NEWS & VIEWS could have been inappropriately assigned to receive localized focal treatments. Also of note is that transperineal template biopsies are invasive and not without associated adverse effects. Indeed, Singh et al.2 noted significant haematuria that required admission after 2% of 291 biopsies and urinary retention after 7% of the procedures, but did not assess rates of erectile dysfunction. Thus, if ascertaining suitability for focal therapy requires transperineal biopsies, its purported low-morbidity benefits might be somewhat compromised.
‘‘
…any form of preselection in a population-based study is clearly pertinent…
’’
The study’s criteria for ‘suitability’ also raise other questions. Currently, too few long-term prospective trials have been performed for us to know which patients are better suited for localized treatments than for active surveillance or radical therapies. The optimal management of patients with multifocal disease is particularly uncertain as not all lesions behave similarly. Singh et al.2 have defined men with multifocal disease with one dominant lesion as suitable for focal therapy, but this criterion is based on the assumption that the smaller foci are indolent and represent inconsequential disease. Although this hypothesis is supported by the monoclonal origin of prostatic metastases,5,6 the extended conclusion that focal therapy for the index lesion results in disease control remains unproven. Furthermore, the majority of patients who were categorized as suitable had low-risk to intermediate-risk prostate cancer, with a median PSA concentration of 6.8 ng/ml and an average of eight positive cores out of 29 cores. Thus, active surveillance, which is generally free of adverse effects, might actually be more suitable for many of these men with low-volume disease than focal therapy. The prevention of unnecessary treatment is underlined by the challenge of surveillance following focal treatments; PSA is unreliable, MRI is difficult to interpret, and additional invasive biopsies might be required. Long-term functional outcome data are similarly awaited and needed to prove the intuitive presumption that focal therapy is associated with reduced morbidity. Early findings are encouraging, but focal techniques (such as HIFU and cryotherapy) are by no means completely safe, with some studies showing significant adverse effects.7–9 8 | JANUARY 2014 | VOLUME 11
Looking at outcomes after HIFU, one study reported dysuria in 22%, urinary tract infection in 17%, and acute urinary retention requiring admission in 2% of men.7 Another study reported similar outcomes and also noted urethral strictures in 7% of patients post-HIFU.8 Of greater concern is the fact that potentially devastating complications— such as rectovesical fistula—have also been reported.9 Singh et al.2 specifically considered patients with lesions that encroach on a single neurovascular bundle as viable candidates for focal therapy, with the view that preservation of the contralateral bundle prevents erectile dysfunction. Although logical, further research is needed to support this hypothesis, emphasized by a recent series that found a concerning reduction in erectile function scores in patients after focal treatment.9 Focal therapies still require considerable further study, hence their current classification as experimental by the European Association of Urology and the lack of FDA approval for the techniques. Nevertheless, Singh et al.2 make important headway in characterizing localized prostate cancer in this cohort of men and in guiding thera peutic choice. We look forward to the conclusions from long-term outcome studies to develop suitability criteria and validated localized treatment protocols. Ultimately, until we know which prostate cancers are ideally managed with these focal modalities, the proportion of men best suited to focal therapy remains debatable.
Guy’s, King’s and St Thomas’ School of Medicine, Department of Urology, 1st Floor Southwark Wing, London SE1 9RT, UK (B. Challacombe, L. Dixon). Correspondence to: B. Challacombe [email protected] Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Sanda, M. G. et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N. Engl. J. Med. 358, 1250–1261 (2008). Singh, P. B. et al. Prostate cancer tumour features on template prostate-mapping biopsies: implications for focal therapy. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2013.09.045. Crawford, E. D. et al. Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens. Prostate 73, 778–787 (2013). Huo, A. S. et al. Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens. J. Urol. 187, 2044–2049 (2012). Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15, 559–565 (2009). Ahmed, H. U. The index lesion and the origin of prostate cancer. N. Engl. J. Med. 361, 1704–1706 (2009). Ahmed, H. U. et al. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol. 13, 622–632 (2012). Challacombe, B. J., Murphy, D. G., Zakri, R. & Cahill, D. J. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2‑year follow-up. BJU Int. 104, 200–204 (2009). Barret, E. et al. Morbidity of focal therapy in the treatment of localized prostate cancer. Eur. Urol. 63, 618–622 (2013).
BLADDER CANCER
Conditional survival after radical cystectomy Giorgio Gandaglia and Maxine Sun
In a recent retrospective institutional analysis, the prognosis of patients with muscle-invasive bladder cancer improved over time after surgical intervention. Indeed, duration of survivorship after radical cystectomy was inversely correlated with risk of mortality, suggesting that follow-up regimens should be modelled according to this parameter. Gandaglia, G. & Sun, M. Nat. Rev. Urol. 11, 8–9 (2014); published online 17 December 2013; doi:10.1038/nrurol.2013.301
The concept of conditional survival—the likelihood that an individual, having already survived for a certain duration after being diagnosed with cancer, will continue to survive for a specified duration—is compelling when considering diseases associated with unfavourable prognosis at initial
diagnosis or treatment, such as bladder cancer. For this disease, data suggest that long-term cancer survivors have a better prognosis than newly diagnosed individuals.1 Immediately after radical cystectomy, the 5-year overall survival rate is 60% for patients with bladder cancer. 2,3 However, www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS provided an individual survives for at least 2 years after surgery, his or her prognosis invariably improves, with 5-year overall survival rates of >60%. In a recent publication in European Urology, Ploussard and colleagues4 tested this hypothesis. By retrospectively assessing a multi-institutional cohort of individuals treated with radical cystectomy from 1979– 2012, the researchers examined whether the concept of conditional survival applies to patients with muscle-invasive bladder cancer. To generate conditional survival estimates, the authors applied what statisticians refer to as the multiplicative law of probability.1 Using this statistical approach, the investigators observed that the 5-year overall survival rate improved in patients who survived for a certain period of time after surgery. Specifically, the 5-year survival rate was 57.5% immediately after surgery, rising to 63.1%, 65.9%, 65.1%, 60.5%, and 59.4% after 1 year, 2 years, 3 years, 5 years, and 10 years of survival, respectively. Furthermore, the overall survival rate for patients with adverse pathological character istics drastically improved 2 years and 3 years after surgery, reaching levels that were comparable to patients with more favourable disease characteristics. For example, patients with lymph node invasion had a 30% 5-year overall survival rate immediately after surgery, which doubled to 60% in patients who survived for 3 years. A similar effect was observed in patients with positive surgical margins and those with pT3–pT4 disease, whose postoperative 5-year survival rates increased from 26% to 73% and from 39% to 64%, respectively.
‘‘
…provided an individual survives for at least 2 years after surgery, his or her prognosis invariably improves…
’’
The findings of Ploussard et al.4 confirm the conclusions of a previous study conducted by our group. 5 Relying on the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database, we observed that a survivorship of 2 years after radical cystectomy markedly improved individual patient prognosis. Much like the report by Ploussard and colleagues,4 such survival gains were particularly notable for patients with aggressive disease patterns (for example, positive lymph nodes and advanced tumour stage). Both studies consensually conclude that a patient’s risk profile changes
iSt ock /Th ink sto ck
over time, with increasing survivorship correlating with decreasing risk of mortality. Conceptually, conditional survival might seem to be perfectly intuitive to most clini cians. However, its role is not apparent for all malignancies. For example, for patients with cancers that have a favourable prognosis upfront, such as thyroid or prostate cancers, little improvement can be expected.6 Another exception is chronic lymphocytic leukaemia, for which a clear lack of survival gains has been recorded, despite the unfavourable prognosis at diagnosis.7 That said, the prognoses for most patients with cancer who have survived the initial years after treatment is generally better than it was at initial presentation. Such improvements generate great optimism among patients, and help care providers and physicians to plan follow-up management. Conditional survival clearly merits consideration in the context of patients with bladder cancer who have been treated with surgery. Both the Ploussard et al.4 and our own5 studies distinctively demonstrate that, after an initial period of 2–3 years following radical cystectomy, when the risk of cancer-related death is at its peak, prognosis can improve substantially and earlier ominous survival estimates no longer apply. From a practical perspective, these observations demonstrate the importance of opting for multimodal treatment management to optimize therapeutic benefit. In this regard, two randomized trials have reported a benefit of neoadjuvant chemotherapy in surgical candidates with muscle-invasive bladder cancer.8 However, the medical community seems divided on the role of neoadjuvant and adjuvant chemotherapy for the treatment of bladder cancer; despite guideline recommendations to administer preoperative chemotherapy to all eligible patients with muscle-invasive bladder cancer, this therapeutic approach remains largely underutilized.9 Another clinical implication of conditional survival data for patients with bladder cancer is that, although patients with aggressive tumours require intensive follow-up regimens during
NATURE REVIEWS | UROLOGY
the first 2–3 years after surgery, these patients can be monitored less rigorously thereafter. In the latest assessment of trends in the incidence of bladder cancer and associated mortality over the past few decades in the USA, Abdollah et al.10 showed that mortal ity rates have not improved over time. Consequently, although the effect of conditional survival in patients with bladder cancer is of interest, more urgent considerations perhaps include the need for a multi disciplinary approach to the management of patients with bladder cancer, increased physician adherence to guideline recommendations, greater consideration of multimodal treatment modalities, and the search for biomarkers that could help with identifying patients at higher risk of recurrence after radical cystectomy. Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, 264 Boulevard Rene-Levesque Est, Room 228, Montreal, QC H2X 1P1, Canada (G. Gandaglia, M. Sun). Correspondence to: M. Sun [email protected] Competing interests The authors declare no competing interests. 1.
Skuladottir, H. & Olsen, J. H. Conditional survival of patients with the four major histologic subgroups of lung cancer in Denmark. J. Clin. Oncol. 21, 3035–3040 (2003). 2. Stein, J. P. et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J. Clin. Oncol. 19, 666–675 (2001). 3. Gakis, G. et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur. Urol. 63, 45–57 (2013). 4. Ploussard, G. et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2013.09.050. 5. Sun, M. et al. Conditional survival of patients with urothelial carcinoma of the urinary bladder treated with radical cystectomy. Eur. J. Cancer 48, 1503–1511 (2012). 6. Janssen-Heijnen, M. L. et al. Clinical relevance of conditional survival of cancer patients in europe: age-specific analyses of 13 cancers. J. Clin. Oncol. 28, 2520–2528 (2010). 7. Ellison, L. F., Bryant, H., Lockwood, G. & Shack, L. Conditional survival analyses across cancer sites. Health Rep. 22, 21–25 (2011). 8. Sonpavde, G. & Sternberg, C. N. Neoadjuvant chemotherapy for invasive bladder cancer. Curr. Urol. Rep. 13, 136–146 (2012). 9. Feifer, A. et al. Multi-institutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder. J.Clin. Oncol. 29, 240 (2011). 10. Abdollah, F. et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 37, 219–225 (2013).
VOLUME 11 | JANUARY 2014 | 9 © 2014 Macmillan Publishers Limited. All rights reserved
‘‘
…any form of preselection in a population-based study is clearly pertinent…
’’
The study’s criteria for ‘suitability’ also raise other questions. Currently, too few long-term prospective trials have been performed for us to know which patients are better suited for localized treatments than for active surveillance or radical therapies. The optimal management of patients with multifocal disease is particularly uncertain as not all lesions behave similarly. Singh et al.2 have defined men with multifocal disease with one dominant lesion as suitable for focal therapy, but this criterion is based on the assumption that the smaller foci are indolent and represent inconsequential disease. Although this hypothesis is supported by the monoclonal origin of prostatic metastases,5,6 the extended conclusion that focal therapy for the index lesion results in disease control remains unproven. Furthermore, the majority of patients who were categorized as suitable had low-risk to intermediate-risk prostate cancer, with a median PSA concentration of 6.8 ng/ml and an average of eight positive cores out of 29 cores. Thus, active surveillance, which is generally free of adverse effects, might actually be more suitable for many of these men with low-volume disease than focal therapy. The prevention of unnecessary treatment is underlined by the challenge of surveillance following focal treatments; PSA is unreliable, MRI is difficult to interpret, and additional invasive biopsies might be required. Long-term functional outcome data are similarly awaited and needed to prove the intuitive presumption that focal therapy is associated with reduced morbidity. Early findings are encouraging, but focal techniques (such as HIFU and cryotherapy) are by no means completely safe, with some studies showing significant adverse effects.7–9 8 | JANUARY 2014 | VOLUME 11
Looking at outcomes after HIFU, one study reported dysuria in 22%, urinary tract infection in 17%, and acute urinary retention requiring admission in 2% of men.7 Another study reported similar outcomes and also noted urethral strictures in 7% of patients post-HIFU.8 Of greater concern is the fact that potentially devastating complications— such as rectovesical fistula—have also been reported.9 Singh et al.2 specifically considered patients with lesions that encroach on a single neurovascular bundle as viable candidates for focal therapy, with the view that preservation of the contralateral bundle prevents erectile dysfunction. Although logical, further research is needed to support this hypothesis, emphasized by a recent series that found a concerning reduction in erectile function scores in patients after focal treatment.9 Focal therapies still require considerable further study, hence their current classification as experimental by the European Association of Urology and the lack of FDA approval for the techniques. Nevertheless, Singh et al.2 make important headway in characterizing localized prostate cancer in this cohort of men and in guiding thera peutic choice. We look forward to the conclusions from long-term outcome studies to develop suitability criteria and validated localized treatment protocols. Ultimately, until we know which prostate cancers are ideally managed with these focal modalities, the proportion of men best suited to focal therapy remains debatable.
Guy’s, King’s and St Thomas’ School of Medicine, Department of Urology, 1st Floor Southwark Wing, London SE1 9RT, UK (B. Challacombe, L. Dixon). Correspondence to: B. Challacombe [email protected] Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Sanda, M. G. et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N. Engl. J. Med. 358, 1250–1261 (2008). Singh, P. B. et al. Prostate cancer tumour features on template prostate-mapping biopsies: implications for focal therapy. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2013.09.045. Crawford, E. D. et al. Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens. Prostate 73, 778–787 (2013). Huo, A. S. et al. Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens. J. Urol. 187, 2044–2049 (2012). Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15, 559–565 (2009). Ahmed, H. U. The index lesion and the origin of prostate cancer. N. Engl. J. Med. 361, 1704–1706 (2009). Ahmed, H. U. et al. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol. 13, 622–632 (2012). Challacombe, B. J., Murphy, D. G., Zakri, R. & Cahill, D. J. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2‑year follow-up. BJU Int. 104, 200–204 (2009). Barret, E. et al. Morbidity of focal therapy in the treatment of localized prostate cancer. Eur. Urol. 63, 618–622 (2013).
BLADDER CANCER
Conditional survival after radical cystectomy Giorgio Gandaglia and Maxine Sun
In a recent retrospective institutional analysis, the prognosis of patients with muscle-invasive bladder cancer improved over time after surgical intervention. Indeed, duration of survivorship after radical cystectomy was inversely correlated with risk of mortality, suggesting that follow-up regimens should be modelled according to this parameter. Gandaglia, G. & Sun, M. Nat. Rev. Urol. 11, 8–9 (2014); published online 17 December 2013; doi:10.1038/nrurol.2013.301
The concept of conditional survival—the likelihood that an individual, having already survived for a certain duration after being diagnosed with cancer, will continue to survive for a specified duration—is compelling when considering diseases associated with unfavourable prognosis at initial
diagnosis or treatment, such as bladder cancer. For this disease, data suggest that long-term cancer survivors have a better prognosis than newly diagnosed individuals.1 Immediately after radical cystectomy, the 5-year overall survival rate is 60% for patients with bladder cancer. 2,3 However, www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS provided an individual survives for at least 2 years after surgery, his or her prognosis invariably improves, with 5-year overall survival rates of >60%. In a recent publication in European Urology, Ploussard and colleagues4 tested this hypothesis. By retrospectively assessing a multi-institutional cohort of individuals treated with radical cystectomy from 1979– 2012, the researchers examined whether the concept of conditional survival applies to patients with muscle-invasive bladder cancer. To generate conditional survival estimates, the authors applied what statisticians refer to as the multiplicative law of probability.1 Using this statistical approach, the investigators observed that the 5-year overall survival rate improved in patients who survived for a certain period of time after surgery. Specifically, the 5-year survival rate was 57.5% immediately after surgery, rising to 63.1%, 65.9%, 65.1%, 60.5%, and 59.4% after 1 year, 2 years, 3 years, 5 years, and 10 years of survival, respectively. Furthermore, the overall survival rate for patients with adverse pathological character istics drastically improved 2 years and 3 years after surgery, reaching levels that were comparable to patients with more favourable disease characteristics. For example, patients with lymph node invasion had a 30% 5-year overall survival rate immediately after surgery, which doubled to 60% in patients who survived for 3 years. A similar effect was observed in patients with positive surgical margins and those with pT3–pT4 disease, whose postoperative 5-year survival rates increased from 26% to 73% and from 39% to 64%, respectively.
‘‘
…provided an individual survives for at least 2 years after surgery, his or her prognosis invariably improves…
’’
The findings of Ploussard et al.4 confirm the conclusions of a previous study conducted by our group. 5 Relying on the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database, we observed that a survivorship of 2 years after radical cystectomy markedly improved individual patient prognosis. Much like the report by Ploussard and colleagues,4 such survival gains were particularly notable for patients with aggressive disease patterns (for example, positive lymph nodes and advanced tumour stage). Both studies consensually conclude that a patient’s risk profile changes
iSt ock /Th ink sto ck
over time, with increasing survivorship correlating with decreasing risk of mortality. Conceptually, conditional survival might seem to be perfectly intuitive to most clini cians. However, its role is not apparent for all malignancies. For example, for patients with cancers that have a favourable prognosis upfront, such as thyroid or prostate cancers, little improvement can be expected.6 Another exception is chronic lymphocytic leukaemia, for which a clear lack of survival gains has been recorded, despite the unfavourable prognosis at diagnosis.7 That said, the prognoses for most patients with cancer who have survived the initial years after treatment is generally better than it was at initial presentation. Such improvements generate great optimism among patients, and help care providers and physicians to plan follow-up management. Conditional survival clearly merits consideration in the context of patients with bladder cancer who have been treated with surgery. Both the Ploussard et al.4 and our own5 studies distinctively demonstrate that, after an initial period of 2–3 years following radical cystectomy, when the risk of cancer-related death is at its peak, prognosis can improve substantially and earlier ominous survival estimates no longer apply. From a practical perspective, these observations demonstrate the importance of opting for multimodal treatment management to optimize therapeutic benefit. In this regard, two randomized trials have reported a benefit of neoadjuvant chemotherapy in surgical candidates with muscle-invasive bladder cancer.8 However, the medical community seems divided on the role of neoadjuvant and adjuvant chemotherapy for the treatment of bladder cancer; despite guideline recommendations to administer preoperative chemotherapy to all eligible patients with muscle-invasive bladder cancer, this therapeutic approach remains largely underutilized.9 Another clinical implication of conditional survival data for patients with bladder cancer is that, although patients with aggressive tumours require intensive follow-up regimens during
NATURE REVIEWS | UROLOGY
the first 2–3 years after surgery, these patients can be monitored less rigorously thereafter. In the latest assessment of trends in the incidence of bladder cancer and associated mortality over the past few decades in the USA, Abdollah et al.10 showed that mortal ity rates have not improved over time. Consequently, although the effect of conditional survival in patients with bladder cancer is of interest, more urgent considerations perhaps include the need for a multi disciplinary approach to the management of patients with bladder cancer, increased physician adherence to guideline recommendations, greater consideration of multimodal treatment modalities, and the search for biomarkers that could help with identifying patients at higher risk of recurrence after radical cystectomy. Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, 264 Boulevard Rene-Levesque Est, Room 228, Montreal, QC H2X 1P1, Canada (G. Gandaglia, M. Sun). Correspondence to: M. Sun [email protected] Competing interests The authors declare no competing interests. 1.
Skuladottir, H. & Olsen, J. H. Conditional survival of patients with the four major histologic subgroups of lung cancer in Denmark. J. Clin. Oncol. 21, 3035–3040 (2003). 2. Stein, J. P. et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J. Clin. Oncol. 19, 666–675 (2001). 3. Gakis, G. et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur. Urol. 63, 45–57 (2013). 4. Ploussard, G. et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur. Urol. http://dx.doi.org/10.1016/ j.eururo.2013.09.050. 5. Sun, M. et al. Conditional survival of patients with urothelial carcinoma of the urinary bladder treated with radical cystectomy. Eur. J. Cancer 48, 1503–1511 (2012). 6. Janssen-Heijnen, M. L. et al. Clinical relevance of conditional survival of cancer patients in europe: age-specific analyses of 13 cancers. J. Clin. Oncol. 28, 2520–2528 (2010). 7. Ellison, L. F., Bryant, H., Lockwood, G. & Shack, L. Conditional survival analyses across cancer sites. Health Rep. 22, 21–25 (2011). 8. Sonpavde, G. & Sternberg, C. N. Neoadjuvant chemotherapy for invasive bladder cancer. Curr. Urol. Rep. 13, 136–146 (2012). 9. Feifer, A. et al. Multi-institutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder. J.Clin. Oncol. 29, 240 (2011). 10. Abdollah, F. et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 37, 219–225 (2013).
VOLUME 11 | JANUARY 2014 | 9 © 2014 Macmillan Publishers Limited. All rights reserved
