NEWS & VIEWS PROSTATE CANCER
Primary ADT monotherapy not suitable for localized disease Oliver Sartor and Jonathan Silberstein
Although current guidelines do not endorse the use of primary androgen deprivation therapy (PADT) as monotherapy for localized prostate cancer, many patients continue to receive this treatment. New outcomes research confirms that there is no clear reason for use of PADT in men with localized prostate cancer. Sartor, O. & Silberstein, J. Nat. Rev. Urol. 11, 309–310 (2014); published online 27 May 2014; doi:10.1038/nrurol.2014.119
‘‘
Given that no published data support PADT, why was it being used in clinical practice?
’’
Two large, multicentre, prospective, randomized trials have previously analysed the effects of treatment with ADT alone compared with ADT plus definitive local therapy in patients with localized or locally advanced prostate cancer. In the SPCG‑7 study, 875 patients with locally advanced prostate cancer were randomly assigned to either 3 months of ADT with a luteinizinghormone-releasing hormone analogue together with the antiandrogen flutamide, followed by flutamide alone until progression or death, or the same ADT regimen combined with EBRT. 4 This trial had a median follow-up time of 7.6 years, and
ock kst hin k/T toc /iS on kip Yu
Androgen deprivation therapy (ADT) can be used to slow the progression of androgen- dependent prostate cancer, but ADT is also associated with multiple morbidities, including increased rates of cardiac adverse events, glucose intolerance, and osteoporotic fractures.1 Current guidelines recommend that ADT should be used in conjunction with external beam radiation therapy (EBRT) for localized prostate cancer treatment, but ADT monotherapy is still widely used.2 A retrospective study 3 has now provided evidence that although primary ADT (PADT) is associated with a modest survival benefit for patients with high-risk disease, patients with low-risk disease who receive PADT have a greatly increased risk of death. In this study, PADT was defined as receipt of ADT within 12 months of dia gnosis, without treatment with curative intent.
demonstrated that men treated with ADT plus EBRT had a relative risk (RR) of prostate cancer death of 0.44 (95% CI 0.30–0.66) compared with men receiving ADT alone. With respect to overall survival, the combined therapy was also superior (RR 0.8, 95% CI 0.52–0.89). At 10 years, the estimated incidence of PSA recurrence with ADT monotherapy was 74.7%, compared with 25.9% for combined therapy (RR 0.16, 95% CI 0.12–0.20). A small increase was seen in EBRT-related effects including various urinary, gastrointestinal, and sexual adverse events. The second trial (NCIC CTG PR.3/MRC UK PR07) randomly assigned 1,205 men with localized or locally advanced prostate cancer to receive EBRT plus ADT or ADT alone.5 Receipt of ADT was lifelong for both groups, with a median follow-up time of 6 years. Compared with ADT alone, the combination of EBRT plus ADT reduced deaths from prostate cancer (hazard ratio [HR] 0.54, 95% CI 0.27–0.78) and improved overall survival (HR 0.77, 95% CI 0.61–0.98). Small effects of EBRT on gastrointestinal and urinary adverse events were noted. These trials both
NATURE REVIEWS | UROLOGY
provided evidence to suggest that ADT as a monotherapy compares poorly with EBRT plus ADT with regard to the most important end point, overall survival, and EBRT adds little toxicity. Although no similar randomized study has compared radical prostatectomy with PADT, various retrospective analyses have demonstrated the benefits of radical prostatectomy for men with localized cancers.6 So, what does the study by Potosky et al.3 add to our current knowledge? In their study, 15,170 men with localized or locally advanced prostate cancer, with or without PADT, were examined for all-cause mortality and prostate-cancer-specific mortality (PCSM) after conventional adjusted-risk modelling or propensity matching. Over all, neither end point was affected by PADT. The authors also explored how the aggressiveness of a prostate cancer affects outcomes after PADT, demonstrating that, in patients with low-risk disease (defined as Gleason score ≤6, PSA 40% increased risk of death from all causes (HR 1.41, 95% CI 0.99–1.82, P = 0.02). On the other hand, for patients with high-risk disease (defined as Gleason score ≥8, PSA >20 ng/ml, stage ≥cT2c), an overall survival benefit of about 12% was reported for PADT compared with observation (HR 0.88, 95% CI 0.78–0.97, P = 0.02). Outcomes for patients with intermediaterisk disease were similar for those receiving PADT and observation. The study by Potosky et al.3 has certain limitations. First, it is not clear why patients in this study received nonstandard treatments. Given that no published data support PADT, why was it being used in clinical VOLUME 11 | JUNE 2014 | 309
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…the vast majority of men with localized prostate cancer do not derive benefit from PADT…
Department of Urology, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112, USA (O.S., J.S.). Correspondence to: O.S. [email protected]
4.
practice? The authors note that they did not have imaging data for most of the patients and that the cancer stage at diagnosis was often unclear, which might have influenced treatment choice. Although true, this observation does not justify a treatment choice that is unsupported by current data. Second, it is unclear how many patients received a curative treatment >12 months after diagnosis and how long patients continued on PADT. Third, patients with high-risk disease, who were grouped together in this analysis, are a heterogeneous group and their outcomes can vary widely.7 Fourth, the median follow-up time in the PADT group was 54 months versus 64 months in the group without PADT; owing to the long natural history of prostate cancer, these data are not fully mature. Lastly, although not within the scope of this study, quality of life, which is known to be greatly diminished while on ADT, was not considered. When patients were risk-stratified, the authors found differences in all-cause mortality, but, importantly, no differences were noted in PCSM. For patients with low-risk disease, increased mortality from PADT is probably a result of adverse effects not related to prostate cancer, and it is not surprising that PCSM was equivalent with and without PADT. Conversely, for patients with high-risk disease, any benefit of PADT results from slowing the progression of disease, and differences in PCSM would be expected, but were not observed. The authors suggest that this discrepancy might result from the small proportion (7%) of patients whose death was attributed to prostate cancer, and note that, in their dataset, there could have been some death ‘mis classifications’. Further review and attribution of the cause of death might be helpful for future analyses but we fully recognize the difficulties with death attribution in a retrospective cohort analysis. Despite the inherent limitations of a retrospective analysis, this study clearly demonstrates that the vast majority of men with localized prostate cancer do not derive benefit from PADT and that diminished overall survival can be expected for men with low-risk disease who are treated with PADT. To summarize, in clinical practice, no clear reason exists for treating men with localized prostate cancer with PADT.
Competing interests The authors declare no competing interests.
5.
310 | JUNE 2014 | VOLUME 11
’’
1.
2.
3.
Taylor, L. G., Canfield, S. E. & Du, X. L. Review of major adverse effects of androgendeprivation therapy in men with prostate cancer. Cancer 115, 2388–2399 (2009). Cooperberg, M. R., Broering, J. M. & Carroll, P. R. Time trends and local variation in primary treatment of localized prostate cancer. J. Clin. Oncol. 28, 1117–1123 (2010). Potosky, A. L. et al. Effectiveness of primary androgen-deprivation therapy for clinically
6.
7.
localized prostate cancer. J. Clin. Oncol. http:// dx.doi.org/JCO.2013.52.5782. Widmark, A. et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG‑7/SFUO‑3): an open randomised phase III trial. Lancet 373, 301–308 (2009). Warde, P. et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 378, 2104–2111 (2011). Liu, J. et al. Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients. Onco. Targets Ther. 6, 725–732 (2013). Yossepowitch, O. et al. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J. Urol. 178, 493–499 (2007).
BLADDER CANCER
Bladder preservation—learning what we don’t know Maha Hussain and Dan Theodorescu
Bladder preservation for patients with muscle-invasive bladder cancer has the potential to offer a quality-of-life advantage, but owing to the lack of randomized trials oncological equivalence to surgery has not been demonstrated. A new article provides a comprehensive overview of the current status of this procedure, but raises timely and important questions. Hussain, M. & Theodorescu, D. Nat. Rev. Urol. 11, 310–312 (2014); published online 20 May 2014; doi:10.1038/nrurol.2014.102
A group of experts in bladder cancer led by Guillaume Ploussard1 have written a comprehensive review of bladder-sparing strategies using trimodal therapy (transurethral tumour resection, radiation and chemotherapy) for muscle-invasive bladder cancer. Their review was based on a systematic literature search of PubMed and Cochrane databases for articles published from 1980 to July 2013. The authors objectively present a growing body of data suggesting that bladder preservation with trimodal therapy leads to acceptable oncological outcomes and, therefore, might be considered a reasonable treatment option for well-selected patients. They frame the data in the context of limitations that we have recognized for years, such as the lack of conclusive randomized studies comparing trimodal therapy with radical surgery, while indirectly raising some new questions that we would like to discuss. First, we must go back to basics and ask ourselves, what is the ultimate objective of treating muscle-invasive bladder cancer? The bladder is an organ that ‘can be’ and is ‘worth’ sparing, and sparing can be achieved without detectable reduction in survival rates or increases in morbidity or
cost compared with radical cystectomy plus pelvic lymph node dissection. However, it’s an organ we can live without, especially if there is a risk that its presence might reduce cure rates and, therefore, affect quantity or quality of life (QOL). Thus, we must objectively evaluate the outcomes of bladder- sparing and radical therapies in prospective randomi zed compararative studies with long-term outcomes.
‘‘
Should patient age be taken into account when choosing a treatment option?
’’
How should we measure the success of bladder-sparing treatment? Several metrics are critical to gauging the success of such strategies. Adequate local disease control and a functioning bladder are absolute requirements. In addition, low risk of new primary or locoregional extravesical recurrence and, therefore, low risk of needing salvage cystectomy, are also critical for the genitourinary oncology community to routinely adopt this approach. Finally, systemic disease control is essential if cure rates are to be optimized. www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
Primary ADT monotherapy not suitable for localized disease Oliver Sartor and Jonathan Silberstein
Although current guidelines do not endorse the use of primary androgen deprivation therapy (PADT) as monotherapy for localized prostate cancer, many patients continue to receive this treatment. New outcomes research confirms that there is no clear reason for use of PADT in men with localized prostate cancer. Sartor, O. & Silberstein, J. Nat. Rev. Urol. 11, 309–310 (2014); published online 27 May 2014; doi:10.1038/nrurol.2014.119
‘‘
Given that no published data support PADT, why was it being used in clinical practice?
’’
Two large, multicentre, prospective, randomized trials have previously analysed the effects of treatment with ADT alone compared with ADT plus definitive local therapy in patients with localized or locally advanced prostate cancer. In the SPCG‑7 study, 875 patients with locally advanced prostate cancer were randomly assigned to either 3 months of ADT with a luteinizinghormone-releasing hormone analogue together with the antiandrogen flutamide, followed by flutamide alone until progression or death, or the same ADT regimen combined with EBRT. 4 This trial had a median follow-up time of 7.6 years, and
ock kst hin k/T toc /iS on kip Yu
Androgen deprivation therapy (ADT) can be used to slow the progression of androgen- dependent prostate cancer, but ADT is also associated with multiple morbidities, including increased rates of cardiac adverse events, glucose intolerance, and osteoporotic fractures.1 Current guidelines recommend that ADT should be used in conjunction with external beam radiation therapy (EBRT) for localized prostate cancer treatment, but ADT monotherapy is still widely used.2 A retrospective study 3 has now provided evidence that although primary ADT (PADT) is associated with a modest survival benefit for patients with high-risk disease, patients with low-risk disease who receive PADT have a greatly increased risk of death. In this study, PADT was defined as receipt of ADT within 12 months of dia gnosis, without treatment with curative intent.
demonstrated that men treated with ADT plus EBRT had a relative risk (RR) of prostate cancer death of 0.44 (95% CI 0.30–0.66) compared with men receiving ADT alone. With respect to overall survival, the combined therapy was also superior (RR 0.8, 95% CI 0.52–0.89). At 10 years, the estimated incidence of PSA recurrence with ADT monotherapy was 74.7%, compared with 25.9% for combined therapy (RR 0.16, 95% CI 0.12–0.20). A small increase was seen in EBRT-related effects including various urinary, gastrointestinal, and sexual adverse events. The second trial (NCIC CTG PR.3/MRC UK PR07) randomly assigned 1,205 men with localized or locally advanced prostate cancer to receive EBRT plus ADT or ADT alone.5 Receipt of ADT was lifelong for both groups, with a median follow-up time of 6 years. Compared with ADT alone, the combination of EBRT plus ADT reduced deaths from prostate cancer (hazard ratio [HR] 0.54, 95% CI 0.27–0.78) and improved overall survival (HR 0.77, 95% CI 0.61–0.98). Small effects of EBRT on gastrointestinal and urinary adverse events were noted. These trials both
NATURE REVIEWS | UROLOGY
provided evidence to suggest that ADT as a monotherapy compares poorly with EBRT plus ADT with regard to the most important end point, overall survival, and EBRT adds little toxicity. Although no similar randomized study has compared radical prostatectomy with PADT, various retrospective analyses have demonstrated the benefits of radical prostatectomy for men with localized cancers.6 So, what does the study by Potosky et al.3 add to our current knowledge? In their study, 15,170 men with localized or locally advanced prostate cancer, with or without PADT, were examined for all-cause mortality and prostate-cancer-specific mortality (PCSM) after conventional adjusted-risk modelling or propensity matching. Over all, neither end point was affected by PADT. The authors also explored how the aggressiveness of a prostate cancer affects outcomes after PADT, demonstrating that, in patients with low-risk disease (defined as Gleason score ≤6, PSA 40% increased risk of death from all causes (HR 1.41, 95% CI 0.99–1.82, P = 0.02). On the other hand, for patients with high-risk disease (defined as Gleason score ≥8, PSA >20 ng/ml, stage ≥cT2c), an overall survival benefit of about 12% was reported for PADT compared with observation (HR 0.88, 95% CI 0.78–0.97, P = 0.02). Outcomes for patients with intermediaterisk disease were similar for those receiving PADT and observation. The study by Potosky et al.3 has certain limitations. First, it is not clear why patients in this study received nonstandard treatments. Given that no published data support PADT, why was it being used in clinical VOLUME 11 | JUNE 2014 | 309
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…the vast majority of men with localized prostate cancer do not derive benefit from PADT…
Department of Urology, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112, USA (O.S., J.S.). Correspondence to: O.S. [email protected]
4.
practice? The authors note that they did not have imaging data for most of the patients and that the cancer stage at diagnosis was often unclear, which might have influenced treatment choice. Although true, this observation does not justify a treatment choice that is unsupported by current data. Second, it is unclear how many patients received a curative treatment >12 months after diagnosis and how long patients continued on PADT. Third, patients with high-risk disease, who were grouped together in this analysis, are a heterogeneous group and their outcomes can vary widely.7 Fourth, the median follow-up time in the PADT group was 54 months versus 64 months in the group without PADT; owing to the long natural history of prostate cancer, these data are not fully mature. Lastly, although not within the scope of this study, quality of life, which is known to be greatly diminished while on ADT, was not considered. When patients were risk-stratified, the authors found differences in all-cause mortality, but, importantly, no differences were noted in PCSM. For patients with low-risk disease, increased mortality from PADT is probably a result of adverse effects not related to prostate cancer, and it is not surprising that PCSM was equivalent with and without PADT. Conversely, for patients with high-risk disease, any benefit of PADT results from slowing the progression of disease, and differences in PCSM would be expected, but were not observed. The authors suggest that this discrepancy might result from the small proportion (7%) of patients whose death was attributed to prostate cancer, and note that, in their dataset, there could have been some death ‘mis classifications’. Further review and attribution of the cause of death might be helpful for future analyses but we fully recognize the difficulties with death attribution in a retrospective cohort analysis. Despite the inherent limitations of a retrospective analysis, this study clearly demonstrates that the vast majority of men with localized prostate cancer do not derive benefit from PADT and that diminished overall survival can be expected for men with low-risk disease who are treated with PADT. To summarize, in clinical practice, no clear reason exists for treating men with localized prostate cancer with PADT.
Competing interests The authors declare no competing interests.
5.
310 | JUNE 2014 | VOLUME 11
’’
1.
2.
3.
Taylor, L. G., Canfield, S. E. & Du, X. L. Review of major adverse effects of androgendeprivation therapy in men with prostate cancer. Cancer 115, 2388–2399 (2009). Cooperberg, M. R., Broering, J. M. & Carroll, P. R. Time trends and local variation in primary treatment of localized prostate cancer. J. Clin. Oncol. 28, 1117–1123 (2010). Potosky, A. L. et al. Effectiveness of primary androgen-deprivation therapy for clinically
6.
7.
localized prostate cancer. J. Clin. Oncol. http:// dx.doi.org/JCO.2013.52.5782. Widmark, A. et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG‑7/SFUO‑3): an open randomised phase III trial. Lancet 373, 301–308 (2009). Warde, P. et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 378, 2104–2111 (2011). Liu, J. et al. Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients. Onco. Targets Ther. 6, 725–732 (2013). Yossepowitch, O. et al. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J. Urol. 178, 493–499 (2007).
BLADDER CANCER
Bladder preservation—learning what we don’t know Maha Hussain and Dan Theodorescu
Bladder preservation for patients with muscle-invasive bladder cancer has the potential to offer a quality-of-life advantage, but owing to the lack of randomized trials oncological equivalence to surgery has not been demonstrated. A new article provides a comprehensive overview of the current status of this procedure, but raises timely and important questions. Hussain, M. & Theodorescu, D. Nat. Rev. Urol. 11, 310–312 (2014); published online 20 May 2014; doi:10.1038/nrurol.2014.102
A group of experts in bladder cancer led by Guillaume Ploussard1 have written a comprehensive review of bladder-sparing strategies using trimodal therapy (transurethral tumour resection, radiation and chemotherapy) for muscle-invasive bladder cancer. Their review was based on a systematic literature search of PubMed and Cochrane databases for articles published from 1980 to July 2013. The authors objectively present a growing body of data suggesting that bladder preservation with trimodal therapy leads to acceptable oncological outcomes and, therefore, might be considered a reasonable treatment option for well-selected patients. They frame the data in the context of limitations that we have recognized for years, such as the lack of conclusive randomized studies comparing trimodal therapy with radical surgery, while indirectly raising some new questions that we would like to discuss. First, we must go back to basics and ask ourselves, what is the ultimate objective of treating muscle-invasive bladder cancer? The bladder is an organ that ‘can be’ and is ‘worth’ sparing, and sparing can be achieved without detectable reduction in survival rates or increases in morbidity or
cost compared with radical cystectomy plus pelvic lymph node dissection. However, it’s an organ we can live without, especially if there is a risk that its presence might reduce cure rates and, therefore, affect quantity or quality of life (QOL). Thus, we must objectively evaluate the outcomes of bladder- sparing and radical therapies in prospective randomi zed compararative studies with long-term outcomes.
‘‘
Should patient age be taken into account when choosing a treatment option?
’’
How should we measure the success of bladder-sparing treatment? Several metrics are critical to gauging the success of such strategies. Adequate local disease control and a functioning bladder are absolute requirements. In addition, low risk of new primary or locoregional extravesical recurrence and, therefore, low risk of needing salvage cystectomy, are also critical for the genitourinary oncology community to routinely adopt this approach. Finally, systemic disease control is essential if cure rates are to be optimized. www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
