Treatment of Advanced Prostatic Cancer: Changing Landscape

The rising burden of advanced Prostatic Cancer

Advanced prostate cancer typically represents a metastatic disease, which spreads beyond the localized region of prostate to its surrounding tissues and pelvic lymph nodes. Ongoing debates suggest that patients with cancer outside the prostate capsule, and those at high risk of progression and deaths may be considered to have advanced disease state.¹Moul JW. The Evolving Definition of Advanced Prostate Cancer.Reviews in Urology. 2004;6(Suppl 8):S10-S17.   The burden of prostate cancer is immense and its rising trend has been witnessed, especially in the developing nations. In an epidemiological study conducted in 2008, it was estimated that 9,13,000 new cases and 2,15,000 deaths were attributable to prostate cancer worldwide.²Sridharan S, Warde P. The importance of local control in high-risk locally advanced prostate cancer. Current Oncology. 2012;19(Suppl 3):S6-S12.  ³Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G. The Worldwide Epidemiology of Prostate Cancer: Perspectives from Autopsy Studies. The Canadian journal of urology. 2008;15(1):3866-3871.   Remarkably, the burden of the disease is high in the Asia-Pacific region and among the elderly.⁴Baade PD, Youlden DR, Cramb SM, Dunn J, Gardiner RA. Epidemiology of prostate cancer in the Asia-Pacific region. Prostate International. 2013;1(2):47-58.   Cancer registries in India have shown that certain types of cancers are increasing at a rapid pace. These include prostate cancer among the Indian males, which is regarded as the second most common site of cancer in cities like Delhi,Pune, Kolkatta and Thiruvananthapuram, third most common site in Mumbai and Bangalore, and amidst the top ten in the rest of the population-based cancer registries of India. Consistently, according to the population-based cancer registries of India, a rising trend has been observed in the incidence rates over time, with an annual percentage change of 3.4%.5 The high incidence and mortality rates indicate the public health significance of this disorder.³Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G. The Worldwide Epidemiology of Prostate Cancer: Perspectives from Autopsy Studies. The Canadian journal of urology. 2008;15(1):3866-3871.  

Prostate cancers have substantial economic impact,and utilize significant proportion of healthcare resources.⁶Alemayehu B, Buysman E, Parry D, Becker L, Nathan F. Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population. J Med Econ. 2010;13(2):351-61.   A study⁷Yong C, Onukwugha E, Mullins CD, Seal B, Hussain A. The use of health services among elderly patients with stage IV prostate cancer in the initial period following diagnosis. J Geriatr Oncol. 2014 Jul;5(3):290-8.   was conducted to estimate the health resource utilization among aged males with advanced prostate cancer. The study evaluated data of patients more than 66 years of age using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. A total of 3,379 patients with advanced prostate cancer were included in the study. It was observed that healthcare resource utilization was considerably more in patients with advanced diseases.The rate of hospitalization and length of hospital stay was more in patients with metastasis (M1) compared to patients without metastasis (M0). It was found that elderly individuals with advanced prostate cancer experienced substantial clinical burden subsequent to diagnosis.

Additionally, it is important to understand the risk stratification of patients with prostate cancers in order to provide most appropriate therapeutic options, tailored according to the requirement of the patient. Table 1 depicts the risk stratification in prostate cancer; low, intermediate, and high risk.¹Moul JW. The Evolving Definition of Advanced Prostate Cancer.Reviews in Urology. 2004;6(Suppl 8):S10-S17.   It is important to realize that significant changing paradigms in different aspects of advanced prostate cancer may not only contribute to increased burden of the disease but also influence clinical decisions.

Treatment of advanced prostatic cancer

Treatment strategies for prostate cancer are continuously evolving. A vast variety of agents with different efficacies, toxicities, and mechanisms of actions have revolutionized the therapeutic sphere.Regardless of the options available for treatment, a special emphasis is placed on deriving treatment benefits while keeping in mind the risks associated with treatments.¹Moul JW. The Evolving Definition of Advanced Prostate Cancer.Reviews in Urology. 2004;6(Suppl 8):S10-S17.  ⁸Vaishampayan U. Therapeutic Options and Multifaceted Treatment Paradigms In Metastatic Castrate Resistant Prostate Cancer. Current opinion in oncology. 2014;26(3):265-273.   Some of the therapies currently used for advanced prostate cancer are enlisted in Box 1. The currently available agents help the healthcare practitioners in providing their patients with optimal symptomatic relief whilst improving their overall survival. Besides, numerous novel agents such as calcitriol, immunotherapies, small molecule inhibitors,and nucleotide-based targeted therapy are under development.⁹Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: present and future. Curr Urol Rep. 2007 Jan;8(1):53-9.  

The currently recommended therapies are primarily based on patient and tumor characteristics. The main aim of the treatment is to overcome the emerging resistance while imparting therapeutic benefits to the patient. In addition, efforts are being invested to devise predictive biomarkers that may help in optimizing therapeutic outcomes and restrain cost and adverse events associated with different therapies.⁸Vaishampayan U. Therapeutic Options and Multifaceted Treatment Paradigms In Metastatic Castrate Resistant Prostate Cancer. Current opinion in oncology. 2014;26(3):265-273.  

Androgen deprivation therapy is the mainstay in advanced prostatic cancer including metastatic hormone-naïve and castration-resistant prostate cancer.¹⁰Golabek T, Belsey J, Drewa T, KoÅ‚odziej A, Skoneczna I, Milecki P,Dobruch J, SÅ‚ojewski M, ChÅ‚osta PL. Evidence-based recommendations on androgen deprivation therapy for localized and advanced prostate cancer. Cent European J Urol. 2016;69(2):131-8.   Despite androgen deprivation treatment,many cases of prostate cancer progress to castrationresistant state. The acquired resistance may be attributable to persistence of intratumoral androgens,mutation of active androgen receptor proteins,increase in androgen receptor protein expression, exaggerated activity of androgen receptor coregulatory proteins, and excessive signaling of other proliferative pathways. In such events, chemotherapy with docetaxel is assumed to be the preferred therapy;however, due to limited survival benefits, newer therapies are warranted.¹¹Yoo S, Choi SY, You D, Kim CS. New drugs in prostate cancer. Prostate Int. 2016 Jun;4(2):37-42.  

Medical therapy and surgical castration are important aspects of therapy in advanced prostate cancer. Methods for androgen ablation range from invasive options like bilateral orchiectomy to medical therapy with luteinizing hormone-releasing hormone (LHRH) analogues and antagonists, and combined androgen blockade. For patients with advanced disease, and within a managed care environment, the following aspects merit a dialogue:

• LHRH agonists versus bilateral orchiectomy;medical therapy or surgical castration
• Combined androgen blockade versus monotherapy
• LHRH agonists versus antagonists
• Modifying LHRH dosing according to serum testosterone levels.

Surgical option such as orchiectomy is regarded as a gold standard for androgen ablation; however,LHRH agents have conferred equivalent therapeutic advantages. Of note, medical management has an edge over surgical castration partially owing to the psychological implication of the latter.¹²Dreicer R. Managing advanced prostate cancer: the rapidly changing treatment landscape. Am J Manag Care. 2014 Dec;20(12 Suppl):S282-9.  

In advanced prostatic cancer, combined androgen blockade has been widely used. However, evidences regarding superiority of combined androgen blockade compared to monotherapy are equivocal. The survival benefits, cost effectiveness, impact on quality of life,and safety profile of combined androgen therapy remain arguable. It is presumed that combined androgen blockade with castration may be a better mode of therapy than castration alone, as oftentimes castration alone is insufficient to eliminate androgens.Nonetheless, results from various studies have been inconsistent, and therefore, in such a setting, it may not appear feasible to refute or accept combined androgen blockade therapy.¹³Iida K. Monotherapy versus combined androgen blockade for advanced/metastatic prostate cancer. Gan To Kagaku Ryoho. 2011 Dec;38(13):2553-7.   ¹⁴Akaza H. Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness. Cancer Sci. 2011 Jan;102(1):51-6.  

For more than two decades, LHRH agonists and antagonists have been used as methods of androgen deprivation in patients with advanced prostate cancer. Nonetheless, there have been variations in clinical responses to both these therapies. The agonists and antagonists primarily target the LHRH receptors; however, they differ in their mechanisms of action. The agonists act via pituitary receptors and produce initial surge in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels that ultimately translate into continuous overstimulation resulting in down-regulation of LH and castrate levels of testosterone. Conversely, LHRH antagonists block the LHRH-receptor signaling,therefore causing a sharp and sustained inhibition of LH, FSH, and testosterone.¹⁵Crawford ED, Hou AH. The role of LHRH antagonists in the treatment of prostate cancer. Oncology (Williston Park). 2009 Jun;23(7):626-30.   ¹⁶Tolkach Y, Joniau S, Van Poppel H. Luteinizing hormone-releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors? BJU Int. 2013 Jun;111(7):1021-30.   LHRH antagonists are believed to have modest benefits like rapid decline in testosterone levels, decrease in testosterone induced flare, and prolonged maintenance of castration levels.Thereby, LHRH antagonists appear to be a practical alternative to LHRH agonists in advanced prostate cancers.¹⁵Crawford ED, Hou AH. The role of LHRH antagonists in the treatment of prostate cancer. Oncology (Williston Park). 2009 Jun;23(7):626-30.  

Modifying doses of LHRH according to serum testosterone levels appear to be the most efficient way to maintain optimal castrate levels of testosterone. It seems to be rational and functions according to the patient’s physiological parameters, accounting for the variabilities in end organ response in patients with prostate cancer. Testosterone-guided LHRH therapy offers advantages such as effectiveness, safety and cost-effectiveness, and accurate suppression.¹⁷Pathak AS, Pacificar JS, Shapiro CE, Williams SG. Determining dosing intervals for luteinizing hormone releasing hormone agonists based on serum testosterone levels: a prospective study. J Urol. 2007 Jun;177(6):2132-5;discussion 2135.  

New drugs in prostate cancer

The therapeutic armamentarium for the management of advanced prostate cancer is perpetually expanding with time. Newer chemotherapeutic agents, immunotherapies, bone microenvironmenttargeted agents, new androgen receptor blockers,antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, radiotherapeutics and hormonal therapies are being added regularly.The advanced and newer agents primarily target various aspects of prostate cancer biology such as the modulation of androgen signaling and biosynthesis,critical oncogenic intracellular pathways, cell division, bone microenvironment, epigenetic alterations, and cancer immunology. In the clinical conglomerate of novel therapies, several agents are in initial phase of development while several others have been either approved or are in advanced stages of development.¹⁸Clarke JM, Armstrong AJ. Novel therapies for the treatment of advanced prostate cancer. Curr Treat Options Oncol. 2013 Mar;14(1):109-26.   ¹⁹Heidegger I, Massoner P, Eder IE, Pircher A, Pichler R, Aigner F, Bektic J, Horninger W, Klocker H. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer. J Steroid Biochem Mol Biol. 2013 Nov;138:248-56.  

Novel compounds such as sipuleucel-T, cabazitaxel,abiraterone acetate, and denosumab have shown promising results in advanced prostate cancer. These agents have demonstrated overall survival benefits with improved tolerability profile. Other methods like androgen biosynthesis and receptor inhibitors,radiotherapy with radium-223, angiogenesis inhibitors such as thalidomide, lenalidomine, aflibercept,tasquinimod, and immunomodulating agents such as Prostvac-VF are being vigorously tested.²⁰Osanto S, Van Poppel H. Emerging novel therapies for advanced prostate cancer. Therapeutic Advances in Urology. 2012;4(1):3-12.  

Potential biomarkers in prostate cancer

Prostate-specific antigen is an established biomarker used for formulating the diagnosis, making treatment decisions and assessing the response to therapy in patients with prostate cancer. It is routinely measured along with physical examination. Nonetheless, this biomarker lacks specificity and may sometimes lead to overdiagnosis and overtreatment. Therefore,novel biomarkers with excellent specificity and sensitivity are required to overcome the limitations associated with conventional biomarkers.²¹Schalken J, Dijkstra S, Baskin-Bey E, van Oort I. Potential utility of cancer-specific biomarkers for assessing response to hormonal treatments in metastatic prostate cancer. Therapeutic Advances in Urology. 2014;6(6):245-252.   Moreover, as the therapeutic options are increasing continuously, there is a need to discover predictive and prognostic biomarkers in order to assess the therapeutic efficacy and tolerability of novel compounds.¹⁸Clarke JM, Armstrong AJ. Novel therapies for the treatment of advanced prostate cancer. Curr Treat Options Oncol. 2013 Mar;14(1):109-26.   A plethora of biomarkers have been identified, which help in disease prognosis, predicting therapeutic response, and drug development (Figure 1). The use of these biomarkers supports the clinician in sound decision making by estimating the expected outcomes. Different categories of biomarkers such as protein, circulating tumor cells, genomic, metabolomics and imaging biomarkers, have been found to be useful in prostate cancer (Table 2).

As the modern era of personalized care is evolving,advancements in cancer care is becoming essential. In such a milieu, development of novel biomarkers that help in cancer detection, treatment, and prevention appear to be a benchmark for improving overall healthcare.²²Liu Y, Hegde P, Zhang F, Hampton G, Jia S. Prostate cancer – a biomarker perspective. Frontiers in Endocrinology. 2012;3:72.  

Conclusion

There is a rapid increase in the burden of prostate cancer in the developing countries, which is associated with significant healthcare resource utilization. Consistently, there is an urgent need to improve managed care environment in order to provide maximal benefits to the patients, and curb the increasing menace of the disease. In this direction,the therapeutic arena has witnessed a rapid turnover.Novel therapeutic options and biomarkers are being continuously introduced to improve the care of patients with advanced prostate cancer. In essence,the judicious use of available and evolving resources would help in prolonging the survival and improving the quality of life of patients with prostate cancer.

References

1. Moul JW. The Evolving Definition of Advanced Prostate Cancer.Reviews in Urology. 2004;6(Suppl 8):S10-S17.
2. Sridharan S, Warde P. The importance of local control in high-risk locally advanced prostate cancer. Current Oncology. 2012;19(Suppl 3):S6-S12.
3. Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G. The Worldwide Epidemiology of Prostate Cancer: Perspectives from Autopsy Studies. The Canadian journal of urology. 2008;15(1):3866-3871.
4. Baade PD, Youlden DR, Cramb SM, Dunn J, Gardiner RA. Epidemiology of prostate cancer in the Asia-Pacific region. Prostate International. 2013;1(2):47-58.
5. Jain S, Saxena S, Kumar A. Epidemiology of prostate cancer in India.Meta Gene. 2014;2:596-605.
6. Alemayehu B, Buysman E, Parry D, Becker L, Nathan F. Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population. J Med Econ. 2010;13(2):351-61.
7. Yong C, Onukwugha E, Mullins CD, Seal B, Hussain A. The use of health services among elderly patients with stage IV prostate cancer in the initial period following diagnosis. J Geriatr Oncol. 2014 Jul;5(3):290-8.
8. Vaishampayan U. Therapeutic Options and Multifaceted Treatment Paradigms In Metastatic Castrate Resistant Prostate Cancer. Current opinion in oncology. 2014;26(3):265-273.
9. Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: present and future. Curr Urol Rep. 2007 Jan;8(1):53-9.
10. Golabek T, Belsey J, Drewa T, Kołodziej A, Skoneczna I, Milecki P,Dobruch J, Słojewski M, Chłosta PL. Evidence-based recommendations on androgen deprivation therapy for localized and advanced prostate cancer. Cent European J Urol. 2016;69(2):131-8.
11. Yoo S, Choi SY, You D, Kim CS. New drugs in prostate cancer. Prostate Int. 2016 Jun;4(2):37-42.
12. Dreicer R. Managing advanced prostate cancer: the rapidly changing treatment landscape. Am J Manag Care. 2014 Dec;20(12 Suppl):S282-9.
13. Iida K. Monotherapy versus combined androgen blockade for advanced/metastatic prostate cancer. Gan To Kagaku Ryoho. 2011 Dec;38(13):2553-7.
14. Akaza H. Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness. Cancer Sci. 2011 Jan;102(1):51-6.
15. Crawford ED, Hou AH. The role of LHRH antagonists in the treatment of prostate cancer. Oncology (Williston Park). 2009 Jun;23(7):626-30.
16. Tolkach Y, Joniau S, Van Poppel H. Luteinizing hormone-releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors? BJU Int. 2013 Jun;111(7):1021-30.
17. Pathak AS, Pacificar JS, Shapiro CE, Williams SG. Determining dosing intervals for luteinizing hormone releasing hormone agonists based on serum testosterone levels: a prospective study. J Urol. 2007 Jun;177(6):2132-5;discussion 2135.
18. Clarke JM, Armstrong AJ. Novel therapies for the treatment of advanced prostate cancer. Curr Treat Options Oncol. 2013 Mar;14(1):109-26.
19. Heidegger I, Massoner P, Eder IE, Pircher A, Pichler R, Aigner F, Bektic J, Horninger W, Klocker H. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer. J Steroid Biochem Mol Biol. 2013 Nov;138:248-56.
20. Osanto S, Van Poppel H. Emerging novel therapies for advanced prostate cancer. Therapeutic Advances in Urology. 2012;4(1):3-12.
21. Schalken J, Dijkstra S, Baskin-Bey E, van Oort I. Potential utility of cancer-specific biomarkers for assessing response to hormonal treatments in metastatic prostate cancer. Therapeutic Advances in Urology. 2014;6(6):245-252.
22. Liu Y, Hegde P, Zhang F, Hampton G, Jia S. Prostate cancer – a biomarker perspective. Frontiers in Endocrinology. 2012;3:72.