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Focal Therapy in the Treatment of Localised Prostate Cancer: Primum Non Nocere
EUROPEAN UROLOGY 63 (2013) 623–626
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the article published on pp. 618–622 of this issue
Focal Therapy in the Treatment of Localised Prostate Cancer: Primum Non Nocere Ben J. Challacombe a,*, Declan G. Murphy b,c a
Guy’s and St Thomas’ Hospitals, and King’s College London, London, UK; b The Peter MacCallum Cancer Centre, Melbourne, Australia; c Australian Prostate
Cancer Research Centre, Epworth Healthcare, Melbourne, Australia
The concept of treating an index lesion in the prostate to control prostate cancer (PCa) is of increasing interest to urologists and oncologists alike. The goals of focal therapy itself are commendable, namely reducing the morbidity of treatment while ensuring at least equivalent oncologic outcomes when compared with established interventions for localised PCa such as radical prostatectomy and external-beam radiation therapy. However, concerns exist about the validity of the index lesion theory, the ablative technologies being used to deliver focal therapy, and the design of recent and current studies evaluating focal therapy for localised prostate cancer [1]. The interesting paper by Barret et al. in this issue of European Urology [2] is a retrospective review of the early morbidity of four very different focal treatment modalities (high-intensity focussed ultrasound [HIFU], brachytherapy, cryotherapy, and photodynamic therapy) used to hemiablate the prostates of 106 men who had low-risk and localised PCa. To make such a comparison with mainstream PCa treatments, one needs to ensure similar cohorts are compared. In fact, the men in the current series by Barret and coworkers actually had very low-risk PCa with a prostate-specific antigen (PSA) level <10 ng/ml, stage T2a or T1c disease, Gleason 3 + 3 grade, and only one or two biopsy cores involved (median involvement was one core) and 3-mm median tumour length. This is similar to the characteristics of men most suitable for active surveillance by both the European Association of Urology (EAU) and UK National Institute for Health and Clinical Excellence guidelines [3,4]. Indeed, many men with far more significant disease in terms of tumour volume, core percentage, and
numbers involved are now managed with active surveillance. The patients included were also relatively old with a median age of 66.5 yr, but commendably almost all men (97%) had a transperineal saturation biopsy, and many underwent magnetic resonance (MR) imaging to accurately risk-stratify their disease. Having established that this is a group that many would manage with active surveillance alone [5], one would hope that low morbidity would be associated with focal therapy, the most minimally invasive of all current treatments for localised PCa. These are, after all, men who would have done very well in the medium to long term with absolutely no intervention whatsoever and could therefore have reasonably expected trivial or no morbidity with focal therapy. Coupled with this, we now know that treating these kinds of patients with a much more radical treatment, namely radical prostatectomy, produces no survival benefit at 10 yr [6]. The fact that 13% of patients had a complication and 2% of these were Clavien score 3–4 is disappointing, to say the least. The majority of the Clavien 1 complications involved urinary retention after the focal therapy (9 of 10 cases), and although assigned Clavien score 1, this complication is a cause of significant bother and discomfort to any patient. Recurrent urinary retention may lead to a transurethral resection of the prostate (TURP), and TURP, with all its own morbidity, is often performed simultaneously with HIFU [7]. Indeed, this Clavien grading for urinary retention seems incongruous with the rest of the Clavien system; if one uses the radiation oncology complication stratification of the Radiation Therapy Oncology Group, which ranges from grades 1 to 4, this event is a grade 4 complication [8]. Another patient required a catheter (presumably a three-way
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2012.11.057. * Corresponding author. Department of Urology, 1st Floor Southwark Wing, Guy’s Hospital, London, SE1 9RT, UK. Tel. +44 2071886797; Fax: +44 2071886787. E-mail addresses: [email protected], [email protected] (B.J. Challacombe). 0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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EUROPEAN UROLOGY 63 (2013) 623–626
catheter) with bladder irrigation and transfusion; a transfusion figure of 1% is equivalent to many of the contemporary series of robotic radical prostatectomy. The minor complication figure does not even include the inconvenience of a 1–2 d stay in hospital for some of these modalities, including a planned period of catheterisation. Another patient required an optical urethrotomy for a urethral stricture after cryotherapy, which although successfully managed initially, has a high chance of recurrence and may leave the man requiring intermittent self-catheterisation, which could be regarded as a complication every time a catheter is passed. Although not a complication, the International Index of Erectile Function score seems to have dropped from 19 to 23 pretreatment to 13–14 at follow-up. This is concerning because focal therapy is supposed to maximise functional outcomes, and one might reasonably have assumed that men on active surveillance would not have incurred such a drop in erectile function. Clearly, the most significant complication in this series occurred to the patient who had a rectal fistula, abscess, and defunctioning colostomy following focal cryotherapy. This is not just a complication but a life-changing disaster for the patient and his family, and a major issue for the urologic team who must provide months of intensive care and support while trying to resolve the many complex issues surrounding this awful situation. Although the authors state the morbidity is acceptable, the man with the colostomy and fistula may not have chosen this modality if asked again for his treatment decision for his very low-risk disease. One of the primary tenets of surgery and medicine in general and part of the Hippocratic Oath is primum non nocere: First do no harm. We will have to wait a long time to know whether these focal treatments have been oncologically successful, and proving that they have been is a difficult to do, so understandably no statements on this can be made here with a median follow-up of only 9 mo. This is due to the PSA value becoming extremely difficult to interpret after half the gland has been treated and because recurrent low-risk PCa often fails to appear on current MR imaging, therefore leading to a requirement for further biopsies. This, of course, carries its own morbidity. Also, although Barrett et al. state that all patients underwent a whole-gland biopsy at 12 mo or at biochemical recurrence, no results of these biopsies are reported in this paper. This is despite 91 of 106 patients having reached 12-mo follow-up. Therefore, no conclusions can be reached regarding the oncologic outcome of these patients. It should also be considered that salvage therapy
following failure of ablative therapies such as HIFU is associated with very considerable morbidity [9]. This is why the current EAU guidelines consider such interventions to be experimental at this time. Patients should be fully informed of this. We now have strong evidence to effectively counsel men with very low-risk PCa and are increasingly able to do so through expanded teams of specialist nurses and dedicated PCa specialists. As a result, stating excessive anxiety as a reason to treat trivial disease in 8% of men is disappointing. With more extensive counselling and reassurance, many of these men could have been reassured and left alone on prolonged active surveillance with little or no chance of treatment morbidity and an excellent quality of life. All procedures carry some risk; the trick is to know not just when to intervene but, importantly, when not to. Conflicts of interest: The authors have nothing to disclose.
References [1] Murphy DG, Walton TJ, Connolly S, Costello AJ. Focal therapy for localised prostate cancer: are we asking the correct research questions? BJU Int 2012;109:1–3. [2] Barret E, Ahallal Y, Sanchez-Salas R, et al. Morbidity of focal therapy in the treatment of localized prostate cancer. Eur Urol 2013;63: 618–22. [3] Heidenreich A, Bastian PF, Bellmunt J, et al. Guidelines on prostate cancer. European Association of Urology Web site. http://www. uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th %202012.pdf. Updated 2012. [4] NICE guidelines. National Institute for Health and Clinical Excellence Web site. http://www.nice.org.uk/cg58. [5] Dall’era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012;62:976–83. [6] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367: 203–13. [7] Challacombe BJ, Murphy DG, Zakri R, Cahill DJ. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU Int 2009;104:200–4. [8] Acute radiation morbidity scoring criteria. Radiation Therapy Oncology Group Web site. http://www.rtog.org/researchassociates/adversee ventreporting/acuteradiationmorbidityscoringcriteria.aspx. [9] 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;185:862–8. http://dx.doi.org/10.1016/j.eururo.2012.12.027
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the article published on pp. 618–622 of this issue
Focal Therapy in the Treatment of Localised Prostate Cancer: Primum Non Nocere Ben J. Challacombe a,*, Declan G. Murphy b,c a
Guy’s and St Thomas’ Hospitals, and King’s College London, London, UK; b The Peter MacCallum Cancer Centre, Melbourne, Australia; c Australian Prostate
Cancer Research Centre, Epworth Healthcare, Melbourne, Australia
The concept of treating an index lesion in the prostate to control prostate cancer (PCa) is of increasing interest to urologists and oncologists alike. The goals of focal therapy itself are commendable, namely reducing the morbidity of treatment while ensuring at least equivalent oncologic outcomes when compared with established interventions for localised PCa such as radical prostatectomy and external-beam radiation therapy. However, concerns exist about the validity of the index lesion theory, the ablative technologies being used to deliver focal therapy, and the design of recent and current studies evaluating focal therapy for localised prostate cancer [1]. The interesting paper by Barret et al. in this issue of European Urology [2] is a retrospective review of the early morbidity of four very different focal treatment modalities (high-intensity focussed ultrasound [HIFU], brachytherapy, cryotherapy, and photodynamic therapy) used to hemiablate the prostates of 106 men who had low-risk and localised PCa. To make such a comparison with mainstream PCa treatments, one needs to ensure similar cohorts are compared. In fact, the men in the current series by Barret and coworkers actually had very low-risk PCa with a prostate-specific antigen (PSA) level <10 ng/ml, stage T2a or T1c disease, Gleason 3 + 3 grade, and only one or two biopsy cores involved (median involvement was one core) and 3-mm median tumour length. This is similar to the characteristics of men most suitable for active surveillance by both the European Association of Urology (EAU) and UK National Institute for Health and Clinical Excellence guidelines [3,4]. Indeed, many men with far more significant disease in terms of tumour volume, core percentage, and
numbers involved are now managed with active surveillance. The patients included were also relatively old with a median age of 66.5 yr, but commendably almost all men (97%) had a transperineal saturation biopsy, and many underwent magnetic resonance (MR) imaging to accurately risk-stratify their disease. Having established that this is a group that many would manage with active surveillance alone [5], one would hope that low morbidity would be associated with focal therapy, the most minimally invasive of all current treatments for localised PCa. These are, after all, men who would have done very well in the medium to long term with absolutely no intervention whatsoever and could therefore have reasonably expected trivial or no morbidity with focal therapy. Coupled with this, we now know that treating these kinds of patients with a much more radical treatment, namely radical prostatectomy, produces no survival benefit at 10 yr [6]. The fact that 13% of patients had a complication and 2% of these were Clavien score 3–4 is disappointing, to say the least. The majority of the Clavien 1 complications involved urinary retention after the focal therapy (9 of 10 cases), and although assigned Clavien score 1, this complication is a cause of significant bother and discomfort to any patient. Recurrent urinary retention may lead to a transurethral resection of the prostate (TURP), and TURP, with all its own morbidity, is often performed simultaneously with HIFU [7]. Indeed, this Clavien grading for urinary retention seems incongruous with the rest of the Clavien system; if one uses the radiation oncology complication stratification of the Radiation Therapy Oncology Group, which ranges from grades 1 to 4, this event is a grade 4 complication [8]. Another patient required a catheter (presumably a three-way
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2012.11.057. * Corresponding author. Department of Urology, 1st Floor Southwark Wing, Guy’s Hospital, London, SE1 9RT, UK. Tel. +44 2071886797; Fax: +44 2071886787. E-mail addresses: [email protected], [email protected] (B.J. Challacombe). 0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
624
EUROPEAN UROLOGY 63 (2013) 623–626
catheter) with bladder irrigation and transfusion; a transfusion figure of 1% is equivalent to many of the contemporary series of robotic radical prostatectomy. The minor complication figure does not even include the inconvenience of a 1–2 d stay in hospital for some of these modalities, including a planned period of catheterisation. Another patient required an optical urethrotomy for a urethral stricture after cryotherapy, which although successfully managed initially, has a high chance of recurrence and may leave the man requiring intermittent self-catheterisation, which could be regarded as a complication every time a catheter is passed. Although not a complication, the International Index of Erectile Function score seems to have dropped from 19 to 23 pretreatment to 13–14 at follow-up. This is concerning because focal therapy is supposed to maximise functional outcomes, and one might reasonably have assumed that men on active surveillance would not have incurred such a drop in erectile function. Clearly, the most significant complication in this series occurred to the patient who had a rectal fistula, abscess, and defunctioning colostomy following focal cryotherapy. This is not just a complication but a life-changing disaster for the patient and his family, and a major issue for the urologic team who must provide months of intensive care and support while trying to resolve the many complex issues surrounding this awful situation. Although the authors state the morbidity is acceptable, the man with the colostomy and fistula may not have chosen this modality if asked again for his treatment decision for his very low-risk disease. One of the primary tenets of surgery and medicine in general and part of the Hippocratic Oath is primum non nocere: First do no harm. We will have to wait a long time to know whether these focal treatments have been oncologically successful, and proving that they have been is a difficult to do, so understandably no statements on this can be made here with a median follow-up of only 9 mo. This is due to the PSA value becoming extremely difficult to interpret after half the gland has been treated and because recurrent low-risk PCa often fails to appear on current MR imaging, therefore leading to a requirement for further biopsies. This, of course, carries its own morbidity. Also, although Barrett et al. state that all patients underwent a whole-gland biopsy at 12 mo or at biochemical recurrence, no results of these biopsies are reported in this paper. This is despite 91 of 106 patients having reached 12-mo follow-up. Therefore, no conclusions can be reached regarding the oncologic outcome of these patients. It should also be considered that salvage therapy
following failure of ablative therapies such as HIFU is associated with very considerable morbidity [9]. This is why the current EAU guidelines consider such interventions to be experimental at this time. Patients should be fully informed of this. We now have strong evidence to effectively counsel men with very low-risk PCa and are increasingly able to do so through expanded teams of specialist nurses and dedicated PCa specialists. As a result, stating excessive anxiety as a reason to treat trivial disease in 8% of men is disappointing. With more extensive counselling and reassurance, many of these men could have been reassured and left alone on prolonged active surveillance with little or no chance of treatment morbidity and an excellent quality of life. All procedures carry some risk; the trick is to know not just when to intervene but, importantly, when not to. Conflicts of interest: The authors have nothing to disclose.
References [1] Murphy DG, Walton TJ, Connolly S, Costello AJ. Focal therapy for localised prostate cancer: are we asking the correct research questions? BJU Int 2012;109:1–3. [2] Barret E, Ahallal Y, Sanchez-Salas R, et al. Morbidity of focal therapy in the treatment of localized prostate cancer. Eur Urol 2013;63: 618–22. [3] Heidenreich A, Bastian PF, Bellmunt J, et al. Guidelines on prostate cancer. European Association of Urology Web site. http://www. uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th %202012.pdf. Updated 2012. [4] NICE guidelines. National Institute for Health and Clinical Excellence Web site. http://www.nice.org.uk/cg58. [5] Dall’era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012;62:976–83. [6] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367: 203–13. [7] Challacombe BJ, Murphy DG, Zakri R, Cahill DJ. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU Int 2009;104:200–4. [8] Acute radiation morbidity scoring criteria. Radiation Therapy Oncology Group Web site. http://www.rtog.org/researchassociates/adversee ventreporting/acuteradiationmorbidityscoringcriteria.aspx. [9] 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;185:862–8. http://dx.doi.org/10.1016/j.eururo.2012.12.027