genitourinary disorders
Prostate Cancer
Treatment of Prostate Cancer
For localized cancer within the prostate, surgery, radiation therapy, or active surveillance For cancer outside of the prostate, palliation with hormonal therapy, radiation therapy, or chemotherapy For some men who have low-risk cancers, active surveillance without treatment Treatment is guided by prostate-specific antigen (PSA) level, grade and stage of tumor, patient age, coexisting disorders, life expectancy, and patient preferences. The goal of therapy can be Active surveillance Local (aimed at cure) Systemic (aimed at decreasing or limiting tumor extent) and extending quantity and quality of life Many patients, regardless of age, prefer definitive therapy if cancer is life-threatening and potentially curable. However, therapy is palliative rather than definitive if cancer has spread outside the prostate because cure is unlikely. Active surveillance can be used for men unlikely to benefit from definitive therapy (eg, because of older age or comorbidity); these patients are treated with palliative measures if symptoms develop. Active surveillance is appropriate for many asymptomatic patients with low-risk, or possibly even intermediate-risk, localized prostate cancer or if life-limiting disorders coexist; in these patients, risk of death due to other causes is greater than that due to prostate cancer. This approach requires periodic digital rectal examination (DRE), PSA measurement, and monitoring of symptoms. In healthy younger men with low-risk cancer, active surveillance also requires periodic repeat biopsies. The optimal interval between biopsies has not been established, but most experts agree that it should be≥1 year, possibly less frequently if biopsies have been repeatedly negative. If the cancer progresses, treatment is required. About 30% of patients undergoing active surveillance eventually require therapy. In older men, active surveillance results in the same overall survival rate as prostatectomy; however, patients who had surgery have a significantly lower risk of distant metastases and disease-specific mortality. Local therapy is aimed at curing prostate cancer and may thus also be called definitive therapy. Radical prostatectomy, some forms of radiation therapy, and cryotherapy are the primary options. Careful counseling concerning the risks and benefits of these treatments and considerations of patient-specific characteristics (age, health, tumor characteristics) are critical in decision making. 75 years old with a life expectancy of > 10 to 15 years and a tumor confined to the prostate. Prostatectomy is appropriate for some older men, based on life expectancy, coexisting disorders, and ability to tolerate surgery and anesthesia. Prostatectomy was historically done through an incision in the lower abdomen. Now, most prostatectomies are done via a robot-assisted laparoscopic approach that minimizes blood loss and hospital stay but has not been shown to alter morbidity or mortality. Complications of radical prostatectomy include urinary incontinence (which is severe in about 5 to 10%), bladder neck contracture or Urethral Stricture (in about 7 to 20%), usually delivers 70 grays (Gy) in 7 weeks, but this technique has been supplanted by conformal 3-dimensional radiation therapy and by intensity-modulated radiation therapy (IMRT), which safely deliver doses approaching 80 Gy to the prostate; data indicate that the rate of local control is higher, especially for high-risk patients. Some decrease in erectile function occurs in at least 40%. Other adverse effects include radiation proctitis, cystitis, diarrhea, fatigue, and possibly urethral strictures, particularly in patients with a prior history of transurethral resection of the prostate. Results with external-beam radiation therapy, radical prostatectomy, and active monitoring were shown to be comparable at a median of 10 years after treatment for localized prostate cancer, as demonstrated in the ProtecT trial ( Treatment references ). Newer forms of external radiation therapy such as proton therapy cost more, an expense that may not be justifiable given that the benefits in men with prostate cancer have not been clearly established. External beam radiation therapy also has a role if cancer is left after radical prostatectomy or if the PSA level begins to rise after surgery and no metastasis can be found. Recent evidence ( Treatment references ) also supports the use of radiation to the prostate in men with low-volume metastatic disease, often called Brachytherapyinvolves the implantation of radioactive seeds into the prostate through the perineum. These seeds emit a burst of radiation over a finite period (usually 3 to 6 months) and are then inert. Research protocols are examining whether high-quality implants used as monotherapy or implants plus external beam radiation therapy are superior for intermediate-risk patients. Brachytherapy also decreases erectile function, although onset may be delayed and patients may be more responsive to phosphodiesterase type 5 inhibitors than patients whose neurovascular bundles are resected or injured during surgery. Urinary frequency, urgency, and, less often, retention are common but usually subside over time. Other adverse effects include increased bowel movements; rectal urgency, bleeding, or ulceration; and prostatorectal fistulas. (destruction of prostate cancer cells by freezing with cryoprobes, followed by thawing) is less well established; long-term outcomes are unknown. Adverse effects include Obstructive Uropathy , HIFU (high-intensity focused ultrasound)uses intense ultrasound energy administered transrectally to ablate prostate tissue. It has been used for many years in Europe and Canada and has recently become more widely available in the United States. The role of this technology in the management of prostate cancer is evolving; presently, it appears to be best suited for radiation-recurrent prostate cancer or low-risk cancer with individual tumors that can be treated by focal therapy. Several other investigational therapies to treat focal lesions are under study, such as laser ablation and catheter electroporation. If cancer localized to the prostate is high risk, various therapies may need to be combined (eg, for high-risk prostate cancer treated with external beam radiation, addition of hormonal therapy for periods varying from 6 months to 2 to 3 years). If cancer has spread beyond the prostate gland, cure is unlikely; systemic treatment aimed at decreasing or limiting tumor extent is usually given ( Treatment references ). Patients with a locally advanced tumor or metastases may benefit from androgen deprivation therapy (ADT) by castration, either surgically with bilateral orchiectomy or medically with luteinizing hormone–releasing hormone (LHRH) agonists, such asleuprolide,goserelin,triptorelin,histrelin, and buserelin, with or without radiation therapy. LHRH antagonists (eg, parenteraldegarelix, oralrelugolix) lower thetestosteronelevel more rapidly than LHRH agonists. LHRH agonists and LHRH antagonists usually reduce serumtestosteronealmost as much as bilateral orchiectomy. Androgen-receptor targeted therapies (abirateroneacetate withprednisone,enzalutamide,apalutamide,darolutamide) or chemotherapy (docetaxel) can be given in combination with ADT; choice of therapy is determined by volume of metastatic disease and patient comorbidities. All androgen-deprivation treatments cause loss of libido and Erectile Dysfunction and may cause Androgen deprivation may impair quality of life significantly (eg, self-image, attitude toward the cancer and its treatment, energy levels) and cause osteoporosis, anemia, and loss of muscle mass with long-term treatment. Exogenous estrogens are rarely used because they have a risk of cardiovascular and thromboembolic complications. Hormonal therapy is effective in metastatic prostate cancer for a limited amount of time. Cancer that progresses (indicated by an increasing PSA level) despite atestosteronelevel consistent with castration (<50 ng/dL [1.74 nmol/L]) is classified ascastrate-resistant prostate cancer.Castrate-resistant prostate cancer (CRPC) can be further classified as M0 (nonmetastatic) CRPC or M1 (metastatic) prostate cancer. An increasing PSA despite lowtestosteroneand absence of lesions on CT or bone scan is called nonmetastatic castrate-resistant prostate cancer. Risk of metastases is high.Apalutamide,darolutamide, andenzalutamideare now available and can slow progression from M0 to M1 CRPC. Treatments that prolong survival in metastatic CRPC (most have been FDA approved since 2010) that should be combined withtestosteronesuppression include Docetaxel(a taxane chemotherapy drug) Sipuleucel-T(a patient-derived vaccine designed to induce immunity against prostate cancer cells) Abiraterone(which blocks androgen synthesis in the tumor as well as in the testes and adrenal glands) Enzalutamide,darolutamide,apalutamide(which block binding of androgens to their receptors) Cabazitaxel(a taxane chemotherapy drug that may have activity in tumors that have become resistant todocetaxel) Radium-233 (which emits alpha radiation, recently found to prolong survival as well as prevent complications due to bone metastases in men with CRPC) External beam radiation therapy (EBRT) PARP (poly [ADP-ribose]) inhibitors (olaparib,rucaparib), which appear active when used as monotherapy in patients with mCRPC and BRCA1/2 and other mutations. The PARP inhibitortalazoparibis available in combination withenzalutamide, andolaparibis now also used in combination withabiraterone/prednisoneas well with BRCA-mutated metastatic castration-resistant prostate cancer. Lutetium Lu 177 vipivotide tetraxetan, which specifically targets a molecule on the surface of prostate cancer cells and is given with a PSMA-positive PET/CT scan. Some data suggest thatsipuleucel-Tshould be used at the earliest sign of CRPC with low PSA and no major symptoms of metastatic cancer (eg, pain). In general, treatments for CRPC are being tried earlier during the course of prostate cancer and are now showing benefit in hormone-sensitive metastatic prostate cancer. However, choice of treatment may involve many factors, and few data may be available to help predict results; thus familiarity with current clinical trials, patient education, and shared decision-making are recommended. To help treat and prevent complications due tobone metastases(eg, pathologic fractures, pain, spinal cord compression), an osteoclast inhibitor (eg,denosumab,zoledronic acid) can be used. All men on ADT should be givenvitamin Dand calcium supplements with the selective use of DEXA scans to detect osteoporosis or osteopenia. Weight-bearing exercise may also help maintain weight, bone density, muscle mass, and core strength. Traditional external beam radiation therapy has been used to treat individual bone metastases. 1.Hamdy FC, Donovan JL, Lane JA, et al: 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer.N Engl Med375(15):1415-1424, 2016. doi: 10.1056/NEJMoa1606220 2.Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial.Lancet392(10162):2353-2366, 2018. doi: 10.1016/S0140-6736(18)32486-3 3.Posdzich P, Darr C, Hilser T, et al: Metastatic prostate cancer—A review of current treatment options and promising new approaches.Cancers15(2):461, 2023. https://doi.org/10.3390/cancers15020461 