NEWS & VIEWS
‘‘
Treatment with abiraterone followed by enzalutamide (and vice versa) does not seem to be appropriate…
’’
remission rate was 12%. Clearly, differ‑ ences exist between first-line and secondline docetaxel, supporting the hypothesis that docetaxel resistance might be triggered by AR overexpression or mutation. On the other hand, studies have demonstrated a good response to cabazitaxel when given after abiraterone, with a PSA response rate of 56%, which is similar to that achieved in the TROPIC trial.1,3 With regard to enzalutamide, both nonAR-related mechanisms and AR splice variants have been identified as mediators of resistance and progression.9 In xenograft models, increasing concentrations of AR splice variants are associated with disease resistance. Furthermore, loss of the tumour suppressor gene PTEN has been shown to induce resistance to second-generation antiandrogens. Events triggering resistance to enzalutamide are currently not well established. In a recent study of 60 patients with mCRPC, cross-resistance between abiraterone and enzalutamide resulted in a PSA response rate of only 5% in men who had received abiraterone after progressing on enzalutamide. Schrader et al.10 evaluated the outcomes of 35 patients who under‑ went second-line treatment with enzalu‑ tamide following progression during, or after, therapy with abiraterone. Treatment response rates were disappointing, with an objective remission observed in only one patient and a median time to progression of just 4 months despite a PSA response rate of 51%. In conclusion, the report by Pezaro et al.2 should be interpreted in the context of the minimal data that are available for opti mal treatment sequencing for men with mCRPC. The evidence points to the fact that cross-resistance exists between andro‑ gen biosynthesis inhibitors, AR signalling pathway inhibitors, and docetaxel, such that the introduction of cabazitaxel after failure with abiraterone or enzalutamide seems to be advisable. Treatment with abiraterone fol‑ lowed by enzalutamide (and vice versa) does not seem to be appropriate, although more studies are needed to validate this finding. Cabazitaxel can be administered without significant treatment-related toxic ity, even in elderly men, provided preventive measures are taken.1 8
190 | APRIL 2014 | VOLUME 11
Department of Urology, RWTH University Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany (A.H., D.P.). Correspondence to: A.H. [email protected] Competing interests A.H. has received honoraria and research grants, and served on advisory boards for the following companies: Amgen, Astellas, Bayer AG, Ferring, IPSEN, Jansen Cilag, Pfizer, Sanofi Aventis, and Takeda. D.P. declares no competing interests. 1.
2.
3.
Heidenreich, A. et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur. Urol. 65, 467–479 (2014). Pezaro, C. J. et al. Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur. Urol. http://dx.doi.org/ 10.1016/j.eururo.2013.11.044. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010).
4.
Fizazi, K. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU‑AA‑301 randomised, double-blind, placebocontrolled phase 3 study. Lancet Oncol. 13, 983–992 (2012). 5. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). 6. Zhu, M. L. et al. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 70, 7992–8002 (2010). 7. Mezynski, J. et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for crossresistance? Ann. Oncol. 23, 2943–2947 (2012). 8. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004). 9. Guo, Z. & Qiu, Y. A new trick of an old molecule: androgen receptor splice variants taking the stage?! Int. J. Biol. Sci. 7, 815–822 (2011). 10. Schrader, A. J. et al. Enzalutamide in castrationresistant prostate cancer patients progressing after docetaxel and abiraterone. Eur. Urol. 65, 30–36 (2014).
PROSTATE CANCER
A consensus on trial design for focal therapy Sangeet Ghai and John Trachtenberg
Focal therapy of prostate cancer enables treatment of the index lesion while sparing the rest of the gland and surrounding vital structures, thereby decreasing the risk of morbidity. As clinicians acknowledge its potential, the recently published multidisciplinary consensus is timely and provides new insight into trial design for focal therapy. Ghai, S. & Trachtenberg, J. Nat. Rev. Urol. 11, 190–192 (2014); published online 18 March 2014; doi:10.1038/nrurol.2014.64
In recent years, focal therapy for prostate cancer has become the topic of intense debate, emerging from the fringes of onco‑ logical practice into urological clinics. However, a multitude of important factors still need to be considered. Firstly, what is its role? Who is the ideal patient, and which technique should be used to diagnose, local‑ ize, and define the extent of tumour destruc‑ tion necessary to cure this patient? What constitutes optimal therapy? Can only the most modern, complex, and costly techno‑ logical solutions offer precise but complete tumour-targeted therapy? Finally, is this therapy clinically necessary in an era when clinical equipoise to radical prostatectomy might be considered active surveillance or even observation? If so, how should we define successful treatment, and how might we design a clinical trial to prove its usefulness or ineffectiveness? With respect to this last
question, van den Bos et al.1 have proposed a feasible standard for the design of clinical trials of focal therapy for prostate cancer. The authors of this study have correctly stated that clear definitions of eligibility criteria and end points are required for a successful trial of focal ablation for prostate cancer. Proper patient selection is of utmost importance, and depends upon the ablative template, whether targeted ablation, hemi ablation, or zonal ablation. At this point, we should note that the term ‘focal therapy’ is something of a misnomer for hemiablation or zonal (subtotal) ablation approaches, wherein the goal is elimination of every pos‑ sible focus of cancer within the gland, irre‑ spective of possible iatrogenic adverse effects. One could argue that these patients might benefit from a more radical form of treat‑ ment. True focal therapy would be tissue pre‑ serving with the aim of eradicating the index www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
tumour while causing minimal or no adverse effects from the targeted treatment, thereby providing the best balance between oncologi‑ cal control and maintenance of quality of life. Regardless, focal therapy is best performed using real-time imaging guidance—for example, MRI-guided focal laser thermal therapy (MRgFLTT) 2,3 or MRI-guided focused ultrasonography (MRgFUS)4—as the target might move as a result of the force of the laser fibre, small movements of the patient, or deformation of the prostate caused by the ablative process (no matter how wellsecured the prostate might be), positioning the virtual target at a different location to the real target. Use of MRI-transrectal ultra‑ sonography (TRUS) fusion might mean that truly focal treatment can be performed under TRUS guidance in the future, but deformable registration (resulting from the current lack of accuracy with this technique) has prevented precise localization of the target lesion. Furthermore, the use of MRI as an imaging tool during treatment has the added advantage of accurate MRI thermo metry, which enables real-time closed-loop monitoring and targeted treatment, ensur‑ ing selective and adequate thermal tumour ablation, as well as simultaneous continuous monitored preservation of the sensitive sur‑ rounding tissues that control continence, potency, and bowel and bladder function.
‘‘
The authors recommend performing state-of-the-art mpMRI for all patients selected for focal therapy…
’’
The authors recommend performing stateof-the-art mpMRI for all patients selected for focal therapy, although they suggest that it is not necessary for MRI-visible lesions to be concordant with biopsy. Given the high rates of interobserver variability associated with the assessment of prostatic MRI and the widely accepted decision to exclude men with highrisk prostate cancer from focal treatment, we strongly disagree with the authors on this issue and feel that it is important to substanti‑ ate MRI findings with a positive biopsy result. This criterion is a prerequisite for inclusion in focal therapy trials at our clinic in the Princess Margaret Cancer Centre, Toronto, and might be best performed using MRI-TRUS fusion or real-time MRI guidance. We recommend that tumour length in the positive sample be taken into account when selecting candidates for treatment, rather than the percentage of tumour in the positive samples, as the sample
Jacob Wackerhausen/iStock/Thinkstock
NEWS & VIEWS
length at biopsy is often less than a full core of 20 mm and might also be fragmented. For MRI-visible lesions, Sartor et al.5 have sug‑ gested that lesion size on imaging should be added as a criterion for patient selection; they recommend that a single lesion should not exceed 15 mm in its largest dimension in any plane on imaging, with capsular contact of no more than 5 mm. Adequately identifying the extent of tumour for treatment contouring is impera tive, but far from easy. Sparse prostate tumours, which often contain normal tissue intermixed with prostate cancer, might have similar apparent diffusion coefficient (ADC) and T2 values to normal peripheral zone tissue and, therefore, might not be detectable on MRI.6 Some investigators suggest adding a margin of ablation to the MRI-visible tumour, but there are no guidelines or con‑ sistent data to support this practice. Should the tissue at the periphery of the MRI-visible tumour be included in the zone of ablation? And, if so, does the circumferential margin of sparse tumour around the more-dense visible tumour depend on the Gleason grade or size of the visible tumour? Future research might help us to answer these questions. In the meantime, it is important to establish the expected post-therapy changes that can be demonstrated on MRI and evaluate the ability of MRI to distinguish these changes from residual or recurrent disease. Dynamic contrast-enhanced (DCE)-MRI has been shown to be superior to diffusion-weighted imaging (DWI) and T2-weighted imaging for the prediction of recurrent disease follow‑ ing focal therapy with high-intensity focused ultrasonography.7 According to our own, as yet unpublished, initial data, DCE-MRI enhancement curves show promise for differentiating residual disease from fibrosis after laser ablation. We have also found that ADC maps are not always useful for predict‑ ing the presence of tumour after therapy, as fibrosis at the site of ablation will also cause restricted diffusion.
NATURE REVIEWS | UROLOGY
Until mpMRI findings have been defini‑ tively validated in the postablation setting, alterations in MRI signal cannot act as the primary end point in clinical trials and must be corroborated by biopsy results, just as we feel that it is important to substantiate the MRI findings with biopsy as an inclu‑ sion criterion. We propose that the biopsy strategy at 6 months after ablation should only include samples from the site of treat‑ ment, with about 4–6 samples taken from the area (including the margins of the ablation zone). This approach accounts for thermal deformation of the prostate gland at the site of ablation and, in our experience, might be achieved reliably with the use of MRI-TRUS fusion combined with imageable pellets left in situ after treatment at the periphery of the targeted zone. A clear challenge for any focal therapy trial is defining a successful result. Treatment outcomes need to be assessed in the context of ablation, as opposed to entire-gland treatment; thus, we recommend sampling only at the site of ablation at the 6-month follow-up biopsy and not of the entire gland as has been proposed by the authors.1 The authors have correctly stated that detect‑ ing significant cancer at sites other than the area of treatment would be deemed selection failure and not treatment failure. To avoid selection failure, we recommend that, in addition to MRI-targeted biopsy, every patient also has at least two sets of 12-core biopsy of the prostate gland within 6–12 months before treatment. We suggest that men without MRI-detectable cancer but clinically insignificant disease detected on a 4–6 sample biopsy strategy at the site of abla‑ tion should be considered to be successfully treated, in keeping with the central premise of treatment, which is destruction of the index lesion. However, we acknowledge that more-mature oncological follow-up data are needed to substantiate this recommendation. In summary, the authors are to be com‑ mended for their efforts in putting together a consensus proposal on how to design, execute, and evaluate the outcomes of a focal therapy trial, so as to enable uniform evalu‑ ation. Although we agree with the authors on many of the criteria put forward, we have tried to highlight some caveats that we recommend as crucial for designing a focal therapy trial. This manuscript is a major step forwards compared with previous con‑ sensus group proposals;8,9 however, there are still many unanswered questions, warrant‑ ing further research into focal therapy for prostate cancer. VOLUME 11 | APRIL 2014 | 191
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Joint Department of Medical Imaging, Toronto General Hospital, University of Toronto, 585 University Avenue, Toronto, ON M5G 2N2, Canada (S.G.). Department of Urology and Surgical Oncology, Princess Margaret Hospital, University of Toronto, 620 University Avenue, Toronto, ON M5G 2M9, Canada (J.T.). Correspondence to: J.T. [email protected]
4.
5.
6.
Acknowledgements The authors would like to thank Alexandre R. Zlotta for advice during the preparation of the manuscript. Competing interests The authors declare no competing interests. 1.
2.
3.
Van den Bos, W. et al. Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur. Urol. http:// dx.doi.org/10.1016/j.eururo.2014.01.001. Lindner, U. et al. Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy. Eur. Urol. 57, 1111–1114 (2010). Raz, O. et al. Real-time magnetic resonance imaging-guided focal laser therapy in patients
7.
8.
9.
discomfort related to pelvic floor symptoms.3 Prior to this trial, some evidence existed to suggest that patients with symptomatic pelvic organ prolapse can benefit from pelvic physiotherapy;4 however, robust randomized controlled trials had not been performed. In the POPPY trial, the studied interven‑ tion is described as ‘pelvic floor muscle train‑ ing’ rather than ‘pelvic physiotherapy’, even though women visited a pelvic physiotherapist on average 4.2 times over a 3‑month period. During these visits, the emphasis was on teaching the patient how to adequately con‑ tract the pelvic floor; biofeedback and electro stimulation (typical components of pelvic physiotherapy) were not allowed. These exclu‑ sions raise the issue of whether the observed beneficial effect of pelvic floor muscle training would have occurred if there was no involve‑ ment of a pelvic physiotherapist. If the only task of the physiotherapist was to motivate the patient to perform the exercise, then perhaps the involvement of another type of person (a coach, for example) would have given the same result. The authors do not discuss this in their manuscript. Previous studies evaluating the effects of physiotherapy have revealed that motivation and adherence are crucial to treatment effi‑ cacy.5 In this trial, Hagen et al.1 report high adherence to the intervention. However, they do not address the selection bias of their trial, owing to the fact that only motivated patients are willing to participate in a study like this. The assertion that all patients recruited felt positively towards the benefits of pelvic physiotherapy is demonstrated by the large percentage of patients in the control group who decided to conduct pelvic floor exer‑ cises; 69% of the control group undertook pelvic floor exercises in the last 4 weeks of the 12-month follow-up period. In daily clinical practice, most women are far less motivated to perform pelvic floor muscle exercises con‑ sistently. Thus, the generalizability of these trial results to average women presenting with symptomatic pelvic organ prolapse is limited.
with low-risk prostate cancer. Eur. Urol. 58, 173–177 (2010). Lindner, U. et al. Focal magnetic resonance guided focused ultrasound for prostate cancer: Initial North American experience. Can. Urol. Assoc. J. 6, E283–E286 (2012). Sartor, A. O. et al. Evaluating localized prostate cancer and identifying candidates for focal therapy. Urology 72, S12–S24 (2008). Langer, D. L. et al. Intermixed normal tissue within prostate cancer: effect on MR imaging measurements of apparent diffusion coefficient and T2--sparse versus dense cancers. Radiology 249, 900–908 (2008). Kim, C. K., Park, B. K., Lee, H. M., Kim, S. S. & Kim, E. MRI techniques for prediction of local tumour progression after high-intensity focused ultrasonic ablation of prostate cancer. Am. J. Roentgenol. 190, 1180–1186 (2008). Bostwick, D. G. et al. Group consensus reports from the Consensus Conference on Focal Treatment of Prostatic Carcinoma, Celebration, Florida, February 24, 2006. Urology 70, S42–S44 (2007). Eggener, S. E. et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J. Urol. 178, 2260–2267 (2007).
FEMALE UROLOGY
The benefits of pelvic floor muscle training for prolapse Jan-Paul Roovers
A newly published randomized controlled trial shows that pelvic floor muscle training can significantly reduce prolapse symptoms compared with provision of a prolapse lifestyle advice leaflet and no muscle training. However, the important role of surgery in the treatment of these women must be taken into account. For the multicentre Pelvic Organ Prolapse Physiotherapy (POPPY) trial, Hagen and coworkers1 randomly compared pelvic floor muscle training from a physiotherapist with provision of a lifestyle advice leaflet, in 447 women with symptomatic pelvic organ pro‑ lapse. The primary outcome was the pelvic organ prolapse symptom score (POP-SS), measured with a validated disease-specific quality-of-life questionnaire. Women in the intervention group reported fewer pro‑ lapse symptoms at 12 months (in other words, a significantly greater reduction in POP-SS) than those in the control group (mean reduction in POP-SS from baseline was 3.77 ± 5.62 for physiotherapy compared with 2.09 ± 5.39 for control; adjusted differ‑ ence 1.52, 95% CI 0.46–2.59; P = 0.0053). In addition, although not statistically signifi‑ cant, there was a tendency towards greater improvement of anatomical abnormalities in the intervention group than the control 192 | APRIL 2014 | VOLUME 11
group, and more re-interventions were per‑ formed within the first year of follow-up assessment in the control group than in the physiotherapy group. Difference in costs of subsequent treatment was UK£38.63 in favour of the intervention group, and the cost per quality-adjusted life year gained was about £16,000. Based on their findings, the authors conclude that pelvic floor muscle training should be recommended for the conservative management of prolapse. Given that the lifetime risk of undergoing surgery for pelvic organ prolapse is estimated to be 11%,2 and there is a known association between surgery and risk of recurrence (one in three procedures are performed for recur‑ rent prolapse),2 conservative management should be explored before surgery. Pelvic physiotherapy is a type of conservative therapy that is intended to increase pelvic floor muscle force, improve pelvic floor muscle coordina‑ tion and endurance and decrease experienced
Wavebreakmedia Ltd/Wavebreak Media/Thinkstock
Roovers, J.-P. Nat. Rev. Urol. 11, 192–193 (2014); published online 4 March 2014; doi:10.1038/nrurol.2014.35
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
‘‘
Treatment with abiraterone followed by enzalutamide (and vice versa) does not seem to be appropriate…
’’
remission rate was 12%. Clearly, differ‑ ences exist between first-line and secondline docetaxel, supporting the hypothesis that docetaxel resistance might be triggered by AR overexpression or mutation. On the other hand, studies have demonstrated a good response to cabazitaxel when given after abiraterone, with a PSA response rate of 56%, which is similar to that achieved in the TROPIC trial.1,3 With regard to enzalutamide, both nonAR-related mechanisms and AR splice variants have been identified as mediators of resistance and progression.9 In xenograft models, increasing concentrations of AR splice variants are associated with disease resistance. Furthermore, loss of the tumour suppressor gene PTEN has been shown to induce resistance to second-generation antiandrogens. Events triggering resistance to enzalutamide are currently not well established. In a recent study of 60 patients with mCRPC, cross-resistance between abiraterone and enzalutamide resulted in a PSA response rate of only 5% in men who had received abiraterone after progressing on enzalutamide. Schrader et al.10 evaluated the outcomes of 35 patients who under‑ went second-line treatment with enzalu‑ tamide following progression during, or after, therapy with abiraterone. Treatment response rates were disappointing, with an objective remission observed in only one patient and a median time to progression of just 4 months despite a PSA response rate of 51%. In conclusion, the report by Pezaro et al.2 should be interpreted in the context of the minimal data that are available for opti mal treatment sequencing for men with mCRPC. The evidence points to the fact that cross-resistance exists between andro‑ gen biosynthesis inhibitors, AR signalling pathway inhibitors, and docetaxel, such that the introduction of cabazitaxel after failure with abiraterone or enzalutamide seems to be advisable. Treatment with abiraterone fol‑ lowed by enzalutamide (and vice versa) does not seem to be appropriate, although more studies are needed to validate this finding. Cabazitaxel can be administered without significant treatment-related toxic ity, even in elderly men, provided preventive measures are taken.1 8
190 | APRIL 2014 | VOLUME 11
Department of Urology, RWTH University Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany (A.H., D.P.). Correspondence to: A.H. [email protected] Competing interests A.H. has received honoraria and research grants, and served on advisory boards for the following companies: Amgen, Astellas, Bayer AG, Ferring, IPSEN, Jansen Cilag, Pfizer, Sanofi Aventis, and Takeda. D.P. declares no competing interests. 1.
2.
3.
Heidenreich, A. et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur. Urol. 65, 467–479 (2014). Pezaro, C. J. et al. Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur. Urol. http://dx.doi.org/ 10.1016/j.eururo.2013.11.044. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010).
4.
Fizazi, K. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU‑AA‑301 randomised, double-blind, placebocontrolled phase 3 study. Lancet Oncol. 13, 983–992 (2012). 5. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). 6. Zhu, M. L. et al. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 70, 7992–8002 (2010). 7. Mezynski, J. et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for crossresistance? Ann. Oncol. 23, 2943–2947 (2012). 8. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004). 9. Guo, Z. & Qiu, Y. A new trick of an old molecule: androgen receptor splice variants taking the stage?! Int. J. Biol. Sci. 7, 815–822 (2011). 10. Schrader, A. J. et al. Enzalutamide in castrationresistant prostate cancer patients progressing after docetaxel and abiraterone. Eur. Urol. 65, 30–36 (2014).
PROSTATE CANCER
A consensus on trial design for focal therapy Sangeet Ghai and John Trachtenberg
Focal therapy of prostate cancer enables treatment of the index lesion while sparing the rest of the gland and surrounding vital structures, thereby decreasing the risk of morbidity. As clinicians acknowledge its potential, the recently published multidisciplinary consensus is timely and provides new insight into trial design for focal therapy. Ghai, S. & Trachtenberg, J. Nat. Rev. Urol. 11, 190–192 (2014); published online 18 March 2014; doi:10.1038/nrurol.2014.64
In recent years, focal therapy for prostate cancer has become the topic of intense debate, emerging from the fringes of onco‑ logical practice into urological clinics. However, a multitude of important factors still need to be considered. Firstly, what is its role? Who is the ideal patient, and which technique should be used to diagnose, local‑ ize, and define the extent of tumour destruc‑ tion necessary to cure this patient? What constitutes optimal therapy? Can only the most modern, complex, and costly techno‑ logical solutions offer precise but complete tumour-targeted therapy? Finally, is this therapy clinically necessary in an era when clinical equipoise to radical prostatectomy might be considered active surveillance or even observation? If so, how should we define successful treatment, and how might we design a clinical trial to prove its usefulness or ineffectiveness? With respect to this last
question, van den Bos et al.1 have proposed a feasible standard for the design of clinical trials of focal therapy for prostate cancer. The authors of this study have correctly stated that clear definitions of eligibility criteria and end points are required for a successful trial of focal ablation for prostate cancer. Proper patient selection is of utmost importance, and depends upon the ablative template, whether targeted ablation, hemi ablation, or zonal ablation. At this point, we should note that the term ‘focal therapy’ is something of a misnomer for hemiablation or zonal (subtotal) ablation approaches, wherein the goal is elimination of every pos‑ sible focus of cancer within the gland, irre‑ spective of possible iatrogenic adverse effects. One could argue that these patients might benefit from a more radical form of treat‑ ment. True focal therapy would be tissue pre‑ serving with the aim of eradicating the index www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
tumour while causing minimal or no adverse effects from the targeted treatment, thereby providing the best balance between oncologi‑ cal control and maintenance of quality of life. Regardless, focal therapy is best performed using real-time imaging guidance—for example, MRI-guided focal laser thermal therapy (MRgFLTT) 2,3 or MRI-guided focused ultrasonography (MRgFUS)4—as the target might move as a result of the force of the laser fibre, small movements of the patient, or deformation of the prostate caused by the ablative process (no matter how wellsecured the prostate might be), positioning the virtual target at a different location to the real target. Use of MRI-transrectal ultra‑ sonography (TRUS) fusion might mean that truly focal treatment can be performed under TRUS guidance in the future, but deformable registration (resulting from the current lack of accuracy with this technique) has prevented precise localization of the target lesion. Furthermore, the use of MRI as an imaging tool during treatment has the added advantage of accurate MRI thermo metry, which enables real-time closed-loop monitoring and targeted treatment, ensur‑ ing selective and adequate thermal tumour ablation, as well as simultaneous continuous monitored preservation of the sensitive sur‑ rounding tissues that control continence, potency, and bowel and bladder function.
‘‘
The authors recommend performing state-of-the-art mpMRI for all patients selected for focal therapy…
’’
The authors recommend performing stateof-the-art mpMRI for all patients selected for focal therapy, although they suggest that it is not necessary for MRI-visible lesions to be concordant with biopsy. Given the high rates of interobserver variability associated with the assessment of prostatic MRI and the widely accepted decision to exclude men with highrisk prostate cancer from focal treatment, we strongly disagree with the authors on this issue and feel that it is important to substanti‑ ate MRI findings with a positive biopsy result. This criterion is a prerequisite for inclusion in focal therapy trials at our clinic in the Princess Margaret Cancer Centre, Toronto, and might be best performed using MRI-TRUS fusion or real-time MRI guidance. We recommend that tumour length in the positive sample be taken into account when selecting candidates for treatment, rather than the percentage of tumour in the positive samples, as the sample
Jacob Wackerhausen/iStock/Thinkstock
NEWS & VIEWS
length at biopsy is often less than a full core of 20 mm and might also be fragmented. For MRI-visible lesions, Sartor et al.5 have sug‑ gested that lesion size on imaging should be added as a criterion for patient selection; they recommend that a single lesion should not exceed 15 mm in its largest dimension in any plane on imaging, with capsular contact of no more than 5 mm. Adequately identifying the extent of tumour for treatment contouring is impera tive, but far from easy. Sparse prostate tumours, which often contain normal tissue intermixed with prostate cancer, might have similar apparent diffusion coefficient (ADC) and T2 values to normal peripheral zone tissue and, therefore, might not be detectable on MRI.6 Some investigators suggest adding a margin of ablation to the MRI-visible tumour, but there are no guidelines or con‑ sistent data to support this practice. Should the tissue at the periphery of the MRI-visible tumour be included in the zone of ablation? And, if so, does the circumferential margin of sparse tumour around the more-dense visible tumour depend on the Gleason grade or size of the visible tumour? Future research might help us to answer these questions. In the meantime, it is important to establish the expected post-therapy changes that can be demonstrated on MRI and evaluate the ability of MRI to distinguish these changes from residual or recurrent disease. Dynamic contrast-enhanced (DCE)-MRI has been shown to be superior to diffusion-weighted imaging (DWI) and T2-weighted imaging for the prediction of recurrent disease follow‑ ing focal therapy with high-intensity focused ultrasonography.7 According to our own, as yet unpublished, initial data, DCE-MRI enhancement curves show promise for differentiating residual disease from fibrosis after laser ablation. We have also found that ADC maps are not always useful for predict‑ ing the presence of tumour after therapy, as fibrosis at the site of ablation will also cause restricted diffusion.
NATURE REVIEWS | UROLOGY
Until mpMRI findings have been defini‑ tively validated in the postablation setting, alterations in MRI signal cannot act as the primary end point in clinical trials and must be corroborated by biopsy results, just as we feel that it is important to substantiate the MRI findings with biopsy as an inclu‑ sion criterion. We propose that the biopsy strategy at 6 months after ablation should only include samples from the site of treat‑ ment, with about 4–6 samples taken from the area (including the margins of the ablation zone). This approach accounts for thermal deformation of the prostate gland at the site of ablation and, in our experience, might be achieved reliably with the use of MRI-TRUS fusion combined with imageable pellets left in situ after treatment at the periphery of the targeted zone. A clear challenge for any focal therapy trial is defining a successful result. Treatment outcomes need to be assessed in the context of ablation, as opposed to entire-gland treatment; thus, we recommend sampling only at the site of ablation at the 6-month follow-up biopsy and not of the entire gland as has been proposed by the authors.1 The authors have correctly stated that detect‑ ing significant cancer at sites other than the area of treatment would be deemed selection failure and not treatment failure. To avoid selection failure, we recommend that, in addition to MRI-targeted biopsy, every patient also has at least two sets of 12-core biopsy of the prostate gland within 6–12 months before treatment. We suggest that men without MRI-detectable cancer but clinically insignificant disease detected on a 4–6 sample biopsy strategy at the site of abla‑ tion should be considered to be successfully treated, in keeping with the central premise of treatment, which is destruction of the index lesion. However, we acknowledge that more-mature oncological follow-up data are needed to substantiate this recommendation. In summary, the authors are to be com‑ mended for their efforts in putting together a consensus proposal on how to design, execute, and evaluate the outcomes of a focal therapy trial, so as to enable uniform evalu‑ ation. Although we agree with the authors on many of the criteria put forward, we have tried to highlight some caveats that we recommend as crucial for designing a focal therapy trial. This manuscript is a major step forwards compared with previous con‑ sensus group proposals;8,9 however, there are still many unanswered questions, warrant‑ ing further research into focal therapy for prostate cancer. VOLUME 11 | APRIL 2014 | 191
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Joint Department of Medical Imaging, Toronto General Hospital, University of Toronto, 585 University Avenue, Toronto, ON M5G 2N2, Canada (S.G.). Department of Urology and Surgical Oncology, Princess Margaret Hospital, University of Toronto, 620 University Avenue, Toronto, ON M5G 2M9, Canada (J.T.). Correspondence to: J.T. [email protected]
4.
5.
6.
Acknowledgements The authors would like to thank Alexandre R. Zlotta for advice during the preparation of the manuscript. Competing interests The authors declare no competing interests. 1.
2.
3.
Van den Bos, W. et al. Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur. Urol. http:// dx.doi.org/10.1016/j.eururo.2014.01.001. Lindner, U. et al. Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy. Eur. Urol. 57, 1111–1114 (2010). Raz, O. et al. Real-time magnetic resonance imaging-guided focal laser therapy in patients
7.
8.
9.
discomfort related to pelvic floor symptoms.3 Prior to this trial, some evidence existed to suggest that patients with symptomatic pelvic organ prolapse can benefit from pelvic physiotherapy;4 however, robust randomized controlled trials had not been performed. In the POPPY trial, the studied interven‑ tion is described as ‘pelvic floor muscle train‑ ing’ rather than ‘pelvic physiotherapy’, even though women visited a pelvic physiotherapist on average 4.2 times over a 3‑month period. During these visits, the emphasis was on teaching the patient how to adequately con‑ tract the pelvic floor; biofeedback and electro stimulation (typical components of pelvic physiotherapy) were not allowed. These exclu‑ sions raise the issue of whether the observed beneficial effect of pelvic floor muscle training would have occurred if there was no involve‑ ment of a pelvic physiotherapist. If the only task of the physiotherapist was to motivate the patient to perform the exercise, then perhaps the involvement of another type of person (a coach, for example) would have given the same result. The authors do not discuss this in their manuscript. Previous studies evaluating the effects of physiotherapy have revealed that motivation and adherence are crucial to treatment effi‑ cacy.5 In this trial, Hagen et al.1 report high adherence to the intervention. However, they do not address the selection bias of their trial, owing to the fact that only motivated patients are willing to participate in a study like this. The assertion that all patients recruited felt positively towards the benefits of pelvic physiotherapy is demonstrated by the large percentage of patients in the control group who decided to conduct pelvic floor exer‑ cises; 69% of the control group undertook pelvic floor exercises in the last 4 weeks of the 12-month follow-up period. In daily clinical practice, most women are far less motivated to perform pelvic floor muscle exercises con‑ sistently. Thus, the generalizability of these trial results to average women presenting with symptomatic pelvic organ prolapse is limited.
with low-risk prostate cancer. Eur. Urol. 58, 173–177 (2010). Lindner, U. et al. Focal magnetic resonance guided focused ultrasound for prostate cancer: Initial North American experience. Can. Urol. Assoc. J. 6, E283–E286 (2012). Sartor, A. O. et al. Evaluating localized prostate cancer and identifying candidates for focal therapy. Urology 72, S12–S24 (2008). Langer, D. L. et al. Intermixed normal tissue within prostate cancer: effect on MR imaging measurements of apparent diffusion coefficient and T2--sparse versus dense cancers. Radiology 249, 900–908 (2008). Kim, C. K., Park, B. K., Lee, H. M., Kim, S. S. & Kim, E. MRI techniques for prediction of local tumour progression after high-intensity focused ultrasonic ablation of prostate cancer. Am. J. Roentgenol. 190, 1180–1186 (2008). Bostwick, D. G. et al. Group consensus reports from the Consensus Conference on Focal Treatment of Prostatic Carcinoma, Celebration, Florida, February 24, 2006. Urology 70, S42–S44 (2007). Eggener, S. E. et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J. Urol. 178, 2260–2267 (2007).
FEMALE UROLOGY
The benefits of pelvic floor muscle training for prolapse Jan-Paul Roovers
A newly published randomized controlled trial shows that pelvic floor muscle training can significantly reduce prolapse symptoms compared with provision of a prolapse lifestyle advice leaflet and no muscle training. However, the important role of surgery in the treatment of these women must be taken into account. For the multicentre Pelvic Organ Prolapse Physiotherapy (POPPY) trial, Hagen and coworkers1 randomly compared pelvic floor muscle training from a physiotherapist with provision of a lifestyle advice leaflet, in 447 women with symptomatic pelvic organ pro‑ lapse. The primary outcome was the pelvic organ prolapse symptom score (POP-SS), measured with a validated disease-specific quality-of-life questionnaire. Women in the intervention group reported fewer pro‑ lapse symptoms at 12 months (in other words, a significantly greater reduction in POP-SS) than those in the control group (mean reduction in POP-SS from baseline was 3.77 ± 5.62 for physiotherapy compared with 2.09 ± 5.39 for control; adjusted differ‑ ence 1.52, 95% CI 0.46–2.59; P = 0.0053). In addition, although not statistically signifi‑ cant, there was a tendency towards greater improvement of anatomical abnormalities in the intervention group than the control 192 | APRIL 2014 | VOLUME 11
group, and more re-interventions were per‑ formed within the first year of follow-up assessment in the control group than in the physiotherapy group. Difference in costs of subsequent treatment was UK£38.63 in favour of the intervention group, and the cost per quality-adjusted life year gained was about £16,000. Based on their findings, the authors conclude that pelvic floor muscle training should be recommended for the conservative management of prolapse. Given that the lifetime risk of undergoing surgery for pelvic organ prolapse is estimated to be 11%,2 and there is a known association between surgery and risk of recurrence (one in three procedures are performed for recur‑ rent prolapse),2 conservative management should be explored before surgery. Pelvic physiotherapy is a type of conservative therapy that is intended to increase pelvic floor muscle force, improve pelvic floor muscle coordina‑ tion and endurance and decrease experienced
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Roovers, J.-P. Nat. Rev. Urol. 11, 192–193 (2014); published online 4 March 2014; doi:10.1038/nrurol.2014.35
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