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Current Trends in Detection and Management of Prostate Cancer

Prostate cancer: The rising burden and associated risk factors

Development of cancer is associated with underlying genetic alterations, which endow the involved cell-lines with many of the hallmarks of carcinogenesis, such as selfsufficient proliferation and evasion of apoptosis.1Rakoff-Nahoum S. Why Cancer and Inflammation? 1. Yale J Biol Med. 2006 Dec;79(3-4):123-130.   Cancer accounted for nearly 7.6 million deaths (around 13% of all deaths) globally in 2008, and nearly 0.63 million deaths are estimated to have occurred in India alone (Globocan 2008 and International Agency for Research on Cancer 2010).2D’Souza ND, Murthy NS, Aras RY. Projection of burden of 2. cancer mortality for India, 2011-2026. Asian Pac J Cancer Prev. 2013;14(7):4387-92.   Records of National cancer registries have indicated that India is witnessing a growing burden of cancer, with a rise in incidences of certain organ-specific malignancies, such as prostate, mouth, lung, and kidney, especially amongst the male population. Prostate cancer (PCa) is the second most common cancer and represents the sixth leading cause of cancer-associated mortality among the men worldwide.3Jain S, Saxena S, Kumarb A. Epidemiology of prostate cancer in 3. India. Meta Gene. 2014 Dec;2:596-605.    Despite such staggering statistics, the etiological basis of PCa remains to be elucidated. Nearly 40% of all PCa cases can be attributed to genetic defects. Data from migrant studies is also suggestive of the impact of lifestyle and environmental factors on the development of this malignancy. Diet is one of these environmental factors, which shape up the initiation, promotion, and advancement of PCa. The most convincing epidemiological evidence has shown that consumption of dairy/meat products is directly proportional to the risk of development of PCa. Besides, other significant factors that serve as a risk for PCa include age, race, and positive family history.4Wolk A. Diet, lifestyle and risk of prostate cancer. 4. Acta Oncol. 2005;44(3):277-81.   Growing age alone is presumed to increase the number of new cases and new deaths to 1.7 million and 4,99,000, respectively by 2030.3Jain S, Saxena S, Kumarb A. Epidemiology of prostate cancer in 3. India. Meta Gene. 2014 Dec;2:596-605.    Other than these, the onus of rising rate of incidence of PCa is also on the increased testing for prostate specific antigen (PSA). As a result of this, a major stage shift has been observed towards the localized disease, as many individuals are now diagnosed with low volume and low grade disease.5Albertsen PC. When is active surveillance the appropriate treatment 5. for prostate cancer? Acta Oncol. 2011 Jun;50 Suppl 1:120-6.  

Low-risk localized prostate cancer

While some cancers are invariably fatal, the latent ones will not influence the patient’s lifespan.6Jang TL, Yossepowitch O, Bianco FJ Jr, Scardino PT. Low risk prostate 6. cancer in men under age 65: the case for definitive treatment. Urol Oncol. 2007 Nov-Dec;25(6):510-4.   Localized form of PCa is categorized into risk groups according to the serum PSA level, biopsy Gleason score, and clinical tumor stage.7McVey GP, McPhail S, Fowler S, McIntosh G, Gillatt D, Parker CC. 7. Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry. BJU Int. 2010 Oct;106(8):1161-4.   Epstein and coworkers devised four criteria to explain clinically insignificant tumors. These are tumor volume 5Albertsen PC. When is active surveillance the appropriate treatment 5. for prostate cancer? Acta Oncol. 2011 Jun;50 Suppl 1:120-6.   Based on this definition, low-risk prostate cancer is designated to the one with clinical tumor stage T1-T2a, Gleason score < 6, and PSA 8Hoffman KE, Niu J, Shen Y, Jiang J, Davis JW, Kim J, Kuban DA, 8. Perkins GH, Shah JB, Smith GL, Volk RJ, Buchholz TA, Giordano SH, Smith BD. Physician variation in management of low-risk prostate cancer: a population-based cohort study. JAMA Intern Med. 2014 Sep;174(9):1450-9.   As the natural history of low-risk localized PCa remains unknown, such affected individuals usually come across difficulties in opting for a therapeutic strategy, with modalities ranging from radical surgery (through external beam radiotherapy and brachytherapy), experimental approaches (for instance, high-intensity focused ultrasound and cryotherapy), to just watchful waiting.7McVey GP, McPhail S, Fowler S, McIntosh G, Gillatt D, Parker CC. 7. Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry. BJU Int. 2010 Oct;106(8):1161-4.   These concerns have made the physicians at various medical centers to choose a conservative approach for such patients with very low risk of disease progression. This approach comprises procrastination of immediate intervention, supervision of disease advancement, and treatment initiation only after a tumor becomes clinically significant.5Albertsen PC. When is active surveillance the appropriate treatment 5. for prostate cancer? Acta Oncol. 2011 Jun;50 Suppl 1:120-6.   Therefore, active surveillance (AS) has now been accepted for the management of low-risk localized PCa.9Kim JH, Hong SK. Potential Utility of Novel Biomarkers in Active 9. Surveillance of Low-Risk Prostate Cancer. Biomed Res Int. 2015;2015:475920.   

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Clinical approach towards prostate cancer: Focus on active surveillance

Active surveillance is a protocol formulated for men with low-risk localized PCa, which includes regular testing of PSA and periodic biopsy examinations. Although, AS is considered most suitable for men aged 70 years or above (with a life expectancy of 15 to 20 years or less), it can also be taken up by any individual not desiring immediate treatment intervention.5Albertsen PC. When is active surveillance the appropriate treatment 5. for prostate cancer? Acta Oncol. 2011 Jun;50 Suppl 1:120-6.   However, detection of disease progression in a patient recruited for AS is challenging. Essential to this protocol is knowledge of the parameter that would correctly identify the tumor likely to advance to a more aggressive phenotype, so that the curability window is not lost.9Kim JH, Hong SK. Potential Utility of Novel Biomarkers in Active 9. Surveillance of Low-Risk Prostate Cancer. Biomed Res Int. 2015;2015:475920.   Therefore, early detection of the PCa serves to reduce the mortality associated with PCa with the intended user as the urologist.10Early detection of prostate cancer: AUA guideline. Available 10. at: https://www.auanet.org/common/pdf/education/clinicalguidance/Prostate-Cancer-Detection.pdf. Accessed on: 24.11.15.  

Strategies for diagnosis of prostate cancer

Currently, assessment of risk of early-stage PCa in men selected for AS is done by serial PSA measurements, digital rectal examination (DRE), and repeat prostate biopsies.9Kim JH, Hong SK. Potential Utility of Novel Biomarkers in Active 9. Surveillance of Low-Risk Prostate Cancer. Biomed Res Int. 2015;2015:475920.    As previously mentioned, regular serum PSA testing has lead to an important stage migration and, traditional imaging modalities conventionally used to label the tumor stage are no longer reliable in determining small amounts of PCa. Molecular imaging techniques are highly sensitive and specific for detection of cancer with the help of specific attributes, which are fundamental of disease biology. Similarly, other imaging techniques have evolved to benefit the management of PCa.11Taneja SS. Imaging in the Diagnosis and Management of Prostate 11. Cancer. Rev Urol. 2004 Summer;6(3):101-113.   Moreover, numerous biomarkers as novel tools are now being investigated to enhance the PCa risk assessments.9Kim JH, Hong SK. Potential Utility of Novel Biomarkers in Active 9. Surveillance of Low-Risk Prostate Cancer. Biomed Res Int. 2015;2015:475920.    Elaborated view of certain diagnostic interventions is mentioned below:

1. Prostate-specific antigen: The dilemma of its testing

  • In 1979, Wang et al separated an antigen from
  • prostate tissue, found to be prostate specific in nature Prostate-specific antigen belongs to the human
  • kallikrein gene family, is a 33-kilodalton serine protease
  • Released by the epithelial lining of the prostate and periurethral glands
  • Functional role : Liquefaction of the seminal coagulum, thereby enabling the release of spermatozoa
  • Dilemma:The routine screening of PCa via PSA

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over the past 2 decades has heightened the rate of disease detection and consequently, a stage shift at the time of diagnosis. For more than a decade, 4.0 ng/mL of serum PSA was believed to be the upper limit of normal. However, according to a recent report from the Prostate Cancer Prevention Trial, even the PSA levels ranging between 0 to 4.0 ng/mL were associated with a positive predictive value of 6.6-26.9%12Hernandez J, Thompson IM. Prostate-specific antigen: a review 12 of the validation of the most commonly used cancer biomarker. Cancer. 2004 Sep 1;101(5):894-904.  

  • Although controversial, PSA >10 ng/mL is considered as an exclusion criterion in number of large AS series. Despite the fact that greater the value of PSA, more is the risk of high-grade cancer, outcomes of Prostate Cancer Intervention Versus Observation Trial postulate that localized carcinoma with PSA 13Toren P, Wong LM, Timilshina N, Alibhai S, Trachtenberg J, Fleshner 13. N, Finelli A. Active surveillance in patients with a PSA >10 ng/mL. Can Urol Assoc J. 2014 Sep;8(9-10):E702-7.  

2. Role of Imaging

  • associated with poor specificity and negative predictive value
  • Novel imaging modalities attempt to correctly identify the tumor. These include endorectal coil magnetic resonance imaging (MRI), magnetic resonance spectroscopic imaging (MRSI), and molecular imaging studies
  • Endorectal coil magnetic resonance imaging : Offers the benefit of better visualization of prostate zonal anatomy, along with location and extent of tumor within the gland. Patients are examined with a whole body scanner (with pelvic phased array coil) and an endorectal coil (which is a magnetic coil placed directly into the rectum). T1 and T2 weighted images can be obtained, however cancer visualization is preferred on T2 weighted images, where the tumor appears dark
  • Magnetic resonance spectroscopic imaging : It is a type of MRI technique. It detects the cancer through analysis of tissue metabolites. It produces a spatial map of signal intensity over frequency as a spectral display of peaks, which represent the metabolites within the tissue. Supplementation of MRI with MRSI has enhanced the specificity to 70% to 80%, thereby improving the accuracy of recognition of tumor
  • Molecular imaging studies:Comprise ProstaScint and positron emission tomography (PET). These demonstrate greatest potential to detect extraprostatic recurrence. Of these, PET possesses a laudable ability to better ascertain the PCa progression and thereby add to our understanding of its biology.11Taneja SS. Imaging in the Diagnosis and Management of Prostate 11. Cancer. Rev Urol. 2004 Summer;6(3):101-113.  

3. Biomarkers

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Therapeutic interventions for the management of prostate cancer

A number of controversies have raged regarding the therapeutic management of localized PCa, as the efficacy and advantages of any treatment modality over the other remain indefinite. Radical prostatectomy has been considered the cornerstone treatment for clinically localised prostate cancer. Data from cumulative records is supportive of the therapy, as it indicates that this procedure has a survival advantage over radiotherapy. However, it may also lead to the development of associated surgical morbidity, particularly erectile dysfunction and incontinence.17Dehn T. Prostate Cancer Treatment. 17. Ann R Coll Surg Engl. 2006 Sep;88(5):439-444.   Other conventional therapies for the management of prostate cancer have been elaborated in box 2.

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Comprehension of the developments in the underlying molecular mechanisms responsible for progression of PCa has provided an insight into the possible therapeutic targets. Novel agents include angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines, and immunotherapies.18Bracarda S, Logothetis C, Sternberg CN, Oudard S. Current and 18. emerging treatment modalities for metastatic castration-resistant prostate cancer. BJU Int. 2011 Apr;107 Suppl 2:13-20.   Moreover, since the role of diet, especially polyphenols, in the prevention of prostate cancer is well established, these polyphenols appear to have prospective therapeutic applications in the succeeding years.19Lall RK, Syed DN, Adhami VM, Khan MI, Mukhtar H. Dietary 19. polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci. 2015 Feb 3;16(2):3350-76.   Few of the emerging therapies are discussed below:

1. Dietary polyphenols

Polyphenols are the food compounds that occur naturally within the fruits, vegetables, cereals, and beverages, such as strawberries, pineapples, bananas, lemons, red and white wine, tea leaves, oak bark, and apple peels. These compounds demonstrate cellular, molecular, and biochemical actions, which target signaling molecules, such as growth factors, transcription factors, cytokines, enzymes, and genes regulating apoptosis. As a result, these actively regulate inflammation, apoptosis, angiogenesis, and processes involved in auto-immune diseases (figure 1). Besides, dietary polyphenols in plasma have been observed to modify the risk of PCa by modulating the inflammatory genes and repairing oxidative deoxyribonucleic acid (DNA) damage. Furthermore, the cross interactions amongst various dietary polyphenols are also known to influence the PCa risk via anti-oxidant and non-anti-oxidant mechanisms.19Lall RK, Syed DN, Adhami VM, Khan MI, Mukhtar H. Dietary 19. polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci. 2015 Feb 3;16(2):3350-76.  

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2. Bone targeting agents

Preservation of bone health, although important, is equally challenging in individuals with PCa who are susceptible to metastatic bone disease and cancertreatment induced bone loss, which impair the bone

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stability and heightens the risk of fractures, resulting in immobility, pain, and significant compromise in quality of life. In such patients, treatment with vitamin D and antiresorptive agents has displayed improvement in bone mineral density, thus making them less likely to experience fractures.20Todenhofer T, Stenzl A, Hofbauer LC, Rachner TD. Targeting bone 20. metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202.  

3. Prostate cancer vaccines and immunotherapies

Cancer immunotherapy emerged as a revolutionary therapeutic tool in 2013, for its rapid, durable, selfpropagating, and adaptable immune response. It is considered a viable and attractive treatment strategy for PCa cases, as prostate is a non-essential organ that makes it an excellent target for immunotherapy.21Singh BH, Gulley JL. Therapeutic vaccines as a promising treatment 21. modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines. 2014 Sep;2(5):137-148.   22Basler M, Groettrup M. Advances in prostate cancer immunotherapies. 22. Drugs Aging. 2007;24(3):197-221.  

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To date, two classes of immunotherapy, namely therapeutic cancer vaccines and immune checkpoint inhibitors, have improved the overall survival rate amongst the patient population with advanced tumors.21Singh BH, Gulley JL. Therapeutic vaccines as a promising treatment 21. modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines. 2014 Sep;2(5):137-148.   Immunotherapy involves the supplementation of antibodies, which target the human epidermal growth factor receptor-2 or the prostate-specific membrane antigen, thereby eventually stabilizing the levels of PSA in several patients.22Basler M, Groettrup M. Advances in prostate cancer immunotherapies. 22. Drugs Aging. 2007;24(3):197-221.   The Food and Drug Administration (FDA) in 2010 approved the use of sipuleucel-T for asymptomatic or minimally symptomatic metastatic PCa, which laid the foundation for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. These approved immune-based therapies have illustrated multitude of benefits in terms of overall survival without any shortterm changes in disease progression, as these apparently slow down the net tumor growth rate.21Singh BH, Gulley JL. Therapeutic vaccines as a promising treatment 21. modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines. 2014 Sep;2(5):137-148.  

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References

    1. Rakoff-Nahoum S. Why Cancer and Inflammation? 1. Yale J Biol Med. 2006 Dec;79(3-4):123-130.
    2. D’Souza ND, Murthy NS, Aras RY. Projection of burden of 2. cancer mortality for India, 2011-2026. Asian Pac J Cancer Prev. 2013;14(7):4387-92.
    3. Jain S, Saxena S, Kumarb A. Epidemiology of prostate cancer in 3. India. Meta Gene. 2014 Dec;2:596-605.
    4. Wolk A. Diet, lifestyle and risk of prostate cancer. 4. Acta Oncol. 2005;44(3):277-81.
    5. Albertsen PC. When is active surveillance the appropriate treatment 5. for prostate cancer? Acta Oncol. 2011 Jun;50 Suppl 1:120-6.
    6. Jang TL, Yossepowitch O, Bianco FJ Jr, Scardino PT. Low risk prostate 6. cancer in men under age 65: the case for definitive treatment. Urol Oncol. 2007 Nov-Dec;25(6):510-4.
    7. McVey GP, McPhail S, Fowler S, McIntosh G, Gillatt D, Parker CC. 7. Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry. BJU Int. 2010 Oct;106(8):1161-4.
    8. Hoffman KE, Niu J, Shen Y, Jiang J, Davis JW, Kim J, Kuban DA, 8. Perkins GH, Shah JB, Smith GL, Volk RJ, Buchholz TA, Giordano SH, Smith BD. Physician variation in management of low-risk prostate cancer: a population-based cohort study. JAMA Intern Med. 2014 Sep;174(9):1450-9.
    9. Kim JH, Hong SK. Potential Utility of Novel Biomarkers in Active 9. Surveillance of Low-Risk Prostate Cancer. Biomed Res Int. 2015;2015:475920.
    10. Early detection of prostate cancer: AUA guideline. Available 10. at: https://www.auanet.org/common/pdf/education/clinicalguidance/Prostate-Cancer-Detection.pdf. Accessed on: 24.11.15.
    11. Taneja SS. Imaging in the Diagnosis and Management of Prostate 11. Cancer. Rev Urol. 2004 Summer;6(3):101-113.
    12. Hernandez J, Thompson IM. Prostate-specific antigen: a review 12 of the validation of the most commonly used cancer biomarker. Cancer. 2004 Sep 1;101(5):894-904.
    13. Toren P, Wong LM, Timilshina N, Alibhai S, Trachtenberg J, Fleshner 13. N, Finelli A. Active surveillance in patients with a PSA >10 ng/mL. Can Urol Assoc J. 2014 Sep;8(9-10):E702-7.
    14. Loeb S, Partin AW. Review of the literature: PCA3 for prostate cancer 14. risk assessment and prognostication. Rev Urol. 2011;13(4):e191-5.
    15. Eguchi FC, Faria EF, Scapulatempo Neto C, Longatto-Filho 15. A, Zanardo-Oliveira C, Taboga SR, Campos SG. The role of TMPRSS2:ERG in molecular stratification of PCa and its association with tumor aggressiveness: a study in Brazilian patients. Sci Rep. 2014 Jul 10;4:5640.
    16. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. 16. Nat Rev Cancer. 2002 May;2(5):389-96.
    17. Dehn T. Prostate Cancer Treatment. 17. Ann R Coll Surg Engl. 2006 Sep;88(5):439-444.
    18. Bracarda S, Logothetis C, Sternberg CN, Oudard S. Current and 18. emerging treatment modalities for metastatic castration-resistant prostate cancer. BJU Int. 2011 Apr;107 Suppl 2:13-20.
    19. Lall RK, Syed DN, Adhami VM, Khan MI, Mukhtar H. Dietary 19. polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci. 2015 Feb 3;16(2):3350-76.
    20. Todenhofer T, Stenzl A, Hofbauer LC, Rachner TD. Targeting bone 20. metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202.
    21. Singh BH, Gulley JL. Therapeutic vaccines as a promising treatment 21. modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines. 2014 Sep;2(5):137-148.
    22. Basler M, Groettrup M. Advances in prostate cancer immunotherapies. 22. Drugs Aging. 2007;24(3):197-221.
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