Salvage radiotherapy following radical prostatectomy.

Catton C, Milosevic M.  World J Urol. 2003 Sep;21(4):243-52. Epub 2003 Aug 16.

Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto,

Biochemical relapse will occur in 17-64% of men who undergo radical prostatectomy, and up to a third of men with biochemical relapse will progress to develop metastatic disease and ultimately die of prostate cancer. Postoperative salvage radiotherapy (RT) to the prostatic fossa is well-tolerated and potentially curative treatment and should be considered for all men who have biochemical relapse following prostatectomy. Gleason score <8, prostate-specific antigen (PSA) doubling time >10 months and PSA re-emergence >2 years following surgery predict for a low risk of early metastatic failure, but even men with no favourable prognostic factors may have a long-term durable response to RT and should not be excluded from consideration of treatment on the basis of these factors alone. Positive surgical margin status and a positive anastomotic biopsy do not predict response to RT, and routine biopsy is not recommended. PSA level at time of RT is a strong indicator of durable response to RT. No one PSA cutpoint level appears to be more significant, and early RT is likely more effective than late. Contemporary PSA assays can detect biochemical relapse in the 0.01-0.2 range, and this may provide additional therapeutic advantage if treatment can be given when tumour burden is smallest. There is an urgent need for prospective data from randomised trials to optimally select patients for salvage RT, to determine the optimal time to initiate treatment and to determine the role of adjuvant hormone therapy, and all patients should be considered for entry into ongoing and future clinical trials.

Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate.

Catton C, Gospodarowicz M, Warde P, Panzarella T, Catton P, McLean M, Milosevic M.  Radiother Oncol. 2001 Apr;59(1):51-60.

Department of Radiation Oncology, The Princess Margaret Hospital and The University of Toronto, Ontario, Toronto, Canada.

PURPOSE: To evaluate the outcome of adjuvant and salvage radiotherapy (RT) after radical prostatectomy (RP) for clinically localized prostate cancer using conventional clinical end-points, and the biochemical relapse-free rate (bRFR). METHODS: Between 1987 and 1994, 113 node negative, hormonally naive men received RT 1 month to 12 years after RP. Adjuvant RT was given for positive resection margins and/or pT3 disease. Salvage RT was given for a persistently elevated prostatic specific antigen (PSA), a rising PSA, or palpable recurrence post RP. Clinical and biochemical endpoints determined outcome. Log-rank testing and the Cox proportional hazards model identified factors predictive for biochemical relapse free rate. RESULTS: Median follow-up after RT was 3.7 years (range 0.2-9 years). Five-year clinical local control was 95% for patients with no palpable evidence of disease and 59% for those with palpable recurrence. 5-year bRFR was 81% for adjuvant RT, 19% for salvage of biochemical recurrence, 0% for patients with palpable disease . Improved bRFR for adjuvant and salvage RT was predicted by a Gleason score < 7 vs. 7 vs. > 7 (hazard ratio 1.53) and an undetectable pre-RT PSA vs. PSA < 2.0 ng/ml vs. PSA > 2.0 ng/ml (hazard ratio 3.81). Seminal vesicle involvement was not a statistically significant independent predictor of bRFR.

CONCLUSIONS: The most favourable bRFR was observed for adjuvant therapy. Salvage was most successful with a pre-RT PSA < 2.0 ng/ml, or Gleason score < 7. Few patients with a pre-RT PSA > 2.0 ng/ml were salvaged, and none with palpable recurrence. These patients require investigation of alternative salvage strategies.

Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors.

Chawla AK, Thakral HK, Zietman AL, Shipley WU.  Urology. 2002 May;59(5):726-31.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

OBJECTIVES: To determine the probability of biochemical control for patients treated with salvage irradiation and identify prognostic factors associated with successful salvage. The optimal management of prostate cancer in patients with an elevated prostate-specific antigen (PSA) level after radical prostatectomy remains unclear. METHODS: We reviewed the records of 54 patients with node-negative prostate cancer treated with radiotherapy alone between 1991 and 1998 for isolated biochemical relapse after prostatectomy. The median preoperative PSA level was 15 ng/mL, and the median salvage PSA level was 1.3 ng/mL. Complete pathologic information was recorded, as was the interval to postoperative PSA failure. Radiotherapy was delivered to the prostatic fossa using appropriate techniques. The primary endpoint was biochemical failure, measured from radiotherapy initiation to the first detectable PSA level. Biochemical control rates were determined using Kaplan-Meier methods. The median follow-up was 45 months. RESULTS: The initial complete response rate was 76%. Only seminal vesicle status demonstrated borderline significance for the rate of the initial complete response. The 5-year actuarial biochemical control rate was 35%. The presence of seminal vesicle invasion, Gleason score greater than 6, and an immediately detectable postoperative PSA level all predicted for decreased 5-year biochemical control. Gleason score and detectable postoperative PSA retained significance on multivariate analysis. Those with a salvage PSA level of 1.2 ng/mL or less had a trend toward a decreased 5-year biochemical control rate . CONCLUSIONS: Salvage radiotherapy yields a 76% complete response rate, with 35% of treated patients free of a detectable PSA at 5 years. Those with favorable biochemical and pathologic tumor features are most likely to remain disease free.

Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31. Radiation Therapy Oncology Group.

Corn BW, Winter K, Pilepich MV.  Urology. 1999 Sep;54(3):495-502.

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

OBJECTIVES: To evaluate the effect of immediate androgen suppression in conjunction with standard external beam irradiation (RT) versus RT alone on a group of men after prostatectomy who had indications for adjuvant treatment. METHODS: A national prospective randomized trial (Radiation Therapy Oncology Group [RTOG] 85-31) comparing standard external beam RT plus immediate androgen suppression versus external beam RT alone with delayed hormonal treatment at relapse was initiated for patients with locally advanced adenocarcinoma of the prostate. One hundred thirty-nine of the patients in this trial had indications for adjuvant treatment after prostatectomy (eg, capsular penetration, seminal vesicle involvement). Seventy-one of the patients received RT with immediate androgen suppression (luteinizing hormone-releasing hormone [LHRH] agonist); 68 patients received RT alone with hormonal manipulation instituted only at the time of relapse. RESULTS: With a median follow-up of 5 years, the estimated progression-free survival rate (failure defined as prostate-specific antigen [PSA] greater than 0.5 ng/mL) was 65% for the men who received combination therapy and 42% for those treated by RT alone with hormones reserved for relapse (P = 0.002). Differences in the rates of freedom from biochemical relapse were observed when failure was defined as PSA of 1.0 to 3.9 ng/mL (71% versus 46%) and PSA greater than 4.0 ng/mL (76% versus 55%), respectively. No differences were observed between the groups with respect to the end points of local control, distant failure, and overall survival. The use of immediate androgen suppression (ie, LHRH agonists) and the absence of pathologic nodal involvement were independently associated with prolongation of freedom from biochemical relapse by multivariate analysis. CONCLUSIONS: Patients with prostate cancer and indications for postoperative RT should be considered for combined RT and hormonal manipulation. Because statistically significant advantages for this experimental approach could not be defined for all end points studied (in particular, overall survival), efforts should be made to enroll these patients in the recently activated RTOG trial (96-01) comparing RT plus placebo to the combination of RT plus Casodex in the postoperative setting.

Postoperative radiotherapy for carcinoma of the prostate: impact on both local control and distant disease-free survival.

Do LV, Do TM, Smith R, Parker RG.  Am J Clin Oncol. 2002 Feb;25(1):1-8.

University of California Irvine, College of Medicine, UCI Medical Center, Irvine, California, U.S.A.

The role of postoperative irradiation in patients with clinically localized prostate cancer, either as an adjuvant or salvage radiotherapy, remains controversial. In this study, we evaluate the impact of postoperative radiotherapy on patients diagnosed with prostate cancer with respect to biochemical and clinical disease free survival. Between 1987 and 1996, 179 patients with clinically localized prostate cancer were found to have adverse histopathologic findings on radical prostatectomy specimens (positive surgical margins, extracapsular extension, and seminal vesicle invasion). Of these patients, 42 were referred for postoperative adjuvant radiotherapy, whereas 73 were referred for salvage irradiation because of rising serum prostate-specific antigen (PSA) levels postoperatively. The remaining 64 patients underwent prostatectomy only. The 10-year biochemical relapse-free survival (RFS) from date of surgery were 88%, 45%, and 25% for patients treated with postoperative adjuvant radiotherapy, salvage irradiation, and with surgery alone, respectively (p = 0.046). Ten-year distant RFS from date of surgery were 82%, 74%, and 44% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0180). Ten-year overall disease RFS from date of surgery was 89%, 76%, and 30% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0237). Multivariate analyses revealed that a preoperative PSA greater than 20 ng/ml and pathologic Gleason Score of 8 to 10 were adverse predictors for biochemical relapse, whereas pathologic Gleason Score of 8 to 10, seminal vesicle invasion, and extracapsular extension were adverse predictors of distant metastases. Postoperative radiotherapy, either delivered as adjuvant treatment for adverse histopathologic findings or as salvage therapy for local relapses, appear to confer superior local, distant disease RFS, and overall disease RFS than surgery alone.

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

Katz MS, Zelefsky MJ, Venkatraman ES, Fuks Z, Hummer A, Leibel SA. J Clin Oncol. 2003 Feb 1;21(3):483-9.

Departments of Radiation Oncology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

Salvage radiotherapy for biochemical failure of radical prostatectomy: a single-institution experience.

Liauw SL, Webster WS, Pistenmaa DA, Roehrborn CG. Urology. 2003 Jun;61(6):1204-10.

Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, 75390-9110, USA.

OBJECTIVES: To review the efficacy of salvage radiotherapy (RT), to treat elevated prostate-specific antigen (PSA) levels for presumed local recurrence of prostatic adenocarcinoma after retropubic prostatectomy, and identify the factors that may predict for successful treatment. METHODS: Fifty-one patients with hormonally naive pT2-3N0-1M0 prostate cancer were treated with RT for locally persistent or recurrent disease. The patients received a median dose of 65.7 Gy (range 61.2 to 72.3) to the prostate bed. Successfully treated patients had undetectable PSA levels; the endpoint of the study was biochemical failure. RESULTS: The median follow-up was 3.8 years; 42 of 51 patients had at least 2 years of follow-up. Twenty-three patients (45%) were biochemically free of disease. The estimated biochemically free of disease rate at 3 and 5 years was 56% and 16%, respectively. Whether the patients were treated for persistently elevated PSA levels or for rising PSA levels from undetectable levels after retropubic prostatectomy, their PSA values were equally likely to drop to undetectable levels (65%). Univariate analysis demonstrated two factors that significantly predicted for successful salvage treatment: the absence of seminal vesicle invasion and the absence of lymphovascular invasion. A pretreatment PSA level less than 0.425 ng/mL trended toward statistical significance (P = 0.059). Only seminal vesicle invasion maintained significance on multivariate analysis. The RT was well tolerated, and the gastrointestinal and genitourinary toxicity was largely Radiation Therapy Oncology Group grade 1. CONCLUSIONS: Salvage RT is moderately effective in treating patients with locally persistent or recurrent prostate adenocarcinoma. Seminal vesicle invasion and lymphovascular invasion predicted for unsuccessful treatment.

Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy.

Macdonald OK, Schild SE, Vora SA, Andrews PE, Ferrigni RG, Novicki DE, Swanson SK, Wong WW. J Urol. 2003 Nov;170(5):1833-7.

Department of Radiation Oncology, Section of Urology, Mayo Clinic Scottsdale, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA.

PURPOSE: In this retrospective study we determined the results of salvage external beam radiation therapy (RT) to the prostate bed for isolated increase of serum prostate specific antigen (PSA) after radical prostatectomy. MATERIALS AND METHODS: A total of 60 patients underwent RT for PSA failure after radical prostatectomy from 1993 to 1999. Median followup was 51 months. Biochemical disease-free survival (bDFS) with a serum PSA of 0.3 ng/ml or less was estimated using the Kaplan-Meier method. Potential prognostic factors were evaluated for significant associations with bDFS. RESULTS: Median PSA before RT was 0.69 ng/ml. Median radiation dose was 64.8 Gy. The 5-year actuarial bDFS was 45%. There were 32 patients with a minimum followup of 4 years (median 73 months) who experienced a 5-year bDFS rate of 43%. PSA before RT (p = 0.016), RT dose (p = 0.026), surgical margin involvement (p = 0.017) and Gleason score (p = 0.018) were identified as prognostic factors for bDFS. A significant association with bDFS was present at 5 years of 65%, 34% and 0% for PSA before RT less than 0.6, 0.6 to 1.2, and greater than 1.2 ng/ml, respectively (p = 0.036). Patients with PSA before RT less than 0.6 ng/ml and total RT dose greater than 64.8 Gy had improved bDFS at 5 years compared to all others (77% vs 32%, p = 0.04). Of 60 patients 3 (5%) experienced chronic grade 3 toxicity. CONCLUSIONS: Optimal benefit from salvage RT was achieved in patients with a PSA less than 0.6 ng/ml and doses of RT greater than 64.8 Gy. Early treatment with a sufficiently high dose of RT maximizes the potential for salvage.
 

Salvage radiotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients.

Peyromaure M, Allouch M, Eschwege F, Verpillat P, Debre B, Zerbib M.  Urology. 2003 Sep;62(3):503-7.

Department of Urology, Cochin Hospital, Paris, France.

OBJECTIVES: To determine the predictive factors of prostate-specific antigen (PSA) recurrence after salvage radiotherapy (RT) for biochemical recurrence following radical prostatectomy (RP) to identify patients who may benefit from this treatment. METHODS: From June 1992 to January 2002, 62 patients experiencing PSA recurrence after RP were treated with RT at a dose of 65 Gy. No patient received hormonal therapy. PSA recurrence after RT was defined as three consecutive increased PSA measurements. The risk of experiencing PSA recurrence after RT was analyzed according to 10 factors: patient age, pre-RP PSA level, pathologic stage, Gleason score, surgical margin status, PSA nadir after RP, time to PSA recurrence after RP, pre-RT PSA level, PSA nadir after RT, and length of follow-up after RT. RESULTS: With a mean follow-up of 44 months (range 3 to 110), 23 patients (37.1%) experienced PSA recurrence after RT. Using univariate analysis, six factors were found to be predictive of PSA recurrence after RT: the length of follow-up after RT (P <0.0001), PSA nadir after RP (P = 0.0004), time to PSA recurrence after RP (P = 0.003), pre-RP PSA level (P = 0.008), Gleason score (P = 0.011), and pre-RT PSA level (P = 0.028). Using multivariate analysis, only the Gleason score (P = 0.015) and length of follow-up after RT (P = 0.02) were found to be predictive of PSA recurrence after RT. A Gleason score greater than 7 was a significant predictor of PSA recurrence after salvage RT (P = 0.04). CONCLUSIONS: In our experience, the Gleason score and length of follow-up were the sole independent predictors of PSA recurrence after salvage RT. Our findings suggest that patients with a Gleason score of 7 or less are more likely to benefit from salvage RT after RP and that the durability of the PSA response may be only transient.

Radiation therapy (RT) after prostatectomy: The case for salvage therapy as opposed to adjuvant therapy.

Schild SE.  Int J Cancer. 2001 Apr 20;96(2):94-8.

Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona 85259, USA. sschild@mayo.edu

Patients with pathologic stage T3 or T4 prostate cancer who have undetectable PSA levels following radical retropubic prostatectomy (RRP) have a substantial risk of recurrence. Radiotherapy (RT) can be administered immediately following the RRP (immediate adjuvant RT) or may be postponed until the PSA level has risen to a level that is indicative of residual or recurrent prostate cancer (salvage RT). Immediate adjuvant RT can significantly reduce the risk of relapse, but does not appear to increase the rate of survival. Approximately two-thirds of patients with rising PSA levels after RRP can be salvaged with RT alone. This result was achieved in patients treated with an adequate dose of radiation before the PSA rose to > 1.1 ng/ml. While no one can be certain which approach (adjuvant or salvage RT) is better, future studies should examine this issue. Whether immediate postoperative adjuvant RT is of value to patients is the subject of two randomized prospective studies. The benefit of adjuvant RT is a matter of controversy. Salvage RT treats only those patients with proven residual prostate cancer. The salvage RT approach has several advantages. This approach spares approximately 40% of patients who have had an RRP for T3 or T4 prostate cancer and eliminates the risks and costs associated with adjuvant RT. Additionally, it appears that the results of immediate adjuvant RT are similar to those achieved with early salvage RT.

Salvage radiotherapy for rising or persistent PSA after radical prostatectomy.

Song DY, Thompson TL, Ramakrishnan V, Harrison R, Bhavsar N, Onaodowan O, DeWeese TL. Urology. 2002 Aug;60(2):281-7.

Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.

OBJECTIVES: To assess the effectiveness of salvage radiotherapy (RT) for a persistent or rising prostate-specific antigen (PSA) level after radical prostatectomy, and to identify the pretreatment factors that may predict for patients likely to benefit from this treatment. METHODS: Seventy-three consecutive patients were treated during a 10-year period (1989 to 1999) with RT after radical prostatectomy. Twelve patients were excluded from analysis because of either an undetectable PSA level before RT or lack of follow-up data. No patients had clinical or radiographic evidence of distant disease. An undetectable PSA level (less than 0.1 ng/mL) was required to be considered disease free. RESULTS: The median PSA level before RT was 0.8 ng/mL (range 0.1 to 63). The median radiation dose prescribed was 66.6 Gy. The actuarial PSA-free survival rate at 4 years was 39%. Failure was uncommon in patients followed up beyond 4 years. Univariate analysis revealed that a pre-RT PSA level of less than 1.0 ng/mL (P = 0.001), Gleason score less than 8 (P = 0.003), and achievement of an undetectable PSA level after prostatectomy (P = 0.018) were significant predictors of improved disease-free survival. On multivariate analysis, both a pre-RT PSA level of less than 1.0 ng/mL and a Gleason score less than 8 maintained statistical significance. CONCLUSIONS: Salvage RT provides a reasonable chance of intermediate-term disease-free survival in patients with PSA persistence or relapse after radical prostatectomy. Patients with a higher PSA level (greater than 1 ng/mL) and Gleason score of 8 or more are less likely to benefit from this treatment, and improved therapies are needed for this subset of patients. Patients should be referred promptly for salvage RT after detection of relapse.