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Focal Therapy for Prostate Cancer: Don’t Believe the Hype
Opposing Views 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57
Why Focal Therapy is a Legitimate and Necessary Response to a Changing World THE 3 themes that I would like to reflect upon in relation to focal (targeted, selective or tissue preserving) therapy, which in my view warrant further thought are 1) extending our thinking on surveillance, 2) reconsideration of our surgical margin and 3) our professional response to a rapidly changing diagnostic pathway. Active surveillance (AS) is an approach to care that now enjoys something close to universal acceptance. The principles that underpin this process of care are important. When we recommend AS to a patient we make a judgment that there exists a threshold of disease that, if not exceeded, confers a negligible risk of a prostate cancer related death within a 10 to 15-year period. This form of risk stratification is executed at the patient level. Focal or selective therapy to the prostate relies on the same type of judgment and the same threshold as AS but the only difference is that the risk stratification takes place at the level of the prostate. For AS we ask the question, “Does this man have sufficiently low risk disease that we can defer or avoid treatment?”. For focal therapy we ask, “Does this prostate contain any elements of disease that I am concerned about?”. If the answer is yes then the next question may be, “Is it possible to treat this higher risk element selectively and preserve sufficient normal tissue so that genitourinary function is not compromised?”. By applying the principles of AS to the prostate as well as to the person, we are able to offer prostate preservation to a broader spectrum of men (men who would otherwise have been offered radical intervention), and thereby continue to mitigate the harm associated with treatment. The second issue relates to surgical margins. During the last few decades an overall reduction in the margins surgically resected has been implemented with patient benefit in mind without compromising survival. In urology we have seen this reduction applied most emphatically in the management of penile and renal cancer. The historical approach to both cancers was organ excision, whereas today it is organ preservation when possible. This transformation in our approach to
0022-5347/15/1944-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
care was made possible by developments in imaging. Location and burden are the key attributes of cancer that imaging provides. It is worth reflecting for a moment that the management of localized prostate cancer has historically been na€ıve to both attributes. The position of the tumor in the prostate has not influenced the choice of treatment or the manner in which it is applied. Tumor volume, rather unusually for a cancer staging system, has not contributed to our TNM classification. The margins that we have been applying to localized prostate cancer have not been subject to challenge since Young first treated the disease more than 100 years ago. Surgery in its various forms has defined the margin anatomically at the organ level as has radiotherapy. Most of the treatment related toxicity associated with surgery and radiotherapy can be attributed to a margin that, when applied, overlaps with vital structures subject to injury in the process. Focal or selective therapy of the prostate cancer lesion together with a margin provides us our first opportunity to explore variation of the margin (usually reduction) which has worked so well for other cancers. The way we diagnose prostate cancer is changing. It is almost a certainty now that imaging in the form of multiparametric magnetic resonance (MR) imaging is going to be the modern response to assessing a man who is deemed to be at risk for clinically significant prostate cancer whether by virtue of family history, ethnicity or prostate specific antigen. Use of imaging will result in the performance of fewer biopsies and those that are performed will increasingly be used to target areas of interest. Fewer biopsies will result in a reduction in the proportion of men diagnosed with low risk prostate cancer and an increase in the proportion of men diagnosed with clinically significant prostate cancer. Moreover, the risk attribution that results from this process will come with a precision that we have not been used to previously. The proof that this has occurred will be the disappearance of pathological upgrading (a direct measure of our diagnostic imprecision) between biopsy and radical prostatectomy.
http://dx.doi.org/10.1016/j.juro.2015.07.049 Vol. 194, 1-3, October 2015 Printed in U.S.A.
www.jurology.com Dochead: Opposing Views
DIS 5.2.0 DTD JURO12776_12777_proof 16 July 2015 8:19 pm EO:
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OPPOSING VIEWS
How this change in approach will affect our thinking, our language and, most importantly, our approach to our patients is hard to overestimate. The focus will move away from the current dichotomous position of, “You have prostate cancer/you are clear of prostate cancer” towards a different conversation. Multiparametric magnetic resonance imaging will create the initial context: “There is an abnormality in the prostate that we can see just about here.”. The conversation might then evolve to discussing our response to this new information: “We can observe it and perhaps repeat the imaging in 6 to 12 months, or we can target the area and find out what is generating the abnormal signal.” Some refinement of the risk might be possible: “The lesion has the appearances of a small cancer, given the changes that we see on dynamic sequences (PIRADS 4).” More information might be volunteered: “It measures 6 mm in its greatest diameter and is probably no more than 0.4 cc in volume.” The prior probabilities associated with this information might
be shared: “If we target it the chances of verifying that it is a cancer are about 70% to 80%. The chances that it may be significant and warrant some treatment are about 50%.” One can quickly appreciate that the modern conversation is dominated by location and how we might best use this novel information. It remains a small step to introduce to the patient the idea that all that might be needed, if indeed the cancer warrants treatment, is that the cancer focus might be selectively treated as a day procedure with little or no measurable harm to the patient. Mark Emberton* Division of Surgery and Interventional Science University College London London, United Kingdom *Recipient of a United Kingdom National Institute of Health Research (NIHR) Senior Investigator award and research support from the UCLH/UCL NIHR Biomedical Research Centre.
Focal Therapy for Prostate Cancer: don’t Believe the Hype THE goal of focal therapy is to treat clinically important disease while minimizing side effects. There are inherent challenges that must be overcome to safely define a new treatment paradigm related to focal therapy for prostate cancer. First of all, prostate cancer is a multifocal disease. Pathological analyses of radical prostatectomy specimens have demonstrated that multifocal tumors are present in nearly 90% of cases and an average of 2 to 4 tumors are found in each patient. Does focal therapy for a multifocal disease make sense? It is perplexing how focal therapy has shifted from whole gland ablation to hemiablation to now targeting only the so-called index lesion. Even in the setting of whole or hemigland ablation, significant cancers are still found following salvage radical prostatectomy.1 The idea that treating only the index lesion is as effective as treating the whole prostate gland has been perpetuated. While this practice may reduce the morbidity associated with focal therapy, it may compromise cancer control because of inadequate treatment of potentially lethal disease. Identification of the index lesion is frequently based on the largest tumor size rather than Gleason score or molecular characteristics. If an index lesion is identified, ideally it would be unilateral and of limited volume. However, there is significant interfocal tumor heterogeneity in prostate cancer and from a molecular standpoint, metastasis may arise from secondary tumor foci. To date, there remains no good scientific evidence to support the fundamental basis Dochead: Opposing Views
of the index lesion theory. In fact, recent data suggest that more aggressive and potentially lethal disease can be found outside of the index lesion.2 Advocates of focal therapy frequently cite breast cancer and renal cancer as examples of how treatments have shifted from organ excision to organ preservation. However, in breast cancer the dominant lesion is removed. A risk adapted approach is also frequently used in breast cancer focal therapy and in the event that pathology is shown to harbor adverse features, external beam radiation is added. Although contemporary surgical management of renal cancer has shifted from radical nephrectomy to nephron sparing surgery when feasible, it is still based on complete removal of the primary tumor. Furthermore, we must acknowledge that nephron sparing surgery has been shown to be less effective compared to radical nephrectomy in terms of overall survival in a prospective randomized trial.3 Simply stated, there are important differences between focal therapy for prostate cancer and lumpectomy for breast cancer or partial nephrectomy for renal cancer. Focal therapy for prostate cancer is monotherapy and the comparison to breast cancer or renal cancer treatment is not valid. Do we really have the tools to accurately localize and treat disease? While there has been improvement in prostate imaging technology, MR/ultrasound fusion biopsy can still miss significant cancers. Siddiqui et al showed that 18% of men with no cancer and 33% with low risk cancer found on
DIS 5.2.0 DTD JURO12776_12777_proof 16 July 2015 8:19 pm EO:
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OPPOSING VIEWS
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targeted MR/ultrasound fusion biopsy actually had either intermediate or high risk disease on whole mount pathological examination of prostatectomy specimens.4 Finally, if an anteriorly or apically located tumor is identified, the question remains whether this type of lesion can be adequately treated with focal therapy. Who are appropriate candidates for focal therapy? An international focal therapy consensus group attempted to define criteria for entry into focal therapy clinical trials. Eligible patients included men with PSA less than 15 ng/mL, clinical stage T1c-T2a, Gleason score 3 þ 3 or 3 þ 4, life expectancy greater than 10 years and any prostate volume.5 For men with very low or low risk disease, many would argue that focal therapy is unnecessary. For men with intermediate or high risk disease, focal therapy remains unproven. Using one of the available molecular tests that analyze prostate biopsy specimens may help improve risk stratification of patients for inclusion in focal therapy trials.
3
How is treatment success defined? The international consensus group recommended a negative biopsy at 12 months after treatment as the primary end point.5 Alterations on MR imaging and in PSA levels were not included as end points. Use of PSA kinetics in focal therapy has not been determined. But is a 12-month post-treatment biopsy acceptable for determining long-term success of cancer control? When considering focal therapy for prostate cancer, there are many unanswered questions related to complications, options for salvage therapy and cost efficacy. In theory, focal therapy may be a good idea that aims to kill cancer while minimizing side effects but for now it appears that the hype associated with focal therapy outweighs the hope. Mark L. Gonzalgo Department of Urology University of Miami Miller School of Medicine Miami, Florida
REFERENCES 1. Lawrentschuk N, Finelli A, Van der Kwast TH et al: Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer. J Urol 2011; 185: 862. 2. Boutros PC, Fraser M, Harding NJ et al: Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet 2015; 47: 736. 3. Van Poppel H, Da Pozzo L, Albrecht W et al: A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59: 543. 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. 5. van den Bos W, Muller BG, Ahmed H et al: Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur Urol 2014; 65: 1078.
Dochead: Opposing Views
DIS 5.2.0 DTD JURO12776_12777_proof 16 July 2015 8:19 pm EO:
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Why Focal Therapy is a Legitimate and Necessary Response to a Changing World THE 3 themes that I would like to reflect upon in relation to focal (targeted, selective or tissue preserving) therapy, which in my view warrant further thought are 1) extending our thinking on surveillance, 2) reconsideration of our surgical margin and 3) our professional response to a rapidly changing diagnostic pathway. Active surveillance (AS) is an approach to care that now enjoys something close to universal acceptance. The principles that underpin this process of care are important. When we recommend AS to a patient we make a judgment that there exists a threshold of disease that, if not exceeded, confers a negligible risk of a prostate cancer related death within a 10 to 15-year period. This form of risk stratification is executed at the patient level. Focal or selective therapy to the prostate relies on the same type of judgment and the same threshold as AS but the only difference is that the risk stratification takes place at the level of the prostate. For AS we ask the question, “Does this man have sufficiently low risk disease that we can defer or avoid treatment?”. For focal therapy we ask, “Does this prostate contain any elements of disease that I am concerned about?”. If the answer is yes then the next question may be, “Is it possible to treat this higher risk element selectively and preserve sufficient normal tissue so that genitourinary function is not compromised?”. By applying the principles of AS to the prostate as well as to the person, we are able to offer prostate preservation to a broader spectrum of men (men who would otherwise have been offered radical intervention), and thereby continue to mitigate the harm associated with treatment. The second issue relates to surgical margins. During the last few decades an overall reduction in the margins surgically resected has been implemented with patient benefit in mind without compromising survival. In urology we have seen this reduction applied most emphatically in the management of penile and renal cancer. The historical approach to both cancers was organ excision, whereas today it is organ preservation when possible. This transformation in our approach to
0022-5347/15/1944-0001/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
care was made possible by developments in imaging. Location and burden are the key attributes of cancer that imaging provides. It is worth reflecting for a moment that the management of localized prostate cancer has historically been na€ıve to both attributes. The position of the tumor in the prostate has not influenced the choice of treatment or the manner in which it is applied. Tumor volume, rather unusually for a cancer staging system, has not contributed to our TNM classification. The margins that we have been applying to localized prostate cancer have not been subject to challenge since Young first treated the disease more than 100 years ago. Surgery in its various forms has defined the margin anatomically at the organ level as has radiotherapy. Most of the treatment related toxicity associated with surgery and radiotherapy can be attributed to a margin that, when applied, overlaps with vital structures subject to injury in the process. Focal or selective therapy of the prostate cancer lesion together with a margin provides us our first opportunity to explore variation of the margin (usually reduction) which has worked so well for other cancers. The way we diagnose prostate cancer is changing. It is almost a certainty now that imaging in the form of multiparametric magnetic resonance (MR) imaging is going to be the modern response to assessing a man who is deemed to be at risk for clinically significant prostate cancer whether by virtue of family history, ethnicity or prostate specific antigen. Use of imaging will result in the performance of fewer biopsies and those that are performed will increasingly be used to target areas of interest. Fewer biopsies will result in a reduction in the proportion of men diagnosed with low risk prostate cancer and an increase in the proportion of men diagnosed with clinically significant prostate cancer. Moreover, the risk attribution that results from this process will come with a precision that we have not been used to previously. The proof that this has occurred will be the disappearance of pathological upgrading (a direct measure of our diagnostic imprecision) between biopsy and radical prostatectomy.
http://dx.doi.org/10.1016/j.juro.2015.07.049 Vol. 194, 1-3, October 2015 Printed in U.S.A.
www.jurology.com Dochead: Opposing Views
DIS 5.2.0 DTD JURO12776_12777_proof 16 July 2015 8:19 pm EO:
j
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OPPOSING VIEWS
How this change in approach will affect our thinking, our language and, most importantly, our approach to our patients is hard to overestimate. The focus will move away from the current dichotomous position of, “You have prostate cancer/you are clear of prostate cancer” towards a different conversation. Multiparametric magnetic resonance imaging will create the initial context: “There is an abnormality in the prostate that we can see just about here.”. The conversation might then evolve to discussing our response to this new information: “We can observe it and perhaps repeat the imaging in 6 to 12 months, or we can target the area and find out what is generating the abnormal signal.” Some refinement of the risk might be possible: “The lesion has the appearances of a small cancer, given the changes that we see on dynamic sequences (PIRADS 4).” More information might be volunteered: “It measures 6 mm in its greatest diameter and is probably no more than 0.4 cc in volume.” The prior probabilities associated with this information might
be shared: “If we target it the chances of verifying that it is a cancer are about 70% to 80%. The chances that it may be significant and warrant some treatment are about 50%.” One can quickly appreciate that the modern conversation is dominated by location and how we might best use this novel information. It remains a small step to introduce to the patient the idea that all that might be needed, if indeed the cancer warrants treatment, is that the cancer focus might be selectively treated as a day procedure with little or no measurable harm to the patient. Mark Emberton* Division of Surgery and Interventional Science University College London London, United Kingdom *Recipient of a United Kingdom National Institute of Health Research (NIHR) Senior Investigator award and research support from the UCLH/UCL NIHR Biomedical Research Centre.
Focal Therapy for Prostate Cancer: don’t Believe the Hype THE goal of focal therapy is to treat clinically important disease while minimizing side effects. There are inherent challenges that must be overcome to safely define a new treatment paradigm related to focal therapy for prostate cancer. First of all, prostate cancer is a multifocal disease. Pathological analyses of radical prostatectomy specimens have demonstrated that multifocal tumors are present in nearly 90% of cases and an average of 2 to 4 tumors are found in each patient. Does focal therapy for a multifocal disease make sense? It is perplexing how focal therapy has shifted from whole gland ablation to hemiablation to now targeting only the so-called index lesion. Even in the setting of whole or hemigland ablation, significant cancers are still found following salvage radical prostatectomy.1 The idea that treating only the index lesion is as effective as treating the whole prostate gland has been perpetuated. While this practice may reduce the morbidity associated with focal therapy, it may compromise cancer control because of inadequate treatment of potentially lethal disease. Identification of the index lesion is frequently based on the largest tumor size rather than Gleason score or molecular characteristics. If an index lesion is identified, ideally it would be unilateral and of limited volume. However, there is significant interfocal tumor heterogeneity in prostate cancer and from a molecular standpoint, metastasis may arise from secondary tumor foci. To date, there remains no good scientific evidence to support the fundamental basis Dochead: Opposing Views
of the index lesion theory. In fact, recent data suggest that more aggressive and potentially lethal disease can be found outside of the index lesion.2 Advocates of focal therapy frequently cite breast cancer and renal cancer as examples of how treatments have shifted from organ excision to organ preservation. However, in breast cancer the dominant lesion is removed. A risk adapted approach is also frequently used in breast cancer focal therapy and in the event that pathology is shown to harbor adverse features, external beam radiation is added. Although contemporary surgical management of renal cancer has shifted from radical nephrectomy to nephron sparing surgery when feasible, it is still based on complete removal of the primary tumor. Furthermore, we must acknowledge that nephron sparing surgery has been shown to be less effective compared to radical nephrectomy in terms of overall survival in a prospective randomized trial.3 Simply stated, there are important differences between focal therapy for prostate cancer and lumpectomy for breast cancer or partial nephrectomy for renal cancer. Focal therapy for prostate cancer is monotherapy and the comparison to breast cancer or renal cancer treatment is not valid. Do we really have the tools to accurately localize and treat disease? While there has been improvement in prostate imaging technology, MR/ultrasound fusion biopsy can still miss significant cancers. Siddiqui et al showed that 18% of men with no cancer and 33% with low risk cancer found on
DIS 5.2.0 DTD JURO12776_12777_proof 16 July 2015 8:19 pm EO:
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228
OPPOSING VIEWS
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targeted MR/ultrasound fusion biopsy actually had either intermediate or high risk disease on whole mount pathological examination of prostatectomy specimens.4 Finally, if an anteriorly or apically located tumor is identified, the question remains whether this type of lesion can be adequately treated with focal therapy. Who are appropriate candidates for focal therapy? An international focal therapy consensus group attempted to define criteria for entry into focal therapy clinical trials. Eligible patients included men with PSA less than 15 ng/mL, clinical stage T1c-T2a, Gleason score 3 þ 3 or 3 þ 4, life expectancy greater than 10 years and any prostate volume.5 For men with very low or low risk disease, many would argue that focal therapy is unnecessary. For men with intermediate or high risk disease, focal therapy remains unproven. Using one of the available molecular tests that analyze prostate biopsy specimens may help improve risk stratification of patients for inclusion in focal therapy trials.
3
How is treatment success defined? The international consensus group recommended a negative biopsy at 12 months after treatment as the primary end point.5 Alterations on MR imaging and in PSA levels were not included as end points. Use of PSA kinetics in focal therapy has not been determined. But is a 12-month post-treatment biopsy acceptable for determining long-term success of cancer control? When considering focal therapy for prostate cancer, there are many unanswered questions related to complications, options for salvage therapy and cost efficacy. In theory, focal therapy may be a good idea that aims to kill cancer while minimizing side effects but for now it appears that the hype associated with focal therapy outweighs the hope. Mark L. Gonzalgo Department of Urology University of Miami Miller School of Medicine Miami, Florida
REFERENCES 1. Lawrentschuk N, Finelli A, Van der Kwast TH et al: Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer. J Urol 2011; 185: 862. 2. Boutros PC, Fraser M, Harding NJ et al: Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet 2015; 47: 736. 3. Van Poppel H, Da Pozzo L, Albrecht W et al: A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59: 543. 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. 5. van den Bos W, Muller BG, Ahmed H et al: Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur Urol 2014; 65: 1078.
Dochead: Opposing Views
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