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Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer
Mark P. Ritter / Urologic Oncology: Seminars and Original Investigations 22 (2004) 378 –385
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I versus 103Pd for low-risk prostate cancer: preliminary PSA outcomes from a prospective randomized multicenter trial. Wallner K, Merrick G, True L, Sutlief S, Cavanagh W, Butler W, Department of Radiation Oncology, Puget Sound Health Care System, Department of Veterans Affairs, Seattle, WA. Int J Radiat Oncol Biol Phys 2003;57:1297–1303 Purpose: To compare prostate cancer control rates in patients who received 125I vs. 103Pd. Materials and Methods: Of a planned total of 600 patients with 1997 American Joint Committee on Cancer clinical Stage T1c-T2a prostate carcinoma (Gleason score 5– 6, prostate-specific antigen [PSA] 4 –10 ng/mL), 126 were randomized to implantation with 125I (144 Gy) vs. 103Pd (125 Gy). The prostate biopsies were reviewed for Gleason score by one of us (L.T.). A single manufacturer of 125I sources (Model 6711, Amersham, Chicago, IL) and 103Pd sources (Theraseed, Theragenics, Buford, GA) was used. Isotope implantation was performed with standard techniques, using a modified peripheral loading pattern. Of a total of 126 patients randomized, 11 were excluded, leaving 115 randomized patients for this analysis. Twenty patients received a short course of preimplant hormonal therapy, none of which continued hormonal therapy after their implant procedure. Postimplant CT was obtained 2 to 4 h after implantation. The dosimetric parameters analyzed included the percentage of the postimplant prostate or rectal volume covered by the prescription dose [V (100)] and the dose that covered 90% of the postimplant prostate volume [D (90)]. Freedom from biochemical failure was defined as a serum PSA level less than or equal to 0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA level was still decreasing. Patients whose serum PSA had reached a nadir at a value ⬎0.5 ng/mL were scored as having failure at the time at which their PSA had reached a nadir. The follow-up period for patients without failure ranged from 2.0 to 4.9 yr (median 2.9). Freedom-from-failure curves were calculated by the Kaplan-Meier method. Differences between groups were determined by the log-rank method. Results: The actuarial biochemical freedom-from-failure rate at 3 yr was 89% for 125I patients vs. 91% for 103Pd patients (P ⫽ 0.76). The 3-yr biochemical freedom-from-failure rate for patients with a D (90) ⬍100% of the prescription dose was 82% vs. 97% for patients with a D (90) ⱖ100% of the prescription dose (P ⫽ 0.01). Similarly, the 3-yr biochemical freedom-from-failure rate for patients with a V (100) ⬍90% of the prescription dose was 87% vs. 97% for patients with a V (100) ⱖ90% of the prescription dose (P ⫽ 0.01). The effect of the dosimetric parameters on biochemical control was most pronounced for 125I, but also apparent for 103Pd. Conclusions: The 3-yr actuarial biochemical control rates for low early stage prostate cancer are similar after 125I and 103Pd.
Commentary There has been a great deal of discussion concerning the theoretical advantages of one radioisotope versus another for prostate brachytherapy. These investigators have initiated a randomized trial for patients with early stage prostate cancer comparing 144 Gy of 125I to 125 Gy of 103Pd. 125I has a half-life of 60 days and a dose rate of 6 cGy/h while 103Pd has a half-life of 17 days and a dose rate of 21 cGy/h. The authors demonstrate that among the first 115 patients randomized (of a planned 600 patients) no differences were observed in biochemical control between the treatment arms Yet, the follow-up of the study was under 3 yr. The authors did note, however, that biochemical control was more dependent upon the dose delivered to the prostate based on standard postimplant dosimetric parameters rather than the seed type. These results are not surprising. While these isotopes have different physical characteristics such as the dose rate and half-life, the variations are not dramatic enough to expect differences in biochemical control between the two treatment arms. Yet these authors have only accrued less than 25% of their planned number and will require more patients to detect a difference (if there will be a tangible difference). In the meantime there is currently no evidence that a particular radioisotope will provide the patient with superior outcomes compared to another. doi:10.1016/j.urolonc.2004.04.017 Michael Zelefsky, M.D.
Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. Kattan MW, Zelefsky MJ, Kupelian PA, Cho D, Scardino PT, Fuks Z, Leibel SA, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY. J Clin Oncol 2003;21:4568 –71 Purpose: There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 yr after three-dimensional conformal radiation therapy (CRT). Patients and Methods: We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-yr probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients. Results: After three-dimensional CRT, 159 patients developed metastasis. At 5 yr, 11% of patients experienced metastasis by cumulative
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Mark P. Ritter / Urologic Oncology: Seminars and Original Investigations 22 (2004) 378 –385
incidence analysis (95% CI, 9 –13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81. Conclusion: A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 yr after three-dimensional CRT.
Commentary Several nomograms have been constructed for prostate cancer that can approximately predict the likelihood of biochemical failure after either radiation therapy or radical prostatectomy. These nomograms can be useful both in counseling patients regarding the likelihood of treatment success and in providing guidance regarding optimal treatment strategies. The ultimate usefulness of these nomograms is limited, however, by the unclear significance of biochemical failure with respect to the more clinically relevant endpoint of cause-specific survival. This paper, rather, focuses on the development of metastasis, a more meaningful endpoint with a more clear-cut relationship to subsequent death from prostate cancer. This paper describes the development of a nomogram that predicts the probability of progression to metastasis within 5 yr after a patient receives primary external beam radiotherapy. In the overall patient groups, this metastasis rate was 11%. The nomogram is based upon a proportional hazards regression model using a very large patient database of 1,677 patients. The results were subsequently validated in an independent patient data set of 1,626 patients from a second institution. Three clinicopathological characteristics were used: pretreatment PSA, biopsy Gleason score and clinical stage. Prior studies by others have analyzed similar clinicopathological characteristics, but the significant strength of this study by Kattan et al. is the very large number of patients analyzed both in the primary study and the validation studies. A limitation of the study is that about 8% of patients received hormonal therapy at the time of biochemical failure, possibly delaying their development of detectable metastatic disease. Overall, however, this report represents a significant contribution to the literature regarding pretreatment prognostic factors in radiation therapy for clinically localized prostate cancer. doi:10.1016/j.urolonc.2004.04.023 Mark P. Ritter, M.D., Ph.D.
Identification of factors predicting response to adjuvant radiation therapy in patients with positive margins after radical prostatectomy. Kamat AM, Babaian K, Cheung MR, Naya Y, Huang SH, Kuban D, Babaian RJ, Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX. J Urol 2003;170:1860 –3 Purpose: Radical prostatectomy (RP) is a highly effective treatment for patients with prostate cancer. However, patients with positive surgical margins after radical prostatectomy have less than ideal outcomes with 5-yr progression rates between 36% and 50%. Postoperative radiation therapy (RT) is often advocated for improving these outcomes. We identified predictors of response to adjuvant RT given for positive margins after RP. Materials and Methods: We retrospectively reviewed the clinical records of men who underwent RP between 1987 and 1999 at our institution and who received adjuvant RT for positive surgical margins. Only patients in whom prostate specific antigen (PSA) was undetectable after RP as well as before the initiation of RT were included. Numerous clinicopathological variables, including pre-RP PSA, pathological stage, margin length and location, and extracapsular extension or seminal vesicle involvement, were assessed for their adverse effect on the biochemical recurrence rate after adjuvant RT. Results: A total of 62 men met our inclusion criteria. Median age at surgery was 60.7 ⫾ 6.1 yr and median PSA at presentation was 9.0 ng/mL (range 1.4 – 64.9). The median RT dose was 60.0 ⫾ 3.6 Gy. RT was started a median of 5.0 ⫾ 3.6 months after RP. The 5 and 10-yr biochemical disease-free survival rates for the whole group were 90.2% and 87.9%, respectively. Of all parameters tested only Gleason score 4 ⫹ 3 or greater (P ⫽ 0.037) and pre-RP PSA greater than 10.9 ng/mL (P ⫽ 0.040) were predictive of biochemical recurrence after adjuvant RT on univariate analysis. On multivariate analysis only pre-RP PSA greater than 10.9 ng/mL remained an independent predictor (P ⫽ 0.031). Conclusions: In the setting of true adjuvant RT in patients with positive margins after RP and undetectable PSA those with predominant Gleason Grade 4 or greater, or PSA greater than 10.9 ng/mL at presentation are at increased risk for recurrence after adjuvant RT.
Commentary Radiation therapy has been applied in a postprostatectomy setting in both adjuvant and salvage fashions. In a salvage mode (a rising PSA after radical prostatectomy), a number of studies have indicated that a high preradiotherapy PSA, high Gleason score, seminal vesicle invasion, negative surgical margins and rapid postprostatectomy PSA doubling time all reduce the success of the radiotherapy salvage attempt. Overall, the chances of salvage radiotherapy producing biochemical relapse-free status at 5 yr averages about 50%, but with actual success rates ranging between only 20% to as high as nearly 80%, depending upon these factors. Controversy remains over the optimal timing of salvage radiotherapy, with some analyses suggesting that earlier intervention produces better outcomes.
381
125
I versus 103Pd for low-risk prostate cancer: preliminary PSA outcomes from a prospective randomized multicenter trial. Wallner K, Merrick G, True L, Sutlief S, Cavanagh W, Butler W, Department of Radiation Oncology, Puget Sound Health Care System, Department of Veterans Affairs, Seattle, WA. Int J Radiat Oncol Biol Phys 2003;57:1297–1303 Purpose: To compare prostate cancer control rates in patients who received 125I vs. 103Pd. Materials and Methods: Of a planned total of 600 patients with 1997 American Joint Committee on Cancer clinical Stage T1c-T2a prostate carcinoma (Gleason score 5– 6, prostate-specific antigen [PSA] 4 –10 ng/mL), 126 were randomized to implantation with 125I (144 Gy) vs. 103Pd (125 Gy). The prostate biopsies were reviewed for Gleason score by one of us (L.T.). A single manufacturer of 125I sources (Model 6711, Amersham, Chicago, IL) and 103Pd sources (Theraseed, Theragenics, Buford, GA) was used. Isotope implantation was performed with standard techniques, using a modified peripheral loading pattern. Of a total of 126 patients randomized, 11 were excluded, leaving 115 randomized patients for this analysis. Twenty patients received a short course of preimplant hormonal therapy, none of which continued hormonal therapy after their implant procedure. Postimplant CT was obtained 2 to 4 h after implantation. The dosimetric parameters analyzed included the percentage of the postimplant prostate or rectal volume covered by the prescription dose [V (100)] and the dose that covered 90% of the postimplant prostate volume [D (90)]. Freedom from biochemical failure was defined as a serum PSA level less than or equal to 0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA level was still decreasing. Patients whose serum PSA had reached a nadir at a value ⬎0.5 ng/mL were scored as having failure at the time at which their PSA had reached a nadir. The follow-up period for patients without failure ranged from 2.0 to 4.9 yr (median 2.9). Freedom-from-failure curves were calculated by the Kaplan-Meier method. Differences between groups were determined by the log-rank method. Results: The actuarial biochemical freedom-from-failure rate at 3 yr was 89% for 125I patients vs. 91% for 103Pd patients (P ⫽ 0.76). The 3-yr biochemical freedom-from-failure rate for patients with a D (90) ⬍100% of the prescription dose was 82% vs. 97% for patients with a D (90) ⱖ100% of the prescription dose (P ⫽ 0.01). Similarly, the 3-yr biochemical freedom-from-failure rate for patients with a V (100) ⬍90% of the prescription dose was 87% vs. 97% for patients with a V (100) ⱖ90% of the prescription dose (P ⫽ 0.01). The effect of the dosimetric parameters on biochemical control was most pronounced for 125I, but also apparent for 103Pd. Conclusions: The 3-yr actuarial biochemical control rates for low early stage prostate cancer are similar after 125I and 103Pd.
Commentary There has been a great deal of discussion concerning the theoretical advantages of one radioisotope versus another for prostate brachytherapy. These investigators have initiated a randomized trial for patients with early stage prostate cancer comparing 144 Gy of 125I to 125 Gy of 103Pd. 125I has a half-life of 60 days and a dose rate of 6 cGy/h while 103Pd has a half-life of 17 days and a dose rate of 21 cGy/h. The authors demonstrate that among the first 115 patients randomized (of a planned 600 patients) no differences were observed in biochemical control between the treatment arms Yet, the follow-up of the study was under 3 yr. The authors did note, however, that biochemical control was more dependent upon the dose delivered to the prostate based on standard postimplant dosimetric parameters rather than the seed type. These results are not surprising. While these isotopes have different physical characteristics such as the dose rate and half-life, the variations are not dramatic enough to expect differences in biochemical control between the two treatment arms. Yet these authors have only accrued less than 25% of their planned number and will require more patients to detect a difference (if there will be a tangible difference). In the meantime there is currently no evidence that a particular radioisotope will provide the patient with superior outcomes compared to another. doi:10.1016/j.urolonc.2004.04.017 Michael Zelefsky, M.D.
Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. Kattan MW, Zelefsky MJ, Kupelian PA, Cho D, Scardino PT, Fuks Z, Leibel SA, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY. J Clin Oncol 2003;21:4568 –71 Purpose: There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 yr after three-dimensional conformal radiation therapy (CRT). Patients and Methods: We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-yr probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients. Results: After three-dimensional CRT, 159 patients developed metastasis. At 5 yr, 11% of patients experienced metastasis by cumulative
382
Mark P. Ritter / Urologic Oncology: Seminars and Original Investigations 22 (2004) 378 –385
incidence analysis (95% CI, 9 –13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81. Conclusion: A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 yr after three-dimensional CRT.
Commentary Several nomograms have been constructed for prostate cancer that can approximately predict the likelihood of biochemical failure after either radiation therapy or radical prostatectomy. These nomograms can be useful both in counseling patients regarding the likelihood of treatment success and in providing guidance regarding optimal treatment strategies. The ultimate usefulness of these nomograms is limited, however, by the unclear significance of biochemical failure with respect to the more clinically relevant endpoint of cause-specific survival. This paper, rather, focuses on the development of metastasis, a more meaningful endpoint with a more clear-cut relationship to subsequent death from prostate cancer. This paper describes the development of a nomogram that predicts the probability of progression to metastasis within 5 yr after a patient receives primary external beam radiotherapy. In the overall patient groups, this metastasis rate was 11%. The nomogram is based upon a proportional hazards regression model using a very large patient database of 1,677 patients. The results were subsequently validated in an independent patient data set of 1,626 patients from a second institution. Three clinicopathological characteristics were used: pretreatment PSA, biopsy Gleason score and clinical stage. Prior studies by others have analyzed similar clinicopathological characteristics, but the significant strength of this study by Kattan et al. is the very large number of patients analyzed both in the primary study and the validation studies. A limitation of the study is that about 8% of patients received hormonal therapy at the time of biochemical failure, possibly delaying their development of detectable metastatic disease. Overall, however, this report represents a significant contribution to the literature regarding pretreatment prognostic factors in radiation therapy for clinically localized prostate cancer. doi:10.1016/j.urolonc.2004.04.023 Mark P. Ritter, M.D., Ph.D.
Identification of factors predicting response to adjuvant radiation therapy in patients with positive margins after radical prostatectomy. Kamat AM, Babaian K, Cheung MR, Naya Y, Huang SH, Kuban D, Babaian RJ, Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX. J Urol 2003;170:1860 –3 Purpose: Radical prostatectomy (RP) is a highly effective treatment for patients with prostate cancer. However, patients with positive surgical margins after radical prostatectomy have less than ideal outcomes with 5-yr progression rates between 36% and 50%. Postoperative radiation therapy (RT) is often advocated for improving these outcomes. We identified predictors of response to adjuvant RT given for positive margins after RP. Materials and Methods: We retrospectively reviewed the clinical records of men who underwent RP between 1987 and 1999 at our institution and who received adjuvant RT for positive surgical margins. Only patients in whom prostate specific antigen (PSA) was undetectable after RP as well as before the initiation of RT were included. Numerous clinicopathological variables, including pre-RP PSA, pathological stage, margin length and location, and extracapsular extension or seminal vesicle involvement, were assessed for their adverse effect on the biochemical recurrence rate after adjuvant RT. Results: A total of 62 men met our inclusion criteria. Median age at surgery was 60.7 ⫾ 6.1 yr and median PSA at presentation was 9.0 ng/mL (range 1.4 – 64.9). The median RT dose was 60.0 ⫾ 3.6 Gy. RT was started a median of 5.0 ⫾ 3.6 months after RP. The 5 and 10-yr biochemical disease-free survival rates for the whole group were 90.2% and 87.9%, respectively. Of all parameters tested only Gleason score 4 ⫹ 3 or greater (P ⫽ 0.037) and pre-RP PSA greater than 10.9 ng/mL (P ⫽ 0.040) were predictive of biochemical recurrence after adjuvant RT on univariate analysis. On multivariate analysis only pre-RP PSA greater than 10.9 ng/mL remained an independent predictor (P ⫽ 0.031). Conclusions: In the setting of true adjuvant RT in patients with positive margins after RP and undetectable PSA those with predominant Gleason Grade 4 or greater, or PSA greater than 10.9 ng/mL at presentation are at increased risk for recurrence after adjuvant RT.
Commentary Radiation therapy has been applied in a postprostatectomy setting in both adjuvant and salvage fashions. In a salvage mode (a rising PSA after radical prostatectomy), a number of studies have indicated that a high preradiotherapy PSA, high Gleason score, seminal vesicle invasion, negative surgical margins and rapid postprostatectomy PSA doubling time all reduce the success of the radiotherapy salvage attempt. Overall, the chances of salvage radiotherapy producing biochemical relapse-free status at 5 yr averages about 50%, but with actual success rates ranging between only 20% to as high as nearly 80%, depending upon these factors. Controversy remains over the optimal timing of salvage radiotherapy, with some analyses suggesting that earlier intervention produces better outcomes.