ORIGINAL ARTICLE
Results of Dose-adapted Salvage Radiotherapy After Radical Prostatectomy Based on an Endorectal MRI Target Definition Model Thomas Zilli, MD,* Sandra Jorcano, MD,w Nicolas Peguret, MD,* Francesca Caparrotti, MD,* Alberto Hidalgo, MD,z Haleem G. Khan, MD,y Hansjo¨rg Vees, MD,* and Raymond Miralbell, MD*w
Objectives: To assess the outcome of patients treated with a doseadapted salvage radiotherapy (SRT) protocol based on an endorectal magnetic resonance imaging (erMRI) failure definition model after radical prostatectomy (RP). Methods: We report on 171 relapsing patients after RP who had undergone an erMRI before SRT. 64 Gy were prescribed to the prostatic bed with, in addition, a boost of 10 Gy to the suspected local relapse as detected on erMRI in 131 patients (76.6%). Results: The 3-year biochemical relapse-free survival (bRFS), local relapse-free survival, distant metastasis-free survival, cancer-specific survival, and overall survival were 64.2 ± 4.3%, 100%, 85.2 ± 3.2%, 100%, and 99.1 ± 0.9%, respectively. A PSA value >1 ng/mL before salvage (P = 0.006) and an absence of biochemical progression during RT (P = 0.001) were both independently correlated with bRFS on multivariate analysis. No significant difference in 3-year bRFS was observed between the boost and no-boost groups (68.4 ± 4.6% vs. 49.7 ± 10%, P = 0.251). Conclusions: A PSA value >1 ng/mL before salvage and a biochemical progression during RT were both independently correlated with worse bRFS after SRT. By using erMRI to select patients who are most likely expected to benefit from dose-escalated SRT protocols, this dose-adapted SRT approach was associated with good biochemical control and outcome, serving as a hypothesis-generating basis for further prospective trials aimed at improving the therapeutic ratio in the salvage setting. Key Words: prostate cancer, salvage radiotherapy, dose escalation, radical prostatectomy, endorectal MRI
(Am J Clin Oncol 2014;00:000–000)
S
everal retrospective studies and a multi-institutional pooled data analysis have demonstrated the role of salvage radiotherapy (SRT) for biochemical relapse after radical prostatectomy (RP).1 In analogy with clinical prospective trials on radical RT for localized prostate cancer, dose escalation may also improve outcome in the setting of SRT after RP.2 If late genitourinary (GU) or gastrointestinal (GI) toxicities after From the *Department of Radiation Oncology, Hoˆpitaux Universitaires de Gene`ve; yInstitute of Radiology Jean Violette, Geneva, Switzerland; wServei de Radio-oncologia; and zServei de Radiodiagno`stic, Institut Onco`logic Teknon, Barcelona, Spain. The authors declare no conflicts of interest. Reprints: Thomas Zilli, MD, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000130
American Journal of Clinical Oncology
postprostatectomy RT at a dose of about 64 Gy are considered acceptable,3 an increase in long-term side effects cannot be excluded with doses of 70 Gy or above.2 As demonstrated by a dose-response study of Okunieff et al,4 the effective dose necessary to achieve biochemical control in an SRT setting may be different if the tumor recurrence is microscopic or macroscopic. Multiparametric endorectal-coil magnetic resonance imaging (erMRI) may be used in this context to select which patients with residual disease or local failure in the prostatic bed (PB) might benefit most from higher SRT doses.5 We previously reported on the toxicity rates of patients from 2 associated institutions treated with the same dose-adapted SRT protocol, based on either the presence or the absence of locally recurrent tumor after RP as defined by multiparametric erMRI studies.6 In the present study, we aim to report on the outcome of this series.
METHODS Patients, Tumors, and Treatment Characteristics A total of 171 consecutive patients with biochemical recurrence after RP and treated with the same SRT approach from March 2001 to February 2010 were retrospectively analyzed. As previously reported,6 all patients underwent multiparametric erMRI studies, detecting in 131 a suspected local relapse. Patient demographics, disease, and work-up characteristics are shown in Table 1. In the majority of the patients (n = 163), postoperative biochemical relapse was defined as an increase of Z2 consecutive prostate-specific antigen (PSA) levels after RP. PSA at salvage was >0.2 ng/mL in 151 patients, whereas it ranged between 0.1 and 0.19 ng/mL after 2 consecutive rises in 12 patients. Six patients had a detectable postprostatectomy PSA level Z0.2 ng/mL before SRT. Median age at surgery was 63 years (range, 39 to 78 y). The median PSA at diagnosis before RP was 8.0 ng/mL (range, 2.1 to 50 ng/mL) and the median interval time between RP and SRT 32 months (range, 4 to 144 mo). Treatment modalities have been previously described in detail and are reported on Table 2.6 To summarize, all treatment plans were CT-based, with 80 patients treated from 2001 to 2004 with a clinical target volume (CTV) defined by the anatomical limits of surgery (CTVstandard), as used in the European Organization for Research and Treatment of Cancer (EORTC) trial 22911 of postoperative RT.7 Later on, based on a study of our group aiming to explore local patterns of failure after RP with erMRI, 91 patients were treated with a new CTV definition paradigm (CTVnew) for adjuvant postoperative RT,
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
which was assumed to be able to cover 95% of local failure possibilities in the PB region.8 Both CTVs for PB with adequate margins were treated with a median delivered dose of 64 Gy (range, 64.0 to 64.4 Gy), in 1.8 to 2 Gy fractions. An additional boost dose of 10 Gy in 5 fractions was delivered in 131 patients to a smaller volume, corresponding to the suspected local failure as detected on erMRI studies with 15 to 20 mm additional field margins. For the boost group (n = 131, 76.6%), the median total delivered dose was 74 Gy (range, 72 to 78 Gy). All patients were treated with 6 to 18-MV x-ray beams from a linear accelerator, mostly using 3-dimensional conformal RT (3D-CRT) techniques (n = 152, 89%). The dose was prescribed according to International Commission on Radiation Units & Measurements 50 guidelines, with 100% of the dose prescribed to the isocenter and the 95% isodose encompassing the planning target volume. Thirty-four patients at high-risk of nodal disease based on the clinical (PSA) and histopathologic (Gleason score [GS], pT3b tumors) features received elective whole-pelvic RT (WPRT). This subgroup of patients was more likely to present with a higher PSA value at salvage (mean 3.2 ± 3.8 ng/mL), with a pathologic GS of Z8 (n = 17, 50%), and/or with a seminal vesicles involvement (n = 18, 53%). Thirty-eight (22.2%) patients with high-risk features (PSA value before SRT > 2 ng/mL, pT3a/pT3b stage, and Gleason score Z8 in the pathologic specimen after RP) received neoadjuvant and/or concomitant androgen deprivation (AD) for a median duration of 6.7 months (range, 3 to 34 mo). TABLE 1. Patient Demographics, Disease and erMRI Work-up Characteristics (n = 171)
Volume 00, Number 00, ’’ 2014
Follow-up and Statistical Analysis The median follow-up (FU) for the whole population calculated from the start of salvage treatment (ie, RT and/or AD) was 36 months (range, 3.1 to 98 mo). All patients were seen once a week while on treatment and 6 weeks after treatment completion, every 3 months during the first year, and every 6 months thereafter in the radiation oncology department and/or the urology clinic. A digital rectal examination and a PSA dosage were performed on each visit and reported by the attending physician. In 126 out of 133 patients treated without AD, a PSA value was obtained just before the first fraction (first day of treatment) and after receiving a cumulated dose of 44 to 45 Gy (fifth week of treatment).9 On the basis of the definition of Stephenson et al,1 the time to biochemical failure after SRT was established either when the PSA reached a value of 0.2 ng/mL or more above the post-RT nadir followed by a second increase, and/or in case of clinical progression. Comparisons between the 2 treatment groups (boost vs. no-boost) were assessed using the w2 and 2-sample Student t test for categorical and continuous variables, respectively. Actuarial 3- and 5-year biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS) were estimated from the start of salvage treatment using the Kaplan-Meier method. Local failure was defined as tumor persistence after treatment or as an in-field recurrence. Differences between groups were assessed with the Log-rank test. Multivariate Cox proportional hazard regression analyses were implemented to evaluate the effect of different patient factors, tumor factors, and treatment factors influencing bRFS. Hazard ratios (HR), 95% confidence intervals (95% CI), and P-values were calculated. All statistical tests were 2-sided and a P-value < 0.05
N (%) Age at SRT (y) Median (range) pT-stage status (n = 171) T2a/b T2c T3a T3b T4 Unknown PSA at RP (ng/mL) (n = 171) Median (range) Gleason Score (n = 171) r3 + 4 Z4 + 3 Unknown Lymphadenectomy (n = 171) Yes No Surgical margins (n = 171) Positive Negative Unknown PSA at salvage (ng/mL) Mean ± SD all pts (n = 169) Relapse erMRI location (n = 131) Anastomosis Penile bulb Seminal vesicles Prostatic bed/bladder neck Anastomosis and prostatic bed Unknown
66 (41-82) 22 48 59 37 3 2
(13.1) (28.1) (34.5) (21.6) (1.7) (1.2)
8 (2.1-50) 114 (66.7) 54 (31.6) 3 (1.7) 109 (63.8) 62 (36.2) 103 (60.3) 56 (32.7) 12 (7.0) 1.89 ± 2.8 47 25 5 44 1 9
(35.9) (19.0) (3.8) (33.6) (0.8) (6.9)
erMRI indicates endorectal magnetic resonance imaging; PSA, prostatespecific antigen; RP, radical prostatectomy; SRT, salvage radiotherapy.
2 | www.amjclinicaloncology.com
TABLE 2. Treatment Characteristics (n = 171)
N (%) RT Boost No boost Median RT dose (range, Gy) Boost group No boost group WPRT Yes No Median dose (range, Gy) CTV definition CTVstandard CTVnew RT technique for PB (n = 171) 3D-CRT IMRT RT technique for boost (n = 131) 3D-CRT IMRT/Dynamic Arc RT AD Yes No AD duration (mo) Median (range)
131 (76.6) 40 (23.4) 74 (72-78) 64 (64-64.4) 34* (19.9) 137 (80.1) 50.4 (48-50.4) 80 (46.8) 91 (53.2) 152w (89) 19 (11) 106 (81) 25 (19) 38 (22.2) 133 (77.8) 6.7 (3-34)
*With a 4-field 3D-CRT technique. wA 4-, 6-, and 3-field 3D-CRT beam arrangement was used in 106 (62%), 43 (25%), and 3 (2%) patients, respectively. 3D-CRT indicates 3-dimensional conformal RT; AD, androgen deprivation; CTV, clinical target volume; IMRT, intensity-modulated RT; PB, prostatic bed; RT, radiotherapy; WPRT, whole pelvic RT.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
was considered statistically significant. Statistical analyses were performed using the SPSS 17.0 statistics software package (SPSS Inc., Chicago, IL).
RESULTS The 3- and 5-year bRFS rates were 64.2 ± 4.3% and 45.6 ± 5.6%, respectively. Overall, 61 patients (35.7%) developed a biochemical relapse after salvage treatment, of whom almost two thirds (59%) recurred within 2 years after salvage. Results of univariate and multivariate analyses of clinical, pathologic, and treatment factors predicting for bRFS after salvage RT are presented in Table 3. Despite a better 3-year bRFS rate for patients treated with a boost, the difference observed between the boost and noboost groups was not statistically significant (68.4 ± 4.6% vs. 49.7 ± 10%, P = 0.251). No differences in age at diagnosis (P = 0.634), PSA at diagnosis (P = 0.443), presence of pathologic extracapsular extension and/or seminal vesicles invasion (P = 0.588), GS (r3 + 4 vs. Z4 + 3) (P = 0.564), and surgical margin status (P = 0.243) were found between patients treated with or without a boost. Nevertheless, patients with a gross tumor recurrence on erMRI showed a higher mean presalvage PSA (2.08 vs. 1.26 ng/mL, P = 0.04) and were more likely to recur later after RP compared with those with no visible loco-
Dose-adapted Prostate Salvage RT
regional failure and treated without a boost (mean 47.5 vs. 28.7 mo, P = 0.001). WPRT was equally used in patients treated with or without a boost (P = 0.074), whereas AD was more frequently delivered to the boosted patients (P = 0.049). The median PSA value in patients treated with salvage RT only (n = 126) was 0.75 ng/mL (range, 0.1 to 15.6 ng/mL) and 0.55 ng/mL (range, 0.04 to 15.7 ng/mL) on day 1 and on the fifth week of RT, respectively. On univariate analysis, a decrease or a stability of the PSA value between day 1 and the fifth week of RT was significantly associated with a better 3-year bRFS compared with patients showing a biochemical progression during the same interval (71.8 ± 5.4% vs. 31.1 ± 10.6%, respectively, P = 0.001) (Table 3). No significant differences in PSA kinetics during RT were observed between patients treated with or without a boost. Overall, 76.2% of patients (n = 96) had a decreased or stable PSA value between day 1 and the fifth week of RT, whereas 23.8% (n = 30) progressed biochemically during RT. On multivariate Cox regression analysis, the PSA value before salvage (r1 ng/mL vs. >1 ng/mL) (HR, 2.672; 95% CI, 1.334-5.351; P = 0.006) and the PSA kinetics between day 1/ fifth week of RT (HR, 3.401; 95% CI, 1.617-7.152; P = 0.001) were independently correlated with bRFS (Table 3). By combining the above 2 independent variables, it was possible to define 3 risk categories: a low-risk group (n = 63) including
TABLE 3. Univariate and Multivariate Analysis of Clinical, Pathologic, and Treatment Factors Predicting for Biochemical Relapse-free Survival After Salvage RT
Univariate Variables RT group Boost (n = 131) No boost (n = 40) WPRT Yes (n = 34) No (n = 137) CTV definition CTVstandard (n = 80) CTVnew (n = 91) AD use Yes (n = 38) No (n = 133) PSA at salvage (ng/mL) r1 (n = 101) > 1 (n = 69) Surgical margins Positive (n = 103) Negative (n = 56) pT3a/b stage Yes (n = 99) No (n = 70) Pathologic GS r3 + 4 (n = 114) Z4 + 3 (n = 54) PSA 1-5th week Decreased-stable (n = 96) Increased (n = 30) RP to RT interval (y) r2 (n = 66) > 2 (n = 105)
Multivariate
3 y-bRFS
P*
HR (95% CI)
Pw
68.4 ± 4.6 49.7 ± 10.0
0.251
—
0.130
68.9 ± 8.8 62.9 ± 4.9
0.833
—
0.997
57.4 ± 6.3 70.9 ± 5.7
0.541
—
0.571
74.8 ± 7.8 61.0 ± 5.0
0.674
—
—
68.4 ± 5.5 58.4 ± 6.8
0.208
2.672 (1.334-5.351)
0.006
67.6 ± 5.4 58.3 ± 8.3
0.410
—
0.635
59.6 ± 5.7 70.1 ± 6.6
0.069
—
0.214
65.8 ± 5.4 64.2 ± 7.4
0.766
—
0.215
71.8 ± 5.4 31.1 ± 10.6
0.001
3.401 (1.617-7.152)
0.001
62.4 ± 7.1 65.3 ± 5.4
0.887
—
0.444
*The Kaplan-Meier analysis log-rank P-value. wCox proportional hazards model P-value. HR not given for P > 0.1. AD indicates androgen deprivation therapy; bRFS, biochemical relapse free-survival; CI, confidence interval; HR, hazards ratio; PSA, prostate-specific antigen; RT, radiotherapy; WPRT, whole pelvic RT.
r
2014 Lippincott Williams & Wilkins
www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
patients with a PSA value before salvage r1 ng/mL and a stable or decreasing PSA value between day 1/fifth week of RT (80.2 ± 5.7%, 3-year bRFS); a high-risk group (n = 9) including patients with a PSA > 1 ng/mL before salvage and an increasing PSA value between day 1/fifth week of RT (22.2 ± 13.9%, 3-year bRFS), and an intermediate-risk group (n = 54) of patients with both a favorable and an unfavorable variable, (48.7 ± 8.5%, 3-year bRFS) (P = 0.0001) (Fig. 1). Overall, 3 patients, all treated according to the CTVstandard definition, failed locally in-field 5 or more years after salvage. Two of these patients received 64 Gy to the PB only, whereas the third patient received an additional 10 Gy boost. All 3 patients with postsalvage local relapses were investigated with erMRI and/or with positron emission tomography with computed tomography. Confirmatory biopsies were performed in only 1 patient. The 3- and 5-year DMFS, CSS, and OS were 85.2 ± 3.2% and 78.4 ± 4.5%, 100% and 93.4 ± 3.3%, and 99.1 ± 0.9% and 92.5 ± 3.4%, respectively.
DISCUSSION The optimization of SRT in patients with biochemical recurrence after curative RP for prostate cancer represents an area of ongoing investigation. Several retrospective studies have analyzed the role of dose escalation,10 pelvic RT,11 and AD12,13 to define the best therapeutic approach for recurrent patients. Four prospective randomized trials, which are currently recruiting or have recently closed to accrual, aim to settle this issue (RTOG 0534, RADICALS, EORTC 2204330041, and SAKK 09/10). Our study reports the results of an original treatment approach using a selective dose-adapted RT regimen according to the presence or absence of a macroscopic local recurrence on erMRI. The American Society for Therapeutic Radiology and Oncology consensus guidelines suggest a minimum of 64 Gy in a salvage setting to achieve a durable biochemical
FIGURE 1. The Kaplan-Meier estimates of biochemical relapse free-survival (bRFS) according to the following risk classes and restricted to patients treated without androgen deprivation: lowrisk (PSA before salvage r1 ng/mL and a stable or decreasing PSA value between day-1/5th week of RT); high-risk (PSA before salvage > 1 ng/mL and an increasing PSA value between day-1/ 5th week of RT); intermediate-risk (patients with both a favorable and an unfavorable variable). PSA indicates prostate-specific antigen; RT, radiotherapy.
4 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
control.14 However, the tumor burden at salvage and its surrogate marker represented by the pre-RT PSA level may differ largely among patients. For every 0.1 ng/mL increment in PSA at salvage, a loss of approximately 4% in biochemical control has been reported by King.15 In a meta-analysis by Ohri et al2 the 5-year bRFS decreased by 18.3% (95% CI, 10.4%-26.3%) for every 1 ng/ mL increase of pre-RT PSA. Furthermore, increasing the dose to the macroscopic recurrence above 64 Gy may well increase the probability of tumor-control of approximately 2.5% per Gy.2 Indeed, King and Kapp16 observed a TCD50 (ie, dose necessary to achieve a biochemical tumor control in 50% of patients) of about 66 Gy for localized prostate cancer. Assuming that for microscopic disease the TCD50 is about 6 Gy lower,4 a dose-adapted treatment approach based on tumor burden may be appropriate to obtain a similar biochemical control probability for micro versus macroscopic local residual disease. This is what we have observed in the present study as patients treated with 74 Gy for gross residual recurrence visible on erMRI studies and those treated for local microscopic disease with a lesser dose (64 Gy) presented with a not-statistically different 3-year bRFS. In contrast, the knowledge of the disease site in patients with positive erMRI studies might explain why a higher SRT dose compensates for a macroscopic tumor volume, whereas patients without visible locoregional disease might be more likely to have distant metastases. However, we acknowledge that biases deriving from the heterogeneity of the patients and treatments may have influenced our findings, with a nonsignificant 18.5% difference rate in bRFS at 3-years between patients treated with high-dose versus low-dose SRT. Irrespective of the 3-year median follow-up of the present study, our results are at least comparable to previous studies on SRT and especially those reported from series using dose-escalation treatment protocols1,10,12,13,17–23 (Table 4). Although in some of these studies results may have been favorably biased by a higher percent of patients receiving concurrent AD ( > 50% as reported by Soto et al,13 whereas only 22% in the present study), we have not been able to detect so far a significant benefit from AD when added to salvage RT. Several aspects of the present study need to be highlighted. First, erMRI studies may be very helpful in defining local relapse in the PB after RP. The relatively high rate (76.6%) of positive findings visualized by MRI in this study may well be explained by the use of multiparametric acquisitions realized with an endorectal coil and interpreted by a stable team of 2 experienced uro-radiologists. Despite the lack in this series of histopathologic confirmation of the suspected relapse, previous published works have demonstrated the high reliability of erMRI in detecting local recurrence after RP,24,25 even for PSA levels at SRT of 1 ng/mL before salvage and an increasing PSA kinetic during RT may be associated with a worse biochemical outcome after salvage treatment. In addition, a dose escalation delivering 64 Gy to the PB with a 10 Gy dose increment to the gross local recurrent tumor as detected by erMRI, was associated with good biochemical control and outcome. By selecting patients who are most likely to benefit from SRT doses above 70 Gy as well as by reducing the size of the highest-dose target volume, this approach may serve as a www.amjclinicaloncology.com |
5
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
hypothesis-generating basis to improve the therapeutic ratio in patients recurring after RP and salvaged by SRT. Further prospective trials are warranted in the future to investigate the use of erMRI and dose-adapted SRT protocols in the salvage setting. REFERENCES 1. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035–2041. 2. Ohri N, Dicker AP, Trabulsi EJ, et al. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837–844. 3. Feng M, Hanlon AL, Pisansky TM, et al. Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1417–1423. 4. Okunieff P, Morgan D, Niemierko A, et al. Radiation doseresponse of human tumors. Int J Radiat Oncol Biol Phys. 1995;32:1227–1237. 5. Alfarone A, Panebianco V, Schillaci O, et al. Comparative analysis of multiparametric magnetic resonance and pet-ct in the management of local recurrence after radical prostatectomy for prostate cancer. Crit Rev Oncol Hematol. 2012;84:109–121. 6. Zilli T, Jorcano S, Peguret N, et al. Dose-adapted salvage radiotherapy after radical prostatectomy based on an ermri target definition model: toxicity analysis. Acta Oncol. 2014;53:96–102. 7. Davis JB, Reiner B, Dusserre A, et al. Quality assurance of the eortc trial 22911. A phase iii study of post-operative external radiotherapy in pathological stage t3n0 prostatic carcinoma: the dummy run. Radiother Oncol. 2002;64:65–73. 8. Miralbell R, Vees H, Lozano J, et al. Endorectal mri assessment of local relapse after surgery for prostate cancer: a model to define treatment field guidelines for adjuvant radiotherapy in patients at high risk for local failure. Int J Radiat Oncol Biol Phys. 2007;67:356–361. 9. Do T, Dave G, Parker R, et al. Serum psa evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes. Int J Radiat Oncol Biol Phys. 2001;50:1220–1225. 10. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys. 2008;71:23–27. 11. Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: Improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys. 2007;69:54–61. 12. Ost P, Lumen N, Goessaert AS, et al. High-dose salvage intensitymodulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol. 2011;60:842–849. 13. Soto DE, Passarelli MN, Daignault S, et al. Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves
6 | www.amjclinicaloncology.com
14.
15. 16. 17.
18. 19.
20. 21.
22.
23.
24.
25. 26.
27.
Volume 00, Number 00, ’’ 2014
treatment outcomes in high-risk patients. Int J Radiat Oncol Biol Physics. 2012;82:1227–1232. Cox JD, Gallagher MJ, Hammond EH, et al. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate rebiopsy 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. King CR. Adjuvant radiotherapy after prostatectomy: does waiting for a detectable prostate-specific antigen level make sense? Int J Radiat Oncol Biol Phys. 2011;80:1–3. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys. 2008;71:346–350. Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol. 2006;176:985–990. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology. 2002;59:726–731. Jereczek-Fossa BA, Zerini D, Vavassori A, et al. Sooner or later? Outcome analysis of 431 prostate cancer patients treated with postoperative or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74:115–125. Kruser TJ, Jarrard DF, Graf AK, et al. Early hypofractionated salvage radiotherapy for postprostatectomy biochemical recurrence. Cancer. 2011;117:2629–2636. Neuhof D, Hentschel T, Bischof M, et al. Long-term results and predictive factors of three-dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy. Int J Radiat Oncol Biol Phys. 2007;67:1411–1417. Wiegel T, Lohm G, Bottke D, et al. Achieving an undetectable psa after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome—results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009–1016. Geinitz H, Riegel MG, Thamm R, et al. Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2012;82:1930–1937. Casciani E, Polettini E, Carmenini E, et al. Endorectal and dynamic contrast-enhanced mri for detection of local recurrence after radical prostatectomy. Am J Roentgenol. 2008;190: 1187–1192. Sella T, Schwartz LH, Swindle PW, et al. Suspected local recurrence after radical prostatectomy: endorectal coil mr imaging. Radiology. 2004;231:379–385. Cozzarini C, Fiorino C, Da Pozzo LF, et al. Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients. Int J Radiat Oncol Biol Phys. 2012;82:191–199. Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol. 2011;60: 1142–1148.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Results of Dose-adapted Salvage Radiotherapy After Radical Prostatectomy Based on an Endorectal MRI Target Definition Model Thomas Zilli, MD,* Sandra Jorcano, MD,w Nicolas Peguret, MD,* Francesca Caparrotti, MD,* Alberto Hidalgo, MD,z Haleem G. Khan, MD,y Hansjo¨rg Vees, MD,* and Raymond Miralbell, MD*w
Objectives: To assess the outcome of patients treated with a doseadapted salvage radiotherapy (SRT) protocol based on an endorectal magnetic resonance imaging (erMRI) failure definition model after radical prostatectomy (RP). Methods: We report on 171 relapsing patients after RP who had undergone an erMRI before SRT. 64 Gy were prescribed to the prostatic bed with, in addition, a boost of 10 Gy to the suspected local relapse as detected on erMRI in 131 patients (76.6%). Results: The 3-year biochemical relapse-free survival (bRFS), local relapse-free survival, distant metastasis-free survival, cancer-specific survival, and overall survival were 64.2 ± 4.3%, 100%, 85.2 ± 3.2%, 100%, and 99.1 ± 0.9%, respectively. A PSA value >1 ng/mL before salvage (P = 0.006) and an absence of biochemical progression during RT (P = 0.001) were both independently correlated with bRFS on multivariate analysis. No significant difference in 3-year bRFS was observed between the boost and no-boost groups (68.4 ± 4.6% vs. 49.7 ± 10%, P = 0.251). Conclusions: A PSA value >1 ng/mL before salvage and a biochemical progression during RT were both independently correlated with worse bRFS after SRT. By using erMRI to select patients who are most likely expected to benefit from dose-escalated SRT protocols, this dose-adapted SRT approach was associated with good biochemical control and outcome, serving as a hypothesis-generating basis for further prospective trials aimed at improving the therapeutic ratio in the salvage setting. Key Words: prostate cancer, salvage radiotherapy, dose escalation, radical prostatectomy, endorectal MRI
(Am J Clin Oncol 2014;00:000–000)
S
everal retrospective studies and a multi-institutional pooled data analysis have demonstrated the role of salvage radiotherapy (SRT) for biochemical relapse after radical prostatectomy (RP).1 In analogy with clinical prospective trials on radical RT for localized prostate cancer, dose escalation may also improve outcome in the setting of SRT after RP.2 If late genitourinary (GU) or gastrointestinal (GI) toxicities after From the *Department of Radiation Oncology, Hoˆpitaux Universitaires de Gene`ve; yInstitute of Radiology Jean Violette, Geneva, Switzerland; wServei de Radio-oncologia; and zServei de Radiodiagno`stic, Institut Onco`logic Teknon, Barcelona, Spain. The authors declare no conflicts of interest. Reprints: Thomas Zilli, MD, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000130
American Journal of Clinical Oncology
postprostatectomy RT at a dose of about 64 Gy are considered acceptable,3 an increase in long-term side effects cannot be excluded with doses of 70 Gy or above.2 As demonstrated by a dose-response study of Okunieff et al,4 the effective dose necessary to achieve biochemical control in an SRT setting may be different if the tumor recurrence is microscopic or macroscopic. Multiparametric endorectal-coil magnetic resonance imaging (erMRI) may be used in this context to select which patients with residual disease or local failure in the prostatic bed (PB) might benefit most from higher SRT doses.5 We previously reported on the toxicity rates of patients from 2 associated institutions treated with the same dose-adapted SRT protocol, based on either the presence or the absence of locally recurrent tumor after RP as defined by multiparametric erMRI studies.6 In the present study, we aim to report on the outcome of this series.
METHODS Patients, Tumors, and Treatment Characteristics A total of 171 consecutive patients with biochemical recurrence after RP and treated with the same SRT approach from March 2001 to February 2010 were retrospectively analyzed. As previously reported,6 all patients underwent multiparametric erMRI studies, detecting in 131 a suspected local relapse. Patient demographics, disease, and work-up characteristics are shown in Table 1. In the majority of the patients (n = 163), postoperative biochemical relapse was defined as an increase of Z2 consecutive prostate-specific antigen (PSA) levels after RP. PSA at salvage was >0.2 ng/mL in 151 patients, whereas it ranged between 0.1 and 0.19 ng/mL after 2 consecutive rises in 12 patients. Six patients had a detectable postprostatectomy PSA level Z0.2 ng/mL before SRT. Median age at surgery was 63 years (range, 39 to 78 y). The median PSA at diagnosis before RP was 8.0 ng/mL (range, 2.1 to 50 ng/mL) and the median interval time between RP and SRT 32 months (range, 4 to 144 mo). Treatment modalities have been previously described in detail and are reported on Table 2.6 To summarize, all treatment plans were CT-based, with 80 patients treated from 2001 to 2004 with a clinical target volume (CTV) defined by the anatomical limits of surgery (CTVstandard), as used in the European Organization for Research and Treatment of Cancer (EORTC) trial 22911 of postoperative RT.7 Later on, based on a study of our group aiming to explore local patterns of failure after RP with erMRI, 91 patients were treated with a new CTV definition paradigm (CTVnew) for adjuvant postoperative RT,
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
which was assumed to be able to cover 95% of local failure possibilities in the PB region.8 Both CTVs for PB with adequate margins were treated with a median delivered dose of 64 Gy (range, 64.0 to 64.4 Gy), in 1.8 to 2 Gy fractions. An additional boost dose of 10 Gy in 5 fractions was delivered in 131 patients to a smaller volume, corresponding to the suspected local failure as detected on erMRI studies with 15 to 20 mm additional field margins. For the boost group (n = 131, 76.6%), the median total delivered dose was 74 Gy (range, 72 to 78 Gy). All patients were treated with 6 to 18-MV x-ray beams from a linear accelerator, mostly using 3-dimensional conformal RT (3D-CRT) techniques (n = 152, 89%). The dose was prescribed according to International Commission on Radiation Units & Measurements 50 guidelines, with 100% of the dose prescribed to the isocenter and the 95% isodose encompassing the planning target volume. Thirty-four patients at high-risk of nodal disease based on the clinical (PSA) and histopathologic (Gleason score [GS], pT3b tumors) features received elective whole-pelvic RT (WPRT). This subgroup of patients was more likely to present with a higher PSA value at salvage (mean 3.2 ± 3.8 ng/mL), with a pathologic GS of Z8 (n = 17, 50%), and/or with a seminal vesicles involvement (n = 18, 53%). Thirty-eight (22.2%) patients with high-risk features (PSA value before SRT > 2 ng/mL, pT3a/pT3b stage, and Gleason score Z8 in the pathologic specimen after RP) received neoadjuvant and/or concomitant androgen deprivation (AD) for a median duration of 6.7 months (range, 3 to 34 mo). TABLE 1. Patient Demographics, Disease and erMRI Work-up Characteristics (n = 171)
Volume 00, Number 00, ’’ 2014
Follow-up and Statistical Analysis The median follow-up (FU) for the whole population calculated from the start of salvage treatment (ie, RT and/or AD) was 36 months (range, 3.1 to 98 mo). All patients were seen once a week while on treatment and 6 weeks after treatment completion, every 3 months during the first year, and every 6 months thereafter in the radiation oncology department and/or the urology clinic. A digital rectal examination and a PSA dosage were performed on each visit and reported by the attending physician. In 126 out of 133 patients treated without AD, a PSA value was obtained just before the first fraction (first day of treatment) and after receiving a cumulated dose of 44 to 45 Gy (fifth week of treatment).9 On the basis of the definition of Stephenson et al,1 the time to biochemical failure after SRT was established either when the PSA reached a value of 0.2 ng/mL or more above the post-RT nadir followed by a second increase, and/or in case of clinical progression. Comparisons between the 2 treatment groups (boost vs. no-boost) were assessed using the w2 and 2-sample Student t test for categorical and continuous variables, respectively. Actuarial 3- and 5-year biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS) were estimated from the start of salvage treatment using the Kaplan-Meier method. Local failure was defined as tumor persistence after treatment or as an in-field recurrence. Differences between groups were assessed with the Log-rank test. Multivariate Cox proportional hazard regression analyses were implemented to evaluate the effect of different patient factors, tumor factors, and treatment factors influencing bRFS. Hazard ratios (HR), 95% confidence intervals (95% CI), and P-values were calculated. All statistical tests were 2-sided and a P-value < 0.05
N (%) Age at SRT (y) Median (range) pT-stage status (n = 171) T2a/b T2c T3a T3b T4 Unknown PSA at RP (ng/mL) (n = 171) Median (range) Gleason Score (n = 171) r3 + 4 Z4 + 3 Unknown Lymphadenectomy (n = 171) Yes No Surgical margins (n = 171) Positive Negative Unknown PSA at salvage (ng/mL) Mean ± SD all pts (n = 169) Relapse erMRI location (n = 131) Anastomosis Penile bulb Seminal vesicles Prostatic bed/bladder neck Anastomosis and prostatic bed Unknown
66 (41-82) 22 48 59 37 3 2
(13.1) (28.1) (34.5) (21.6) (1.7) (1.2)
8 (2.1-50) 114 (66.7) 54 (31.6) 3 (1.7) 109 (63.8) 62 (36.2) 103 (60.3) 56 (32.7) 12 (7.0) 1.89 ± 2.8 47 25 5 44 1 9
(35.9) (19.0) (3.8) (33.6) (0.8) (6.9)
erMRI indicates endorectal magnetic resonance imaging; PSA, prostatespecific antigen; RP, radical prostatectomy; SRT, salvage radiotherapy.
2 | www.amjclinicaloncology.com
TABLE 2. Treatment Characteristics (n = 171)
N (%) RT Boost No boost Median RT dose (range, Gy) Boost group No boost group WPRT Yes No Median dose (range, Gy) CTV definition CTVstandard CTVnew RT technique for PB (n = 171) 3D-CRT IMRT RT technique for boost (n = 131) 3D-CRT IMRT/Dynamic Arc RT AD Yes No AD duration (mo) Median (range)
131 (76.6) 40 (23.4) 74 (72-78) 64 (64-64.4) 34* (19.9) 137 (80.1) 50.4 (48-50.4) 80 (46.8) 91 (53.2) 152w (89) 19 (11) 106 (81) 25 (19) 38 (22.2) 133 (77.8) 6.7 (3-34)
*With a 4-field 3D-CRT technique. wA 4-, 6-, and 3-field 3D-CRT beam arrangement was used in 106 (62%), 43 (25%), and 3 (2%) patients, respectively. 3D-CRT indicates 3-dimensional conformal RT; AD, androgen deprivation; CTV, clinical target volume; IMRT, intensity-modulated RT; PB, prostatic bed; RT, radiotherapy; WPRT, whole pelvic RT.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
was considered statistically significant. Statistical analyses were performed using the SPSS 17.0 statistics software package (SPSS Inc., Chicago, IL).
RESULTS The 3- and 5-year bRFS rates were 64.2 ± 4.3% and 45.6 ± 5.6%, respectively. Overall, 61 patients (35.7%) developed a biochemical relapse after salvage treatment, of whom almost two thirds (59%) recurred within 2 years after salvage. Results of univariate and multivariate analyses of clinical, pathologic, and treatment factors predicting for bRFS after salvage RT are presented in Table 3. Despite a better 3-year bRFS rate for patients treated with a boost, the difference observed between the boost and noboost groups was not statistically significant (68.4 ± 4.6% vs. 49.7 ± 10%, P = 0.251). No differences in age at diagnosis (P = 0.634), PSA at diagnosis (P = 0.443), presence of pathologic extracapsular extension and/or seminal vesicles invasion (P = 0.588), GS (r3 + 4 vs. Z4 + 3) (P = 0.564), and surgical margin status (P = 0.243) were found between patients treated with or without a boost. Nevertheless, patients with a gross tumor recurrence on erMRI showed a higher mean presalvage PSA (2.08 vs. 1.26 ng/mL, P = 0.04) and were more likely to recur later after RP compared with those with no visible loco-
Dose-adapted Prostate Salvage RT
regional failure and treated without a boost (mean 47.5 vs. 28.7 mo, P = 0.001). WPRT was equally used in patients treated with or without a boost (P = 0.074), whereas AD was more frequently delivered to the boosted patients (P = 0.049). The median PSA value in patients treated with salvage RT only (n = 126) was 0.75 ng/mL (range, 0.1 to 15.6 ng/mL) and 0.55 ng/mL (range, 0.04 to 15.7 ng/mL) on day 1 and on the fifth week of RT, respectively. On univariate analysis, a decrease or a stability of the PSA value between day 1 and the fifth week of RT was significantly associated with a better 3-year bRFS compared with patients showing a biochemical progression during the same interval (71.8 ± 5.4% vs. 31.1 ± 10.6%, respectively, P = 0.001) (Table 3). No significant differences in PSA kinetics during RT were observed between patients treated with or without a boost. Overall, 76.2% of patients (n = 96) had a decreased or stable PSA value between day 1 and the fifth week of RT, whereas 23.8% (n = 30) progressed biochemically during RT. On multivariate Cox regression analysis, the PSA value before salvage (r1 ng/mL vs. >1 ng/mL) (HR, 2.672; 95% CI, 1.334-5.351; P = 0.006) and the PSA kinetics between day 1/ fifth week of RT (HR, 3.401; 95% CI, 1.617-7.152; P = 0.001) were independently correlated with bRFS (Table 3). By combining the above 2 independent variables, it was possible to define 3 risk categories: a low-risk group (n = 63) including
TABLE 3. Univariate and Multivariate Analysis of Clinical, Pathologic, and Treatment Factors Predicting for Biochemical Relapse-free Survival After Salvage RT
Univariate Variables RT group Boost (n = 131) No boost (n = 40) WPRT Yes (n = 34) No (n = 137) CTV definition CTVstandard (n = 80) CTVnew (n = 91) AD use Yes (n = 38) No (n = 133) PSA at salvage (ng/mL) r1 (n = 101) > 1 (n = 69) Surgical margins Positive (n = 103) Negative (n = 56) pT3a/b stage Yes (n = 99) No (n = 70) Pathologic GS r3 + 4 (n = 114) Z4 + 3 (n = 54) PSA 1-5th week Decreased-stable (n = 96) Increased (n = 30) RP to RT interval (y) r2 (n = 66) > 2 (n = 105)
Multivariate
3 y-bRFS
P*
HR (95% CI)
Pw
68.4 ± 4.6 49.7 ± 10.0
0.251
—
0.130
68.9 ± 8.8 62.9 ± 4.9
0.833
—
0.997
57.4 ± 6.3 70.9 ± 5.7
0.541
—
0.571
74.8 ± 7.8 61.0 ± 5.0
0.674
—
—
68.4 ± 5.5 58.4 ± 6.8
0.208
2.672 (1.334-5.351)
0.006
67.6 ± 5.4 58.3 ± 8.3
0.410
—
0.635
59.6 ± 5.7 70.1 ± 6.6
0.069
—
0.214
65.8 ± 5.4 64.2 ± 7.4
0.766
—
0.215
71.8 ± 5.4 31.1 ± 10.6
0.001
3.401 (1.617-7.152)
0.001
62.4 ± 7.1 65.3 ± 5.4
0.887
—
0.444
*The Kaplan-Meier analysis log-rank P-value. wCox proportional hazards model P-value. HR not given for P > 0.1. AD indicates androgen deprivation therapy; bRFS, biochemical relapse free-survival; CI, confidence interval; HR, hazards ratio; PSA, prostate-specific antigen; RT, radiotherapy; WPRT, whole pelvic RT.
r
2014 Lippincott Williams & Wilkins
www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
patients with a PSA value before salvage r1 ng/mL and a stable or decreasing PSA value between day 1/fifth week of RT (80.2 ± 5.7%, 3-year bRFS); a high-risk group (n = 9) including patients with a PSA > 1 ng/mL before salvage and an increasing PSA value between day 1/fifth week of RT (22.2 ± 13.9%, 3-year bRFS), and an intermediate-risk group (n = 54) of patients with both a favorable and an unfavorable variable, (48.7 ± 8.5%, 3-year bRFS) (P = 0.0001) (Fig. 1). Overall, 3 patients, all treated according to the CTVstandard definition, failed locally in-field 5 or more years after salvage. Two of these patients received 64 Gy to the PB only, whereas the third patient received an additional 10 Gy boost. All 3 patients with postsalvage local relapses were investigated with erMRI and/or with positron emission tomography with computed tomography. Confirmatory biopsies were performed in only 1 patient. The 3- and 5-year DMFS, CSS, and OS were 85.2 ± 3.2% and 78.4 ± 4.5%, 100% and 93.4 ± 3.3%, and 99.1 ± 0.9% and 92.5 ± 3.4%, respectively.
DISCUSSION The optimization of SRT in patients with biochemical recurrence after curative RP for prostate cancer represents an area of ongoing investigation. Several retrospective studies have analyzed the role of dose escalation,10 pelvic RT,11 and AD12,13 to define the best therapeutic approach for recurrent patients. Four prospective randomized trials, which are currently recruiting or have recently closed to accrual, aim to settle this issue (RTOG 0534, RADICALS, EORTC 2204330041, and SAKK 09/10). Our study reports the results of an original treatment approach using a selective dose-adapted RT regimen according to the presence or absence of a macroscopic local recurrence on erMRI. The American Society for Therapeutic Radiology and Oncology consensus guidelines suggest a minimum of 64 Gy in a salvage setting to achieve a durable biochemical
FIGURE 1. The Kaplan-Meier estimates of biochemical relapse free-survival (bRFS) according to the following risk classes and restricted to patients treated without androgen deprivation: lowrisk (PSA before salvage r1 ng/mL and a stable or decreasing PSA value between day-1/5th week of RT); high-risk (PSA before salvage > 1 ng/mL and an increasing PSA value between day-1/ 5th week of RT); intermediate-risk (patients with both a favorable and an unfavorable variable). PSA indicates prostate-specific antigen; RT, radiotherapy.
4 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
control.14 However, the tumor burden at salvage and its surrogate marker represented by the pre-RT PSA level may differ largely among patients. For every 0.1 ng/mL increment in PSA at salvage, a loss of approximately 4% in biochemical control has been reported by King.15 In a meta-analysis by Ohri et al2 the 5-year bRFS decreased by 18.3% (95% CI, 10.4%-26.3%) for every 1 ng/ mL increase of pre-RT PSA. Furthermore, increasing the dose to the macroscopic recurrence above 64 Gy may well increase the probability of tumor-control of approximately 2.5% per Gy.2 Indeed, King and Kapp16 observed a TCD50 (ie, dose necessary to achieve a biochemical tumor control in 50% of patients) of about 66 Gy for localized prostate cancer. Assuming that for microscopic disease the TCD50 is about 6 Gy lower,4 a dose-adapted treatment approach based on tumor burden may be appropriate to obtain a similar biochemical control probability for micro versus macroscopic local residual disease. This is what we have observed in the present study as patients treated with 74 Gy for gross residual recurrence visible on erMRI studies and those treated for local microscopic disease with a lesser dose (64 Gy) presented with a not-statistically different 3-year bRFS. In contrast, the knowledge of the disease site in patients with positive erMRI studies might explain why a higher SRT dose compensates for a macroscopic tumor volume, whereas patients without visible locoregional disease might be more likely to have distant metastases. However, we acknowledge that biases deriving from the heterogeneity of the patients and treatments may have influenced our findings, with a nonsignificant 18.5% difference rate in bRFS at 3-years between patients treated with high-dose versus low-dose SRT. Irrespective of the 3-year median follow-up of the present study, our results are at least comparable to previous studies on SRT and especially those reported from series using dose-escalation treatment protocols1,10,12,13,17–23 (Table 4). Although in some of these studies results may have been favorably biased by a higher percent of patients receiving concurrent AD ( > 50% as reported by Soto et al,13 whereas only 22% in the present study), we have not been able to detect so far a significant benefit from AD when added to salvage RT. Several aspects of the present study need to be highlighted. First, erMRI studies may be very helpful in defining local relapse in the PB after RP. The relatively high rate (76.6%) of positive findings visualized by MRI in this study may well be explained by the use of multiparametric acquisitions realized with an endorectal coil and interpreted by a stable team of 2 experienced uro-radiologists. Despite the lack in this series of histopathologic confirmation of the suspected relapse, previous published works have demonstrated the high reliability of erMRI in detecting local recurrence after RP,24,25 even for PSA levels at SRT of 1 ng/mL before salvage and an increasing PSA kinetic during RT may be associated with a worse biochemical outcome after salvage treatment. In addition, a dose escalation delivering 64 Gy to the PB with a 10 Gy dose increment to the gross local recurrent tumor as detected by erMRI, was associated with good biochemical control and outcome. By selecting patients who are most likely to benefit from SRT doses above 70 Gy as well as by reducing the size of the highest-dose target volume, this approach may serve as a www.amjclinicaloncology.com |
5
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Zilli et al
hypothesis-generating basis to improve the therapeutic ratio in patients recurring after RP and salvaged by SRT. Further prospective trials are warranted in the future to investigate the use of erMRI and dose-adapted SRT protocols in the salvage setting. REFERENCES 1. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035–2041. 2. Ohri N, Dicker AP, Trabulsi EJ, et al. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837–844. 3. Feng M, Hanlon AL, Pisansky TM, et al. Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1417–1423. 4. Okunieff P, Morgan D, Niemierko A, et al. Radiation doseresponse of human tumors. Int J Radiat Oncol Biol Phys. 1995;32:1227–1237. 5. Alfarone A, Panebianco V, Schillaci O, et al. Comparative analysis of multiparametric magnetic resonance and pet-ct in the management of local recurrence after radical prostatectomy for prostate cancer. Crit Rev Oncol Hematol. 2012;84:109–121. 6. Zilli T, Jorcano S, Peguret N, et al. Dose-adapted salvage radiotherapy after radical prostatectomy based on an ermri target definition model: toxicity analysis. Acta Oncol. 2014;53:96–102. 7. Davis JB, Reiner B, Dusserre A, et al. Quality assurance of the eortc trial 22911. A phase iii study of post-operative external radiotherapy in pathological stage t3n0 prostatic carcinoma: the dummy run. Radiother Oncol. 2002;64:65–73. 8. Miralbell R, Vees H, Lozano J, et al. Endorectal mri assessment of local relapse after surgery for prostate cancer: a model to define treatment field guidelines for adjuvant radiotherapy in patients at high risk for local failure. Int J Radiat Oncol Biol Phys. 2007;67:356–361. 9. Do T, Dave G, Parker R, et al. Serum psa evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes. Int J Radiat Oncol Biol Phys. 2001;50:1220–1225. 10. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys. 2008;71:23–27. 11. Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: Improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys. 2007;69:54–61. 12. Ost P, Lumen N, Goessaert AS, et al. High-dose salvage intensitymodulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol. 2011;60:842–849. 13. Soto DE, Passarelli MN, Daignault S, et al. Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves
6 | www.amjclinicaloncology.com
14.
15. 16. 17.
18. 19.
20. 21.
22.
23.
24.
25. 26.
27.
Volume 00, Number 00, ’’ 2014
treatment outcomes in high-risk patients. Int J Radiat Oncol Biol Physics. 2012;82:1227–1232. Cox JD, Gallagher MJ, Hammond EH, et al. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate rebiopsy 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. King CR. Adjuvant radiotherapy after prostatectomy: does waiting for a detectable prostate-specific antigen level make sense? Int J Radiat Oncol Biol Phys. 2011;80:1–3. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys. 2008;71:346–350. Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol. 2006;176:985–990. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology. 2002;59:726–731. Jereczek-Fossa BA, Zerini D, Vavassori A, et al. Sooner or later? Outcome analysis of 431 prostate cancer patients treated with postoperative or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74:115–125. Kruser TJ, Jarrard DF, Graf AK, et al. Early hypofractionated salvage radiotherapy for postprostatectomy biochemical recurrence. Cancer. 2011;117:2629–2636. Neuhof D, Hentschel T, Bischof M, et al. Long-term results and predictive factors of three-dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy. Int J Radiat Oncol Biol Phys. 2007;67:1411–1417. Wiegel T, Lohm G, Bottke D, et al. Achieving an undetectable psa after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome—results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009–1016. Geinitz H, Riegel MG, Thamm R, et al. Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2012;82:1930–1937. Casciani E, Polettini E, Carmenini E, et al. Endorectal and dynamic contrast-enhanced mri for detection of local recurrence after radical prostatectomy. Am J Roentgenol. 2008;190: 1187–1192. Sella T, Schwartz LH, Swindle PW, et al. Suspected local recurrence after radical prostatectomy: endorectal coil mr imaging. Radiology. 2004;231:379–385. Cozzarini C, Fiorino C, Da Pozzo LF, et al. Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients. Int J Radiat Oncol Biol Phys. 2012;82:191–199. Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol. 2011;60: 1142–1148.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
![[Adjuvant vs. salvage radiotherapy after radical prostatectomy].](/assets/img/hold.png)
