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Risk Stratification in Hormone-sensitive Metastatic Prostate Cancer: More Questions than Answers
EUROPEAN UROLOGY 68 (2015) 205–206
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 196–204 of this issue
Risk Stratification in Hormone-sensitive Metastatic Prostate Cancer: More Questions than Answers Sarah P. Psutka *, Igor Frank, R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, MN, USA
The approach to metastatic prostate cancer in 2014 has changed little from that detailed by Huggins and Hodges in 1941. Although the mainstay of therapy for newly diagnosed noncastrate metastatic prostate cancer (NCMPC) remains androgen deprivation therapy (ADT), the landscape of options available in 2014 has evolved considerably beyond surgical castration [1]. Despite this proliferation of therapeutic options, our understanding of prognostic factors relating to overall survival and optimal response to novel pharmacologic strategies remains relatively rudimentary. Current options for men with NCMPC extend beyond classic medical castration, and include combined androgen blockade, peripheral androgen blockade, and, as recently reported, up-front cytotoxic chemotherapy [2]. Furthermore, the merits of intermittent versus continuous ADT continue to be debated [3], and the role of locally directed therapy has entered the arena as a potential strategy to postpone palliative ADT in those with oligometastatic prostate cancer [4–6]. The net effect of these advances has been a reduction in the mortality rate for patients with NCMPC [7]. With increasing therapeutic options and treatment strategies, however, the ability to risk-stratify a patient with NCMPC becomes ever more important. In this issue of European Urology, Gravis et al [8] sought to contribute to the sparse literature addressing prognostic factors for overall survival in NCMPC, building on the model developed by Glass and colleagues in 2003 [9] in which good, intermediate, and poor risk groups were identified from 1076 patients accrued in the SWOG 8894 trial on the basis of appendicular versus axial skeletal bone metastases, performance status 1, prostate-specific antigen (PSA) 65 ng/ml, and Gleason score 8. Gravis et al tested the
Glass model in a post hoc analysis of the GETUG-15 cohort, in which 385 men with NCMPC were randomized 1:1 to ADT with or without docetaxel. The model performed disappointingly in this contemporary cohort (c-index 0.59), which was attributed to improvements in NCMPC management, as well as lead-time bias due to widespread PSA screening. Patients enrolled in GETUG-15 additionally differed from those in SWOG 8894 in that they were younger, they had better performance status, and a smaller proportion had poor-risk disease. Furthermore, in the GETUG-15 trial, variable subsequent therapies were used in the majority of both arms following progression, which potentially confounded the study outcomes. Following the methodology of Glass et al, Gravis and colleagues developed and validated new prognostic risk groups. Alkaline phosphatase (ALP), Gleason score, and pain intensity provided the greatest degree of discrimination, with ALP alone outperforming the Glass model (c-index 0.64), although the confidence intervals for both indices overlapped. The authors assert that ALP may be used alone as an inexpensive and readily available prognostic factor in patients with NCMPC. However, in clinical practice, the utility of a single measure, even if easily obtained and costeffective, that predicts all-cause mortality only slightly better than the flip of a coin is arguable. Furthermore, in the GETUG-15 study, abnormal ALP was not independently associated with response to up-front docetaxel with ADT (hazard ratio 0.98, 95% confidence interval 0.66–1.45, p = 0.94) [10], further drawing into question its clinical utility if it is ineffective in predicting response to treatment. Candidate predictors that have emerged as potentially useful include both the location and volume of the disease,
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.09.022. * Corresponding author. Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Tel. +1 507 2841330; Fax: +1 507 2844951. E-mail address: [email protected] (S.P. Psutka). http://dx.doi.org/10.1016/j.eururo.2014.10.007 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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EUROPEAN UROLOGY 68 (2015) 205–206
neither of which was available for examination in the GETUG-15 study data set, although ALP may function as a surrogate for the volume of bony metastases. Consensus definitions for location and volume are lacking: higher risk was assigned to disease involving the appendicular skeleton in the Glass model, whereas SWOG trials define extensive disease as involvement of the ribs, long bones, or visceral organs. In the ECOG 3805 trial, up-front docetaxel plus ADT was found to confer a median survival benefit of 13 mo over ADT alone, with the largest benefit noted among patients with high-volume disease, defined as involvement of visceral metastases and/or four or more bone metastases [2]. In contrast, among patients with low-volume disease, there is mounting evidence supporting the use of locally directed therapy in an attempt to prolong the time before introduction of ADT and its attendant toxicities. A recent systematic review suggested that salvage lymphadenectomy (SLND) for isolated regional or retroperitoneal nodal recurrence delayed clinical progression and time to ADT in up to one-third of patients. At 5 yr following SLND, 9–19% of patients remained free of biochemical recurrence and 26–34% were free of clinical recurrence [5]. Furthermore, a meta-analysis of 450 patients treated with metastasisdirected therapy found that 51% of patients were progression-free at 1–3 yr, albeit in the setting of variable adjuvant therapy use [6]. Unfortunately, when attempting to determine if a patient is a candidate for up-front ADT, cytotoxic therapy, or cytoreductive surgery, crude metrics such as raw numbers of metastatic sites remain those we rely on. One might imagine a scenario in which one patient has four small bony metastases and another has a solitary large pelvic metastasis. Which is the more relevant marker of aggressiveness: number of metastatic foci or absolute disease burden? Current data support frontline docetaxel plus ADT in the first but not the second patient; however the available data may not generalize effectively to either case. Thus, classifications of clinically significant disease volume need to be further defined. Further research regarding prognostic factors in the setting of NCMPC is much needed. Gravis and colleagues are to be congratulated on their efforts to improve risk stratification in this arena; however, additional work is necessary to validate their findings. This includes further study regarding the utility of ALP and other biomarkers identified (hemoglobin, lactate dehydrogenase, and PSA),
factors not included in the study (location and volume of disease), and host factors such as immune-related factors and variations in the androgen steroid pathways, all of which may have implications for outcomes among patients with NCMPC. Finally, although general determinants of overall survival are important, the more meaningful clinical question that remains is: which factors predict response to therapy and can thus reliably guide clinical decisionmaking for men with NCMPC. Conflicts of interest: The authors have nothing to disclose.
References [1] Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467–79. [2] Sweeney C, Chen Y, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol 2014;32, LBA2. [3] Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314–25. [4] Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058–66. [5] Abdollah F, Briganti A, Montorsi F, et al. Contemporary role of salvage lymphadenectomy in patients with recurrence following radical prostatectomy. Eur Urol 2015;67:839–49. [6] Ost P, Bossi A, Decaestecker K, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol 2015;67:852–63. [7] Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol 2012;188:1164–9. [8] Gravis G, Boher J-M, Fizazi K, et al. Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the Glass model and development of a novel simplified prognostic model. Eur Urol 2015;68:196–204. [9] Glass TR, Tangen CM, Crawford ED, Thompson I. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol 2003;169:164–9. [10] Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013;14:149–58.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 196–204 of this issue
Risk Stratification in Hormone-sensitive Metastatic Prostate Cancer: More Questions than Answers Sarah P. Psutka *, Igor Frank, R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, MN, USA
The approach to metastatic prostate cancer in 2014 has changed little from that detailed by Huggins and Hodges in 1941. Although the mainstay of therapy for newly diagnosed noncastrate metastatic prostate cancer (NCMPC) remains androgen deprivation therapy (ADT), the landscape of options available in 2014 has evolved considerably beyond surgical castration [1]. Despite this proliferation of therapeutic options, our understanding of prognostic factors relating to overall survival and optimal response to novel pharmacologic strategies remains relatively rudimentary. Current options for men with NCMPC extend beyond classic medical castration, and include combined androgen blockade, peripheral androgen blockade, and, as recently reported, up-front cytotoxic chemotherapy [2]. Furthermore, the merits of intermittent versus continuous ADT continue to be debated [3], and the role of locally directed therapy has entered the arena as a potential strategy to postpone palliative ADT in those with oligometastatic prostate cancer [4–6]. The net effect of these advances has been a reduction in the mortality rate for patients with NCMPC [7]. With increasing therapeutic options and treatment strategies, however, the ability to risk-stratify a patient with NCMPC becomes ever more important. In this issue of European Urology, Gravis et al [8] sought to contribute to the sparse literature addressing prognostic factors for overall survival in NCMPC, building on the model developed by Glass and colleagues in 2003 [9] in which good, intermediate, and poor risk groups were identified from 1076 patients accrued in the SWOG 8894 trial on the basis of appendicular versus axial skeletal bone metastases, performance status 1, prostate-specific antigen (PSA) 65 ng/ml, and Gleason score 8. Gravis et al tested the
Glass model in a post hoc analysis of the GETUG-15 cohort, in which 385 men with NCMPC were randomized 1:1 to ADT with or without docetaxel. The model performed disappointingly in this contemporary cohort (c-index 0.59), which was attributed to improvements in NCMPC management, as well as lead-time bias due to widespread PSA screening. Patients enrolled in GETUG-15 additionally differed from those in SWOG 8894 in that they were younger, they had better performance status, and a smaller proportion had poor-risk disease. Furthermore, in the GETUG-15 trial, variable subsequent therapies were used in the majority of both arms following progression, which potentially confounded the study outcomes. Following the methodology of Glass et al, Gravis and colleagues developed and validated new prognostic risk groups. Alkaline phosphatase (ALP), Gleason score, and pain intensity provided the greatest degree of discrimination, with ALP alone outperforming the Glass model (c-index 0.64), although the confidence intervals for both indices overlapped. The authors assert that ALP may be used alone as an inexpensive and readily available prognostic factor in patients with NCMPC. However, in clinical practice, the utility of a single measure, even if easily obtained and costeffective, that predicts all-cause mortality only slightly better than the flip of a coin is arguable. Furthermore, in the GETUG-15 study, abnormal ALP was not independently associated with response to up-front docetaxel with ADT (hazard ratio 0.98, 95% confidence interval 0.66–1.45, p = 0.94) [10], further drawing into question its clinical utility if it is ineffective in predicting response to treatment. Candidate predictors that have emerged as potentially useful include both the location and volume of the disease,
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.09.022. * Corresponding author. Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Tel. +1 507 2841330; Fax: +1 507 2844951. E-mail address: [email protected] (S.P. Psutka). http://dx.doi.org/10.1016/j.eururo.2014.10.007 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
206
EUROPEAN UROLOGY 68 (2015) 205–206
neither of which was available for examination in the GETUG-15 study data set, although ALP may function as a surrogate for the volume of bony metastases. Consensus definitions for location and volume are lacking: higher risk was assigned to disease involving the appendicular skeleton in the Glass model, whereas SWOG trials define extensive disease as involvement of the ribs, long bones, or visceral organs. In the ECOG 3805 trial, up-front docetaxel plus ADT was found to confer a median survival benefit of 13 mo over ADT alone, with the largest benefit noted among patients with high-volume disease, defined as involvement of visceral metastases and/or four or more bone metastases [2]. In contrast, among patients with low-volume disease, there is mounting evidence supporting the use of locally directed therapy in an attempt to prolong the time before introduction of ADT and its attendant toxicities. A recent systematic review suggested that salvage lymphadenectomy (SLND) for isolated regional or retroperitoneal nodal recurrence delayed clinical progression and time to ADT in up to one-third of patients. At 5 yr following SLND, 9–19% of patients remained free of biochemical recurrence and 26–34% were free of clinical recurrence [5]. Furthermore, a meta-analysis of 450 patients treated with metastasisdirected therapy found that 51% of patients were progression-free at 1–3 yr, albeit in the setting of variable adjuvant therapy use [6]. Unfortunately, when attempting to determine if a patient is a candidate for up-front ADT, cytotoxic therapy, or cytoreductive surgery, crude metrics such as raw numbers of metastatic sites remain those we rely on. One might imagine a scenario in which one patient has four small bony metastases and another has a solitary large pelvic metastasis. Which is the more relevant marker of aggressiveness: number of metastatic foci or absolute disease burden? Current data support frontline docetaxel plus ADT in the first but not the second patient; however the available data may not generalize effectively to either case. Thus, classifications of clinically significant disease volume need to be further defined. Further research regarding prognostic factors in the setting of NCMPC is much needed. Gravis and colleagues are to be congratulated on their efforts to improve risk stratification in this arena; however, additional work is necessary to validate their findings. This includes further study regarding the utility of ALP and other biomarkers identified (hemoglobin, lactate dehydrogenase, and PSA),
factors not included in the study (location and volume of disease), and host factors such as immune-related factors and variations in the androgen steroid pathways, all of which may have implications for outcomes among patients with NCMPC. Finally, although general determinants of overall survival are important, the more meaningful clinical question that remains is: which factors predict response to therapy and can thus reliably guide clinical decisionmaking for men with NCMPC. Conflicts of interest: The authors have nothing to disclose.
References [1] Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467–79. [2] Sweeney C, Chen Y, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol 2014;32, LBA2. [3] Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314–25. [4] Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058–66. [5] Abdollah F, Briganti A, Montorsi F, et al. Contemporary role of salvage lymphadenectomy in patients with recurrence following radical prostatectomy. Eur Urol 2015;67:839–49. [6] Ost P, Bossi A, Decaestecker K, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol 2015;67:852–63. [7] Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol 2012;188:1164–9. [8] Gravis G, Boher J-M, Fizazi K, et al. Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the Glass model and development of a novel simplified prognostic model. Eur Urol 2015;68:196–204. [9] Glass TR, Tangen CM, Crawford ED, Thompson I. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol 2003;169:164–9. [10] Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013;14:149–58.