The Washington Manual of Oncology, 3 Ed.

Prostate Cancer

Ramakrishna Venkatesh • Seth Strope • Bruce Roth

 I. PRESENTATION

1. Subjective. Prostate cancer rarely causes symptoms early in the course of the disease as most of the adenocarcinomas arise in the periphery of the gland away from the urethra.

 In the prostate-specific antigen (PSA) era, the most common finding is the absence of symptoms. The presence of symptoms due to prostate cancer often suggests locally advanced or metastatic disease. Growth of prostate cancer around or into the urethra, or involvement of bladder neck can result in decreased urinary force of stream, frequency, urgency, nocturia, or hematuria. However, many of these symptoms are not specific and may occur with benign prostatic hyperplasia and aging. Involvement of ejaculatory ducts can cause hemospermia, and extraprostatic disease involving the branches of pelvic plexus can cause erectile dysfunction (ED).

 Metastatic disease can cause a wide variety of symptoms related to the sites of metastases. Bone is the favored site of metastasis, with pain being a common, and at times, debilitating symptom. Men with spinal metastases may live for years; therefore, careful and thoughtful serial histories and examinations are mandatory. The most devastating consequences of bone involvement are pain, fractures, and spinal cord or nerve root compression. Spinal cord compression is usually accompanied by back pain that is often made worse by coughing, sneezing, or straining (and other activities that increase intradural pressure). Unlike nonmalignant causes of back pain, the back pain of metastatic prostate cancer is usually worse at night. If a peripheral nerve is pinched by tumor, the back pain may radiate around to the front of the patient in the thorax or abdomen or down the legs. Patients with early spinal cord compression will have weakness, with progression to paralysis occurring, on the one hand, over a period of weeks to even months. On the other hand, late spinal cord compromise leads to loss of sensation distal to the level of metastasis, urinary retention, and incontinence in a matter of minutes to hours. The classic symptoms of cauda equina syndrome are low back pain, bilateral sciatica, sensory and motor deficits, including sacral and perianal anesthesia, and loss of sphincter control of bladder and anus. Delays in management result in permanent loss of sensation, motor function, and continence.

 Fatigue is a prominent complaint of patients, but it may occur for very different reasons depending on the state of the tumor and the patient. If due to advanced or metastatic disease, it may be an indicator of bone marrow infiltration by tumor with associated anemia. Liver involvement occurs in only 15%, usually at the end of life. Hepatic metastases are usually due to poorly differentiated adenocarcinomas or to tumors with small cell (neuroendocrine) differentiation.

 Androgen deprivation therapy (ADT) and/or chemotherapy can cause anemia, but the former is usually mild, whereas the latter may be moderate or severe. Lower limb edema can result from pelvic lymph node involvement, compression of iliac veins, and/or deep vein thrombosis (DVT).

 Shortness of breath may be due to chemotherapy treatment, anemia, pulmonary embolism, and/or lung metastases, but the latter occurs late in only 15% of patients. Later in the course of the disease, older men complain of fatigue and gradually fail to thrive at home, with debilitating bone pain, weakened legs, decreased activity, poor appetite, weight loss, and other symptoms of advanced metastatic disease.

1. Objective. With the widespread use of PSA screening and early detection programs, the most common finding on examination of the prostate is the absence of findings. Despite the lead time bias that PSA screening introduces, physicians must be able to perform an excellent digital rectal examination (DRE) to diagnose and clinically stage localized prostate cancer. Attention should be directed to defining the presence or absence of a nodule and its location with respect to the right or left lobe and median raphe. Clearly, the absence of a nodule does not preclude the diagnosis of prostate cancer, and simply hardness of the prostate may indicate the presence of tumor. As patients become more obese, the DRE becomes more difficult to perform, but one should try to define extracapsular extension and/or involvement of the seminal vesicles. The sensitivity and specificity of the DRE is modest to poor, depending on the examiner, which can lead to both over- and underdiagnosis.

 As with all cancer patients, the oncologist must do a careful, comprehensive physical examination, with special attention to signs of anemia, lymphadenopathy, bone tenderness, neuropathy, and lower extremity edema. For men treated with ADT, the testicular examination ought to show atrophy, whereas its absence should alert the physician that the patient does not have castrate levels of testosterone. Because of the potential for extended periods of good quality of life (QOL) and survival, even with metastatic disease, prostate cancer remains one of several neoplasms that physicians must rule out in the evaluation of carcinoma of unknown primary tumor.

1. WORKUP AND STAGING. Autopsy studies have shown localized prostate cancer in approximately 30% of men older than 50 years and 70% of men older than 80 years. However, with the availability of serum PSA and transrectal ultrasonogram-guided needle biopsy of the prostate, clinically organ-confined prostate cancer is increasingly diagnosed, with continuing uncertainty regarding the clinical significance of some tumors. Defining the grade of the tumor and anatomic stage are critical in understanding the prognosis and formulation of a treatment plan. Various predictive models (e.g., Partin table, Kattan nomograms) have been developed and are available for use in clinical practice for counseling patients and for planning a rational management plan. Most of these validated models include prognostic variables such as PSA, Gleason score, and clinical stage of the cancer.
2. Laboratory testing
3. PSA. PSA is a serum marker that is central to the diagnosis and management of prostate cancer. The use of PSA testing has helped to identify cases of prostate cancer that are or will become clinically significant, rather than simply identifying cases of cancer that are unlikely to be detected until autopsy. PSA is directly associated with tumor volume and clinical stage. Normal PSA ranges depend on factors such as age and race, and PSA level is affected by prostatic biopsy but not significantly by DREs.

 Absolute PSA levels and the rate of change of those levels with respect to time can predict the likelihood of organ-confined disease and influence opinions on the likelihood of a cure. PSA levels greater than 10 µg/L are associated with increased risk for extracapsular extension. The positive predictive value for a PSA between 4 and 10 ng/mL in patients with normal DRE is only 30% approximately. To improve the performance of the PSA test, modifications, such as PSA velocity, PSA density, and free-to-total PSA ratio have been used. Some physicians advocate the use of free PSA versus bound PSA to quantify further the risk of cancer and need for biopsy; higher percentage free PSA levels are associated with more favorable histopathologic features in prostate tumors. A cutoff of 25% free PSA detects 95% of cancer while avoiding 20% of unnecessary biopsies.

 PSA kinetics has been explored to improve PSA testing. A study showed men whose PSA level increased by more than 2.0 ng/mL during the year before diagnosis of prostate cancer were at high risk for cancer-specific death even if they had “favorable” clinical parameters (such as a PSA level <10 ng/mL and Gleason score <6 at diagnosis) and that they should undergo radical prostatectomy (RP). For these men, active surveillance may not be an appropriate option. Their increased risk also makes them candidates for enrollment in clinical trials examining various combination treatment strategies. Physicians must use caution when using such measures because men with tumors with Gleason scores of 8, 9, and 10 may be so poorly differentiated that they do not synthesize and secrete large amounts of PSA.

2. Complete blood count and chemistries. The laboratory workup should include a complete blood count and comprehensive metabolic panel. Widely metastatic disease may cause anemia or thrombocytopenia because of marrow infiltration, but most patients will have normal peripheral counts and normal chemistries at the time of diagnosis. Abnormal tests should prompt investigation, especially in patients thought to have only localized disease. For example, an elevated alkaline phosphatase may be due to bone metastases and, therefore, a bone scan should be done to rule out this possibility.
3. Imaging. Computed tomography (CT), magnetic resonance imaging (MRI), and bone scans are important in the assessment of advanced disease, but they are not indicated in the standard workup of low risk prostate cancer because of their low sensitivity and high cost. Physicians should adopt a symptom-directed approach to the use of imaging of low risk disease. Patients with high risk disease are more likely to have benefit from routine imaging, and many physicians use CT of the abdomen and bone scan as adjuncts to clinical staging in this group. Imaging in these patients may help to identify those with lymph node involvement, but sensitivity is poor even in this risk group. It has been suggested that MRI of the prostate can be used to categorize risk further in intermediate risk tumors by identifying seminal vesicle involvement and extraprostatic extension before surgery. Additionally, MRI is a possible adjunct for patients considering active surveillance to help rule out larger tumors that may have been missed in the initial prostate biopsy. Current imaging studies (CT, MRI, or positron emission tomography [PET] scan) cannot accurately show metastatic disease in most patients with newly diagnosed prostate cancer.
4. Pelvic lymphadenectomy. Pelvic lymphadenopathy is rarely performed in isolation in current practice. It can be safely omitted at the time of surgical therapy in patients with low risk of lymph node spread (PSA <10, Gleason 6, and T1c cancer). In an occasional patient with high risk disease, laparoscopic pelvic lymphadenectomy should be considered to rule out metastatic disease before definitive therapy. However, most of these high risk patients will receive either surgical resection or multimodality therapy with radiation and androgen deprivation.
5. Staging. The first purpose of a staging system is to provide a well-accepted classification where health care workers from around the world may interpret the extent of disease of the patient. However, in addition, the clinical and/or pathologic stage of the prostate cancer patient may guide discussions about the optimal modality for treatment. The clinical or pathologic stage of the patient is the stage that is defined at the time of initial diagnosis.

 To answer queries from patients about prognosis and treatment options, one must weigh the clinical and/or pathologic tumor, node, metastasis (TNM) staging, Gleason grade, and serum PSA level in the context of the general health of the patient. The oncologist should give estimates of both prostate cancer–specific survival and overall survival. The median age at diagnosis for U.S. men is declining, but is still approximately 68 years, and the average man lives to 75 years at this time. In the future, men will get diagnosed earlier and will live longer, leading to more treatment, more “cures,” more PSA relapses, and longer times with side effects from therapies for recurrent disease.

1. Prostate cancer is staged according to the AJCC Cancer Staging Manual 7th edition. T stage is divided into T1 (clinically undetectable tumor by palpation or imaging), T2 (tumor confined to the prostate; T2a—one-half or less of a lobe, T2b—more than one-half of one lobe, T2c—bilateral lobe involvement), T3 (Extension through the prostate capsule; T3a—extracapsular extension; T3b—seminal vesicle invasion), and T4 (invasion of adjacent structures such as rectum, levator muscles, and pelvic wall). N1 is defined as the involvement of regional lymph nodes and M1 as metastases to non-regional lymph nodes, bones, or other sites. In addition to the TNM status, both PSA (<10, ≥10 to <20, ≥20) and Gleason score (G1 ≤6, G2 7, G3 >7) are used in the final staging. Stage I is defined by the presence of T1–T2a plus G1. Stage IIA is defined by T1–T2b plus PSA <20 and Gleason ≤7, and stage IIB is defined as T2c or T1–T2 with PSA >20 or Gleason score >7. Stage III is defined by the presence of T3 and stage IV by the presence of T3 and T4, N1 or M1.
2. Histologic grade is best determined with the Gleason scoring system. The Gleason grade is a classification of gland formation from a relatively low power view. It is not a histologic classification in the basic sense, such as a comment on nucleoli, nuclear-to-cytoplasmic ratio, and so on. The tumor pattern is graded from 1 for well-differentiated to grade 5 for poorly differentiated pattern. Gleason score is the sum of the scores for the primary and secondary Gleason patterns seen on the biopsy or prostatectomy specimen. If there is a tertiary pattern 5 on a biopsy, that score is reported as the secondary pattern to better describe the disease risk. Because the prognosis varies according to the primary and secondary Gleason grades, each should be assessed along with the sum score. Most men have intermediate-range Gleason scores (Gleason 6 or 7), and it is important to recognize that Gleason scores from transrectal ultrasonogram-guided biopsies may underscore a tumor. Pathologic review from subsequent prostatectomy may increase Gleason scores; for example, a “Gleason 3 + 3 = 6” may be upgraded to a “Gleason 3 + 4 = 7.”
3. The combination of clinical stage, Gleason score, and PSA level allows physicians to prognosticate most accurately. Patients may be classified as low risk (PSA ≤10, Gleason score <7 and stage up to T2a), intermediate risk (PSA 10–20, Gleason score 7, stage T2b) or high -risk (PSA >20, Gleason score >7, stage T2c). Histologic grade is a good predictor of the outcome, but is not as good as the Gleason sum score. Patients with well-differentiated, moderately differentiated, and poorly differentiated tumors had 15-year death rates for untreated disease of 9%, 28%, and 51%, respectively.

 III. TREATMENT

1. Localized disease (T1 to T2 N0 M0). The discussion of treatment options for localized disease should include risks and benefits of surgery, radiation (either external beam or brachytherapy), or active surveillance. The 5-year disease-free survival for both RP and radiation therapy (XRT) is approximately 60% to 70%. Recently, the PIVOT study showed no benefit for surgical intervention compared to observation for low risk disease. These results contrast to the SPOG-4 trial where a survival benefit was seen for prostatectomy versus observation.
2. RP. The optimal post-RP outcome for the patient is to be cancer-free (with undetectable serum PSA) and to recover preoperative urinary and erectile function. Anatomic RP, also known as radical retropubic prostatectomy, is the most common technique for resection currently and allows for the possibility of nerve-sparing techniques that increase the likelihood of preserving potency as well as total continence. The procedure is performed through a midline lower abdominal incision and may involve pelvic (hypogastric and obturator) lymph node dissection. External iliac nodes are not generally removed to reduce the risk of future lower extremity edema. Nerve-sparing techniques allow preservation of neurovascular bundles if uninvolved by tumor. RP is likely curative for organ-confined prostate cancer and rarely curative in lymph node–positive/metastatic disease.
3. Laparoscopic radical prostatectomy (LRP) with or without robotic assistance. Surgeons have demonstrated that LRP with or without robotic assistance can be performed with excellent results. LRP is technically demanding, requiring a significant learning curve. The average intraoperative blood loss is less with robotic or laparoscopic approach. The perceived advantages that laparoscopic or robotic prostatectomy with a magnified surgical image would markedly improve patient outcomes has not been realized. However, the short-term outcomes of robotic RP are no worse than open prostatectomy. Robotic prostatectomy is more expensive than RP. To date, no prospective randomized trials have compared the two approaches. As with open surgical procedures, laparoscopic outcomes, including surgical margin status, continence, and potency, reflect technique more than approach.
4. Pelvic lymphadenectomy does not provide additional curative benefit, but may provide prognostic information. However, more recently, some authors have recommended extended pelvic lymph node dissection for high risk disease patients to adequately stage the disease with potential therapeutic benefit. Pelvic lymphadenectomy can be especially useful in patients with high risk or locally advanced disease in which future hormonal therapy will be an important consideration.
5. Radiation therapy. Radiation therapy for the prostate is a continually evolving field as new and better technologies make it possible to deliver higher doses of targeted local radiation, sparing normal tissues, with less local toxicity.
6. External-beam radiation. At least two prospective studies have shown that a dose of 78 to 79 Gy is better than 70 Gy. Advanced computer modeling has led to the development of intensely modulated radiation therapy (IMRT). This technique uses complicated tools that precisely control both the dose of radiation and the tissue targeted. Outcomes for T1/T2 disease are similar to those seen with surgery, with 87% of patients free of local recurrence at 10 years.
7. Brachytherapy. An alternative to external-beam therapy is interstitial XRT with seed implants (brachytherapy). High-dose-rate (HDR) brachytherapy has been reported to be associated with lesser incidence of dysuria, frequency, and rectal pain compared to the low-dose-rate brachytherapy.
8. Active surveillance (AS). Active surveillance may be a safe alternative to immediate treatment in compliant men with a low risk of cancer progression. The goal of AS is to avoid overtreatment for most patients while administering curative therapy to those in need of more aggressive treatment. Additional baseline reevaluation, including imaging study of the prostate (MRI with spectroscopy) and ultrasonogram-guided systematic needle biopsy can be considered prior to starting AS. If these studies confirm a low risk cancer, and the patient chooses AS, checkups with DRE and PSA every 3 to 6 months indefinitely are recommended, with repeat imaging and biopsy 12 to 18 months after the baseline evaluation and then every 2 to 3 years.
9. Cryotherapy. With better ultrasonographic imaging along with real-time monitoring of freezing and improvements in the cryotherapy technology with smaller cryoprobes, interest in cryotherapy has been rekindled. With the “third generation” cryotherapy technology, the reported morbidity is significantly less compared to the older generation cryotechnology. Cryotherapy is currently limited to patients who are poor candidates for RP or XRT and who have poor sexual function. It can also be used as salvage therapy for locally recurrent prostate cancer following RP or failed brachytherapy or external-beam XRT. However, currently the role of cryotherapy as a primary treatment of prostate cancer continues to be controversial.
10. Locally advanced disease (T3 N0). For high risk patients with locally advanced disease, both surgery and radiation therapy may be used as standard therapy.
11. Surgery. Radical prostatectomy can be successfully employed in patients with clinical stage T3 disease. Patients should be counseled on the possibility of adverse findings at final pathology including positive margins, extracapsular disease, and seminal vesical invasion. Should these pathologic findings exist, patients are candidates for adjuvant XRT. Current ASTRO/AUA guidelines recommend providing adjuvant XRT to these patients based on improved biochemical recurrence free survival in three randomized clinical trials. The role of adjuvant versus salvage XRT is not known. However, the efficacy of salvage radiation therapy is greatest when XRT is given at a PSA level less than 0.5.
12. Radiation. The combination of hormone therapy with radiation alone in locally advanced disease (intermediate and high risk disease) has also been evaluated. The combination of XRT and hormonal therapy in high risk disease has been shown to result in superior survival when compared with XRT alone, and there appears to be a benefit for ADT in intermediate risk disease as well. The duration of ADT (4 months vs. 36 months) and the role of ADT with higher doses of XRT (greater than 72 Gy) remain to be determined. An additional unanswered question is the role of whole pelvic versus prostate-only XRT. The combination of hormonal therapy with brachytherapy in locally advanced disease has not yet shown convincing evidence of survival benefit.
13. Increasing PSA after prostatectomy or radiation. Asymptomatic progressive increase in PSA is a common problem in patients with prostate cancer after XRT or surgery. Prognostic factors to consider in this setting are doubling time of PSA, time from definitive therapy to increase in PSA, age of the patient, and comorbidities. Many methods have been used to predict failure, and most physicians consider higher risk patients to be those with seminal vesicle involvement, aggressive histology (Gleason greater than 6), and PSA greater than 10. D’Amico et al. reported that PSA doubling time of less than 6 months is highly predictive of disease progression compared to doubling time of more than 10 months.

 Local control after initial failure can be attempted. XRT may provide additional local control after RP, but it has not shown survival benefit and may be associated with higher rates of radiation-related complications. Salvage prostatectomy after XRT is an option, but is associated with higher surgical complication rates. Other surgical options in this setting include cryotherapy and brachytherapy, but no conclusive clinical trials supporting use of these modalities are available.

 Most men who have increasing PSA levels after initial management are given medical therapy (see Section III.C). Ongoing trials will attempt to determine whether combined hormonal and XRT is beneficial in patients with increasing PSA after definitive surgery.

1. Metastatic disease (N1 or M1)
2. Initial therapy (hormone-sensitive disease). Medical or surgical castration remains the first-line therapy for metastatic disease, as it is associated with a response rate greater than 80% and can often reduce PSA levels to undetectable levels. In the recent past, metastatic prostate cancers have remained sensitive to the effects of hormonal blockade for an average of 12 to 18 months. Currently, with lead time bias of diagnosis, more widespread use of PSA as a serum marker, improved imaging, and early hormonal intervention, men can respond to androgen deprivation for 2 or more years, with some living up to a decade.

 Given the psychological impact of surgical castration, most men in the United States prefer medical androgen blockade to bilateral orchiectomy. However, surgery is certainly the most cost-effective treatment. Gonadotropin-releasing hormone (GnRH) agonists are the most commonly employed first-line agents. Because these agents are agonists, they will initially increase serum testosterone levels and could result in progression of pain, disease, and even spinal cord compression. Therefore, before GnRH injection, treatment with an androgen receptor antagonist (bicalutamide 50 mg daily; nilutamide 150 mg daily, or flutamide 250 mg three times a day) is warranted. Routinely, these drugs are started 2 weeks before injections and are prescribed for 1 month. Then, leuprolide acetate (Lupron) may be given as 4-month (30 mg), 3-month (22.5 mg) or 1-month (7.5 mg) intramuscular injections. Another GnRH agonist, goserelin (Zoladex), is introduced as a depot injection into the anterior abdominal wall, subcutaneously, every 3 months (10.6 mg) or every month (3.6 mg). The most common side effects are hot flashes and ED. However, over the first year of ADT, many men will become anemic and fatigued, lose muscle mass and gain fat tissue, and lose bone density. Combined androgen blockade (CAB), with both a GnRH agonist and an androgen-receptor blockade (ARB), is not substantially better than GnRH agonist alone.

 Failure of first-line ADT is often marked by an asymptomatic rise in PSA, although symptoms of urinary track outlet obstruction, bone pain, and so on may be observed as well. This transition may be referred to as castrate-independent disease, but the androgen receptor is still present and can still respond to androgens. Therefore, it is important to maintain patients on ADT with GnRH agonists. If the patient was treated with a GnRH agonist alone, then one may add an ARB. If the patient was managed with CAB, then it is wise to stop treatment with the ARB, to rule out “antiandrogen withdrawal syndrome.” Only approximately 10% of these patients will respond, but sometimes it may take 6 weeks to observe a decrease in PSA levels. Some data suggest that in tumors of a subset of patients, mutations of the androgen receptor result in flutamide acting as an agonist, instead of an antagonist of the androgen receptor.

 Eventually, second-line hormonal therapy will no longer work and this stage may be treated with inhibitors of adrenal androgen synthesis (ketoconazole, hydrocortisone, or the combination), estrogens, and progestins. Although randomized trials have not shown a clear benefit to the use of third-line hormonal therapy, there is clearly a subset of patients that respond.

2. Hormone refractory disease. Once the tumor has progressed through ADT plus antiandrogen therapy, it is considered to be castration-recurrent prostate cancer. Nevertheless, the tumor can still respond to androgens, so it is important to maintain castrate levels of testosterone.

Abiraterone (1,000 mg daily) combined with prednisone (5 mg b.i.d) showed improved outcomes compared to prednisone alone. There was a trend toward improved survival in the phase III randomized study in the pre-docetaxel setting (N Engl J Med 2013;378:138). The agent was approved by the FDA for use in this setting. Side effects of abiraterone include hypertension, hypokalemia, peripheral edema, atrial fibrillation, congestive heart failure, liver injury, and fatigue.

 The second agent being tested in this setting is enzalutamide. A randomized study for FDA approval has been completed in the setting prior to docetaxel chemotherapy, and preliminary results were reported at the Genitourinary Cancer Symposium in February of 2014. Approval for the agent is pending the final review of the full trial.

 Importantly, both enzalutamide and abiraterone were tested in men who were asymptomatic or mildly symptomatic. This study population is different from that of the docetaxel trials where men were symptomatic from their metastatic disease. Also, both studies enrolled men with metastatic disease. PSA progression alone was not an indication for starting either medication.

 Sipuleucel-T is an alternative for men with asymptomatic or minimally symptomatic metastatic castration refractory prostate cancer. It was FDA-approved in this setting from a phase III trial showing an extension in survival to 25.8 months in the treatment arm compared to 21.7 months in the control arm. Side effects included chills, pyrexia, and headache (N Engl J Med 2010;363:411).

 Chemotherapy was tried in metastatic prostate cancer for four decades and was considered a failure. However, the improvement with antiemetics, supportive care, pain control, and hematopoietic growth factors finally allowed for adequate trials in this elderly group of men. In a randomized trial, the anthracycline, mitoxantrone, plus prednisone proved to be superior to prednisone alone in terms of QOL, but not in survival. Nevertheless, this regimen became the control group for future chemotherapy trials. Finally, the taxanes and other microtubule inhibitors showed activity in prostate cancer in the late 1990s. Then, two randomized, controlled, prospective, multicenter studies were performed testing docetaxel-based chemotherapy versus mitoxantrone plus prednisone in castrate-independent, metastatic prostate cancer. For the first time, docetaxel-based therapy resulted in superior median and overall survival rates. Docetaxel plus prednisone was approved by the U.S. Food and Drug Administration (FDA) and is considered the standard of care in the United States. Current studies are designed to ask whether the addition of antiangiogenesis agents will improve outcome. The prominent side effects of docetaxel include fatigue, aches and pain in muscles and joints, nail changes, diarrhea, and sequelae of bone marrow suppression. Due to the possible side effects, docetaxel should be used in patients who have symptomatic castration-resistant prostate cancer.

 ²²³Ra is an alternative therapy for men with hormone-recurrent prostate cancer who are not candidates for chemotherapy. ²²³Ra admits alpha particles and is absorbed by bone. In a phase III study of men with symptomatic bone metastases, the median overall survival was 14 months for men treated with ²²³Ra and 11.2 months for the placebo arm. Some men in the trial had received prior docetaxel therapy. The medication is not for use in men with visceral metastases. Side effects included nausea, diarrhea, vomiting, and swelling of the lower extremities.

3. Approved agents after chemotherapy. Multiple agents are approved for use in patients who have disease recurrence or progression after docetaxel-based chemotherapy. Cabazitaxel with prednisone was FDA-approved based on a phase III randomized study showing prolonged overall and progression-free survival. (Lancet 2010;376:1147). This agent has a high risk of neutropenia, and also patients with severe neuropathy are not candidates for this therapy.

 Additionally, enzalutamide and abiraterone are approved for use in the post-docetaxel setting for men with symptomatic castration-resistant metastatic prostate cancer. Both agents showed prolongation in survival in randomized phase III trials.

4. Preservation of bone health. Both zoledronic acid and denosumab are effective agents for preservation of bone health in men with metastatic castration-recurrent prostate cancer. Zoledronic acid is a bisphosphonate and is administered intravenously. In a randomized study, men with asymptomatic or mildly symptomatic bone metastases had a significant reduction in skeletal-related events (33% zoledronic acid, 44% placebo). Denosumab is a RANK ligand inhibitor that was compared to zoledronic acid in a double-blind placebo-controlled study. The incidence of skeletal related events was similar for the two agents, but time to first event was delayed by 3.6 months in the denosumab arm. Denosumab is administered subcutaneously.

 IV. COMPLICATIONS

1. Complications of therapy
2. Complications of surgery. The complications of RP are predominantly urinary incontinence and impotence, but the nerve-sparing and retropubic approach has decreased complication rates. In the best series, an estimated 8% of men will have stress incontinence after surgery, with only 1% to 2% requiring more than one pad daily. Larger, population-based studies, unfortunately, have shown higher complication rates. Patients are less likely to complain about urinary incontinence to their surgeons, and in some reports, 11% of men after prostatectomy were using two or more pads per day.

 Impotence is still a major problem, and the rate of total impotence increases with advanced disease, advanced age, and poor surgical technique. An estimated 20% to 80% of men who are fully potent before surgery will retain potency after the procedure, but the erections may not be of the same quality. In men younger than 50 years, some degree of potency is preserved in an estimated 91%, even if one neurovascular bundle is excised. However, in men older than 70 years, potency rates decrease to approximately 25% with excision of the neurovascular bundles. It is important to make men aware of available therapies designed to restore potency, both pharmacologic and nonpharmacologic. Sensation to the penis is preserved after RP (through the pudendal nerve), although the autonomic innervation of the corporal bodies are damaged. Medications such as sildenafil, vardanafil, and tadalafil may help men regain erectile function and improved sexual activity and QOL.

 The reported blood transfusion rate for robotic or laparoscopic prostatectomy is 1% to 2% compared to 5% to 10% for open RP. Other rare complications include DVT (1% to 3%) and rectal injury (less than 1%). The risk of postoperative mortality after RP is relatively low (less than 0.5%) for otherwise healthy older men up to age 79. In one large study, 61,039 patients with prostate cancer had undergone RP as the principal procedure at 1,552 U.S. hospitals. The post-RP mortality rate was 0.11% (66 deaths). Procedure-specific volumes predominantly affected the odds of in-hospital mortality from RP.

2. Complications of XRT. Toxicities of XRT most commonly involve the rectum and the bladder. An estimated 60% of patients will have moderate rectal symptoms including pain, tenesmus, or diarrhea. Others will have symptoms of cystitis, hematuria, impotence, incontinence, or difficulty with urination around the period of XRT. Most of these symptoms resolve on completion of the therapy. Less than 1% of conventional XRT patients require hospitalization for local toxicities including rectal pain, rectal/urinary bleeding, or other urinary complaints.
3. Complications of hormone deprivation therapy and antiandrogens. Men who are contemplating treatment with ADT should be made aware of the potential side effects of therapy. Decreased total and free serum testosterone levels lead to hypogonadism, impotence, and decreased libido. In addition, over the first year or so, the patient will notice decreased muscle mass and increased adipose tissue, especially centripetally. A decrease in bone mineral density may lead to osteoporosis. An increase in estrogen to testosterone ratio may result in hot flashes, sweats, and gynecomastia. Endocrine changes may result in an increase in components of the metabolic syndrome, such as hyperglycemia, hyperinsulinemia and insulin resistance, dyslipidemia (hypertriglyceridemia and low high density lipoprotein [HDL] cholesterol levels). These metabolic changes may lead to an increased risk of cardiovascular disease. As we detect more men with prostate cancer at younger ages and these men live longer, the metabolic consequences of ADT will work against the very benefits of treatment.
4. Complications of chemotherapy. Docetaxel has a complicated structure that is poorly soluble in water. Therefore, it is formulated in polysorbate-60, and the side effects of treatment may be due to both the chemotherapy agent and its solvent. Allergic reactions such as shortness of breath, facial flushing, fever, chest pain, dizziness, lightheadedness, or skin rash may occur, but are rare with premedication with dexamethasone. Musculoskeletal and bone and joint symptoms of pain and stiffness are among the most common reported by patients.
5. Complications of bisphosphonate and RANK ligand inhibitor therapy. Hypocalcemia, arthralgias, and osteonecrosis of the jaw may occur with these therapies. Preexisting dental problems significantly increase the risk of osteonecrosis of the jaw.
6. BACKGROUND. Prostate cancer is the most common malignancy and the second most common cause of cancer-related death in men in the United States. The lifetime risk of a prostate cancer diagnosis is approximately 16%, but the lifetime risk of prostate cancer death is only 3.4%. With the unproven, yet widespread use of PSA screening, the clinical presentation of prostate cancer has changed from advanced to localized disease in more than 80% at the time of diagnosis. The current challenge of research is to use this lead time bias to our advantage to achieve better overall survival and QOL with new treatments. However, the price of early detection and screening is “overdiagnosis,” which results in diagnosis, treatment, side effects, and anxiety in tens of thousands of men who would not have manifested symptoms of prostate cancer within their lifetime.

 With improved understanding of the molecular aberrations and their influence on clinical outcomes, it is likely that we will individualize therapy for this common malignancy.

SUGGESTED READINGS

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Catalona WJ, Carvalhal GF, Mager DE, et al. Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999;162:433–438.

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