- Email: [email protected]
Re: Radical Prostatectomy versus Watchful Waiting in Localized Prostate Cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial
european urology 55 (2009) 989–994
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom
Re: Radical Prostatectomy versus Watchful Waiting in Localized Prostate Cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial Bill-Axelson A, Holmberg L, Filen F, et al J Natl Cancer Inst 2008;100:1144–54 Expert’s summary: The Scandinavian Prostate Cancer Group Study 4 (SPCG-4) recently reported follow-up data concerning the 695 men randomized to prostatectomy versus observation between October 1, 1989, and February 28, 1999. Since randomization, 137 men in the surgery group and 156 in the watchful waiting group have died ( p = 0.09). At 12 yr, 12.5% of the surgery group and 17.9% of the watchful waiting group have died of prostate cancer ( p = 0.03), and 19.3% of the surgery group and 26% of the watchful waiting group have distant metastases ( p = 0.006). Surprisingly, neither prostate-specific antigen (PSA) nor Gleason score modified the effect of radical prostatectomy ( p > 0.20). Furthermore, none of the men age 65 appeared to benefit from intervention. Men with Gleason score 8–10 disease had an exceptionally poor outcome. More than 30% were dead of prostate cancer within 12 yr of diagnosis, compared with none of the men harboring Gleason 6 disease. Finally, the rate of recurrence in each of these groups has been relatively similar after a lead time of about 6 yr in favor of surgery. Expert’s comments: The SPCG-4 study data provide important insights concerning screening and treatment. First, the data support the US Preventive Task Force recommendation against prostate cancer screening after age 75 and question the efficacy of screening patients after age 65 [1]. As a consequence of repeated testing for PSA, men with newly diagnosed prostate cancer, 0302-2838/$ – see back matter
especially those in North America, are much more likely to present with low-volume, low-grade disease. When the impact of lead times associated with PSA screening is factored in, the SPCG-4 data suggest that few men of age >65 will benefit from intervention within 20 yr of diagnosis [2]. The failure to demonstrate a difference in overall survival after 12 yr raises concerns surrounding treatment efficacy. A statistically significant decrease in prostate cancer mortality was associated with surgery, but the absolute difference between the two groups was modest. No data suggest that radiation, cryosurgery, or thermotherapy is superior to surgery. In fact, these therapies may be even less effective. The absence of disease recurrence following intervention is not sufficient to demonstrate treatment efficacy in contemporary practice. There is no substitute for data derived from welldesigned, randomized trials. Groups such as the Scandinavian Prostate Cancer Study Group, the European Randomized Study of Screening for Prostate Cancer (ERSPC), and, most recently, the Prostate Testing for Cancer and Treatment (ProtecT) should be congratulated for their extraordinary efforts to bring science to the art of prostate cancer management [3,4]. Conflicts of interest: The author has nothing to disclose.
References [1] US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185–91. [2] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 2003;95:868–78.
990
european urology 55 (2009) 989–994
[3] Roobol MJ, Schro¨der FH, eds. European Randomized Study of Screening for Prostate Cancer (ERSPC): rationale, structure and preliminary results. BJU Int 2003;92(Suppl 2). [4] Donovan J, Mills N, Smith M, et al. Improving design and conduct of randomized trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study. BMJ 2002;325:766–70.
Re: Surgical Morbidity Associated with Administration of Targeted Molecular Therapies before Cytoreductive Nephrectomy or Resection of Locally Recurrent Renal Cell Carcinoma Margulis V, Matin SF, Tannir N, et al J Urol 2008;180:94–8 Experts’ summary: While there is a growing body of evidence from the general surgery literature demonstrating the safety of targeted molecular therapy (TMT) prior to colorectal cancer surgery, the authors from the MD Anderson Cancer Center are the first to report on the use of these agents prior to surgical therapy for renal cell carcinoma (RCC). The surgical parameters and perioperative complications among a group of 44 patients who underwent cytoreductive nephrectomy or resection of retroperitoneal RCC recurrence following preoperative TMT were compared with those of a contemporary cohort of 58 patients who were managed with immediate surgery. The targeted agents administered preoperatively included bevacizumab, sorafenib, and sunitinib in 17, 12, and 15 patients, respectively. Although a greater proportion of patients in the preoperative systemic therapy group had an Eastern Cooperative Oncology Group performance status (ECOG PS) >1, the groups were well matched in terms of clinical and pathologic characteristics. No differences in blood loss, hospital stay, and overall morbidity, including woundrelated complications, were observed between the groups. Experts’ comments: Since the advent of TMT and its rapid acceptance as first-line treatment in patients with metastatic RCC, there has been a great deal of discussion in the literature regarding the role and timing of cytoreductive nephrectomy in the setting of metastatic disease. Recently, Margulis and Wood highlighted the potential advantages and pitfalls of presurgical TMT in this population [1]. They point out that in the Southwest Oncology Group (SWOG)
Peter Albertsen University of Connecticut Health Center, Division of Urology, MC 3955, 263 Farmington Avenue, Farmington, CT 06030-3955, USA E-mail address: [email protected] DOI: 10.1016/j.eururo.2009.01.009
and European Organization for Research and Treatment of Cancer (EORTC) trials comparing cytoreductive nephrectomy and interferon (IFN) versus IFN alone, despite a 6-mo overall survival advantage in the surgery group, a significant number of patients in each arm died shortly after enrollment. Thus, presurgical therapy could selectively target patients who are most likely to derive a benefit from surgery. In addition, while immunotherapy rarely causes a reduction in tumor volume—a feature that limited its use in the neoadjuvant setting—there are reports that targeted molecular agents can result in a significant response in the primary tumor [2,3]. Finally, the oral route of administration and tolerability of these agents makes them attractive for neoadjuvant use. Thus, certain centers have adopted a new paradigm of presurgical targeted therapy, with or without nephrectomy, based on response. While there are theoretical advantages of using presurgical targeted therapy, at this time, there are no objective data available to support this approach. In the trials that led to the approval of these targeted therapies, the majority of patients had undergone prior nephrectomy. Thus, the effectiveness of these agents has largely been demonstrated within the paradigm of upfront cytoreductive nephrectomy. At our institution, we continue to employ cytoreductive nephrectomy in appropriately selected patients with metastatic disease followed by targeted therapy or high-dose interleukin 2 (IL-2) in select cases. Future randomized comparative studies are urgently needed to clarify the exact role and timing of targeted agents in patients with metastatic disease, specifically to answer the following questions: (1) Does cytoreductive nephrectomy have a role in the era of TMT therapy? (2) Does a neoadjuvant approach to the use of TMTs result in improved overall survival compared with an adjuvant approach? (3) Does neoadjuvant TMT therapy really identify those patients most likely to achieve increased survival with cytoreduction and, hence, identify those patients who will not benefit from cytoreduction?
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom
Re: Radical Prostatectomy versus Watchful Waiting in Localized Prostate Cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial Bill-Axelson A, Holmberg L, Filen F, et al J Natl Cancer Inst 2008;100:1144–54 Expert’s summary: The Scandinavian Prostate Cancer Group Study 4 (SPCG-4) recently reported follow-up data concerning the 695 men randomized to prostatectomy versus observation between October 1, 1989, and February 28, 1999. Since randomization, 137 men in the surgery group and 156 in the watchful waiting group have died ( p = 0.09). At 12 yr, 12.5% of the surgery group and 17.9% of the watchful waiting group have died of prostate cancer ( p = 0.03), and 19.3% of the surgery group and 26% of the watchful waiting group have distant metastases ( p = 0.006). Surprisingly, neither prostate-specific antigen (PSA) nor Gleason score modified the effect of radical prostatectomy ( p > 0.20). Furthermore, none of the men age 65 appeared to benefit from intervention. Men with Gleason score 8–10 disease had an exceptionally poor outcome. More than 30% were dead of prostate cancer within 12 yr of diagnosis, compared with none of the men harboring Gleason 6 disease. Finally, the rate of recurrence in each of these groups has been relatively similar after a lead time of about 6 yr in favor of surgery. Expert’s comments: The SPCG-4 study data provide important insights concerning screening and treatment. First, the data support the US Preventive Task Force recommendation against prostate cancer screening after age 75 and question the efficacy of screening patients after age 65 [1]. As a consequence of repeated testing for PSA, men with newly diagnosed prostate cancer, 0302-2838/$ – see back matter
especially those in North America, are much more likely to present with low-volume, low-grade disease. When the impact of lead times associated with PSA screening is factored in, the SPCG-4 data suggest that few men of age >65 will benefit from intervention within 20 yr of diagnosis [2]. The failure to demonstrate a difference in overall survival after 12 yr raises concerns surrounding treatment efficacy. A statistically significant decrease in prostate cancer mortality was associated with surgery, but the absolute difference between the two groups was modest. No data suggest that radiation, cryosurgery, or thermotherapy is superior to surgery. In fact, these therapies may be even less effective. The absence of disease recurrence following intervention is not sufficient to demonstrate treatment efficacy in contemporary practice. There is no substitute for data derived from welldesigned, randomized trials. Groups such as the Scandinavian Prostate Cancer Study Group, the European Randomized Study of Screening for Prostate Cancer (ERSPC), and, most recently, the Prostate Testing for Cancer and Treatment (ProtecT) should be congratulated for their extraordinary efforts to bring science to the art of prostate cancer management [3,4]. Conflicts of interest: The author has nothing to disclose.
References [1] US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185–91. [2] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 2003;95:868–78.
990
european urology 55 (2009) 989–994
[3] Roobol MJ, Schro¨der FH, eds. European Randomized Study of Screening for Prostate Cancer (ERSPC): rationale, structure and preliminary results. BJU Int 2003;92(Suppl 2). [4] Donovan J, Mills N, Smith M, et al. Improving design and conduct of randomized trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study. BMJ 2002;325:766–70.
Re: Surgical Morbidity Associated with Administration of Targeted Molecular Therapies before Cytoreductive Nephrectomy or Resection of Locally Recurrent Renal Cell Carcinoma Margulis V, Matin SF, Tannir N, et al J Urol 2008;180:94–8 Experts’ summary: While there is a growing body of evidence from the general surgery literature demonstrating the safety of targeted molecular therapy (TMT) prior to colorectal cancer surgery, the authors from the MD Anderson Cancer Center are the first to report on the use of these agents prior to surgical therapy for renal cell carcinoma (RCC). The surgical parameters and perioperative complications among a group of 44 patients who underwent cytoreductive nephrectomy or resection of retroperitoneal RCC recurrence following preoperative TMT were compared with those of a contemporary cohort of 58 patients who were managed with immediate surgery. The targeted agents administered preoperatively included bevacizumab, sorafenib, and sunitinib in 17, 12, and 15 patients, respectively. Although a greater proportion of patients in the preoperative systemic therapy group had an Eastern Cooperative Oncology Group performance status (ECOG PS) >1, the groups were well matched in terms of clinical and pathologic characteristics. No differences in blood loss, hospital stay, and overall morbidity, including woundrelated complications, were observed between the groups. Experts’ comments: Since the advent of TMT and its rapid acceptance as first-line treatment in patients with metastatic RCC, there has been a great deal of discussion in the literature regarding the role and timing of cytoreductive nephrectomy in the setting of metastatic disease. Recently, Margulis and Wood highlighted the potential advantages and pitfalls of presurgical TMT in this population [1]. They point out that in the Southwest Oncology Group (SWOG)
Peter Albertsen University of Connecticut Health Center, Division of Urology, MC 3955, 263 Farmington Avenue, Farmington, CT 06030-3955, USA E-mail address: [email protected] DOI: 10.1016/j.eururo.2009.01.009
and European Organization for Research and Treatment of Cancer (EORTC) trials comparing cytoreductive nephrectomy and interferon (IFN) versus IFN alone, despite a 6-mo overall survival advantage in the surgery group, a significant number of patients in each arm died shortly after enrollment. Thus, presurgical therapy could selectively target patients who are most likely to derive a benefit from surgery. In addition, while immunotherapy rarely causes a reduction in tumor volume—a feature that limited its use in the neoadjuvant setting—there are reports that targeted molecular agents can result in a significant response in the primary tumor [2,3]. Finally, the oral route of administration and tolerability of these agents makes them attractive for neoadjuvant use. Thus, certain centers have adopted a new paradigm of presurgical targeted therapy, with or without nephrectomy, based on response. While there are theoretical advantages of using presurgical targeted therapy, at this time, there are no objective data available to support this approach. In the trials that led to the approval of these targeted therapies, the majority of patients had undergone prior nephrectomy. Thus, the effectiveness of these agents has largely been demonstrated within the paradigm of upfront cytoreductive nephrectomy. At our institution, we continue to employ cytoreductive nephrectomy in appropriately selected patients with metastatic disease followed by targeted therapy or high-dose interleukin 2 (IL-2) in select cases. Future randomized comparative studies are urgently needed to clarify the exact role and timing of targeted agents in patients with metastatic disease, specifically to answer the following questions: (1) Does cytoreductive nephrectomy have a role in the era of TMT therapy? (2) Does a neoadjuvant approach to the use of TMTs result in improved overall survival compared with an adjuvant approach? (3) Does neoadjuvant TMT therapy really identify those patients most likely to achieve increased survival with cytoreduction and, hence, identify those patients who will not benefit from cytoreduction?