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Metastatic Prostate Cancer: An Update on Treatments and a Review of Patient Symptom Management

Lawrence Drudge-Coates
Anthony Delacruz
Richard Gledhill
Philiz Goh
Brian Tomlinson
CJON 2020, 24(4), 369-378 DOI: 10.1188/20.CJON.369-378

Background: Available treatment options have improved overall survival and contributed to delayed progression, but metastatic prostate cancer remains incurable. Treatment strategies are based on disease progression assessed by a combination of biochemical, radiographic, and symptomatic changes.

Objectives: The aim of this article is to review metastatic prostate cancer, symptoms representing disease progression, disease treatments, and symptom management.

Methods: A PubMed® search restricted to English-language articles published since 1990 was conducted in August 2018 with combinations of the keywords “metastatic prostate cancer,” “symptom assessment,” and “treatment.” Review articles were excluded, but their reference lists were reviewed to identify additional articles. Information from relevant articles published after August 2018 was added as appropriate based on author consensus.

Findings: Nursing professionals play vital roles in symptom recognition and reporting, identification of disease progression, patient education, and implementation of individualized treatment strategies.

The burden of prostate cancer is significant. Worldwide, it was the fourth most frequently diagnosed cancer type, with an estimated incidence of 1.27 million cases, and was ranked eighth among causes of cancer-related deaths, with an estimated 358,989 deaths among men in 2018 (International Agency for Research on Cancer & World Health Organization, 2018). In the United States, it is the leading cancer type among men in terms of incidence, with an estimated 191,930 new cases diagnosed in 2020, and the second most frequent cause of cancer-related death among men, with an estimated 33,330 deaths in 2020 (Siegel et al., 2020). At diagnosis, the disease is local, regionally disseminated, or distant in 78%, 12%, and 5% of men, respectively (Siegel et al., 2020). Estimates from Europe indicate that prostate cancer ranks fourth among the most frequently diagnosed cancer types overall, with an estimated 450,000 new cases being diagnosed in 2018 (Ferlay et al., 2018). Estimates indicate that prostate cancer will account for 78,800 deaths in Europe in 2020 (Carioli et al., 2020).

Despite therapies that have improved survival and delayed progression, metastatic prostate cancer remains incurable (Chi et al., 2019; Davis et al., 2019; Fizazi et al., 2017, 2019; Hussain et al., 2018; James et al., 2016; Parker et al., 2018; Smith et al., 2018). Disease progression, determined by biochemical, radiographic, and symptomatic changes (Saad et al., 2018; Scher et al., 2016), drives treatment decisions. As members of interprofessional teams, nurses provide assessments and symptom management in a safe and cost- and time-efficient manner (Drudge-Coates et al., 2019). This article provides an update about prostate cancer treatment management.

Disease Course

Disease progression in prostate cancer occurs in stages characterized by the development of metastases over time and appearance of symptoms. Localized prostate cancer is curable, with five-year survival rates being close to 100% (Siegel et al., 2018). Although prostate cancer that recurs after localized therapy is initially responsive to androgen deprivation therapy (ADT) involving surgical or chemical castration or nonsystemic salvage treatments (i.e., radiation therapy, surgery, or ablation), the disease progresses eventually within five years (Crawford et al., 2017). This stage, known as castration-resistant prostate cancer (CRPC), is classified as nonmetastatic CRPC (nmCRPC) if characterized by the lack of detectable disease at the primary location, lack of involvement of lymph nodes as detected by computed tomography or magnetic resonance imaging, or lack of detectable disease in bone or visceral organs (Mateo et al., 2019). Antiandrogen therapies apalutamide (Chi et al., 2019; Smith et al., 2018), enzalutamide (Davis et al., 2019; Hussain et al., 2018), and darolutamide (Fizazi et al., 2019) offer the promise of improved metastasis-free survival in patients with nmCRPC (see Tables 1 and 2).

nmCRPC eventually progresses to metastatic CRPC (mCRPC), characterized by the appearance of metastases in addition to a rise in serum prostate-specific antigen (PSA) levels. To best determine disease progression, providers evaluate PSA levels, clinical symptoms, and radiographic evidence (Karzai et al., 2015). The time for progression from nmCRPC to mCRPC varies, with 60% of men being reported to develop metastases within five years and most of these metastases occurring within the first 36 months (Moreira et al., 2016). mCRPC is incurable, despite the availability of multiple classes of therapeutic agents, including taxanes (e.g., docetaxel, cabazitaxel), antihormonal therapies (e.g., enzalutamide, abiraterone), immunotherapy (e.g., sipuleucel-T), and targeted alpha therapy (e.g., radium-223) (Dong et al., 2019). The median overall survival in patients with newly diagnosed mCRPC is about 42 months (James et al., 2015). Five-year survival among men with distant metastases in the United States is 30% (Siegel et al., 2018).

It has been shown that men with prostate cancer often do not understand the information given regarding the diagnosis of prostate cancer, its treatment, and subsequent side effects, such as sexual function, continence, and fatigue; such lack of knowledge has been shown to lead to anger, fear, and uncertainty for patients (Carter et al., 2011).

mCRPC Sequelae

Bone Metastases

Although prostate cancer can metastasize to the lymph nodes, liver, lungs, and brain, it predominantly spreads to bone, with evidence of bone metastases having been documented in as many as 90% of men with advanced prostate cancer (Gandaglia et al., 2015; Walz et al., 2019). Of 8,820 men with mCRPC enrolled in phase 3 clinical trials from 1999 to 2012, 73% had bone metastases at study entry and 43% had only bone metastases (Halabi et al., 2016). In the initial stages, bone metastases are frequently asymptomatic (Drudge-Coates et al., 2018).

Once metastasis to the bone has occurred, a complex interaction between tumor cells, bone cells, and the bone microenvironment results in bone remodeling (Kolb & Bussard, 2019). Although bone metastases are traditionally thought of as being osteoblastic, based on their radiographic appearance, it is now clear that osteoblastic (bone formation) and osteoclastic (bone resorption) processes are dysregulated in patients who have bone metastases (Kolb & Bussard, 2019; Suominen et al., 2017).

Bone metastases are associated with significant morbidity and increased mortality (Scher et al., 2015). Other symptoms of bone metastases include spinal cord compression, which may sometimes be the first sign of malignancy (Wänman et al., 2017), and bone fractures. Pain necessitating radiation therapy, spinal cord compressions, bone fractures, and surgery to the bones are collectively referred to as symptomatic skeletal-related events (SSEs) and have a detrimental effect on quality of life, in addition to being associated with enhanced mortality (Howard et al., 2016; Walz et al., 2019). In a survey that examined symptom burden in patients with mCRPC, of whom more than half had bone metastases, 73% reported fatigue, 63% reported urinary symptoms (difficulties/incontinence), 62% reported sexual dysfunction, and 52% reported bone pain as being the most commonly occurring symptoms (Drudge-Coates et al., 2018).

Fatigue

As the most prevalent symptom, fatigue has been shown to be the most distressing symptom experienced by patients with mCRPC, and it is one of the major symptoms negatively affecting quality of life (Rodríguez Antolín et al., 2019). Vigilant assessment of fatigue allows prompt management using interventions such as resistance training combined with aerobic exercise, which can optimize patient quality of life (Baguley et al., 2017; Taaffe et al., 2017). For example, physical exercise has been shown to significantly reduce fatigue and increase vitality in men undergoing treatment with ADT, with patients reporting the highest levels of fatigue and lowest vitality having the greatest benefits (Taaffe et al., 2017).

Treatment of mCRPC

Treatment decisions for patients with mCRPC are based on symptoms, patient performance status, and extent of disease (Lowrance et al., 2016; Saad et al., 2015). Symptoms suggesting disease progression include cancer-related pain, analgesic use, and deterioration in health-related quality-of-life scores. During the past 30 years, prostate cancer treatments have progressed; in the past 15 years, treatments for mCRPC have included docetaxel, abiraterone, enzalutamide, and radium-223. Table 3 reviews treatment management of CRPC. Use of these therapeutic agents is based on guidelines published by the Canadian Urological Association, European Association of Urology, European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network in the United States (ESMO, 2019; Mohler et al., 2019; Mottet et al., 2019; Saad et al., 2015).

Before 2018, the only approved treatment for metastatic castration-sensitive prostate cancer (mCSPC) and nmCRPC was ADT. However, several agents have been approved during the past two years based on findings of large pivotal phase 3 trials. Patients with newly diagnosed metastatic prostate cancer (hormone-sensitive) can be given ADT with abiraterone or docetaxel, and options for patients with mCRPC include abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, and sipuleucel-T (United States only). For patients with nmCRPC, the therapeutic options are the hormonal therapies enzalutamide, apalutamide, and darolutamide.

Treatment Complications

Patients with mCRPC are at an elevated risk for bone-related complications (Litwin & Tan, 2017). In addition, the evolving treatment landscape in prostate cancer leads to prolonged exposure to antihormonal therapy and ADT, which are associated with a heightened risk of osteoporosis and fractures (Joseph et al., 2019; Poulsen et al., 2019; Rachner et al., 2018). Patients receiving ADT experience a higher rate of bone loss (2%–5% per year), with the relative risk of bone fractures increasing by 21%–54% with longer ADT treatment durations (Cianferotti et al., 2017; Rachner et al., 2018). Therefore, patients with mCRPC and those receiving ADT and antihormonal therapy are periodically assessed for fracture risk so that a management plan can follow. Treatment with bone health agents is recommended for osteoporosis prophylaxis or when the absolute fracture risk warrants drug therapy, although patients are also required to be monitored for osteonecrosis of the jaw, which is a potential adverse effect of agents used for treatment of prostate cancer. Supportive bone health agents recommended for patients with mCRPC and those on antihormonal therapies include zoledronic acid (a bisphosphonate) and denosumab, which prevent bone resorption and help delay and prevent SSEs (ESMO, 2019; Mohler et al., 2019; Mottet et al., 2019).

In addition, patients on ADT can experience a number of adverse effects, including hot flashes from andropause syndrome, night sweats, gynecomastia (breast enlargement), cognitive decline, and changes in sexual function, which can have a negative effect on a patient’s quality of life (Basketter et al., 2018).

Symptom Management

According to a global survey of patients and caregivers, fatigue, urinary symptoms, impaired sexual function, bone pain, and difficulty sleeping are the most frequent patient-reported symptoms in men with mCRPC (Drudge-Coates et al., 2018). When determining treatments, providers consider the patient’s symptoms (Lowrance et al., 2016; Saad et al., 2015). Providers also evaluate symptoms when determining changes in treatment (Saad et al., 2018). When determining progression, providers consider biochemical (e.g., higher PSA levels), radiographic (e.g., changes on computed tomography and bone scans), and clinical factors (e.g., heightened symptoms) (Saad et al., 2018; Scher et al., 2016).

Pain is a symptom that is consistently associated with reduced survival (Broder et al., 2015; Saad et al., 2018). Patients rank pain as a major challenge associated with metastatic prostate cancer (Drudge-Coates et al., 2018). Because pain is subjective, patients may delay reporting pain changes to providers because they may perceive pain as a sign of disease progression (Drudge-Coates et al., 2018; Saad et al., 2018). In addition, patients may be uncertain about whether their pain is related to their cancer or to other causes, such as aging or arthritis. Other symptoms associated with progression are fatigue, urinary symptoms, impaired sexual function, bone pain, and difficulty sleeping (Drudge-Coates et al., 2018). These symptoms may be experienced differently at the various disease stages (Saad et al., 2018). For patients with mCRPC in clinical trials, guidelines recommend reporting a core set of patient-reported symptoms so that symptom management interventions can be studied; these include urinary incontinence, urinary obstruction and irritation, bowel-related symptoms, sexual dysfunction, and hormonal symptoms for patients with localized prostate cancer and pain, fatigue, mental well-being, and physical well-being (Chen et al., 2014).

Symptom Assessment Instruments

Several symptom assessment instruments focus on the clinical care of patients with metastatic prostate cancer (Saad et al., 2018). The Functional Assessment of Cancer Therapy–Prostate, which is applicable across all disease stages, consists of 27 core items that assess patient function in four domains: physical, social/family, emotional, and functional well-being, addressing issues including those related to sexuality, bowel/bladder function, and pain (Esper et al., 1997). The questionnaire is designed for patient self-administration and can be completed by patients prior to their clinical appointment, thereby helping nurses and clinicians address issues as part of the clinical consultation. It also can be used repeatedly to assess the success of an intervention.

The Brief Pain Inventory, which is available in short- and long-form versions (with 9 and 17 items, respectively), is a validated tool that permits the capture of detailed descriptions of pain using a visual analog scale and can be self-administered by patients (Daut et al., 1983; Poquet & Lin, 2016). In addition, it provides an anatomic drawing of the human form from which patients can mark where their pain is located. It can be used free of charge in clinical practice, and instructions for its use and scoring are available (Poquet & Lin, 2016).

The Edmonton Symptom Assessment System, which is also amenable to self-administration and captures levels of pain, activity, nausea, depression, anxiety, drowsiness, appetite, and sensation of well-being, is brief and helps identify areas of concern, engage patients in their symptom assessment, and monitor symptom changes over time (Bruera et al., 1991; Schulman-Green et al., 2010). However, inclusion rules and frequency of assessments were unclear, and there were difficulties in interpreting the numeric symptom rating scale.

The Expanded Prostate Cancer Index Composite (EPIC) tool was developed by expanding the 20-item University of California–Los Angeles Prostate Cancer Index to a 50-item instrument that measures a wide range of urinary, bowel, sexual, and hormonal symptoms (Wei et al., 2000). A shortened 26-item version, EPIC-26, was developed and validated to retain the ability to measure the same five prostate cancer–specific quality-of-life domains as the original 50-item version (Szymanski et al., 2010). However, it does not capture events occurring outside of a clinic visit (Saad et al., 2018).

In 2018, Saad et al. designed a simplified 10-point assessment tool scale that permits patients to rate their mobility, ability to conduct activities of daily living, sleep, overall quality of life, and pain levels, with higher numbers indicating worse symptoms (see Figure 1). According to Saad et al. (2018), this simplified instrument, which has yet to be validated, can be used by patients of any age and education level who are treated in nonacademic medical centers. The instrument includes an outline of the human anatomy so that patients can show where they are in pain.

Implications for Nursing

Nurses are in an ideal position to provide individualized patient care approaches to help patients understand their disease and its implications and enable them to make informed treatment decisions by simplifying the often complex data surrounding the benefits and side effects of treatments. Nurses also can provide holistic support for patients and their families. Developments in treatments have invariably added to the complexity of the decisions that many patients face; therefore, a key role for nurses is encouraging patients to participate in clinical decision making (Basketter et al., 2018). Nurses can also play an essential role in discussing treatment side effects with patients and their partners, and how these can be treated, supported, or minimized, where possible.

Conclusion

Taken together, the discussed studies highlight the importance of symptom recognition and reporting as a means to identify clinical progression, which, in turn, has implications for disease assessment and management. Nursing professionals, being involved in the direct day-to-day care of patients with prostate cancer, are uniquely positioned to play a pivotal role in these important aspects of patient care (symptom recognition and reporting, identification of clinical progression, and intervention to enable implementation of disease stage-specific treatment strategies). To do this efficiently, they will need to be well-informed of the latest advances not only in treatment, but also in symptom assessment and reporting. The advances in treatment and the currently available symptom assessment tools that have been discussed in this article based on expert consensus will better equip nurses to provide optimal levels of patient care.

About the Author(s)

Lawrence Drudge-Coates, MSc, Dip/He, RGN, is a urological oncology clinical nurse specialist and an honorary lecturer at King’s College Hospital National Health Service (NHS) Foundation Trust in Denmark Hill, London, United Kingdom (UK); Anthony Delacruz, RN, ANP-BC, is an adult nurse practitioner in the Prostate Cancer Clinical Trials Consortium at Memorial Sloan Kettering Cancer Center in New York, NY; Richard Gledhill, BSc, RGN, is a prostate cancer nurse specialist at University Hospitals Birmingham NHS Foundation Trust in Birmingham, UK; Philiz Goh, RN, BScN, CON(c), BSc, MN-HSLA(c), is an RN at Sunnybrook Health Sciences Centre at the University of Toronto in Ontario, Canada; and Brian Tomlinson, MPA, is the director of patient and professional partnerships at Foundation Medicine in Cambridge, MA. The authors take full responsibility for this content. Drudge-Coates has served on advisory boards and received honoraria from Astellas Pharma, Amgen, and Bayer Pharmaceuticals. Gledhill has served on advisory boards and received honoraria from Ferring Pharmaceuticals. Medical writing support was provided by Prasad Kulkarni, PhD, CMPP, of Asclepius Medical Communications LLC in Ridgewood, NJ, and Zara Jethani, MS, MBA, of Laasya Design in Woodland Hills, CA, and was funded by Bayer HealthCare Pharmaceuticals Inc. in Whippany, NJ. The article has been reviewed by independent peer reviewers to ensure that it is objective and free from bias. Drudge-Coates can be reached at ldrudge-coates@nhs.net, with copy to CJONEditor@ons.org. (Submitted October 2019. Accepted February 10, 2020.)

 

References 

Baguley, B.J., Bolam, K.A., Wright, O.R.L., & Skinner, T.L. (2017). The effect of nutrition therapy and exercise on cancer-related fatigue and quality of life in men with prostate cancer: A systematic review. Nutrients, 9(9), pii: E1003. https://doi.org/10.3390/nu9091003

Basketter, V., Benney, M., Causer, L., Fleure, L., Hames, D., Jones, S., . . . White, L. (2018). Continuous, comprehensive and crucial care: The role of the CNS in the metastatic castration-resistant prostate cancer patient pathway. British Journal of Nursing, 27(Sup4b), S1–S8. https://doi.org/10.12968/bjon.2018.27.Sup4b.S1

Broder, M.S., Gutierrez, B., Cherepanov, D., & Linhares, Y. (2015). Burden of skeletal-related events in prostate cancer: Unmet need in pain improvement. Supportive Care in Cancer, 23(1), 237–247. https://doi.org/10.1007/s00520-014-2437-3

Bruera, E., Kuehn, N., Miller, M.J., Selmser, P., & Macmillan, K. (1991). The Edmonton Symptom Assessment System (ESAS): A simple method for the assessment of palliative care patients. Journal of Palliative Care, 7(2), 6–9. https://doi.org/10.1177/082585979100700202

Carioli, G., Bertuccio, P., Boffetta, P., Levi, F., La Vecchia, C., Negri, E., & Malvezzi, M. (2020). European cancer mortality predictions for the year 2020 with a focus on prostate cancer. Annals of Oncology, 31(5), 650–658. https://doi.org/10.1016/j.annonc.2020.02.009

Carter, N., Bryant-Lukosius, D., DiCenso, A., Blythe, J., & Neville, A.J. (2011). The supportive care needs of men with advanced prostate cancer. Oncology Nursing Forum, 38(2), 189–198. https://doi.org/10.1188/11.ONF.189-198

Chen, R.C., Chang, P., Vetter, R.J., Lukka, H., Stokes, W.A., Sanda, M.G., . . . Sandler, H.M. (2014). Recommended patient-reported core set of symptoms to measure in prostate cancer treatment trials. Journal of the National Cancer Institute, 106(7). https://doi.org/10.1093/jnci/dju132

Chi, K.N., Agarwal, N., Bjartell, A., Chung, B.H., Pereira de Santana Gomes, A.J., Given, R., . . . Chowdhury, S. (2019). Apalutamide for metastatic, castration-sensitive prostate cancer. New England Journal of Medicine, 381(1), 13–24. https://doi.org/10.1056/NEJMoa1903307

Cianferotti, L., Bertoldo, F., Carini, M., Kanis, J.A., Lapini, A., Longo, N., . . . Brandi, M.L. (2017). The prevention of fragility fractures in patients with non-metastatic prostate cancer: A position statement by the international osteoporosis foundation. Oncotarget, 8(43), 75646–75663. https://doi.org/10.18632/oncotarget.17980

Crawford, E.D., Petrylak, D., & Sartor, O. (2017). Navigating the evolving therapeutic landscape in advanced prostate cancer. Urologic Oncology, 35(Suppl.), S1–S13. https://doi.org/10.1016/j.urolonc.2017.01.020

Daut, R.L., Cleeland, C.S., & Flanery, R.C. (1983). Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain, 17(2), 197–210. https://doi.org/10.1016/0304-3959(83)90143-4

Davis, I.D., Martin, A.J., Stockler, M.R., Begbie, S., Chi, K.N., Chowdhury, S., . . . Sweeney, C.J. (2019). Enzalutamide with standard first-line therapy in metastatic prostate cancer. New England Journal of Medicine, 381(2), 121–131. https://doi.org/10.1056/NEJMoa1903835

dela Rama, F., & Pratz, C. (2015). Navigating treatment of metastatic castration-resistant prostate cancer: Nursing perspectives. Clinical Journal of Oncology Nursing, 19(6), 723–732. https://doi.org/10.1188/15.CJON.723-732

Dong, L., Zieren, R.C., Xue, W., de Reijke, T.M., & Pienta, K.J. (2019). Metastatic prostate cancer remains incurable, why? Asian Journal of Urology, 6(1), 26–41. https://doi.org/10.1016/j.ajur.2018.11.005

Dreicer, R. (2014). How to approach sequencing therapy in patients with metastatic castration resistant prostate cancer. Canadian Journal of Urology, 21(2, Suppl. 1), 93–97.

Drudge-Coates, L., Khati, V., Ballesteros, R., Martyn-Hemphill, C., Brown, C., Green, J., . . . Muir, G. (2019). A nurse practitioner model for the assessment of suspected prostate cancer referrals is safe, cost and time efficient. eCancer, 13, 994. https://doi.org/10.3332/ecancer.2019.994

Drudge-Coates, L., Oh, W.K., Tombal, B., Delacruz, A., Tomlinson, B., Ripley, A.V., . . . Shore, N.D. (2018). Recognizing symptom burden in advanced prostate cancer: A global patient and caregiver survey. Clinical Genitourinary Cancer, 16(2), e411–e419. https://doi.org/10.1016/j.clgc.2017.09.015

Esper, P., Mo, F., Chodak, G., Sinner, M., Cella, D., & Pienta, K.J. (1997). Measuring quality of life in men with prostate cancer using the Functional Assessment of Cancer Therapy–Prostate instrument. Urology, 50(6), 920–928. https://doi.org/10.1016/S0090-4295(97)00459-7

European Society for Medical Oncology. (2019, April 2). Cancer of the prostate: ESMO clinical practice guidelines. https://www.esmo.org/Guidelines/Genitourinary-Cancers/Cancer-of-the-Pros...

Ferlay, J., Colombet, M., Soerjomataram, I., Dyba, T., Randi, G., Bettio, M., . . . Bray, F. (2018). Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. European Journal of Cancer, 103, 356–387. https://doi.org/10.1016/j.ejca.2018.07.005

Fizazi, K., Shore, N., Tammela, T.L., Ulys, A., Vjaters, E., Polyakov, S., . . . Smith, M.R. (2019). Darolutamide in nonmetastatic, castration-resistant prostate cancer. New England Journal of Medicine, 380(13), 1235–1246. https://doi.org/10.1056/NEJMoa1815671

Fizazi, K., Tran, N., Fein, L., Matsubara, N., Rodriguez-Antolin, A., Alekseev, B.Y., . . . Chi, K.N. (2017). Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. New England Journal of Medicine, 377(4), 352–360. https://doi.org/10.1056/NEJMoa1704174

Gandaglia, G., Karakiewicz, P.I., Briganti, A., Passoni, N.M., Schiffmann, J., Trudeau, V., . . . Sun, M. (2015). Impact of the site of metastases on survival in patients with metastatic prostate cancer. European Urology, 68(2), 325–334. https://doi.org/10.1016/j.eururo.2014.07.020

Gartrell, B.A., Coleman, R., Efstathiou, E., Fizazi, K., Logothetis, C.J., Smith, M.R., . . . Saad, F. (2015). Metastatic prostate cancer and the bone: Significance and therapeutic options. European Urology, 68(5), 850–858. https://doi.org/10.1016/j.eururo.2015.06.039

Halabi, S., Kelly, W.K., Ma, H., Zhou, H., Solomon, N.C., Fizazi, K., . . . Small, E.J. (2016). Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. Journal of Clinical Oncology, 34(14), 1652–1659. https://doi.org/10.1200/jco.2015.65.7270

Heidegger, I., Brandt, M.P., & Heck, M.M. (2020). Treatment of non-mestastatic castration resistant prostate cancer in 2020: What is the best? Urologic Oncology, 38(4), 129–136. https://doi.org/10.1016/j.urolonc.2019.11.007

Howard, L.E., De Hoedt, A.M., Aronson, W.J., Kane, C.J., Amling, C.L., Cooperberg, M.R., . . . Freedland, S.J. (2016). Do skeletal-related events predict overall survival in men with metastatic castration-resistant prostate cancer? Prostate Cancer and Prostatic Diseases, 19(4), 380–384. https://doi.org/10.1038/pcan.2016.26

Hussain, M., Fizazi, K., Saad, F., Rathenborg, P., Shore, N., Ferreira, U., . . . Sternberg, C.N. (2018). Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. New England Journal of Medicine, 378(26), 2465–2474. https://doi.org/10.1056/NEJMoa1800536

International Agency for Research on Cancer & World Health Organization. (2018). Prostate. Global Cancer Observatory. http://gco.iarc.fr/today/data/factsheets/cancers/27-Prostate-fact-sheet.pdf

James, N.D., Spears, M.R., Clarke, N.W., Dearnaley, D.P., De Bono, J.S., Gale, J., . . . Sydes, M.R. (2015). Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). European Urology, 67(6), 1028–1038. https://doi.org/10.1016/j.eururo.2014.09.032

James, N.D., Sydes, M.R., Clarke, N.W., Mason, M.D., Dearnaley, D.P., Spears, M.R., . . . Parmar, M.K.B. (2016). Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet, 387(10024), 1163–1177.

Joseph, J.S., Lam, V., & Patel, M.I. (2019). Preventing osteoporosis in men taking androgen deprivation therapy for prostate cancer: A systematic review and meta-analysis. European Urology Oncology, 2(5), 551–561. https://doi.org/10.1016/j.euo.2018.11.001

Karzai, F.H., Madan, R.A., & Figg, W.D. (2015). Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer. Southern Medical Journal, 108(4), 224–228. https://doi.org/10.14423/smj.0000000000000266

Kolb, A.D., & Bussard, K.M. (2019). The bone extracellular matrix as an ideal milieu for cancer cell metastases. Cancers, 11(7), 1020. https://doi.org/10.3390/cancers11071020

Litwin, M.S., & Tan, H.J. (2017). The diagnosis and treatment of prostate cancer: A review. JAMA, 317(24), 2532–2542. https://doi.org/10.1001/jama.2017.7248

Lowrance, W.T., Roth, B.J., Kirkby, E., Murad, M.H., & Cookson, M.S. (2016). Castration-resistant prostate cancer: AUA guideline amendment 2015. Journal of Urology, 195(5), 1444–1452.

Mateo, J., Fizazi, K., Gillessen, S., Heidenreich, A., Perez-Lopez, R., Oyen, W.J.G., . . . de Bono, J.S. (2019). Managing nonmetastatic castration-resistant prostate cancer. European Urology, 75(2), 285–293. https://doi.org/10.1016/j.eururo.2018.07.035

Mohler, J.L., Antonarakis, E.S., Armstrong, A.J., D’Amico, A.V., Davis, B.J., Dorff, T., . . . Freedman-Cass, D.A. (2019). Prostate cancer, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 17(5), 479–505.

Moreira, D.M., Howard, L.E., Sourbeer, K.N., Amarasekara, H.S., Chow, L.C., Cockrell, D.C., . . . Freedland, S.J. (2016). Predictors of time to metastasis in castration-resistant prostate cancer. Urology, 96, 171–176. https://doi.org/10.1016/j.urology.2016.06.011

Mottet, N., Cornford, P., van den Bergh, R.C.N., Briers, E., De Santis, M., Fanti, S., . . . Wiegel, T. (2019). Prostate cancer. UROsource. https://uroweb.org/guideline/prostate-cancer

National Cancer Institute. (2019, August 23). Drugs approved for prostate cancer. National Institutes of Health. https://www.cancer.gov/about-cancer/treatment/drugs/prostate

Parker, C.C., James, N.D., Brawley, C.D., Clarke, N.W., Hoyle, A.P., Ali, A., . . . Sydes, M.R. (2018). Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial. Lancet, 392(10162), 2353–2366.

Poquet, N., & Lin, C. (2016). The Brief Pain Inventory (BPI). Journal of Physiotherapy, 62(1), 52. https://doi.org/10.1016/j.jphys.2015.07.001

Poulsen, M.H., Frost, M., Abrahamsen, B., Gerke, O., Walter, S., & Lund, L. (2019). Osteoporosis and prostate cancer; a 24-month prospective observational study during androgen deprivation therapy. Scandanavian Journal of Urology, 53(1), 34–39.

Rachner, T.D., Coleman, R., Hadji, P., & Hofbauer, L.C. (2018). Bone health during endocrine therapy for cancer. Lancet Diabetes and Endocrinology, 6(11), 901–910.

Rodríguez Antolín, A., Martínez-Piñeiro, L., Jiménez Romero, M.E., García Ramos, J.B., López Bellido, D., Muñoz Del Toro, J., . . . Gómez Veiga, F. (2019). Prevalence of fatigue and impact on quality of life in castration-resistant prostate cancer patients: The VITAL study. BMC Urology, 19(1), 92. https://doi.org/10.1186/s12894-019-0527-8

Saad, F., Chi, K.N., Finelli, A., Hotte, S.J., Izawa, J., Kapoor, A., . . . Fleshner, N.E. (2015). The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). Canadian Urological Association Journal, 9(3-4), 90–96. https://doi.org/10.5489/cuaj.2526

Saad, F., Pouliot, F., Danielson, B., Catton, C., & Kapoor, A. (2018). Symptom assessment to guide treatment selection and determine progression in metastatic castration-resistant prostate cancer: Expert opinion and review of the evidence. Canadian Urological Association Journal, 12(9), E415–E420. https://doi.org/10.5489/cuaj.5145

Scher, H.I., Morris, M.J., Stadler, W.M., Higano, C., Basch, E., Fizazi, K., . . . Armstrong, A.J. (2016). Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the prostate cancer clinical trials working group 3. Journal of Clinical Oncology, 34(12), 1402–1418. https://doi.org/10.1200/jco.2015.64.2702

Scher, H.I., Solo, K., Valant, J., Todd, M.B., & Mehra, M. (2015). Prevalence of prostate cancer clinical states and mortality in the United States: Estimates using a dynamic progression model. PLOS ONE, 10(10), e0139440. https://doi.org/10.1371/journal.pone.0139440

Schulman-Green, D., Cherlin, E.J., McCorkle, R., Carlson, M.D.A., Pace, K.B., Neigh, J., . . . Bradley, E.H. (2010). Benefits and challenges in use of a standardized symptom assessment instrument in hospice. Journal of Palliative Medicine, 13(2), 155–159.

Siegel, R.L., Miller, K.D., & Jemal, A. (2018). Cancer statistics, 2018. CA: A Cancer Journal for Clinicians, 68(1), 7–30. https://doi.org/10.3322/caac.21442

Siegel, R.L., Miller, K.D., & Jemal, A. (2020). Cancer statistics, 2020. CA: A Cancer Journal for Clinicians, 70(1), 7–30. https://doi.org/10.3322/caac.21590

Smith, M.R., Saad, F., Chowdhury, S., Oudard, S., Hadaschik, B.A., Graff, J.N., . . . Small, E.J. (2018). Apalutamide treatment and metastasis-free survival in prostate cancer. New England Journal of Medicine, 378(15), 1408–1418. https://doi.org/10.1056/NEJMoa1715546

Suominen, M.I., Fagerlund, K.M., Rissanen, J.P., Konkol, Y.M., Morko, J.P., Peng, Z., . . . Scholz, A. (2017). Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clinical Cancer Research, 23(15), 4335–4346. https://doi.org/10.1158/1078-0432.Ccr-16-2955

Suzman, D.L., Boikos, S.A., & Carducci, M.A. (2014). Bone-targeting agents in prostate cancer. Cancer and Metastasis Reviews, 33(2-3), 619–628. https://doi.org/10.1007/s10555-013-9480-2

Szymanski, K.M., Wei, J.T., Dunn, R.L., & Sanda, M.G. (2010). Development and validation of an abbreviated version of the Expanded Prostate Cancer Index Composite instrument for measuring health-related quality of life among prostate cancer survivors. Urology, 76(5), 1245–1250. https://doi.org/10.1016/j.urology.2010.01.027

Taaffe, D.R., Newton, R.U., Spry, N., Joseph, D., Chambers, S.K., Gardiner, R.A., . . . Galvão, D.A. (2017). Effects of different exercise modalities on fatigue in prostate cancer patients undergoing androgen deprivation therapy: A year-long randomised controlled trial. European Urology, 72(2), 293–299. https://doi.org/10.1016/j.eururo.2017.02.019

Traboulsi, S.L., & Saad, F. (2018). Management of nonmetastatic castration-resistant prostate cancer. Current Opinion in Supportive and Palliative Care, 12(3), 366–371.

Walz, S., Maas, M., Stenzl, A., & Todenhöfer, T. (2019). Bone health issues in patients with prostate cancer: An evidence-based review. World Journal of Men’s Health, 38(2), 151.

Wänman, J., Grabowski, P., Nyström, H., Gustafsson, P., Bergh, A., Widmark, A., & Crnalic, S. (2017). Metastatic spinal cord compression as the first sign of malignancy. Acta Orthopaedica, 88(4), 457–462. https://doi.org/10.1080/17453674.2017.1319179

Wei, J.T., Dunn, R.L., Litwin, M.S., Sandler, H.M., & Sanda, M.G. (2000). Development and validation of the Expanded Prostate Cancer Index Composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology, 56(6), 899–905. https://doi.org/10.1016/s0090-4295%2800%2900858-x