- Email: [email protected]
Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy
Int. J. Radiation Oncology Biol. Phys., Vol. 54, No. 4, pp. 1047–1054, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter
PII S0360-3016(02)03034-1
CLINICAL INVESTIGATION
Prostate
BIOCHEMICAL DISEASE-FREE SURVIVAL FOLLOWING ADJUVANT AND SALVAGE IRRADIATION AFTER RADICAL PROSTATECTOMY JOHN A. KALAPURAKAL, M.D.,* CHENG-FANG HUANG, M.S.,† MANOJ M. NERIAMPARAMPIL, M.D.,* WILLIAM J. SMALL, JR, M.D.,* MICHAEL R. PINS, M.D.,‡ BHARAT B. MITTAL, M.D.,* STEVEN C. CAMPBELL, M.D.,§ JOHN T. GRAYHACK, M.D.,§ AND RAMANANDA M. SHETTY, M.D.*㛳 *Division of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center; and Departments of ‡Pathology and §Urology, Robert H. Lurie Comprehensive Cancer Center—Northwestern University, Chicago, IL; †Department of Preventive Medicine, Northwestern Memorial Hospital, Chicago, IL Purpose: To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. Methods and Materials: Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of <0.2 ng/mL. Results: The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. Conclusion: This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT. © 2002 Elsevier Science Inc. Prostate cancer, Prostate-specific antigen, Prostatectomy, Radiotherapy, Adjuvant therapy, Salvage therapy.
76 patients who received postoperative RT after radical prostatectomy.
INTRODUCTION Radical prostatectomy is widely used for the treatment of early-stage prostate cancer. Approximately 30 – 60% of patients initially thought to have organ-confined disease will have their disease upstaged postoperatively after radical prostatectomy. At least one-half of these patients will have positive surgical margins or seminal vesicle invasion and will be likely to develop relapse (1–5). Serum prostatespecific antigen (PSA), clinical tumor stage, and biopsy Gleason score are among the factors that predict the postoperative tumor stage (1). Approximately 15– 40% of patients with pathologically confirmed organ-confined disease will subsequently develop biochemical failure within 3 years of surgery (6). Postoperative irradiation (RT) has been widely used for the treatment of patients at high risk of relapse after radical prostatectomy (7–21). In this report, we present a retrospective analysis of biochemical disease-free survival (biochemically no evidence of disease [bNED]) in
Patient characteristics Between 1990 and 1997, 76 patients who underwent radical prostatectomy and adjuvant/salvage RT were included in this analysis. None of these patients received hormonal therapy as part of their initial treatment. No patient had known metastatic disease. All patients had pre- and postoperative serum PSA data available. The median patient age was 60 years (range 48 –78), with approximately 50% ⬍60 years of age. Of 74 patients, 12 (16%) had a family history of prostate cancer. All patients underwent pelvic lymph node resection or sampling and radical retropubic prostatectomy. The median preoperative PSA was 12.0 ng/mL (range 4 – 82). A post-
Reprint requests to: John A. Kalapurakal, M.D., Division of Radiation Oncology, Northwestern Memorial Hospital, 251 E. Huron St., LC-178, Chicago, IL 60611. Tel: (312) 926-3761; Fax: (312) 926-6374; E-mail: [email protected]
Presented in part at the 86th Annual meeting of the RSNA, November 2000, Chicago, IL. Received Jan 2, 2002, and in revised form Jun 25, 2002. Accepted for publication Jun 28, 2002.
METHODS AND MATERIALS
1047
1048
I. J. Radiation Oncology
● Biology ● Physics
operative serum PSA nadir of ⱕ0.1 or ⱕ0.2 ng/mL was noted in 66 patients (87%). Patients were referred for RT because of the presence of high-risk features on pathologic examination of the prostatectomy specimen and an undetectable serum PSA (adjuvant RT group 46% [35 of 76]) or rising serum PSA after radical prostatectomy (salvage RT group 54% [41 of 76]). Among the 41 patients referred for salvage RT, 71% (29 of 41) had a pre-RT PSA level of 0.3–1 ng/mL, 19% (8 of 41) had a PSA level between 1 and 3 ng/mL and 10% (4 of 41) had a PSA level between 3.1 and 10 ng/mL. The median serum PSA level in this group of patients was 0.5 ng/mL (range 0.2– 6.5). None of the patients had palpable tumor recurrence in the prostate bed on digital rectal examination before RT. Biopsies of the prostate bed were not routinely performed to document pathologic evidence of residual/recurrent disease. Pathologic evaluation A detailed pathologic examination of the prostatectomy specimen and lymph nodes was performed. The prostate glands were fixed for 6 –24 h in 10% neutral-buffered formalin. The apical and base margins were subjected to multiple perpendicular sectioning, and the remaining gland was sectioned transversely at 4 – 6-mm intervals. All the prostate tissue and one-third of each seminal vesicle were submitted for histopathologic examination. Lymphovascular invasion was defined as the unequivocal presence of tumor cells within an endothelial lined space, often with associated fibrin. In comparison with the transrectal biopsy Gleason scores, the postprostatectomy Gleason score was higher in 29% of the patients (22 of 76). The postprostatectomy Gleason score was ⬍7 in 87% (66 of 76) and 8 –10 in 13% (10 of 76). A Gleason grade of 4 was encountered in 38% (29 of 76), and 11% (8 of 76) had a Gleason grade of 5. Prostate capsular perforation was noted in 78% (59 of 76). The surgical margins were involved with tumor in 53% (40 of 76). Perineural invasion by tumor was encountered in 74% (56 of 76). Seminal vesicle invasion was noted in 22% (17 of 76). Lymphovascular invasion was encountered in 17% (13 of 76). Lymph node involvement was noted in 4% (3 of 76). Radiotherapy The median time between radical prostatectomy and RT was 4 months (range 2 months to 5.5 years). The RT was administered ⱕ6 months after surgery in 69% (52 of 76) and ⬎6 months in 31% (24 of 76). Before RT, all patients underwent simulation using urethrography and oral/rectal barium. CT scan information and surgical clips at the seminal vesicles were used to determine the location of the tumor bed. RT was administered using 10-MV X-rays with a four-field box or bilateral 120° arc technique. The whole pelvis was included in a portion of the irradiated field to a dose of 40 – 45 Gy in 20% (15 of 76). The median radiation dose administered to the tumor bed was 60 Gy (range 60 –70) in 30 fractions prescribed to the 95–100% isodose
Volume 54, Number 4, 2002
line. The median total dose in the adjuvant RT group and salvage RT group was 60 Gy (range 60 – 65) and 65 Gy (range 60 –70), respectively. Follow-up Patients were followed with a detailed history and physical examination, including digital rectal examination and serum PSA levels at each 3– 6-month visit. A detectable PSA, as defined below, was judged to represent recurrent disease. A complete physical examination and CT and bone scans were used to identify the site and extent of recurrence. Acute and late complications were graded using the Radiation Therapy Oncology Group (RTOG) grading criteria (21). The median follow-up in the adjuvant RT group was 3 years (range 0.7– 8.7) from the date of surgery and 2 years (range 0.6 – 6.6) from the date of RT. In the salvage RT group, the median follow-up from date of surgery was 5.3 years (range 0.9 –9.6) and 2.6 years (0.4 –9.2 years) from the date of RT. Definition of biochemical control (bNED) A number of definitions have been used to define biochemical cure rates after radical prostatectomy and postprostatectomy RT. In several large surgical series, PSA levels of ⬍0.2 ng/mL (2), ⬍0.3 ng/mL (3), and ⬍0.4 ng/mL (4, 5) have been used to define biochemical control. Likewise, after postprostatectomy RT, biochemical controls have been variously defined as serum PSA levels of ⬍0.05 ng/mL (7), ⬍0.1 ng/mL (8), ⱕ0.2 ng/mL (9 –13), ⱕ0.3 ng/mL (14), ⱕ0.4 ng/mL (15, 16), and ⱕ0.5 ng/mL (17–19) and as two consecutive rises in the serum PSA level after a PSA nadir (20). In the present report, biochemical cure or bNED was defined by a serum PSA of ⱕ0.2 ng/mL (Hybritech, San Diego, CA) or ⱕ0.1 ng/mL (Abbot Laboratories, Abbott Park, IL). All patients in this report had their serum PSA estimated using either the Hybritech assays (Hybritech) or the Abbott assays (Abbott Laboratories). Patients were judged as having biochemical recurrence if they had two successive elevated PSA levels as defined above from the date of surgery or RT. Statistical analysis Biochemical disease-free survival (bNED) was the primary end point studied. Univariate analyses were used to examine the influence of several clinical, pathologic, and treatment-related factors on bNED survival. The factors studied included patient age, family history, Gleason score (ⱕ7 vs. 8 –10), Gleason grade (no 4, any 4, any 5 and no 4 vs. any 4 or 5), perineural invasion, capsular perforation, surgical margin status, seminal vesicle invasion, lymphovascular invasion, lymph node invasion, radiation dose (60 vs. ⬎60 Gy), radiation field (whole pelvis vs. small fields), preoperative PSA (⬍5, 5–10, ⬎10 ng/mL and ⱕ10 vs. ⬎10 ng/mL), pre-RT PSA (⬍0.1 vs. ⱖ0.1 ng/mL and 0.1–1 ng/mL, 1.1–3 ng/mL, 3.1–10 ng/mL), and interval between surgery and RT (ⱕ6 vs. ⬎6 months). The disease-free and
bNED after prostatectomy and RT
● J. KALAPURAKAL et al.
1049
Fig. 1. Kaplan-Meier estimate of overall biochemical disease-free survival (bNED) from date of surgery in patients with or without seminal vesicle invasion.
overall survival times were analyzed using the KaplanMeier product limit method (23). The log–rank test was used to test the homogeneity of survival functions across strata (24). For those significant variables from the log–rank test, the stepwise procedure of proportional hazards (Cox) regression models was used to select the most significantly associated variable (25). RESULTS Overall biochemical disease-free survival (bNED) For the entire patient group, the 3- and 5-year KaplanMeier bNED rate calculated from the date of surgery was 89% and 77%, respectively. At last follow-up, 81.5% of patients achieved biochemical control (bNED). The mean time to biochemical failure from the date of surgery to the first PSA elevation was 29 months (range 9 – 68). Seminal vesicle invasion was the only significant variable for bNED calculated from the date of surgery on univariate (p ⫽ 0.03) and multivariate (p ⫽ 0.03) analysis. The 3and 5-year bNED rate in the absence of seminal vesicle involvement was 94% and 85%, respectively. However, when seminal vesicle invasion was present, the 3- and 5-year bNED rate was 76% and 57%, respectively (Fig. 1). The 3- and 5-year bNED rate calculated from the end of RT for the entire patient group was 85% and 70%, respectively. The mean time to biochemical failure calculated from the end of RT to the first PSA elevation was 21 months (range 3– 46). On univariate (p ⫽ 0.02) and
multivariate (p ⫽ 0.02) analysis, for bNED calculated from the date of RT completion, the only significant factor was the pre-RT serum PSA level. The 3- and 5-year bNED rate for those with an undetectable pre-RT serum PSA level (adjuvant RT group; ⱕ0.1 ng/mL [Abbott assay] or ⱕ0.2 ng/mL [Hybritech assay]) was 97% and 86%, respectively. However, when the pre-RT serum PSA was detectable (salvage RT group; ⬎0.1 ng/mL [Abbott assay] or ⬎0.2 ng/mL [Hybritech assay]), the 3and 5-year bNED rate was 76% and 57%, respectively (Fig. 2). Among 76 patients, 10 (13%) had a detectable PSA level after prostatectomy. Eight of these patients had both positive margins and seminal vesicle invasion, and 3 had a Gleason grade of 4/5. The 3- and 5-year bNED rate after RT in these patients was 50% and 50%, respectively. The corresponding 3- and 5-year bNED rate among patients with an undetectable PSA after prostatectomy was 91% and 72%, respectively (p ⫽ 0.006).
Adjuvant RT The 3- and 5-year bNED rate for the adjuvant RT group was 97% and 86%, respectively. Univariate analysis for bNED in the adjuvant RT group revealed only seminal vesicle invasion to be significant (p ⫽ 0.04). The 3- and 5-year bNED rate was 100% and 100%, respectively, in the absence of seminal vesicle invasion, compared with 90% and 60%, respectively, in the presence of seminal vesicle invasion (Fig. 3).
1050
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 4, 2002
Fig. 2. Kaplan-Meier estimate of overall biochemical disease-free survival (bNED) after adjuvant or salvage RT.
Salvage RT The 3- and 5-year bNED rate for the salvage RT group was 76% and 57%, respectively. Univariate analysis for bNED revealed only the presence of Gleason grade 4/5 to be significant (p ⫽ 0.04). The 3- and 5-year bNED rate was 95% and 74%, respectively, in the absence of Gleason grade 4/5 compared with 54% and 41%, respectively, in the presence of Gleason grade 4/5 (Fig. 4). Local control and distant metastases The clinical local control in this group of patients was 100%. Two patients with rising PSA levels had distant metastases. No patient had died of prostate cancer at last follow-up. Treatment sequelae At last follow-up, 21 (28%) of 76 patients had some degree of urinary incontinence. No evidence suggested a worsening of urinary incontinence after RT. Among 50 patients in whom information on potency was available, 44 (88%) were impotent at last follow-up. Grade 1 rectal bleeding was present in 3 (4%) of 76 patients. No patient had any Grade 2 or higher late urinary or rectal complications after RT. DISCUSSION Approximately 20 –50% of patients will experience biochemical relapse within 10 years after radical prostatectomy
(2–5). The factors that identify a predisposition to biochemical relapse after surgery include a preoperative serum PSA level ⬎10 ng/mL (2–5), Gleason score ⱖ7 (3–5, 26), and a variety of pathologic observations, including extraprostatic extension (3, 4), multiple positive surgical margins (4, 26), seminal vesicle invasion (3, 4, 26), lymphovascular invasion (27), and lymph node status (4). The use of serum PSA to monitor posttreatment status has significantly increased the recognition of failure rates after radical prostatectomy. In a series of 226 patients reported from Duke University, the clinical failure rate for organ-confined, specimen-confined, and margin-positive disease was 3.9%, 7%, and 13.2%, respectively. However, the corresponding biochemical failure rates (PSA ⬎0.5 ng/mL) in these three groups of patients were 9.8%, 39.4%, and 66% (28). Patients who have biochemical failure after prostatectomy have a 30 – 60% incidence of local recurrence and distant metastases. In a report from Johns Hopkins University, among patients with biochemical failure, local recurrence was detected within 3 years in 62%. The median time to metastases from the time of biochemical failure was 8 years (2, 29). Adjuvant vs. salvage RT In this report, the only significant factor predicting for bNED calculated from the date of RT completion was the pre-RT serum PSA. Adjuvant RT in high-risk patients with undetectable serum PSA levels has been shown to result in significantly superior bNED rates compared with salvage RT (11, 12, 16, 18). The smaller tumor burden is
bNED after prostatectomy and RT
● J. KALAPURAKAL et al.
1051
Fig. 3. Kaplan-Meier estimate of biochemical disease-free survival (bNED) among adjuvant RT patients with or without seminal vesicle invasion.
probably the reason for the higher bNED rates. Another reason may be the higher likelihood of developing distant metastases from persistent untreated locoregional disease in the salvage group (29). The bNED rates in this series are similar to that in other published reports. In the Jefferson University series, the 3-year bNED rate was 93% in the adjuvant group compared with 44% in the salvage group (11). In the William Beaumont Hospital series, the 5-year bNED rate was 67% and 16% in the adjuvant and salvage groups, respectively (16). In a report from Massachusetts General Hospital, the 3-year bNED rate was 88% and 68% for the adjuvant and salvage RT groups, respectively (18). Salvage RT If adjuvant RT is not initiated in high-risk patients after prostatectomy, these patients should be carefully followed so that salvage RT can be performed early. Several reports have shown superior biochemical control rates when the pre-RT PSA was ⬍1–1.5 ng/mL (7, 11, 14, 15, 20). The American Society for Therapeutic Radiology and Oncology consensus panel stated that waiting for a serum PSA elevation of 0.5 ng/mL would not decrease the likelihood of being cured by RT. The threshold serum PSA level beyond which a significant decline in biochemical cure rates resulted was 1.5 ng/mL. The dose of RT
to be used in these patients was recommended as ⱖ64 Gy in 1.8 –2 Gy/fraction (31). Gleason score The Gleason score, together with the serum PSA level and clinical stage, is a significant predictor of pathologic stage after radical prostatectomy (1). In this report, the presence of Gleason grade 4/5 was shown to be a significant prognostic factor among patients undergoing salvage RT. A number of reports have highlighted the adverse prognostic significance of a high Gleason score for the biochemical cure rate after radical prostatectomy (3–5, 26) and adjuvant/salvage RT (8, 21, 31). In a report from Johns Hopkins University, the factors that predicted for distant rather than local failure were PSA velocity, pathologic stage, and Gleason grade (28). The importance of Gleason grade 4 among patients with a Gleason score of 7 has also been demonstrated. Patients with a Gleason score of 4 ⫹ 3 were shown to have a higher biochemical failure rate than did patients with a score of 3 ⫹ 4 (33). In this report, the inferior biochemical cure rates after RT in patients with higher Gleason grade tumors may have been because of occult spread of disease at distant sites. The superior biochemical cure rates in high-grade tumors with a combination of hormonal therapy and RT in patients treated with primary RT in RTOG 85-10 may point toward a similar benefit of such therapy
1052
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 4, 2002
Fig. 4. Kaplan-Meier estimate of biochemical disease-free survival (bNED) among salvage RT patients with and without Gleason grade 4/5.
among patients with high-grade tumors after radical prostatectomy (34). Seminal vesicle invasion In this report and in others, seminal vesicle invasion has been shown to be an important predictor of biochemical failure (18, 32). The factors that predispose to seminal vesicle invasion include larger tumor volume, capsular penetration, poorly differentiated tumors, and lymph node metastases. These features also predispose to local recurrence. In the Mayo Clinic series, the 3-year biochemical control rate after RT when the seminal vesicles were not involved was 79% compared with 45% with seminal vesicle invasion (14). In a report from Thomas Jefferson University, 53 men with seminal vesicle invasion after prostatectomy were either followed or administered early RT or salvage RT. The 3-year bNED rate was 86% in the adjuvant RT group compared with 48% in the observation group (10). Seminal vesicle invasion is an ominous feature predicting for distant failure and local recurrence, hence the addition of hormonal therapy to RT should be considered in these patients. Local control As shown in this report and others, the local control rate after postprostatectomy RT is 95–100% (7–20). In a report from the University of British Columbia, the 5-year freedom from local relapse rate was 79% in the surgery-only group and 100% in the early RT group (p ⫽
0.005). The median interval to local relapse was 9 years in the surgery-only group and had not yet been reached in early RT group (17). The excellent local control rates reported in most RT series are an indicator of the efficacy of RT in these patients. The efficacy of RT can be underestimated by an endpoint such as serum PSA level that is not specific for local control. If high-risk patients do not undergo RT, the incidence of local tumor recurrence in the pelvis may be higher. Locally recurrent tumors are difficult to control even with higher doses of RT and can cause considerable quality-of-life impairment because of tumor invasion into adjacent organs (17). Hormonal therapy and RT Patients at high risk of biochemical failure after radical prostatectomy are likely to develop both local recurrence and distant metastases (29). A number of reports have shown superior biochemical relapse-free survival after prostatectomy with hormonal therapy and RT compared with RT alone (19, 35). In RTOG 85-31, patients with capsular penetration to the surgical margin and/or seminal vesicle involvement after radical prostatectomy were randomized to RT (60 – 65 Gy) and adjuvant goserelin (Zoladex, Zeneca Pharmaceuticals, Wilmington, DE) (Arm I) or RT alone (Arm II). The 5-year freedom from biochemical relapse rate was 65% in Arm I vs. 42% in Arm II (p ⫽ 0.002). Multivariate analysis revealed that immediate hormonal therapy was a significant predictor of improved biochemical freedom from relapse (19). A randomized RTOG study is pres-
bNED after prostatectomy and RT
ently examining the value of hormonal therapy and adjuvant RT in high-risk patients after prostatectomy. In the salvage RT group, particularly with a pre-RT PSA ⬎1 ng/mL and/or local tumor recurrence, the addition of hormonal therapy should be considered to improve on the results achieved with RT alone (8, 16, 19). Treatment sequelae This report, as well as several others, has shown that postprostatectomy RT is well tolerated (7–21). In a prospective randomized study from the University of Louvain, Brussels, adjuvant RT to a dose of 60 Gy delivered 3– 4 months after radical prostatectomy did not increase the incidence of urinary incontinence. After a mean follow-up of 2 years, 77% of the irradiated group and 83% of the surveillance group were totally dry (36).
● J. KALAPURAKAL et al.
1053
CONCLUSION Controversy exists regarding the optimal treatment of patients with high-risk prostate cancer after radical prostatectomy. This report, as well as others, has documented the clinical benefits of RT after radical prostatectomy. In this high-risk group of patients, the overall bNED rate of 82% compares favorably with the results in similar-risk patients treated with prostatectomy alone. RT was associated with minimal sequelae. The significant predictors of biochemical failure after RT were seminal vesicle invasion, salvage RT, and presence of Gleason grade 4 or 5 in the salvage RT group. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.
REFERENCES 1. Partin AW, Subong EN, Walsh PC, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer: A multi-institutional update. JAMA 1997;222:1445–1451. 2. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–1597. 3. Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical prostatectomy for prostate cancer: Intermediate-term results. J Urol 1998;160:2428 –2434. 4. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17:1499 –1507. 5. Amling CL, Blute ML, Bergstralh EJ, et al. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: Continued risk of biochemical failure after 5 years. J Urol 2000;164:101–105. 6. D’Amico AV, Whittington R, Malkowicz SB, et al. Prostatespecific antigen failure despite pathologically organ-confined and margin negative prostate cancer: The basis for an adjuvant therapy trial. J Clin Oncol 1997;1:1465–1469. 7. Forman JD, Duclos M, Shamsa F, et al. Predicting the need for adjuvant systemic therapy in patients receiving postprostatectomy irradiation. Urology 1996;47:382–386. 8. Rogers R, Grossfeld GD, Roach M, et al. Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 1998;160:1738 –1753. 9. Valicenti RK, Gomella LG, Ismail M, et al. The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: A matched-pair analysis. Int J Radiat Oncol Biol Phys 1999;45: 53–58. 10. Valicenti RK, Gomella LG, Ismail M, et al. Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: Effect of early adjuvant radiation therapy on biochemical control. Cancer 1998;82:1909 –1914. 11. Valicenti RK, Gomella LG, Ismail M, et al. Durable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: The importance of radiation dose. Urology 1998;52:1034 –1040. 12. Anscher MS, Robertson CN, Prosnitz LR. Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: Ten year update. Int J Radiat Oncol Biol Phys 1995;33:37– 43. 13. Leibovich BC, Engen DE, Patterson DE, et al. Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin. J Urol 2000;163:1178 –1182.
14. Buskirk SJ, Schild SE, Durr ED, et al. Evaluation of serum prostate-specific antigen levels after postoperative radiation therapy for pathologic stage T3N0 prostate cancer. Mayo Clin Proc 1996;71:242–248. 15. Zelefsky MJ, Aschkenasy E, Kelsen S, et al. Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1997; 39:327–333. 16. Vicini FA, Ziaja EL, Kestin LL, et al. Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 1999;54:111–117. 17. Syndikus I, Pickles T, Kostashuk E, et al. Postoperative radiotherapy for stage pT3 carcinoma of the prostate: Improved local control. J Urol 1996;155:1983–1986. 18. Morris MM, Dallow KC, Zietman AL, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–736. 19. Corn BW, Winter K, Plepich MV. Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31. Urology 1999;54:495–502. 20. Do T, Parker RG, Do C, et al. Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Can J Sci Am 1998;4:324 –330. 21. Catton C, Gospodarowicz M, Warde P, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiat Oncol 2001;59:51– 60. 22. Lawton CA, Won M, Pilepich MV, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935–936. 23. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 24. Mantel N. Evaluation of survival data and two rank order statistics arising in its consideration. Cancer Chemo Rep 1966; 50:163–170. 25. Cox DR. Regression models and life tables. J Roy Stat Soc 1972;34:187–220. 26. D’Amico AV, Whittington R, Malkowicz SB, et al. A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154:131–138. 27. Herman CM, Wilcox GE, Kattan MW, et al. Lymphovascular invasion as a predictor of disease progression in prostate cancer. Am J Surg Pathol 2000;24:859 – 863. 28. Frazier HA, Robertson JE, Humphrey PA, et al. Is prostate
1054
29.
30.
31.
32.
I. J. Radiation Oncology
● Biology ● Physics
specific antigen of clinical importance in evaluating outcome after radical prostatectomy. J Urol 1993;149:516 –518. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649 – 659. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991;21:537–547. Consensus statements on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. J Clin Oncol 1999;17:1155–1163. Epstein JI, Carmichael M, Walsh PC. Adenocarcinoma of the prostate invading the seminal vesicle: Definition and relation of tumor volume, grade and margins of resection to prognosis. J Urol 1993;149:1535–1538.
Volume 54, Number 4, 2002
33. Sakr WA, Tefilli MV, Grignon DJ, et al. Gleason score 7 prostate cancer: A heterogeneous entity? Correlation with pathologic parameters and disease-free survival. Urology 2000;56:730 –734. 34. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49:937–946. 35. Eulau SM, Tate DJ, Stamey TA, et al. Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:735–740. 36. VanCangh PJ, Francoise R, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: Results of a prospective randomized study. J Urol 1998;159:164 –166.
PII S0360-3016(02)03034-1
CLINICAL INVESTIGATION
Prostate
BIOCHEMICAL DISEASE-FREE SURVIVAL FOLLOWING ADJUVANT AND SALVAGE IRRADIATION AFTER RADICAL PROSTATECTOMY JOHN A. KALAPURAKAL, M.D.,* CHENG-FANG HUANG, M.S.,† MANOJ M. NERIAMPARAMPIL, M.D.,* WILLIAM J. SMALL, JR, M.D.,* MICHAEL R. PINS, M.D.,‡ BHARAT B. MITTAL, M.D.,* STEVEN C. CAMPBELL, M.D.,§ JOHN T. GRAYHACK, M.D.,§ AND RAMANANDA M. SHETTY, M.D.*㛳 *Division of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center; and Departments of ‡Pathology and §Urology, Robert H. Lurie Comprehensive Cancer Center—Northwestern University, Chicago, IL; †Department of Preventive Medicine, Northwestern Memorial Hospital, Chicago, IL Purpose: To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. Methods and Materials: Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of <0.2 ng/mL. Results: The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. Conclusion: This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT. © 2002 Elsevier Science Inc. Prostate cancer, Prostate-specific antigen, Prostatectomy, Radiotherapy, Adjuvant therapy, Salvage therapy.
76 patients who received postoperative RT after radical prostatectomy.
INTRODUCTION Radical prostatectomy is widely used for the treatment of early-stage prostate cancer. Approximately 30 – 60% of patients initially thought to have organ-confined disease will have their disease upstaged postoperatively after radical prostatectomy. At least one-half of these patients will have positive surgical margins or seminal vesicle invasion and will be likely to develop relapse (1–5). Serum prostatespecific antigen (PSA), clinical tumor stage, and biopsy Gleason score are among the factors that predict the postoperative tumor stage (1). Approximately 15– 40% of patients with pathologically confirmed organ-confined disease will subsequently develop biochemical failure within 3 years of surgery (6). Postoperative irradiation (RT) has been widely used for the treatment of patients at high risk of relapse after radical prostatectomy (7–21). In this report, we present a retrospective analysis of biochemical disease-free survival (biochemically no evidence of disease [bNED]) in
Patient characteristics Between 1990 and 1997, 76 patients who underwent radical prostatectomy and adjuvant/salvage RT were included in this analysis. None of these patients received hormonal therapy as part of their initial treatment. No patient had known metastatic disease. All patients had pre- and postoperative serum PSA data available. The median patient age was 60 years (range 48 –78), with approximately 50% ⬍60 years of age. Of 74 patients, 12 (16%) had a family history of prostate cancer. All patients underwent pelvic lymph node resection or sampling and radical retropubic prostatectomy. The median preoperative PSA was 12.0 ng/mL (range 4 – 82). A post-
Reprint requests to: John A. Kalapurakal, M.D., Division of Radiation Oncology, Northwestern Memorial Hospital, 251 E. Huron St., LC-178, Chicago, IL 60611. Tel: (312) 926-3761; Fax: (312) 926-6374; E-mail: [email protected]
Presented in part at the 86th Annual meeting of the RSNA, November 2000, Chicago, IL. Received Jan 2, 2002, and in revised form Jun 25, 2002. Accepted for publication Jun 28, 2002.
METHODS AND MATERIALS
1047
1048
I. J. Radiation Oncology
● Biology ● Physics
operative serum PSA nadir of ⱕ0.1 or ⱕ0.2 ng/mL was noted in 66 patients (87%). Patients were referred for RT because of the presence of high-risk features on pathologic examination of the prostatectomy specimen and an undetectable serum PSA (adjuvant RT group 46% [35 of 76]) or rising serum PSA after radical prostatectomy (salvage RT group 54% [41 of 76]). Among the 41 patients referred for salvage RT, 71% (29 of 41) had a pre-RT PSA level of 0.3–1 ng/mL, 19% (8 of 41) had a PSA level between 1 and 3 ng/mL and 10% (4 of 41) had a PSA level between 3.1 and 10 ng/mL. The median serum PSA level in this group of patients was 0.5 ng/mL (range 0.2– 6.5). None of the patients had palpable tumor recurrence in the prostate bed on digital rectal examination before RT. Biopsies of the prostate bed were not routinely performed to document pathologic evidence of residual/recurrent disease. Pathologic evaluation A detailed pathologic examination of the prostatectomy specimen and lymph nodes was performed. The prostate glands were fixed for 6 –24 h in 10% neutral-buffered formalin. The apical and base margins were subjected to multiple perpendicular sectioning, and the remaining gland was sectioned transversely at 4 – 6-mm intervals. All the prostate tissue and one-third of each seminal vesicle were submitted for histopathologic examination. Lymphovascular invasion was defined as the unequivocal presence of tumor cells within an endothelial lined space, often with associated fibrin. In comparison with the transrectal biopsy Gleason scores, the postprostatectomy Gleason score was higher in 29% of the patients (22 of 76). The postprostatectomy Gleason score was ⬍7 in 87% (66 of 76) and 8 –10 in 13% (10 of 76). A Gleason grade of 4 was encountered in 38% (29 of 76), and 11% (8 of 76) had a Gleason grade of 5. Prostate capsular perforation was noted in 78% (59 of 76). The surgical margins were involved with tumor in 53% (40 of 76). Perineural invasion by tumor was encountered in 74% (56 of 76). Seminal vesicle invasion was noted in 22% (17 of 76). Lymphovascular invasion was encountered in 17% (13 of 76). Lymph node involvement was noted in 4% (3 of 76). Radiotherapy The median time between radical prostatectomy and RT was 4 months (range 2 months to 5.5 years). The RT was administered ⱕ6 months after surgery in 69% (52 of 76) and ⬎6 months in 31% (24 of 76). Before RT, all patients underwent simulation using urethrography and oral/rectal barium. CT scan information and surgical clips at the seminal vesicles were used to determine the location of the tumor bed. RT was administered using 10-MV X-rays with a four-field box or bilateral 120° arc technique. The whole pelvis was included in a portion of the irradiated field to a dose of 40 – 45 Gy in 20% (15 of 76). The median radiation dose administered to the tumor bed was 60 Gy (range 60 –70) in 30 fractions prescribed to the 95–100% isodose
Volume 54, Number 4, 2002
line. The median total dose in the adjuvant RT group and salvage RT group was 60 Gy (range 60 – 65) and 65 Gy (range 60 –70), respectively. Follow-up Patients were followed with a detailed history and physical examination, including digital rectal examination and serum PSA levels at each 3– 6-month visit. A detectable PSA, as defined below, was judged to represent recurrent disease. A complete physical examination and CT and bone scans were used to identify the site and extent of recurrence. Acute and late complications were graded using the Radiation Therapy Oncology Group (RTOG) grading criteria (21). The median follow-up in the adjuvant RT group was 3 years (range 0.7– 8.7) from the date of surgery and 2 years (range 0.6 – 6.6) from the date of RT. In the salvage RT group, the median follow-up from date of surgery was 5.3 years (range 0.9 –9.6) and 2.6 years (0.4 –9.2 years) from the date of RT. Definition of biochemical control (bNED) A number of definitions have been used to define biochemical cure rates after radical prostatectomy and postprostatectomy RT. In several large surgical series, PSA levels of ⬍0.2 ng/mL (2), ⬍0.3 ng/mL (3), and ⬍0.4 ng/mL (4, 5) have been used to define biochemical control. Likewise, after postprostatectomy RT, biochemical controls have been variously defined as serum PSA levels of ⬍0.05 ng/mL (7), ⬍0.1 ng/mL (8), ⱕ0.2 ng/mL (9 –13), ⱕ0.3 ng/mL (14), ⱕ0.4 ng/mL (15, 16), and ⱕ0.5 ng/mL (17–19) and as two consecutive rises in the serum PSA level after a PSA nadir (20). In the present report, biochemical cure or bNED was defined by a serum PSA of ⱕ0.2 ng/mL (Hybritech, San Diego, CA) or ⱕ0.1 ng/mL (Abbot Laboratories, Abbott Park, IL). All patients in this report had their serum PSA estimated using either the Hybritech assays (Hybritech) or the Abbott assays (Abbott Laboratories). Patients were judged as having biochemical recurrence if they had two successive elevated PSA levels as defined above from the date of surgery or RT. Statistical analysis Biochemical disease-free survival (bNED) was the primary end point studied. Univariate analyses were used to examine the influence of several clinical, pathologic, and treatment-related factors on bNED survival. The factors studied included patient age, family history, Gleason score (ⱕ7 vs. 8 –10), Gleason grade (no 4, any 4, any 5 and no 4 vs. any 4 or 5), perineural invasion, capsular perforation, surgical margin status, seminal vesicle invasion, lymphovascular invasion, lymph node invasion, radiation dose (60 vs. ⬎60 Gy), radiation field (whole pelvis vs. small fields), preoperative PSA (⬍5, 5–10, ⬎10 ng/mL and ⱕ10 vs. ⬎10 ng/mL), pre-RT PSA (⬍0.1 vs. ⱖ0.1 ng/mL and 0.1–1 ng/mL, 1.1–3 ng/mL, 3.1–10 ng/mL), and interval between surgery and RT (ⱕ6 vs. ⬎6 months). The disease-free and
bNED after prostatectomy and RT
● J. KALAPURAKAL et al.
1049
Fig. 1. Kaplan-Meier estimate of overall biochemical disease-free survival (bNED) from date of surgery in patients with or without seminal vesicle invasion.
overall survival times were analyzed using the KaplanMeier product limit method (23). The log–rank test was used to test the homogeneity of survival functions across strata (24). For those significant variables from the log–rank test, the stepwise procedure of proportional hazards (Cox) regression models was used to select the most significantly associated variable (25). RESULTS Overall biochemical disease-free survival (bNED) For the entire patient group, the 3- and 5-year KaplanMeier bNED rate calculated from the date of surgery was 89% and 77%, respectively. At last follow-up, 81.5% of patients achieved biochemical control (bNED). The mean time to biochemical failure from the date of surgery to the first PSA elevation was 29 months (range 9 – 68). Seminal vesicle invasion was the only significant variable for bNED calculated from the date of surgery on univariate (p ⫽ 0.03) and multivariate (p ⫽ 0.03) analysis. The 3and 5-year bNED rate in the absence of seminal vesicle involvement was 94% and 85%, respectively. However, when seminal vesicle invasion was present, the 3- and 5-year bNED rate was 76% and 57%, respectively (Fig. 1). The 3- and 5-year bNED rate calculated from the end of RT for the entire patient group was 85% and 70%, respectively. The mean time to biochemical failure calculated from the end of RT to the first PSA elevation was 21 months (range 3– 46). On univariate (p ⫽ 0.02) and
multivariate (p ⫽ 0.02) analysis, for bNED calculated from the date of RT completion, the only significant factor was the pre-RT serum PSA level. The 3- and 5-year bNED rate for those with an undetectable pre-RT serum PSA level (adjuvant RT group; ⱕ0.1 ng/mL [Abbott assay] or ⱕ0.2 ng/mL [Hybritech assay]) was 97% and 86%, respectively. However, when the pre-RT serum PSA was detectable (salvage RT group; ⬎0.1 ng/mL [Abbott assay] or ⬎0.2 ng/mL [Hybritech assay]), the 3and 5-year bNED rate was 76% and 57%, respectively (Fig. 2). Among 76 patients, 10 (13%) had a detectable PSA level after prostatectomy. Eight of these patients had both positive margins and seminal vesicle invasion, and 3 had a Gleason grade of 4/5. The 3- and 5-year bNED rate after RT in these patients was 50% and 50%, respectively. The corresponding 3- and 5-year bNED rate among patients with an undetectable PSA after prostatectomy was 91% and 72%, respectively (p ⫽ 0.006).
Adjuvant RT The 3- and 5-year bNED rate for the adjuvant RT group was 97% and 86%, respectively. Univariate analysis for bNED in the adjuvant RT group revealed only seminal vesicle invasion to be significant (p ⫽ 0.04). The 3- and 5-year bNED rate was 100% and 100%, respectively, in the absence of seminal vesicle invasion, compared with 90% and 60%, respectively, in the presence of seminal vesicle invasion (Fig. 3).
1050
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 4, 2002
Fig. 2. Kaplan-Meier estimate of overall biochemical disease-free survival (bNED) after adjuvant or salvage RT.
Salvage RT The 3- and 5-year bNED rate for the salvage RT group was 76% and 57%, respectively. Univariate analysis for bNED revealed only the presence of Gleason grade 4/5 to be significant (p ⫽ 0.04). The 3- and 5-year bNED rate was 95% and 74%, respectively, in the absence of Gleason grade 4/5 compared with 54% and 41%, respectively, in the presence of Gleason grade 4/5 (Fig. 4). Local control and distant metastases The clinical local control in this group of patients was 100%. Two patients with rising PSA levels had distant metastases. No patient had died of prostate cancer at last follow-up. Treatment sequelae At last follow-up, 21 (28%) of 76 patients had some degree of urinary incontinence. No evidence suggested a worsening of urinary incontinence after RT. Among 50 patients in whom information on potency was available, 44 (88%) were impotent at last follow-up. Grade 1 rectal bleeding was present in 3 (4%) of 76 patients. No patient had any Grade 2 or higher late urinary or rectal complications after RT. DISCUSSION Approximately 20 –50% of patients will experience biochemical relapse within 10 years after radical prostatectomy
(2–5). The factors that identify a predisposition to biochemical relapse after surgery include a preoperative serum PSA level ⬎10 ng/mL (2–5), Gleason score ⱖ7 (3–5, 26), and a variety of pathologic observations, including extraprostatic extension (3, 4), multiple positive surgical margins (4, 26), seminal vesicle invasion (3, 4, 26), lymphovascular invasion (27), and lymph node status (4). The use of serum PSA to monitor posttreatment status has significantly increased the recognition of failure rates after radical prostatectomy. In a series of 226 patients reported from Duke University, the clinical failure rate for organ-confined, specimen-confined, and margin-positive disease was 3.9%, 7%, and 13.2%, respectively. However, the corresponding biochemical failure rates (PSA ⬎0.5 ng/mL) in these three groups of patients were 9.8%, 39.4%, and 66% (28). Patients who have biochemical failure after prostatectomy have a 30 – 60% incidence of local recurrence and distant metastases. In a report from Johns Hopkins University, among patients with biochemical failure, local recurrence was detected within 3 years in 62%. The median time to metastases from the time of biochemical failure was 8 years (2, 29). Adjuvant vs. salvage RT In this report, the only significant factor predicting for bNED calculated from the date of RT completion was the pre-RT serum PSA. Adjuvant RT in high-risk patients with undetectable serum PSA levels has been shown to result in significantly superior bNED rates compared with salvage RT (11, 12, 16, 18). The smaller tumor burden is
bNED after prostatectomy and RT
● J. KALAPURAKAL et al.
1051
Fig. 3. Kaplan-Meier estimate of biochemical disease-free survival (bNED) among adjuvant RT patients with or without seminal vesicle invasion.
probably the reason for the higher bNED rates. Another reason may be the higher likelihood of developing distant metastases from persistent untreated locoregional disease in the salvage group (29). The bNED rates in this series are similar to that in other published reports. In the Jefferson University series, the 3-year bNED rate was 93% in the adjuvant group compared with 44% in the salvage group (11). In the William Beaumont Hospital series, the 5-year bNED rate was 67% and 16% in the adjuvant and salvage groups, respectively (16). In a report from Massachusetts General Hospital, the 3-year bNED rate was 88% and 68% for the adjuvant and salvage RT groups, respectively (18). Salvage RT If adjuvant RT is not initiated in high-risk patients after prostatectomy, these patients should be carefully followed so that salvage RT can be performed early. Several reports have shown superior biochemical control rates when the pre-RT PSA was ⬍1–1.5 ng/mL (7, 11, 14, 15, 20). The American Society for Therapeutic Radiology and Oncology consensus panel stated that waiting for a serum PSA elevation of 0.5 ng/mL would not decrease the likelihood of being cured by RT. The threshold serum PSA level beyond which a significant decline in biochemical cure rates resulted was 1.5 ng/mL. The dose of RT
to be used in these patients was recommended as ⱖ64 Gy in 1.8 –2 Gy/fraction (31). Gleason score The Gleason score, together with the serum PSA level and clinical stage, is a significant predictor of pathologic stage after radical prostatectomy (1). In this report, the presence of Gleason grade 4/5 was shown to be a significant prognostic factor among patients undergoing salvage RT. A number of reports have highlighted the adverse prognostic significance of a high Gleason score for the biochemical cure rate after radical prostatectomy (3–5, 26) and adjuvant/salvage RT (8, 21, 31). In a report from Johns Hopkins University, the factors that predicted for distant rather than local failure were PSA velocity, pathologic stage, and Gleason grade (28). The importance of Gleason grade 4 among patients with a Gleason score of 7 has also been demonstrated. Patients with a Gleason score of 4 ⫹ 3 were shown to have a higher biochemical failure rate than did patients with a score of 3 ⫹ 4 (33). In this report, the inferior biochemical cure rates after RT in patients with higher Gleason grade tumors may have been because of occult spread of disease at distant sites. The superior biochemical cure rates in high-grade tumors with a combination of hormonal therapy and RT in patients treated with primary RT in RTOG 85-10 may point toward a similar benefit of such therapy
1052
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 4, 2002
Fig. 4. Kaplan-Meier estimate of biochemical disease-free survival (bNED) among salvage RT patients with and without Gleason grade 4/5.
among patients with high-grade tumors after radical prostatectomy (34). Seminal vesicle invasion In this report and in others, seminal vesicle invasion has been shown to be an important predictor of biochemical failure (18, 32). The factors that predispose to seminal vesicle invasion include larger tumor volume, capsular penetration, poorly differentiated tumors, and lymph node metastases. These features also predispose to local recurrence. In the Mayo Clinic series, the 3-year biochemical control rate after RT when the seminal vesicles were not involved was 79% compared with 45% with seminal vesicle invasion (14). In a report from Thomas Jefferson University, 53 men with seminal vesicle invasion after prostatectomy were either followed or administered early RT or salvage RT. The 3-year bNED rate was 86% in the adjuvant RT group compared with 48% in the observation group (10). Seminal vesicle invasion is an ominous feature predicting for distant failure and local recurrence, hence the addition of hormonal therapy to RT should be considered in these patients. Local control As shown in this report and others, the local control rate after postprostatectomy RT is 95–100% (7–20). In a report from the University of British Columbia, the 5-year freedom from local relapse rate was 79% in the surgery-only group and 100% in the early RT group (p ⫽
0.005). The median interval to local relapse was 9 years in the surgery-only group and had not yet been reached in early RT group (17). The excellent local control rates reported in most RT series are an indicator of the efficacy of RT in these patients. The efficacy of RT can be underestimated by an endpoint such as serum PSA level that is not specific for local control. If high-risk patients do not undergo RT, the incidence of local tumor recurrence in the pelvis may be higher. Locally recurrent tumors are difficult to control even with higher doses of RT and can cause considerable quality-of-life impairment because of tumor invasion into adjacent organs (17). Hormonal therapy and RT Patients at high risk of biochemical failure after radical prostatectomy are likely to develop both local recurrence and distant metastases (29). A number of reports have shown superior biochemical relapse-free survival after prostatectomy with hormonal therapy and RT compared with RT alone (19, 35). In RTOG 85-31, patients with capsular penetration to the surgical margin and/or seminal vesicle involvement after radical prostatectomy were randomized to RT (60 – 65 Gy) and adjuvant goserelin (Zoladex, Zeneca Pharmaceuticals, Wilmington, DE) (Arm I) or RT alone (Arm II). The 5-year freedom from biochemical relapse rate was 65% in Arm I vs. 42% in Arm II (p ⫽ 0.002). Multivariate analysis revealed that immediate hormonal therapy was a significant predictor of improved biochemical freedom from relapse (19). A randomized RTOG study is pres-
bNED after prostatectomy and RT
ently examining the value of hormonal therapy and adjuvant RT in high-risk patients after prostatectomy. In the salvage RT group, particularly with a pre-RT PSA ⬎1 ng/mL and/or local tumor recurrence, the addition of hormonal therapy should be considered to improve on the results achieved with RT alone (8, 16, 19). Treatment sequelae This report, as well as several others, has shown that postprostatectomy RT is well tolerated (7–21). In a prospective randomized study from the University of Louvain, Brussels, adjuvant RT to a dose of 60 Gy delivered 3– 4 months after radical prostatectomy did not increase the incidence of urinary incontinence. After a mean follow-up of 2 years, 77% of the irradiated group and 83% of the surveillance group were totally dry (36).
● J. KALAPURAKAL et al.
1053
CONCLUSION Controversy exists regarding the optimal treatment of patients with high-risk prostate cancer after radical prostatectomy. This report, as well as others, has documented the clinical benefits of RT after radical prostatectomy. In this high-risk group of patients, the overall bNED rate of 82% compares favorably with the results in similar-risk patients treated with prostatectomy alone. RT was associated with minimal sequelae. The significant predictors of biochemical failure after RT were seminal vesicle invasion, salvage RT, and presence of Gleason grade 4 or 5 in the salvage RT group. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.
REFERENCES 1. Partin AW, Subong EN, Walsh PC, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer: A multi-institutional update. JAMA 1997;222:1445–1451. 2. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–1597. 3. Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical prostatectomy for prostate cancer: Intermediate-term results. J Urol 1998;160:2428 –2434. 4. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17:1499 –1507. 5. Amling CL, Blute ML, Bergstralh EJ, et al. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: Continued risk of biochemical failure after 5 years. J Urol 2000;164:101–105. 6. D’Amico AV, Whittington R, Malkowicz SB, et al. Prostatespecific antigen failure despite pathologically organ-confined and margin negative prostate cancer: The basis for an adjuvant therapy trial. J Clin Oncol 1997;1:1465–1469. 7. Forman JD, Duclos M, Shamsa F, et al. Predicting the need for adjuvant systemic therapy in patients receiving postprostatectomy irradiation. Urology 1996;47:382–386. 8. Rogers R, Grossfeld GD, Roach M, et al. Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 1998;160:1738 –1753. 9. Valicenti RK, Gomella LG, Ismail M, et al. The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: A matched-pair analysis. Int J Radiat Oncol Biol Phys 1999;45: 53–58. 10. Valicenti RK, Gomella LG, Ismail M, et al. Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: Effect of early adjuvant radiation therapy on biochemical control. Cancer 1998;82:1909 –1914. 11. Valicenti RK, Gomella LG, Ismail M, et al. Durable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: The importance of radiation dose. Urology 1998;52:1034 –1040. 12. Anscher MS, Robertson CN, Prosnitz LR. Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: Ten year update. Int J Radiat Oncol Biol Phys 1995;33:37– 43. 13. Leibovich BC, Engen DE, Patterson DE, et al. Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin. J Urol 2000;163:1178 –1182.
14. Buskirk SJ, Schild SE, Durr ED, et al. Evaluation of serum prostate-specific antigen levels after postoperative radiation therapy for pathologic stage T3N0 prostate cancer. Mayo Clin Proc 1996;71:242–248. 15. Zelefsky MJ, Aschkenasy E, Kelsen S, et al. Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1997; 39:327–333. 16. Vicini FA, Ziaja EL, Kestin LL, et al. Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 1999;54:111–117. 17. Syndikus I, Pickles T, Kostashuk E, et al. Postoperative radiotherapy for stage pT3 carcinoma of the prostate: Improved local control. J Urol 1996;155:1983–1986. 18. Morris MM, Dallow KC, Zietman AL, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–736. 19. Corn BW, Winter K, Plepich MV. Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31. Urology 1999;54:495–502. 20. Do T, Parker RG, Do C, et al. Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Can J Sci Am 1998;4:324 –330. 21. Catton C, Gospodarowicz M, Warde P, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiat Oncol 2001;59:51– 60. 22. Lawton CA, Won M, Pilepich MV, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935–936. 23. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. 24. Mantel N. Evaluation of survival data and two rank order statistics arising in its consideration. Cancer Chemo Rep 1966; 50:163–170. 25. Cox DR. Regression models and life tables. J Roy Stat Soc 1972;34:187–220. 26. D’Amico AV, Whittington R, Malkowicz SB, et al. A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154:131–138. 27. Herman CM, Wilcox GE, Kattan MW, et al. Lymphovascular invasion as a predictor of disease progression in prostate cancer. Am J Surg Pathol 2000;24:859 – 863. 28. Frazier HA, Robertson JE, Humphrey PA, et al. Is prostate
1054
29.
30.
31.
32.
I. J. Radiation Oncology
● Biology ● Physics
specific antigen of clinical importance in evaluating outcome after radical prostatectomy. J Urol 1993;149:516 –518. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649 – 659. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991;21:537–547. Consensus statements on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. J Clin Oncol 1999;17:1155–1163. Epstein JI, Carmichael M, Walsh PC. Adenocarcinoma of the prostate invading the seminal vesicle: Definition and relation of tumor volume, grade and margins of resection to prognosis. J Urol 1993;149:1535–1538.
Volume 54, Number 4, 2002
33. Sakr WA, Tefilli MV, Grignon DJ, et al. Gleason score 7 prostate cancer: A heterogeneous entity? Correlation with pathologic parameters and disease-free survival. Urology 2000;56:730 –734. 34. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49:937–946. 35. Eulau SM, Tate DJ, Stamey TA, et al. Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:735–740. 36. VanCangh PJ, Francoise R, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: Results of a prospective randomized study. J Urol 1998;159:164 –166.