Prostate Cancer Review

Ekaterina Kachur, PharmD

Disclosures

US Pharmacist. 2018;43(8):HS7-13. 

In This Article

Treatment

The initial management of newly diagnosed prostate cancer should consider the extended natural history of this malignancy and the risk of progression to more aggressive disease. Shared decision-making, the patient's life expectancy, and personal preferences play an increasing role in the choice of appropriate treatment options.[12] The clinical course of prostate cancer varies from indolent, well-differentiated tumors to aggressive, high-grade cancers that can lead to metastases, significant morbidity, and death. Traditionally, newly diagnosed cases were stratified into low, intermediate, and high risk.[12] However, to account for heterogeneity among these groups, a number of more selective risk stratification tools have been developed.[12,13] For instance, the National Comprehensive Cancer Network (NCCN) subdivides newly diagnosed localized disease into six risk groups.[12] This stratification allows for more individualized treatment approaches, sparing those with low-risk disease from morbidity associated with treatment of localized prostate cancer. The summary of treatment recommendations by risk score is provided in Table 2.

Localized Prostate Cancer

Very Low- and Low-risk Disease. For patients with low-risk disease, the three main treatment modalities are expectant management, radical prostatectomy, and radiation.[12] The expectant management is further subdivided into observation and active surveillance.[12,14] Observation entails less frequent monitoring and palliative treatment of symptoms, whereas active surveillance consists of more frequent monitoring with a goal of initiating curative treatment if cancer progresses.[12,14] The choice of treatment modality takes into consideration the patient's age, comorbidities, and preferences, with more aggressive treatment options recommended to patients with life expectancy >10 years.[12] The pros and cons of these treatment modalities are listed in Table 3.

Intermediate, High Risk, and Locally Advanced Disease. For patients with intermediate-risk disease, concurrent radiation and short-term (4-6 months) androgen deprivation therapy (ADT) may be indicated.[12] This recommendation is based on the results of several randomized trials demonstrating significant improvement in overall and cancer-specific survival with the addition of ADT.[15–17]

For high- and very high-risk patients, a combination of external beam radiation therapy and long-term (2-3 years) ADT is an NCCN category 1 recommendation.[12] This combination has shown improvement in overall and cancer-specific survival over either treatment alone.[18,19] Supporting evidence for extended duration of ADT comes from the EORTC 22961 trial demonstrating inferior survival with short-term (6 months) versus long-term (2.5 years) ADT among 970 patients with stage T2c-T3 or N1 disease.[20] However, ADT should not be used alone or in combination with radical prostatectomy in clinically localized prostate cancer due to lack of survival benefit.[12]

The goal of ADT is to lower testosterone to <50 ng/dL, a level equivalent to castration.[12] The therapeutic options include bilateral orchiectomy or medical castration with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, which are considered equally effective.[12] Monotherapy with an antiandrogen is not currently recommended.[12,21] FDA-approved agents are described in Table 4. ADT has a variety of adverse effects, including osteoporosis, dyslipidemia, cardiovascular disease, and increased risk of diabetes and requires thorough patient education and monitoring.

Recurrent and Metastatic Disease

For patients with rising PSA levels, further evaluation is necessary to distinguish between biochemical recurrence and metastatic disease. For patients with biochemical recurrence alone, initiation of ADT or observation could be offered based on PSA velocity, patient's life expectancy, and comorbidities.[12] For patients with shorter PSA doubling time, early consideration of ADT might be preferred.[12] Intermittent ADT should be considered in these situations.[22] A meta-analysis of six randomized trials of men with locally advanced cancer showed no difference in overall or progression-free survival between intermittent or continuous ADT.[22] Patients on intermittent ADT had a better quality of life and fewer side effects. Generally, intermittent ADT refers to discontinuation of therapy once PSA falls below prespecified levels (<4 ng/dL) and reinitiating when PSA rises (usually 10–20 ng/dL).

For men with newly diagnosed metastatic prostate cancer, ADT continues to be the first-line treatment option. Intermittent ADT can be considered in these cases. Several meta-analyses have shown no difference in survival between intermittent and continuous approaches, with significant improvement of quality of life with intermittent ADT demonstrated in most studies.[23,24] For men starting on LHRH, combined androgen blockage (CAB) with antiandrogen is recommended to prevent tumor flare. The tumor flare is caused by initial induction of luteinizing hormone and follicle-stimulating hormone by LHRH agonists and usually resolves within 2 weeks of treatment initiation. CAB continued beyond that provides limited-to-no benefit.[12] More recent options for newly diagnosed metastatic disease include a combination of ADT with docetaxel or abiraterone with prednisone.[12] Two randomized trials assessed the new role of docetaxel, previously reserved for castration-resistant prostate cancer (CRPC). The CHAARTED trial compared ADT alone versus ADT with docetaxel for 6 cycles in 790 ADT-naive metastatic prostate cancer patients.[25] Median survival was prolonged from 44.0 to 57.6 months and progression was delayed from 11.7 to 20.2 months with the addition of docetaxel. Greater benefit was seen in high-volume disease, defined as visceral metastases or ≥4 bone metastases with at least one beyond the pelvis column. The benefit for low-volume disease is less certain and docetaxel therapy is not appropriate for patients without metastases or with low-volume metastatic disease. Additional toxicities associated with docetaxel included mucositis, fatigue, diarrhea, neutropenia, and neuropathy. Results of the STAMPEDE trial confirmed the survival benefit seen in the CHAARTED trial.[26] A recent meta-analysis evaluated three trials analyzing the addition of abiraterone with prednisone to ADT.[27] The authors found a 38% death-risk reduction with the addition of abiraterone compared with ADT alone, suggesting that this is viable therapeutic option.

Castration-resistant Prostate Cancer

CRPC refers to disease that progresses while on ADT. Possible mechanisms include an increase in autocrine and paracrine androgen synthesis or androgen-receptor activation.[28] ADT is continued beyond progression to maintain testosterone levels equivalent to castration.[12,29] Choice of therapeutic options for patients with CRPC depends on the presence or absence of metastases as well as disease symptoms.[12]

For minimally symptomatic disease, the options are to change antiandrogen, add abiraterone, or switch to second-line hormonal therapy such as ketoconazole, estrogens, or progesterones.[12,29] Due to similar mechanism of action, ketoconazole should not be offered to patients who progressed on abiraterone.

In the past decade, several novel treatment options have been shown to improve survival and quality of life for patients with CRPC.[30–36] Abiraterone and enzalutamide both work on the androgen axis and are described in more detail in Table 3. Both drugs have been studied in the pre- and postdocetaxel setting and have been shown to improve survival and secondary endpoints, such as pain and quality of life, compared with placebo.[30–33] Sipuleucel-T is an alternative treatment option for patients with metastatic CRPC who have minimal symptoms, good performance status (e.g., Eastern Cooperative Oncology Group Scale score 0–1), no liver metastases, and ≥6 months life expectancy.[12] Sipuleucel-T is an autologous cellular immunotherapy that demonstrated a 4.1-month improvement in overall survival (22% reduction in mortality) compared with placebo among patients who met the aforementioned criteria.[34] Therapy was generally well tolerated with flulike symptoms as the major adverse effect.[34] Another form of immunotherapy, pembrolizumab, may be offered for patients who are microsatellite instability-high or mismatch repair deficient and have progressed through at least one systemic therapy.[12]

For patients with symptomatic metastatic CRPC, docetaxel with a corticosteroid remains an NCCN category 1 recommendation.[12] Only 21-day docetaxel cycles have demonstrated survival advantage.[12] For patients who are symptomatic with bone-only metastases Radium-223 may be offered. This alpha-emitting radiopharmaceutical has been shown to improve survival in patients with symptomatic bone metastases as the only site of disease.[35] The most common grade 3 to 4 toxicities were hematologic.[35] Radium-223 should not be combined with any other chemotherapy due to risk of increased myelosuppression.[12] Cabazitaxel is a tubulin-binding taxane derivative that, in combination with a steroid, is considered the standard of care for patients who progress post docetaxel. In the postdocetaxel setting, cabazitaxel combined with prednisone significantly improved overall and progression-free survival compared with mitoxantrone and prednisone.[36] However, the incidence of neutropenia, diarrhea, and febrile neutropenia was higher in the cabazitaxel arm.[36] Thus, appropriate patient monitoring and use of prophylactic granulocyte growth factors should be considered. A lower cabazitaxel dose of 20 mg/m2 can be considered for frail patients.[37] This dose was shown to be noninferior to a standard 25-mg/m2 dose and caused fewer severe adverse events, including neutropenia.[37] Currently, there are no therapies that have been shown to offer survival advantage postcabazitaxel progression.[12] Mitoxantrone combined with prednisone offers palliation of symptoms, but failed to show improvement in overall survival compared with prednisone alone.[12] Men with advanced CRPC should be encouraged to participate in clinical trials.[12]

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