TREATMENT BLADDER CANCER

Management depends on whether the tumor invades muscle and whether it has spread to the regional lymph nodes and beyond. The probability of spread increases with increasing T stage.

NON–MUSCLE-INVASIVE DISEASE

At a minimum, the management is complete endoscopic resection with or without intravesical therapy. The decision to recommend intravesical therapy depends on the histologic subtype, number of lesions, depth of invasion, presence or absence of CIS, and antecedent history. Recurrences develop in upward of 50% of cases, of which 5–20% progress to a more advanced stage. In general, solitary papillary lesions are managed by transurethral surgery alone. CIS and recurrent disease are treated by transurethral surgery followed by intravesical therapy.

Intravesical therapies are used in two general contexts: as an adjuvant to a complete endoscopic resection to prevent recurrence or to eliminate disease that cannot be controlled by endoscopic resection alone. Intravesical treatments are advised for patients with diffuse CIS, recurrent disease, >40% involvement of the bladder surface by tumor, or T1 disease. The standard therapy, based on randomized comparisons, is Bacillus Calmette-Guérin (BCG) in six weekly instillations, often followed by maintenance administrations for ≥1 year. Other agents with activity include mitomycin C, interferon, and gemcitabine. The side effects of intravesical therapies include dysuria, urinary frequency, and, depending on the drug, myelosuppression or contact dermatitis. Rarely, intravesical BCG may produce a systemic illness associated with granulomatous infections in multiple sites requiring antituberculin therapy.

Following the endoscopic resection, patients are monitored for recurrence at 3-month intervals during the first year. Recurrence may develop anywhere along the urothelial tract, including the renal pelvis, ureter, or urethra. Persistent disease in the bladder and new tumors are treated with a second course of BCG or intravesical chemotherapy with valrubicin or gemcitabine. In some cases, cystectomy is recommended. Tumors in the ureter or renal pelvis are typically managed by resection during retrograde examination or, in some cases, by instillation through the renal pelvis. Prostatic urethral tumors may require cystoprostatectomy if the tumor cannot be resected completely.

MUSCLE-INVASIVE DISEASE

The treatment of a tumor that has invaded muscle can be separated into control of the primary tumor and systemic chemotherapy to treat micrometastatic disease. Radical cystectomy is the standard treatment in the United States, although in selected cases, a bladder-sparing approach is used. This approach includes complete endoscopic resection; partial cystectomy; or a combination of resection, systemic chemotherapy, and external beam radiation therapy. In some countries, external beam radiation therapy is considered standard. In the United States, it is generally limited to those patients deemed unfit for cystectomy, those with unresectable local disease, or as part of an experimental bladder-sparing approach.

Indications for cystectomy include muscle-invading tumors not suitable for segmental resection; non–muscle-invasive tumors unsuitable for conservative management (e.g., due to multicentric and frequent recurrences resistant to intravesical instillations); high-grade T1 tumors especially if associated with CIS; and bladder symptoms (e.g., frequency or hemorrhage) that impair quality of life.

Radical cystectomy is major surgery that requires appropriate preoperative evaluation and management. It involves removal of the bladder and pelvic lymph nodes and creation of a conduit or reservoir for urinary flow. Grossly abnormal lymph nodes are evaluated by frozen section. If metastases are confirmed, the procedure is often aborted. In males, radical cystectomy includes the removal of the prostate, seminal vesicles, and proximal urethra. Impotence is universal unless the nerves responsible for erectile function are preserved. In females, the procedure includes removal of the bladder, urethra, uterus, fallopian tubes, ovaries, anterior vaginal wall, and surrounding fascia.

Several options are frequently used for urinary diversion. Ileal conduits bring urine directly from the ureter to the abdominal wall. Some patients receive either a continent cutaneous reservoir constructed from detubularized bowel or an orthotopic neobladder. Approximately 25% of men receive a neobladder, leading to 85–90% continence during the day. Cutaneous reservoirs are drained by intermittent catheterization. Contraindications to a neobladder include renal insufficiency, an inability to self-catheterize, or CIS or an exophytic tumor in the urethra. Diffuse CIS in the bladder is a relative contraindication based on the risk of a urethral recurrence. Concurrent ulcerative colitis or Crohn’s disease may hinder the use of bowel.

A partial cystectomy may be considered when the disease is limited to the dome of the bladder, a ≥2 cm margin can be achieved, there is no associated CIS, and the bladder capacity is adequate after resection. This occurs in 5–10% of cases. Carcinomas in the ureter or in the renal pelvis are treated with nephroureterectomy with a bladder cuff to remove the tumor.

The probability of recurrence following surgery is based on pathologic stage, presence or absence of lymphatic or vascular invasion, and nodal spread. Among those whose cancers recur, the recurrence develops in a median of 1 year. Long-term outcomes vary by pathologic stage and histology (Table 114-1). The number of lymph nodes removed is also prognostic, whether or not the nodes contained tumor.

Chemotherapy (described below) has been shown to prolong the survival of patients with muscle-invasive disease when combined with definitive treatment of the bladder by radical cystectomy or radiation therapy. Presurgical (or neoadjuvant) chemotherapy has been the most thoroughly explored, and increases the cure rate by 5–15%, whereas postsurgical (adjuvant) chemotherapy has not been proven definitively beneficial. For the majority of patients, chemotherapy alone is inadequate to eradicate the disease. Use of neoadjuvant chemotherapy is increasing, although it still remains underused. Experimental studies are evaluating bladder preservation strategies by combining chemotherapy and radiation therapy in patients whose tumors were endoscopically removed.

METASTATIC DISEASE

The primary goal of metastatic disease treatment is to achieve complete remission with chemotherapy alone or with a combined-modality approach of chemotherapy followed by surgical resection of residual disease. One can define a goal in terms of cure or palliation on the basis of the probability of achieving a complete response to chemotherapy using prognostic factors, such as Karnofsky performance status (KPS) (<80%) and whether the pattern of spread is nodal or visceral (liver, lung, or bone). For those with zero, one, or two risk factors, the probability of complete remission is 38, 25, and 5%, respectively, and median survival is 33, 13.4, and 9.3 months, respectively. Patients who have low KPS or who have visceral disease or bone metastases rarely achieve long-term survival. The toxicities also vary as a function of risk, and treatment-related mortality rates are as high as 3–4% using some combinations in these poor-risk patient groups. For most patients, treatment is palliative, aimed at delaying or relieving cancer-related symptoms, because few patients experience durable complete remissions.

CHEMOTHERAPY

A number of chemotherapeutic drugs have activity as single agents; cisplatin, paclitaxel, and gemcitabine are considered most active. Standard therapy consists of two-, three-, or four-drug combinations. Overall response rates of >50% have been reported using combinations such as methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); gemcitabine and cisplatin (GC); or gemcitabine, paclitaxel, and cisplatin (GPC). MVAC was considered standard, but the toxicities of neutropenia and fever, mucositis, diminished renal and auditory function, and peripheral neuropathy led to the development of alternative regimens. At present, GC is used more commonly than MVAC based on the results of a comparative trial of MVAC versus GC that showed less neutropenia and fever and less mucositis for the GC regimen with similar response rates and median overall survival. Anemia and thrombocytopenia were more common with GC. GPC is not more effective than GC.

Chemotherapy has also been tested in the neoadjuvant and adjuvant settings. In a randomized trial, patients receiving three cycles of neoadjuvant MVAC followed by cystectomy had a significantly better median (6.2 years) and 5-year survival (57%) compared to cystectomy alone (median survival 3.8 years; 5-year survival 42%). Similar results were obtained in an international study of three cycles of cisplatin, methotrexate, and vinblastine (CMV) followed by either radical cystectomy or radiation therapy. The decision to administer adjuvant therapy is based on recurrence risk after cystectomy. Studies of adjuvant chemotherapy have been underpowered, and most closed for lack of accrual. One underpowered study using the GPC regimen suggested that adjuvant treatment improved survival, although many patients never received chemotherapy for metastases. Another underpowered study did not show a benefit for GC chemotherapy. Therefore, preoperative chemotherapy is preferred when medically appropriate. Indications for adjuvant chemotherapy in patients who did not receive neoadjuvant treatment include nodal disease, extravesical tumor extension, or vascular invasion in the resected specimen.

The management of bladder cancer is summarized in Table 114-2.

TREATMENT RENAL CELL CARCINOMA

LOCALIZED TUMOR

The standard management for stage I or II tumors and selected cases of stage III disease is radical or partial nephrectomy. A radical nephrectomy involves en bloc removal of Gerota’s fascia and its contents, including the kidney, the ipsilateral adrenal gland in some cases, and adjacent hilar lymph nodes. The role of a regional lymphadenectomy is controversial. Extension into the renal vein or inferior vena cava (stage III disease) does not preclude resection even if cardiopulmonary bypass is required. If the tumor is resected, half of these patients have prolonged survival.

Nephron-sparing approaches via open or laparoscopic surgery may be appropriate for patients who have only one kidney, depending on the size and location of the lesion. A nephron-sparing approach can also be used for patients with bilateral tumors. Partial nephrectomy techniques are applied electively to resect small masses for patients with a normal contralateral kidney. Adjuvant therapy following this surgery does not improve outcome, even in cases with a poor prognosis.

ADVANCED DISEASE

Surgery has a limited role for patients with metastatic disease. Long-term survival may occur in patients who relapse after nephrectomy in a solitary site that is removed. One indication for nephrectomy with metastases at initial presentation is to alleviate pain or hemorrhage of a primary tumor. Also, a cytoreductive nephrectomy before systemic treatment improves survival for carefully selected patients with stage IV tumors.

Metastatic renal cell carcinoma is refractory to chemotherapy. Cytokine therapy with IL-2 or interferon α (IFN-α) produces regression in 10–20% of patients. IL-2 produces durable complete remission in a small proportion of cases. In general, cytokine therapy is considered unsatisfactory for most patients.

The situation changed dramatically when two large-scale randomized trials established a role for antiangiogenic therapy, as predicted by the genetic studies. These trials separately evaluated two orally administered antiangiogenic agents, sorafenib and sunitinib, that inhibited receptor tyrosine kinase signaling through the VEGF and PDGF receptors. Both showed efficacy as second-line treatment following progression during cytokine treatment, resulting in approval by regulatory authorities for the treatment of advanced renal cell carcinoma. A randomized phase III trial comparing sunitinib to IFN-α showed superior efficacy for sunitinib with an acceptable safety profile. The trial resulted in a change in the standard first-line treatment from IFN to sunitinib. Sunitinib is usually given orally at a dose of 50 mg/d for 4 out of 6 weeks. Pazopanib and axitinib are newer agents of the same class. Pazopanib was compared to sunitinib in a randomized first-line phase III trial. Efficacy was similar, and there was less fatigue and skin toxicity, resulting in better quality of life scores for pazopanib compared with sunitinib. Temsirolimus and everolimus, inhibitors of the mammalian target of rapamycin (mTOR), show activity in patients with untreated poor-prognosis tumors and in sunitinib/sorafenib-refractory tumors. Patients benefit from the sequential use of axitinib and everolimus following progression to sunitinib or pazopanib first-line therapy.

The prognosis of metastatic renal cell carcinoma is variable. In one analysis, no prior nephrectomy, a KPS <80, low hemoglobin, high corrected calcium, and abnormal lactate dehydrogenase were poor prognostic factors. Patients with zero, one or two, and three or more factors had a median survival of 24, 12, and 5 months, respectively. These tumors may follow an unpredictable and protracted clinical course. It may be best to document progression before considering systemic treatment.

CLINICALLY LOCALIZED PROSTATE CANCER

Clinically localized prostate cancers are those that appear to be nonmetastatic after staging studies are performed. Patients with clinically localized disease are managed by radical prostatectomy, radiation therapy, or active surveillance. Choice of therapy requires the consideration of several factors: the presence of symptoms, the probability that the untreated tumor will adversely affect the quality or duration of survival and thus require treatment, and the probability that the tumor can be cured by single-modality therapy directed at the prostate or that it will require both local and systemic therapy to achieve cure.

Data from the literature do not provide clear evidence for the superiority of any one treatment relative to another. Comparison of outcomes of various forms of therapy is limited by the lack of prospective trials, referral bias, the experience of the treating teams, and differences in endpoints and cancer control definitions. Often, PSA relapse–free survival is used because an effect on metastatic progression or survival may not be apparent for years. After radical surgery to remove all prostate tissue, PSA should become undetectable in the blood within 6 weeks. If PSA remains or becomes detectable after radical prostatectomy, the patient is considered to have persistent disease. After radiation therapy, in contrast, PSA does not become undetectable because the remaining nonmalignant elements of the gland continue to produce PSA even if all cancer cells have been eliminated. Similarly, cancer control is not well defined for a patient managed by active surveillance because PSA levels will continue to rise in the absence of therapy. Other outcomes are time to objective progression (local or systemic), cancer-specific survival, and overall survival; however, these outcomes may take years to assess.

The more advanced the disease, the lower the probability of local control and the higher the probability of systemic relapse. More important is that within the categories of T1, T2, and T3 disease are cancers with a range of prognoses. Some T3 tumors are curable with therapy directed solely at the prostate, and some T1 lesions have a high probability of systemic relapse that requires the integration of local and systemic therapy to achieve cure. For T1c cancers in particular, stage alone is inadequate to predict outcome and select treatment; other factors must be considered.

Nomograms     To better assess risk and guide treatment selection, many groups have developed prognostic models or nomograms that use a combination of the initial clinical T stage, biopsy Gleason score, and baseline PSA. Some use discrete cut points (PSA <10 or ≥10 ng/mL; Gleason score of ≤6, 7, or ≥8); others employ nomograms that use PSA and Gleason score as continuous variables. More than 100 nomograms have been reported to predict the probability that a clinically significant prostate cancer is present, disease extent (organ-confined vs non–organ-confined, node-negative or -positive), or the probability of success of treatment for specific local therapies using pretreatment variables. Considerable controversy exists over what constitutes “high risk” based on a predicted probability of success or failure. In these situations, nomograms and predictive models can only go so far. Exactly what probability of success or failure would lead a physician to recommend and a patient to seek alternative approaches is controversial. As an example, it may be appropriate to recommend radical surgery for a younger patient with a low probability of cure. Nomograms are being refined continually to incorporate additional clinical parameters, biologic determinants, and year of treatment, which can also affect outcomes, making treatment decisions a dynamic process.

Treatment-Related Adverse Events     The frequency of adverse events varies by treatment modality and the experience of the treating team. For example, following radical prostatectomy, incontinence rates range from 2–47% and impotence rates range from 25–89%. Part of the variability relates to how the complication is defined and whether the patient or physician is reporting the event. The time of the assessment is also important. After surgery, impotence is immediate but may reverse over time, while with radiation therapy impotence is not immediate but may develop over time. Of greatest concern to patients are the effects on continence, sexual potency, and bowel function.

Radical Prostatectomy     The goal of radical prostatectomy is to excise the cancer completely with a clear margin, to maintain continence by preserving the external sphincter, and to preserve potency by sparing the autonomic nerves in the neurovascular bundle. The procedure is advised for patients with a life expectancy of 10 years or more and is performed via a retropubic or perineal approach or via a minimally invasive robotic-assisted or hand-held laparoscopic approach. Outcomes can be predicted using postoperative nomograms that consider pretreatment factors and the pathologic findings at surgery. PSA failure is usually defined as a value greater than 0.1 or 0.2 ng/mL. Specific criteria to guide the choice of one approach over another are lacking. Minimally invasive approaches offer the advantage of a shorter hospital stay and reduced blood loss. Rates of cancer control, recovery of continence, and recovery of erectile function are comparable between open and minimally invasive approaches. The individual surgeon rather than the surgical approach used is most important in determining outcomes after surgery.

Neoadjuvant hormonal therapy has also been explored in an attempt to improve the outcomes of surgery for high-risk patients, using a variety of definitions. The results of several large trials testing 3 or 8 months of androgen depletion before surgery showed that serum PSA levels decreased by 96%, prostate volumes decreased by 34%, and margin positivity rates decreased from 41% to 17%. Unfortunately, hormones did not produce an improvement in PSA relapse–free survival. Thus, neoadjuvant hormonal therapy is not recommended.

Factors associated with incontinence following radical prostatectomy include older age and urethral length, which impacts the ability to preserve the urethra beyond the apex and the distal sphincter. The skill and experience of the surgeon are also factors. Recovery of erectile function is associated with younger age, quality of erections before surgery, and the absence of damage to the neurovascular bundles. In general, erectile function begins to return about 6 months after surgery if both neurovascular bundles are preserved. Potency is reduced by half if at least one neurovascular bundle is sacrificed. Overall, with the availability of drugs such as phosphodiesterase-5 (PDE5) inhibitors, intraurethral inserts of alprostadil, and intracavernosal injections of vasodilators, many patients recover satisfactory sexual function.

Radiation Therapy     Radiation therapy is given by external beam, by radioactive sources implanted into the gland, or by a combination of the two techniques.

EXTERNAL-BEAM RADIATION THERAPY     Contemporary external-beam radiation therapy requires three-dimensional conformal treatment plans to maximize the dose to the prostate and to minimize the exposure of the surrounding normal tissue. Intensity-modulated radiation therapy (IMRT) permits shaping of the dose and allows the delivery of higher doses to the prostate and a further reduction in normal tissue exposure than three-dimensional conformal treatment alone. These advances have enabled the safe administration of doses >80 Gy and resulted in higher local control rates and fewer side effects.

Cancer control after radiation therapy has been defined by various criteria, including a decline in PSA to <0.5 or 1 ng/mL, “nonrising” PSA values, and a negative biopsy of the prostate 2 years after completion of treatment. The current standard definition of biochemical failure (the Phoenix definition) is a rise in PSA by ≥2 ng/mL higher than the lowest PSA achieved. The date of failure is “at call” and not backdated.

Radiation dose is critical to the eradication of prostate cancer. In a representative study, a PSA nadir of <1.0 ng/mL was achieved in 90% of patients receiving 75.6 or 81.0 Gy versus 76% and 56% of those receiving 70.2 and 64.8 Gy, respectively. Positive biopsy rates at 2.5 years were 4% for those treated with 81 Gy versus 27% and 36% for those receiving 75.6 and 70.2 Gy, respectively.

Overall, radiation therapy is associated with a higher frequency of bowel complications (mainly diarrhea and proctitis) than surgery. The frequency relates directly to the volume of the anterior rectal wall receiving full-dose treatment. In one series, grade 3 rectal or urinary toxicities were seen in 2.1% of patients who received a median dose of 75.6 Gy, whereas grade 3 urethral strictures requiring dilatation developed in 1% of cases, all of whom had undergone a transurethral resection of the prostate (TURP). Pooled data show that the frequency of grade 3 and 4 toxicities is 6.9% and 3.5%, respectively, for patients who received >70 Gy. The frequency of erectile dysfunction is related to the age of the patient, the quality of erections pretreatment, the dose administered, and the time of assessment. Postradiation erectile dysfunction is related to a disruption of the vascular supply and not the nerve fibers.

Neoadjuvant hormone therapy before radiation therapy has the aim of decreasing the size of the prostate and, consequently, reducing the exposure of normal tissues to full-dose radiation, increasing local control rates, and decreasing the rate of systemic failure. Short-term hormone therapy can reduce toxicities and improve local control rates, but long-term treatment (2–3 years) is needed to prolong the time to PSA failure and lower the risk of metastatic disease in men with high-risk cancers. The impact on survival has been less clear.

BRACHYTHERAPY     Brachytherapy is the direct implantation of radioactive sources (seeds) into the prostate. It is based on the principle that the deposition of radiation energy in tissues decreases as a function of the square of the distance from the source (Chap. 103e). The goal is to deliver intensive irradiation to the prostate, minimizing the exposure of the surrounding tissues. The current standard technique achieves a more homogeneous dose distribution by placing seeds according to a customized template based on imaging assessment of the cancer and computer-optimized dosimetry. The implantation is performed transperineally as an outpatient procedure with real-time imaging.

Improvements in brachytherapy techniques have resulted in fewer complications and a marked reduction in local failure rates. In a series of 197 patients followed for a median of 3 years, 5-year actuarial PSA relapse–free survival for patients with pretherapy PSA levels of 0–4, 4–10, and >10 ng/mL were 98%, 90%, and 89%, respectively. In a separate report of 201 patients who underwent posttreatment biopsies, 80% were negative, 17% were indeterminate, and 3% were positive. The results did not change with longer follow-up. Nevertheless, many physicians feel that implantation is best reserved for patients with good or intermediate prognostic features.

Brachytherapy is well tolerated, although most patients experience urinary frequency and urgency that can persist for several months. Incontinence has been seen in 2–4% of cases. Higher complication rates are observed in patients who have undergone a prior TURP, whereas those with obstructive symptoms at baseline are at a higher risk for retention and persistent voiding symptoms. Proctitis has been reported in <2% of patients.

Active Surveillance     Although prostate cancer is the most common form of cancer affecting men in the United States, patients are being diagnosed earlier and more frequently present with early-stage disease. Active surveillance, described previously as watchful waiting or deferred therapy, is the policy of monitoring the illness at fixed intervals with DREs, PSA measurements, and repeat prostate biopsies as indicated until histopathologic or serologic changes correlative of progression warrant treatment with curative intent. It evolved from studies that evaluated predominantly elderly men with well-differentiated tumors who demonstrated no clinically significant progression for protracted periods, recognition of the contrast between incidence and disease-specific mortality, the high prevalence of autopsy cancers, and an effort to reduce overtreatment. A recent screening study estimated that between 50–100 men with low-risk disease would need to be treated to prevent one prostate cancer–specific death.

Arguing against active surveillance are the results of a Swedish randomized trial of radical prostatectomy versus active surveillance. With a median follow-up of 6.2 years, men treated by radical surgery had a lower risk of prostate cancer death relative to active surveillance patients (4.6% vs 8.9%) and a lower risk of metastatic progression (hazard ratio 0.63). Case selection is critical, and determining clinical parameters predictive of cancer aggressiveness that can be used to reliably select men most likely to benefit from active surveillance is an area of intense study. In one prostatectomy series, it was estimated that 10–15% of those treated had “insignificant” disease. One set of criteria includes men with clinical T1c tumors that are biopsy Gleason grade 6 or less involving three or fewer cores, each of them having less than 50% involvement by tumor and a PSA density of less than 0.15.

Concerns about active surveillance include the limited ability to predict pathologic findings by needle biopsy even when multiple cores are obtained, the recognized multifocality of the disease, and the possibility of a missed opportunity to cure the disease. Nomograms to help predict which patients can safely be managed by active surveillance continue to be refined, and as their predictive accuracy improves, it can be anticipated that more patients will be candidates.

RISING PSA AFTER DEFINITIVE LOCAL THERAPY

This term is applied to a group of patients in whom the sole manifestation of disease is a rising PSA after surgery and/or radiation therapy. By definition, there is no evidence of disease on an imaging study. For these patients, the central issue is whether the rise in PSA results from persistent disease in the primary site, systemic disease, or both. In theory, disease in the primary site may still be curable by additional local treatment.

The decision to recommend radiation therapy after prostatectomy is guided by the pathologic findings at surgery, because imaging studies such as CT and bone scan are typically uninformative. Some recommend a choline-11 positron emission tomography (PET) scan, but availability in the United States is limited. Others recommend that a biopsy of the urethrovesical anastomosis be obtained before considering radiation, whereas others treat empirically based on risk. Factors that predict for response to salvage radiation therapy are a positive surgical margin, lower Gleason score in the radical prostatectomy specimen, long interval from surgery to PSA failure, slow PSA doubling time, absence of disease in the lymph nodes, and a low (<0.5–1 ng/mL) PSA value at the time of radiation treatment. Radiation therapy is generally not recommended if the PSA was persistently elevated after surgery, which usually indicates that the disease has spread outside of the area of the prostate bed and is unlikely to be controlled with radiation therapy. As is the case for other disease states, nomograms to predict the likelihood of success are available.

For patients with a rising PSA after radiation therapy, salvage local therapy can be considered if the disease was “curable” at the time of diagnosis, if persistent disease has been documented by a biopsy of the prostate, and if no metastatic disease is seen on imaging studies. Unfortunately, case selection is poorly defined in most series, and morbidities are significant. Options include salvage radical prostatectomy, salvage cryotherapy, salvage radiation therapy, and salvage irreversible electroporation.

The rise in PSA after surgery or radiation therapy may indicate subclinical or micrometastatic disease with or without local recurrence. In these cases, the need for treatment depends, in part, on the estimated probability that the patient will develop clinically detectable metastatic disease on a scan and in what time frame. That immediate therapy is not always required was shown in a series where patients who developed a biochemical recurrence after radical prostatectomy received no systemic therapy until metastatic disease was documented. Overall, the median time to metastatic progression by imaging was 8 years, and 63% of the patients with rising PSA values remained free of metastases at 5 years. Factors associated with progression included the Gleason score of the radical prostatectomy specimen, time to recurrence, and PSA doubling time. For those with Gleason grade ≥8, the probability of metastatic progression was 37%, 51%, and 71% at 3, 5, and 7 years, respectively. If the time to recurrence was <2 years and PSA doubling time was long (>10 months), the proportions with metastatic disease at the same time intervals were 23%, 32%, and 53%, versus 47%, 69%, and 79% if the doubling time was short (<10 months). PSA doubling times are also prognostic for survival. In one series, all patients who succumbed to disease had PSA doubling times of 3 months or less.

Most physicians advise treatment if the PSA doubling time is 12 months or less. A difficulty with predicting the risk of metastatic spread, symptoms, or death from disease in the rising PSA state is that most patients receive some form of therapy before the development of metastases. Nevertheless, predictive models continue to be refined.

METASTATIC DISEASE: NONCASTRATE

The state of noncastrate metastatic prostate cancer includes men with metastases visible on an imaging study and noncastrate levels of testosterone (>150 ng/dL). The patient may be newly diagnosed or have a recurrence after treatment for localized disease. Symptoms of metastatic disease include pain from osseous spread, although many patients are asymptomatic despite extensive spread. Less common are symptoms related to marrow compromise (myelophthisis), spinal cord compression, or a coagulopathy.

Standard treatment is to deplete/lower androgens by medical or surgical means and/or to block androgen binding to the AR with antiandrogens. More than 90% of male hormones originate in the testes; <10% are synthesized in the adrenal gland. Surgical orchiectomy is the “gold standard” but is rarely used due to the availability of effective medical therapies and the more widespread use of hormones on an intermittent basis by which patients are treated for defined periods of time, following which the treatments are intentionally discontinued (discussed further below) (Fig. 115-3).

FIGURE 115-3   Sites of action of different hormone therapies. ACTH, adrenocorticotropic hormone; AR, androgen receptor; ARE, androgen-response element; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulphate; DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

Testosterone-Lowering Agents     Medical therapies that lower testosterone levels include the gonadotropin-releasing hormone (GnRH) agonists/antagonists, 17,20-lyase inhibitors, CYP17 inhibitors, estrogens, and progestational agents. Of these, GnRH analogues such as leuprolide acetate and goserelin acetate initially produce a rise in luteinizing hormone and follicle-stimulating hormone, followed by a downregulation of receptors in the pituitary gland, which effects a chemical castration. They were approved on the basis of randomized comparisons showing an improved safety profile (specifically, reduced cardiovascular toxicities) relative to diethylstilbestrol (DES), with equivalent potency. The initial rise in testosterone may result in a clinical flare of the disease. As such, these agents are relatively contraindicated in men with significant obstructive symptoms, cancer-related pain, or spinal cord compromise. GnRH antagonists such as degarelix achieve castrate levels of testosterone within 48 h without the initial rise in serum testosterone and do not cause a flare in the disease. Estrogens such as DES are rarely used due to the risk of vascular complications such as fluid retention, phlebitis, embolic events, and stroke. Progestational agents alone are less efficacious.

Agents that lower testosterone are associated with an androgen-depletion syndrome that includes hot flushes, weakness, fatigue, loss of libido, impotence, sarcopenia, anemia, change in personality, and depression. Changes in lipids, obesity, and insulin resistance, along with an increased risk of diabetes and cardiovascular disease, can also occur, mimicking the metabolic syndrome. A decrease in bone density may also result that worsens over time and results in an increased risk of clinical fractures. This is a particular concern, often underappreciated, for men with preexisting osteopenia secondary to hypogonadism or glucocorticoid or alcohol use. Baseline fracture risk can be assessed using the Fracture Risk Assessment Scale (FRAX), and to minimize fracture risk, patients are advised to take calcium and vitamin D supplementation, along with a bisphosphonate or the RANK ligand inhibitor, denosumab.

Antiandrogens     First-generation nonsteroidal antiandrogens such as flutamide, bicalutamide, and nilutamide block ligand binding to the AR and were initially approved to block the disease flare that may occur with the rise in serum testosterone associated with GnRH agonist therapy. When antiandrogens are given alone, testosterone levels typically increase above baseline, but relative to testosterone-lowering therapies, they cause fewer hot flushes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss. Gynecomastia remains a significant problem but can be alleviated in part by tamoxifen.

Most reported randomized trials suggest that the cancer-specific outcomes are inferior when antiandrogens are used alone. Bicalutamide, even at 150 mg (three times the recommended dose), was associated with a shorter time to progression and inferior survival compared to surgical castration for patients with established metastatic disease. Nevertheless, some men may accept the trade-off of a potentially inferior cancer outcome for an improved quality of life.

Combined androgen blockade, the administration of an antiandrogen plus a GnRH analogue or surgical orchiectomy, and triple androgen blockade, which includes the addition of a 5ARI, have not been shown to be superior to androgen depletion monotherapies and are no longer recommended. In practice, most patients who are treated with a GnRH agonist receive an antiandrogen for the first 2–4 weeks of treatment to protect against the flare.

Intermittent Androgen Deprivation Therapy (IADT)     The use of hormones in an “on-and-off” approach was initially proposed as a way to prevent the selection of cells that are resistant to androgen depletion and to reduce side effects. The hypothesis is that by allowing endogenous testosterone levels to rise, the cells that survive androgen depletion will induce a normal differentiation pathway. It is postulated that by allowing the surviving cells to proliferate in the presence of androgen, sensitivity to subsequent androgen depletion will be retained and the chance of developing a castration-resistant state will be reduced. Applied in the clinic, androgen depletion is continued for 2–6 months beyond the point of maximal response. Once treatment is stopped, endogenous testosterone levels increase, and the symptoms associated with hormone treatment abate. PSA levels also begin to rise, and at some level, treatment is restarted. With this approach, multiple cycles of regression and proliferation have been documented in individual patients. It is unknown whether the intermittent approach increases, decreases, or does not change the overall duration of sensitivity to androgen depletion. The approach is safe, but long-term data are needed to assess the course in men with low PSA levels. A randomized trial showed similar survival time between patients treated with intermittent versus continuous treatment, with a slightly higher risk of prostate cancer–specific mortality in the intermittent group, and higher cardiovascular mortality in patients on continuous therapy. The intermittent therapy was better tolerated.

Outcomes of Androgen Depletion     The anti–prostate cancer effects of the various androgen depletion/blockade strategies are similar, and the outcomes predictable: an initial response, then a period of stability in which tumor cells are dormant and nonproliferative, followed after a variable period of time by a rise in PSA and tumor regrowth as a castration-resistant lesion that for most men is invariably lethal. Androgen depletion is not curative because cells that survive castration are present when the disease is first diagnosed. Considered by disease manifestation, PSA levels return to normal in 60–70% of cases, and measurable lesions regress in about 50%; improvements in bone scan occur in 25% of cases, but the majority of cases remain stable. The duration of response and survival is inversely proportional to disease extent at the time androgen depletion is first started, whereas the degree of PSA decline at 6 months has been shown to be prognostic. In a large-scale trial, PSA nadir proved prognostic.

An active question is whether hormones should be given in the adjuvant setting after surgery or radiation treatment of the primary tumor or whether to wait until PSA recurrence, metastatic disease, or symptoms are documented. Trials in support of early therapy have often been underpowered relative to the reported benefit or have been criticized on methodologic grounds. One trial showing a survival benefit for patients treated with radiation therapy and 3 years of androgen depletion, relative to radiation alone, was criticized for the poor outcomes of the control group. Another showing a survival benefit for patients with positive lymph nodes who were randomized to immediate medical or surgical castration compared to observation (p = .02) was criticized because the confidence intervals around the 5- and 8-year survival distributions for the two groups overlapped. A large randomized study comparing early to late hormone treatment (orchiectomy or GnRH analogue) in patients with locally advanced or asymptomatic metastatic disease showed that patients treated early were less likely to progress from M0 to M1 disease, to develop pain, and to die of prostate cancer. This trial was criticized because therapy was delayed “too long” in the late-treatment group. Noteworthy is that the American Society of Clinical Oncology Guidelines recommend deferring treatment until the disease has recurred and the prognosis has been reassessed. These guidelines do not support immediate therapy.

METASTATIC DISEASE: CASTRATE

Castration-resistant prostate cancer (CRPC) is defined as disease that progresses despite androgen suppression by medical or surgical therapies where the measured levels of testosterone are 50 ng/mL or lower. The rise in PSA indicates continued signaling through the AR signaling axis, the result of a series of oncogenic changes that include overexpression of androgen biosynthetic enzymes that can lead to increased intratumoral androgens, and overexpression of the receptor itself that enables signaling to occur even in the setting of low levels of androgen. The majority of CRPC cases are not “hormone-refractory,” and considering them as such can deny patients safe and effective treatment. CRPC can manifest in many ways. For some, it is a rise in PSA with no change in radiographs and no new symptoms. In others, it is a rising PSA and progression in bone with or without symptoms of disease. Still others will show soft tissue disease with or without osseous metastases, and others have visceral spread.

For the individual patient, it is first essential to ensure that a castrate status be documented. Patients receiving an antiandrogen alone, whose serum testosterone levels are elevated, should be treated first with a GnRH analogue or orchiectomy and observed for response. Patients on an antiandrogen in combination with a GnRH analogue should have the antiandrogen discontinued, because approximately 20% will respond to the selective discontinuation of the antiandrogen.

Chemotherapy and New Agents     Through 2009, docetaxel was the only systemic therapy proven to prolong life. As a single agent, the drug produced PSA declines in 50% of patients, measurable disease regression in 25%, and improvement in both preexisting pain and prevention of future cancer-related pain. Since then, six agents with diverse mechanisms of action that target the tumor itself or other aspects of the metastatic process have been proven to prolong life and were FDA approved. The first was sipuleucel-T, the first biologic approach shown to prolong life in which antigen-presenting cells are activated ex vivo, pulsed with antigen, and reinfused. The second, cabazitaxel, a non–cross-resistant taxane, was shown to be superior to mitoxantrone in the post-docetaxel setting. This was followed by the CYP17 inhibitor abiraterone acetate, which lowers androgen levels in the tumor, adrenal glands, and testis, and the next-generation antiandrogen enzalutamide, which not only has a higher binding affinity to the AR relative to first-generation compounds, but uniquely inhibits nuclear location and DNA binding of the receptor complex. Both abiraterone acetate and enzalutamide were first approved for postchemotherapy treated patients on the basis of placebo-controlled phase III trials—a further indication that these tumors are not uniformly hormone-refractory. The indication for abiraterone acetate was later expanded to the prechemotherapy setting, based on a second trial using a co-primary endpoint of radiographic progression–free survival and overall survival. Similar results were seen with enzalutamide, for which an expanded indication is also anticipated. Alpharadin (radium-223 chloride), an alpha-emitting bone-seeking radioisotope, has been shown to prolong life in patients with symptoms related to osseous disease. The alpharadin result validated the bone microenvironment as a therapeutic target independent of direct effects on the tumor itself, as no declines in PSA were observed in the trial. Notable is that in addition to a survival benefit, the drug also reduced the development of significant skeletal events.

Other bone-targeted agents, such as the bisphosphonates and the RANK ligand inhibitor denosumab, protect against bone loss associated with androgen depletion and also reduce skeletal-related events by targeting bone osteoclasts. In one trial, denosumab was shown to be superior to zoledronic acid with respect to skeletal-related events, but had a slightly higher frequency of osteonecrosis of the jaw.

In clinical practice, most men seek to avoid chemotherapy and are first treated with a biologic agent and/or newer hormonal agent approved for this indication. It is crucial to the management of the individual patient to define therapeutic objectives before initiating treatment, as there are defined standards of care for different disease manifestations. For example, sipuleucel-T is not indicated for patients with symptoms or visceral disease because the effects on the disease occur late. Similarly, alpharadin is not indicated for patients with disease that is predominantly in soft tissue or who have osseous disease that is not causing symptoms.

Pain Management     Management of pain secondary to osseous metastatic disease is a critical part of therapy. Optimal palliation requires assessing whether the symptoms are from metastases that threaten or that are already affecting the spinal cord, the cauda equina, or the base of the skull, which are best treated with external-beam radiation, as are single sites of pain. Neurologic symptoms require emergency evaluation because loss of function may be permanent if not addressed quickly. Because the disease is often diffuse, palliation at one site is often followed by the emergence of symptoms in a separate site that had not received radiation. In these cases, bone-seeking radioisotopes such as alpharadin or the beta emitter ¹⁵³Sm-EDTMP (Quadramet) can be considered in addition to abiraterone acetate, docetaxel, and mitoxantrone, each of which is formally approved for the palliation of pain due to prostate cancer metastases.

TREATMENT BENIGN PROSTATIC HYPERTROPHY

The symptoms are generally measured using a validated, reproducible index that is designed to determine disease severity and response to therapy—the AUA’s Symptom Index (AUASI), also adopted as the International Prostate Symptom Score (IPSS) (Table 115–2). Serial AUASI is particularly useful in following patients as they are treated with various forms of therapy. Asymptomatic patients do not require treatment regardless of the size of the gland, whereas patients with an inability to urinate, gross hematuria, recurrent infection, or bladder stones may require surgery. In patients with symptoms, uroflowmetry can identify those with normal flow rates who are unlikely to benefit from treatment, and bladder ultrasound can identify those with high postvoid residuals who may need intervention. Pressure-flow (urodynamic) studies detect primary bladder dysfunction. Cystoscopy is recommended if hematuria is documented and to assess the urinary outflow tract before surgery. Imaging of the upper tracts is advised for patients with hematuria, a history of calculi, or prior urinary tract problems.

Symptomatic relief is the most common reason men seek treatment for BPH, and therefore the goal of therapy for BPH is usually relief of these symptoms. Alpha-adrenergic receptor antagonists are thought to treat the dynamic aspect of BPH by reducing sympathetic tone of the bladder outlet, thereby decreasing resistance and improving urinary flow. 5ARIs are thought to treat the static aspect of BPH by reducing prostate volume and having a similar, albeit delayed effect. They have also proven to be beneficial in the prevention of BPH progression, as measured by prostate volume, the risk of developing acute urinary retention, and the risk of having BPH-related surgery. The use of an alpha-adrenergic receptor antagonist and a 5ARI as combination therapy seeks to provide symptomatic relief while preventing progression of BPH.

Another class of medications that has shown improvement in lower urinary tract symptoms secondary to BPH is PDE5 inhibitors, used currently in the treatment of erectile dysfunction. All three of the PDE5 inhibitors available in the United States, sildenafil, vardenafil, and tadalafil, appear to be effective in the treatment of symptoms secondary to BPH. The use of PDE5 inhibitors is not without controversy, however, given the fact that short-acting phosphodiesterase inhibitors such as sildenafil need to be dosed separately from alpha blockers such as tamsulosin because of potential hypotensive effects. Newer classes of pharmacologic agents have been used to treat symptoms secondary to BPH. Symptoms due to BPH often coexist with symptoms due to overactive bladder, and the most common pharmacologic agents for the treatment of overactive bladder symptoms are anticholinergics. This has led to multiple studies evaluating the efficacy of anticholinergics for the treatment of lower urinary tract symptoms secondary to BPH. Surgical therapy is now considered second-line therapy and is usually reserved for patients after a trial of medical therapy. The goal of surgical therapy is to reduce the size of the prostate, effectively reducing resistance to urine flow.

Surgical approaches include TURP, transurethral incision, or removal of the gland via a retropubic, suprapubic, or perineal approach. Also used are transurethral ultrasound-guided laser-induced prostatectomy (TULIP), stents, and hyperthermia.

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