- Email: [email protected]
Salvage radiation for a rising PSA following radical prostatectomy
Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
Seminar article
Salvage radiation for a rising PSA following radical prostatectomy Jordan Maier, M.D.a, Jeffrey Forman, M.D.a,*, Samuel Tekyi-Mensah, Ph.D.a, Susan Bolton, M.S.a, Rajiv Patel, M.D.a, J. Edson Pontes, M.D.b a
Gershenson Radiation Oncology Center of the Barbara Ann Karmanos Center Institute, Wayne State University, Detroit, MI, USA b Department of Urology, Wayne State University, Detroit, MI, USA
Abstract The purpose of this study was to evaluate the efficacy and complications of postprostatectomy therapeutic irradiation (RT) in patients with known residual disease. Between 1991 and 2003, 170 patients received therapeutic irradiation for a rising PSA following radical prostatectomy. No patients had clinical or radiological evidence of metastatic disease. The median pre-RT PSA level was 1.2 ng/mL (range, 0.2– 43 ng/mL). During irradiation, the PSA level was checked weekly (median PSA determinations: 5, range, 2–7). A patient was considered to have a rise/fall of PSA if the level changed by ⱖ0.2 ng/mL. There were 149 patients who received photon irradiation (median dose, 6800 cGy) and 21 patients received a combination of photon and neutron irradiation to a median photon dose equivalent of 7800 cGy. A patient was considered to have biochemical failure if his PSA level postnadir was measured at ⬎0.2 ng/mL. Complications were graded according to the RTOG toxicity scale. The median follow-up time was 49 months (range, 1-137 months). Sixty-four patients (38%) had evidence of biochemical failure. The 7 year overall survival was 84%. At 7 years, the actuarial biochemical relapse free survival (bRFS) was 44%. Of the 59 patients with a preradiation PSA ⬍1 ng/mL, the 5 year bRFS was 81%. This compares with 45% for both the PSA 1-4 and PSA ⬎4 ng/mL group (P ⫽ 0.00008). The 3-year bRFS rates for patients whose PSA levels increased, decreased, and remained the same during radiation were 20%, 65%, and 76%, respectively (P ⫽ 0.0005). Overall survival at 7 years in the decreased PSA group was 88% compared to 67% for those whose PSA level increased (P ⫽ 0.43). Thirty-three percent and 19% of the patients experienced Grade 2 genitourinary (GU) and gastrointestinal (GI) complications, respectively. Six percent and 3% of the patients had Grade 3 GU and GI complications, respectively. On univariate and multivariate analysis, the factors significantly associated with a favorable outcome were a declining PSA during RT and a pre-RT PSA ⬍1 ng/mL (P ⬍ 0.001). Radiation therapy is an effective treatment modality for select patients with a biochemical recurrence following radical prostatectomy. Patients with a low preradiation PSA level (⬍1.0 ng/mL) had a significantly better outcome, which supports the early use of therapeutic radiation. The observation that patients with a rising PSA level during treatment do poorly supports the routine practice of monitoring these levels during radiotherapy. © 2004 Elsevier Inc. All rights reserved. Keywords: Salvage radiation; Postprostatectomy; Prostate cancer
Introduction Over the past two decades a downward stage migration has occurred in the diagnosis of prostate cancer. The increased detection of early stage disease has led to an increase in the number of patients treated with radical prostatectomy (RP). Between 1988 and 1992, curative treatment with radical prostatectomy had increased from 17.4 to 54.6 per 100,000 organ confined cases [1]. A significant percentage of patients are upstaged at the time of surgery that may
* Corresponding author. Tel.: ⫹1-313-745-2593; fax: ⫹1-313-7452314. E-mail address: [email protected] (J. Forman). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2003.12.001
increase the probability of recurrence. Between 20 to 40% of patients will experience a biochemical failure—manifested by a rise in the prostate specific antigen (PSA)— within 5 years of RP [2,3] and may require additional therapy. The treatment of a biochemical recurrence (BCR) following radical prostatectomy is the subject of much debate. Radiation therapy (RT) is often utilized to treat patients who fail primary surgery in hopes of curing patients with localized disease, preventing disease dissemination, and improving overall survival. Previously reported data on the benefit of postprostatectomy RT has been inconsistent because of small patient numbers, poor patient selection, short followup, and inadequate radiation doses. The purpose of this study was to evaluate the efficacy, complications, and prog-
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56 Table 1 Patient characteristics Factors Age (years) Median (range) Race African American White Other Gleason score (at prostatectomy) 4 5 6 7 8 9 Unknown Pathologic stage T2a/b T2c T3a/b T3c Other (T4, NI, etc.) Unknown Preradiation hormones Yes No Pre-RT PSA ⬍1 ng/mL 1–4 ng/mL ⬎4 ng/mL Time from surgery to radiation ⬍1 year ⬎1 year Follow-up time (months) Median
Results 64 (49–76) 43 (25%) 121 (71%) 6 (4%) 2 (1.2%) 9 (5.3%) 26 (15.3%) 84 (49.4%) 29 (17.1%) 14 (8.2%) 6 (3.5%) 40 (23.5%) 5 (2.9%) 24 (14.1%) 16 (9.4%) 16 (9.4%) 69 (40.1%) 27 (15.9%) 143 (84.1%) 59 (34.7%) 62 (36.4%) 49 (28.8%) 12 (7.0%) 158 (92.9%) 49
nostic factors associated with postprostatectomy therapeutic RT in patients with known residual disease.
Methods and materials Between 1991 and 2003, 170 patients received therapeutic irradiation for a rising PSA following radical prostatectomy at the Department of Radiation Oncology, Wayne State University. No patients had clinical or radiological evidence of metastatic disease. The median interval from surgery to radiation was 34 months (range, 7–123 months). Twenty-seven patients (15.9%) received pre-RT hormones for a median time of 3 months (range, 1–18 months). The patients’ characteristics are listed in Table 1. The median pre-RT PSA level was 1.2 ng/mL (range, 0.2– 43 ng/mL). During irradiation, the PSA level was checked weekly (median PSA determinations: 5, range, 2–7). A patient was considered to have a rise or fall of PSA during irradiation if the level changed by ⱖ0.2 ng/mL. All patients underwent computed tomography (CT) simulation using alpha cradle immobilization with fields de-
51
signed to conform to the size, shape, and location of the 3-dimensionally reconstructed preoperative prostate and seminal vesicle volumes. There were 149 patients who received photon irradiation (10 –15 MV) to a median dose of 6800 cGy with a combination of axial and non-coplanar fields. Twenty-one patients received a combination of photon and neutron irradiation to a median photon dose equivalent of 7800 cGy. The photon treatment planning was similar to the photon only group and the neutrons were delivered via a 6-field technique. Patients were routinely followed every 4 to 6 months following RT with a physical exam and PSA measurement. Bone scan and CT scan were obtained only as warranted by a patient’s symptoms or rise in his PSA. A patient was considered to have biochemical failure if his PSA level postnadir was measured at ⱖ0.2 ng/mL. The median follow-up time was 49 months (range, 1–137 months). The STATISTICA statistical software package was used to conduct statistical analyses of the data. All actuarial event-free survival curves were generated using the KaplanMeier product limit method. Comparisons of survival curves were based on the log-rank test. Univariate and multivariable analyses were performed with the Cox proportional hazards model. Statistical significance was established at the 5% level and all tests were 2-sided.
Results Sixty-four patients (38%) had evidence of biochemical failure. The 7-year overall survival was 84% (Fig. 1) and the 7 year actuarial biochemical relapse free survival (bRFS) was 44% (Fig. 2). Of the 59 patients with a preradiation PSA ⬍1 ng/mL, the 5 year bRFS was 81%. This compares with 45% for both the PSA 1– 4 and ⬎4 ng/mL groups (P ⫽ 0.00008) (Fig. 3). The 3-year bRFS rates for patients whose PSA levels increased, decreased, or remained the same during radiation were 20%, 65%, and 76%, respectively (P ⫽ 0.0005) (Fig. 4). Overall survival at 7 years in the patient group whose PSA levels decreased during irradiation or remained stable was 88% compared to 67% for those whose PSA level increased (P ⫽ 0.43). Twenty-one patients received hormones following radiation therapy for a rising PSA or radiographic evidence of progression. Complications were graded according to the RTOG toxicity scale. Thirty-three and 19% of the patients experienced Grade 2 genitourinary (GU) and gastrointestinal (GI) complications, respectively. Six and 3% of the patients had Grade 3 GU and GI complications, respectively (Fig. 5a and b). On univariate and multivariate analysis, the factors significantly associated with a favorable outcome were a stable or declining PSA during RT and a pre-RT PSA ⬍1 ng/mL (P ⬍ 0.001). Factors not found to be significant were preoperative Gleason score, use of pretreatment hormones, use of neutrons, and the time from surgery to radiation.
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J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
Fig. 1. Overall survival.
Discussion This review is one of the largest single institutional analyses of postprostatectomy radiation in patients with a biochemical recurrence. Our reported overall survival rate
of 84% was comparable to other institutional reviews [6] as was our 48% 5 year bRFS rate [4 – 6]. It compared favorably to the estimates of the 1997 ASTRO Consensus Panel, which concluded that a 5-year failure free survival rate of 27 to 45% was accurate based on retrospective pooled analysis
Fig. 2. Overall bNED survival.
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
53
Fig. 3. Significance of pre-RT PSA.
[7]. The data further supports the notion that radiation therapy can result in a high complete response rate for a significant percentage of patients with a relapse following radical prostatectomy. Local disease control and prevention of disease progression can, at the least, result in the postponement of systemic therapy and its associated side effects. With longer follow-up, perhaps a survival advantage will result as well.
The treatment of a biochemical recurrence following radical prostatectomy is controversial. The clinical significance of a rising PSA is unclear because it does not necessarily correlate with a patient’s morbidity/mortality. The long and variable natural history of prostate cancer further distorts treatment decision-making. In a large cohort of patients with a BCR following RP, Pound et al. showed that the median interval from biochemical recurrence to bone
Fig. 4. Significance of PSA trend during radiotherapy.
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J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
Fig. 5. A: Incidence of Grade 3 GU toxicity. B: Incidence of Grade 3 GI toxicity.
metastasis was 8 years and the median time from the development of metastasis to death another 5 years. Thirtyseven percent of patients with BCR had clinical evidence of metastatic disease and 57% of patients with metastasis died of prostate cancer within 5 years [8]. Frazier et al. showed that 93% of patients with post-RP BCR did not experience clinical evidence of disease at 5 years [9]. Data from Jhaveri et al. demonstrated no survival difference between patients
with and without biochemical recurrence [10]. Clinicians have traditionally debated the need for therapy in a group of patients that has been older and sicker than today’s patient. With the widespread use of PSA testing, a younger, healthier population is being diagnosed with prostate cancer [11]. While most patients in the past could be observed with no clinical consequence, an increasing number of patients would now live to experience disease progression.
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
The difficulty in identifying the site of disease (local vs. systemic) provides an additional area of treatment uncertainty. While a rising PSA is indicative of recurrent/residual disease, it is not specific to disease location. As current diagnostic imaging such as bone scan, CT scan, PET scan, prostascint scan, and TRUS guided biopsy lacks sensitivity in this setting [12–15], clinicopathologic factors have been used to identify those at risk of harboring systemic disease. These factors include a high Gleason score, high PSA velocity, short PSA doubling time, seminal vesicle invasion, and time to failure [16 –19]. Patients in our study with a BCR within 1 year of surgery had a higher median pre-RT PSA level (3.9 vs. 1.03 ng/mL) and a higher percentage of patients with PSA levels that rose during treatment (25% vs. 7%), likely indicating the presence of occult metastatic disease. The lack of a statistically significant difference in outcome between the patients who failed less than 1 year from surgery versus those who failed after a year is attributable to the low sample size in the former group. Time to failure was previously shown to a strong predictor of distant metastasis. Pound’s data showed that while 7% of those who failed within 1 year of surgery had only local failure, 74% of those who failed after 3 years had local failure [8]. The pattern of change of PSA levels during the course of radiation likewise indicates whether the recurrent disease is localized. Inter-treatment PSA measurements have now been shown to be an independent predictor of who will benefit from salvage radiotherapy. Because radiation therapy only affects disease in its targeted field, a rising PSA level would likely represent systemic disease not affected by the localized treatment. In our study, patients who had a stable or declining PSA during radiation had a statistically significant better bRFS than those with a rising PSA. This finding was previously reported in our earlier analysis [20]. Radiation can be stopped early in patients with a rising PSA— under the presumption that disease is beyond the prostatic fossa—thereby avoiding the unnecessary toxicities of radiation and allowing these patients to begin systemic therapy. Several other factors have been previously reported as statistically significant predictors of outcome. These include pathologic T stage, seminal vesicle invasion, tumor grade, and pre-RT PSA [6,20 –24]. Perhaps the most important of these is pre-RT PSA. In our review, pre-RT PSA was a significant factor for bRFS. Patients with a PSA ⬍1 had a 7-year bRFS rate of 81% compared to 45% for those with a PSA level greater than 1. Our previously reported data [24] demonstrated that patients with a PSA ⬍2 had a bRFS of 78 vs. 31% for those with a PSA greater than 2. The data from Duke University showed that 52% of patients with a PSA ⬍2.5 were NED compared to 8% for those with a greater PSA [22]. The ASTRO Consensus Committee recommended initiation of radiotherapy at a threshold PSA of ⬍1.5 ng/mL for optimal response [7]. The data is overwhelmingly in favor of early intervention, i.e., beginning radiation when the PSA level is low.
55
Conclusion Radiation therapy is an effective treatment modality for select patients with a biochemical recurrence following radical prostatectomy. Patients with a low preradiation PSA level (⬍1.0 ng/mL) had a significantly better outcome, which supports the early use of therapeutic radiation. The observation that patients with a rising PSA level during treatment do poorly supports the practice of monitoring these levels during radiotherapy and changing strategies from local to systemic in patients with a rising PSA level.
References [1] Stephenson RA. Population based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) Program. Monogr Urol 1988;19:1. [2] Catalona WJ, Smith DS. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152:1837– 42. [3] Kupelian PA, Katcher J, Levin HS, et al. 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;37:1043–52. [4] Anscher MS, Cough R. Radiotherapy for a rising PSA after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 1999; 45:357. [5] Pisansky TM, Kozelsky TF, Myers RP, et al. Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 2000;16:845–50. [6] Schild SE, Pisansky TM. The role of radiotherapy after radical prostatectomy. Urol Clin North Am 2001;28(3):629 –37. [7] Cox JD, Gallagher MJ, Hammond EH, et al. 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. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 1999;17:1155. [8] Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7. [9] Frazier HA, Robertson JE, Humphrey PA, et al. Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy? J Urol 1993;149:516 – 8. [10] Jhaveri FM, Zippe CD, Klein EA, et al. Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10 year results. Urology 1999;54:884 –90. [11] Moul JW, Wu H, Sun L, et al. Epidemiology of radical prostatectomy for localized prostate cancer in the era of prostate-specific antigen: an overview of the Department of Defense Center for Prostate Disease Research national database. Surgery 2002;132(2):213–9. [12] Salomen CG, Flisak MC, Olson, et al. Radical prostatectomy: transrectal sonographic evaluation to assess for local recurrence. Radiology 1993; 189:713-9. [13] Kramer S, Gorich J, Gottfried HW, et al. Sensitivity of computed tomography in detecting local recurrence of prostatic carcinoma following radical prostatectomy. Br J Radiol 1997;70:2041– 6. [14] Cher ML, Bianco FJ, Lam JS, et al. Limited role of radionuclide bone scintigraphy in patients with prostate antigen elevations after radical prostatectomy. J Urol 1998;160:1387. [15] Kahn D, Williams RD, Seldin DW, et al. Radioimmunoscintigraphy with 111indium labeled CYT—356 for the detection of occult prostate cancer recurrence. J Urol 1994;152:1490.
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[16] Pound CR, Partin AW, Epstein JI, et al. Prostate-specific antigen after anatomic radical retropubic prostatectomy: patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395– 406. [17] Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastasis. Urology 1994;43: 649 –59. [18] Patel A, Dorey F, Franklin J, et al. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 1997;158:1441–5. [19] Youssef, E, Tekyi-Mensah, S, Hart, K, et al The prognostic significance of changes in prostatic specific antigen (PSA) levels during the course of therapeutic post prostatectomy irradiation. Presented at the American Society for Therapeutic Radiation Oncology, San Antonio, Texas, November, 1999.
[20] 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(4):731– 6. [21] Leventis AK, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001;19(4):1030 –9. [22] Wu JJ, King SC, Montana GS, et al. The efficacy of postprostatectomy radiotherapy in patients with an isolated elevation of serum prostate specific antigen. Int J Radiat Oncol Biol Phys 1995;32(2): 317–23. [23] Forman JD, Duclos M, Shamsa F, et al. Predicting the need for adjuvant systemic therapy in patients receiving post prostatectomy irradiation. Urology 1996;47(3):382– 6. [24] Garg MK, Tekyi-Mensah S, Bolton S, et al. Impact of post prostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology 1998;51(6):998 –1002.
Seminar article
Salvage radiation for a rising PSA following radical prostatectomy Jordan Maier, M.D.a, Jeffrey Forman, M.D.a,*, Samuel Tekyi-Mensah, Ph.D.a, Susan Bolton, M.S.a, Rajiv Patel, M.D.a, J. Edson Pontes, M.D.b a
Gershenson Radiation Oncology Center of the Barbara Ann Karmanos Center Institute, Wayne State University, Detroit, MI, USA b Department of Urology, Wayne State University, Detroit, MI, USA
Abstract The purpose of this study was to evaluate the efficacy and complications of postprostatectomy therapeutic irradiation (RT) in patients with known residual disease. Between 1991 and 2003, 170 patients received therapeutic irradiation for a rising PSA following radical prostatectomy. No patients had clinical or radiological evidence of metastatic disease. The median pre-RT PSA level was 1.2 ng/mL (range, 0.2– 43 ng/mL). During irradiation, the PSA level was checked weekly (median PSA determinations: 5, range, 2–7). A patient was considered to have a rise/fall of PSA if the level changed by ⱖ0.2 ng/mL. There were 149 patients who received photon irradiation (median dose, 6800 cGy) and 21 patients received a combination of photon and neutron irradiation to a median photon dose equivalent of 7800 cGy. A patient was considered to have biochemical failure if his PSA level postnadir was measured at ⬎0.2 ng/mL. Complications were graded according to the RTOG toxicity scale. The median follow-up time was 49 months (range, 1-137 months). Sixty-four patients (38%) had evidence of biochemical failure. The 7 year overall survival was 84%. At 7 years, the actuarial biochemical relapse free survival (bRFS) was 44%. Of the 59 patients with a preradiation PSA ⬍1 ng/mL, the 5 year bRFS was 81%. This compares with 45% for both the PSA 1-4 and PSA ⬎4 ng/mL group (P ⫽ 0.00008). The 3-year bRFS rates for patients whose PSA levels increased, decreased, and remained the same during radiation were 20%, 65%, and 76%, respectively (P ⫽ 0.0005). Overall survival at 7 years in the decreased PSA group was 88% compared to 67% for those whose PSA level increased (P ⫽ 0.43). Thirty-three percent and 19% of the patients experienced Grade 2 genitourinary (GU) and gastrointestinal (GI) complications, respectively. Six percent and 3% of the patients had Grade 3 GU and GI complications, respectively. On univariate and multivariate analysis, the factors significantly associated with a favorable outcome were a declining PSA during RT and a pre-RT PSA ⬍1 ng/mL (P ⬍ 0.001). Radiation therapy is an effective treatment modality for select patients with a biochemical recurrence following radical prostatectomy. Patients with a low preradiation PSA level (⬍1.0 ng/mL) had a significantly better outcome, which supports the early use of therapeutic radiation. The observation that patients with a rising PSA level during treatment do poorly supports the routine practice of monitoring these levels during radiotherapy. © 2004 Elsevier Inc. All rights reserved. Keywords: Salvage radiation; Postprostatectomy; Prostate cancer
Introduction Over the past two decades a downward stage migration has occurred in the diagnosis of prostate cancer. The increased detection of early stage disease has led to an increase in the number of patients treated with radical prostatectomy (RP). Between 1988 and 1992, curative treatment with radical prostatectomy had increased from 17.4 to 54.6 per 100,000 organ confined cases [1]. A significant percentage of patients are upstaged at the time of surgery that may
* Corresponding author. Tel.: ⫹1-313-745-2593; fax: ⫹1-313-7452314. E-mail address: [email protected] (J. Forman). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2003.12.001
increase the probability of recurrence. Between 20 to 40% of patients will experience a biochemical failure—manifested by a rise in the prostate specific antigen (PSA)— within 5 years of RP [2,3] and may require additional therapy. The treatment of a biochemical recurrence (BCR) following radical prostatectomy is the subject of much debate. Radiation therapy (RT) is often utilized to treat patients who fail primary surgery in hopes of curing patients with localized disease, preventing disease dissemination, and improving overall survival. Previously reported data on the benefit of postprostatectomy RT has been inconsistent because of small patient numbers, poor patient selection, short followup, and inadequate radiation doses. The purpose of this study was to evaluate the efficacy, complications, and prog-
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56 Table 1 Patient characteristics Factors Age (years) Median (range) Race African American White Other Gleason score (at prostatectomy) 4 5 6 7 8 9 Unknown Pathologic stage T2a/b T2c T3a/b T3c Other (T4, NI, etc.) Unknown Preradiation hormones Yes No Pre-RT PSA ⬍1 ng/mL 1–4 ng/mL ⬎4 ng/mL Time from surgery to radiation ⬍1 year ⬎1 year Follow-up time (months) Median
Results 64 (49–76) 43 (25%) 121 (71%) 6 (4%) 2 (1.2%) 9 (5.3%) 26 (15.3%) 84 (49.4%) 29 (17.1%) 14 (8.2%) 6 (3.5%) 40 (23.5%) 5 (2.9%) 24 (14.1%) 16 (9.4%) 16 (9.4%) 69 (40.1%) 27 (15.9%) 143 (84.1%) 59 (34.7%) 62 (36.4%) 49 (28.8%) 12 (7.0%) 158 (92.9%) 49
nostic factors associated with postprostatectomy therapeutic RT in patients with known residual disease.
Methods and materials Between 1991 and 2003, 170 patients received therapeutic irradiation for a rising PSA following radical prostatectomy at the Department of Radiation Oncology, Wayne State University. No patients had clinical or radiological evidence of metastatic disease. The median interval from surgery to radiation was 34 months (range, 7–123 months). Twenty-seven patients (15.9%) received pre-RT hormones for a median time of 3 months (range, 1–18 months). The patients’ characteristics are listed in Table 1. The median pre-RT PSA level was 1.2 ng/mL (range, 0.2– 43 ng/mL). During irradiation, the PSA level was checked weekly (median PSA determinations: 5, range, 2–7). A patient was considered to have a rise or fall of PSA during irradiation if the level changed by ⱖ0.2 ng/mL. All patients underwent computed tomography (CT) simulation using alpha cradle immobilization with fields de-
51
signed to conform to the size, shape, and location of the 3-dimensionally reconstructed preoperative prostate and seminal vesicle volumes. There were 149 patients who received photon irradiation (10 –15 MV) to a median dose of 6800 cGy with a combination of axial and non-coplanar fields. Twenty-one patients received a combination of photon and neutron irradiation to a median photon dose equivalent of 7800 cGy. The photon treatment planning was similar to the photon only group and the neutrons were delivered via a 6-field technique. Patients were routinely followed every 4 to 6 months following RT with a physical exam and PSA measurement. Bone scan and CT scan were obtained only as warranted by a patient’s symptoms or rise in his PSA. A patient was considered to have biochemical failure if his PSA level postnadir was measured at ⱖ0.2 ng/mL. The median follow-up time was 49 months (range, 1–137 months). The STATISTICA statistical software package was used to conduct statistical analyses of the data. All actuarial event-free survival curves were generated using the KaplanMeier product limit method. Comparisons of survival curves were based on the log-rank test. Univariate and multivariable analyses were performed with the Cox proportional hazards model. Statistical significance was established at the 5% level and all tests were 2-sided.
Results Sixty-four patients (38%) had evidence of biochemical failure. The 7-year overall survival was 84% (Fig. 1) and the 7 year actuarial biochemical relapse free survival (bRFS) was 44% (Fig. 2). Of the 59 patients with a preradiation PSA ⬍1 ng/mL, the 5 year bRFS was 81%. This compares with 45% for both the PSA 1– 4 and ⬎4 ng/mL groups (P ⫽ 0.00008) (Fig. 3). The 3-year bRFS rates for patients whose PSA levels increased, decreased, or remained the same during radiation were 20%, 65%, and 76%, respectively (P ⫽ 0.0005) (Fig. 4). Overall survival at 7 years in the patient group whose PSA levels decreased during irradiation or remained stable was 88% compared to 67% for those whose PSA level increased (P ⫽ 0.43). Twenty-one patients received hormones following radiation therapy for a rising PSA or radiographic evidence of progression. Complications were graded according to the RTOG toxicity scale. Thirty-three and 19% of the patients experienced Grade 2 genitourinary (GU) and gastrointestinal (GI) complications, respectively. Six and 3% of the patients had Grade 3 GU and GI complications, respectively (Fig. 5a and b). On univariate and multivariate analysis, the factors significantly associated with a favorable outcome were a stable or declining PSA during RT and a pre-RT PSA ⬍1 ng/mL (P ⬍ 0.001). Factors not found to be significant were preoperative Gleason score, use of pretreatment hormones, use of neutrons, and the time from surgery to radiation.
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J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
Fig. 1. Overall survival.
Discussion This review is one of the largest single institutional analyses of postprostatectomy radiation in patients with a biochemical recurrence. Our reported overall survival rate
of 84% was comparable to other institutional reviews [6] as was our 48% 5 year bRFS rate [4 – 6]. It compared favorably to the estimates of the 1997 ASTRO Consensus Panel, which concluded that a 5-year failure free survival rate of 27 to 45% was accurate based on retrospective pooled analysis
Fig. 2. Overall bNED survival.
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
53
Fig. 3. Significance of pre-RT PSA.
[7]. The data further supports the notion that radiation therapy can result in a high complete response rate for a significant percentage of patients with a relapse following radical prostatectomy. Local disease control and prevention of disease progression can, at the least, result in the postponement of systemic therapy and its associated side effects. With longer follow-up, perhaps a survival advantage will result as well.
The treatment of a biochemical recurrence following radical prostatectomy is controversial. The clinical significance of a rising PSA is unclear because it does not necessarily correlate with a patient’s morbidity/mortality. The long and variable natural history of prostate cancer further distorts treatment decision-making. In a large cohort of patients with a BCR following RP, Pound et al. showed that the median interval from biochemical recurrence to bone
Fig. 4. Significance of PSA trend during radiotherapy.
54
J. Maier et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 50 –56
Fig. 5. A: Incidence of Grade 3 GU toxicity. B: Incidence of Grade 3 GI toxicity.
metastasis was 8 years and the median time from the development of metastasis to death another 5 years. Thirtyseven percent of patients with BCR had clinical evidence of metastatic disease and 57% of patients with metastasis died of prostate cancer within 5 years [8]. Frazier et al. showed that 93% of patients with post-RP BCR did not experience clinical evidence of disease at 5 years [9]. Data from Jhaveri et al. demonstrated no survival difference between patients
with and without biochemical recurrence [10]. Clinicians have traditionally debated the need for therapy in a group of patients that has been older and sicker than today’s patient. With the widespread use of PSA testing, a younger, healthier population is being diagnosed with prostate cancer [11]. While most patients in the past could be observed with no clinical consequence, an increasing number of patients would now live to experience disease progression.
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The difficulty in identifying the site of disease (local vs. systemic) provides an additional area of treatment uncertainty. While a rising PSA is indicative of recurrent/residual disease, it is not specific to disease location. As current diagnostic imaging such as bone scan, CT scan, PET scan, prostascint scan, and TRUS guided biopsy lacks sensitivity in this setting [12–15], clinicopathologic factors have been used to identify those at risk of harboring systemic disease. These factors include a high Gleason score, high PSA velocity, short PSA doubling time, seminal vesicle invasion, and time to failure [16 –19]. Patients in our study with a BCR within 1 year of surgery had a higher median pre-RT PSA level (3.9 vs. 1.03 ng/mL) and a higher percentage of patients with PSA levels that rose during treatment (25% vs. 7%), likely indicating the presence of occult metastatic disease. The lack of a statistically significant difference in outcome between the patients who failed less than 1 year from surgery versus those who failed after a year is attributable to the low sample size in the former group. Time to failure was previously shown to a strong predictor of distant metastasis. Pound’s data showed that while 7% of those who failed within 1 year of surgery had only local failure, 74% of those who failed after 3 years had local failure [8]. The pattern of change of PSA levels during the course of radiation likewise indicates whether the recurrent disease is localized. Inter-treatment PSA measurements have now been shown to be an independent predictor of who will benefit from salvage radiotherapy. Because radiation therapy only affects disease in its targeted field, a rising PSA level would likely represent systemic disease not affected by the localized treatment. In our study, patients who had a stable or declining PSA during radiation had a statistically significant better bRFS than those with a rising PSA. This finding was previously reported in our earlier analysis [20]. Radiation can be stopped early in patients with a rising PSA— under the presumption that disease is beyond the prostatic fossa—thereby avoiding the unnecessary toxicities of radiation and allowing these patients to begin systemic therapy. Several other factors have been previously reported as statistically significant predictors of outcome. These include pathologic T stage, seminal vesicle invasion, tumor grade, and pre-RT PSA [6,20 –24]. Perhaps the most important of these is pre-RT PSA. In our review, pre-RT PSA was a significant factor for bRFS. Patients with a PSA ⬍1 had a 7-year bRFS rate of 81% compared to 45% for those with a PSA level greater than 1. Our previously reported data [24] demonstrated that patients with a PSA ⬍2 had a bRFS of 78 vs. 31% for those with a PSA greater than 2. The data from Duke University showed that 52% of patients with a PSA ⬍2.5 were NED compared to 8% for those with a greater PSA [22]. The ASTRO Consensus Committee recommended initiation of radiotherapy at a threshold PSA of ⬍1.5 ng/mL for optimal response [7]. The data is overwhelmingly in favor of early intervention, i.e., beginning radiation when the PSA level is low.
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Conclusion Radiation therapy is an effective treatment modality for select patients with a biochemical recurrence following radical prostatectomy. Patients with a low preradiation PSA level (⬍1.0 ng/mL) had a significantly better outcome, which supports the early use of therapeutic radiation. The observation that patients with a rising PSA level during treatment do poorly supports the practice of monitoring these levels during radiotherapy and changing strategies from local to systemic in patients with a rising PSA level.
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