NEWS & VIEWS
‘‘
…these authors define NNS as the number needed to screen to detect one prostate cancer, rather than to prevent one death or adverse event
’’
parameters can be used to compare the efficacy of screening strategies, with higher values indicating a less-effective strategy. Data from the study by van Leeuwen et al.8 showed that, for men with a serum PSA level of 0–1.9 ng/ml, the NNS was 24,642 and the NNT was 724. This finding is in sharp contrast to the outcomes rep orted in men with a baseline PSA of 4.0– 9.9 ng/ml, who have an NNS and an NNT of 492 and 152, respectively, suggesting minimal benefits of aggressive investigation for men with a low serum PSA level. However, the NNS presented by Randazzo and colleagues3 might cause confusion as, contrary to the generally used definition of NNS, these authors define NNS as the number needed to screen to detect one prostate cancer, rather than to prevent one death or adverse event. This definition is confusing as not all prostate cancers that are detected in a screening programme are ‘overdiagnosed’ (which can indeed be regarded as an adverse event). It is, therefore, important to realize that the NNS calculated by Randazzo et al.3 cannot be compared with the NNS reported in other studies, such as the ERSPC.5 In light of these previous studies, we can see that the conclusions presented by Randazzo et al.3 are not entirely novel. In addition to their proposed PSA-based strategy, the authors correctly highlight the diffic ulties associated with identifying men who have an increased risk of harbouri ng a life-threatening prostate cancer on the basis of a serum PSA level alone, and outline the importance of using other relevant information alongside the serum PSA level, especially for men with PSA levels of ≥2.0 ng/ml. As PSA is the mainstay for the early detection of prostate cancer and the presence of this biomarker in the serum is strongly associated with prostate volume, we must correct for the so-called ‘benign’ fraction of the total serum PSA level,7 either by measuring prostate volume with ultrasonography,6 estimating the volume by DRE,7 or using other serum markers. 9 In addition, although DRE is not adequate as the sole screening test, the outcome of a DRE has additional value in a 430 | AUGUST 2014 | VOLUME 11
multivariate setting.6 The same is true for imaging; although the standard imaging modality for the prostate is still trans rectal ultrasonography, promising data are starting to emerge for MRI. In the absence of a prostate cancer biomarker that can infallibly identify men with a potentially aggressive prostate cancer who can be cured by early detection and sub sequent treatment, the best approach is to combine relevant prebiopsy information. Multivariate decision tools that enable a calculation of current prostate cancer risk are now widely available2 and, on also the basis of the ERSPC Rotterdam data, a multivariate future 4-year risk calculator has now been developed to help determine a safe repeat screening interval (Box 1).9 As most guidelines promote shared decision making and an individualized approach, it seems logical to adhere to these guidelines as much as possible; for example, by using a contemporary multivariate approach, preferably in the form of an objective nomogram.
1.
Department of Urology, Erasmus Medical Centre, Room NH-227, PO Box 2040, 3000 CA Rotterdam, Netherlands. [email protected]
8.
Competing interests The author declares no competing interests.
2.
3.
4.
5.
6.
7.
9.
Roobol, M. J. & Carlsson, S. V. Risk stratification in prostate cancer screening. Nat. Rev. Urol. 10, 38–48 (2013). Randazzo, M. et al. A “PSA pyramid” for men with initial prostate-specific antigen ≤3 ng/ml: a plea for individualized prostate cancer screening. Eur. Urol. http://dx.doi.org/ 10.1016/j.eururo.2014.04.005. Roobol, M. J. et al. Screening for prostate cancer: results of the Rotterdam section of the European randomized study of screening for prostate cancer. Eur. Urol. 64, 530–539 (2013). Schröder, F. H. et al. Prostate-cancer mortality at 11 years of follow-up. N. Engl. J. Med. 366, 981–990 (2012). Kranse, R., Roobol, M. J. & Schröder, F. H. A graphical device to represent the outcomes of a logistic regression analysis. Prostate 68, 1674–1680 (2008). Roobol, M. J. et al. Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group. World J. Urol. 30, 149–155 (2012). Bul, M., van Leeuwen, P. J., Zhu, X., Schröder, F. H. & Roobol, M. J. Prostate cancer incidence and disease-specific survival of men with initial prostate-specific antigen less than 3.0 ng/ml who are participating in ERSPC Rotterdam. Eur. Urol. 59, 498–505 (2011). van Leeuwen, P. J. et al. Balancing the harms and benefits of early detection of prostate cancer. Cancer 116, 4857–4865 (2010). Roobol, M. J. et al. A calculator for prostate cancer risk 4 years after an initially negative screen: findings from ERSPC Rotterdam. Eur. Urol. 63, 627–633 (2013).
BLADDER CANCER
Defining intermediate-risk non‑muscle-invasive bladder cancer S. Bruce Malkowicz
The pathology of intermediate-risk non-muscle-invasive bladder cancer is less well-defined than both high-risk and low-risk presentations of this disease. Recently reported guidelines seek to aid clinicians in classification of intermediate-risk patients, and also provide treatment recommendations for this subgroup. Malkowicz, S. B. Nat. Rev. Urol. 11, 430–432 (2014); published online 22 July 2014; doi:10.1038/nrurol.2014.172
Treatment of non-muscle-invasive bladder cancer (NMIBC) is now relatively welldefined for high-risk and low-risk disease presentation, and awaits further refinement through improvements in therapeutic options. Solitary low-grade tumours, especially smaller lesions (3 cm or less), respond best to resection and immediate instillation of intravesical agents, whereas higher risk lesions, such as carcinoma in situ and high-grade T1 stage disease, have demonstrated good response to BCG
when given on a schedule of induction (an initial 6-week course) and maintenance (3-weekly courses every 6 months as tolerated).1,2 The pathology of intermediate-risk NMIBC is less well-defined, and the treatment recommendations for this disease presentation are not as clear as for highrisk and low-risk disease. Intermediate-risk classification is not currently standardized and encompasses multiple metrics over space and time, contributing to this lack of clarity. Also, a paucity of clinical trials www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
specifically directed at this heterogeneous subgroup of patients with NMIBC means information is lacking. Most of our treatment knowledge of this population comes from post-hoc analysis and inference from larger trials that include these patients. The American Urological Association (AUA) and the International Bladder Cancer Group (IBCG) have sought to address this lack of clarity by offering a functional, circumscribed definition of intermediate-risk NMIBC as multiple or recurrent low-grade Ta stage lesions. 3,4 Now, in a reiteration of this subject, the IBCG has consolidated recent knowledge of this subgroup in order to provide the most accurate, contemporary definition of intermediate-r isk NMIBC, and has produced clinical treatment recommendations based on stratification of these patients.3 This feat was achieved by expert review of available data on this subject as of September 2013, and the findings and recommendations are based on consensus authority opinion. Although a more rigor ous methodology would be preferable, the available data on intermediate-risk NMIBC are not stringent enough, and are not amenable to a classic form of Cochrane review guideline analysis. Thus, although this exercise has limitations, it is a significant effort in a clinical space that begs for some order. Current recommendations for therapy from several organizations, such as the AUA, EAU (European Association of Uro logy), NCCN (National Comprehensive Cancer Network) and ICUD (International Consultation on Urological Diseases), sug gest a basic role for induction and mainten ance therapy with either an intravesical chemotherapeutic agent or BCG. Recent data reinforce the opinion that a more robust and lasting response is generally achieved with the use of BCG than chemo therapy.5 Considerable discretion is left to the treating physician with appreciation for the clinical ‘feel’ for the patient. The current IBCG review of the available data revealed several quantifiable basic characteristics of the disease.6 Key components included tumour multiplicity, tumour size (greater or less than 3 cm), early recur rence and frequency of recurrence, enab ling stratification of the intermediate-risk group based on the sum of the risk factors from zero to >3. The median range of 1–2 associated factors is assigned a true intermediate-risk status with lower values treated as low risk, and scores of ≥3 as
high risk. In the defined intermediate-risk group, consideration is given to previous intravesical treatment, which further guides decisions regarding therapy. An important consideration when applying this algorithm, or any other treatment paradigm, is the primacy placed on accurate initial and subsequent classification of each clinical presentation. There is a subtle elegance to well-performed transurethral resection of a bladder tumour, and attention to a complete resection as well as the detection of carcinoma in situ is important. Consideration of cytology results and the potential use of cystoscopy adjuvants, such as narrow band optics or photodynamic agents, might aid in better categorization of particular patients. Furthermore, host considerations such as competing comorbidity, bladder function and tolerance to therapeutic agents might be involved in modulating the options available in a well-constructed algorithm. The addition of one or more tumour markers to existing stratification tools could prove very useful in further stratify ing intermediate-risk patients. Several potential tumour markers, in a classical sense, are candidates for investigation with regard to their role in predicting tumour behaviour, but the majority of existing data are retrospective. Well-performed prospective trials are desirable, but they are resource-intensive endeavours. The value added to a straightforward algorithm by including these markers would also need to be assessed prior to implementation. The same might be said for access to deeper sequencing of tumours, and the whole range of ‘omics’ that are becoming potential clinical instruments for indivi dual patients, rather than rarefied research tools.7 Although ‘personalized medicine’ is a term that has been introduced in medical practice with emphasis in oncology, the concept currently exceeds the achievable benefits in almost all disease states, including NMIBC. It is a desirable goal to tailor a specific therapy for each tumour, but we still have a way to go in accurately defining each tumour and having a broad array of effective therapies. There is also the possibility that need for subcategorization and classification of patients could be supplanted by more effective therapies for NMIBC. For example, better delivery of standard therapies, using techniques such as electromotive distribution of chemo therapy, comes to mind. 8 Other novel agents in the realm of immunotherapeutics
NATURE REVIEWS | UROLOGY
moodboard/moodboard/Thinkstock
NEWS & VIEWS
or gene therapy might also have the potential to negate the need for subcategorization by improving treatment options. This newly recommended approach to intermediate-risk NMIBC from the IBCG based on the latest available data and authority opinion applies empirical common sense to a regularly encountered problem in urological oncology. 3 It serves as a solid framework for basic clinical decision-making and derives considerable strength from high quality, wellconstructed trials. Though the trials do not specifically address intermediate-risk patients, these patients are incorporated in the fabric of the studies and provide insight into high level clinical care. Future trials of novel agents that include primary end points for intermediate-risk patients might improve outcomes for these individuals, but a considerable amount of clinical discernment will always be necessary in treating this heterogeneous patient population. Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected] Competing interests The author declares no competing interests. 1.
2.
3.
Lamm, D. L. Maintenance bacillus CalmetteGuerin immunotherapy for recurrent, TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J. Urol. 163, 1124–1129 (2000). Sylvester, R. J., Oosterlinck, W. & van der Meijden, A. P. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a metaanalysis of published results of randomized clinical trials. J. Urol. 171, 2186–2190 (2004). Hall, M. C. et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J. Urol. 178, 2314–2330 (2007).
VOLUME 11 | AUGUST 2014 | 431 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 4.
5.
6.
Brausi, M. et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J. Urol. 186, 2158–2167 (2011). Shariat, S. F., Chade, D. C., Karakiewicz, P. I., Scherr, D. S. & Dalbagni, G. Update on intravesival agents for non-muscle invasive bladder cancer. Immunotherapy 2, 381–392 (2010). Kamat, A. M., Witjes, J. A. & Brausi, M. Defining and treating the spectrum of
7.
8.
cryptorchid position later in childhood, the AUA guidelines recommend immediate referral for orchiopexy, which should then be performed during the following year. Acquired cryptorchidism has only been recognized as a true clinical entity over the past 10 years. Older literature (published in the 20th century) on the sequelae of cryptor chidism tended to report mixed cohorts of patients with congenital and acquired cryptorchidism, which probably led to some misunderstanding. According to a Dutch study, acquired ascended testes tend to re-descend spontaneously at puberty and surgical treatment does not improve the growth of the testes.6 These findings contrast those in congenital cryptorchidism, which show improved testicular growth after early orchiopexy.7 Dutch urologists have experimented, therefore, with a policy for acquired cryptorchidism of wait-andsee until puberty. Given that the long-term effects of acquired cryptorchidism remain uncertain, the guidelines recommend early action for these patients. Primary hormonal therapy with human chorionic gonadotropin or gonadotropinreleasing hormone (GnRH) has been suggested as an alternative to first-line surgery. Efficacy studies have typically not taken into account whether the patients had congenit al or acquired cryptorchidism, which might be one reason for variability in results. Although no clear statistics exist about the use of hormonal therapy, it seems as if the treatment has been more popular in Europe than in the USA. The AUA guidelines do not recommend use of hormone therapy with either agent, because their efficacy is poor and they might cause adverse late effects.8 Indeed, damage to germ cells, interstitial bleeding and inflammatory reaction in the testes after hormonal therapy have been reported;8 none of the existing guidelines
intermediate-risk NMIBC. J. Urol. http:// dx.doi.org/10.1016/j.juro.2014.02.2573. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014). Di Stasi, S. M. et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomized controlled trial. Lancet Oncol. 12, 871–879 (2011).
PAEDIATRICS
New cryptorchidism guidelines reach a consensus Jorma Toppari
The American Urological Association has released a new guideline on the evaluation and treatment of cryptorchidism, recommending early orchiopexy as the first-line treatment for both the congenital and acquired forms of the disease; hormonal therapy is not recommended. Given similarities with current European recommendations, transatlantic consensus has been achieved. Cryptorchidism is the most common congenital urological disorder in boys, affecting 2–9% at birth; almost as many boys experience acquired cryptorchidism later in childhood (cumulative incidence 2–7% up to 7 years of age). 1 Cryptorchidism is associated with an increased risk of testicular germ cell cancer and impaired fertility later in life. Although these detri mental effects occur after puberty, their origin lies much earlier in fetal and childhood developm ent. Early treatment of undescended testes undoubtedly improves the fertility potential of affected individuals; however, the influence of early treatment on risk of testicular cancer is less clear. Furthermore, the most suitable treatment of cryptorchidism is still the source of some confusion.
‘‘
…the AUA guidelines are aligned with those of the European Association of Urology … and the Nordic consensus…
’’
To provide some clarity, the American Urological Association (AUA) recently published a new set of guidelines on the evaluation and treatment of cryptorchidism. 2 The new guidelines are based on a systematic review and meta-analysis of the published literature. Included in 432 | AUGUST 2014 | VOLUME 11
the analysis were peer-reviewed articles published in English from 1980 to 2013. Where suffic ient evidence-based data were missing, the guidelines were developed using cl inical principles and expert opinions. For congenital cryptorchidism, the AUA guidelines state that orchiopexy before the age of 18 months is recommended as the first line of treatment. Spontaneous descent of the testes often occurs in the first 3 months after birth, but if the testes remain undescended at 6 months, the child should be referred for surgery. In this regard, the AUA guidelines are aligned with those of the European Association of Urology (EAU)3 and the Nordic consensus on treatment of undescended testes.4 Guidelines put together by Swiss researchers and published in Swiss Medical Weekly are also similar.5 The timing of surgery differs slightly between guidelines; the EAU guidelines recommend surgical treatment before the age of 1 year, but in practice orchiopexy is often delayed for local reasons; for example, many hospitals have a 1‑year age limit for procedures in which the patient is discharged the same day. In other cases, the need for a paediatric anaesthesiologist can be another limiting factor. Thus, the time window of 6–18 months seems realistic. In patients with acquired cryptorchidism, where the testis has ascended to a
solidcolours/iStock/Thinkstock
Toppari, J. Nat. Rev. Urol. 11, 432–433 (2014); published online 29 July 2014; doi:10.1038/nrurol.2014.180
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
‘‘
…these authors define NNS as the number needed to screen to detect one prostate cancer, rather than to prevent one death or adverse event
’’
parameters can be used to compare the efficacy of screening strategies, with higher values indicating a less-effective strategy. Data from the study by van Leeuwen et al.8 showed that, for men with a serum PSA level of 0–1.9 ng/ml, the NNS was 24,642 and the NNT was 724. This finding is in sharp contrast to the outcomes rep orted in men with a baseline PSA of 4.0– 9.9 ng/ml, who have an NNS and an NNT of 492 and 152, respectively, suggesting minimal benefits of aggressive investigation for men with a low serum PSA level. However, the NNS presented by Randazzo and colleagues3 might cause confusion as, contrary to the generally used definition of NNS, these authors define NNS as the number needed to screen to detect one prostate cancer, rather than to prevent one death or adverse event. This definition is confusing as not all prostate cancers that are detected in a screening programme are ‘overdiagnosed’ (which can indeed be regarded as an adverse event). It is, therefore, important to realize that the NNS calculated by Randazzo et al.3 cannot be compared with the NNS reported in other studies, such as the ERSPC.5 In light of these previous studies, we can see that the conclusions presented by Randazzo et al.3 are not entirely novel. In addition to their proposed PSA-based strategy, the authors correctly highlight the diffic ulties associated with identifying men who have an increased risk of harbouri ng a life-threatening prostate cancer on the basis of a serum PSA level alone, and outline the importance of using other relevant information alongside the serum PSA level, especially for men with PSA levels of ≥2.0 ng/ml. As PSA is the mainstay for the early detection of prostate cancer and the presence of this biomarker in the serum is strongly associated with prostate volume, we must correct for the so-called ‘benign’ fraction of the total serum PSA level,7 either by measuring prostate volume with ultrasonography,6 estimating the volume by DRE,7 or using other serum markers. 9 In addition, although DRE is not adequate as the sole screening test, the outcome of a DRE has additional value in a 430 | AUGUST 2014 | VOLUME 11
multivariate setting.6 The same is true for imaging; although the standard imaging modality for the prostate is still trans rectal ultrasonography, promising data are starting to emerge for MRI. In the absence of a prostate cancer biomarker that can infallibly identify men with a potentially aggressive prostate cancer who can be cured by early detection and sub sequent treatment, the best approach is to combine relevant prebiopsy information. Multivariate decision tools that enable a calculation of current prostate cancer risk are now widely available2 and, on also the basis of the ERSPC Rotterdam data, a multivariate future 4-year risk calculator has now been developed to help determine a safe repeat screening interval (Box 1).9 As most guidelines promote shared decision making and an individualized approach, it seems logical to adhere to these guidelines as much as possible; for example, by using a contemporary multivariate approach, preferably in the form of an objective nomogram.
1.
Department of Urology, Erasmus Medical Centre, Room NH-227, PO Box 2040, 3000 CA Rotterdam, Netherlands. [email protected]
8.
Competing interests The author declares no competing interests.
2.
3.
4.
5.
6.
7.
9.
Roobol, M. J. & Carlsson, S. V. Risk stratification in prostate cancer screening. Nat. Rev. Urol. 10, 38–48 (2013). Randazzo, M. et al. A “PSA pyramid” for men with initial prostate-specific antigen ≤3 ng/ml: a plea for individualized prostate cancer screening. Eur. Urol. http://dx.doi.org/ 10.1016/j.eururo.2014.04.005. Roobol, M. J. et al. Screening for prostate cancer: results of the Rotterdam section of the European randomized study of screening for prostate cancer. Eur. Urol. 64, 530–539 (2013). Schröder, F. H. et al. Prostate-cancer mortality at 11 years of follow-up. N. Engl. J. Med. 366, 981–990 (2012). Kranse, R., Roobol, M. J. & Schröder, F. H. A graphical device to represent the outcomes of a logistic regression analysis. Prostate 68, 1674–1680 (2008). Roobol, M. J. et al. Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group. World J. Urol. 30, 149–155 (2012). Bul, M., van Leeuwen, P. J., Zhu, X., Schröder, F. H. & Roobol, M. J. Prostate cancer incidence and disease-specific survival of men with initial prostate-specific antigen less than 3.0 ng/ml who are participating in ERSPC Rotterdam. Eur. Urol. 59, 498–505 (2011). van Leeuwen, P. J. et al. Balancing the harms and benefits of early detection of prostate cancer. Cancer 116, 4857–4865 (2010). Roobol, M. J. et al. A calculator for prostate cancer risk 4 years after an initially negative screen: findings from ERSPC Rotterdam. Eur. Urol. 63, 627–633 (2013).
BLADDER CANCER
Defining intermediate-risk non‑muscle-invasive bladder cancer S. Bruce Malkowicz
The pathology of intermediate-risk non-muscle-invasive bladder cancer is less well-defined than both high-risk and low-risk presentations of this disease. Recently reported guidelines seek to aid clinicians in classification of intermediate-risk patients, and also provide treatment recommendations for this subgroup. Malkowicz, S. B. Nat. Rev. Urol. 11, 430–432 (2014); published online 22 July 2014; doi:10.1038/nrurol.2014.172
Treatment of non-muscle-invasive bladder cancer (NMIBC) is now relatively welldefined for high-risk and low-risk disease presentation, and awaits further refinement through improvements in therapeutic options. Solitary low-grade tumours, especially smaller lesions (3 cm or less), respond best to resection and immediate instillation of intravesical agents, whereas higher risk lesions, such as carcinoma in situ and high-grade T1 stage disease, have demonstrated good response to BCG
when given on a schedule of induction (an initial 6-week course) and maintenance (3-weekly courses every 6 months as tolerated).1,2 The pathology of intermediate-risk NMIBC is less well-defined, and the treatment recommendations for this disease presentation are not as clear as for highrisk and low-risk disease. Intermediate-risk classification is not currently standardized and encompasses multiple metrics over space and time, contributing to this lack of clarity. Also, a paucity of clinical trials www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
specifically directed at this heterogeneous subgroup of patients with NMIBC means information is lacking. Most of our treatment knowledge of this population comes from post-hoc analysis and inference from larger trials that include these patients. The American Urological Association (AUA) and the International Bladder Cancer Group (IBCG) have sought to address this lack of clarity by offering a functional, circumscribed definition of intermediate-risk NMIBC as multiple or recurrent low-grade Ta stage lesions. 3,4 Now, in a reiteration of this subject, the IBCG has consolidated recent knowledge of this subgroup in order to provide the most accurate, contemporary definition of intermediate-r isk NMIBC, and has produced clinical treatment recommendations based on stratification of these patients.3 This feat was achieved by expert review of available data on this subject as of September 2013, and the findings and recommendations are based on consensus authority opinion. Although a more rigor ous methodology would be preferable, the available data on intermediate-risk NMIBC are not stringent enough, and are not amenable to a classic form of Cochrane review guideline analysis. Thus, although this exercise has limitations, it is a significant effort in a clinical space that begs for some order. Current recommendations for therapy from several organizations, such as the AUA, EAU (European Association of Uro logy), NCCN (National Comprehensive Cancer Network) and ICUD (International Consultation on Urological Diseases), sug gest a basic role for induction and mainten ance therapy with either an intravesical chemotherapeutic agent or BCG. Recent data reinforce the opinion that a more robust and lasting response is generally achieved with the use of BCG than chemo therapy.5 Considerable discretion is left to the treating physician with appreciation for the clinical ‘feel’ for the patient. The current IBCG review of the available data revealed several quantifiable basic characteristics of the disease.6 Key components included tumour multiplicity, tumour size (greater or less than 3 cm), early recur rence and frequency of recurrence, enab ling stratification of the intermediate-risk group based on the sum of the risk factors from zero to >3. The median range of 1–2 associated factors is assigned a true intermediate-risk status with lower values treated as low risk, and scores of ≥3 as
high risk. In the defined intermediate-risk group, consideration is given to previous intravesical treatment, which further guides decisions regarding therapy. An important consideration when applying this algorithm, or any other treatment paradigm, is the primacy placed on accurate initial and subsequent classification of each clinical presentation. There is a subtle elegance to well-performed transurethral resection of a bladder tumour, and attention to a complete resection as well as the detection of carcinoma in situ is important. Consideration of cytology results and the potential use of cystoscopy adjuvants, such as narrow band optics or photodynamic agents, might aid in better categorization of particular patients. Furthermore, host considerations such as competing comorbidity, bladder function and tolerance to therapeutic agents might be involved in modulating the options available in a well-constructed algorithm. The addition of one or more tumour markers to existing stratification tools could prove very useful in further stratify ing intermediate-risk patients. Several potential tumour markers, in a classical sense, are candidates for investigation with regard to their role in predicting tumour behaviour, but the majority of existing data are retrospective. Well-performed prospective trials are desirable, but they are resource-intensive endeavours. The value added to a straightforward algorithm by including these markers would also need to be assessed prior to implementation. The same might be said for access to deeper sequencing of tumours, and the whole range of ‘omics’ that are becoming potential clinical instruments for indivi dual patients, rather than rarefied research tools.7 Although ‘personalized medicine’ is a term that has been introduced in medical practice with emphasis in oncology, the concept currently exceeds the achievable benefits in almost all disease states, including NMIBC. It is a desirable goal to tailor a specific therapy for each tumour, but we still have a way to go in accurately defining each tumour and having a broad array of effective therapies. There is also the possibility that need for subcategorization and classification of patients could be supplanted by more effective therapies for NMIBC. For example, better delivery of standard therapies, using techniques such as electromotive distribution of chemo therapy, comes to mind. 8 Other novel agents in the realm of immunotherapeutics
NATURE REVIEWS | UROLOGY
moodboard/moodboard/Thinkstock
NEWS & VIEWS
or gene therapy might also have the potential to negate the need for subcategorization by improving treatment options. This newly recommended approach to intermediate-risk NMIBC from the IBCG based on the latest available data and authority opinion applies empirical common sense to a regularly encountered problem in urological oncology. 3 It serves as a solid framework for basic clinical decision-making and derives considerable strength from high quality, wellconstructed trials. Though the trials do not specifically address intermediate-risk patients, these patients are incorporated in the fabric of the studies and provide insight into high level clinical care. Future trials of novel agents that include primary end points for intermediate-risk patients might improve outcomes for these individuals, but a considerable amount of clinical discernment will always be necessary in treating this heterogeneous patient population. Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected] Competing interests The author declares no competing interests. 1.
2.
3.
Lamm, D. L. Maintenance bacillus CalmetteGuerin immunotherapy for recurrent, TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J. Urol. 163, 1124–1129 (2000). Sylvester, R. J., Oosterlinck, W. & van der Meijden, A. P. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a metaanalysis of published results of randomized clinical trials. J. Urol. 171, 2186–2190 (2004). Hall, M. C. et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J. Urol. 178, 2314–2330 (2007).
VOLUME 11 | AUGUST 2014 | 431 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 4.
5.
6.
Brausi, M. et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J. Urol. 186, 2158–2167 (2011). Shariat, S. F., Chade, D. C., Karakiewicz, P. I., Scherr, D. S. & Dalbagni, G. Update on intravesival agents for non-muscle invasive bladder cancer. Immunotherapy 2, 381–392 (2010). Kamat, A. M., Witjes, J. A. & Brausi, M. Defining and treating the spectrum of
7.
8.
cryptorchid position later in childhood, the AUA guidelines recommend immediate referral for orchiopexy, which should then be performed during the following year. Acquired cryptorchidism has only been recognized as a true clinical entity over the past 10 years. Older literature (published in the 20th century) on the sequelae of cryptor chidism tended to report mixed cohorts of patients with congenital and acquired cryptorchidism, which probably led to some misunderstanding. According to a Dutch study, acquired ascended testes tend to re-descend spontaneously at puberty and surgical treatment does not improve the growth of the testes.6 These findings contrast those in congenital cryptorchidism, which show improved testicular growth after early orchiopexy.7 Dutch urologists have experimented, therefore, with a policy for acquired cryptorchidism of wait-andsee until puberty. Given that the long-term effects of acquired cryptorchidism remain uncertain, the guidelines recommend early action for these patients. Primary hormonal therapy with human chorionic gonadotropin or gonadotropinreleasing hormone (GnRH) has been suggested as an alternative to first-line surgery. Efficacy studies have typically not taken into account whether the patients had congenit al or acquired cryptorchidism, which might be one reason for variability in results. Although no clear statistics exist about the use of hormonal therapy, it seems as if the treatment has been more popular in Europe than in the USA. The AUA guidelines do not recommend use of hormone therapy with either agent, because their efficacy is poor and they might cause adverse late effects.8 Indeed, damage to germ cells, interstitial bleeding and inflammatory reaction in the testes after hormonal therapy have been reported;8 none of the existing guidelines
intermediate-risk NMIBC. J. Urol. http:// dx.doi.org/10.1016/j.juro.2014.02.2573. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014). Di Stasi, S. M. et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomized controlled trial. Lancet Oncol. 12, 871–879 (2011).
PAEDIATRICS
New cryptorchidism guidelines reach a consensus Jorma Toppari
The American Urological Association has released a new guideline on the evaluation and treatment of cryptorchidism, recommending early orchiopexy as the first-line treatment for both the congenital and acquired forms of the disease; hormonal therapy is not recommended. Given similarities with current European recommendations, transatlantic consensus has been achieved. Cryptorchidism is the most common congenital urological disorder in boys, affecting 2–9% at birth; almost as many boys experience acquired cryptorchidism later in childhood (cumulative incidence 2–7% up to 7 years of age). 1 Cryptorchidism is associated with an increased risk of testicular germ cell cancer and impaired fertility later in life. Although these detri mental effects occur after puberty, their origin lies much earlier in fetal and childhood developm ent. Early treatment of undescended testes undoubtedly improves the fertility potential of affected individuals; however, the influence of early treatment on risk of testicular cancer is less clear. Furthermore, the most suitable treatment of cryptorchidism is still the source of some confusion.
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…the AUA guidelines are aligned with those of the European Association of Urology … and the Nordic consensus…
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To provide some clarity, the American Urological Association (AUA) recently published a new set of guidelines on the evaluation and treatment of cryptorchidism. 2 The new guidelines are based on a systematic review and meta-analysis of the published literature. Included in 432 | AUGUST 2014 | VOLUME 11
the analysis were peer-reviewed articles published in English from 1980 to 2013. Where suffic ient evidence-based data were missing, the guidelines were developed using cl inical principles and expert opinions. For congenital cryptorchidism, the AUA guidelines state that orchiopexy before the age of 18 months is recommended as the first line of treatment. Spontaneous descent of the testes often occurs in the first 3 months after birth, but if the testes remain undescended at 6 months, the child should be referred for surgery. In this regard, the AUA guidelines are aligned with those of the European Association of Urology (EAU)3 and the Nordic consensus on treatment of undescended testes.4 Guidelines put together by Swiss researchers and published in Swiss Medical Weekly are also similar.5 The timing of surgery differs slightly between guidelines; the EAU guidelines recommend surgical treatment before the age of 1 year, but in practice orchiopexy is often delayed for local reasons; for example, many hospitals have a 1‑year age limit for procedures in which the patient is discharged the same day. In other cases, the need for a paediatric anaesthesiologist can be another limiting factor. Thus, the time window of 6–18 months seems realistic. In patients with acquired cryptorchidism, where the testis has ascended to a
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Toppari, J. Nat. Rev. Urol. 11, 432–433 (2014); published online 29 July 2014; doi:10.1038/nrurol.2014.180
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