SALVAGE RADIATION THERAPY FOR PROSTATE SPECIFIC ANTIGEN PROGRESSION FOLLOWING RADICAL PROSTATECTOMY: 10-YEAR OUTCOME ESTIMATES

0022-5347/05/1744-1282/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 174, 1282–1286, October 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000173911.82467.f9

SALVAGE RADIATION THERAPY FOR PROSTATE SPECIFIC ANTIGEN PROGRESSION FOLLOWING RADICAL PROSTATECTOMY: 10-YEAR OUTCOME ESTIMATES JOSEPH F. PAZONA, MISOP HAN,* SHEILA A. HAWKINS, KIMBERLY A. ROEHL AND WILLIAM J. CATALONA† From the Department of Urology (JFP, MH, SAH, WJC), Northwestern University, Feinberg School of Medicine, Chicago, Illinois, and Departments of Psychiatry (KAR) and Surgery/Urology (WJC), Washington University, School of Medicine, St. Louis, Missouri

ABSTRACT

Purpose: We evaluated men treated with salvage radiation therapy for increasing serum prostate specific antigen (PSA) following radical retropubic prostatectomy (RRP). Materials and Methods: We retrospectively reviewed the records of 3,478 consecutive men who underwent radical retropubic prostatectomy (RRP) between 1983 and 2003, as performed by a single surgeon. A total of 307 men received salvage radiation therapy for persistently increased or increasing PSA after RRP. We compared perioperative and peri-radiotherapy clinicopathological parameters in men who achieved an undetectable PSA level after radiation therapy (responders) vs those who did not (nonresponders). We then evaluated the durability of the PSA response. Results: Median time from RRP to PSA progression was 23 months (range 1 to 129). Median followup from RRP was 104 months (range 7 to 225). Median followup from salvage radiotherapy was 56 months (range 0 to 188). Of 223 men with sufficient followup information 162 (73%) subsequently had undetectable PSA (less than 0.3 ng/ml) in response to salvage radiation therapy. There was no significant difference between responders and nonresponders in the distribution of clinical and pathological tumor stages, age at RRP, surgical margin status, and the interval between RRP and salvage radiation therapy. A Gleason score of 8 to 10 was more prevalent in nonresponders than responders (28% vs 13%). Median PSA at salvage radiation therapy was 1.2 ng/ml in nonresponders vs 0.7 ng/ml in responders. Actuarial 5 and 10-year progression-free (PSA less than 0.3 ng/ml) survival probabilities in all 223 men following salvage radiation therapy were 40% (95% CI 32 to 48) and 25% (95% CI 15 to 36), respectively. Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in responders only were 55% (95% CI 45 to 64) and 35% (95% CI 21 to 49), respectively. Only seminal vesicle invasion was significantly associated with progression-free survival following radiation therapy on multivariate analysis. Conclusions: An undetectable PSA level following salvage radiation therapy is more frequently achieved in men with lower pre-radiation serum PSA and those without seminal vesicle or lymph node involvement. Overall approximately a fourth of men with PSA evidence of cancer progression following RRP had a durable response 10 years after the initiation of salvage radiation therapy in the protocols used in this patient cohort. KEY WORDS: prostate, prostatic neoplasms, salvage therapy, radiation therapy, prostatectomy

Progression-free survival following radical prostatectomy is excellent in men with clinically localized prostate cancer. However, some men have biochemical evidence of cancer progression with detectable serum prostate specific antigen (PSA) levels following surgery.1⫺5 Patients observed without subsequent treatment may have distant metastasis and ultimately die of prostate cancer.2 Salvage radiation therapy is given in men with biochemical evidence of recurrence after surgery with the hope of preventing the untoward outcomes of advanced prostate cancer.

It is controversial whether salvage radiation therapy provides a survival advantage over observation alone in men with biochemical recurrence following radical retropubic prostatectomy (RRP). In addition, most reported series of salvage radiation therapy provide only short-term outcome estimates. In this study we evaluated the long-term effectiveness of salvage radiation therapy in men with increased serum PSA following radical prostatectomy. We also evaluated the clinicopathological features of men who experienced initial and durable responses to salvage radiation therapy in a large, single surgeon patient cohort.

Submitted for publication August 31, 2004. Supported by a grant from Beckman Coulter, Inc., Fullerton, CalMATERIALS AND METHODS ifornia, the Urological Research Foundation (KAR and WJC) and a The study population consisted of 3,478 consecutive men Northwestern University Prostate Cancer SPORE Career Developwho underwent anatomical RRP between May 1983 and Febment Award (MH). * Correspondence: Department of Urology, 675 North Saint Clair ruary 2003, as performed by a single surgeon (WJC). Mean St., Suite 20 –150, Chicago, Illinois 60611 (telephone: 312-695-8146; patient age ⫾ SD at surgery was 61.3 ⫾ 7.4 years (range 36 FAX: 312-695-7030; e-mail: [email protected]). † Current address: Department of Urology, Northwestern Univer- to 80). Followup included semiannual measurement of serum PSA and yearly digital rectal examination. sity, Feinberg School of Medicine, Chicago, Illinois 60611. 1282

SALVAGE RADIATION FOR PROGRESSION AFTER PROSTATECTOMY

Of 3,478 men 631 (18%) experienced cancer progression following RRP.6 Of 631 patients with progression 307 (49%) underwent salvage external beam radiation therapy for PSA progression (PSA 0.1 ng/ml or greater). A total of 64 men (10%) received adjuvant/immediate radiation therapy with or without hormonal therapy, while 101 (16%) only received hormonal therapy. In 159 men (26%) there was no record of additional therapy after surgery (fig. 1). Of 307 men who received salvage radiation therapy 223 (72.6%) had sufficient followup information available for further analysis. Clinicopathological data were gathered prospectively from a radical prostatectomy database. The table lists the disease characteristics of the men according to age, preoperative PSA, clinical and pathological tumor stage, surgical margin status, surgical Gleason score, pre-radiation PSA, interval between surgery and radiation, PSA doubling time and radiation dose. The clinical response to radiation therapy was defined as a decrease in serum PSA to less than 0.3 ng/ml. External beam radiation therapy was given at various institutions. We did not record the details of radiation therapy other than total radiation dose in our database. Ten men (4.5%) received short-term hormonal therapy prior to salvage radiation therapy. We used the Stata SE 8.2 software package (Stata Corp., College Station, Texas) for statistical analyses. The chisquare and Student t tests were used to compare clinicopathological features in the 2 groups. Actuarial PSA progressionfree survival was estimated using the Kaplan-Meier method. The Cox proportional hazards regression model was used to determine the association between clinicopathological factors and PSA progression-free survival. The log rank test was used to compare differences in progression-free survival. All statistical tests were 2-tailed. Statistical significance was considered at p ⬍0.05. RESULTS

Median followup after radical prostatectomy was 104 months (range 7 to 225) and median followup after salvage radiation therapy was 56 months (range 0 to 188). Of the men 82 men (37%) had persistently detectable PSA following RRP, while the remainder had a delayed increase in PSA. Patients received a median radiation dose of 63 Gy (see table). Of the 223 men with sufficient followup information available 162 responders (73%) had an initial decrease in PSA to undetectable levels (less than 0.3 ng/ml) (fig. 1). There was no significant difference between responders and nonresponders in terms of age at surgery, clinical and pathological tumor stage, surgical margin status and the

FIG. 1. Study cohort

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interval between radical prostatectomy and salvage radiotherapy (see table). However, a lower percent of responders had Gleason score 8 to 10 tumors (13% vs 28%), PSA doubling time less than 10 months (39% vs 57%) and preoperative serum PSA greater than 20 ng/ml (47% vs 67%). Mean PSA at salvage radiation therapy was significantly lower in responders than in nonresponders (1.1 vs 2.1 ng/ml, p ⬍0.01, see table). Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in all 223 men were 40% (95% CI 32 to 48) and 25% (95% CI 15 to 36), respectively (fig. 2). Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in responders only were 55% (95% CI 45 to 64) and 35% (95% CI 21 to 49), respectively (fig. 3). Men with lower serum PSA (less than 1.3 ng/ml) at salvage radiotherapy had a higher biochemical progression-free survival rate following radiotherapy than those with higher PSA (1.3 ng/ml or greater) (p ⫽ 0.027, fig. 4). In addition, men without seminal vesicle or lymph node involvement had a higher biochemical progression-free survival rate following salvage radiotherapy than those with seminal vesical and/or lymph node involvement (p ⫽ 0.002, fig. 5). Men with PSA doubling time greater than 10 months had a nonsignificant trend toward a higher biochemical progression-free survival rate following salvage radiotherapy than those with a PSA doubling time of 10 months or less (p ⫽ 0.06, fig. 6). In the stepwise multivariate Cox proportional hazards model seminal vesicle involvement was the only significant predictor of biochemical progression after salvage radiation therapy (HR 1.84, 95% CI 1.23 to 2.77, p ⫽ 0.003). DISCUSSION

For salvage radiation therapy to be most effective residual prostate cancer must be confined within the radiation fields. However, it is difficult to predict which patients will benefit from salvage radiation therapy. For example, only 25% of men with a detectable postoperative PSA level of less than 1 ng/ml have histological confirmation of local recurrence at biopsy of the prostatic fossa.7 However, up to 70% of men with negative prostatic fossa biopsies have a decrease in serum PSA to undetectable levels after radiation therapy.8 In addition, previous studies of salvage radiation therapy have been based on short-term followup information.9, 10 In the current study we evaluated the criteria for the effectiveness of salvage radiation therapy in a large patient cohort. We also studied the short-term and long-term effectiveness of salvage radiation therapy in men with increased serum PSA following radical prostatectomy. The published results of salvage radiation therapy vary markedly depending on the clinicopathological parameters of the patient cohort, such as pre-radiation PSA, Gleason score, seminal vesical involvement, surgical margin status, lymph node metastases, radiation dose and the timing of PSA failure.9, 11–15 For example, the actuarial 5-year PSA progressionfree survival rate was less than 20% in some salvage radiation series.12, 15 However, the average pre-radiation PSA in these studies was approximately 3 ng/ml.12, 15 In contrast, other investigators reported a 5-year PSA progression-free survival estimate of greater than 40% in men in whom median PSA was less than 1 ng/ml at the time that radiotherapy was initiated.9, 13, 14 The most appropriate PSA level at which to initiate salvage radiation therapy is unknown.16 Delaying salvage radiotherapy until PSA is 2 ng/ml has been reported to decrease the proportion of patients receiving unnecessary radiation therapy, while achieving durable biochemical progression-free rates.9 In our study median PSA in responders and nonresponders was 0.7 and 1.2 ng/ml, respectively. Although there was a statistically significant difference in

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SALVAGE RADIATION FOR PROGRESSION AFTER PROSTATECTOMY Characteristics of 223 men who underwent salvage radiation therapy with sufficient followup information available

No. men (%) No. age at surgery (%): Younger than 40 41–50 51–60 61–70 Older than 70 No. ng/ml preop PSA (%): Less than 2.6 2.6–4.0 4.1–10.0 10.0–20.0 Greater than 20 No. clinical stage (%): T1a/b T1c T2a T2b T2c T3 No. pathological stage (%): T2 T3a/b T3c N1 No. surgical margins (%): Pos Neg No. Gleason score (%): 2–4 5 6 7 8–10 Time to radiation (mos): Range Mean Median PSA doubling time (mos): 10 or Less Greater than 10 PSA at radiation (ng/ml): Range Mean Median Radiation dose (Gy): No. less than 45 No. 45–60 (%) No. 60–65 (%) No. 65–70 (%) No. greater than 70 Mean Median

Responders

Nonresponders

All

162 (73)

61 (27)

223 (100)

0 9 (5.6) 59 (36.4) 79 (48.8) 15 (9.3)

1 (1.6) 2 (3.3) 17 (27.9) 33 (54.1) 8 (13.1)

1 (0.5) 11 (4.9) 76 (34.1) 112 (50.2) 23 (10.3)

1 (0.6) 0 9 (5.6) 76 (46.9) 76 (46.9)

1 (1.6) 0 2 (3.3) 17 (27.9) 41 (67.2)

2 (0.9) 0 11 (4.9) 93 (41.7) 117 (52.5)

3 (1.9) 31 (19.1) 43 (26.5) 77 (47.5) 2 (1.2) 6 (3.7)

2 (3.3) 11 (18.3) 11 (18.3) 31 (51.7) 0 5 (8.3)

5 (2.3) 42 (18.9) 54 (24.3) 108 (48.6) 2 (0.9) 11 (5.0)

58 (36.0) 78 (48.5) 22 (13.6) 3 (1.9)

20 (33.3) 22 (36.7) 17 (28.3) 1 (1.7)

78 (35.3) 100 (45.2) 39 (17.6) 4 (1.8)

75 (46.3) 87 (53.7)

28 (45.9) 33 (54.1)

103 (46.2) 120 (53.8)

14 (8.8) 22 (13.8) 40 (25.2) 63 (39.6) 20 (12.6)

2 (3.3) 7 (11.5) 15 (24.6) 20 (32.8) 17 (27.9)

1.3–151.2 46.2 38.3

1.7–123.6 39.3 35.4

1.3–151.2 44.3 37.2

56 (39.2) 87 (60.8)

28 (57.1) 21 (42.9)

84 (43.7) 108 (56.3)

p Value 0.29 (chi-square test)

0.04 (chi-square test)

0.49 (chi-square test)

0.08 (chi-square test)

0.96 (chi-square test) 0.07 (chi-square test)

0.1–13.6 1.1 0.7

0.1–15.6 2.1 1.2

1 (0.7) 9 (6.6) 84 (61.8) 34 (25.0) 8 (5.9) 6,368 6,400

0 3 (5.7) 33 (62.3) 13 (24.5) 4 (7.6) 6,386 6,300

FIG. 2. Kaplan-Meier biochemical progression-free survival estimate in 223 responders and nonresponders who received salvage radiation therapy. Actuarial 10-year progression-free survival probability in all men who received salvage radiation therapy was 25% (95% CI 15 to 36).

16 29 55 83 37

(7.3) (13.2) (25) (37.7) (16.8)

0.1–15.6 1.3 0.8 1 (0.5) 12 (6.4) 117 (61.9) 47 (24.9) 12 (6.3) 6,373 6,300

0.16 (Student’s t test) 0.03 (chi-square test)

⬍0.01 (Student’s t test)

0.87 (Student’s t test)

FIG. 3. Kaplan-Meier biochemical progression-free survival estimate in responders to salvage radiation therapy. Actuarial 10-year progression-free survival probability in all men who received salvage radiation therapy was 35% (95% CI 21 to 49).

SALVAGE RADIATION FOR PROGRESSION AFTER PROSTATECTOMY

FIG. 4. Kaplan-Meier biochemical progression-free survival estimate following salvage radiation therapy according to pre-radiation serum PSA (log rank test p ⫽ 0.03).

FIG. 5. Kaplan-Meier biochemical progression-free survival estimate following salvage radiation therapy according to pathological stage (log rank test p ⬍0.01). SV, seminal vesicle. LN, lymph node.

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radiation therapy.9 The overall actuarial 4-year PSA progression-free survival probability was 45% but actuarial 4-year PSA progression-free probability in subgroups was 12% to 81% depending on clinicopathological features.9 When we attempted to validate this model, actuarial 4-year PSA progression-free survival probabilities in the overall group and subgroups were quite similar to those reported by Stephenson et al. However, when similar analysis was performed with longer followup information in our study cohort, there was a significant decrease in PSA progression-free survival probabilities at 10 years regardless of clinicopathological features. In our entire study cohort the actuarial PSA progression-free survival probability 10 years following salvage radiation therapy was only 25%. Several limitations of our study deserve mention. 1) Our study is from a single surgeon retrospective series. Although our series provides long-term followup information, a multiinstitutional study with a larger number of patients may allow better delineation of predictive factors for a favorable response to salvage radiation therapy.9 2) Our patient cohort included many men who underwent treatment in the prePSA era. We expect that there would be more favorable outcomes of salvage radiation therapy in men treated currently since more men present with lower stage and grade disease in the PSA era and also since more effective radiotherapy protocols have been developed, such as intensity modulated radiotherapy. 3) We did not measure the cancer specific mortality rate in our study because our database is insufficiently mature to provide reliable information concerning this parameter. A future study of prostate cancer specific mortality would be helpful for determining the true effectiveness of salvage radiation therapy. 4) Adverse outcomes of salvage radiation therapy were not available for analysis in the current study. Improved recurrence-free survival with salvage radiation therapy may be achieved if radiation is given at the first evidence of biochemical recurrence, although the decision to offer radiation therapy should be balanced against its potential adverse outcomes and the sometimes benign nature of low level, gradual PSA recurrences. 5) There was a wide range of intervals between surgery and radiation therapy, and a wide range of radiation doses, although more than 93% of the men received at least 60 Gy. In addition, the majority of our patients received radiation therapy elsewhere and many did not receive the most advanced radiation therapy techniques, such as 3-dimensional conformal radiation therapy or intensity modulated radiation therapy. A standardized salvage radiation protocol using more effective treatment protocols might result in a better recurrence-free survival rate. CONCLUSIONS

FIG. 6. Kaplan-Meier biochemical progression-free survival estimate following salvage radiation therapy according to PSA doubling time (log rank test p ⫽ 0.06).

mean pre-radiation PSA between the 2 groups, there was a large overlap. Therefore, using an absolute PSA cutoff that excludes men from receiving salvage radiation therapy should be avoided since some potentially durable responses occur in men with unfavorable prognostic parameters.9 In a large, multi-institutional study Stephenson et al developed a model that estimates response rates to salvage

In men with biochemical failure after radical prostatectomy salvage radiation therapy achieved an initial PSA response in 73%. Lower pre-radiation PSA and absent seminal vesicle or lymph node involvement are associated with a more favorable response. Of all patients with biochemical failure after radical prostatectomy only 25% had a durable PSA response 10 years after the initiation of salvage radiation therapy, while 35% with an initial complete response had a durable response. Close followup after prostatectomy is imperative because prompt initiation of adjuvant radiation at the time of early biochemical failure can have favorable long-term results in properly selected patients. REFERENCES

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