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Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation
Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 1, pp. 129 –136, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter
PII S0360-3016(99)00526-X
CLINICAL INVESTIGATION
Prostate
COMPARISON OF BIOCHEMICAL DISEASE-FREE SURVIVAL OF PATIENTS WITH LOCALIZED CARCINOMA OF THE PROSTATE UNDERGOING RADICAL PROSTATECTOMY, TRANSPERINEAL ULTRASOUND-GUIDED RADIOACTIVE SEED IMPLANTATION, OR DEFINITIVE EXTERNAL BEAM IRRADIATION STEVEN H. STOKES, M.D. Department of Radiation Oncology, Southeast Regional Radiation Oncology Center, Dothan, Alabama Purpose: This retrospective study compares the long-term biochemical disease-free survival for patients undergoing radical prostatectomy, transperineal ultrasound-guided 125Iodine implantation, or external beam irradiation alone in a tertiary referral community-based hospital. Methods and Materials: Five hundred forty patients were available for evaluation, which included: external beam, 132; 125I, 186; and radical prostatectomy, 222. For the 318 patients referred to the Department of Radiation Oncology, those with T3 disease underwent external beam irradiation while patients with T1 or T2 underwent 125I implantation or external beam irradiation as definitive treatment. No patient received androgen ablation. Patients undergoing irradiation were considered a biochemical failure if their PSA nadir was > 1 at 1 year or, if following a nadir PSA < 1, the patient subsequently experienced three consecutive rising PSA values obtained at a minimum 3-month interval. Patients undergoing prostatectomy were considered a biochemical failure if their postop PSA remained detectable > 0.2 ng/mL or if they had three consecutive increases in their PSA or an increase in their postoperative PSA warranting intervention with androgen ablation or external beam irradiation to the pelvis. Results: Patients were stratified by pretreatment risk groups predicting for post-treatment PSA recurrence. Patients were considered to be at a low or intermediate risk for recurrence if their clinical stage was T1c, T2a, T2b, pretreatment PSA level was < 20, or their biopsy Gleason score was < 6. Patients were considered to be at high risk for failure if they were clinically stage T2c, T3, PSA at diagnosis > 20, or Gleason score was > 7. For 132 patients undergoing external beam irradiation, 28 of 37 low or intermediate risk obtained a 1 year nadir PSA of < 1 (76%) while 40% of high risk patients obtained nadir < 1. Of 186 patients undergoing 125I, 112 of 147 low or intermediate risk (76%) obtained a nadir PSA < 1. Twenty of 39 (51%) high risk obtained a nadir PSA < 1. Of the 222 patients undergoing prostatectomy, 83 of 88 (94%) low or intermediate risk had undetectable levels of PSA at 1 year. One hundred seventeen of 134 (86%) were high risk and had undetectable levels of PSA at 1 year. The biochemical disease-free survival for patients with low or intermediate risk at 5 years is approximately 70% with no significant difference between those patients treated with radical prostatectomy, external beam, or 125I. For those patients with high risk factors for recurrence, there is no significant difference between ultrasound-guided implant or external beam, but there is a significant improvement in biochemical disease-free survival with radical prostatectomy. Conclusion: For patients with low or intermediate risk disease, external beam, ultrasound-guided 125I, or a radical prostatectomy give comparable long-term biochemical disease-free survival. For patients with high risk disease, a radical prostatectomy provides a significantly improved biochemical disease-free survival. Our current protocols utilize androgen ablation in combination with conformal three-dimensional external beam irradiation or androgen ablation in conjunction with external beam irradiation and 103Pd seed implantation for patients at high risk for extra capsular disease. It is too early to determine if this combination therapy will give results comparable to radical prostatectomy. For patients who obtain a 1 year nadir PSA of < 1, the biochemical disease-free survival is durable with little risk of subsequent recurrence. © 2000 Elsevier Science Inc. Prostate cancer, Radiotherapy, Prostatectomy, Biochemical disease-free survival.
Reprint requests to: Steven H. Stokes, M.D., Department of Radiation Oncology, Southeast Regional Radiation Oncology Center, P.O. Box 5526, Dothan, AL 36302. This material was presented at the American Brachytherapy Society meeting, San Diego, CA, May 1999.
Acknowledgments—Biostatistical Analysis of Patient Material was supported in part by a $1000 educational grant by Indigo Corporation. Assistance and preparation of this manuscript was provided by Sue Ivey, Angela Gray, and Monnette Creamer. Accepted for publication 23 November 1999. 129
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Table 2. Risk groups predicting biochemical failure
INTRODUCTION Management of operable carcinoma of the prostate has traditionally been with radical prostatectomy (1– 4); however, there are no completed prospective randomized trials that compare definitive local treatment options for localized disease. Retrospective comparisons stratified by known prognostic factors and using actuarial analysis have been published comparing radical prostatectomy, external beam irradiation, and ultrasound-guided interstitial radioactive seed implantation (5, 6), however, follow-up is short or results are confused by the addition of neoadjuvant androgen deprivation or combining external beam irradiation with interstitial implantation (7, 8). The purpose of this study was to evaluate the long-term biochemical disease-free survival data stratified by the pretreatment PSA, biopsy Gleason score, AJCC T-stage in men treated with radical prostatectomy, external beam irradiation, or ultrasound-guided seed implantation alone without the addition of neoadjuvant androgen deprivation. METHODS Patient population Between 1988 and 1994, 585 patients were diagnosed with organ-confined carcinoma of the prostate. Patients were initially evaluated by the Department of Urology and 234 were felt to be surgical candidates undergoing pelvic lymphadenectomy and retropubic radical prostatectomy. Patients not felt to be candidates for resection, due to coexisting medical conditions or who declined surgery, were referred for irradiation. Patients with clinical stage T3 disease were offered external beam irradiation while patients with T1-2 underwent either ultrasound guided 125Iodine seed implantation or full course external beam irradiation as definitive therapy. Following treatment, patients were followed with serial PSA levels and digital exams at minimum 3- to 6-month intervals. Patients were followed for a minimum of 2 years to a maximum of 10 years. Patients who died of intercurrent disease, or were lost to follow-up with inadequate PSA determinations, were ex-
Table 1. Patient characteristics Age at diagnosis External beam: Range: 49–87 Mean: 71.57 Median: 72 Implant: Range: 55–91 Mean: 73.67 Median: 74 Prostatectomy: Range: 43–79 Mean: 65.47 Median: 66
Volume 47, Number 1, 2000
Follow-up
PSA at diagnosis
2–10 years 73.3 (6 years, 1 month) 75.5 (6 years, 6 months)
1.0–625.0 19.7 45.4
2–10 years 68.2 (5 years, 8 months) 78 (5 years, 8 months)
0.7–66.7 7.6 10.56
2–10 years 77.9 (6 years, 5 months) 73 (6 years, 1 month)
0.4–171.6 8.2 12.78
Clinical stage Gleason score Pretreatment PSA
Low
Intermediate
High
T1C, T2A ⱕ6/10 ⱕ10
T2B ⱕ6/10 10–20
T2C, T3 ⱖ7/10 ⬎20
Table 3. Patient population by risk group
External XRT Implant Prostatectomy
Low/intermediate
High
Totals
37 147 88
95 39 134
132 186 222
cluded from the study: external beam, 16; 125Iodine, 17; and radical prostatectomy, 12. Five hundred forty patients remained available for evaluation: 132 external beam treatment, 186 125Iodine, and 222 prostatectomy. Table 1 demonstrates patient material by treatment regimen. Staging Patient charts were reviewed and patients retrospectively assigned a T stage by the author using 1992 AJCC clinical staging. Pretreatment serum PSA levels were available for all patients. All patients with a PSA ⬎ 10 at diagnosis underwent a bone scan, however, computer tomography scan of the pelvis was not routinely performed. Transrectal ultrasound-guided needle biopsy of the prostate was used to determine if bilobar disease was present and Gleason score histologic grading allowed stratification of patients according to their pretreatment Gleason score. PSA measurements were by the Hybritech assay. Treatment All patients were treated at Southeast Alabama Medical Center, a community hospital providing tertiary cancer services. Surgical treatment consisted of a radical retropubic prostatectomy and bilateral pelvic lymphadenectomy. Two hundred thirty-four patients underwent surgery. Seven patients expired of intercurrent disease and five were lost to follow-up, without serial PSA levels within 2 years, allowing 222 patients available for evaluation. Patients were routinely followed at 3- to 6-month intervals with serial PSA levels and digital rectal exam. Patients were considered a surgical failure if they had persistent detectable PSA (⬎ 0.2 ng/mL) following surgery, they experienced three conTable 4. One-year nadir PSA ⱕ1 by prognostic risk group
Implant External beam Prostatectomy*
Low-intermediate
High
112/147 (76%) 28/37 (76%) 83/88 (94%)
20/39 (51%) 38/95 (40%) 117/134 (87%)
* Undetectable PSA at 1 year (⬍ 0.2 ng/mL).
Biochemical disease-free survival from prostate cancer
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Fig. 1. Actuarial biochemical disease-free survival for patients undergoing external irradiation by risk group.
Fig. 2. Actuarial biochemical disease-free survival for patients undergoing radioactive 125Iodine implantation by risk group.
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Fig. 3. Actuarial biochemical disease-free survival for patients undergoing prostatectomy by risk group.
Fig. 4. Actuarial biochemical disease-free survival for AJCC stage T1 and T2, and low to intermediate risk group undergoing external irradiation or implant.
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Fig. 5. Actuarial biochemical disease-free survival for low to intermediate risk group undergoing external irradiation, implant, or prostatectomy.
secutive increases in their PSA at minimum 3-month intervals, or if they had a substantial increase in PSA warranting intervention with androgen ablation or pelvic irradiation. Patients were considered a biochemical failure from the date of the first initial PSA increase. One hundred forty-eight patients underwent definitive irradiation of 4500 cGy to the pelvis with a four-field box technique using 10 to 18 MeV photons. The periprostatic region was then boosted with a bilateral arc rotational field to the final target dose of 6500 –7000 cGy at 180- to 200cGy fractions. This group of patients was treated prior to our current era of CT-guided three-dimensional conformal therapy. No patient received neoadjuvant or concurrent androgen ablation. Following treatment, patients were followed at 3- to 6-month intervals with digital rectal exams and serial PSA levels. Fifteen patients died of coexisting medical disease and one had inadequate follow-up PSA levels within 2 years and were excluded from the study, leaving 132 available for analysis. Patients were considered a biochemical failure if their nadir PSA at 1 year was ⱖ 1. Patients who experienced a nadir PSA of ⬍ 1 at 1 year, but who subsequently had three consecutive increases in their PSA, were considered a failure from the date of the initial PSA increase (9). Two hundred three patients underwent interstitial implantation as described by Blasko et al. (10). This involved
utilizing a pretreatment ultrasound volume study to formulate a scheme of insertion to deliver 160 Gy minimum prostatic dose with 125Iodine seeds. We modified the technique to reduce the intensity of the seeds in the periurethral area to one-half strength, typically 10% of the total seeds implanted. This simple modification reduced the RTOG grade 3/4 morbidity from 11% to 4% and no patient experienced urethral necrosis (11). Ultrasound-guided seed implantation was offered to those patients who were considered by the urologist to be medically inoperable, who had prostate volumes of ⬍ 50 cm3, Gleason scores of 6 or less, a PSA of ⬍ 50, and without significant obstructive symptoms. Fifteen patients expired of intercurrent disease at ⬍ 2 years, and two patients had inadequate PSA levels and were excluded from the study, leaving 186 patients available for analysis. No patient underwent neoadjuvant androgen ablation. Statistical analysis Patients were retrospectively classified into currently accepted pretreatment risk groups based on prognostic factors. See Tables 2 and 3 (7) for details. These prognostic factors included PSA level at diagnosis, biopsy Gleason score, and 1992 AJCC T stage. Patients with AJCC T2c, T3, Gleason scores ⱖ 7, and PSA ⬎ 20 were considered at high risk for post-therapy PSA failure. Patients with PSA levels ⬍ 20,
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Fig. 6. Actuarial biochemical disease-free survival for high risk group undergoing external irradiation, implant, or prostatectomy.
Gleason scores 6 or less, and AJCC stage T1, T2a, T2b were considered low to intermediate risk for post-therapy failure. The statistical analysis was performed by the Department of Biostatistics, University of Alabama (Birmingham, AL). The actuarial biochemical disease-free survival was determined using Kaplan-Meier survival curves. The p values are based on log names (Mantel–Haenszel) statistics. RESULTS Nadir PSA of ⱕ 1 at 1 year following external irradiation or seed implantation or undetectable levels of PSA after prostatectomy are considered a favorable prognostic factor (12). Table 4 shows 1 year nadir or undetectable PSA by treatment and prognostic factors. Figure 1 compares the biochemical disease-free survival for patients undergoing external beam irradiation according to their risk category at diagnosis. As demonstrated, there is a significant difference between low, intermediate, and high risk patients resulting in 85%, 50%, and 30% of patients being free of disease at 5 years, respectively. Figure 2 demonstrates biochemical disease-free survival for patients undergoing 125I implantation by risk group. Patients at high risk for recurrence experienced approximately 35% 5-year disease-free survival, which was significantly less than the 70%– 80% ex-
perienced with intermediate and low risk patients. Figure 3 demonstrates the biochemical disease-free survival for patients undergoing a radical prostatectomy by risk group. Patients at high risk had approximately 60% 5-year diseasefree survival, which was significantly less than the 70%– 80% for the patients with intermediate to low risk disease. In order to compare comparable patients who would undergo 125I seed implantation or external beam, the T3 patients were removed for analysis from the external beam category. Figure 4 shows the comparison of stage T1 and T2 with low or intermediate risk categories treated with either external beam or implantation. There is no significant difference between these two forms of treatment, with approximately 70% of patients free of disease at 5 years. Figure 5 compares patients with low to intermediate risk factors treated by prostatectomy, external beam, or implantation. As demonstrated, there is no significant difference in survival for patients treated with either external beam, implantation, or prostatectomy. Figure 6 compares the biochemical disease-free survival for patients with high risk factors undergoing external beam, radical prostatectomy, or implantation. Prostatectomy provides an improved 5-year disease-free survival of approximately 60% as compared with implantation and external beam irradiation.
Biochemical disease-free survival from prostate cancer
DISCUSSION The options of treatment for men with early stage organconfined carcinoma of the prostate remains controversial (5–7). Patients with organ-confined carcinoma continue to be offered radical prostatectomy in our institution. However, a substantial number of men have coexisting medical illness that precludes radical surgery or decline surgery due to the potential morbidity. Only recently are long-term studies starting to appear that attempt to compare biochemical disease-free survival for patients treated with surgery, external beam irradiation, or interstitial implantation (7). These studies support that the combination of AJCC clinical T stage, pretreatment PSA, and biopsy Gleason score can predict the subsequent biochemical recurrence for patients managed with definitive local therapy. In order to compare PSA outcome across different treatment modalities, it is important to control for these prognostic factors and allow for a true comparison between different modalities of treatment. Utilizing the actuarial Kaplan–Meier biochemical disease-free interval, we have attempted to compare the long-term follow-up of patients treated at a single institution with radical prostatectomy, external beam irradiation, or ultrasound 125Iodine seed implantation without androgen deprivation stratified by pretreatment risk groups. Our results indicate that for patients defined to be at low or intermediate risk for post-therapy PSA failure, there was no significant difference in long-term disease-free survival whether they were treated with a radical prostatectomy, external beam irradiation, or ultrasound-guided radioactive seed implantation. Patients at high risk for post-treatment biochemical recurrence have improved survival with radical prostatectomy as compared with external beam or ultrasound-guided seed implantation alone. This group of patients treated by surgery, external beam irradiation, or implantation alone without the confusing effect of androgen ablation will serve as a
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baseline for future comparison utilizing our current protocols. Patients at high risk for extracapsular disease are no longer treated with irradiation alone. Those receiving external beam therapy are encouraged to undergo 6 to 12 months of total androgen blockade. Our technique of treatment utilizes three-dimensional conformal therapy to a minimum of 7000 –7200 cGy. Patients desiring an ultrasound-guided seed implantation and who are at high risk for extracapsular disease receive 4500 cGy external beam preoperative therapy with 3 months of androgen ablation followed by implantation with 103Palladium seeds. Recent reports (13) indicate that this combined modality protocol can result in higher rates of biochemical disease-free survival. It will require further follow-up to determine whether these improved rates are durable. CONCLUSION For patients with low to intermediate risk disease, external beam, ultrasound-guided 125 Iodine seed implantation, or radical prostatectomy result in comparable long-term biochemical disease-free survival. Patients with a high risk of extracapsular disease, radical prostatectomy provides a significantly improved biochemical disease-free survival when compared with ultrasound-guided seed implantation or external beam irradiation alone. Our current protocols utilize androgen ablation in combination with conformal three-dimensional external beam irradiation or androgen ablation in combination with external beam irradiation and 103Palladium seed implantation for patients at high risk for extracapsular disease. Early reports utilizing these combined modality protocols show promise for patients with adverse prognostic factors. However, it is unclear as to whether these initial results will be durable and comparable to radical prostatectomy.
REFERENCES 1. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281: 1591–1597. 2. Kupelien PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37:1043–1052. 3. Trapasso JB, DeKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152: 1821–1825. 4. Kupelian PA, Katcher J, Levin HS, Zippe C, Klein E. Correlation of clinical and pathologic factors with rising prostatespecific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 1996;48:249 – 260. 5. Kupelian PA, Katcher J, Levin H, et al. External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: therapeutic implications of stratification by
6.
7.
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9.
10.
pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am 1997;3:78 – 87. Keyser D, Kupelian PA, Zippe CD, Levin HS, Klein EA. Stage T1-2 prostate cancer with pretreatment prostate-specific antigen level ⱕ 10 ng/ml: radiation therapy or surgery? Int J Radiat Oncol Biol Phys 1997;38:723–729. D⫽Amico AV, Whittington R, Malkowicz B, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969 –974. Critz FA, Levinson A, Williams W, Holladay C, Griffin V, Holladay D. Simultaneous radiotherapy for prostate cancer: 125 I prostate implant followed by external-beam radiation. Cancer J Sci Am 1998;4:359 –363. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. Blasko JC, Wallner K, Grimm P, Ragde H. Prostate specific antigen based disease control following ultrasound guided
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125 Iodine implantation for stage T1-T2 prostatic carcinoma. J Urol 1995;154:1096 –1099. 11. Stokes SH, Real JD, Adams PW, Clements JC, Wuertzer S, Kan W. Transperineal ultrasound-guided radioactive seed implantation for organ-confined carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1997;37:337–341. 12. Zagars GK, Pollack A, Kavadi VS, Eschenbach AC. Prostate-
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specific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:293– 306. 13. Dattoli M, Wallner K, Sorace R, et al. Disease-free survival after external beam irradiation and Palladium-103 brachytherapy boost for high-risk prostatic carcinoma. J Brachyther Int 1997;13:347–354.
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CLINICAL INVESTIGATION
Prostate
COMPARISON OF BIOCHEMICAL DISEASE-FREE SURVIVAL OF PATIENTS WITH LOCALIZED CARCINOMA OF THE PROSTATE UNDERGOING RADICAL PROSTATECTOMY, TRANSPERINEAL ULTRASOUND-GUIDED RADIOACTIVE SEED IMPLANTATION, OR DEFINITIVE EXTERNAL BEAM IRRADIATION STEVEN H. STOKES, M.D. Department of Radiation Oncology, Southeast Regional Radiation Oncology Center, Dothan, Alabama Purpose: This retrospective study compares the long-term biochemical disease-free survival for patients undergoing radical prostatectomy, transperineal ultrasound-guided 125Iodine implantation, or external beam irradiation alone in a tertiary referral community-based hospital. Methods and Materials: Five hundred forty patients were available for evaluation, which included: external beam, 132; 125I, 186; and radical prostatectomy, 222. For the 318 patients referred to the Department of Radiation Oncology, those with T3 disease underwent external beam irradiation while patients with T1 or T2 underwent 125I implantation or external beam irradiation as definitive treatment. No patient received androgen ablation. Patients undergoing irradiation were considered a biochemical failure if their PSA nadir was > 1 at 1 year or, if following a nadir PSA < 1, the patient subsequently experienced three consecutive rising PSA values obtained at a minimum 3-month interval. Patients undergoing prostatectomy were considered a biochemical failure if their postop PSA remained detectable > 0.2 ng/mL or if they had three consecutive increases in their PSA or an increase in their postoperative PSA warranting intervention with androgen ablation or external beam irradiation to the pelvis. Results: Patients were stratified by pretreatment risk groups predicting for post-treatment PSA recurrence. Patients were considered to be at a low or intermediate risk for recurrence if their clinical stage was T1c, T2a, T2b, pretreatment PSA level was < 20, or their biopsy Gleason score was < 6. Patients were considered to be at high risk for failure if they were clinically stage T2c, T3, PSA at diagnosis > 20, or Gleason score was > 7. For 132 patients undergoing external beam irradiation, 28 of 37 low or intermediate risk obtained a 1 year nadir PSA of < 1 (76%) while 40% of high risk patients obtained nadir < 1. Of 186 patients undergoing 125I, 112 of 147 low or intermediate risk (76%) obtained a nadir PSA < 1. Twenty of 39 (51%) high risk obtained a nadir PSA < 1. Of the 222 patients undergoing prostatectomy, 83 of 88 (94%) low or intermediate risk had undetectable levels of PSA at 1 year. One hundred seventeen of 134 (86%) were high risk and had undetectable levels of PSA at 1 year. The biochemical disease-free survival for patients with low or intermediate risk at 5 years is approximately 70% with no significant difference between those patients treated with radical prostatectomy, external beam, or 125I. For those patients with high risk factors for recurrence, there is no significant difference between ultrasound-guided implant or external beam, but there is a significant improvement in biochemical disease-free survival with radical prostatectomy. Conclusion: For patients with low or intermediate risk disease, external beam, ultrasound-guided 125I, or a radical prostatectomy give comparable long-term biochemical disease-free survival. For patients with high risk disease, a radical prostatectomy provides a significantly improved biochemical disease-free survival. Our current protocols utilize androgen ablation in combination with conformal three-dimensional external beam irradiation or androgen ablation in conjunction with external beam irradiation and 103Pd seed implantation for patients at high risk for extra capsular disease. It is too early to determine if this combination therapy will give results comparable to radical prostatectomy. For patients who obtain a 1 year nadir PSA of < 1, the biochemical disease-free survival is durable with little risk of subsequent recurrence. © 2000 Elsevier Science Inc. Prostate cancer, Radiotherapy, Prostatectomy, Biochemical disease-free survival.
Reprint requests to: Steven H. Stokes, M.D., Department of Radiation Oncology, Southeast Regional Radiation Oncology Center, P.O. Box 5526, Dothan, AL 36302. This material was presented at the American Brachytherapy Society meeting, San Diego, CA, May 1999.
Acknowledgments—Biostatistical Analysis of Patient Material was supported in part by a $1000 educational grant by Indigo Corporation. Assistance and preparation of this manuscript was provided by Sue Ivey, Angela Gray, and Monnette Creamer. Accepted for publication 23 November 1999. 129
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Table 2. Risk groups predicting biochemical failure
INTRODUCTION Management of operable carcinoma of the prostate has traditionally been with radical prostatectomy (1– 4); however, there are no completed prospective randomized trials that compare definitive local treatment options for localized disease. Retrospective comparisons stratified by known prognostic factors and using actuarial analysis have been published comparing radical prostatectomy, external beam irradiation, and ultrasound-guided interstitial radioactive seed implantation (5, 6), however, follow-up is short or results are confused by the addition of neoadjuvant androgen deprivation or combining external beam irradiation with interstitial implantation (7, 8). The purpose of this study was to evaluate the long-term biochemical disease-free survival data stratified by the pretreatment PSA, biopsy Gleason score, AJCC T-stage in men treated with radical prostatectomy, external beam irradiation, or ultrasound-guided seed implantation alone without the addition of neoadjuvant androgen deprivation. METHODS Patient population Between 1988 and 1994, 585 patients were diagnosed with organ-confined carcinoma of the prostate. Patients were initially evaluated by the Department of Urology and 234 were felt to be surgical candidates undergoing pelvic lymphadenectomy and retropubic radical prostatectomy. Patients not felt to be candidates for resection, due to coexisting medical conditions or who declined surgery, were referred for irradiation. Patients with clinical stage T3 disease were offered external beam irradiation while patients with T1-2 underwent either ultrasound guided 125Iodine seed implantation or full course external beam irradiation as definitive therapy. Following treatment, patients were followed with serial PSA levels and digital exams at minimum 3- to 6-month intervals. Patients were followed for a minimum of 2 years to a maximum of 10 years. Patients who died of intercurrent disease, or were lost to follow-up with inadequate PSA determinations, were ex-
Table 1. Patient characteristics Age at diagnosis External beam: Range: 49–87 Mean: 71.57 Median: 72 Implant: Range: 55–91 Mean: 73.67 Median: 74 Prostatectomy: Range: 43–79 Mean: 65.47 Median: 66
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Follow-up
PSA at diagnosis
2–10 years 73.3 (6 years, 1 month) 75.5 (6 years, 6 months)
1.0–625.0 19.7 45.4
2–10 years 68.2 (5 years, 8 months) 78 (5 years, 8 months)
0.7–66.7 7.6 10.56
2–10 years 77.9 (6 years, 5 months) 73 (6 years, 1 month)
0.4–171.6 8.2 12.78
Clinical stage Gleason score Pretreatment PSA
Low
Intermediate
High
T1C, T2A ⱕ6/10 ⱕ10
T2B ⱕ6/10 10–20
T2C, T3 ⱖ7/10 ⬎20
Table 3. Patient population by risk group
External XRT Implant Prostatectomy
Low/intermediate
High
Totals
37 147 88
95 39 134
132 186 222
cluded from the study: external beam, 16; 125Iodine, 17; and radical prostatectomy, 12. Five hundred forty patients remained available for evaluation: 132 external beam treatment, 186 125Iodine, and 222 prostatectomy. Table 1 demonstrates patient material by treatment regimen. Staging Patient charts were reviewed and patients retrospectively assigned a T stage by the author using 1992 AJCC clinical staging. Pretreatment serum PSA levels were available for all patients. All patients with a PSA ⬎ 10 at diagnosis underwent a bone scan, however, computer tomography scan of the pelvis was not routinely performed. Transrectal ultrasound-guided needle biopsy of the prostate was used to determine if bilobar disease was present and Gleason score histologic grading allowed stratification of patients according to their pretreatment Gleason score. PSA measurements were by the Hybritech assay. Treatment All patients were treated at Southeast Alabama Medical Center, a community hospital providing tertiary cancer services. Surgical treatment consisted of a radical retropubic prostatectomy and bilateral pelvic lymphadenectomy. Two hundred thirty-four patients underwent surgery. Seven patients expired of intercurrent disease and five were lost to follow-up, without serial PSA levels within 2 years, allowing 222 patients available for evaluation. Patients were routinely followed at 3- to 6-month intervals with serial PSA levels and digital rectal exam. Patients were considered a surgical failure if they had persistent detectable PSA (⬎ 0.2 ng/mL) following surgery, they experienced three conTable 4. One-year nadir PSA ⱕ1 by prognostic risk group
Implant External beam Prostatectomy*
Low-intermediate
High
112/147 (76%) 28/37 (76%) 83/88 (94%)
20/39 (51%) 38/95 (40%) 117/134 (87%)
* Undetectable PSA at 1 year (⬍ 0.2 ng/mL).
Biochemical disease-free survival from prostate cancer
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Fig. 1. Actuarial biochemical disease-free survival for patients undergoing external irradiation by risk group.
Fig. 2. Actuarial biochemical disease-free survival for patients undergoing radioactive 125Iodine implantation by risk group.
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Fig. 3. Actuarial biochemical disease-free survival for patients undergoing prostatectomy by risk group.
Fig. 4. Actuarial biochemical disease-free survival for AJCC stage T1 and T2, and low to intermediate risk group undergoing external irradiation or implant.
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Fig. 5. Actuarial biochemical disease-free survival for low to intermediate risk group undergoing external irradiation, implant, or prostatectomy.
secutive increases in their PSA at minimum 3-month intervals, or if they had a substantial increase in PSA warranting intervention with androgen ablation or pelvic irradiation. Patients were considered a biochemical failure from the date of the first initial PSA increase. One hundred forty-eight patients underwent definitive irradiation of 4500 cGy to the pelvis with a four-field box technique using 10 to 18 MeV photons. The periprostatic region was then boosted with a bilateral arc rotational field to the final target dose of 6500 –7000 cGy at 180- to 200cGy fractions. This group of patients was treated prior to our current era of CT-guided three-dimensional conformal therapy. No patient received neoadjuvant or concurrent androgen ablation. Following treatment, patients were followed at 3- to 6-month intervals with digital rectal exams and serial PSA levels. Fifteen patients died of coexisting medical disease and one had inadequate follow-up PSA levels within 2 years and were excluded from the study, leaving 132 available for analysis. Patients were considered a biochemical failure if their nadir PSA at 1 year was ⱖ 1. Patients who experienced a nadir PSA of ⬍ 1 at 1 year, but who subsequently had three consecutive increases in their PSA, were considered a failure from the date of the initial PSA increase (9). Two hundred three patients underwent interstitial implantation as described by Blasko et al. (10). This involved
utilizing a pretreatment ultrasound volume study to formulate a scheme of insertion to deliver 160 Gy minimum prostatic dose with 125Iodine seeds. We modified the technique to reduce the intensity of the seeds in the periurethral area to one-half strength, typically 10% of the total seeds implanted. This simple modification reduced the RTOG grade 3/4 morbidity from 11% to 4% and no patient experienced urethral necrosis (11). Ultrasound-guided seed implantation was offered to those patients who were considered by the urologist to be medically inoperable, who had prostate volumes of ⬍ 50 cm3, Gleason scores of 6 or less, a PSA of ⬍ 50, and without significant obstructive symptoms. Fifteen patients expired of intercurrent disease at ⬍ 2 years, and two patients had inadequate PSA levels and were excluded from the study, leaving 186 patients available for analysis. No patient underwent neoadjuvant androgen ablation. Statistical analysis Patients were retrospectively classified into currently accepted pretreatment risk groups based on prognostic factors. See Tables 2 and 3 (7) for details. These prognostic factors included PSA level at diagnosis, biopsy Gleason score, and 1992 AJCC T stage. Patients with AJCC T2c, T3, Gleason scores ⱖ 7, and PSA ⬎ 20 were considered at high risk for post-therapy PSA failure. Patients with PSA levels ⬍ 20,
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Fig. 6. Actuarial biochemical disease-free survival for high risk group undergoing external irradiation, implant, or prostatectomy.
Gleason scores 6 or less, and AJCC stage T1, T2a, T2b were considered low to intermediate risk for post-therapy failure. The statistical analysis was performed by the Department of Biostatistics, University of Alabama (Birmingham, AL). The actuarial biochemical disease-free survival was determined using Kaplan-Meier survival curves. The p values are based on log names (Mantel–Haenszel) statistics. RESULTS Nadir PSA of ⱕ 1 at 1 year following external irradiation or seed implantation or undetectable levels of PSA after prostatectomy are considered a favorable prognostic factor (12). Table 4 shows 1 year nadir or undetectable PSA by treatment and prognostic factors. Figure 1 compares the biochemical disease-free survival for patients undergoing external beam irradiation according to their risk category at diagnosis. As demonstrated, there is a significant difference between low, intermediate, and high risk patients resulting in 85%, 50%, and 30% of patients being free of disease at 5 years, respectively. Figure 2 demonstrates biochemical disease-free survival for patients undergoing 125I implantation by risk group. Patients at high risk for recurrence experienced approximately 35% 5-year disease-free survival, which was significantly less than the 70%– 80% ex-
perienced with intermediate and low risk patients. Figure 3 demonstrates the biochemical disease-free survival for patients undergoing a radical prostatectomy by risk group. Patients at high risk had approximately 60% 5-year diseasefree survival, which was significantly less than the 70%– 80% for the patients with intermediate to low risk disease. In order to compare comparable patients who would undergo 125I seed implantation or external beam, the T3 patients were removed for analysis from the external beam category. Figure 4 shows the comparison of stage T1 and T2 with low or intermediate risk categories treated with either external beam or implantation. There is no significant difference between these two forms of treatment, with approximately 70% of patients free of disease at 5 years. Figure 5 compares patients with low to intermediate risk factors treated by prostatectomy, external beam, or implantation. As demonstrated, there is no significant difference in survival for patients treated with either external beam, implantation, or prostatectomy. Figure 6 compares the biochemical disease-free survival for patients with high risk factors undergoing external beam, radical prostatectomy, or implantation. Prostatectomy provides an improved 5-year disease-free survival of approximately 60% as compared with implantation and external beam irradiation.
Biochemical disease-free survival from prostate cancer
DISCUSSION The options of treatment for men with early stage organconfined carcinoma of the prostate remains controversial (5–7). Patients with organ-confined carcinoma continue to be offered radical prostatectomy in our institution. However, a substantial number of men have coexisting medical illness that precludes radical surgery or decline surgery due to the potential morbidity. Only recently are long-term studies starting to appear that attempt to compare biochemical disease-free survival for patients treated with surgery, external beam irradiation, or interstitial implantation (7). These studies support that the combination of AJCC clinical T stage, pretreatment PSA, and biopsy Gleason score can predict the subsequent biochemical recurrence for patients managed with definitive local therapy. In order to compare PSA outcome across different treatment modalities, it is important to control for these prognostic factors and allow for a true comparison between different modalities of treatment. Utilizing the actuarial Kaplan–Meier biochemical disease-free interval, we have attempted to compare the long-term follow-up of patients treated at a single institution with radical prostatectomy, external beam irradiation, or ultrasound 125Iodine seed implantation without androgen deprivation stratified by pretreatment risk groups. Our results indicate that for patients defined to be at low or intermediate risk for post-therapy PSA failure, there was no significant difference in long-term disease-free survival whether they were treated with a radical prostatectomy, external beam irradiation, or ultrasound-guided radioactive seed implantation. Patients at high risk for post-treatment biochemical recurrence have improved survival with radical prostatectomy as compared with external beam or ultrasound-guided seed implantation alone. This group of patients treated by surgery, external beam irradiation, or implantation alone without the confusing effect of androgen ablation will serve as a
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baseline for future comparison utilizing our current protocols. Patients at high risk for extracapsular disease are no longer treated with irradiation alone. Those receiving external beam therapy are encouraged to undergo 6 to 12 months of total androgen blockade. Our technique of treatment utilizes three-dimensional conformal therapy to a minimum of 7000 –7200 cGy. Patients desiring an ultrasound-guided seed implantation and who are at high risk for extracapsular disease receive 4500 cGy external beam preoperative therapy with 3 months of androgen ablation followed by implantation with 103Palladium seeds. Recent reports (13) indicate that this combined modality protocol can result in higher rates of biochemical disease-free survival. It will require further follow-up to determine whether these improved rates are durable. CONCLUSION For patients with low to intermediate risk disease, external beam, ultrasound-guided 125 Iodine seed implantation, or radical prostatectomy result in comparable long-term biochemical disease-free survival. Patients with a high risk of extracapsular disease, radical prostatectomy provides a significantly improved biochemical disease-free survival when compared with ultrasound-guided seed implantation or external beam irradiation alone. Our current protocols utilize androgen ablation in combination with conformal three-dimensional external beam irradiation or androgen ablation in combination with external beam irradiation and 103Palladium seed implantation for patients at high risk for extracapsular disease. Early reports utilizing these combined modality protocols show promise for patients with adverse prognostic factors. However, it is unclear as to whether these initial results will be durable and comparable to radical prostatectomy.
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