- Email: [email protected]
A House Divided: The Irradiation Versus Prostatectomy Debate Continues
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
COMMENTARY
A House Divided: The Irradiation Versus Prostatectomy Debate Continues Harras B. Zaid, MD, and R. Jeffrey Karnes, MD Department of Urology, Mayo Clinic, Rochester, Minnesota Received Mar 6, 2016, and in revised form Jan 14, 2017. Accepted for publication Jan 23, 2017.
We read with interest the recent Red Journal article “Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?” by Roach et al (1). This was a thoughtful and critical analysis of the complex literature relating to irradiation versus prostatectomy in men with localized prostate cancer. Overall, the authors assigned low reliability scores to many of the studies evaluated, citing an inadequate (or unreported) duration of androgen deprivation therapy (ADT) with radiation therapy for intermediate- or high-risk disease, unadjusted survival metrics, or incomplete reporting of patient or disease features. They concluded that many published studies are not adequate to answer the question of whether prostatectomy or radiation therapy is preferred. In contrast, a systematic review and meta-analysis conducted by Wallis et al (2) in 2016 on this same subject included only those studies (19 total) that reported adjusted hazard ratios for overall survival or cancer-specific survival, thereby (at least partly) accounting for differences in baseline disease characteristics and patient comorbidity. The meta-analysis suggested that pooled adjusted hazard ratios for overall mortality and cancerspecific mortality were 1.63 and 2.08, respectively (both P<.05), favoring surgery over irradiation. These 2 articles are just a pair among many that highlight the discordant literature on the subject of “best” treatment of localized prostate cancer. It is especially challenging to evaluate retrospective institutional and registry-based studies with all their inherent flaws including
Reprint requests to: R. Jeffrey Karnes, MD, Department of Urology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Tel: (507) 2669968; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 99, No. 3, pp. 512e514, 2017 0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2017.01.220
selection bias and residual confounding that cannot be completely addressed by even the most complex statistical analyses. Assuredly, then, a well-designed randomized controlled study would be able to answer the question of which treatment type is better. Enter the Prostate Testing for Cancer and Treatment (ProtecT) trial (3). The authors are to be applauded for the immense effort this prospective study represents. Over a 10-year period (1999-2009), the investigators randomized 1643 men to radical prostatectomy, radiation therapy, or active surveillance. At a median follow-up of 10 years, there were 17 prostate cancererelated deaths. The majority (8) were in the active surveillance arm, and the remainder were split between the irradiation (4) and surgical (5) arms. The 10-year cancer-specific survival rates were 98.8%, 99%, and 99.6% for the active surveillance, radical prostatectomy, and irradiation arms, respectively. Furthermore, metastatic disease developed in 33, 13, and 16 patients, respectively. While the higher incidence of metastatic disease in the active surveillance arm is likely due to multiple factorsdsuch as the inclusion of men with a Gleason score 7 and nonstandard surveillance protocols (exclusion of magnetic resonance imaging, repeat biopsies)dthe data still demonstrate near parity in cancer-specific survival regardless of initial treatment modality selected. The mortality rate at 10 years was approximately 1% irrespective of treatment received, which was lower than expected. Another notable, albeit nonprimary, finding was biochemical recurrence after initial definitive treatment: 14% of men receiving radiation treatment (55 of 405) compared
Conflict of interest: none.
Volume 99 Number 3 2017
with 4% of men under undergoing radical prostatectomy (18 of 391). So, then, is this the say-all end-all in counseling our patients with prostate cancer about cancer-specific survival? Unfortunately, despite its strength as a randomized trial and robust 10-year follow-up, ProtecT may not settle some of the discordant findings from the studies of Roach et al (1) and Wallis et al (2). For example, one of the notable limitations of the ProtecT study is its cohort, which entails patients primarily with lower-risk disease: about three-quarters of patients had cT1c and Gleason 6 disease, with a median prostate-specific antigen level of 4.7 ng/ml (<5% of patients had Gleason 8-10 disease). Patients with intermediate- and high-risk prostate cancerdthose who are most likely to benefit from definitive local therapydmay not find the answers they need in the ProtecT study. Indeed, this will be an ever-relevant patient population, as fallout from the US Preventive Services Task Force grade D recommendation against prostate-specific antigen screening may lead to a stage migration in prostate cancer (4). Aside from its lower-risk cohort, we must also remember that the ProtecT trial was conceived and initiated in the late 1990s. As such, the treatments administered in the trialdincluding the protocol for active surveillance, type of surgery (the vast majority were open rather than robotic), irradiation modality, and ADT usedare not in line with what would be the standard of care in 2017. Notable in this trial, for example, is the fact that 24% of patients undergoing prostatectomy had a positive surgical margin, which is significantly higher than other large contemporary series (5). Furthermore, the majority of patients in ProtecT received 3-dimensional conformal therapy, not intensity modulated radiation therapy, and the duration of ADT was not standardized (varying between 3 and 6 months). Furthermore, variations in dosimetry and fields used add another dimension of uncertainty and were not completely standardized. A post-hoc analysis of the ProtecT study evaluated 492 patients who were not candidates for inclusion in the trial because of locally advanced or metastatic disease (6). Specifically, 54 patients underwent prostatectomy; 245, radiation therapy; and 122, primary ADT. In an unadjusted analysis, cancer-specific survival at a median follow-up of 7.4 years was similar for the patients undergoing prostatectomy and the patients undergoing radiation therapy, and it was significantly better in both of these groups than in patients receiving no definitive local treatment. While these data support the use of irradiation or radical prostatectomy in men with advanced disease, interpretation of these data is limited by the small population size, post hocetype analysis, and short follow-up. From ProtecT’s inception to its 10-year median followup, furthermore, radiation treatment evolved, as did
A house divided
513
adjunctive therapy. Surgery also changed, with widespread embracing of robotic prostatectomy during this trial period (5). Nonetheless, there is more at hand than survival; while short- and intermediate-term patient-reported quality-of-life measures in this trial may favor irradiation (7), long-term quality of life (>10 years) is fairly equivalent, save for some nuances (8). Lastly, 2 recent population-based, propensity-adjusted studies analyzed complications following definitive local treatment of prostate cancer, albeit with differently defined outcome measures (9, 10). That is, one was a Surveillance, Epidemiology, and End ResultseMedicare study with a median follow-up of 4.1 years evaluating rates of adverse urinary events, which were highest in patients undergoing prostatectomy plus external beam radiation therapy (37.8%), with 26.6% in the prostatectomy-only group and 19.7% in the external beameonly group (9). In contrast, the other study, a population-based study out of Ontario, Canada, separately evaluated cumulative 5-year outcomes following definitive treatment in several domains: hospital admissions; secondary malignancies; and subsequent urologic procedures, rectal-anal procedures, and open surgical procedures (10). The rate of urologic procedures was highest in the group undergoing prostatectomy plus irradiation (42.4%), followed by prostatectomy alone (34.2%) and irradiation alone (30.0%). All other complication outcomes were highest in the irradiation group. While these 2 datasets provide useful insight, they are again limited by biases already discussed and cannot be used to definitively recommend one form of treatment over another. Meanwhile, the debate of surgery versus irradiation, and its participants, can remind one of the impetus for the “House Divided” speech by United States President Abraham Lincoln. On this note, in regard to “high-risk” prostate cancer, “If we could first know where we are, and whither we are tending, we could then better judge what to do, and how to do it”; urologists and radiation oncologists should continue to work together to determine, for example, if there are cancers that are best treated up front with a radical prostatectomy and thorough pelvic lymph node dissection to ensure accurate grading and staging and which patients best benefit from adjuvant therapy (11). How, then, are we to counsel our patients about their treatment options for intermediate- and high-risk localized prostate cancer? At our institution, when speaking with patients, we acknowledge the lack of level 1 evidence to support surgery over irradiation, but we do make mention of the pooled studies suggesting a benefit to surgery in higher-risk disease, as well as the availability of radiation therapy as a salvage option in the event of treatment failure. Regardless, we offer a full consultation with our radiation oncology colleagues up front and help guide patientsdin the context of their personal preferencesdto
514
Zaid and Karnes
the treatment modality that fits their values and priorities. The real answer to what is truly “better” may not ever be known.
References 1. Roach M III, Ceron Lizarraga TL, Lazar AA. Radical prostatectomy versus radiation and androgen deprivation therapy for clinically localized prostate cancer: How good is the evidence? Int J Radiat Oncol Biol Phys 2015;93:1064-1070. 2. Wallis CJ, Saskin R, Choo R, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: A systematic review and metaanalysis. Eur Urol 2016;70:21-30. 3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-1424. 4. Jemal A, Fedewa SA, Ma J, et al. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 2015;314:2054-2061.
International Journal of Radiation Oncology Biology Physics 5. Yaxley JW, Coughlin GD, Chambers SK, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: Early outcomes from a randomised controlled phase 3 study. Lancet 2016;388:1057-1066. 6. Johnston TJ, Shaw GL, Lamb AD, et al. Mortality among men with advanced prostate cancer excluded from the ProtecT trial. Eur Urol 2017;71:381-388. 7. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425-1437. 8. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013;368:436-445. 9. Jarosek SL, Virnig BA, Chu H, et al. Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both. Eur Urol 2015;67:273-280. 10. Wallis CJ, Cheung P, Herschorn S, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer 2015;112:977-982. 11. Abdollah F, Karnes RJ, Suardi N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol 2014;32:3939-3947.
Radiation Oncology biology
physics
www.redjournal.org
COMMENTARY
A House Divided: The Irradiation Versus Prostatectomy Debate Continues Harras B. Zaid, MD, and R. Jeffrey Karnes, MD Department of Urology, Mayo Clinic, Rochester, Minnesota Received Mar 6, 2016, and in revised form Jan 14, 2017. Accepted for publication Jan 23, 2017.
We read with interest the recent Red Journal article “Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?” by Roach et al (1). This was a thoughtful and critical analysis of the complex literature relating to irradiation versus prostatectomy in men with localized prostate cancer. Overall, the authors assigned low reliability scores to many of the studies evaluated, citing an inadequate (or unreported) duration of androgen deprivation therapy (ADT) with radiation therapy for intermediate- or high-risk disease, unadjusted survival metrics, or incomplete reporting of patient or disease features. They concluded that many published studies are not adequate to answer the question of whether prostatectomy or radiation therapy is preferred. In contrast, a systematic review and meta-analysis conducted by Wallis et al (2) in 2016 on this same subject included only those studies (19 total) that reported adjusted hazard ratios for overall survival or cancer-specific survival, thereby (at least partly) accounting for differences in baseline disease characteristics and patient comorbidity. The meta-analysis suggested that pooled adjusted hazard ratios for overall mortality and cancerspecific mortality were 1.63 and 2.08, respectively (both P<.05), favoring surgery over irradiation. These 2 articles are just a pair among many that highlight the discordant literature on the subject of “best” treatment of localized prostate cancer. It is especially challenging to evaluate retrospective institutional and registry-based studies with all their inherent flaws including
Reprint requests to: R. Jeffrey Karnes, MD, Department of Urology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Tel: (507) 2669968; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 99, No. 3, pp. 512e514, 2017 0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2017.01.220
selection bias and residual confounding that cannot be completely addressed by even the most complex statistical analyses. Assuredly, then, a well-designed randomized controlled study would be able to answer the question of which treatment type is better. Enter the Prostate Testing for Cancer and Treatment (ProtecT) trial (3). The authors are to be applauded for the immense effort this prospective study represents. Over a 10-year period (1999-2009), the investigators randomized 1643 men to radical prostatectomy, radiation therapy, or active surveillance. At a median follow-up of 10 years, there were 17 prostate cancererelated deaths. The majority (8) were in the active surveillance arm, and the remainder were split between the irradiation (4) and surgical (5) arms. The 10-year cancer-specific survival rates were 98.8%, 99%, and 99.6% for the active surveillance, radical prostatectomy, and irradiation arms, respectively. Furthermore, metastatic disease developed in 33, 13, and 16 patients, respectively. While the higher incidence of metastatic disease in the active surveillance arm is likely due to multiple factorsdsuch as the inclusion of men with a Gleason score 7 and nonstandard surveillance protocols (exclusion of magnetic resonance imaging, repeat biopsies)dthe data still demonstrate near parity in cancer-specific survival regardless of initial treatment modality selected. The mortality rate at 10 years was approximately 1% irrespective of treatment received, which was lower than expected. Another notable, albeit nonprimary, finding was biochemical recurrence after initial definitive treatment: 14% of men receiving radiation treatment (55 of 405) compared
Conflict of interest: none.
Volume 99 Number 3 2017
with 4% of men under undergoing radical prostatectomy (18 of 391). So, then, is this the say-all end-all in counseling our patients with prostate cancer about cancer-specific survival? Unfortunately, despite its strength as a randomized trial and robust 10-year follow-up, ProtecT may not settle some of the discordant findings from the studies of Roach et al (1) and Wallis et al (2). For example, one of the notable limitations of the ProtecT study is its cohort, which entails patients primarily with lower-risk disease: about three-quarters of patients had cT1c and Gleason 6 disease, with a median prostate-specific antigen level of 4.7 ng/ml (<5% of patients had Gleason 8-10 disease). Patients with intermediate- and high-risk prostate cancerdthose who are most likely to benefit from definitive local therapydmay not find the answers they need in the ProtecT study. Indeed, this will be an ever-relevant patient population, as fallout from the US Preventive Services Task Force grade D recommendation against prostate-specific antigen screening may lead to a stage migration in prostate cancer (4). Aside from its lower-risk cohort, we must also remember that the ProtecT trial was conceived and initiated in the late 1990s. As such, the treatments administered in the trialdincluding the protocol for active surveillance, type of surgery (the vast majority were open rather than robotic), irradiation modality, and ADT usedare not in line with what would be the standard of care in 2017. Notable in this trial, for example, is the fact that 24% of patients undergoing prostatectomy had a positive surgical margin, which is significantly higher than other large contemporary series (5). Furthermore, the majority of patients in ProtecT received 3-dimensional conformal therapy, not intensity modulated radiation therapy, and the duration of ADT was not standardized (varying between 3 and 6 months). Furthermore, variations in dosimetry and fields used add another dimension of uncertainty and were not completely standardized. A post-hoc analysis of the ProtecT study evaluated 492 patients who were not candidates for inclusion in the trial because of locally advanced or metastatic disease (6). Specifically, 54 patients underwent prostatectomy; 245, radiation therapy; and 122, primary ADT. In an unadjusted analysis, cancer-specific survival at a median follow-up of 7.4 years was similar for the patients undergoing prostatectomy and the patients undergoing radiation therapy, and it was significantly better in both of these groups than in patients receiving no definitive local treatment. While these data support the use of irradiation or radical prostatectomy in men with advanced disease, interpretation of these data is limited by the small population size, post hocetype analysis, and short follow-up. From ProtecT’s inception to its 10-year median followup, furthermore, radiation treatment evolved, as did
A house divided
513
adjunctive therapy. Surgery also changed, with widespread embracing of robotic prostatectomy during this trial period (5). Nonetheless, there is more at hand than survival; while short- and intermediate-term patient-reported quality-of-life measures in this trial may favor irradiation (7), long-term quality of life (>10 years) is fairly equivalent, save for some nuances (8). Lastly, 2 recent population-based, propensity-adjusted studies analyzed complications following definitive local treatment of prostate cancer, albeit with differently defined outcome measures (9, 10). That is, one was a Surveillance, Epidemiology, and End ResultseMedicare study with a median follow-up of 4.1 years evaluating rates of adverse urinary events, which were highest in patients undergoing prostatectomy plus external beam radiation therapy (37.8%), with 26.6% in the prostatectomy-only group and 19.7% in the external beameonly group (9). In contrast, the other study, a population-based study out of Ontario, Canada, separately evaluated cumulative 5-year outcomes following definitive treatment in several domains: hospital admissions; secondary malignancies; and subsequent urologic procedures, rectal-anal procedures, and open surgical procedures (10). The rate of urologic procedures was highest in the group undergoing prostatectomy plus irradiation (42.4%), followed by prostatectomy alone (34.2%) and irradiation alone (30.0%). All other complication outcomes were highest in the irradiation group. While these 2 datasets provide useful insight, they are again limited by biases already discussed and cannot be used to definitively recommend one form of treatment over another. Meanwhile, the debate of surgery versus irradiation, and its participants, can remind one of the impetus for the “House Divided” speech by United States President Abraham Lincoln. On this note, in regard to “high-risk” prostate cancer, “If we could first know where we are, and whither we are tending, we could then better judge what to do, and how to do it”; urologists and radiation oncologists should continue to work together to determine, for example, if there are cancers that are best treated up front with a radical prostatectomy and thorough pelvic lymph node dissection to ensure accurate grading and staging and which patients best benefit from adjuvant therapy (11). How, then, are we to counsel our patients about their treatment options for intermediate- and high-risk localized prostate cancer? At our institution, when speaking with patients, we acknowledge the lack of level 1 evidence to support surgery over irradiation, but we do make mention of the pooled studies suggesting a benefit to surgery in higher-risk disease, as well as the availability of radiation therapy as a salvage option in the event of treatment failure. Regardless, we offer a full consultation with our radiation oncology colleagues up front and help guide patientsdin the context of their personal preferencesdto
514
Zaid and Karnes
the treatment modality that fits their values and priorities. The real answer to what is truly “better” may not ever be known.
References 1. Roach M III, Ceron Lizarraga TL, Lazar AA. Radical prostatectomy versus radiation and androgen deprivation therapy for clinically localized prostate cancer: How good is the evidence? Int J Radiat Oncol Biol Phys 2015;93:1064-1070. 2. Wallis CJ, Saskin R, Choo R, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: A systematic review and metaanalysis. Eur Urol 2016;70:21-30. 3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-1424. 4. Jemal A, Fedewa SA, Ma J, et al. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 2015;314:2054-2061.
International Journal of Radiation Oncology Biology Physics 5. Yaxley JW, Coughlin GD, Chambers SK, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: Early outcomes from a randomised controlled phase 3 study. Lancet 2016;388:1057-1066. 6. Johnston TJ, Shaw GL, Lamb AD, et al. Mortality among men with advanced prostate cancer excluded from the ProtecT trial. Eur Urol 2017;71:381-388. 7. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425-1437. 8. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013;368:436-445. 9. Jarosek SL, Virnig BA, Chu H, et al. Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both. Eur Urol 2015;67:273-280. 10. Wallis CJ, Cheung P, Herschorn S, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer 2015;112:977-982. 11. Abdollah F, Karnes RJ, Suardi N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol 2014;32:3939-3947.