- Email: [email protected]
Is Targeted Therapy of Prostate Cancer Ready for Prime Time?
EURURO-6290; No. of Pages 2 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Herbert Lepor * Department of Urology, New York University Langone Medical Center, New York, NY, USA
The urology community in the late 1990s enthusiastically adopted prostate cancer (PCa) screening and curative treatment of screen-detected cancers. The subsequent decline in PCa mortality rates provided validation of progress in the war on PCa. However, over time, many of us who embraced aggressive screening and treatment began to recognize the need to reassess how we screen, detect, and treat PCa. The bottom line is that we need smarter screening and smarter diagnosis; only then will we be able to achieve smarter treatment. Will there be a role for targeted treatment in the evolving paradigm for treating PCa? The primary argument against targeted treatment of PCa is that the disease is multifocal, which mandates excision or destruction of the entire gland to achieve oncologic control. However, in most cases there is a single index or dominant lesion that drives PCa risk [1]. Magnetic resonance imaging (MRI) of the prostate has been a game changer, enabling targeted therapy. Recent studies provide compelling evidence that multiparametric MRI reliably identifies significant PCa [2]. MRI-targeted biopsy improves the ability to localize and risk-stratify PCa [3,4]. The cancers missed by MRI are typically Gleason 6 disease [3,4]. We have reported that no men with pathologic Gleason 6 disease developed metastasis following radical prostatectomy, which raises the question of whether Gleason 6 is a cancer [5]. Now that we can find significant disease, we can utilize the multitude of energy sources at our disposal to destroy prostate tissue [6]. Today there is an emerging and compelling rationale for targeted treatment of PCa. The study by Feijoo et al [7] in this issue of European Urology contributes to an increasing body of evidence that targeted therapy safely achieves early oncologic disease control with minimal adverse impact on functional
outcomes. The authors are to be congratulated for designing a prospective study rigorously evaluating targeted highintensity focused ultrasound (HIFU) for the treatment of clinically localized PCa. Eligibility was primarily based on transrectal ultrasound (US)-guided biopsy. The median (range) number of total cores obtained on pretreatment biopsy was 22 (20–60). Eligibility criteria included <33% of cores with Gleason < 4 + 3 disease. Surprisingly, large prostate glands were not excluded. All men underwent baseline prostate MRI and functional assessments at baseline and 3 mo. Differences in mean American Urological Association (AUA) symptom score and International Index of Erectile Function (IIEF) between baseline and 3 mo were not significant. Among 67 (94.6%) men who underwent a post-treatment 12-core random biopsy to assess oncologic control, no cancer was detected in the ablation zone in 56 (83.5%) of the post-treatment biopsies. A few questions arise. Whole-gland HIFU is limited by prostate size because of the focal length of US energy. How were anterior tumors managed in larger glands? One criticism of the literature on targeted therapy is that candidates often have insignificant disease best managed with active surveillance (AS). How many men treated by Feijoo et al had extremely low risk disease? This is a concern since 37% had no cancer suspicious regions on MRI. Finally, only 21 (31%) men were potent at baseline, and mean IIEF decreased by 4 points. This was not statistically significant because of the small sample size. Was there recovery of potency over longer follow-up? We recently reported on a series of 25 men who underwent focal laser ablation of the prostate [8]. All men had at least one MRI biopsy-proven target; 56% had Gleason 7 disease and none fulfilled the Hopkins criteria for AS. When anatomically feasible, the ablation zone was extended 1 cm
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.06.018. * Department of Urology, NYU Langone Medical Center, 150 East 32nd Street, New York, NY 10016, USA. Tel. +1 646 8256340; Fax: +1 646 8256380. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.06.049 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Lepor H. Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Eur Urol (2015), http:// dx.doi.org/10.1016/j.eururo.2015.06.049
EURURO-6290; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
beyond the lesion visible on MRI. The procedure was performed under local anesthesia. The mean time to return to work, unrestricted activities, and sexual activity was 2.9, 4.9, and 10.4 d, respectively. No man experienced a single incontinence episode. Between baseline and 3 mo, the mean AUA symptom score improved and there was no change in sexual function. Mean prostate-specific antigen (PSA) decreased by 40%, and 96% of the MRI/US co-registration biopsies targeting the ablation zone between 3 and 6 mo were cancer-free. Is targeted treatment of PCa ready for prime time? The answer is unequivocally no. The optimal candidates for targeted ablation have yet to be defined. Should we offer hemiablation or AS to men with normal MRI and very lowvolume Gleason 6 disease on random biopsy? Should we offer hemiablation or more focally targeted ablation when there is an MRI-visible lesion? How far beyond the MRIvisible lesion should the ablation zone extend? Should initial oncologic control be based on PSA, MRI, posttreatment biopsy, or all the above? If an initial posttreatment biopsy shows no cancer, do we need to repeat the biopsy if PSA and MRI show no indication of residual disease? Should residual disease be reablated? Will the ablation complicate further whole-gland treatment? What is the surveillance regimen for non-ablated prostate glands? The published short-term functional and oncologic outcomes are very encouraging. It is imperative now to define intermediate- and long-term oncologic outcomes. One patient with a negative target biopsy of the ablation zone and nonsuspicious MRI at 3 mo recently developed metastasis 2 yr after focal laser ablation. An extensive rebiopsy showed minimal disease in the ablation zone. Would he have benefited from radical prostatectomy or was metastasis present when the ablation was performed? There is an unmet need for truly minimally invasive treatment for selected men with prostate cancer. Advances in MRI now facilitate localization of significant disease. Technology is advancing and co-registration of a MRI lesion with ultrasound will soon allow us to not only biopsy lesions but also focally treat lesions under US guidance. Urology has the opportunity to make transformative advances in the treatment of prostate cancer if we can optimize selection of candidates, extent of ablation,
follow-up and ultimately demonstrate long-term oncologic and functional outcomes following target ablation. The urology community will not wait for randomized long-term studies before offering targeted treatment. Therefore, industry must invest in training and registries and resist the creation of a market before we know the true benefits and harms of targeted ablation. The rationale for targeted therapy is compelling. We must be disciplined to assess the long-term outcomes. If as a specialty we get it right, we will truly advance the management of prostate cancer. Conflicts of interest: The author is co-owner of the health publication MedReviews, has investment interests in Serenity Pharmaceuticals and SonaCare Medical, is a consultant to Serenity Pharmaceuticals, TheraCoat, and Biozeus, and has received speaker fees from Watson Pharmaceuticals.
References [1] Huang CC, Deng FM, Kong MX, Ren Q, Melamed J, Zhou M. Reevaluating the concept of ‘‘dominant/index tumor nodule’’ in multifocal prostate cancer. Virchows Arch 2014;464:589–94. [2] Arumainayagam N, Ahmed HU, Moore CM, et al. Multiparametric MR imaging for detection of clinically significant prostate cancer: a validation cohort study with transperineal template prostate mapping as the reference standard. Radiology 2013;268:761–9. [3] Bratan F, Niaf E, Melodelima C, et al. Influence of imaging and histological factors on prostate cancer detection and localization on multiparametric MRI: a prospective study. Eur Radiol 2013;23: 2019–29. [4] Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015;313:390–7. [5] Emberton M. Has magnetic resonance-guided biopsy of the prostate become the standard of care? Eur Urol 2013;64:720–1. [6] Donin NM, Laze J, Zhou M, Ren Q, Lepor H. Gleason 6 prostate tumors diagnosed in the PSA era do not demonstrate the capacity for metastatic spread at the time of radical prostatectomy. Urology 2013;82:148–52. [7] Cordeiro Feijoo ER, Sivaraman A, Barret E, Sanchez-Salas R, Galiano M, Rozet F, et al. Focal high-intensity focused ultrasound targeted hemiablation of unilateral prostate cancer: a prospective evaluation of oncologic and functional outcomes. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2015.06.018 [8] Lepor H, Llukani E, Sperling D, Fu¨tterer JJ. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.04.029
Please cite this article in press as: Lepor H. Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Eur Urol (2015), http:// dx.doi.org/10.1016/j.eururo.2015.06.049
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Herbert Lepor * Department of Urology, New York University Langone Medical Center, New York, NY, USA
The urology community in the late 1990s enthusiastically adopted prostate cancer (PCa) screening and curative treatment of screen-detected cancers. The subsequent decline in PCa mortality rates provided validation of progress in the war on PCa. However, over time, many of us who embraced aggressive screening and treatment began to recognize the need to reassess how we screen, detect, and treat PCa. The bottom line is that we need smarter screening and smarter diagnosis; only then will we be able to achieve smarter treatment. Will there be a role for targeted treatment in the evolving paradigm for treating PCa? The primary argument against targeted treatment of PCa is that the disease is multifocal, which mandates excision or destruction of the entire gland to achieve oncologic control. However, in most cases there is a single index or dominant lesion that drives PCa risk [1]. Magnetic resonance imaging (MRI) of the prostate has been a game changer, enabling targeted therapy. Recent studies provide compelling evidence that multiparametric MRI reliably identifies significant PCa [2]. MRI-targeted biopsy improves the ability to localize and risk-stratify PCa [3,4]. The cancers missed by MRI are typically Gleason 6 disease [3,4]. We have reported that no men with pathologic Gleason 6 disease developed metastasis following radical prostatectomy, which raises the question of whether Gleason 6 is a cancer [5]. Now that we can find significant disease, we can utilize the multitude of energy sources at our disposal to destroy prostate tissue [6]. Today there is an emerging and compelling rationale for targeted treatment of PCa. The study by Feijoo et al [7] in this issue of European Urology contributes to an increasing body of evidence that targeted therapy safely achieves early oncologic disease control with minimal adverse impact on functional
outcomes. The authors are to be congratulated for designing a prospective study rigorously evaluating targeted highintensity focused ultrasound (HIFU) for the treatment of clinically localized PCa. Eligibility was primarily based on transrectal ultrasound (US)-guided biopsy. The median (range) number of total cores obtained on pretreatment biopsy was 22 (20–60). Eligibility criteria included <33% of cores with Gleason < 4 + 3 disease. Surprisingly, large prostate glands were not excluded. All men underwent baseline prostate MRI and functional assessments at baseline and 3 mo. Differences in mean American Urological Association (AUA) symptom score and International Index of Erectile Function (IIEF) between baseline and 3 mo were not significant. Among 67 (94.6%) men who underwent a post-treatment 12-core random biopsy to assess oncologic control, no cancer was detected in the ablation zone in 56 (83.5%) of the post-treatment biopsies. A few questions arise. Whole-gland HIFU is limited by prostate size because of the focal length of US energy. How were anterior tumors managed in larger glands? One criticism of the literature on targeted therapy is that candidates often have insignificant disease best managed with active surveillance (AS). How many men treated by Feijoo et al had extremely low risk disease? This is a concern since 37% had no cancer suspicious regions on MRI. Finally, only 21 (31%) men were potent at baseline, and mean IIEF decreased by 4 points. This was not statistically significant because of the small sample size. Was there recovery of potency over longer follow-up? We recently reported on a series of 25 men who underwent focal laser ablation of the prostate [8]. All men had at least one MRI biopsy-proven target; 56% had Gleason 7 disease and none fulfilled the Hopkins criteria for AS. When anatomically feasible, the ablation zone was extended 1 cm
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.06.018. * Department of Urology, NYU Langone Medical Center, 150 East 32nd Street, New York, NY 10016, USA. Tel. +1 646 8256340; Fax: +1 646 8256380. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.06.049 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Lepor H. Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Eur Urol (2015), http:// dx.doi.org/10.1016/j.eururo.2015.06.049
EURURO-6290; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
beyond the lesion visible on MRI. The procedure was performed under local anesthesia. The mean time to return to work, unrestricted activities, and sexual activity was 2.9, 4.9, and 10.4 d, respectively. No man experienced a single incontinence episode. Between baseline and 3 mo, the mean AUA symptom score improved and there was no change in sexual function. Mean prostate-specific antigen (PSA) decreased by 40%, and 96% of the MRI/US co-registration biopsies targeting the ablation zone between 3 and 6 mo were cancer-free. Is targeted treatment of PCa ready for prime time? The answer is unequivocally no. The optimal candidates for targeted ablation have yet to be defined. Should we offer hemiablation or AS to men with normal MRI and very lowvolume Gleason 6 disease on random biopsy? Should we offer hemiablation or more focally targeted ablation when there is an MRI-visible lesion? How far beyond the MRIvisible lesion should the ablation zone extend? Should initial oncologic control be based on PSA, MRI, posttreatment biopsy, or all the above? If an initial posttreatment biopsy shows no cancer, do we need to repeat the biopsy if PSA and MRI show no indication of residual disease? Should residual disease be reablated? Will the ablation complicate further whole-gland treatment? What is the surveillance regimen for non-ablated prostate glands? The published short-term functional and oncologic outcomes are very encouraging. It is imperative now to define intermediate- and long-term oncologic outcomes. One patient with a negative target biopsy of the ablation zone and nonsuspicious MRI at 3 mo recently developed metastasis 2 yr after focal laser ablation. An extensive rebiopsy showed minimal disease in the ablation zone. Would he have benefited from radical prostatectomy or was metastasis present when the ablation was performed? There is an unmet need for truly minimally invasive treatment for selected men with prostate cancer. Advances in MRI now facilitate localization of significant disease. Technology is advancing and co-registration of a MRI lesion with ultrasound will soon allow us to not only biopsy lesions but also focally treat lesions under US guidance. Urology has the opportunity to make transformative advances in the treatment of prostate cancer if we can optimize selection of candidates, extent of ablation,
follow-up and ultimately demonstrate long-term oncologic and functional outcomes following target ablation. The urology community will not wait for randomized long-term studies before offering targeted treatment. Therefore, industry must invest in training and registries and resist the creation of a market before we know the true benefits and harms of targeted ablation. The rationale for targeted therapy is compelling. We must be disciplined to assess the long-term outcomes. If as a specialty we get it right, we will truly advance the management of prostate cancer. Conflicts of interest: The author is co-owner of the health publication MedReviews, has investment interests in Serenity Pharmaceuticals and SonaCare Medical, is a consultant to Serenity Pharmaceuticals, TheraCoat, and Biozeus, and has received speaker fees from Watson Pharmaceuticals.
References [1] Huang CC, Deng FM, Kong MX, Ren Q, Melamed J, Zhou M. Reevaluating the concept of ‘‘dominant/index tumor nodule’’ in multifocal prostate cancer. Virchows Arch 2014;464:589–94. [2] Arumainayagam N, Ahmed HU, Moore CM, et al. Multiparametric MR imaging for detection of clinically significant prostate cancer: a validation cohort study with transperineal template prostate mapping as the reference standard. Radiology 2013;268:761–9. [3] Bratan F, Niaf E, Melodelima C, et al. Influence of imaging and histological factors on prostate cancer detection and localization on multiparametric MRI: a prospective study. Eur Radiol 2013;23: 2019–29. [4] Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015;313:390–7. [5] Emberton M. Has magnetic resonance-guided biopsy of the prostate become the standard of care? Eur Urol 2013;64:720–1. [6] Donin NM, Laze J, Zhou M, Ren Q, Lepor H. Gleason 6 prostate tumors diagnosed in the PSA era do not demonstrate the capacity for metastatic spread at the time of radical prostatectomy. Urology 2013;82:148–52. [7] Cordeiro Feijoo ER, Sivaraman A, Barret E, Sanchez-Salas R, Galiano M, Rozet F, et al. Focal high-intensity focused ultrasound targeted hemiablation of unilateral prostate cancer: a prospective evaluation of oncologic and functional outcomes. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2015.06.018 [8] Lepor H, Llukani E, Sperling D, Fu¨tterer JJ. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.04.029
Please cite this article in press as: Lepor H. Is Targeted Therapy of Prostate Cancer Ready for Prime Time? Eur Urol (2015), http:// dx.doi.org/10.1016/j.eururo.2015.06.049