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A prospective study of plasma selenium levels and prostate cancer risk
496
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
肁8 was 100% for combined therapy and 54% for RT alone (p ⫽ 0.04). On multivariable analysis, only SV involvement (p ⫽ 0.0145) and the addition of short-course TAS to postoperative RT (p ⫽ 0.0019) were significant covariates predicting for bNED and, similarly, approached significance for overall survival (p ⫽ 0.0594 and p ⫽ 0.0856, respectively). Conclusions: Radiotherapy combined with a short-course TAS after radical prostatectomy appears to confer a PSA relapse-free survival advantage and possibly an overall survival advantage when compared with RT alone. The hypothesis that a transient course of androgen suppression with salvage or adjuvant RT after prostatectomy improves outcomes will need to be tested in a randomized trial.
Commentary Randomized studies have supported the concept of neoadjuvant and adjuvant androgen deprivation therapy with radiation treatment for locally advanced carcinoma of the prostate. Whether the advantage is primarily from the debulking effect of androgen deprivation or some potentiation of the radiation itself is uncertain. Whether this same concept can be extrapolated to microscopic disease, such as the patient with a detectable PSA after radical prostatectomy, is a matter of considerable debate. In this circumstance, debulking would presumably not be pertinent. This comparative series does not seem to answer the question. Although patients treated with androgen deprivation had a better outcome than those treated with radiation alone, the treatment groups were not contemporaneous. Even more important, they were strongly imbalanced in terms of tumor burden. The median PSA in the radiation-only group was 1.55 ng/mL compared to only 0.3 ng/mL in those receiving adjuvant hormonal therapy. The PSA ranged as high as 72.0 ng/mL in some of the radiation-only patients. Multiple studies have shown that pretreatment PSA strongly predicts the likelihood of disease-free survival in this setting and that patients with a PSA of ⬍1.0 ng/mL fare better than those with higher values. doi:10.1016/j.urolonc.2004.08.010 Joseph A. Smith, Jr., M.D. Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Hagan M, Zlotecki R, Medina C, Tercilla O, Rivera I, Wajsman Z, Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA. Int J Radiant Oncol Biol Phys 2004;59:329 – 40 Purpose: We compared the long-term results of postprostatectomy radiotherapy (RT) from two institutions, one adapting a prospective policy of adjuvant RT and the other salvage RT. Methods and Materials: Between 1989 and 1997, 69 patients were referred for adjuvant RT to the institution using adjuvant RT and 88 patients with evidence of recurrence were treated in the institution using salvage RT. The salvage group underwent RT after longer postoperative intervals (median, 40.3 vs. 2.9 months; p ⬍ 0.0001) and had higher prostate-specific antigen (PSA) values before starting RT (4.5 vs. 0.86 ng/mL; p ⫽ 0.003). Both groups were routinely treated to a minimal total dose of 60 Gy. The treatment groups were analyzed for overall survival, disease-specific survival, distant metastasis-free survival, and biochemical recurrence-free survival (BRFS) using Cox proportional hazards modeling. Results: Of the 69 patients referred for adjuvant RT, 22 (32%) had nonzero PSA values before RT. Multivariable modeling of BRFS found only the PSA value before RT to be statistically significant (p ⬍ 0.0001). RT after prostatectomy was equally effective in either setting when the pre-RT PSA level was ⬍1 ng/mL. When the PSA value before RT was 肁1 ng/mL, the 5-year BRFS for each group was inferior. Conclusion: Although the adjuvant treatment policy was associated with significantly improved BRFS, this was attributable to low pre-RT PSA values. When the treatment groups were stratified for pre-RT PSA level, the differences in BRFS were not statistically significant. Patients with a rising PSA level after prostatectomy, regardless of their initial risk, should receive prompt referral for RT.
Commentary Just as the role of androgen deprivation for radiation after radical prostatectomy is in question, the value of adjuvant treatment versus so-called salvage therapy is a matter of debate. The benefit of starting treatment before the PSA rises above levels of 1.0 ng/mL is widely supported in the literature. Does this mean, though, that starting treatment based solely on poor prognostic features on pathology is better than initiating therapy as soon as the PSA becomes detectable? Most data would suggest that starting treatment as soon as the PSA rises gives an almost comparable result as using it in a purely adjuvant fashion. These authors conclude the same thing. doi:10.1016/j.urolonc.2004.08.011 Joseph A. Smith, Jr., M.D. A prospective study of plasma selenium levels and prostate cancer risk. Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano JM, Ma J, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. J Natl Cancer Inst 2004;96:696 –703 Background: Epidemiologic studies suggest that low selenium levels are associated with an increased incidence of prostate cancer, although results are conflicting. We examined the association between pre-diagnostic plasma selenium levels and risk of prostate cancer in men enrolled in the Physicians’ Health Study.
P.R. Carroll / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
497
Methods: Using plasma samples obtained in 1982 from healthy men enrolled in the study, we conducted a nested case-control study among 586 men diagnosed with prostate cancer during 13 years of follow-up and 577 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of prostate cancer in pre- (before October 1990) and post- (after October 1990) prostate-specific antigen (PSA) screening eras were calculated using multivariable logistic regression. Results: Pre-diagnostic plasma selenium levels were inversely associated with risk of advanced prostate cancer (5th versus 1st quintile OR ⫽ 0.52, 95% CI ⫽ 0.28 to 0.98; P(trend) ⫽ .05), even among men diagnosed after 1990 (5th versus 1st quintile OR ⫽ 0.39, 95% CI ⫽ 0.16 to 0.97). The inverse association with prostate cancer risk was observed only for case subjects with elevated baseline PSA levels (PSA ⬎4 ng/mL, 5th versus 1st quintile OR ⫽ 0.49, 95% CI ⫽ 0.28 to 0.86; P(trend) ⫽ .002). These inverse associations were observed in both pre- and post-PSA eras. Conclusions: The inverse association between baseline plasma selenium levels and risk of advanced prostate cancer, even among men diagnosed during the post-PSA era, suggests that higher levels of selenium may slow prostate cancer tumor progression. Ongoing randomized trials of selenium supplements may help to further evaluate this issue.
Commentary Although the association of plasma selenium levels and prostate cancer has been studied by many, this study is notable in that the inverse association between baseline plasma selenium was observed for those with serum PSA levels ⬎4 ng/mL, suggesting that higher levels of selenium may slow cancer progression. This is of considerable interest to patients and their physicians, as it is well known that dietary modification and the use of specific supplements are common among men with prostate cancer. It should be noted that this study does have limitations: selenium levels were measured only once; men may have been screened for prostate cancer and the PSA cut-point used was set at 4 ng/mL. The selenium and vitamin E cancer prevention trial (SELECT) may more directly address some of the issues raised in this study. Although dietary modification and supplement use is unproven to be efficacious for those with prostate cancer, such modifications may have a beneficial impact on diseases common to these same men, such as cardiovascular disease [1]. doi:10.1016/j.urolonc.2004.09.001 Peter R. Carroll, M.D.
References [1] Moyad MA, Carroll PR. Lifestyle recommendations to prevent prostate cancer, part I: time to redirect our attention? Urol Clin North Am 2004;31:289 –300.
Detection of prostate cancer using serum proteomics pattern in a histologically confirmed population. Li J, White N, Zhang Z, Rosenzweig J, Mangold LA, Partin AW, Chan DW, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD. J Urol 2004;171:1782–7 Purpose: We retrospectively identified a panel of serum proteins that can discriminate between men with prostate cancer (clinically organ confined) and men with benign prostate disease. Materials and Methods: A contemporary set of 345 men who had an archival serum sample available were included in this study. The cancer group consisted of 246 men who underwent radical prostatectomy at the Johns Hopkins Hospital between March 1999 and April 2001. The noncancer group included 99 men with no histological evidence of prostate cancer on biopsy between April 1997 and April 2001 at the same institution. Serum proteomics mass spectra of these patients were generated using ProteinChip arrays and a ProteinChip Biomarker System II surface enhanced laser desorption/ionization time of flight mass spectrometer (Ciphergen Biosystems, Inc., Fremont, CA). The cases and controls were randomly split into training and testing groups by a stratified sampling procedure. A combination of bioinformatics tools including ProPeak (3Z Informatics, Charleston, SC) was used to reveal the optimal panel of biomarkers for maximum separation of the prostate cancer and the benign prostate disease cohorts. Results: A panel of 3 proteins (PC-1, PC-2 and PC-3) was selected using the training data. Performance of each of the protein markers and a linear regression derived composite index (PC-com3) were evaluated on the testing data. The area under the curve for prostate specific antigen (PSA), PC-1, PC-2, PC-3 and PC-com3 was 0.542, 0.585, 0.600, 0.636 and 0.643, respectively. Improvement of PC-com3 compared to PSA is observed at specificity range 30% to 80%. At a selected specificity of 45% the sensitivity of PC-com3 is 76%, significantly better than the PSA sensitivity of 57% (p ⬍ 0.0001). Conclusions: Serum proteomics patterns may potentially aid in the early detection of prostate cancer.
Commentary A more specific serum tumor marker for prostate cancer would have a significant impact on our ability to efficiently detect this disease. Serum PSA lacks sufficient specificity for cancer detection [1]. The authors used the expression patterns of serum proteins (proteomics) in men to differentiate those with and without prostate cancer. The expression patterns of three proteins appeared to have superior specificity
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
肁8 was 100% for combined therapy and 54% for RT alone (p ⫽ 0.04). On multivariable analysis, only SV involvement (p ⫽ 0.0145) and the addition of short-course TAS to postoperative RT (p ⫽ 0.0019) were significant covariates predicting for bNED and, similarly, approached significance for overall survival (p ⫽ 0.0594 and p ⫽ 0.0856, respectively). Conclusions: Radiotherapy combined with a short-course TAS after radical prostatectomy appears to confer a PSA relapse-free survival advantage and possibly an overall survival advantage when compared with RT alone. The hypothesis that a transient course of androgen suppression with salvage or adjuvant RT after prostatectomy improves outcomes will need to be tested in a randomized trial.
Commentary Randomized studies have supported the concept of neoadjuvant and adjuvant androgen deprivation therapy with radiation treatment for locally advanced carcinoma of the prostate. Whether the advantage is primarily from the debulking effect of androgen deprivation or some potentiation of the radiation itself is uncertain. Whether this same concept can be extrapolated to microscopic disease, such as the patient with a detectable PSA after radical prostatectomy, is a matter of considerable debate. In this circumstance, debulking would presumably not be pertinent. This comparative series does not seem to answer the question. Although patients treated with androgen deprivation had a better outcome than those treated with radiation alone, the treatment groups were not contemporaneous. Even more important, they were strongly imbalanced in terms of tumor burden. The median PSA in the radiation-only group was 1.55 ng/mL compared to only 0.3 ng/mL in those receiving adjuvant hormonal therapy. The PSA ranged as high as 72.0 ng/mL in some of the radiation-only patients. Multiple studies have shown that pretreatment PSA strongly predicts the likelihood of disease-free survival in this setting and that patients with a PSA of ⬍1.0 ng/mL fare better than those with higher values. doi:10.1016/j.urolonc.2004.08.010 Joseph A. Smith, Jr., M.D. Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Hagan M, Zlotecki R, Medina C, Tercilla O, Rivera I, Wajsman Z, Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA. Int J Radiant Oncol Biol Phys 2004;59:329 – 40 Purpose: We compared the long-term results of postprostatectomy radiotherapy (RT) from two institutions, one adapting a prospective policy of adjuvant RT and the other salvage RT. Methods and Materials: Between 1989 and 1997, 69 patients were referred for adjuvant RT to the institution using adjuvant RT and 88 patients with evidence of recurrence were treated in the institution using salvage RT. The salvage group underwent RT after longer postoperative intervals (median, 40.3 vs. 2.9 months; p ⬍ 0.0001) and had higher prostate-specific antigen (PSA) values before starting RT (4.5 vs. 0.86 ng/mL; p ⫽ 0.003). Both groups were routinely treated to a minimal total dose of 60 Gy. The treatment groups were analyzed for overall survival, disease-specific survival, distant metastasis-free survival, and biochemical recurrence-free survival (BRFS) using Cox proportional hazards modeling. Results: Of the 69 patients referred for adjuvant RT, 22 (32%) had nonzero PSA values before RT. Multivariable modeling of BRFS found only the PSA value before RT to be statistically significant (p ⬍ 0.0001). RT after prostatectomy was equally effective in either setting when the pre-RT PSA level was ⬍1 ng/mL. When the PSA value before RT was 肁1 ng/mL, the 5-year BRFS for each group was inferior. Conclusion: Although the adjuvant treatment policy was associated with significantly improved BRFS, this was attributable to low pre-RT PSA values. When the treatment groups were stratified for pre-RT PSA level, the differences in BRFS were not statistically significant. Patients with a rising PSA level after prostatectomy, regardless of their initial risk, should receive prompt referral for RT.
Commentary Just as the role of androgen deprivation for radiation after radical prostatectomy is in question, the value of adjuvant treatment versus so-called salvage therapy is a matter of debate. The benefit of starting treatment before the PSA rises above levels of 1.0 ng/mL is widely supported in the literature. Does this mean, though, that starting treatment based solely on poor prognostic features on pathology is better than initiating therapy as soon as the PSA becomes detectable? Most data would suggest that starting treatment as soon as the PSA rises gives an almost comparable result as using it in a purely adjuvant fashion. These authors conclude the same thing. doi:10.1016/j.urolonc.2004.08.011 Joseph A. Smith, Jr., M.D. A prospective study of plasma selenium levels and prostate cancer risk. Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano JM, Ma J, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. J Natl Cancer Inst 2004;96:696 –703 Background: Epidemiologic studies suggest that low selenium levels are associated with an increased incidence of prostate cancer, although results are conflicting. We examined the association between pre-diagnostic plasma selenium levels and risk of prostate cancer in men enrolled in the Physicians’ Health Study.
P.R. Carroll / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
497
Methods: Using plasma samples obtained in 1982 from healthy men enrolled in the study, we conducted a nested case-control study among 586 men diagnosed with prostate cancer during 13 years of follow-up and 577 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of prostate cancer in pre- (before October 1990) and post- (after October 1990) prostate-specific antigen (PSA) screening eras were calculated using multivariable logistic regression. Results: Pre-diagnostic plasma selenium levels were inversely associated with risk of advanced prostate cancer (5th versus 1st quintile OR ⫽ 0.52, 95% CI ⫽ 0.28 to 0.98; P(trend) ⫽ .05), even among men diagnosed after 1990 (5th versus 1st quintile OR ⫽ 0.39, 95% CI ⫽ 0.16 to 0.97). The inverse association with prostate cancer risk was observed only for case subjects with elevated baseline PSA levels (PSA ⬎4 ng/mL, 5th versus 1st quintile OR ⫽ 0.49, 95% CI ⫽ 0.28 to 0.86; P(trend) ⫽ .002). These inverse associations were observed in both pre- and post-PSA eras. Conclusions: The inverse association between baseline plasma selenium levels and risk of advanced prostate cancer, even among men diagnosed during the post-PSA era, suggests that higher levels of selenium may slow prostate cancer tumor progression. Ongoing randomized trials of selenium supplements may help to further evaluate this issue.
Commentary Although the association of plasma selenium levels and prostate cancer has been studied by many, this study is notable in that the inverse association between baseline plasma selenium was observed for those with serum PSA levels ⬎4 ng/mL, suggesting that higher levels of selenium may slow cancer progression. This is of considerable interest to patients and their physicians, as it is well known that dietary modification and the use of specific supplements are common among men with prostate cancer. It should be noted that this study does have limitations: selenium levels were measured only once; men may have been screened for prostate cancer and the PSA cut-point used was set at 4 ng/mL. The selenium and vitamin E cancer prevention trial (SELECT) may more directly address some of the issues raised in this study. Although dietary modification and supplement use is unproven to be efficacious for those with prostate cancer, such modifications may have a beneficial impact on diseases common to these same men, such as cardiovascular disease [1]. doi:10.1016/j.urolonc.2004.09.001 Peter R. Carroll, M.D.
References [1] Moyad MA, Carroll PR. Lifestyle recommendations to prevent prostate cancer, part I: time to redirect our attention? Urol Clin North Am 2004;31:289 –300.
Detection of prostate cancer using serum proteomics pattern in a histologically confirmed population. Li J, White N, Zhang Z, Rosenzweig J, Mangold LA, Partin AW, Chan DW, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD. J Urol 2004;171:1782–7 Purpose: We retrospectively identified a panel of serum proteins that can discriminate between men with prostate cancer (clinically organ confined) and men with benign prostate disease. Materials and Methods: A contemporary set of 345 men who had an archival serum sample available were included in this study. The cancer group consisted of 246 men who underwent radical prostatectomy at the Johns Hopkins Hospital between March 1999 and April 2001. The noncancer group included 99 men with no histological evidence of prostate cancer on biopsy between April 1997 and April 2001 at the same institution. Serum proteomics mass spectra of these patients were generated using ProteinChip arrays and a ProteinChip Biomarker System II surface enhanced laser desorption/ionization time of flight mass spectrometer (Ciphergen Biosystems, Inc., Fremont, CA). The cases and controls were randomly split into training and testing groups by a stratified sampling procedure. A combination of bioinformatics tools including ProPeak (3Z Informatics, Charleston, SC) was used to reveal the optimal panel of biomarkers for maximum separation of the prostate cancer and the benign prostate disease cohorts. Results: A panel of 3 proteins (PC-1, PC-2 and PC-3) was selected using the training data. Performance of each of the protein markers and a linear regression derived composite index (PC-com3) were evaluated on the testing data. The area under the curve for prostate specific antigen (PSA), PC-1, PC-2, PC-3 and PC-com3 was 0.542, 0.585, 0.600, 0.636 and 0.643, respectively. Improvement of PC-com3 compared to PSA is observed at specificity range 30% to 80%. At a selected specificity of 45% the sensitivity of PC-com3 is 76%, significantly better than the PSA sensitivity of 57% (p ⬍ 0.0001). Conclusions: Serum proteomics patterns may potentially aid in the early detection of prostate cancer.
Commentary A more specific serum tumor marker for prostate cancer would have a significant impact on our ability to efficiently detect this disease. Serum PSA lacks sufficient specificity for cancer detection [1]. The authors used the expression patterns of serum proteins (proteomics) in men to differentiate those with and without prostate cancer. The expression patterns of three proteins appeared to have superior specificity