YEAR IN REVIEW midurethral sling surgery for female SUI were reported in late 2013.6 The primary outcome measure was patient-reported improvement, with secondary outcomes including subjec tive and objective cure. The study allowed crossover between arms, which was revealing in that 49% of women in the physiotherapy group crossed over to surgery, whereas 11.2% of patients in the surgery group crossed over to physiotherapy. Not unexpectedly, the improvement and cure rates were signifi cantly higher in the surgery group than in the physiotherapy group. In the sling group, 91% of patients reported improvement, with 85% subjectively and 76% objectively cured; for physiotherapy, 64% of patients reported improvement, with 53% subjectively and 59% objectively cured. These results provide a useful tool for counselling patients on the response rates to these SUI treatments. This study also gives insight into complica tions arising from mesh suburethral slings. The rate of adverse events in those who received physiotherapy only (no crossover) was essentially zero. By contrast, in the sling surgery group, adverse effects and compli cations included bladder perforation (2.8%), vaginal mesh exposure (3.7%), reoperation for exposure of the mesh (2.3%), reoper ation to loosen the sling (0.5%) and de novo OAB (6%). These complication rates are similar to other published series and high light the safety of synthetic mesh use in suburethral slings, in contrast to the contro versial use of transvaginal synthetic mesh for POP, which uses larger mesh implants. Secondary analysis from the ValUE trial,7 which showed that outcomes for women undergoing treatment for SUI did not change with the addition of preoperative uro dynamic evaluation, were also reported in 2013 by the Urinary Incontinence Treatment Network.8 Researchers showed that uro dynamic assessment significantly changed the clinical diagnosis and the likelihood of additional treatment for urgency inconti nence postoperatively, but did not change global treatment plan or decision-making to modify or cancel surgery. This finding pro vides further support for current guidelines that patients with demonstrable SUI on office evaluation can undergo surgical treatment without urodynamics.9 Finally, long-term data for the use of abdominal sacrocolpopexy as a surgical treatment for POP were presented in a study by the Pelvic Floor Disorders Network.10 The study reported outcomes after a median of 7 years for participants in the CARE (Colpopexy and Urinary Reduction Efforts)
trial. The 2‑year CARE trial initially com pared sacrocolpopexy with and without concomitant Burch urethropexy for SUI and POP outcomes. The latest report used data from the extended CARE trial for 126 women (59% of the original cohort). Failure was defined as symptomatic or anatomical POP failure requiring retreatment, self-reported vaginal bulge or POP quantification evalu ation demonstrating recurrent anatomical prolapse. The estimated composite prob ability of failure of abdominal sacrocolpo pexy at 7 years was 0.48 and 0.34 for patients with and without concomitant urethropexy, respectively—failure rates that increased over time compared with 5‑year POP failure (probability of 0.39 and 0.29 for patients with and without concomitant urethropexy, respectively), indicating that both early and late failures are common. Additionally, the authors reported a symptomatic and exam-detected mesh and suture exposure rate of 9.9% for this population, which also increased over time and is higher than previ ously reported for transabdominally placed mesh, indicating that close follow-up for signs and symptoms of mesh or suture expo sure is as important in this group as it is in patients with transvaginal mesh. Several advances in the treatment of OAB in men and women were actively studied and widely used clinically in 2013 after the pub lication of key clinical trials, including mira begron treatment. Outcomes for treatments for SUI and POP were scrutinized for oppor tunities for improvement. Looking forward, studies in 2014 are likely to investigate how to best integrate these results into clinical guidelines and algorithms and to promote innovation where outcomes can be improved.
Department of Urology, University of Michigan, 1500 East Medical Center Drive, 3875 Taubman Center, SPC 5330, Ann Arbor, MI 48109‑5330, USA (L. Cox, J. Q. Clemens). Correspondence to: J. Q. Clemens [email protected] Competing interests The authors declare no competing interests. 1.
Abrams, P., Cardozo, L., Khoury, S. & Wein, A. J. (Eds) Incontinence: Fifth Edition 2013 (ICUD‑EAU, 2013). 2. Nitti, V. W. et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J. Urol. 189, 1388–1395 (2013). 3. Khullar, V. et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur. Urol. 63, 283–295 (2013). 4. Nitti, V. W. et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebocontrolled, phase III studies. Int. J. Clin. Pract. 67, 619–632 (2013). 5. Nitti, V. W. et al. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J. Urol. 189, 2186–2193 (2013). 6. Labrie, J. et al. Surgery versus physiotherapy for stress urinary incontinence. N. Engl. J. Med. 369, 1124–1133 (2013). 7. Nager, C. W. et al. A randomized trial of urodynamic testing before stress-incontinence surgery. N. Engl. J. Med. 366, 1987–1997 (2012). 8. Sirls, L. T. et al. The effect of urodynamic testing on clinical diagnosis, treatment plan and outcomes in women undergoing stress urinary incontinence surgery. J. Urol. 189, 204–209 (2013). 9. Dmochowski, R. R. et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J. Urol. 183, 1906–1914 (2010). 10. Nygaard, I. et al. Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. JAMA 309, 2016–2024 (2013).
PROSTATE CANCER IN 2013
The changing role of imaging in clinical care Rahul Aggarwal and John Kurhanewicz
Considerable developments in prostate cancer in 2013 have emerged from the imaging field. Hyperpolarized 13C-MRI can monitor metabolic activity to identify high-grade disease and treatment response, and novel PET radiotracers might identify distinct subsets of patients with advanced disease. These examples highlight the progress made at all stages of care. Aggarwal, R. & Kurhanewicz, J. Nat. Rev. Urol. 11, 75–77 (2014); published online 14 January 2014; doi:10.1038/nrurol.2013.319
Alongside advances in drug development, 2013 has arguably been the year of imag ing in prostate cancer. Emerging imaging
NATURE REVIEWS | UROLOGY
modalities are now being applied at all points in the disease process—including at initial diagnosis, during active surveillance of VOLUME 11 | FEBRUARY 2014 | 75
© 2014 Macmillan Publishers Limited. All rights reserved
Macmillan
YEAR IN REVIEW
localized disease, upon biochemical relapse and in metastatic disease—and are likely to considerably shape practice patterns in years to come. Current standard practice of diagnosing prostate cancer involves transrectal samp ling of 10–14 bilateral cores of prostate cancer tissue. However, a substantial false- negative rate is associated with this approach, especially with lesions in the anterior pros tate gland. Multiparametric proton-based (1H) MRI (mpMRI), using T2, diffusionweighted, dynamic co ntrast-enhanced and 1H magnetic resonance spectroscopic imaging (1H-MRSI) sequences can address these issues by assessing the entire prostate— providing guidance for targeted biopsies. For example, Puech et al.1 examined 95 men with suspected prostate cancer on the basis of a suspicious lesion detected on mpMRI. MRI-targeted biopsies in these men yielded higher rates of cancer, including clinically significant prostate cancer defined by any Gleason ≥4 pattern, than a standard sys tematic 12-core ultrasonography-guided biopsy, particularly in the anterior region of the gland.1 Although validation is required in a broader unenriched patient population, as is long-term follow up data to accurately determine false-negative biopsy rate, the use of pre-biopsy mpMRI might eventu ally be incorporated into standard diagnos tic algorithms to increase the sensitivity of this approach to detect clinically significant high‑grade prostate cancer. For patients with an established prostate cancer diagnosis, avoiding overtreatment of low-risk, clinically insignificant localized prostate cancer has spurred the develop ment of active surveillance strategies that incorporate serial biopsies and PSA measure ment. However, despite gains in popularity, concerns regarding the risk of undetected high-grade disease often prompt patients to opt for definitive treatment in the absence of objective evidence of disease upstaging. Novel genomic predictive biomarkers 76 | FEBRUARY 2014 | VOLUME 11
can improve upon standard clinical risk stratification criteria, but are still prone to sampling error related to the biopsy pro cedure. 2 Given this limitation, mpMRI might have clinical utility in expanding the number of patients with confirmed low-risk disease who would be appropriate candi dates for active surveillance. At the same time, the technique can enhance the ability to detect occult high-grade disease and identify patients who should receive defini tive local therapy. One review published in 2013 included 133 patients who underwent mpMRI a median of 60 days before radical prostatec tomy. 3 The researchers showed that mpMRI was better than common clini cal scoring systems (D’Amico, Epstein and UCSF–CAPRA) at correctly classifying patients as appropriate for treatment versus active surveillance on the basis of domi nant tumour volume, predominant Gleason pattern and extracapsular or seminal vesicle invasion. Only one of the 13 patients with high-risk pathological disease was classified as low risk on mpMRI. Although prospec tive validation is required using a standard ized MRI scoring system, and integration of recently validated genomic-based prediction scores is essential, mpMRI has the potential to play a key part in improving the accu racy of selecting appropriate candidates for active surveillance. A new molecular imaging MRI technique, hyperpolarized 13C-MRI, which relies on the detection of carbon nuclei rather than protons, also has the potential to improve cancer diagnosis, risk stratification and, in particular, the monitoring of treatment response. 13C-MRI provides enhanced spatial and temporal resolution compared with 1 H-MRSI and can be used in the noninvasive real-time assessment of metabolic activity to image cancer. For example, 13C-pyruvate—a metabolite involved in the synthesis of lactate
via aerobic glycolysis, a pathway upregulated in cancerous cells by way of the Warburg effect—can be used across a spectrum of malignancies that includes prostate cancer. In the first ever phase I study of metabolic MRI using 13C-pyruvate reported in 2013, 31 treatment-naive patients with biopsyproven localized prostate cancer were enrolled, the majority of whom had Gleason 3 + 3 disease.4 Patients were injected with the 13 C-labelled pyruvate, shortly after which its conversion to lactate could be observed in prostate tumours and, in some cases, in regions of cancer that were not detected by conventional MRI. Although targeted biop sies were not mandatory in the study design, one patient with previously diagnosed Gleason 3 + 3 prostate adenocarcinoma with unilateral disease on MRI was shown to have bilateral elevations in the ratio of lactate to pyruvate on 13C-MRI. This patient’s tumour was subsequently upstaged and upgraded, to bilateral Gleason 3 + 4 cancer, on directed 13 C-MRI-guided biopsy. 13C-MRI of hyper polarized pyruvate might, therefore, have a role in detecting occult high-grade disease to aid in treatment selection and prognostic ation of patients with localized prostate cancer. Future patient studies are needed to define the utility of this imaging modality in assessing treatment response, and pro spective studies will be needed to correlate imaging findings with histological grade at the time of radical prostatectomy. Approximately 25–35% of patients who initially respond to definitive local therapy will experience biochemical relapse. PSA doubling time, Gleason grade at time of diagnosis and time interval from definitive therapy to incidence of relapse are used to predict patterns of recurrence (locoregional versus distant), but there is considerable overlap between these clinical metrics. PETbased imaging might offer a more sensitive
Key advances ■■ Multiparametric MRI (mpMRI)-targeted biopsies yielded higher rates of prostate cancer detection, including clinically significant (Gleason ≥4) disease, than standard 12-core guided biopsy, demonstrating its potential for improved risk stratification1 ■■ mpMRI performed better than clinical assessment scoring systems in predicting which patients were appropriate active surveillance candidates3 ■■ A phase I trial demonstrated the safety and feasibility of hyperpolarized 13C-MRI to provide realtime noninvasive assessment of metabolic activity to aid cancer diagnosis, risk stratification and treatment response monitoring4 ■■ Two PET agents—11C choline and 18F-NaF—have been shown to have improved sensitivity compared with conventional imaging in detecting lymph node involvement4 and the presence of bone metastases5 ■■ New PET-based molecular imaging approaches have promise as biomarkers in advancedstage prostate cancer, distinguishing between androgen-receptor‑dependent8,9 and treatmentemergent neuroendocrine prostate cancer10
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW method of detecting regional disease, distant spread of disease or both than conventional cross-sectional imaging and clinical para meters. A 2013 systematic review and metaanalysis of 19 independent studies high lighted the potential benefit of 11C-choline PET imaging, demonstrating a favour able sensitivity and specificity for detecting recurrent cancer: sensitivity and specific ity for detection in the prostatic fossa were 75.4% and 82% and for lymph node metas tases were 100% and 81.8%, respectively.5 11 C-choline PET was recently approved at the high-volume Mayo Clinic (Rochester, MN, USA) for the detection of recurrent disease. Additionally, 18F-NaF PET has demonstrated increased sensitivity for detecting distant osseous metastases compared with conven tional 99Tc bone scanning, including patients with biochemically relapsed disease who are at elevated risk of metastatic disease owing to a rapid rise in serum PSA level.6 Androgen deprivation therapy is the standard of care for patients with recur rent or metastatic disease, but all patients eventually develop castration-resistant pros tate cancer (CRPC). Considerable molecu lar heterogeneity underlies the biology of CRPC, with continued reliance on andro gen receptor (AR)-mediated signalling that frequently gives rise to AR‑independent, c‑MYC-driven neuroendocrine prostate cancer (NEPC) as a treatment-emergent adaptive response.7 Although no currently available biom arkers are able to readily identify and predict subsets of patients who are most likely to respond to contin ued AR‑directed therapy, new PET-based molecular imaging approaches might offer a suitable alternative and have the potential to accurately distinguish AR‑dependent pros tate cancer from treatment-emergent NEPC. Indeed, 18F-fluoro‑5α-dihydrotestosterone (18F-FDHT)-PET was used as a pharmacody namic biomarker of AR ligand binding in the early phase clinical trials of the second-gen eration AR antagonists ARN‑509 and enzalu tamide, and helped guide the recommended phase II dose selection of these two agents.8 Emerging molecular probes aim to extend the capability of PET imaging to measure downstream AR transcriptional activ ity. In 2013, one such probe was reported; 89 Zr‑J591/PSMA, a radiolabelled prostate membrane specific antigen (PSMA) probe, was shown to be inversely related to AR transcriptional activity.9 In another example, detection of treatment-emergent NEPC driven by c‑MYC was enhanced with the use of 89Zr-transferrin, which binds to the
transferrin receptor—a direct transcriptional target of c‑MYC. Preclinical studies have demonstrated the feasibility of this approach, and results of the initial clinical studies are eagerly awaited.10 Finally, the advantages of MRI and PET imaging of prostate cancer are being merged with the development of clini cal PET–MRI instruments, which will facili tate a more-comprehensive metabolic and functional characterization of both localized and metastatic disease.8 In 2013, key advances in the application of imaging were reported across the spectrum of clinical disease states in prostate cancer. Looking forward, prospectively validating imaging technologies, ideally with concur rent integration of emerging genomic and molecular analyses, will help to further define the role of imaging in the clinical care of men with prostate cancer. Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, 1600 Divasadero Street, Room A717, Box 1711, San Francisco, CA 94115, USA (R. Aggarwal). Departments of Medicine and Radiology and Biomedical Imaging, University of California, San Francisco, 1700 4th Street, Byers Hall, Room 203, San Francisco, CA 94158, USA (J. Kurhanewicz). Correspondence to: J. Kurhanewicz [email protected] Competing interests The authors declare no competing interests.
1.
Puech, P. et al. Prostate cancer diagnosis: multiparametric MR‑targeted biopsy with cognitive and transrectal US‑MR fusion guidance versus systematic biopsy--prospective multicenter study. Radiology 268, 461–469 (2013). 2. Cooperberg, M. R. et al. Validation of a cellcycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J. Clin. Oncol. 31, 1428–1434 (2013). 3. Turkbey, B. et al. Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance? Radiology 268, 144–152 (2013). 4. Nelson, S. J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1‑13C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013). 5. Evangelista, L. et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin. Nucl. Med. 38, 305–314 (2013). 6. Beheshti, M., Langsteger, W. & Fogelman, I. Prostate cancer: role of SPECT and PET in imaging bone metastases. Semin. Nucl. Med. 39, 396–407 (2009). 7. Mosquera, J. M. et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 15, 1–10 (2013). 8. Jadvar, H. Molecular imaging of prostate cancer with PET. J. Nucl. Med. 54, 1685–1688 (2013). 9. Osborne, J. R. et al. A prospective pilot study of 89Zr‑J591/PSMA positron emission tomography (PET) in men with localized prostate cancer undergoing radical prostatectomy. J. Urol. http://dx.doi.org/ 10.1016/j.juro.2013.10.041. 10. Walia, G., Pienta, K. J., Simons, J. W. & Soule, H. R. The 19th annual Prostate Cancer Foundation scientific retreat. Cancer Res. 73, 4988–4991 (2013).
KIDNEY CANCER IN 2013
From molecular understanding to clinical advances Chung-Han Lee and Robert J. Motzer
Big data and computational biology brought to the forefront a number of potential actionable mutations and drug targets in clear cell renal cell carcinoma in 2013. As we continue to unravel the molecular underpinnings of tumorigenesis and progression, the clinical benefits will eventually be reaped. Lee, C.‑H. & Motzer, R. J. Nat. Rev. Urol. 11, 77–79 (2014); published online 24 December 2013; doi:10.1038/nrurol.2013.307
2013 marked a year in which important insights were gained in kidney cancer, from treatment of the disease to its under lying biology. Pazopanib and sunitinib are vascular endothelial growth factor receptor (VEGFR)-targeted receptor tyrosine kinase inhibitors (TKIs) directed selectively toward VEGFR‑2. TKIs often have off-target effects on related kinases, and in vitro screening of panels of kinases suggests that pazopanib
NATURE REVIEWS | UROLOGY
has fewer off-target interactions than suni tinib.1 These drugs were approved for use in the first-line setting in metastatic clear cell renal cell carcinoma (ccRCC) on the basis of comparisons with placebo and IFN‑α, respectively. In 2013, a large randomized phase III trial (COMPARZ; NCT00720941) compared the two drugs head to head in the first-line setting.2 The trial met its primary end point of independently assessed VOLUME 11 | FEBRUARY 2014 | 77
© 2014 Macmillan Publishers Limited. All rights reserved
trial. The 2‑year CARE trial initially com pared sacrocolpopexy with and without concomitant Burch urethropexy for SUI and POP outcomes. The latest report used data from the extended CARE trial for 126 women (59% of the original cohort). Failure was defined as symptomatic or anatomical POP failure requiring retreatment, self-reported vaginal bulge or POP quantification evalu ation demonstrating recurrent anatomical prolapse. The estimated composite prob ability of failure of abdominal sacrocolpo pexy at 7 years was 0.48 and 0.34 for patients with and without concomitant urethropexy, respectively—failure rates that increased over time compared with 5‑year POP failure (probability of 0.39 and 0.29 for patients with and without concomitant urethropexy, respectively), indicating that both early and late failures are common. Additionally, the authors reported a symptomatic and exam-detected mesh and suture exposure rate of 9.9% for this population, which also increased over time and is higher than previ ously reported for transabdominally placed mesh, indicating that close follow-up for signs and symptoms of mesh or suture expo sure is as important in this group as it is in patients with transvaginal mesh. Several advances in the treatment of OAB in men and women were actively studied and widely used clinically in 2013 after the pub lication of key clinical trials, including mira begron treatment. Outcomes for treatments for SUI and POP were scrutinized for oppor tunities for improvement. Looking forward, studies in 2014 are likely to investigate how to best integrate these results into clinical guidelines and algorithms and to promote innovation where outcomes can be improved.
Department of Urology, University of Michigan, 1500 East Medical Center Drive, 3875 Taubman Center, SPC 5330, Ann Arbor, MI 48109‑5330, USA (L. Cox, J. Q. Clemens). Correspondence to: J. Q. Clemens [email protected] Competing interests The authors declare no competing interests. 1.
Abrams, P., Cardozo, L., Khoury, S. & Wein, A. J. (Eds) Incontinence: Fifth Edition 2013 (ICUD‑EAU, 2013). 2. Nitti, V. W. et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J. Urol. 189, 1388–1395 (2013). 3. Khullar, V. et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur. Urol. 63, 283–295 (2013). 4. Nitti, V. W. et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebocontrolled, phase III studies. Int. J. Clin. Pract. 67, 619–632 (2013). 5. Nitti, V. W. et al. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J. Urol. 189, 2186–2193 (2013). 6. Labrie, J. et al. Surgery versus physiotherapy for stress urinary incontinence. N. Engl. J. Med. 369, 1124–1133 (2013). 7. Nager, C. W. et al. A randomized trial of urodynamic testing before stress-incontinence surgery. N. Engl. J. Med. 366, 1987–1997 (2012). 8. Sirls, L. T. et al. The effect of urodynamic testing on clinical diagnosis, treatment plan and outcomes in women undergoing stress urinary incontinence surgery. J. Urol. 189, 204–209 (2013). 9. Dmochowski, R. R. et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J. Urol. 183, 1906–1914 (2010). 10. Nygaard, I. et al. Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. JAMA 309, 2016–2024 (2013).
PROSTATE CANCER IN 2013
The changing role of imaging in clinical care Rahul Aggarwal and John Kurhanewicz
Considerable developments in prostate cancer in 2013 have emerged from the imaging field. Hyperpolarized 13C-MRI can monitor metabolic activity to identify high-grade disease and treatment response, and novel PET radiotracers might identify distinct subsets of patients with advanced disease. These examples highlight the progress made at all stages of care. Aggarwal, R. & Kurhanewicz, J. Nat. Rev. Urol. 11, 75–77 (2014); published online 14 January 2014; doi:10.1038/nrurol.2013.319
Alongside advances in drug development, 2013 has arguably been the year of imag ing in prostate cancer. Emerging imaging
NATURE REVIEWS | UROLOGY
modalities are now being applied at all points in the disease process—including at initial diagnosis, during active surveillance of VOLUME 11 | FEBRUARY 2014 | 75
© 2014 Macmillan Publishers Limited. All rights reserved
Macmillan
YEAR IN REVIEW
localized disease, upon biochemical relapse and in metastatic disease—and are likely to considerably shape practice patterns in years to come. Current standard practice of diagnosing prostate cancer involves transrectal samp ling of 10–14 bilateral cores of prostate cancer tissue. However, a substantial false- negative rate is associated with this approach, especially with lesions in the anterior pros tate gland. Multiparametric proton-based (1H) MRI (mpMRI), using T2, diffusionweighted, dynamic co ntrast-enhanced and 1H magnetic resonance spectroscopic imaging (1H-MRSI) sequences can address these issues by assessing the entire prostate— providing guidance for targeted biopsies. For example, Puech et al.1 examined 95 men with suspected prostate cancer on the basis of a suspicious lesion detected on mpMRI. MRI-targeted biopsies in these men yielded higher rates of cancer, including clinically significant prostate cancer defined by any Gleason ≥4 pattern, than a standard sys tematic 12-core ultrasonography-guided biopsy, particularly in the anterior region of the gland.1 Although validation is required in a broader unenriched patient population, as is long-term follow up data to accurately determine false-negative biopsy rate, the use of pre-biopsy mpMRI might eventu ally be incorporated into standard diagnos tic algorithms to increase the sensitivity of this approach to detect clinically significant high‑grade prostate cancer. For patients with an established prostate cancer diagnosis, avoiding overtreatment of low-risk, clinically insignificant localized prostate cancer has spurred the develop ment of active surveillance strategies that incorporate serial biopsies and PSA measure ment. However, despite gains in popularity, concerns regarding the risk of undetected high-grade disease often prompt patients to opt for definitive treatment in the absence of objective evidence of disease upstaging. Novel genomic predictive biomarkers 76 | FEBRUARY 2014 | VOLUME 11
can improve upon standard clinical risk stratification criteria, but are still prone to sampling error related to the biopsy pro cedure. 2 Given this limitation, mpMRI might have clinical utility in expanding the number of patients with confirmed low-risk disease who would be appropriate candi dates for active surveillance. At the same time, the technique can enhance the ability to detect occult high-grade disease and identify patients who should receive defini tive local therapy. One review published in 2013 included 133 patients who underwent mpMRI a median of 60 days before radical prostatec tomy. 3 The researchers showed that mpMRI was better than common clini cal scoring systems (D’Amico, Epstein and UCSF–CAPRA) at correctly classifying patients as appropriate for treatment versus active surveillance on the basis of domi nant tumour volume, predominant Gleason pattern and extracapsular or seminal vesicle invasion. Only one of the 13 patients with high-risk pathological disease was classified as low risk on mpMRI. Although prospec tive validation is required using a standard ized MRI scoring system, and integration of recently validated genomic-based prediction scores is essential, mpMRI has the potential to play a key part in improving the accu racy of selecting appropriate candidates for active surveillance. A new molecular imaging MRI technique, hyperpolarized 13C-MRI, which relies on the detection of carbon nuclei rather than protons, also has the potential to improve cancer diagnosis, risk stratification and, in particular, the monitoring of treatment response. 13C-MRI provides enhanced spatial and temporal resolution compared with 1 H-MRSI and can be used in the noninvasive real-time assessment of metabolic activity to image cancer. For example, 13C-pyruvate—a metabolite involved in the synthesis of lactate
via aerobic glycolysis, a pathway upregulated in cancerous cells by way of the Warburg effect—can be used across a spectrum of malignancies that includes prostate cancer. In the first ever phase I study of metabolic MRI using 13C-pyruvate reported in 2013, 31 treatment-naive patients with biopsyproven localized prostate cancer were enrolled, the majority of whom had Gleason 3 + 3 disease.4 Patients were injected with the 13 C-labelled pyruvate, shortly after which its conversion to lactate could be observed in prostate tumours and, in some cases, in regions of cancer that were not detected by conventional MRI. Although targeted biop sies were not mandatory in the study design, one patient with previously diagnosed Gleason 3 + 3 prostate adenocarcinoma with unilateral disease on MRI was shown to have bilateral elevations in the ratio of lactate to pyruvate on 13C-MRI. This patient’s tumour was subsequently upstaged and upgraded, to bilateral Gleason 3 + 4 cancer, on directed 13 C-MRI-guided biopsy. 13C-MRI of hyper polarized pyruvate might, therefore, have a role in detecting occult high-grade disease to aid in treatment selection and prognostic ation of patients with localized prostate cancer. Future patient studies are needed to define the utility of this imaging modality in assessing treatment response, and pro spective studies will be needed to correlate imaging findings with histological grade at the time of radical prostatectomy. Approximately 25–35% of patients who initially respond to definitive local therapy will experience biochemical relapse. PSA doubling time, Gleason grade at time of diagnosis and time interval from definitive therapy to incidence of relapse are used to predict patterns of recurrence (locoregional versus distant), but there is considerable overlap between these clinical metrics. PETbased imaging might offer a more sensitive
Key advances ■■ Multiparametric MRI (mpMRI)-targeted biopsies yielded higher rates of prostate cancer detection, including clinically significant (Gleason ≥4) disease, than standard 12-core guided biopsy, demonstrating its potential for improved risk stratification1 ■■ mpMRI performed better than clinical assessment scoring systems in predicting which patients were appropriate active surveillance candidates3 ■■ A phase I trial demonstrated the safety and feasibility of hyperpolarized 13C-MRI to provide realtime noninvasive assessment of metabolic activity to aid cancer diagnosis, risk stratification and treatment response monitoring4 ■■ Two PET agents—11C choline and 18F-NaF—have been shown to have improved sensitivity compared with conventional imaging in detecting lymph node involvement4 and the presence of bone metastases5 ■■ New PET-based molecular imaging approaches have promise as biomarkers in advancedstage prostate cancer, distinguishing between androgen-receptor‑dependent8,9 and treatmentemergent neuroendocrine prostate cancer10
www.nature.com/nrurol © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW method of detecting regional disease, distant spread of disease or both than conventional cross-sectional imaging and clinical para meters. A 2013 systematic review and metaanalysis of 19 independent studies high lighted the potential benefit of 11C-choline PET imaging, demonstrating a favour able sensitivity and specificity for detecting recurrent cancer: sensitivity and specific ity for detection in the prostatic fossa were 75.4% and 82% and for lymph node metas tases were 100% and 81.8%, respectively.5 11 C-choline PET was recently approved at the high-volume Mayo Clinic (Rochester, MN, USA) for the detection of recurrent disease. Additionally, 18F-NaF PET has demonstrated increased sensitivity for detecting distant osseous metastases compared with conven tional 99Tc bone scanning, including patients with biochemically relapsed disease who are at elevated risk of metastatic disease owing to a rapid rise in serum PSA level.6 Androgen deprivation therapy is the standard of care for patients with recur rent or metastatic disease, but all patients eventually develop castration-resistant pros tate cancer (CRPC). Considerable molecu lar heterogeneity underlies the biology of CRPC, with continued reliance on andro gen receptor (AR)-mediated signalling that frequently gives rise to AR‑independent, c‑MYC-driven neuroendocrine prostate cancer (NEPC) as a treatment-emergent adaptive response.7 Although no currently available biom arkers are able to readily identify and predict subsets of patients who are most likely to respond to contin ued AR‑directed therapy, new PET-based molecular imaging approaches might offer a suitable alternative and have the potential to accurately distinguish AR‑dependent pros tate cancer from treatment-emergent NEPC. Indeed, 18F-fluoro‑5α-dihydrotestosterone (18F-FDHT)-PET was used as a pharmacody namic biomarker of AR ligand binding in the early phase clinical trials of the second-gen eration AR antagonists ARN‑509 and enzalu tamide, and helped guide the recommended phase II dose selection of these two agents.8 Emerging molecular probes aim to extend the capability of PET imaging to measure downstream AR transcriptional activ ity. In 2013, one such probe was reported; 89 Zr‑J591/PSMA, a radiolabelled prostate membrane specific antigen (PSMA) probe, was shown to be inversely related to AR transcriptional activity.9 In another example, detection of treatment-emergent NEPC driven by c‑MYC was enhanced with the use of 89Zr-transferrin, which binds to the
transferrin receptor—a direct transcriptional target of c‑MYC. Preclinical studies have demonstrated the feasibility of this approach, and results of the initial clinical studies are eagerly awaited.10 Finally, the advantages of MRI and PET imaging of prostate cancer are being merged with the development of clini cal PET–MRI instruments, which will facili tate a more-comprehensive metabolic and functional characterization of both localized and metastatic disease.8 In 2013, key advances in the application of imaging were reported across the spectrum of clinical disease states in prostate cancer. Looking forward, prospectively validating imaging technologies, ideally with concur rent integration of emerging genomic and molecular analyses, will help to further define the role of imaging in the clinical care of men with prostate cancer. Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, 1600 Divasadero Street, Room A717, Box 1711, San Francisco, CA 94115, USA (R. Aggarwal). Departments of Medicine and Radiology and Biomedical Imaging, University of California, San Francisco, 1700 4th Street, Byers Hall, Room 203, San Francisco, CA 94158, USA (J. Kurhanewicz). Correspondence to: J. Kurhanewicz [email protected] Competing interests The authors declare no competing interests.
1.
Puech, P. et al. Prostate cancer diagnosis: multiparametric MR‑targeted biopsy with cognitive and transrectal US‑MR fusion guidance versus systematic biopsy--prospective multicenter study. Radiology 268, 461–469 (2013). 2. Cooperberg, M. R. et al. Validation of a cellcycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J. Clin. Oncol. 31, 1428–1434 (2013). 3. Turkbey, B. et al. Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance? Radiology 268, 144–152 (2013). 4. Nelson, S. J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1‑13C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013). 5. Evangelista, L. et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin. Nucl. Med. 38, 305–314 (2013). 6. Beheshti, M., Langsteger, W. & Fogelman, I. Prostate cancer: role of SPECT and PET in imaging bone metastases. Semin. Nucl. Med. 39, 396–407 (2009). 7. Mosquera, J. M. et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 15, 1–10 (2013). 8. Jadvar, H. Molecular imaging of prostate cancer with PET. J. Nucl. Med. 54, 1685–1688 (2013). 9. Osborne, J. R. et al. A prospective pilot study of 89Zr‑J591/PSMA positron emission tomography (PET) in men with localized prostate cancer undergoing radical prostatectomy. J. Urol. http://dx.doi.org/ 10.1016/j.juro.2013.10.041. 10. Walia, G., Pienta, K. J., Simons, J. W. & Soule, H. R. The 19th annual Prostate Cancer Foundation scientific retreat. Cancer Res. 73, 4988–4991 (2013).
KIDNEY CANCER IN 2013
From molecular understanding to clinical advances Chung-Han Lee and Robert J. Motzer
Big data and computational biology brought to the forefront a number of potential actionable mutations and drug targets in clear cell renal cell carcinoma in 2013. As we continue to unravel the molecular underpinnings of tumorigenesis and progression, the clinical benefits will eventually be reaped. Lee, C.‑H. & Motzer, R. J. Nat. Rev. Urol. 11, 77–79 (2014); published online 24 December 2013; doi:10.1038/nrurol.2013.307
2013 marked a year in which important insights were gained in kidney cancer, from treatment of the disease to its under lying biology. Pazopanib and sunitinib are vascular endothelial growth factor receptor (VEGFR)-targeted receptor tyrosine kinase inhibitors (TKIs) directed selectively toward VEGFR‑2. TKIs often have off-target effects on related kinases, and in vitro screening of panels of kinases suggests that pazopanib
NATURE REVIEWS | UROLOGY
has fewer off-target interactions than suni tinib.1 These drugs were approved for use in the first-line setting in metastatic clear cell renal cell carcinoma (ccRCC) on the basis of comparisons with placebo and IFN‑α, respectively. In 2013, a large randomized phase III trial (COMPARZ; NCT00720941) compared the two drugs head to head in the first-line setting.2 The trial met its primary end point of independently assessed VOLUME 11 | FEBRUARY 2014 | 77
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