Prostate Cancer : Definition, Pathophysiology, Diagnosis, and Treatment
Prostate cancer is a malignant neoplasm that arises from the prostate gland.
PAthophysiology of Prostate Cancer :
- Genetic mutations involving, for example, E-cahedrin, p53, and the androgen receptor appear to contribute to the development of prostate cancer.
- The normal prostate is composed of acinar secretory cells that are altered when invaded by cancer. The major pathologic cell type is adenocarcinoma (more than 95% of cases).
- Prostate cancer can be graded. Well differentiated tumors grow slowly, whereas poorly differentiated tumors grow rapidly and have a poor prognosis.
- Metastatic spread can occur by local extension, lymphatic drainage, or hema- togenous dissemination. Skeletal metastases from hematogenous spread are the most common sites of distant spread. The lung, liver, brain, and adrenal glands are the most common sites of visceral involvement, but these organs are not usually involved initially.
Clinical Presentation :
- Localized prostate cancer is usually asymptomatic.
- Locally invasive prostate cancer is associated with ureteral dysfunction or impingement, such as alterations in micturition (e.g., urinary frequency, hesitancy, dribbling).
- Patients with advanced disease commonly present with back pain and stiffness due to osseous metastases. Untreated spinal cord lesions can lead to cord compression. Lower extremity edema can occur as a result of lymphatic obstruction. Anemia and weight loss are nonspecific signs of advanced disease.
Screening and Diagnosis :
- Digital rectal exam (DRE) is commonly employed for screening of prostate cancer. It has the advantages of specificity, low cost, safety, and ease of performance. DRE has the disadvantages of not being very sensitive and of interobserver variability.
- Prostate-specific antigen (PSA), a glycoprotein produced only in the cytoplasm of benign and malignant prostate cells, is more sensitive than DRE and is simple to perform. PSA has the disadvantage of low specificity.
- Screening for prostate cancer is controversial. The American Cancer Society recommends annual PSA and DRE for men who are 50 years or older.
- On DRE, prostate cancer is characterized by a rock-hard nodule or mass, whereas in benign prostatic hypertrophy (BPH) the gland is smooth and rubbery.
- The diagnosis must be confirmed by biopsy (e.g., transperianal or transrectal needle biopsy). Biopsy also yields a Gleason score of 1 through 10. Lower Gleason scores are assigned to well differentiated, slowly growing cells, and higher scores are assigned to poorly differentiated, rapidly dividing cells.
- Initial laboratory tests should include a complete blood chemistry, liver function tests, and serum phosphatases.
- Bone scan, excretory urogram, and chest x-ray are performed for staging purposes. Depending on the results, skeletal films, lymph node evaluation (e.g., pelvic computed tomography [CT], indium-111-labeled capromab pendetide scan, bipedal lymphangiogram), and transrectal magnetic resonance imaging (MRI) may also be needed.
Desired Outcome :
The goal of treatment for early-stage prostate cancer is to minimize morbidity and mortality. Advanced prostate cancer (stage D) is not curable, and the goal is to provide symptom relief and maintain quality of life.
Prostate Cancer Treatment:
General Approach to To Treatment :
- The initial treatment for prostate cancer depends on the disease stage, Gleason score, presence of symptoms, and patient’s life expectancy.
- The most appropriate therapy for early-stage prostate cancer is unknown.
- Radical prostatectomy and radiation therapy are generally considered equivalent for localized prostate cancer, and neither has been shown to be superior to observation alone.
- Men with no symptoms, Gleason score of 2 to 6, or PSA of less than 10 ng/mL are at low risk for recurrence and have a high 10-year survival rate. If life expectancy is less than 10 years, options are observation or radiation therapy. If life expectancy is more than 20 years, options are more aggressive (e.g., prostatectomy or radiation therapy).
- Men with T2b-c disease, Gleason score of 7, or PSA of 10 to 20 ng/mL are at intermediate risk for recurrence. If life expectancy is less than 10 years, options are observation, radiation therapy, or radical prostatectomy. If life expectancy is more than 10 years, options are prostatectomy or radiation therapy.
- Men with T3a-b disease, Gleason score of 8 to 10, or PSA of more than 20 ng/mL are at high risk for recurrence. If life expectancy is less than or equal to 5 years, options are observation or hormonal therapy. If life expectancy is more than 5 years, radiation therapy should be combined with hormonal therapy.
- Men with T3c or T4 disease are at very high risk for recurrence. Options are androgen ablation with or without radiation therapy. Hormonal therapy should be initiated at diagnosis instead of waiting for the onset of symptoms.
- The major initial treatment modality for advanced prostate cancer (stage D2) is androgen ablation (e.g., orchiectomy or luteinizing hormone-releasing hormone [LH-RH] agonists with or without antiandrogens). After disease progression, secondary hormonal manipulations, cytotoxic chemotherapy, and supportive care are used.
Rationale For Hormonal Therapy :
- The rationale for hormonal therapy is based on the effect of androgens on the growth and differentiation of the normal prostate.
- The testes and the adrenal glands are the major sources of androgens, specifically dihydrotestosterone (DHT).
- LH-RH from the hypothalamus stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland.
- LH complexes with receptors on the Leydig cell testicular membrane and stimulates the production of testosterone and small amounts of estrogen.
- FSH acts on testicular Sertoli cells to promote maturation of LH receptors and produce an androgen-binding protein.
- Circulating testosterone and estradiol influence the synthesis of LH-RH, LH, and FSH by a negative-feedback loop at the hypothalamic and pituitary level.
- Only 2% of total plasma testosterone is present in the active unbound state that penetrates the prostate cell, where it is converted to DHT by 5 Î±-reductase. DHT subsequently binds with a cytoplasmic receptor and is transported to the cell nucleus where transcription and translation of stored genetic material occur.
SURGERY AND RADIATION THERAPY
- Prostatectomy and radiation therapy are associated with complications that must be weighed against expected benefit. Consequently, many patients postpone therapy until the onset of symptoms.
- Complications of radical prostatectomy include blood loss, stricture formation, incontinence, lymphocele, fistula formation, anesthetic risk, and impotence. Nerve-sparing techniques facilitate return of potency after prostatectomy.
- Acute complications of radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence.
- Chronic complications of radiation therapy include proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence.
- Bilateral orchiectomy rapidly reduces circulating androgen levels. Many patients are not surgical candidates owing to advanced age or perceived unacceptableness. Nonetheless, orchiectomy is the preferred initial treatment for patients with impending spinal cord compression or ureteral obstruction.
LH-RH Agonists :
- LH-RH agonists provide response rates of approximately 80%, which is similar to that of orchiectomy, and have the advantage of being reversible.
- There are no comparative trials of LH-RH agonists, so the choice is usually based on cost (Table 63-1) and on patient and physician preference. Leuprolide acetate is administered daily. Leuprolide depot and goserelin acetate implant can be administered monthly, or every 12 or 16 weeks.
- The most common adverse effects of LH-RH agonists are disease flare-up during the first week of therapy (e.g., increased bone pain, urinary symptoms), hot flashes, erectile impotence, decreased libido, and injection-site reactions.
- Monotherapy with flutamide (50% to 87%), bicalutamide (54% to 70%), and nilutamide (40%) produces objective response rates lower than those of LH-RH agonists. Antiandrogens are indicated for advanced prostate cancer only when combined with an LH-RH agonist (flutamide and bicalutamide) or orchiectomy (nilutamide). In combination, antiandrogens can reduce the LH-RH agonist-induced flare.
- The daily doses are flutamide, 750 mg; bicalutamide, 50 mg; and nilutamide, 300 mg for 1 month, followed by 150 mg.
- The adverse effects of antiandrogens are gynecomastia, hot flashes, gastrointestinal (GI) disturbances, liver function test abnormalities, and breast tenderness. GI disturbances consist of diarrhea for flutamide and bicalutamide and nausea or constipation for nilutamide. Flutamide is also associated with methemoglobinemia, whereas nilutamide causes visual disturbances (impaired dark adaptation), alcohol intolerance, and interstitial pneumonitis.
COMBINED HORMONAL BLOCKADE
- The role of combined hormonal therapy, also referred to as maximal androgen deprivation or total androgen blockade, continues to be evaluated.
- Randomized trial results are mixed when candidates for second-line therapy are treated with combinations of antiandrogens plus either LH-RH agonists or orchiectomy. The most recent meta-analysis showed only a slight survival benefit at 5 years for maximal androgen blockade with flutamide or nilutamide (27.6%) compared with conventional medical or surgical castration alone (24.7%; p = .0005).
- Some investigators consider combination androgen ablation to be the initial hormonal therapy of choice for newly diagnosed patients because the major benefit is seen in patients with minimal disease. Some argue that treatment should not be delayed because combined androgen deprivation trials demonstrate a survival advantage for young patients with good performance status and minimal disease who were initially treated with hormonal therapy.
- Studies are needed to answer questions regarding the selection of modalities used as combined hormonal therapy, with careful consideration of effects on survival, time to progression, quality of life, patient preference, and economics.
Historically, estrogens were an important method of androgen ablation. The major agent, diethylstilbestrol (DES), was removed from the market in 1997. Alternatives (e.g., ethinyl estradiol, conjugated estrogens, chlorotrianisene, and polyestradiol phosphate) have not been as extensively studied and cost more than DES.
- The selection of salvage therapy depends on what was used as initial therapy. Radiotherapy can be used after radical prostatectomy. Androgen ablation can be used after radiation therapy or radical prostatectomy.
- If testosterone levels are not suppressed (i.e., greater than 20 ng/dL) after initial LH-RH agonist therapy, an antiandrogen or orchiectomy may be indicated. If testosterone levels are suppressed, the disease is considered to be androgen independent and should be treated with palliative therapy.
- If initial therapy consisted of an LH-RH agonist and antiandrogen, then androgen withdrawal should be attempted. Mutations of the androgen receptor may allow antiandrogens to become agonists. Withdrawal produces responses lasting 3 to 14 months in up to 35% of patients.
- Androgen synthesis inhibitors provide symptomatic, but brief, relief in approximately 50% of patients. Aminoglutethimide causes adverse effects in 50% of patients, such as lethargy, ataxia, dizziness, and self-limiting rash. The adverse effects of ketoconazole are GI intolerance, transient increases in liver and renal function tests, and hypoadrenalism.
- Bisphosphonates prevent hormone-induced bone loss when used early during androgen deprivation therapy and, in some studies, prevent skeletal morbidity when used for hormone-refractory prostate cancer. Usual dosages are pami- dronate, 90 mg every month, and zoledronic acid, 4 mg every 3 to 4 weeks.
- After hormonal options are exhausted, palliation can be achieved with strontium-89 or samarium-153 lexidronam for bone-related pain, analgesics, glucocorticoids, local radiotherapy, or chemotherapy.
Docetaxel, 75 mg/m2 every 3 weeks, combined with prednisone, 5 mg twice daily, is becoming the standard for hormone-refractory metastatic prostate cancer because it is the first chemotherapy regimen to show a survival benefit. In the randomized study, the most common adverse events were nausea, alopecia, and myelosuppression. Docetaxel can also cause fluid retention and peripheral neuropathy.
Single agents with modest activity include cyclophosphamide, estramustine, fluorouracil, methotrexate, dacarbazine, mitoxantrone, doxorubicin, paclitaxel, gemcitabine, vinorelbine, and cisplatin.
Active combinations include estramustine and vinblastine or mitoxantrone, and mitoxantrone and prednisone. Other possible combinations are ketoconazole and doxorubicin, and estramustine and etoposide or paclitaxel.
EVALUATION OF THERAPEUTIC OUTCOMES
- Monitoring depends on the stage of prostate cancer.
- For definitive, curative therapy, objective parameters include primary tumor size, involved lymph nodes, and tumor markers such as PSA.
- For treatment of metastatic disease, clinical benefit can be documented by evaluating performance status, weight, quality of life, analgesic requirements, and PSA or DRE.
- Patients should be monitored for treatment-related adverse events, especially events that are amenable to intervention.