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Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors
EURURO-6251; 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 articles published on pp. XX–YY and on pp. AA–BB of this issue
Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors Alfred I. Neugut *, Edward P. Gelmann Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Any intelligent oncologist will readily admit that the mainstay of curative treatment for virtually all of the solid tumors when they are not metastatic is surgery. With a few exceptions, the medical and radiation oncologists generally provide adjunctive treatments to improve the local control or cure rates—not unimportant functions but still not central roles in the cure of the cancer patient. In contrast, when patients present with metastatic disease or when recurrence occurs and cure is no longer possible, the surgeons pass the patient along to the medical and radiation oncologists and have limited roles in disease management thereafter. Except in a few solid tumors for which randomized trials have demonstrated survival benefits for surgery despite presentation with metastatic disease, we intuitively do not expect long-term benefit from surgical management of the primary tumor when metastases are already present. There are a few noteworthy exceptions. Surgical removal of the primary lesion despite the presence of metastatic disease has long-term benefits for patients with renal cell carcinoma: Two randomized trials demonstrated that radical nephrectomy improves survival in patients treated initially with interferon for metastatic disease [1,2]. Survival of patients with stage III ovarian cancer is improved by maximal tumor debulking, leaving only small-diameter tumor nodules for chemotherapy [3]. Roughly 70% of patients who present with stage IV colorectal cancer undergo primary tumor resection; this is not based on randomized trials or other observational evidence but nonetheless is common clinical practice. Although metastasectomy for cure in colorectal cancer is
a possibility, the large majority of these primary tumor resections are not undertaken in conjunction with the resection of metastases. A small number of these colectomies are for management of ongoing symptoms, primarily bleeding or obstruction, but the vast majority are simply done without a clear indication [4]. A comprehensive review of primary colectomy in the presence of metastatic disease reminds us that these operations are not without a cost [5]. For example, the postoperative mortality in this setting was approximately 10%. And although a number of small single-institution studies suggested a survival benefit, on the whole, there did not appear to be a clear benefit that resulted from these surgeries. Most surgeons justify this procedure as prophylactic against the future development of significant gastrointestinal bleeding or obstruction; however, if one follows cohorts of patients that do not undergo resection, the actual incidence of these complications tends to be approximately 10%, suggesting that the procedure could be avoided and the surgery withheld unless and until the complication actually occurs. A recent study suggests that routine colectomy in patients with stage IV colon cancer is, in fact, rarely necessary [6]. We are in an era when systemic therapy for metastatic disease, for colorectal cancer as well as a number of other common epithelial cancers (eg, breast, ovarian, prostate, lung), has begun to improve in a substantial way. Thus, patients with metastatic disease have the opportunity to extend their lives with systemic therapy, which, in most circumstances, will also affect the primary tumor. In light
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2015.05.023, http://dx.doi.org/10.1016/j.eururo.2015.04.036. * Corresponding author. Division of Oncology, Columbia University Medical Center, 722 West 168th Street, Room 725, New York, NY 10032, USA. Tel. +1 212 305 9414. E-mail address: [email protected] (A.I. Neugut). http://dx.doi.org/10.1016/j.eururo.2015.06.004 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Neugut AI, Gelmann EP. Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.004
EURURO-6251; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
of this, when is resection of the primary tumor a real consideration? When the primary tumor does indeed cause significant symptoms, and surgery can palliate those symptoms. When, as in colorectal cancer, long-term survival or potential cures can be achieved in combination with metastasectomy. When debulking or removal of the tumor in conjunction with systemic therapy has been shown to improve outcomes by improving access of therapy to target cells, as in ovarian cancer. When removing the primary tumor improves antitumor immunity, as may be the case for renal cell carcinoma.
In light of these exploratory reports and the known complexity of prostate cancer genetics, by the time bone metastases are present, the weight of the evidence at present militates against prostatectomy in those with stage D2 disease, especially in the face of the perturbations it is likely to cause in terms of quality of life in a significant proportion of patients. We believe that there is a steep experiential and theoretical hill to climb to justify radical prostatectomy for men with stage D2 disease. Conflicts of interest: Dr. Neugut has served as a consultant for Pfizer, Teva, Otsuka, United Biosource Corporation, and EHE International. Dr. Gelmann has served as a consultant for Dendreon and Pfizer. Funding support: Dr. Neugut is funded in part by a grant from the Department of Defense Prostate Cancer Research Program (PC094372).
The urologic community is now actively discussing the possible benefits of radical prostatectomy for patients who present with metastatic disease. In this issue of European Urology, Sooriakumaran et al demonstrated that this procedure can be done without morbidity in excess of that experienced by patients with localized prostate cancer [7]. In a comprehensive and thoughtful review, also in this issue, Bayne et al identified many reports suggesting the possible benefits of prostatectomy for prostate cancer patients who present with stage IV disease [8]. Three ongoing trials that randomized patients with metastatic prostate cancer to systemic therapy with or without external beam irradiation may demonstrate a long-term benefit of local therapy for patients with metastatic disease. If the urologic community seeks to replicate the design of these studies to include prostatectomy with systemic treatment of metastatic disease, there are important considerations to be addressed. First, comprehensive genomic studies of metastatic prostate cancer have shown a dynamic relationship between metastases and the primary tumor site. It is clear now that some metastases can give rise to secondary metastases [9]. Consequently, the hypothesis underlying the prostatectomy study must address the malignant independence of metastatic lesions. Second, in men who require androgen ablative therapy, with its well-known and universal morbidity, radical prostatectomy will add additional long-term morbidity. To accrue patients rapidly, a randomized trial is likely to allow a broad range of surgical approaches, including both open and minimally invasive surgery. However, these procedures are not equivalent in their risks of long-term effects, particularly incontinence [10]. A randomized trial should include longterm quality-of-life measurements to ensure that patients with known incurable cancer obtain not only the longest survival but also the optimal therapy for quality of life. Last, the urologic literature reports many attempts to demonstrate that extended pelvic and even abdominal nodal dissection will improve disease-free recurrence rates in prostate cancer that appears localized or that is even known to include nodal metastases [11–13]. However, in these nonrandomized studies, recurrence rates were predictably high, and there was no real indication that surgery alone benefited men with nodal metastatic disease.
References [1] Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966–70. [2] Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655–9. [3] Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009;114:26–31. [4] Temple LK, Hsieh L, Wong WD, Saltz L, Schrag D. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol 2004;22:3475–84. [5] Eisenberger A, Whelan RL, Neugut AI. Survival and symptomatic benefit from palliative primary tumor resection in patients with metastatic colorectal cancer: a review. Int J Colorectal Dis 2008; 23:559–68. [6] McCahill LE, Yothers G, Sharif S, et al. Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol 2012;30:3223–8. [7] Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.05.023 [8] Bayne CE, Williams SB, Cooperberg MR, et al. Treatment of the primary tumor in metastatic prostate cancer: current concepts and future perspectives. Eur Urol. In press. http://dx.doi.org/10.1016/ j.eururo.2015.04.036 [9] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353–7. [10] Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA 2009;302:1557–64. [11] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169:849–54. [12] Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167:1681–6. [13] Sgrignoli AR, Walsh PC, Steinberg GD, Steiner MS, Epstein JI. Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy. J Urol 1994;152:1077–81.
Please cite this article in press as: Neugut AI, Gelmann EP. Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.004
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority–Editorial Referring to the articles published on pp. XX–YY and on pp. AA–BB of this issue
Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors Alfred I. Neugut *, Edward P. Gelmann Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Any intelligent oncologist will readily admit that the mainstay of curative treatment for virtually all of the solid tumors when they are not metastatic is surgery. With a few exceptions, the medical and radiation oncologists generally provide adjunctive treatments to improve the local control or cure rates—not unimportant functions but still not central roles in the cure of the cancer patient. In contrast, when patients present with metastatic disease or when recurrence occurs and cure is no longer possible, the surgeons pass the patient along to the medical and radiation oncologists and have limited roles in disease management thereafter. Except in a few solid tumors for which randomized trials have demonstrated survival benefits for surgery despite presentation with metastatic disease, we intuitively do not expect long-term benefit from surgical management of the primary tumor when metastases are already present. There are a few noteworthy exceptions. Surgical removal of the primary lesion despite the presence of metastatic disease has long-term benefits for patients with renal cell carcinoma: Two randomized trials demonstrated that radical nephrectomy improves survival in patients treated initially with interferon for metastatic disease [1,2]. Survival of patients with stage III ovarian cancer is improved by maximal tumor debulking, leaving only small-diameter tumor nodules for chemotherapy [3]. Roughly 70% of patients who present with stage IV colorectal cancer undergo primary tumor resection; this is not based on randomized trials or other observational evidence but nonetheless is common clinical practice. Although metastasectomy for cure in colorectal cancer is
a possibility, the large majority of these primary tumor resections are not undertaken in conjunction with the resection of metastases. A small number of these colectomies are for management of ongoing symptoms, primarily bleeding or obstruction, but the vast majority are simply done without a clear indication [4]. A comprehensive review of primary colectomy in the presence of metastatic disease reminds us that these operations are not without a cost [5]. For example, the postoperative mortality in this setting was approximately 10%. And although a number of small single-institution studies suggested a survival benefit, on the whole, there did not appear to be a clear benefit that resulted from these surgeries. Most surgeons justify this procedure as prophylactic against the future development of significant gastrointestinal bleeding or obstruction; however, if one follows cohorts of patients that do not undergo resection, the actual incidence of these complications tends to be approximately 10%, suggesting that the procedure could be avoided and the surgery withheld unless and until the complication actually occurs. A recent study suggests that routine colectomy in patients with stage IV colon cancer is, in fact, rarely necessary [6]. We are in an era when systemic therapy for metastatic disease, for colorectal cancer as well as a number of other common epithelial cancers (eg, breast, ovarian, prostate, lung), has begun to improve in a substantial way. Thus, patients with metastatic disease have the opportunity to extend their lives with systemic therapy, which, in most circumstances, will also affect the primary tumor. In light
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2015.05.023, http://dx.doi.org/10.1016/j.eururo.2015.04.036. * Corresponding author. Division of Oncology, Columbia University Medical Center, 722 West 168th Street, Room 725, New York, NY 10032, USA. Tel. +1 212 305 9414. E-mail address: [email protected] (A.I. Neugut). http://dx.doi.org/10.1016/j.eururo.2015.06.004 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Neugut AI, Gelmann EP. Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.004
EURURO-6251; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
of this, when is resection of the primary tumor a real consideration? When the primary tumor does indeed cause significant symptoms, and surgery can palliate those symptoms. When, as in colorectal cancer, long-term survival or potential cures can be achieved in combination with metastasectomy. When debulking or removal of the tumor in conjunction with systemic therapy has been shown to improve outcomes by improving access of therapy to target cells, as in ovarian cancer. When removing the primary tumor improves antitumor immunity, as may be the case for renal cell carcinoma.
In light of these exploratory reports and the known complexity of prostate cancer genetics, by the time bone metastases are present, the weight of the evidence at present militates against prostatectomy in those with stage D2 disease, especially in the face of the perturbations it is likely to cause in terms of quality of life in a significant proportion of patients. We believe that there is a steep experiential and theoretical hill to climb to justify radical prostatectomy for men with stage D2 disease. Conflicts of interest: Dr. Neugut has served as a consultant for Pfizer, Teva, Otsuka, United Biosource Corporation, and EHE International. Dr. Gelmann has served as a consultant for Dendreon and Pfizer. Funding support: Dr. Neugut is funded in part by a grant from the Department of Defense Prostate Cancer Research Program (PC094372).
The urologic community is now actively discussing the possible benefits of radical prostatectomy for patients who present with metastatic disease. In this issue of European Urology, Sooriakumaran et al demonstrated that this procedure can be done without morbidity in excess of that experienced by patients with localized prostate cancer [7]. In a comprehensive and thoughtful review, also in this issue, Bayne et al identified many reports suggesting the possible benefits of prostatectomy for prostate cancer patients who present with stage IV disease [8]. Three ongoing trials that randomized patients with metastatic prostate cancer to systemic therapy with or without external beam irradiation may demonstrate a long-term benefit of local therapy for patients with metastatic disease. If the urologic community seeks to replicate the design of these studies to include prostatectomy with systemic treatment of metastatic disease, there are important considerations to be addressed. First, comprehensive genomic studies of metastatic prostate cancer have shown a dynamic relationship between metastases and the primary tumor site. It is clear now that some metastases can give rise to secondary metastases [9]. Consequently, the hypothesis underlying the prostatectomy study must address the malignant independence of metastatic lesions. Second, in men who require androgen ablative therapy, with its well-known and universal morbidity, radical prostatectomy will add additional long-term morbidity. To accrue patients rapidly, a randomized trial is likely to allow a broad range of surgical approaches, including both open and minimally invasive surgery. However, these procedures are not equivalent in their risks of long-term effects, particularly incontinence [10]. A randomized trial should include longterm quality-of-life measurements to ensure that patients with known incurable cancer obtain not only the longest survival but also the optimal therapy for quality of life. Last, the urologic literature reports many attempts to demonstrate that extended pelvic and even abdominal nodal dissection will improve disease-free recurrence rates in prostate cancer that appears localized or that is even known to include nodal metastases [11–13]. However, in these nonrandomized studies, recurrence rates were predictably high, and there was no real indication that surgery alone benefited men with nodal metastatic disease.
References [1] Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966–70. [2] Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655–9. [3] Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009;114:26–31. [4] Temple LK, Hsieh L, Wong WD, Saltz L, Schrag D. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol 2004;22:3475–84. [5] Eisenberger A, Whelan RL, Neugut AI. Survival and symptomatic benefit from palliative primary tumor resection in patients with metastatic colorectal cancer: a review. Int J Colorectal Dis 2008; 23:559–68. [6] McCahill LE, Yothers G, Sharif S, et al. Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol 2012;30:3223–8. [7] Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.05.023 [8] Bayne CE, Williams SB, Cooperberg MR, et al. Treatment of the primary tumor in metastatic prostate cancer: current concepts and future perspectives. Eur Urol. In press. http://dx.doi.org/10.1016/ j.eururo.2015.04.036 [9] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353–7. [10] Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA 2009;302:1557–64. [11] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169:849–54. [12] Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167:1681–6. [13] Sgrignoli AR, Walsh PC, Steinberg GD, Steiner MS, Epstein JI. Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy. J Urol 1994;152:1077–81.
Please cite this article in press as: Neugut AI, Gelmann EP. Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.004