Management of Genitourinary Cancers in Men

Genitourinary cancers account for a substantial proportion of the cancer burden, especially in men. Prostate cancer is the most common cancer in men in North America, Europe, and parts of Africa; testicular cancer is the most common tumor in men between the ages of 15 and 35 years. Bladder cancer demonstrates a strong male predominance, and renal cell carcinoma is more common in men. Responsibility for management resides largely with the urologic oncology team, but the primary care physician needs to be familiar with key treatment options and their consequences in order to help patients make informed choices about therapy. This is especially important with regard to prostate cancer, where options range from watchful waiting to attempting curative treatment. Other tasks with regard to these cancers include screening and case finding (see Chapters 126 and 128), initial workup (see Chapters 129 and 131), support, and monitoring of patients with advanced disease. The primary care physician and medical home team are well positioned to provide these services.

PROSTATE CANCER

Epidemiology and Risk Factors (1)

Carcinoma of the prostate has become the leading cancer in men in the United States, where incidence rose during the years after the introduction of prostate-specific antigen (PSA) screening. This was in part because of the detection of prevalence cases during the PSA era, but it may also have been due to increases in known and unknown risk factors. Risk for the individual man increases with advancing age; incidence and mortality rise sharply after age 50 years. By the ninth decade, more than 70% of men have at least microscopic evidence of prostate carcinoma at autopsy. Therefore, the aging of the population explains part of the increase in incidence. International age-standardized incidence rates vary dramatically from less than 10 per 100,000 men in parts of China and India to more than 100 per 100,000 in the United States, where African Americans face a 40% higher risk than do Whites. In addition to age and ethnic background, family history is an established risk factor; risk doubles among first-degree relatives. Candidate genes conferring prostate cancer susceptibility have been identified but account for a very small portion of genetic susceptibility. Evidence is mounting for possible pathogenetic roles for insulin growth factor, lycopene, zinc, selenium, and dietary fat. No association with benign prostatic hyperplasia or sexual activity has been found. Smoking, alcohol, vasectomy, and low levels of physical activity have been largely excluded as risk factors. Approximately 30,000 US men die annually from the disease, making it the second leading cause of cancer death among men in the United States. The lifetime risk for a 50-year-old man of developing clinical cancer is estimated to be 10%; the lifetime risk of dying from the cancer is 3%.

Pathophysiology, Clinical Presentation, and Course (2, 3, 4, 5 and 6)

Most of the prostate cancers found at autopsy are incidental and have no clinical import; these are small in volume, well differentiated, diploid, and noninvasive, and they originate from the transition zone. Clinically important lesions are larger, less well differentiated, invasive, and nondiploid, and they usually originate from the peripheral zone. What converts microscopic pathology to clinically evident disease remains a mystery. It is also unclear what percentage of all prostate cancers become clinically important. When clinically evident tumor arises in the periphery of the gland (posterior lobe or lamella), detection by digital examination is possible in many instances. However, fewer than 30% of new cases are now discovered by this means. Most patients now present with nonpalpable, asymptomatic lesions detected by PSA screening followed by prostate ultrasonography and biopsy (see Chapter 126). Other men present with nonspecific symptoms of urethral obstruction (see Chapter 134). Renal insufficiency resulting from prolonged urinary tract obstruction ensues in a small but important fraction. Another important minority of patients have bone pain or other manifestations of metastatic disease as the presenting complaint. Osteoblastic metastases predominate; they can be painful and are the major cause of morbidity. Metastasis to regional lymph nodes is common and usually asymptomatic.

Prognosis is a function of clinical stage at the time of diagnosis, PSA level, and histologic grade of the tumor. Because of the advanced age of this patient population, many men die from other conditions.

Prostate cancers are hormonally sensitive, responsive to androgenic stimulation. Androgen ablation represents an important therapeutic option, but overexpression and mutation of the androgen receptor (as seen in castration-resistant metastatic disease) can blunt responsiveness to such treatment.

Clinical Staging, Tumor Grade, and Risk Stratification (6, 7, 8, 9, 10 and 11)

Determining Extent of Local Disease

The clinical assessment begins with careful palpation of the prostate with a digital rectal examination (DRE). The urologist repeats the DRE and performs a transurethral ultrasound (TRUS) examination. Emphasis is on establishing tumor size and any spread into the surrounding soft tissue. Based on these findings, the tumor is classified as follows:

T1 if it is microscopic and neither palpable nor visible on TRUS (T1a if the tumor is an incidental histologic finding in ≤5% or less of resected tissue, T1b if it is an incidental finding in >5% of resected tissue, and T1c if it is identified by needle biopsy for elevated PSA)
T2 if it is palpable and appears to be confined to the gland (T2a, ≤50% of one lobe; T2b, >50% of one lobe; T2c, both lobes)
T3 if it is protruding beyond the capsule or into the seminal vesicles
T4 if it is fixed and extending well beyond the prostate

It must be kept in mind that the combination of DRE and TRUS understages many patients believed to have disease limited to the prostate. That is, a significant proportion of patients with clinical T1 and T2 tumors are found to have more extensive disease at surgery. Historically, as many as 50% of patients were found to have more extensive disease; in contemporary series, that number is closer to 25%. Because the PSA concentration correlates with tumor volume, higher levels—for
example, greater than 15 ng/mL (Hybritech assay)—suggest extension through the capsule or into the seminal vesicles.

Transrectal ultrasonography and magnetic resonance imaging (MRI) are often used to stage local disease, but the accuracy of such imaging studies has been disappointing. Newer adaptations of MRI are being developed and may prove better. Computed tomography (CT) is neither sensitive nor specific enough to be very useful. Recently, urologists have relied increasingly on tables and nomograms derived from predictive models to estimate the likelihood of organ confinement and the opportunity to affect cure with prostatectomy or, in the case of a nomogram for low-volume/low-grade cancer, to select patients with a high likelihood of a good outcome with active surveillance rather than treatment. These models usually rely on clinical stage as just described, PSA level, and histologic grade in the form of a Gleason score (see later discussion).

Histologic Grading

Histologic grading is highly predictive of outcome. Biopsy specimens are scored using the Gleason system on a scale of 2 to 10. (Two separate areas are graded on a 1-to-5 scale, and those scores are added.) The more disrupted and undifferentiated the normal glandular architecture, the higher is the grade of tumor and the poorer is the prognosis.

Retrospective cohort studies indicate that men who have a Gleason score in the range of 2 to 4 rarely die from prostate cancer in the ensuing 15 years, regardless of age at diagnosis. For men with a Gleason score in the range of 8 to 10, the prognosis is much worse, with 15-year case fatality rates of 80% or more except for the oldest men, who face a higher risk for death from other causes because of their age. Cancers with a Gleason score of 5 confer a prognosis similar to that for cancers with a Gleason score of 2 to 4. Gleason 7 scores are similar to Gleason 8 to 10. The prognosis for men with a Gleason 6 score is intermediate.

Risk Stratification and Workup for Metastatic Disease.

Being a very heterogeneous condition, prostate cancer requires risk stratification to help guide evaluation and management. A composite scoring system based on stage, Gleason score, and PSA level has been constructed by D’Amico and colleagues to help risk-stratify patients in research studies, designating prostate cancers as low, intermediate, or high risk:

Low risk: clinical T stage T1c, T2a; PSA level less than or equal to 10 ng/mL; Gleason score of less than or equal to 6

Intermediate risk: clinical stage T2b, PSA greater than 10 and less than or equal to 20 ng/mL, Gleason score 7

High risk: stage T2c disease, PSA greater than 20 ng/mL, Gleason score of ≥8

Such risk stratification may also help clinically in the choice of therapy as well as in determining the need for metastatic workup. If the PSA concentration is greater than 20 ng/mL, distant metastasis to bone is likely and a bone scan should be ordered. A PSA level of less than 10 ng/mL, or even less than 20 ng/mL, greatly reduces the likelihood of bony involvement and obviates the need for bone scan in a man with a tumor that appears to be confined to the gland, especially if the Gleason score is less than 7. CT of the pelvis and abdomen is often ordered to assess pelvic and retroperitoneal lymph node involvement noninvasively, but sensitivity and specificity are poor. A false-positive result under these circumstances confers a high cost if it eliminates a preferred treatment option. CTs should be reserved for men with high PSA levels or Gleason scores greater than 6. Pelvic lymphadenectomy is the only definitive means of establishing nodal disease, but its morbidity is substantial. It is typically performed when radical prostatectomy (RP) is being considered for cure.

Principles of Management (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 and 59)

The selection of a treatment modality depends heavily on clinical stage and on Gleason score. Because prostate tumors generally grow very slowly, patient age, comorbidity, and resulting life expectancy are important determinants, especially for moderately differentiated tumors.

Clinically Localized Disease

Patients with early, low-risk disease (i.e., clinical stage T1c, T2a; PSA level ≤10 ng/mL; Gleason score of ≤6)—common among those with cancers found by screening—have a very favorable prognosis (estimated 10-year survival over 97%) without treatment, suggesting observation may be a reasonable option. On the other hand, patients with T1 and T2 tumors also do well with immediate treatment, experiencing cure rates of over 90% with either RP or radiation therapy. The two major randomized trials that examine best approach to early-stage disease by comparing observation with RP (Prostate Cancer Intervention Versus Observation Trial [PIVOT] and Scandinavian Prostate Cancer Group Study 4) have produced conflicting results, with one showing no benefit and the other finding a survival benefit (25% reduction in all-cause mortality, 6.6% absolution reduction for men under the age of 65 years). In both studies, persons with higher-risk disease (e.g., PSA >20, Gleason score >7) experienced better outcomes with immediate surgery. Differences in study populations are likely to account for the differences in overall outcomes, with the no-observed-benefit study much richer in persons with disease detected only by PSA screening (50% with stage T1c disease vs. 5% in the other).

Observational Management—Watchful Waiting and Active Surveillance.

Such findings of favorable prognosis for low-risk disease suggest that patients with early-stage prostate cancer have a choice of approaches to care. At present, about 10% choose to forgo immediate curative therapy in favor of expectant management, viewing the potentially adverse consequences of treatment (e.g., urinary incontinence, impotence—see later discussion) as more of a threat to their well-being than the disease itself.

Options for observational management range from watchful waiting (taking action only if symptoms develop—a palliative strategy) to active surveillance (periodic DRE, PSA testing, prostate imaging, prostate biopsy followed by surgery or radiation for cure if findings indicative of disease progression). Among those who choose observational management, watchful waiting is typically chosen by men with a shorter life expectancy; patients with 10 or more years of life expectancy have some risk for disease progression (including change in Gleason grade) that would affect management decisions. The optimum protocol(s) for active surveillance has yet to be defined and studied for their impact on outcomes compared to immediate curative treatment, but cost-effectiveness analysis suggests that watchful waiting and active surveillance are reasonable options in low-risk, early-stage disease.

Radiation Therapy.

Most radiation oncologists consider radiation to be the standard of care for men with clinically localized disease. Radiation may be delivered as external beam (conformal) radiation or as interstitial implant therapy, termed brachytherapy. Compared with surgery, external beam radiation therapy offers similar rates of cure for early-stage disease (T1 to T2) with relatively low morbidity; however, exposure of nearby nonprostate tissue (rectum, femoral head, nerve) remains a source of adverse effects. Bowel problems include temporary diarrhea, tenesmus, and rectal bleeding from radiation colitis; most resolve with time, but some symptoms may persist. Hip fractures can ensue from the radiation exposure. The risk of erectile dysfunction is lower with radiation than with surgery, although it increases
with extended follow-up and may approximate the rates associated with surgery in the longer term. Urinary incontinence is rare following radiation therapy compared with surgery.

Intensity-modulated radiation therapy (IMRT) and proton beam therapy represent advances in technology that improve the accuracy of externally delivered ionizing radiation, allowing delivery of higher doses to the prostate while reducing exposure of surrounding tissues. Although without evidence of improved survival and 50 per cent more expensive than the previous standard of 3-dimensional conformal approach it has largely replaced, IMRT is now almost universally utilized in the United States. Utilization is particularly high in self-referring urology practices that own IMRT machines. In comparative effectiveness study versus conformal radiotherapy, IMRT use is associated with less gastrointestinal morbidity, fewer hip fractures, and less need for additional cancer therapy than conformal radiation, but more erectile dysfunction. Proton beam is purported to further enhance the precision of radiation delivery, but appears to provide no advantage over IMRT in terms of efficacy and side effects, increasing the rate of gastrointestinal side effects.

Brachytherapy is offered in many centers. This less burdensome approach has real appeal for men who want to avoid the complications of other treatment options; nonetheless, all men considering brachytherapy should understand the limited evidence for its long-term efficacy, especially young men at intermediate or high risk for long-term disease progression. In men with localized disease, results of major observational cohort study show poorer long-term outcomes compared to external beam radiation or surgery in patients with moderate- or highrisk disease. In addition, rectal side effects are common.

Surgery.

It has been noted that most radiation oncologists consider radiation to be the standard of care for most men with clinically localized disease. Most urologists consider RP to be the standard for the same men, provided they are under the age of 65 to 70 years and otherwise fit for surgery. Randomized trial evidence shows that RP can lower the risk of disease-specific and overall mortality in men with localized prostate cancer, including those at low risk, but the effect appears limited to men under the age of 65 years and, for the most part, to those with clinically detected cancers. It is not clear that the same result is achievable in men with PSA-detected cancers (stage T1c), although those with higher-risk disease (e.g., PSA >10 ng/mL) in the PIVOT study (where many had PSA-detected disease) did achieve significantly improved survival.

In general, morbidity is greater with RP than with radiation. Erectile dysfunction is a chief concern. In the Prostate Cancer Outcomes Study—a population-based study of 1,291 men who underwent RP for localized prostate cancer and were followed for 2 years—60% of men were unable to have an erection firm enough for intercourse 2 years after surgery. Advances in surgical technique have made the preservation of erectile function more likely, but the so-called nerve-sparing procedures are not always possible and not always successful when they are possible—results are very surgeon-dependent. When impotence does occur after a nerve-sparing procedure, the neurovascular apparatus is more likely to be intact, allowing the capacity for erection with vasoactive agents (see Chapter 132). Although postoperative incontinence occurs in most patients, it clears by 5 weeks in more than 50%. However, it remains a long-term problem for a significant number of men: At 2 years in the Patient Cancer Outcomes Study, 1.6% of men reported no urinary control, and 7% and 42% reported frequent or occasional leakage, respectively.

Advances in surgical technique have led to development of minimally invasive approaches (both robotic and nonrobotic) to RP. Comparative effectiveness study finds that minimally invasive surgery compared to the traditional open procedure shortens length of stay and results in fewer strictures and fewer respiratory and miscellaneous surgical complications; moreover, there is no difference in need for additional cancer therapy, but there are more genitourinary complications, including urinary incontinence and erectile dysfunction.

Androgen-Deprivation Therapy.

Being an androgenically responsive disease, prostate cancer can benefit from treatment that inhibits testosterone production or blocks its action. The socalled medical castration has been made possible by the advent of gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide, goserelin)—the constant signaling paradoxically turning off testosterone synthesis in the testes. Long-acting depot preparations make for convenient use. Application in early-stage disease is typically as a neoadjuvant, given to reduce tumor size prior to radiation. It is usually stopped after completion of radiation therapy, but restarted if there is evidence of disease progression—most often a rising PSA level. When used longer term in combination with radiation therapy, disease-free survival is significantly improved, especially in persons with higher-risk disease. Efficacy in low-risk, early-stage disease is unknown.

Because GnRH agonist therapy causes a temporary surge in testosterone release at the outset, it is often preceded by use of a nonsteroidal antiandrogen (e.g., flutamide, bicalutamide), which binds to the androgen receptor, inhibiting receptor action and accelerating its degradation. Side effects include gynecomastia, impotence, and diarrhea; a chemical hepatitis sometimes develops. In early-stage disease to be treated with radiation, a nonsteroidal antiandrogen is typically started before GnRH agonist therapy to blunt the transient increase in androgen production that will ensue. These drugs cannot be used as monotherapy because they induce an increase in luteinizing hormone release that eventually stimulates sufficient testosterone secretion to overcome their blocking effect.

Choice of Treatment.

After consultations to explore therapeutic options, men under the age of 70 years with early-stage, highgrade disease requiring treatment come to realize there is no single answer regarding best approach to treatment. Longterm overall and cancer-specific survival rates are favorable and appear comparable (though there are no data from randomized trials). Consideration then shifts to side effects and impact on overall health. Long-term observational study provides the best available information to guide decision-making in the absence of data from randomized trials. Data from the Prostate Cancer Outcomes Study (PCOS), the largest and longest-term outcomes assessment, finds urinary incontinence initially more prevalent in radiation-therapy patients (odds ratio 6.22 at 2 years, 5.10 at 5 years), but no difference at 15 years. Erectile dysfunction was more common initially among surgically treated patients (odds ratio 3.46 at 2 years and 1.96 at 5 years), but no different at 15 years. Bowel urgency was less likely with prostatectomy early on (odds ratio 0.39 at 2 years and 0.47 at 5 years) but no different at 15 years. Of note, both groups reported much functional decline over 15 years; the cause(s) for the decline remain unclear and range from age to cancer and cancer treatment.

Locally Advanced Disease

Locally advanced (T3) disease is more of a challenge, especially if there is lymph node involvement. External beam radiation alone may be useful for the local control of tumor, especially for locally recurrent disease after prostatectomy, but often fails to sterilize pelvic nodes, which are highly likely to be involved by tumor. Adjuvant androgen deprivation therapy as described earlier is generally a central component of treatment. Most locally advanced disease is treated with radiation therapy in conjunction with a GnRH agonist, which is continued indefinitely, enhancing disease control and prolonging survival.

However, long-term medical castration is not without its adverse consequences, including osteoporosis (requiring bisphosphonate therapy) and muscle wasting as well as quality-of-life impairments due to hot flashes, sexual dysfunction, and fatigue. Concerns about an increase in cardiovascular risk never materialized; nonetheless, frail elderly men may be especially vulnerable to long-term therapy. Moreover, after about a decade of continuous GnRH agonist therapy, many patients begin to experience the so-called hormonal resistance, in which antiandrogen therapy loses ability to control disease progression. Manifestations range from an unchecked rise in PSA to increase in tumor growth.

To counter the adverse consequences of long-term medical castration, intermittent GnRH agonist therapy has been proposed and studied, using 8-month blocks of treatment followed by a pause until the PSA begins to rise. At 7 years of follow-up in a randomized trial, this intermittent treatment approach demonstrates noninferiority to continuous therapy in terms of overall survival and appears advantageous with respect to quality-oflife measures. Whether this benefit will continue and also delay onset of hormonal resistance remains to be determined as does optimum candidacy for such intermittent therapy. Of note, compared to surgical castration (which is another hormonal treatment option), medical castration by GnRH agonist use makes possible the temporary return of androgen synthesis, conferring the suspected physiologic advantage of intermittent therapy. Intermittent therapy also saves money, though there is an increase in testing expense due to the need to follow the PSA more closely.

Metastatic Disease

Hormonal therapy is the foundation of treatment for metastatic disease, but after about 10 years of GnRH agonist therapy, many persons begin to display hormone resistance. Typically, androgen receptor blockade (e.g., bicalutamide) is added, but often without much benefit. Such castration resistance) has been linked to marked upregulation of androgen receptors on tumor cells, stimulating alterations in treatment strategy (e.g., intermittent rather than continuous androgen deprivation) and development of more potent inhibitors of androgen cellular action and gonadal and extragonadal androgen biosynthesis. The advent of abiraterone, an inhibitor of cytochrome P-450c17 (essential for all androgen synthesis), and enzalutamide, an inhibitor of androgen receptor signaling, provides new treatment options capable of prolonging survival in such “hormonally resistant” patients. Standard chemotherapy is of modest benefit at best.

Chemotherapy becomes a consideration in hormonally refractory patients with symptomatic metastatic disease. In those who can tolerate chemotherapy, docetaxel plus prednisone (to limit hypersensitivity reactions) is the standard treatment, providing some symptom control and modest improvement in survival. In docetaxel-resistant patients, cabazitaxel (in conjunction with prednisone) has been found to achieve disease response and improve survival (on the order of months). Neutropenia is the principal adverse effect.

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