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
NEWS & VIEWS One of the strongest arguments in favour of bladder preservation is the potential to preserve QOL compared with radical cystectomy, but for whom? We have yet to systematically incorporate variables, such as baseline pretreatment voiding function symptoms, into QOL analyses to determine if some patients are more likely to experience trimodal-therapy-induced adverse effects than others. In addition, the ‘lost opportunity’ and subsequent costs of no longer having the option of a neobladder —which most patients with low volume/ low stage muscle-invasive bladder cancer would receive if they were treated up front with radical cystectomy instead of trimodal therapy—must be factored into the decision analysis comparing these modalities, as well as the risk of progression on therapy for these same patients. The advent of robotic cystectomy 2 adds another dimension to the QOL debate, potentially further tipping the argument in favour of radical surgery for young patients who are candidates for a neobladder—QOL after trimodal therapy and robotic cystectomy must be compared. Preserved QOL in trimodal therapy must also be balanced with subsequent risk of disease relapse and morbidity caused by salvage cystectomy. Whether or not pelvic lymph nodes should be treated during trimodal therapy remains unclear. Including pelvic lymph nodes in the targeted volume has not been associated with a difference in outcome, which is surprising given that the percentage of positive nodes found at radical surgery is prognostic of survival. However, the strict criteria used to select patients for trimodal therapy are likely to exclude patients with positive nodes. On the other hand, lymphadenectomy during surgery improves the survival of patients with minimal metastatic load, exactly the group of patients that would be considered ‘ideal’ for trimodal therapy. Are we not delivering sufficient radiation dose to sterilize these nodes and, therefore, make
an impact? Or are we selecting patients for trimodal therapy who have such good prognosis that nodal radiation is unnecessary? We should try to answer these questions by examining larger series and trial data for pelvic nodal recurrences in patients with a high probability of positive nodal areas.
‘‘
bahri altay/iStock/Thinkstock
Do we have reliable and validated predictive factors for the success of trimodal therapy?
’’
Should patient age be taken into account when choosing a treatment option? A small series that retrospectively compared QOL after treatments for muscle-invasive bladder cancer,3 found that QOL was better after conservative management than after radical cystectomy, largely owing to better sexual activity. This finding would justify the selection of young patients for trimodal therapy; however, it also raises the question of whether the increased lifespan of these patients, if cured, allows them more time to develop radiation-induced pelvic malignancies after trimodal therapy, as has been described for prostate cancer treated with radiotherapy.4 The 5‑year cancer-specific survival and overall survival rates for patients who undergo trimodal therapy range from 50% to 82% and from 36% to 74%, respectively. These wide ranges highlight the need for better prognostic and predictive tools. Over the past 15 years, evaluation of the genome has provided a high-throughput ‘snapshot’ of mechanisms operating in a cell or tissue of interest, enabling the formulation of single and multi-gene DNA, RNA or protein prog nostic and predictive biomarkers for different cancers. This scientific ‘revolution’ is hoped to provide the foundation for personal ized bladder cancer management for the 21st century. Many studies have described new prognostic and predictive biomarkers in bladder urothelial cancer,5 but far fewer have been validated in prospectively acquired data sets.6 Even fewer have been discovered for specific use in patients treated with radiotherapy for bladder cancer. So what type of prognostic or predictive markers do we need from the scientific community? And how should they be discovered? One potential area of investigation is metastasis. Metastasis kills patients irrespective of local therapy. Do we really know whether a metastatic lesion detected after radical cystectomy has ‘evolved’ in the same way as a metastatic lesion detected after
NATURE REVIEWS | UROLOGY
trimodal therapy? If metastatic colonization has occurred before therapy they are likely to be the same, but what if it occurs after trimodal therapy? The latter scenario is not impossible given that remnant primary tumour might still be present after trimodal therapy causing local recurrence. Furthermore, although the lack of an effect of neoadjuvant therapy in trimodal therapy trials might be explained by lower stage disease and other selection factors, it is also possible that such therapy is ineffective in preselected micrometastatic cells that have survived radiotherapy. Do we have reliable and validated predictive factors for the success of trimodal ther apy? Do positive outcomes after trimodal therapy represent response to chemotherapy or radiotherapy? Radiosensitization is a key element of the treatment paradigm that has not yet been addressed in the literature, so new thinking and new tools must be used.7,8 Should we aim to predict response of the primary tumour or elimination of surround ing cells harbouring genetic abnormalities that might give rise to intravesical recurrences? Or both? We would argue both are important, but the former is a priority. One aspect of trimodal therapy outcomes that is difficult to understand based on current molecular data is the fact that carcinoma in situ (CIS) is associated with a poor prognosis, owing to these patients having muscle-invasive tumours that harbour gene expression profiles similar to that of CIS.9 So why does trimodal therapy not ‘take care’ of the CIS? Could it be that the stem cell driving the recurrent tumour is different to the one that gave rise to the original invasive tumour and associated CIS when the patient was treated with trimodal therapy? Recent experimental evidence suggests this might be the case, with tumours arising from separate stem cells.10 Bladder preservation with trimodal ther apy is here to stay, but despite being used and studied for nearly 30 years, many questions remain unanswered. Fortunately, clever use of genomic technologies coupled with innovative clinical trial designs will hopefully resolve many of these issues, more rapidly than might have been possible in the past. University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, 7314 CC, Ann Arbor, MI 48109, USA (M.H.). University of Colorado Comprehensive Cancer Center, 13001 East 17th Place, MS #F‑434, Aurora, CO 80045, USA (D.T.). Correspondence to: D.T. [email protected]
VOLUME 11 | JUNE 2014 | 311 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
Ploussard, G. et al. Critical analysis of bladder sparing with trimodal therapy in muscleinvasive bladder cancer: a systematic review. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2014.02.038. Nix, J. et al. Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results. Eur. Urol. 57, 196–201 (2010). Caffo, O., Fellin, G., Graffer, U. & Luciani, L. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire. Cancer 78, 1089–1097 (1996). Moon, K., Stukenborg, G. J., Keim, J. & Theodorescu, D. Cancer incidence after localized therapy for prostate cancer. Cancer 107, 991–998 (2006). Lauss, M., Ringnér, M. & Höglund, M. Prediction of stage, grade, and survival in bladder cancer using genome-wide expression
data: a validation study. Clin. Cancer Res. 16, 4421–4433 (2010). 6. Smith, S. C. et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol. 12, 137–143 (2011). 7. Smith, S. C., Baras, A. S., Lee, J. K. & Theodorescu, D. The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res. 70, 1753–1758 (2010). 8. Williams, P. D. et al. Cyclophilin B expression is associated with in vitro radioresistance and clinical outcome after radiotherapy. Neoplasia 13, 1122–1131 (2011). 9. Dyrskjøt, L. et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 64, 4040–4048 (2004). 10. Dancik, G. M., Owens, C. R., Iczkowski, K. A. & Theodorescu, D. A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors. Stem Cells 32, 974–982 (2014).
PROSTATE CANCER
Surgery versus observation for localized prostate cancer Roderick C. N. van den Bergh and Gianluca Giannarini
A key study comparing radical prostatectomy and watchful waiting for prostate cancer has been updated with extended follow-up observation, demonstrating substantial benefits of surgery for reduced mortality mainly in younger men, but also reduced requirement for palliative treatment in older men. These findings should be interpreted within the current scenario of prostate cancer diagnosis and treatment. van den Bergh, R. C. N. & Giannarini, G. Nat. Rev. Urol. 11, 312–313 (2014); published online 13 May 2014; doi:10.1038/nrurol.2014.109
Bill-Axelson et al.1 recently published an update of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG‑4), one of the key clinical trials in localized prostate cancer treatment. Almost two-thirds of the 695 participants enrolled in this trial and randomly allocated to undergo radical prostatectomy or watchful waiting between 1989 and 1999 had died by the end of 2012. Inclusion criteria were the presence of clinically localized, well-differentiated or moderately well-d ifferentiated prostate cancer, age 10 years, serum PSA level
‘‘
…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
NEWS & VIEWS One of the strongest arguments in favour of bladder preservation is the potential to preserve QOL compared with radical cystectomy, but for whom? We have yet to systematically incorporate variables, such as baseline pretreatment voiding function symptoms, into QOL analyses to determine if some patients are more likely to experience trimodal-therapy-induced adverse effects than others. In addition, the ‘lost opportunity’ and subsequent costs of no longer having the option of a neobladder —which most patients with low volume/ low stage muscle-invasive bladder cancer would receive if they were treated up front with radical cystectomy instead of trimodal therapy—must be factored into the decision analysis comparing these modalities, as well as the risk of progression on therapy for these same patients. The advent of robotic cystectomy 2 adds another dimension to the QOL debate, potentially further tipping the argument in favour of radical surgery for young patients who are candidates for a neobladder—QOL after trimodal therapy and robotic cystectomy must be compared. Preserved QOL in trimodal therapy must also be balanced with subsequent risk of disease relapse and morbidity caused by salvage cystectomy. Whether or not pelvic lymph nodes should be treated during trimodal therapy remains unclear. Including pelvic lymph nodes in the targeted volume has not been associated with a difference in outcome, which is surprising given that the percentage of positive nodes found at radical surgery is prognostic of survival. However, the strict criteria used to select patients for trimodal therapy are likely to exclude patients with positive nodes. On the other hand, lymphadenectomy during surgery improves the survival of patients with minimal metastatic load, exactly the group of patients that would be considered ‘ideal’ for trimodal therapy. Are we not delivering sufficient radiation dose to sterilize these nodes and, therefore, make
an impact? Or are we selecting patients for trimodal therapy who have such good prognosis that nodal radiation is unnecessary? We should try to answer these questions by examining larger series and trial data for pelvic nodal recurrences in patients with a high probability of positive nodal areas.
‘‘
bahri altay/iStock/Thinkstock
Do we have reliable and validated predictive factors for the success of trimodal therapy?
’’
Should patient age be taken into account when choosing a treatment option? A small series that retrospectively compared QOL after treatments for muscle-invasive bladder cancer,3 found that QOL was better after conservative management than after radical cystectomy, largely owing to better sexual activity. This finding would justify the selection of young patients for trimodal therapy; however, it also raises the question of whether the increased lifespan of these patients, if cured, allows them more time to develop radiation-induced pelvic malignancies after trimodal therapy, as has been described for prostate cancer treated with radiotherapy.4 The 5‑year cancer-specific survival and overall survival rates for patients who undergo trimodal therapy range from 50% to 82% and from 36% to 74%, respectively. These wide ranges highlight the need for better prognostic and predictive tools. Over the past 15 years, evaluation of the genome has provided a high-throughput ‘snapshot’ of mechanisms operating in a cell or tissue of interest, enabling the formulation of single and multi-gene DNA, RNA or protein prog nostic and predictive biomarkers for different cancers. This scientific ‘revolution’ is hoped to provide the foundation for personal ized bladder cancer management for the 21st century. Many studies have described new prognostic and predictive biomarkers in bladder urothelial cancer,5 but far fewer have been validated in prospectively acquired data sets.6 Even fewer have been discovered for specific use in patients treated with radiotherapy for bladder cancer. So what type of prognostic or predictive markers do we need from the scientific community? And how should they be discovered? One potential area of investigation is metastasis. Metastasis kills patients irrespective of local therapy. Do we really know whether a metastatic lesion detected after radical cystectomy has ‘evolved’ in the same way as a metastatic lesion detected after
NATURE REVIEWS | UROLOGY
trimodal therapy? If metastatic colonization has occurred before therapy they are likely to be the same, but what if it occurs after trimodal therapy? The latter scenario is not impossible given that remnant primary tumour might still be present after trimodal therapy causing local recurrence. Furthermore, although the lack of an effect of neoadjuvant therapy in trimodal therapy trials might be explained by lower stage disease and other selection factors, it is also possible that such therapy is ineffective in preselected micrometastatic cells that have survived radiotherapy. Do we have reliable and validated predictive factors for the success of trimodal ther apy? Do positive outcomes after trimodal therapy represent response to chemotherapy or radiotherapy? Radiosensitization is a key element of the treatment paradigm that has not yet been addressed in the literature, so new thinking and new tools must be used.7,8 Should we aim to predict response of the primary tumour or elimination of surround ing cells harbouring genetic abnormalities that might give rise to intravesical recurrences? Or both? We would argue both are important, but the former is a priority. One aspect of trimodal therapy outcomes that is difficult to understand based on current molecular data is the fact that carcinoma in situ (CIS) is associated with a poor prognosis, owing to these patients having muscle-invasive tumours that harbour gene expression profiles similar to that of CIS.9 So why does trimodal therapy not ‘take care’ of the CIS? Could it be that the stem cell driving the recurrent tumour is different to the one that gave rise to the original invasive tumour and associated CIS when the patient was treated with trimodal therapy? Recent experimental evidence suggests this might be the case, with tumours arising from separate stem cells.10 Bladder preservation with trimodal ther apy is here to stay, but despite being used and studied for nearly 30 years, many questions remain unanswered. Fortunately, clever use of genomic technologies coupled with innovative clinical trial designs will hopefully resolve many of these issues, more rapidly than might have been possible in the past. University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, 7314 CC, Ann Arbor, MI 48109, USA (M.H.). University of Colorado Comprehensive Cancer Center, 13001 East 17th Place, MS #F‑434, Aurora, CO 80045, USA (D.T.). Correspondence to: D.T. [email protected]
VOLUME 11 | JUNE 2014 | 311 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
Ploussard, G. et al. Critical analysis of bladder sparing with trimodal therapy in muscleinvasive bladder cancer: a systematic review. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2014.02.038. Nix, J. et al. Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results. Eur. Urol. 57, 196–201 (2010). Caffo, O., Fellin, G., Graffer, U. & Luciani, L. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire. Cancer 78, 1089–1097 (1996). Moon, K., Stukenborg, G. J., Keim, J. & Theodorescu, D. Cancer incidence after localized therapy for prostate cancer. Cancer 107, 991–998 (2006). Lauss, M., Ringnér, M. & Höglund, M. Prediction of stage, grade, and survival in bladder cancer using genome-wide expression
data: a validation study. Clin. Cancer Res. 16, 4421–4433 (2010). 6. Smith, S. C. et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol. 12, 137–143 (2011). 7. Smith, S. C., Baras, A. S., Lee, J. K. & Theodorescu, D. The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res. 70, 1753–1758 (2010). 8. Williams, P. D. et al. Cyclophilin B expression is associated with in vitro radioresistance and clinical outcome after radiotherapy. Neoplasia 13, 1122–1131 (2011). 9. Dyrskjøt, L. et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 64, 4040–4048 (2004). 10. Dancik, G. M., Owens, C. R., Iczkowski, K. A. & Theodorescu, D. A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors. Stem Cells 32, 974–982 (2014).
PROSTATE CANCER
Surgery versus observation for localized prostate cancer Roderick C. N. van den Bergh and Gianluca Giannarini
A key study comparing radical prostatectomy and watchful waiting for prostate cancer has been updated with extended follow-up observation, demonstrating substantial benefits of surgery for reduced mortality mainly in younger men, but also reduced requirement for palliative treatment in older men. These findings should be interpreted within the current scenario of prostate cancer diagnosis and treatment. van den Bergh, R. C. N. & Giannarini, G. Nat. Rev. Urol. 11, 312–313 (2014); published online 13 May 2014; doi:10.1038/nrurol.2014.109
Bill-Axelson et al.1 recently published an update of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG‑4), one of the key clinical trials in localized prostate cancer treatment. Almost two-thirds of the 695 participants enrolled in this trial and randomly allocated to undergo radical prostatectomy or watchful waiting between 1989 and 1999 had died by the end of 2012. Inclusion criteria were the presence of clinically localized, well-differentiated or moderately well-d ifferentiated prostate cancer, age 10 years, serum PSA level
