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14 Prostate Cancer Ravi A. Madan and William L. Dahut EPIDEMIOLOGY ■■ ■■ Prostate cancer (CaP) is the most common noncutaneous malignancy and the second most frequent cause of cancer-related mortality in men in the United States; in 2013 there will be an estimated 238,590 men diagnosed with CaP and 29,720 deaths from the disease. The frequency of clinically aggressive disease varies geographically, but the frequency of occult tumors does not, suggesting the influence of environmental factors in the etiology of CaP. Studies of Japanese immigrants to the United States show that the incidence of CaP increases after immigration. RISK FACTORS ■■ ■■ ■■ ■■ ■■ Age: Risk increases progressively with age, with about 70% of cases in men over the age of 65. Family history: Risk increases twofold with a first-degree relative diagnosed with CaP, fivefold with two first-degree relatives. Race: In the United States, incidence is highest among African Americans, followed by whites, then Asians. African-American men are more likely to be diagnosed with advanced disease and have a greater than twofold risk of death from the disease. Geography: Risk is lowest in Asia, high in Scandinavia and the United States. Diet: Consumption of red meat and animal fat has been associated with CaP, while eating cruciferous vegetables, soy products, and lycopene-containing tomato products may be protective. CHEMOPREVENTION TRIALS 5-𝛂 Reductase Inhibitors ■■ ■■ ■■ Two clinical trials have evaluated the ability of 5-α reductase inhibitors to prevent CaP in asymptomatic men older than 50 years. In the Prostate Cancer Prevention trial, finasteride was compared to placebo in more than 9,000 men. There was a reduction in the incidence of CaP from 24.8% in the placebo arm to 18.4% in the finasteride arm within 7 years (P < 0.001). In the REDUCE trial, 8,321 men randomized to receive either dutasteride or placebo. Again, there was a reduction in the incidence of CaP in the treatment arm by 22.8% over the 4-year study period (P < 0.001). 191 87588_ch14_p191-207.indd 191 04/12/13 10:32 PM 192 ■■ ■■ THE BETHESDA HANDBOOK OF CLINIC AL Oncology Both of these therapies are approved for benign prostatic hyperplasia-related symptoms but are not approved for CaP prevention. Both of these prevention studies found an increase in the percentage of aggressive tumors (Gleason score 7 to 10) in patients treated with the respective 5-α reductase inhibitors compared to the placebo. Subsequent pathology reviews of prostatectomy specimens did not confirm this increase, indicating potential sampling bias in the biopsies, perhaps due to a preferential reduction in normal versus tumor tissue caused by the effect of the 5-α reductase inhibitors. Without a definitive explanation for these findings, enthusiasm to use these agents for prevention of CaP has been significantly diminished. Perhaps longer follow-up will provide additional data to better characterize these findings. Selenium and Vitamin E Cancer Prevention Trial ■■ Retrospective data from two previous chemoprevention trials have suggested a preventive role for selenium and vitamin E supplementation. Selenium and Vitamin E Cancer Prevention Trial (SELECT) enrolled over 35,533 men at least 50 years old and found that selenium and vitamin E, alone or in combination, did not prevent CaP. SCREENING ■■ ■■ ■■ ■■ ■■ Screening for CaP involves testing for levels of PSA and/or DRE. Screening of asymptomatic men is controversial. Debate centers on whether biologically and clinically significant cancers are being detected early enough to reduce mortality or, conversely, whether cancers detected by screening would cause clinically significant disease if left undetected and untreated. Autopsy series have shown that more men die with, rather than from, CaP, and the rate of occult CaP in men in their 80s is approximately 75%. The Prostate, Lung, Colon, and Ovary (PLCO) screening trial and the European Study on Screening for Prostate Cancer are evaluating clinical outcomes based on screening versus no screening. Preliminary data from the PLCO trial reveal that the rate of death from CaP was very low and did not differ significantly between subjects assigned to screening or no screening, with 7 to 10 years of follow-up. One caveat is that a high number of patients (about 50%) in the control arm obtained PSA screening outside of the clinical trial. Preliminary data from the European study suggest that PSA screening was associated with a reduction in rate of death from CaP by 20% after a median follow-up of 9 years. However, 1,410 men would need to be screened and 48 additional cases of CaP would need to be treated to prevent one death from CaP. Final results for these studies are expected in the coming years and may provide more conclusive data. Despite the controversy, PSA screening in the United States is widespread. Most advocates recommend annual screening beginning at age 50 for average-risk men and at age 40 for African-American men and men with a family history of CaP. • Most advocates of screening acknowledge the limited benefits in men who are over 75 years of age or men with less than 10 years of projected survival due to other comorbidities. It is likely that most men who fall in this category will not have their lifespan limited by CaP and thus screening may be unnecessary. Frank discussions with patients about the risks and potential benefits of screening should be standard practice. SIGNS AND SYMPTOMS ■■ ■■ With PSA screening now widely practiced in the United States, most men are asymptomatic at diagnosis. Patients with local or regional disease may be asymptomatic or have lower urinary tract symptoms similar to those of benign prostatic hypertrophy. Men with regional disease occasionally have hematuria. 87588_ch14_p191-207.indd 192 04/12/13 10:32 PM chapter 14 ■■ n Prostate C ancer 193 Symptoms of metastatic disease include bone pain and weight loss; spinal cord compression is a rare but serious complication of metastatic disease. WORKUP AND STAGING Biopsy ■■ Abnormal PSA and/or DRE is followed by transrectal ultrasound with core biopsy (generally 10 to 12 cores). Historically, a PSA of >4 ng/mL was the threshold for biopsy, but recent data suggest that cancers can be seen with lower PSA levels. In recent years a greater emphasis has also been placed on rate of PSA rise as a trigger for biopsy. A negative biopsy should prompt reassessment in 6 months with repeat biopsy as needed. Pathology ■■ ■■ ■■ ■■ ■■ ■■ ■■ Ninety-five percent of CaPs are adenocarcinomas. Adenocarcinoma arises in the peripheral zone of the prostate in approximately 70% of patients. Sarcoma, lymphoma, small cell carcinoma, and transitional carcinoma of the prostate are rare. Although visceral or osteolytic bone metastases are found in a few patients with metastatic adenocarcinoma of the prostate, careful pathologic examination should be performed to rule out a nonadenocarcinoma variant, as treatment regimens differ. Primary and secondary Gleason grades are determined by the histologic architecture of biopsy tissue. The primary grade denotes the dominant histologic pattern; the secondary grade represents the bulk of the nondominant pattern or a focal high-grade area. Primary and secondary grades range from 1 (well differentiated) to 5 (poorly differentiated). The combined grades comprise the GS (range 2 to 10). There is no role in re-evaluating GS once treatment has begun. There is growing consensus that the highest GS is most predictive of clinical outcome. With current grading practices, scores <6 are very rare. A GS of 8 to 10 represents poorly differentiated CaP that is likely to be clinically aggressive. Because of sampling bias, GS may change following radical prostatectomy (RP) (20% of scores are upgraded and up to 10% are downgraded). Prostatic intraepithelial neoplasia (PIN), and perhaps proliferative inflammatory atrophy (PIA), are considered precursor lesions. Baseline Evaluation ■■ ■■ ■■ In candidates for local treatment, a bone scan is indicated for patients with bone pain, T3 or T4, GS >7, or PSA >10 ng/mL. There is no clinical evidence that a baseline bone scan improves survival in patients with better prognostic factors. In candidates for surgery, computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis is obtained for T3 and T4 lesions, PSA >20 ng/mL, or GS >7 to detect enlarged lymph nodes. Endorectal MRI may help in determining the presence of extraprostatic extension. CT scans aid in treatment planning for radiation therapy (RT). Baseline laboratory tests include complete blood count, creatinine level, PSA (if not yet done), testosterone and alkaline phosphatase level. PROGNOSTIC FACTORS ■■ ■■ ■■ Stage at diagnosis Gleason grade/score PSA level 87588_ch14_p191-207.indd 193 04/12/13 10:32 PM 194 ■■ ■■ THE BETHESDA HANDBOOK OF CLINIC AL Oncology Number of cores and percentage of each core involved Age at diagnosis TREATMENT OF LOCALIZED DISEASE Active Surveillance For men aged 60 to 75 years with a >10-year life expectancy or low-grade (GS ≤ 6), T1c-T2a tumors, active surveillance is a reasonable alternative to immediate local therapy (Fig. 14.1). In addition, men aged 50 to 60 years with those same features and low-volume (<3 cores, <50% of any one core involved) tumor may also be candidates for active surveillance. For patients with a <10-year life expectancy, CaPspecific mortality is very low and local definitive therapy may not be appropriate. Surgery ■■ ■■ ■■ ■■ ■■ ■■ Radical Prostatectomy Approaches include retropubic (RRP), perineal (RPP), or laparoscopic, with the latter often done with robotic assistance (RALP). Typical hospital stays are 1 to 2 days, with 7 to 14 days of urethral catheterization. Surgeries are somewhat longer with RALP, but hospital stays are usually shorter. Pelvic lymph node dissection may be performed at the time of RP in patients at high risk of developing positive lymph nodes, but may not be necessary in patients with T1c disease, PSA <10 ng/mL, and GS <7. Nerve-sparing RP may conserve potency in men with disease not adjacent to the neurovascular bundles that travel posterior-lateral to the prostate. The bilateral nerve-sparing technique is associated with 60% to 90% of patients recovering spontaneous erections versus only 10% to 50% with the unilateral technique. Both groups, however, may respond to oral therapy for erectile dysfunction. There is no role for neoadjuvant androgen-deprivation therapy (ADT) prior to RP, although ongoing studies in high-risk patients are evaluating ADT with modern antiandrogens to determine the potential to debulk tumor prior to RP. Patients with microscopic lymph node metastasis diagnosed following RP may have a longer overall survival (OS) if given ADT rather than at time of clinical recurrence. Salvage RP following RT may be done in select cases where local disease is organ confined. However, salvage RP is more technically demanding and is associated with higher morbidity. Initial Diagnosis of Prostate Cancer Low-Risk Features Surveillance may be an option for selected patients, although some patients may elect surgery or radiation. Intermediate-Risk Features Surgery and radiation therapy (possibly with shortcourse ADT) are both options. Surveillance may also be an option in selected patients. High-Risk Features Radiation therapy with 2 or 3 years of ADT is the common recommendation, but surgery may be an option in selected patients. FIGURE 14.1 Treatment options for patients diagnosed with localized prostate therapy. RT can include EBRT or brachytherapy (generally reserved for select patients with intermediate- or low-risk disease), or a combination of the two in some high-risk cases. 87588_ch14_p191-207.indd 194 04/12/13 10:32 PM chapter 14 ■■ ■■ ■■ ■■ ■■ ■■ n Prostate C ancer 195 Surgical Complications Immediate morbidity or mortality: 2%. Impotence: 35% to 60%. Urinary incontinence: 10% with frank incontinence; up to 60% require protective garments. Urinary structure. Fecal incontinence: retropubic approach, approximately 5%; perineal approach, 18%. The Prostate Cancer Outcomes Study found statistically significant differences in outcomes following RP or RT. For patients with normal baseline function, RP was associated with inferior urinary function, better bowel function, and similar sexual dysfunction compared with RT. Focal Therapy for Disease Confined to a Region of the Prostate Focal therapy for newly diagnosed CaP confined to a limited area of the prostate remains investigational. This strategy is different from other therapies for localized disease in that only a focal region of the prostate, as opposed to the entire glad, is targeted with hopes of limiting side effects. Cryosurgery destroys CaP cells through probes that subject prostate tissue to freezing followed by thawing. This procedure is associated with high rates of erectile dysfunction due to freezing of the neurovascular bundle. Additional focal therapy strategies include thermal ablation via laser or high-intensity focused ultrasound among other techniques. There are limited data on long-term outcomes for focal therapy. Thus, at most centers prostate focal therapies are largely performed as salvage procedures. Radiation Therapy ■■ ■■ ■■ ■■ ■■ External Beam RT External beam RT (EBRT) targets the whole prostate, frequently including a margin of extraprostatic tissue, seminal vesicles, and pelvic lymph nodes. Higher doses (≥78 Gy) given over approximately 8 weeks are associated with higher PSA control rates; however, survival data are not mature. Three-dimensional (3D) conformal RT allows for maximal doses conforming to the treatment field, while sparing normal tissue. Intensity-modulated RT is a type of 3D conformal RT that is designed to conform even more precisely to the target. Unlike x-rays, which radiate beyond the target volume, proton beam irradiation focuses virtually all its energy within a very small area, thus theoretically minimizing damage to normal tissue. RT with Adjuvant ADT At least three randomized controlled trials have shown that combining ADT with RT in patients at high risk for recurrent disease (Table 14.1) improves OS. ADT is usually given during RT and for 2 to 3 years thereafter. It may also be used for 2 months prior to RT to help decrease tumor size and thus the target volume of RT. Table 14.1 Risk Categories for Posttherapy Prostate-Specific Antigen Failure Stage PSA Gleason score Qualifier Low Intermediate High T1c, T2a <10 ≤6 and T2b 10–20 7 or T2c >20 ≥8 or Adapted from D’Amico AV, Whittington R, Malkowicz SB, et al. Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy Gleason score, and clinical T-stage. Int J Radiat Oncol Biol Phys. 1999;45(5):1227-1233. 87588_ch14_p191-207.indd 195 04/12/13 10:32 PM 196 ■■ THE BETHESDA HANDBOOK OF CLINIC AL Oncology Adjuvant RT General indications for the use of adjuvant RT after RP include positive surgical margins, seminal vesicle involvement, and evidence of extracapsular extension. Nonetheless, the potential for cure with adjuvant RT will vary significantly from patient to patient and thus the risks and benefits of adjuvant RT should be evaluated in each case individually. Salvage RT For select patients with rising PSA after RP and a high likelihood of organ-confined local recurrence (e.g., PSA <1.5 and slowly rising), salvage RT may be considered. However, there are limited data on which to make recommendations. Brachytherapy Interstitial brachytherapy with radioactive palladium or iodine seeds that delivers a much higher dose of radiation to the prostate is used in CaP patients with low-risk tumors and some intermediaterisk patients. Better definitions of tumor volume and radiation dosimetry have made this outpatient technique more accurate. CT and/or transrectal ultrasound are used to guide seed placement. Combined EBRT and Brachytherapy EBRT followed by brachytherapy boost is an increasingly used strategy. Preliminary clinical data support the safety and efficacy of this approach in a selected population of patients. Long-term clinical data including OS data from randomized trials are still pending. Nonetheless, some radiation oncologists are using this treatment combination in patients with high-risk disease. Complications of RT Acute ■■ ■■ ■■ Cystitis Proctitis/enteritis Fatigue Long term ■■ ■■ ■■ ■■ Impotence Incontinence (3%) Frequent bowel movements (10% more than with RP) Urethral stricture (RT delayed 4 weeks after transurethral resection of the prostate) COMPARISON OF PRIMARY TREATMENT MODALITIES Comparing treatment modalities in terms of overall and disease-free survival is difficult because of differences in study design, patient selection, and treatment techniques. ■■ ■■ While there have been no satisfactory randomized trials comparing RT with RP, these approaches appear to have equivalent PSA-free survival (also called biochemical relapse-free survival) in appropriately matched patients at 5 years, but differ in type and frequency of side effects. Brachytherapy appears promising, although most studies have been conducted only in patients with early-stage, low-grade disease. One comparison of 3D conformational RT with 125I implants in comparable patients concluded that these modalities had equivalent efficacy, with higher urinary complications in the brachytherapy group. FOLLOW-UP AFTER DEFINITIVE TREATMENT ■■ Patients treated with curative intent should have PSA levels checked at least every 6 months for 5 years, then annually. Annual DRE is appropriate for detecting recurrence. 87588_ch14_p191-207.indd 196 04/12/13 10:32 PM chapter 14 ■■ n Prostate C ancer 197 After RP, a detectable PSA suggests a relapse. PSA failure after RT is defined as 2 ng/mL over the nadir, whether or not the patient had ADT with RT. TREATMENT FOR MEN WITH RISING PSA AFTER LOCAL THERAPY Treatment for patients who have rising PSA (biochemical failure) after local therapy has not been standardized and participation in clinical trials should be encouraged (Fig. 14.2). As previously mentioned salvage RT, salvage RP, or salvage focal therapy may be offered to select patients with local recurrence. ADT effectively lowers PSA and can be given intermittently to provide periods of normal testosterone. Based on preliminary results from randomized studies, CaP-specific outcomes with intermittent and continuous ADT appear to be similar. However, there are no data suggesting better survival with ADT than with no ADT. Recent data suggest that on average, men live about 14 years after biochemical failure. Thus a more conservative approach (e.g., treating Biochemical Recurrence (Rising PSA after definitive therapy with no evidence of metastatic disease) Salvage Radiation May be considered in selected patients who were initially treated with surgery, depending on PSA value, rate of rise, and time from surgery. Intermittent ADT Surveillance of PSA Values Although there are limited data, it may be reasonable to withhold ADT until the PSA-doubling time is less than 3–6 months. (Patients can be evaluated every 2–3 months to determine doubling time.) Continuous ADT Continuous ADT FIGURE 14.2 Treatment options for biochemical recurrence/nonmetastatic castration-sensitive prostate cancer. Continuous ADT employs repeated doses of GnRH agonists/antagonists to provide a constant testosterone suppression. Orchiectomy would also be an option. Intermittent ADT employs two or three doses of testosterone-lowering therapy, which are then discontinued if the PSA declines as expected. From there, PSA slowly recovers, lagging behind testosterone recovery. In selected patients, this approach can be used to alleviate some ADT toxicity. ADT is often reinstituted based on a PSA doubling time similar to the “surveillance of PSA” approach described in the figure. 87588_ch14_p191-207.indd 197 04/12/13 10:32 PM 198 THE BETHESDA HANDBOOK OF CLINIC AL Oncology when symptomatic) is a reasonable option for many men. Alternatively, using PSA-doubling time (i.e., less than 3 to 6 months) as a trigger to initiate ADT or intermittent ADT is frequently done in clinical practice; however, no randomized trials have prospectively evaluated this approach relative to continuous or delayed ADT based on doubling time. TREATMENT OF SYSTEMIC DISEASE Response Criteria: Using PSA, a Historical Perspective Only 40% of patients with castration-resistant prostate cancer (CRPC), or progressing disease despite castrate levels of testosterone, have soft tissue disease. Therefore, PSA historically has been an important tumor marker for preliminary assessment of efficacy in proof-of-principle trials. PSA response rates (PRRs) are defined as percentage of patients with a PSA decline >50%, a traditionally used criterion. Because of differences in patient selection, it is difficult to compare clinical trials by PRRs alone. Many trials now include all PSA declines in a “waterfall plot.” It is important to note that some agents (particularly cytostatic agents) may upregulate or downregulate PSA expression independent of their effect on cancer growth. Definitive studies historically have utilized skeletal-related events, palliation of symptoms, or OS for CRPC. EVOLUTION OF RESPONSE CRITERIA IN METASTATIC DISEASE The Prostate Cancer Working Group 2 and the Implications for Clinical Practice ■■ ■■ ■■ ■■ ■■ ■■ As the understanding of CaP has evolved in the last decade, in the context of new available therapies and greater experience with older therapies, a general consensus was generated by Prostate Cancer Working Group 2 (PSWG2) on determining response in clinical trials. Perhaps most importantly, PSA should not be used as the sole criteria to discontinue a therapy. Furthermore, the PSWG2 recommends that early changes in PSA and modest increases in pain, which could represent a tumor flare phenomenon, should not result in the discontinuation of therapy. For patients with metastatic CaP, objective changes on imaging studies (CT and bone scan) should be the primary criteria used to assess progression of disease in the absence of clear clinical progression of symptoms. In order to assess imaging, lymph nodes less than 2 cm in diameter are too small to be evaluated for response or progression of disease. Two new bone lesions on bone scan are required to document progressive disease, with one important exception. New lesions on the first bone scan should trigger another bone scan 6 or more weeks later, as these new lesions may have been present on the first scan, but missed on initial imaging or they may represent a the “tumor flare phenomenon.” If the second (and subsequent) bone scans show less than two new lesions and the patient is otherwise clinically stable, he should be considered to have stable disease. For the treatment of patients outside of clinical trials the implications of the PCWG2 are as follows: • Radiographic response criteria should be used to determine disease progression in metastatic CaP as opposed to PSA alone. • Initial changes on bone scan are not sufficient to remove patients from a treatment; patients could continue therapy if subsequent bone scans show less than two new lesions. • Changes in lymph nodes less than 2 cm in diameter should be interpreted with caution. • PSA should still be followed but interpreted with caution and not be used as the sole criteria to determine when to discontinue a therapy. 87588_ch14_p191-207.indd 198 04/12/13 10:32 PM chapter 14 n Prostate C ancer 199 ANDROGEN-DEPRIVATION THERAPY ■■ ADT is the mainstay of treatment for metastatic CaP (Table 14.2). However, as discussed previously, it has also been used to treat localized disease and in neoadjuvant and adjuvant settings with RT. CaP cells usually respond to hormonal manipulations that block the production of androgens, producing durable remissions and significant palliation. Duration of response ranges from 12 to 18 months, with 20% of patients having a complete biochemical response at 5 years. However, ultimately, CRPC cells emerge and lead to disease progression. Table 14.2 Systemic Therapies for Prostate Cancer Treatment Dose Most Common Side Effects Bilateral orchiectomy n/a Impotence, loss of libido, gynecomastia, hot flashes, and osteoporosis GnRH Angonists (Most Common Formulations) Goserelin acetate (Zoladex) 3.6 mg SC every month or 10.8 mg SC every 3 mo Leuprolide acetate (Lupron) 7.5 mg SC every month or 22.5 mg i.m. every 3 mo, or 30 mg SC every 4 mo Potential for tumor flare due to transient initial increase in testosterone, loss of libido, gynecomastia, hot flashes, and osteoporosis Potential for tumor flare due to transient initial increase in testosterone, loss of libido, gynecomastia, hot flashes, and osteoporosis GnRH Agonist Degarelix (Firmagon) 240 mg SC initial dose followed by 80 mg SC every 28 d Hot flashes, weight gain, erectile dysfunction, loss of libido, hypertension, hepatotoxicity, gyecomastia, and osteoporosis Androgen Receptor Antagonists (ARAs) Bicalutamide (Casodex) Flutamide (Eulexin) 50 mg PO daily Nilutamide (Nilandron) 150 mg PO daily 250 mg PO three times per day Nausea, breast tenderness, hepatotoxicity, hot flashes, loss of libido, and impotence Diarrhea, nausea, breast tenderness, hepatotoxicity, loss of libido, and impotence Visual field changes (night blindness or abnormal adaptation to darkness), hepatotoxicity, impotence, loss of libido, hot flashes, nausea, disulfiram-like reaction, and pulmonary fibrosis (rare) Androgen Biosynthesis Inhibitors Ketoconazole (Nizoral) 200 or 400 mg PO 3 times a day with hydrocortisone 20 mg PO in the morning and 10 mg in the evening. (Ketoconazole is absorbed at an acidic pH; therefore, the concomitant use of H2 blockers, antacids, or proton pump inhibitors should be avoided.) Adrenal insufficiency is limited with physiologic dosing of hydrocortisone. Other side effects include impotence, pruritus, nail changes, adrenal insufficiency, nausea, emesis, and hepatotoxicity. (Ketoconazole is a potent inhibitor of CYP3A4, and thus multiple drug interactions are possible so review of medications is important.) (Continued ) 87588_ch14_p191-207.indd 199 04/12/13 10:32 PM 200 THE BETHESDA HANDBOOK OF CLINIC AL Oncology Table 14.2 (Continued) Abiraterone (Zytiga) 1,000 mg PO daily (on an empty stomach) Taken with prednisone 5 mg PO twice a day Peripheral edema, hypertension, fatigue, hypokalemia, hypernatremia, increased triglycerides, hepatotoxicity, and hot flashes. (Abiraterone is a potent inhibitor of CYP3A4, and thus multiple drug interactions are possible, so review of medications is important.) Androgen Receptor Inhibitor Enzaluatmide 160 mg PO once daily Hot flashes, diarrhea, peripheral edema, fatigue, arthralgia, and musculoskeletal pain. Limited risk of seizures (less than 1%) but care should be taken in patients with seizure history or those who are on medications that may lower the seizure threshold Immunotherapy Infusion of ≥50 million autologous CD54+ cells after ex vivo cellular processing given every 2 wk for three total doses Chemotherapy Regimens Fatigue, fever, chills, headache, nausea, emesis, myalgias, and infusion reaction symptoms Docetaxel (Taxotere) 75 mg mg/m2 IV every 21 d with prednisone 5 mg PO twice daily Cabazitaxel (Jevtana) 25 mg mg/m2 IV every 21 d with prednisone 5 mg PO twice daily Mitoxantrone (Novantrone) 12–14 mg mg/m2 IV every 21 d with prednisone 5 mg PO twice daily Docetaxel at 60 mg/m2 with carboplatin AUC 4 every 21 d with daily prednisone 5 mg PO twice daily Granulocytopenia, infection, anemia, fatigue, anemia, neutropenia, fluid retention, sensory neuropathy, nausea, fatigue, myalgia, and alopecia Myelosuppression, infection, fatigue/ weakness, fever, diarrhea, nausea, emesis, peripheral neuropathy, arthralgias, peripheral edema, alopecia, and dyspepsia Edema, myelosuppresion, cardiac toxicity, fever, fatigue, alopecia, nausea, diarrhea, infection, and hepatotoxicity Myelosuppression, infection, hyperglycemia, hypoglycemia, pain, renal failure, and thrombosis. (These were seen in limited experience with 34 patients.) Sipuleucel-T (Provenge) Docetaxel (Taxotere) + carboplatin (Paraplatin) ■■ ■■ Bilateral surgical castration and depot injections of GnRH agonists (e.g., leuprolide, goserelin, and buserelin) and a GnRH antagonist (degarelix) provide equally effective testosterone suppression. Combined androgen blockade can be achieved by adding an oral androgen receptor antagonist (ARA; e.g., nilutamide, flutamide, and bicalutamide). However, this is controversial and provides little if any survival benefit. GnRH agonists initially increase gonadotropin, causing a transient (∼14-day) increase in testosterone that can lead to tumor flare. A lower tumor volume reduces the risk of symptomatic tumor flare. Tumor flare can be prevented by the use of an ARA, which binds to the androgen receptor (AR), effectively stopping the ability of the AR to activate cell growth. An ARA is often given for 1 to 2 weeks prior to GnRH agonist in patients at risk for complications (pain, obstruction, and cord compression) associated with tumor flare. For high-risk patients, bilateral orchiectomy or ketoconazole can decrease testosterone more quickly. 87588_ch14_p191-207.indd 200 04/12/13 10:32 PM chapter 14 ■■ ■■ n Prostate C ancer 201 In patients initially treated with GnRH agonist or surgical castration alone, the addition of an ARA may produce PSA declines or symptomatic improvement in up to 40% of patients. • The use of the GnRH antagonist (degarelix) obviates the concern for tumor flare as it leads to more rapid reduction in testosterone without an initial increase in serum testosterone levels. For this reason, it may be preferred in the setting of initial treatment for men diagnosed with symptomatic metastatic disease. Continuing testosterone suppression after patients develop CRPC is also considered the standard of care for both nonmetastatic and metastatic disease. Androgens still play a very important role in driving the growth of CRPC, as evidenced by the benefits seen with new antiandrogen therapy (enzalutamide and abiraterone) in metastatic CRPC (mCRPC). Levels of AR and intracellular androgens within the tumor cells are significantly elevated in these patients and thus continuing ADT indefinitely in CRPC is recommended. TREATMENT OF NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER AND THE USE OF SECOND-LINE ARAs ■■ ■■ ■■ ■■ ■■ Through the development of resistance mechanisms such as upregulation of the AR or intratumoral production of androgens, patients may develop progressive disease despite castration levels of testosterone. For patients with a rising PSA but no evidence of metastatic disease ARAs can be added to ADT in order to provide a combined androgen blockade, which may delay disease progression or the development of metastasis, although clinical evidence supporting this is limited. Upon progression of disease with ARA and ADT, it is important to note that that up to 20% of patients treated with combined androgen blockade have a PSA decline of ≥50% upon discontinuation of oral ARA (range, 15% to 33%), although these declines generally last only 3 to 5 months. This proportion may be lower with shorter-term use ARA use. This ARA withdrawal response occurs within 4 to 6 weeks, depending on the ARA’s half-life. Some patients with rising PSA (and still no evidence of metastasis) after ARA withdrawal may benefit from switching to other ARAs or initiating treatment with ketoconazole. A proportion of patients (35% to 50%) will have PSA declines with second-line and even third-line antiandrogen therapy. Ketoconazole is a nonspecific inhibitor of secondary androgen production which may include both adrenal production and production of androgens by the tumor itself, a well-described mechanism of CaP resistance to castrate levels of testosterone. Ketoconazole can be combined with ADT to treat non-mCRPC, although ARAs are usually preferred because ARAs are better tolerated. When used, ketoconazole is combined with physiologic replacement of hydrocortisone to compensate for its impact on steroidgenesis within the adrenal glands which could lead to adrenal insufficiency. TREATMENT FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER Multiple treatment options are now available for the treatment of mCRPC as opposed to prior to 2010 when only docetaxel had demonstrated the ability to extend survival in this population. Given multiple forms of therapy including immunotherapy, chemotherapy, radiopharmaceuticals, and modern antiandrogen therapy, symptoms and pace of disease will likely dictate which treatments are most appropriate for each individual patient (Fig. 14.3). Immunotherapy ■■ Sipuleucel-T (Provenge)—is an activated cellular therapy that is derived from a patient’s own immune cells which are collected via leukapheresis. Once removed from circulation, the peripheral immune 87588_ch14_p191-207.indd 201 04/12/13 10:32 PM 202 THE BETHESDA HANDBOOK OF CLINIC AL Oncology Assessment of pain/symptoms, and pace of disease Minimal or no pain/symptoms: Sipuleucel-T, Abiraterone, Enzalutamide1 Progressive disease with minimal or no pain/symptoms: Sipuleucel-T, Abiraterone, Enzalutamide1, 3 Progressive disease with increasing pain/ symptoms/pace of disease: Docetaxel Moderate or significant pain/ symptoms or rapidly progressing disease: Docetaxel2 Progressive disease with stable symptoms: Abiraterone, Enzalutamide3 Progressive disease with increasing pain/symptoms/pace of disease: Cabazitaxel4 FIGURE 14.3 Suggested treatment approach for patients with metastatic castration-resistant prostate cancer. (1) Second-line antiandrogen therapies such as androgen receptor antagonists and ketoconazole could also be used. (2) Abiraterone or enzalutamide may also be an option in asymptomatic patients with rapid disease progression. (3) These agents may be given sequentially if there is disease progression after the initial treatment. (4) Radiopharmaceuticals could also have a role in patients with symptomatic disease. ■■ ■■ cells are sent to a central processing facility where there are exposed to a fusion peptide of PAPGMCSF for 48 hours. The goal is to activate immune cells via ex vivo processing so that when they are reinfused into the patient, they generate an immune-mediated antitumor response. Although sipuleucel-T has been shown to improve survival versus placebo (25.8 vs. 21.7 months; hazard ratio 0.77; P = 0.02), it does not change short-term disease progression or cause decreases in PSA in most patients. This is likely due to the characteristics of immune therapies that make them distinct from more cytotoxic treatments. For this reason, sipuleucel-T should ideally be followed by another therapy to provide short-term control and allow for the potential long-term effects which can potentially improve survival. Patients whose disease on scans, PSA, and symptoms all remain stable after sipuleucel-T could be followed up closely until one of those parameters dictates the initiation of a subsequent therapy. Sipuleucel-T is indicated in patients with minimal symptoms related to their CaP. Although sipuleucel-T can be given 3 months after chemotherapy, given its delayed effects, it would seem most appropriate to give this treatment prior to chemotherapy. Androgen Biosynthesis Inhibitor ■■ ■■ ■■ Abiraterone (Zytiga) is a selective and irreversible CYP17 inhibitor and significantly reduces secondary androgen production (including testosterone precursors dehydroepiandrosterone and androstenedione) from the adrenal glands and likely within CaP cells. Abiraterone has demonstrated improved OS in mCRPC patients treated with chemotherapy relative to placebo (and has shown delayed progression in patient who have not been treated with chemotherapy). Abiraterone can be used in mCRPC patients who are chemotherapy-naïve and who have mild pain from their metastatic disease. It has been shown to delay the need for narcotics in this population. 87588_ch14_p191-207.indd 202 04/12/13 10:32 PM chapter 14 ■■ n Prostate C ancer 203 Abiraterone has been shown to improve pain and quality of life in patients who have already received chemotherapy. Androgen Receptor Inhibitor ■■ ■■ Enzaluatmide (Xtandi) is a modern version of the ARAs previously discussed although this agent has broader anti-AR properties beyond binding to the AR with greater binding affinity. It also significantly reduces AR translocation to the nucleus and limits DNA binding, and inhibits coactivator recruitment and receptor-mediated DNA transcription. In addition, enzalutamide has not demonstrated any agonist properties unlike previous ARAs. A phase 3 trial evaluated 1,199 mCRPC patients who had progressive disease on docetaxel, randomizing them 2:1 to enzalutamide 160 mg per day (n = 800) or placebo (n = 399). The OS-favored patients randomized to the enzalutamide arm 18.4 to 13.6 months. This 4.8 months’ improvement in survival represented a 37% risk reduction in death (hazard ratio 0.63; 95% CI 0.53 to 0.75; P < 0.001), the largest relative and absolute improvement in OS in an appropriately powered phase 3 study in CaP. Median TTP based on radiographic findings was 8.3 versus 2.9 months (HR 0.40; P < 0.001). CHEMOTHERAPY FOR mCRPC In spite of the advent of new antiandrogen therapies for mCRPC, chemotherapy is still important. ■■ ■■ ■■ ■■ Docetaxel (Taxotere) – Improved median OS from 16.5 months (mitoxantrone/prednisone) to 18.9 months (P = 0.0005) and improved quality of life (functional assessment of cancer therapy-prostate, 22% vs. 13%; P = 0.009). Although the absolute magnitude of the difference between the two arms was less than 3 months, it is important to note that the study did employ a cross-over meaning that patients not randomized to docetaxel initially may have received docetaxel when they had progressive disease. – Often used for patients with mCRPC who have intermediate or significant levels of symptoms. – Docetaxel would also be a reasonable option for patients with rapidly progressing disease as determined by objective changes on imaging. Cabazitaxel (Jevtana) – This treatment became the second chemotherapy approved for CaP. A phase 3 study trial compared this taxane with mitoxantrone in patients who already received docetaxel. (Prednisone 5 mg twice daily was also given in both groups.) Cabazitaxel improved time to progression 2.8 versus 1.4 months (P < 0.0001) but also met the primary endpoint of the trial by extending survival 15.1 versus 12.7 months (P < 0.0001). – It is important to note that there was an 8% incidence of febrile neutropenia, and 2% of patients died from neutropenia-related infections. Thus serious consideration should be given for the use of growth factor support in appropriate patients. – Although the true role for cabzitaxel remains elusive, it would be appropriate to consider this treatment in patients who remain symptomatic but also with a good performance status after progression on docetaxel. Mitoxantrone (Novantrone) + prednisone – Shown to improve quality of life, but not disease-free survival or OS, in two earlier randomized controlled trials versus steroids alone. – Mitoxantrone is stopped at a cumulative dose of 140 mg/m2. Prochlorperazine is used as an antiemetic. – Mitoxantrone may be appropriate for symptomatic patients who have either progressed on or who are not candidates for taxane-based chemotherapy regimens. Docetaxel (Taxotere) + carboplatin – A single-arm phase 2 trial of patients (n = 34) who progressed on docetaxel-based chemotherapy evaluated this combination and showed a partial response rate of 14% with a median progressionfree survival of 3 months and an OS of 12.4 months. – This combination may be most appropriate in patients who have a small cell variant of CaP (approximately 2% of patients). 87588_ch14_p191-207.indd 203 04/12/13 10:32 PM 204 THE BETHESDA HANDBOOK OF CLINIC AL Oncology SUPPORTIVE MEASURES ■■ ■■ ■■ Hot flashes from hormonal therapy are most commonly treated with low-dose venlafaxine or gabapentin with variable success. The potential side effects of these medicines also have to be taken into account when using them to treat hot flashes. Painful gynecomastia, often seen when ARAs are used alone, can be prevented with EBRT to the breasts (2 to 5 fractions) or may be treated with tamoxifen. Testosterone-lowering therapy causes a decrease in estradiol, needed to maintain bone density, which may lead to osteoporosis. Many specialists recommend that patients receiving ADT should be given daily vitamin D and calcium supplements unless contraindicated. Obtain baseline bone mineral density before starting long-term ADT. Treatment with bisphosphonates should be considered in patients with low bone mineral density. MANAGEMENT OF BONE METASTASES ■■ ■■ ■■ ■■ ■■ While narcotics can be used to alleviate bone pain, the anti-inflammatory effects of NSAIDs should not be overlooked in patients with bone metastasis. RT directed to painful spinal cord metastases provides palliation in approximately 80% of patients. Side effects generally are limited to fatigue and anemia that are usually reversible. Generally, the painful vertebral lesion and the two vertebrae superior to and inferior to the lesion are treated with 30 Gy. The spinal cord can tolerate radiation up to approximately 50 Gy, so retreatment of some lesions may be considered. The radioisotope strontium-89 (Metastron), a calcium analog that preferentially localizes in the tumor, can provide palliation for widespread metastases. Strontium relieves bone pain in up to 75% of cases, typically after 1 to 3 weeks of treatment and for several months thereafter. Toxicities include flare (15%), often associated with a later response, and a reversible thrombocytopenia (25%) that usually resolves within 3 months. Strontium can often be readministered. Samarium-153 lexidronam (Quadramet) is a newer radioisotope with treatment indications similar to those of strontium, but a shorter half-life and less marrow toxicity. Emerging data with α-particle emitting radium-223 (alpharadin) suggested minimal toxicity and a survival advantage in mCRPC. Its ultimate role in the treatment of mCRPC remains undefined. Bisphosphonates inhibit osteoclastic bone resorption and can decrease skeletal-related events in patients with advanced CRPC. Zoledronic acid 4 mg IV every 3 to 4 weeks has been approved for this indication. Side effects include infusion-related myalgias, renal dysfunction, and osteonecrosis of the jaw. Dose should be adjusted for renal insufficiency. Denosumab (Xgeva) is a fully humanized antibody that binds to RANK-ligand which is crucial in the function of osteoclasts, which play a vital role in bone resorption. Studies show that denosumab can also delay skeletal-related events in mCRPC. Furthermore, data have also indicated that denosumab can delay the development of metastasis in patients with non-mCRPC, although its clinical utility in delaying metastasis has not yet been established. Also, even though it is mechanistically different from bisphosphonates, there is a similar incidence of osteonecrosis of the jaw. SPINAL CORD COMPRESSION ■■ ■■ Vertebral column metastases impinging on the spinal cord can cause spinal cord compression, an oncologic emergency common in patients with CaP who have widespread bone metastases. Pain is an early sign of spinal cord compression in more than 90% of patients. Muscle weakness or neurologic abnormalities are other indicators of spinal cord compression, along with weakness and/ or sensory loss corresponding to the level of spinal cord compression, which often indicate irreversible damage. Genitourinary, gastrointestinal, and autonomic dysfunction are late signs; spinal cord compression usually progresses rapidly at this point. 87588_ch14_p191-207.indd 204 04/12/13 10:32 PM chapter 14 ■■ ■■ ■■ ■■ n Prostate C ancer 205 Diagnosis requires a thorough history and physical, with special attention to musculoskeletal and neurologic examinations. The standard for diagnosing and localizing spinal cord compression is MRI, usually with gadolinium. A myelogram may be used in patients with contraindications to MRI such as a pacemaker. High-dose steroids should be started (e.g., dexamethasone >24 mg IV followed by 4 mg IV or PO every 6 hours) as soon as history or neurologic examination suggests spinal cord compression. Neurologic or orthopedic surgeons and/or radiation oncologists should be consulted soon after diagnosis. RT is the usual treatment modality, given as 3,000 cGy in 10 fractions to the involved vertebra and the two superior and two inferior vertebrae. Surgical resection of the vertebral body should be considered in the following instances: – – – – The patient has had previous RT of the involved area or requires spinal stabilization. The patient experiences progression despite treatment with steroids and RT. RT facilities are not locally available. The patient has a rapidly progressive neurologic deficit. A recent randomized trial showed that patients subjected to decompressive surgical resection followed by RT retained the ability to walk significantly longer than those treated with RT alone. Review Questions 1. A 56-year-old male with a PSA of 7.8 ng/dL has Gleason 4+3 adenocarcinoma of the prostate diagnosed on a biopsy. He elects to have a RP. After surgery, there are pathologic findings that indicate that adjuvant radiotherapy may be of benefit. Which of the following findings would not be an indication for adjuvant radiotherapy? A. Extracapsular extension B. Lymph node–positive disease C. Seminal vesicle involvement D. Positive surgical margins 2. A 72-year-old male with asymptomatic, nonmetastatic CaP has a rising PSA while on ADT. After a discussion of treatment options, the patient agrees to add bicalutamide, an ARA. The patient has a declining PSA for the following 12 months, but then his PSA starts to rise again. The PSA rise is confirmed 1 month after the initial rising value was seen. The patient has no new symptoms since starting the bicalutamide. What is the appropriate next step for this patient? A. Get an MRI to determine if the patient has metastatic disease. B. Initiate chemotherapy for mCRPC. C. Initiate abiraterone for non-mCRPC. D. Evaluate for a bicalutamide withdrawal effect 6 weeks after discontinuing bicalutamide. E. Consider switching from a GnRH agonist to a GnRH antagonist. 3. Which of the following patients would be an inappropriate patient for treatment with sipuleucel-T? A. A chemotherapy-naïve, mCRPC patient who takes occasional NSAIDs for rare pain symptoms B. A patient who completed docetaxel 6 months ago, but has slowly progressing disease and no pain while on treatment with enzalutamide C. A chemotherapy-naïve, mCRPC patient who has just completed treatment with abiraterone and has minimal symptoms D. A newly diagnosed, untreated patient with metastatic disease and minimal symptoms 4. Which of the following treatment strategies has been shown to delay the development of bone metastasis in a phase 3 trial? A. Zoledronic acid B. Denosumab (continued) 87588_ch14_p191-207.indd 205 04/12/13 10:32 PM 206 THE BETHESDA HANDBOOK OF CLINIC AL Oncology C. Calcium/vitamin D D. Cabozantinib E. Alendronate 5. Which of the following statements about the use of docetaxel in CaP is accurate? A. Docetaxel is no longer indicated in CaP because of the advent of abiraterone, enzalutamide, and sipuleucel-T. B. Docetaxel with radiation in high-risk patients can enhance long-term outcomes. C. Docetaxel is the most appropriate therapy for patients moderate to high levels of pain for castration-resistant, metastatic CaP. D. Docetaxel is the most appropriate therapy for patients all patients with castration-resistant, metastatic CaP. E. Docetaxel prior to surgery for high-risk CaP can improve survival. 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