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Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: Characteristics, PSA doubling times, and outcome
Urologic Oncology: Seminars and Original Investigations 25 (2007) 527–533
CLINICAL RESEARCH
Urologic Oncology Survey
Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: Characteristics, PSA doubling times, and outcome. Roemeling S, Roobol MJ, de Vries SH, Wolters T, Gosselaar C, van Leenders GJ, Schröder FH, Department of Urology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Eur Urol 2007;51:1244 –51 Objectives: To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. Patients and Methods: We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. Results: Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 years (25–75p; 66.1–72.8); median PSA 3.6 ng/ml (25–75p; 3.1– 4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 years, 103 men (44.2%) had a PSA doubling time that was negative (i.e., half-life) or longer than 10 years. Men detected at re-screening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 years; the cause-specific survival was 100%. Conclusions: This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men.
Commentary The study by Roemeling and colleagues describes the clinical and pathologic outcome in an important cohort from the ERSPC study. This retrospective report consisted of men who chose active surveillance for newly diagnosed, clinically localized prostate cancer. Similar to other studies [1–3], over 70% of men who began on active surveillance remained without treatment at a median of 3.4 years from diagnosis. What was very striking was the fact that 23% of men had a negative PSADT (i.e., decreasing PSA over time) with follow-up, and an equal proportion had a PSADT of greater than 10 years. Perhaps, most importantly, no men died of prostate cancer during the study period. It should be noted that in the ERSPC there are no clearly defined follow-up protocols with regards to frequency of PSA assessments or repeat prostate biopsies, and it is unclear how many patients underwent repeat biopsies and what the histology revealed. Additionally, the biopsy methods were described as lateral sextant with a seventh lesion-directed biopsy in the case of a hypoechogenic lesion, clearly different from standard practices in the United States [4]. Furthermore, patients in this report were allowed to have a PSA up to 15 and Gleason 7 disease, parameters somewhat different from other published series of active surveillance [1–3]. The practice of active surveillance worldwide has certainly been gaining momentum, as evidenced by multiple published studies, and large, international Phase III clinical trials of active surveillance vs. primary treatment (START and ProtecT trials). The difference between “active surveillance” and “watchful waiting” is more than mere semantics, where active surveillance entails regular and routine diagnostic tests (PSA and biopsy) with intent to cure if the cancer appears to be progressing. The Roemeling et al. study again reveals that active surveillance appears safe with acceptable rates of disease progression and disease-specific survival, further supporting the pursuit of the aforementioned important clinical trials. What is critical for future studies will be the ascertainment and establishment of biomarkers of progression during active surveillance, a goal that will surely involve more than the readily available clinical data and likely involve molecular and genetic signatures of disease. doi:10.1016/j.urolonc.2007.10.010 Daniel Wei Lin, M.D.
References [1] Warlick CA, Allaf ME, Carter HB. Expectant treatment with curative intent in the prostate-specific antigen era: Triggers for definitive therapy. Urol Oncol 2006;24:51–7. [2] Hardie C, Parker C, Norman A, et al. Early outcomes of active surveillance for localized prostate cancer. BJU Int 2005;95:956 – 60. 1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
528
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 25 (2007) 527–533
[3] Klotz L. Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol 2006;24:46 –50. [4] Davis M, Sofer M, Kim SS, et al. The procedure of transrectal ultrasound guided biopsy of the prostate: a survey of patient preparation and biopsy technique. J Urol 2002;167(2 Pt 1):566 –70.
EPCA-2: A highly specific serum marker for prostate cancer. Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, Partin AW, Getzenberg RH, Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD. Urology 2007;69:714 –20 Objectives: To describe the initial assessment of early prostate cancer antigen (EPCA)-2 as a serum marker for the detection of prostate cancer and to examine its sensitivity and specificity. Methods: Serum samples were obtained from 385 men: those with prostate-specific antigen (PSA) levels less than 2.5 ng/ml, PSA levels of 2.5 ng/ml or greater with negative biopsy findings, benign prostatic hyperplasia, organ-confined prostate cancer, nonorgan-confined disease, and prostate cancer with PSA levels less than 2.5 ng/ml. In addition, a diverse group of controls was assessed with an enzyme-linked immunosorbent assay to detect an epitope of the EPCA-2 protein, EPCA-2.22. Results: Using a cutoff of 30 ng/ml, the EPCA-2.22 assay had a 92% specificity (95% confidence interval 85% to 96%) for healthy men and men with benign prostatic hyperplasia and 94% sensitivity (95% confidence interval [CI] 93% to 99%) for overall prostate cancer. The specificity for PSA in these selected groups of patients was 65% (95% CI 55% to 75%). Additionally, EPCA-2.22 was highly accurate in differentiating between localized and extracapsular disease (area under the curve 0.89, 95% CI 0.82 to 0.97, P ⬍ 0.0001) in contrast to PSA (area under the curve 0.62, 95% CI 0.50 to 0.75, P ⫽ 0.05). Conclusions: The results of our study have shown that EPCA-2 is a novel biomarker associated with prostate cancer that has high sensitivity and specificity and accurately differentiates between men with organ-confined and non-organ-confined disease.
Commentary In the past 25 years, the early detection of prostate cancer has changed dramatically, clearly attributable to the discovery and application of PSA. Efforts to improve the performance of this analyte, including free-to-total PSA ratio, PSA density, associated serine proteases (e.g., hK2), and PSA kinetics (PSA velocity and PSA doubling time) remain the focal point of continued studies. Additionally, new advances in molecular profiling have yielded novel markers, such as EPCA-2, examined in the present study by Leman et al. In this study, the authors examined the performance of EPCA-2 in patients with and without PSA and across a wide range of PSA values. Appropriate control samples were abundant, and in this study, EPCA-2 certainly outperformed PSA not only in discriminating normal controls/BPH vs. prostate cancer, but also in stratifying organ-confined vs. extracapsular disease. While this initial report appears extremely promising, the authors appropriately point out that the patient samples in their study were selected from individuals in whom PSA was and was not a good indicator and thus may not reflect the performance of EPCA-2 in a true screening population. If the superior sensitivity and particularly high specificity are confirmed by well-designed screening studies, there would be little argument that EPCA-2 would replace PSA for early detection. However, perhaps the more important biomarkers for development would ascertain which cancers will progress and necessitate early, or perhaps more aggressive, treatment, even among the organ-confined cancers. The early lessons in the active surveillance cohorts suggest that approximately 30% of seemingly “low-risk” disease progresses over time, and biomarkers to aid in identifying these cancers are desperately needed. doi:10.1016/j.urolonc.2007.10.011 Daniel Wei Lin, M.D. Adjuvant weekly docetaxel for patients with high risk prostate cancer after radical prostatectomy: A multi-institutional pilot study. Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA, Chatta GS, Nelson JB, DiPaola RS, Roth BJ, Cookson MS, Wilding G, Jarrard DF, Beer TM, Ryan CW, Petrylak DP, Benson MC, Partin AW, Garrett-Mayer E, Eisenberger MA, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO. J Urol 2007;177:1777– 81 Purpose: Patients with adverse pathological features are at high risk for recurrence following radical prostatectomy. To improve outcomes in this population we performed a Phase II study of adjuvant docetaxel in these high risk patients. Materials and Methods: Patients with nonmetastatic radical prostatectomy at greater than 50% risk for recurrence by 3 years were eligible. Pathological findings were centrally reviewed and risk assessment was based on a validated multivariate Cox proportional hazards model. Treatment consisted of 6 cycles of 35 mg/m [2] docetaxel weekly given 4 to 12 weeks following surgery. Progression was defined as a prostate specific antigen of 0.4 ng/ml or greater, radiological/pathological evidence of recurrent disease or death from any cause. To screen for the potential benefit of adjuvant weekly docetaxel we used nomogram predicted progression-free survival as a historical control. Results: A total of 77 patients were registered between April 2002 and January 2004. Two patients had Grade IV hyperglycemia and 20 had Grade III toxicity. At a median follow-up of 29.2 months (range 1.6 to 39.2) 46 of 76 evaluable cases (60.5%) progressed. Observed median progression-free survival was 15.7 months (95% CI 12.8 –25.1). Predicted median progression-free survival in a matched population was 10 months. Seven patients died, including 4 of prostate cancer, 1 with intra-abdominal bleeding during treatment, and 2 of pneumonia and sudden cardiac death, respectively, following treatment. Conclusions: Adjuvant docetaxel for prostate cancer is feasible with significant reversible but acceptable toxicity. The actual median
CLINICAL RESEARCH
Urologic Oncology Survey
Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: Characteristics, PSA doubling times, and outcome. Roemeling S, Roobol MJ, de Vries SH, Wolters T, Gosselaar C, van Leenders GJ, Schröder FH, Department of Urology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Eur Urol 2007;51:1244 –51 Objectives: To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. Patients and Methods: We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. Results: Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 years (25–75p; 66.1–72.8); median PSA 3.6 ng/ml (25–75p; 3.1– 4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 years, 103 men (44.2%) had a PSA doubling time that was negative (i.e., half-life) or longer than 10 years. Men detected at re-screening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 years; the cause-specific survival was 100%. Conclusions: This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men.
Commentary The study by Roemeling and colleagues describes the clinical and pathologic outcome in an important cohort from the ERSPC study. This retrospective report consisted of men who chose active surveillance for newly diagnosed, clinically localized prostate cancer. Similar to other studies [1–3], over 70% of men who began on active surveillance remained without treatment at a median of 3.4 years from diagnosis. What was very striking was the fact that 23% of men had a negative PSADT (i.e., decreasing PSA over time) with follow-up, and an equal proportion had a PSADT of greater than 10 years. Perhaps, most importantly, no men died of prostate cancer during the study period. It should be noted that in the ERSPC there are no clearly defined follow-up protocols with regards to frequency of PSA assessments or repeat prostate biopsies, and it is unclear how many patients underwent repeat biopsies and what the histology revealed. Additionally, the biopsy methods were described as lateral sextant with a seventh lesion-directed biopsy in the case of a hypoechogenic lesion, clearly different from standard practices in the United States [4]. Furthermore, patients in this report were allowed to have a PSA up to 15 and Gleason 7 disease, parameters somewhat different from other published series of active surveillance [1–3]. The practice of active surveillance worldwide has certainly been gaining momentum, as evidenced by multiple published studies, and large, international Phase III clinical trials of active surveillance vs. primary treatment (START and ProtecT trials). The difference between “active surveillance” and “watchful waiting” is more than mere semantics, where active surveillance entails regular and routine diagnostic tests (PSA and biopsy) with intent to cure if the cancer appears to be progressing. The Roemeling et al. study again reveals that active surveillance appears safe with acceptable rates of disease progression and disease-specific survival, further supporting the pursuit of the aforementioned important clinical trials. What is critical for future studies will be the ascertainment and establishment of biomarkers of progression during active surveillance, a goal that will surely involve more than the readily available clinical data and likely involve molecular and genetic signatures of disease. doi:10.1016/j.urolonc.2007.10.010 Daniel Wei Lin, M.D.
References [1] Warlick CA, Allaf ME, Carter HB. Expectant treatment with curative intent in the prostate-specific antigen era: Triggers for definitive therapy. Urol Oncol 2006;24:51–7. [2] Hardie C, Parker C, Norman A, et al. Early outcomes of active surveillance for localized prostate cancer. BJU Int 2005;95:956 – 60. 1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
528
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 25 (2007) 527–533
[3] Klotz L. Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol 2006;24:46 –50. [4] Davis M, Sofer M, Kim SS, et al. The procedure of transrectal ultrasound guided biopsy of the prostate: a survey of patient preparation and biopsy technique. J Urol 2002;167(2 Pt 1):566 –70.
EPCA-2: A highly specific serum marker for prostate cancer. Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, Partin AW, Getzenberg RH, Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD. Urology 2007;69:714 –20 Objectives: To describe the initial assessment of early prostate cancer antigen (EPCA)-2 as a serum marker for the detection of prostate cancer and to examine its sensitivity and specificity. Methods: Serum samples were obtained from 385 men: those with prostate-specific antigen (PSA) levels less than 2.5 ng/ml, PSA levels of 2.5 ng/ml or greater with negative biopsy findings, benign prostatic hyperplasia, organ-confined prostate cancer, nonorgan-confined disease, and prostate cancer with PSA levels less than 2.5 ng/ml. In addition, a diverse group of controls was assessed with an enzyme-linked immunosorbent assay to detect an epitope of the EPCA-2 protein, EPCA-2.22. Results: Using a cutoff of 30 ng/ml, the EPCA-2.22 assay had a 92% specificity (95% confidence interval 85% to 96%) for healthy men and men with benign prostatic hyperplasia and 94% sensitivity (95% confidence interval [CI] 93% to 99%) for overall prostate cancer. The specificity for PSA in these selected groups of patients was 65% (95% CI 55% to 75%). Additionally, EPCA-2.22 was highly accurate in differentiating between localized and extracapsular disease (area under the curve 0.89, 95% CI 0.82 to 0.97, P ⬍ 0.0001) in contrast to PSA (area under the curve 0.62, 95% CI 0.50 to 0.75, P ⫽ 0.05). Conclusions: The results of our study have shown that EPCA-2 is a novel biomarker associated with prostate cancer that has high sensitivity and specificity and accurately differentiates between men with organ-confined and non-organ-confined disease.
Commentary In the past 25 years, the early detection of prostate cancer has changed dramatically, clearly attributable to the discovery and application of PSA. Efforts to improve the performance of this analyte, including free-to-total PSA ratio, PSA density, associated serine proteases (e.g., hK2), and PSA kinetics (PSA velocity and PSA doubling time) remain the focal point of continued studies. Additionally, new advances in molecular profiling have yielded novel markers, such as EPCA-2, examined in the present study by Leman et al. In this study, the authors examined the performance of EPCA-2 in patients with and without PSA and across a wide range of PSA values. Appropriate control samples were abundant, and in this study, EPCA-2 certainly outperformed PSA not only in discriminating normal controls/BPH vs. prostate cancer, but also in stratifying organ-confined vs. extracapsular disease. While this initial report appears extremely promising, the authors appropriately point out that the patient samples in their study were selected from individuals in whom PSA was and was not a good indicator and thus may not reflect the performance of EPCA-2 in a true screening population. If the superior sensitivity and particularly high specificity are confirmed by well-designed screening studies, there would be little argument that EPCA-2 would replace PSA for early detection. However, perhaps the more important biomarkers for development would ascertain which cancers will progress and necessitate early, or perhaps more aggressive, treatment, even among the organ-confined cancers. The early lessons in the active surveillance cohorts suggest that approximately 30% of seemingly “low-risk” disease progresses over time, and biomarkers to aid in identifying these cancers are desperately needed. doi:10.1016/j.urolonc.2007.10.011 Daniel Wei Lin, M.D. Adjuvant weekly docetaxel for patients with high risk prostate cancer after radical prostatectomy: A multi-institutional pilot study. Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA, Chatta GS, Nelson JB, DiPaola RS, Roth BJ, Cookson MS, Wilding G, Jarrard DF, Beer TM, Ryan CW, Petrylak DP, Benson MC, Partin AW, Garrett-Mayer E, Eisenberger MA, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO. J Urol 2007;177:1777– 81 Purpose: Patients with adverse pathological features are at high risk for recurrence following radical prostatectomy. To improve outcomes in this population we performed a Phase II study of adjuvant docetaxel in these high risk patients. Materials and Methods: Patients with nonmetastatic radical prostatectomy at greater than 50% risk for recurrence by 3 years were eligible. Pathological findings were centrally reviewed and risk assessment was based on a validated multivariate Cox proportional hazards model. Treatment consisted of 6 cycles of 35 mg/m [2] docetaxel weekly given 4 to 12 weeks following surgery. Progression was defined as a prostate specific antigen of 0.4 ng/ml or greater, radiological/pathological evidence of recurrent disease or death from any cause. To screen for the potential benefit of adjuvant weekly docetaxel we used nomogram predicted progression-free survival as a historical control. Results: A total of 77 patients were registered between April 2002 and January 2004. Two patients had Grade IV hyperglycemia and 20 had Grade III toxicity. At a median follow-up of 29.2 months (range 1.6 to 39.2) 46 of 76 evaluable cases (60.5%) progressed. Observed median progression-free survival was 15.7 months (95% CI 12.8 –25.1). Predicted median progression-free survival in a matched population was 10 months. Seven patients died, including 4 of prostate cancer, 1 with intra-abdominal bleeding during treatment, and 2 of pneumonia and sudden cardiac death, respectively, following treatment. Conclusions: Adjuvant docetaxel for prostate cancer is feasible with significant reversible but acceptable toxicity. The actual median