten and based on the sum of the grade of the primary and secondary growth patterns of the tumor. The higher the grade, the more undifferentiated the tumor, and the higher the rate of local tumor spread and metastasis. Additional prognostic factors include age, PSA absolute value, PSA velocity, the number of involved needle biopsy cores, and the percentage of each core involved. [9]
  • Approximately 60-70% of patients with prostate cancer present with a Gleason score of = 6 at diagnosis, while 10% present with a score of = 8.
  • D'Amico et al defined risk stratification groups for patients with clinically localized prostate cancer.
    • Low risk: diagnostic PSA < 10.0ng/ml, and highest biopsy Gleason score = 6, and clinical stage T1c or T2a
    • Intermediate risk: PSA > 10ng/ml but < 20ng/ml, or Gleason score = 7, or stage T2b
    • High risk: PSA > 20ng/ml, or Gleason score = 8, or stage T2c or T3 [10].

Treatment

• Early stage, clinically localized disease (T1, T2)
  • Expectant management: active surveillance or "watchful waiting" may be considered in older men with life expectancies less than 10 years, small, low-grade tumors, slowly rising PSAs, and multiple medical comorbidities, with the expectation to intervene if their cancer progresses or symptoms become imminent [11]. Patients who choose expectant management should undergo DREs and PSAs every 3-6 months. Additionally, they should obtain repeat prostatic biopsies 6-18 months after diagnosis, periodically thereafter, and for any signs of disease progression to ensure that the tumor grade has not progressed.
    • In patients who have chosen expectant management, the 10-year cumulative disease-specific survival is 98.8%. The 10-year incidence of metastasis has been reported to be 6.3% [12].
  • Surgery: radical prostatectomy is an appropriate treatment option for patients with a life expectancy of at least 10 years and who have disease that is clinically confined to the prostate (T1 or T2).
    • A large, multicenter trial recently showed that although the overall mortality was similar between the two groups during the first five years after randomization, compared with expectant management, patients with localized prostate cancer who underwent radical prostatectomy had significantly reduced risks of metastasis and local progression relative to active monitoring. However, disease-specific mortality and all-cause mortality were not significantly different.
    • Common side effects from surgery include urinary incontinence and impotence, which occur with increasing frequency in older patients. These symptoms are often most severe immediately following surgery and may improve months to years after the operation.
    • Radical prostatectomies can be performed retropubically, perineally, or laparoscopically. The retropubic approach is most commonly performed in the United States and allows for pelvic lymph node sampling, which, if positive, may result in an abortion of the prostatectomy. Pelvic nodal dissection can be excluded in patients with a low predicted probability of nodal metastases.
    • Well-selected patients with early-stage disease may undergo a nerve-sparing radical prostatectomy in an attempt to spare the cavernous nerves to improve the chances of potency recovery following surgery, without significantly altering the risk of disease recurrence.
  • Radiation therapy:  External beam radiation therapy, brachytherapy, and radical prostatectomy have been shown to have equivalent rates of overall survival, local control, and PSA recurrence for patients with low-risk localized prostate cancer relative to active monitoring. Choice of treatment modality in low-risk disease is, therefore, largely based on the treatment side effect profile and patient preference. However, radiation therapy is often the preferred treatment modality for patients with significant medical comorbidities, older patients, and patients with high-risk localized disease [10, 11, 12, 15, 16].
    • External beam radiation therapy (EBRT): is an appropriate treatment option for patients with low, intermediate, or high-risk localized prostate cancer with a life expectancy of at least 10 years.
    • Brachytherapy: is a form of internal radiation therapy that implants radioactive materials directly into or near the tumor. Brachytherapy can be used as a monotherapy to treat patients with low-risk localized prostate cancer with equal treatment efficacy as surgery or EBRT. Additionally, brachytherapy may be given as a boost to EBRT for patients with intermediate and, occasionally, high-risk localized disease.
    • Common side effects from radiation therapy, as compared to surgery, include lower urinary incontinence rates and impotence rates. However, impotence often develops months to years following treatment and is usually more amenable to medical management. Additional side effects may include bladder irritation, which can cause urinary frequency and urgency, bladder pain, diarrhea, and rectal bleeding. Urinary retention may be an acute or subacute complication of brachytherapy, while urethral stricture formation is a rare and late complication seen with interstitial radiation [17].
• Locally advanced disease (T3, T4)
  • Radiation therapy: external beam radiation therapy is usually combined with brachytherapy and/or hormonal therapy to treat locally advanced prostate cancer.
    • Radiation and hormonal therapy are used together to control local symptoms and increase symptom-free survival, respectively. Together, these treatment modalities increase the overall five-year survival of patients with locally advanced disease to 79%, compared to 62% with radiation alone [19].
  • Surgery: very selected patients with locally advanced Stage T3 or nodal disease may also be candidates for radical prostatectomy, usually within the context of a multi-modality treatment plan.
    • Radical prostatectomy, in combination with adjuvant therapy, has been shown to improve 15-year cancer-specific survival rates to 79% in patients with Stage T3 disease [18].
    • Another study found that 5-year overall survival in patients with T4 disease who received radiation and hormonal therapy was similar to that of patients who received radical prostatectomy, though both were superior to receiving radiation or hormonal therapy alone [20].
    • Adjuvant radiation following radical prostatectomy in T3N0 prostate cancer patients can reduce the risk of PSA failure and the incidence of local recurrence when compared to radical prostatectomy alone [21].
• Metastatic disease
  • Hormonal therapy: surgical or medical castration has been the mainstay of management of refractory or metastatic prostate cancer ever since the benefits of castration were first elucidated in 1941. Testosterone, an androgenic hormone, is responsible for the growth and development of normal prostate tissue and prostate cancer. Castration decreases the circulating testosterone levels of patients by = 90% [22].
    • Treatment options include bilateral orchiectomy, LHRH analogs such as leuprolide (Lupron, Eligard, Viadur) and goserelin (Zoladex), antiandrogens such as bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron), and GnRH antagonists such as relugolix and degarelix, and the antifungal ketoconazole. Combined androgen blockade is commonly achieved by adding an antiandrogen agent to patients who have undergone bilateral orchiectomy or who are receiving an LHRH analog.
    • Common side effects from hormonal therapy include impotence and loss of libido, both of which are difficult to manage medically. Additionally, hormones can also cause breast enlargement, hot flashes, dyslipidemia, glucose intolerance, and osteoporosis [23].
    • Nearly all patients eventually progress to become hormone-refractory within 18-48 months of beginning treatment. Second-line hormonal therapies, including ketoconazole (Nizoral), an antifungal agent, and aminoglutethimide (Cytadren), an aromatase Inhibitor, can produce symptomatic relief and temporary objective tumor responses in a minority of patients [16].
  • Chemotherapy: patients with hormone-refractory prostate cancer usually require chemotherapy, often docetaxel with steroids. Historically, mitoxantrone (Novantrone) was combined with corticosteroids; however, a phase III trial comparing docetaxel and mitoxantrone showed superior survival and toxicity outcomes, establishing docetaxel and prednisone as the preferred regimen. Alternative regimens include the administration of estramustine (Emcyt) with a taxane agent such as docetaxel (Taxotere) or paclitaxel (Taxol) [24].
  • Radiation therapy: may be used to achieve palliation of pain from bone metastasis and improve patient quality of life. Several studies have concluded that adding radiation therapy to palliative care regimens can improve both survival and quality of life. Additionally, bisphosphonates, agents that inhibit osteoclast-mediated bone resorption, can achieve symptomatic improvement from pain associated with bone metastases [25, 26].

Detection and Treatment of Disease Recurrence

• Following radical prostatectomy: any detectable PSA level following surgery indicates possible disease recurrence. PSA levels above 0.2- 0.4ng/ml often prompt treatment with salvage therapies that include radiation, hormonal therapy, experimental protocols, or continued surveillance [27].
  • In patients with disease recurrences following surgery, the median time to developing metastatic disease and death is 8 years and 13 years, respectively, from the time of PSA elevation [28].
  • Models that predict the probability of disease recurrence following radical prostatectomy include the Kattan and Scardino nomogram and the Cancer and Leukemia Group B criteria [29].
• Following definitive radiation: PSA levels generally decrease according to the 2-3 month half-life of PSA. However, unlike patients who have undergone surgery, PSA levels remain detectable indefinitely in the majority of patients following radiation. Patients should undergo PSA evaluation every 3-6 months following definitive treatment. A rising PSA level two years after definitive radiation therapy, three consecutive rises in PSA levels, or a PSA doubling time of less than one year indicates possible disease recurrence and often prompts treatment with therapies that include androgen ablation, salvage prostatectomy, salvage cryotherapy, experimental protocols, or continued surveillance.
  • Patients who choose continued surveillance have a 50% 5-year actuarial risk of distant metastasis from the time the PSA level begins to rise [16].