NEWS & VIEWS DECADE IN REVIEW—PROSTATE CANCER
A decade of progress in detection and treatment Behfar Ehdaie and Peter T. Scardino
A fundamental shift in the understanding, detection and treatment of prostate cancer has occurred over the past 10 years, especially in the use of screening, active surveillance, novel therapies and radical surgery. These discoveries have changed how clinicians and patients approach prostate cancer. Ehdaie, B. & Scardino, P. T. Nat. Rev. Urol. advance online publication 14 October 2014; doi:10.1038/nrurol.2014.284
iStock/Thinkstock
The past decade has witnessed fundamental shifts in our understanding of prostate cancer and in the detection and treatment of all stages of this common disease. The greatest changes in the approach to prostate cancer have been in attitudes to screening, the role of patient-reported outcomes in documenting the effects of therapy on quality of life (QOL), the move from radical treatment to active surveillance for low-risk prostate cancer, the expanding role of surgery for high-risk cancers and the move towards multimodality treatment for advanced cancers. Despite this progress, prostate cancer remains the second most lethal cancer among men, and it will continue to challenge our best judgement and therapeutic acumen as we work to further reduce morbidity and mortality from this disease in the coming decades. PSA has been widely used for the early detection of prostate cancer in clinical practice since its discovery. However, its value in population-wide screening remains controversial and the results of large randomized
trials have failed to resolve the debate. The US-based Prostate Lung Colorectal and Ovarian Cancer screening trial found no reduction in prostate-cancer-specific mortality (PCSM) over a median of 10 years, but the study was compromised by pretesting for PSA in 40% of the subjects and by contamination of the control recruits (some 70% of the unscreened control cohort received a PSA test during the study period), meaning that the study was only able to report that intense sc reening is no better than opportunistic screening for reducing mortality. 1 In contrast, the European Randomized Study of Screening for Prostate Cancer reported a statistically significant relative reduction of 21% in PCSM at a follow-up duration of 13 years, equivalent to one prostate cancer death averted per 781 men invited for screening, or one per 27 additional prostate cancers detected.2 Despite this substantial reduction in PCSM with PSA screening, in 2012 the US Preventive Services Task Force recommended against PSA screening, concluding that no net benefit is gained from the practice and that the potential harms outweigh the benefits. Nevertheless, the longest trial reported to date—the Göteborg randomized population-based prostate cancer screening trial—showed a 44% reduction in PCSM at a follow-up period of 14 years, with screening of 293 men and diagnosis of 12 cancers preventing one death.3 The power of PSA testing was confirmed by studies investigating the association between PSA levels at mid-life, defined as between 45–60 years, and the lifetime risk of prostate cancer metastases and death,
NATURE REVIEWS | UROLOGY
enabling decisions to be made regarding further screening and treatment options.4 These studies have also shown that men with PSA levels below the reported median concentration (1.1 ng/ml) at 60 years have little chance of dying from prostate cancer and can, therefore, be excluded from further screening. This evidence provides weight to the argument for the value of PSA testing to risk-adjust screening strategies.
‘‘
The past decade has witnessed fundamental shifts in our understanding of prostate cancer…
’’
The harms of early detection as a result of PSA screening arise mostly from the consequences of unnecessary radical therapy for low-risk cancers. Patient-reported outcomes provide objective tools for quantify ing the adverse effects of therapy and its impact on QOL. In a landmark longitudinal observational study of the long-term effects of surgery and radiotherapy on QOL, most men were shown to experience significant short-term reductions in urinary and sexual function after surgery, with less severe reductions in urinary and sexual function, but greater impairment of bowel function, after radiation. Although these functional deficits can improve in some men over time, long-term adverse effects —especially in sexual function—persist in many.5 For this reason, active surveillance for men with low-risk cancer is becoming more common. Men followed in active surveillance programmes have little risk of dying from prostate cancer within 10 years, and many cancers that do progress respond to delayed treatment with surgery or radiation. Nevertheless, longer follow-up periods could reveal greater risks of progression for men on active surveillance than for those given radical treatment. Furthermore, active surveillance requires frequent biopsies, which are invasive and carry a risk of infection and bleeding, and the criteria under which men are assessed for delayed intervention are poorly defined. However, there is a growing consensus that men with lowrisk cancer do not usually need immedi ate definitive therapy (assuming that no ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS high-risk or intermediate-risk cancer is found on careful evaluation) and can be put on active surveillance programmes and men with intermediate-risk and high-risk cancers are less likely to develop metastases or to die of cancer if they are treated with radical prostatectomy or radiation therapy. Prediction tools and nomograms have also been improved and are now widely available to assist physicians and patients in the shared decision-making process about the treatment options available for localized prostate cancer. Together with more accurate biopsy strategies and improved imaging with MRI, these tools provide more accurate risk assessments than were previously available and a greater confidence that active surveillance is safe for men with low‑risk prostate cancer.
‘‘
Despite this progress, prostate cancer remains the second most lethal cancer among men…
’’
The ability to make better medical decisions in collaboration with patients and their families will continue to improve in the next decade, as we standardize the evaluation of candidates for active surveillance. The most promising tools for better characterization of cancer include advanced imaging technologies such as multiparametric MRI, molecular profiling tools-for example Prolaris®(Myriad Genetics, USA) and OncotypeDX®(Genomic Health, USA) -and tests for circulating biomarkers, such as the 4Kscore®(OPKO Diagnostics, USA) and the Prostate Health Index (phi). Improved risk assessment will help to more precisely define eligibility for active surveillance programmes, and the characteristics that indicate that delayed intervention is an appropriate treatment option. During most of the past century, open radical prostatectomy (ORP) has been the standard surgical approach in men with localized prostate cancer. However, over the past decade, robot-assisted laparoscopic prostatectomy (RALP) has been widely adopted, despite an absence of formal evalu ation documenting superior outcomes. In fact, population-based observational studies and single-institution case series continue to show comparable outcomes
for both approaches, except that patients receiving RALP have slightly shorter hospital stays (for example 2 days for RALP versus 3 days for ORP) and fewer blood transfusions.6 According to administrative data RALP does not improve complication rates or readmission rates compared with ORP. The skill level of the surgeon, indepen dent of the technology employed, clearly has the greatest impact on outcomes. The positive association of surgical experience with improved outcomes has been mapped in learning curves charting surgeon experience with biochemical-recurrence rates and patient‑reported functional outcomes.7 Landmark clinical trials have been complemented by breakthroughs in translational research, improving our understanding of the molecular and genetic factors that drive prostate cancer. The fusion between transmembrane protease serine 2 (TMPRSS2) and ERG, a member of the erythroblast transformation-specific transcription factor family, was reported by Tomlins et al. 8 working under Chinnaiyan, and is found in approximately 50% of primary and metastatic prostate cancers. Although the clinical relevance of this fusion gene remains debatable, its high prevalence provides an important pathway for investigating new diagnostic and prognostic markers, as well as potential targets for novel therapeutics. A comprehensive integrated genomic profile of prostate cancer found alterations in key molecular pathways in a surprisingly large number of primary and metastatic tumours, and the degree of copy-number alterations was shown to be associated with prognosis, independent of Gleason grade.9 Perhaps the single greatest advance in prostate cancer biology during the past decade was the finding by the Sawyers group10 that upregulation of the androgen receptor was both necessary and sufficient for the castration-resistant phenotype. This discovery drove the development of novel antiandrogens (for example abiraterone and enzalutamide), which have markedly improved the prognosis of patients with advanced prostate cancer some 75 years after Huggins first identified the effects of androgen deprivation on prostate cancer, and after numerous studies of various regimens of ADT failed to improve survival in these patients.
2 | ADVANCE ONLINE PUBLICATION
In the past decade, the FDA has approved six new therapeutic agents that prolong overall survival in men with castration- resistant prostate cancer, including drugs that target androgen-dependent and androgen- independent pathways, bone metastas es, and cell cycle regulators. Evaluation of these therapies is occurring in multimodality clinical trials, raising the hope that we might one day develop therapeutic programmes that can cure many more men with advanced prostate cancer. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA (B.E., P.T.S.). Correspondence to: P.T.S. [email protected] Competing interests P.T.S. is a paid scientific advisor to OPKO Diagnostics, which has licensed the 4KScore®from P.T.S. and colleagues for commercial development. B.E. declares no competing interests. 1.
Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319 (2009). 2. Schröder, F. H. et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet http://dx.doi.org/10.1016/ S0140-6736(14)60525-0. 3. Hugosson, J. et al. Mortality results from the Göteborg randomized population-based prostate-cancer screening trial. Lancet Oncol. 11, 725–732 (2010). 4. Vickers, A. J. et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40–55 and long term risk of metastasis: case-control study. BMJ 2013, 346–357 (2013). 5. Sanda, M. G. et al. Quality of life and satisfaction with outcome among prostatecancer survivors. N. Engl. J. Med. 358, 1250–1261 (2008). 6. Gandaglia, G. et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J. Clin. Oncol. 32, 1419–1426 (2014). 7. Vickers, A. et al. Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. Eur. Urol. 59, 317–322 (2011). 8. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). 9. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010). 10. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
A decade of progress in detection and treatment Behfar Ehdaie and Peter T. Scardino
A fundamental shift in the understanding, detection and treatment of prostate cancer has occurred over the past 10 years, especially in the use of screening, active surveillance, novel therapies and radical surgery. These discoveries have changed how clinicians and patients approach prostate cancer. Ehdaie, B. & Scardino, P. T. Nat. Rev. Urol. advance online publication 14 October 2014; doi:10.1038/nrurol.2014.284
iStock/Thinkstock
The past decade has witnessed fundamental shifts in our understanding of prostate cancer and in the detection and treatment of all stages of this common disease. The greatest changes in the approach to prostate cancer have been in attitudes to screening, the role of patient-reported outcomes in documenting the effects of therapy on quality of life (QOL), the move from radical treatment to active surveillance for low-risk prostate cancer, the expanding role of surgery for high-risk cancers and the move towards multimodality treatment for advanced cancers. Despite this progress, prostate cancer remains the second most lethal cancer among men, and it will continue to challenge our best judgement and therapeutic acumen as we work to further reduce morbidity and mortality from this disease in the coming decades. PSA has been widely used for the early detection of prostate cancer in clinical practice since its discovery. However, its value in population-wide screening remains controversial and the results of large randomized
trials have failed to resolve the debate. The US-based Prostate Lung Colorectal and Ovarian Cancer screening trial found no reduction in prostate-cancer-specific mortality (PCSM) over a median of 10 years, but the study was compromised by pretesting for PSA in 40% of the subjects and by contamination of the control recruits (some 70% of the unscreened control cohort received a PSA test during the study period), meaning that the study was only able to report that intense sc reening is no better than opportunistic screening for reducing mortality. 1 In contrast, the European Randomized Study of Screening for Prostate Cancer reported a statistically significant relative reduction of 21% in PCSM at a follow-up duration of 13 years, equivalent to one prostate cancer death averted per 781 men invited for screening, or one per 27 additional prostate cancers detected.2 Despite this substantial reduction in PCSM with PSA screening, in 2012 the US Preventive Services Task Force recommended against PSA screening, concluding that no net benefit is gained from the practice and that the potential harms outweigh the benefits. Nevertheless, the longest trial reported to date—the Göteborg randomized population-based prostate cancer screening trial—showed a 44% reduction in PCSM at a follow-up period of 14 years, with screening of 293 men and diagnosis of 12 cancers preventing one death.3 The power of PSA testing was confirmed by studies investigating the association between PSA levels at mid-life, defined as between 45–60 years, and the lifetime risk of prostate cancer metastases and death,
NATURE REVIEWS | UROLOGY
enabling decisions to be made regarding further screening and treatment options.4 These studies have also shown that men with PSA levels below the reported median concentration (1.1 ng/ml) at 60 years have little chance of dying from prostate cancer and can, therefore, be excluded from further screening. This evidence provides weight to the argument for the value of PSA testing to risk-adjust screening strategies.
‘‘
The past decade has witnessed fundamental shifts in our understanding of prostate cancer…
’’
The harms of early detection as a result of PSA screening arise mostly from the consequences of unnecessary radical therapy for low-risk cancers. Patient-reported outcomes provide objective tools for quantify ing the adverse effects of therapy and its impact on QOL. In a landmark longitudinal observational study of the long-term effects of surgery and radiotherapy on QOL, most men were shown to experience significant short-term reductions in urinary and sexual function after surgery, with less severe reductions in urinary and sexual function, but greater impairment of bowel function, after radiation. Although these functional deficits can improve in some men over time, long-term adverse effects —especially in sexual function—persist in many.5 For this reason, active surveillance for men with low-risk cancer is becoming more common. Men followed in active surveillance programmes have little risk of dying from prostate cancer within 10 years, and many cancers that do progress respond to delayed treatment with surgery or radiation. Nevertheless, longer follow-up periods could reveal greater risks of progression for men on active surveillance than for those given radical treatment. Furthermore, active surveillance requires frequent biopsies, which are invasive and carry a risk of infection and bleeding, and the criteria under which men are assessed for delayed intervention are poorly defined. However, there is a growing consensus that men with lowrisk cancer do not usually need immedi ate definitive therapy (assuming that no ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS high-risk or intermediate-risk cancer is found on careful evaluation) and can be put on active surveillance programmes and men with intermediate-risk and high-risk cancers are less likely to develop metastases or to die of cancer if they are treated with radical prostatectomy or radiation therapy. Prediction tools and nomograms have also been improved and are now widely available to assist physicians and patients in the shared decision-making process about the treatment options available for localized prostate cancer. Together with more accurate biopsy strategies and improved imaging with MRI, these tools provide more accurate risk assessments than were previously available and a greater confidence that active surveillance is safe for men with low‑risk prostate cancer.
‘‘
Despite this progress, prostate cancer remains the second most lethal cancer among men…
’’
The ability to make better medical decisions in collaboration with patients and their families will continue to improve in the next decade, as we standardize the evaluation of candidates for active surveillance. The most promising tools for better characterization of cancer include advanced imaging technologies such as multiparametric MRI, molecular profiling tools-for example Prolaris®(Myriad Genetics, USA) and OncotypeDX®(Genomic Health, USA) -and tests for circulating biomarkers, such as the 4Kscore®(OPKO Diagnostics, USA) and the Prostate Health Index (phi). Improved risk assessment will help to more precisely define eligibility for active surveillance programmes, and the characteristics that indicate that delayed intervention is an appropriate treatment option. During most of the past century, open radical prostatectomy (ORP) has been the standard surgical approach in men with localized prostate cancer. However, over the past decade, robot-assisted laparoscopic prostatectomy (RALP) has been widely adopted, despite an absence of formal evalu ation documenting superior outcomes. In fact, population-based observational studies and single-institution case series continue to show comparable outcomes
for both approaches, except that patients receiving RALP have slightly shorter hospital stays (for example 2 days for RALP versus 3 days for ORP) and fewer blood transfusions.6 According to administrative data RALP does not improve complication rates or readmission rates compared with ORP. The skill level of the surgeon, indepen dent of the technology employed, clearly has the greatest impact on outcomes. The positive association of surgical experience with improved outcomes has been mapped in learning curves charting surgeon experience with biochemical-recurrence rates and patient‑reported functional outcomes.7 Landmark clinical trials have been complemented by breakthroughs in translational research, improving our understanding of the molecular and genetic factors that drive prostate cancer. The fusion between transmembrane protease serine 2 (TMPRSS2) and ERG, a member of the erythroblast transformation-specific transcription factor family, was reported by Tomlins et al. 8 working under Chinnaiyan, and is found in approximately 50% of primary and metastatic prostate cancers. Although the clinical relevance of this fusion gene remains debatable, its high prevalence provides an important pathway for investigating new diagnostic and prognostic markers, as well as potential targets for novel therapeutics. A comprehensive integrated genomic profile of prostate cancer found alterations in key molecular pathways in a surprisingly large number of primary and metastatic tumours, and the degree of copy-number alterations was shown to be associated with prognosis, independent of Gleason grade.9 Perhaps the single greatest advance in prostate cancer biology during the past decade was the finding by the Sawyers group10 that upregulation of the androgen receptor was both necessary and sufficient for the castration-resistant phenotype. This discovery drove the development of novel antiandrogens (for example abiraterone and enzalutamide), which have markedly improved the prognosis of patients with advanced prostate cancer some 75 years after Huggins first identified the effects of androgen deprivation on prostate cancer, and after numerous studies of various regimens of ADT failed to improve survival in these patients.
2 | ADVANCE ONLINE PUBLICATION
In the past decade, the FDA has approved six new therapeutic agents that prolong overall survival in men with castration- resistant prostate cancer, including drugs that target androgen-dependent and androgen- independent pathways, bone metastas es, and cell cycle regulators. Evaluation of these therapies is occurring in multimodality clinical trials, raising the hope that we might one day develop therapeutic programmes that can cure many more men with advanced prostate cancer. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA (B.E., P.T.S.). Correspondence to: P.T.S. [email protected] Competing interests P.T.S. is a paid scientific advisor to OPKO Diagnostics, which has licensed the 4KScore®from P.T.S. and colleagues for commercial development. B.E. declares no competing interests. 1.
Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319 (2009). 2. Schröder, F. H. et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet http://dx.doi.org/10.1016/ S0140-6736(14)60525-0. 3. Hugosson, J. et al. Mortality results from the Göteborg randomized population-based prostate-cancer screening trial. Lancet Oncol. 11, 725–732 (2010). 4. Vickers, A. J. et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40–55 and long term risk of metastasis: case-control study. BMJ 2013, 346–357 (2013). 5. Sanda, M. G. et al. Quality of life and satisfaction with outcome among prostatecancer survivors. N. Engl. J. Med. 358, 1250–1261 (2008). 6. Gandaglia, G. et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J. Clin. Oncol. 32, 1419–1426 (2014). 7. Vickers, A. et al. Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. Eur. Urol. 59, 317–322 (2011). 8. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). 9. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010). 10. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
