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J Cancer Res Clin Oncol (2014) 140:1111–1116DOI 10.1007/s00432-014-1673-8

ORIgInal aRtICle – CanCeR ReseaRCh

Biochemical and clinical outcomes after high‑dose salvage radiotherapy as monotherapy for prostate cancer

Angela Botticella · Alessia Guarneri · Niccolo’ Giai Levra · Fernando Munoz · Andrea Riccardo Filippi · Nadia Rondi · Serena Badellino · Francesca Arcadipane · Mario Levis · Riccardo Ragona · Umberto Ricardi

Received: 14 February 2014 / accepted: 3 april 2014 / Published online: 18 april 2014 © springer-Verlag Berlin heidelberg 2014

Conclusions effective biochemical and clinical control rates may be safely achieved administering sRt with high doses (≥72 gy) and using conformal techniques, especially in older patients presenting with lower pre-sRt Psa val-ues. a lower nPsa after sRt predicts for better 5 years bRFs and cRFs rates.

Keywords high-dose external beam radiotherapy · Prostate cancer · nadir Psa · salvage radiotherapy

Introduction

among patients undergoing radical prostatectomy (RP) for clinically localized prostate cancer, 20–35 % will even-tually experience Psa recurrence within 10 years after surgery (han et al. 2003), and this event may precede, in up to 65 % of untreated patients, overt metastatic disease (8 years as median actuarial time to distant metastases) (Pound et al. 1999). emerging evidence suggests that the predominant pattern of failure in patients showing bio-chemical relapse is mainly local (swanson et al. 2007). the available salvage treatment options are either andro-gen deprivation therapy (aDt) or salvage radiotherapy (sRt), which is the only one potentially offering a chance to definitively eradicate recurrent local disease. no ran-domized trial on sRt has ever been conducted, although numerous single-institution retrospective studies, a multi-institutional pooled data analysis (stephenson et al. 2007) and comprehensive reviews of all published studies (King 2012) have been published.

Purpose of the present study is to provide further data on the role of high-dose sRt in a cohort of patients who received sRt as single modality treatment in a single institution.

Abstract Purpose to retrospectively evaluate the role of high-dose salvage radiotherapy (sRt) alone with regard to biochemi-cal and clinical outcomes in patients with biochemical fail-ure (BF) after radical prostatectomy (RP).Methods Between January 2003 and august 2011, 168 hormone-naïve localized prostate cancer patients received sRt alone for post-RP BF in a single institution and were retrospectively analyzed. Multivariate analysis was per-formed to determine the independent prognostic impact of clinical factors on biochemical and clinical outcomes [bio-chemical relapse-free survival (bRFs), clinical relapse-free survival (cRFs), cancer-specific survival (Css) and overall survival (Os)].Results Median follow-up was 54 months. actuarial bRFs, cRFs, Css and Os at 5 years were, respectively, 64, 86.2, 94.5 and 96.3 %. On multivariate analysis, nadir Psa (nPsa) after sRt was significantly associated with bRFs (hR 15, p = 0.001) and cRFs (hR 9, p = 0.001), while Css was associated with Rt dose (≥70 gy; hR 1.9 p = 0.023), pre-Rt Psa (<1.5 vs. ≥1.5 ng/ml; hR 1.3, p = 0.008) and age (>75 years; hR 1.2, p = 0.05). Os was significantly correlated with pre-sRt Psa (linear correla-tion; hR 1.1, p = 0.023) and age (<75 vs. ≥ 75 years; hR 1.1, p = 0.026).

a. Botticella (*) · a. guarneri · n. g. levra · F. Munoz · a. R. Filippi · n. Rondi · s. Badellino · F. arcadipane · M. levis · R. Ragona · U. Ricardi Radiation Oncology Unit, Department of Oncology, University of torino, Via genova 3, 10126 turin, Italye-mail: angela.botticella@gmail.com

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Materials and methods

Patients

Between January 2003 and august 2011, 168 consecutive localized prostate cancer patients received sRt as mono-therapy for post-RP biochemical failure (BF) at our insti-tution, and their charts were retrospectively analyzed. BF post-RP was defined either as (a) a persistently elevated serum Psa after RP (Psa ≥0.2 ng/ml) or (b) a re-rising of serum Psa levels ≥0.2 ng/ml, with a second confirma-tory level of ≥0.2 ng/ml. the timing of initiating sRt was at discretion of the treating radiation oncologist. no patient showed positive lymph node involvement at RP nor received aDt in combination with sRt. all patients were staged after RP using the aJCC 2002 criteria. Before sRt, all patients were generally re-staged with digital rec-tal examination (DRe), a bone scan and a pelvic computed tomography scan in order to rule out metastatic disease, and only cn0M0 patients subsequently underwent sRt. Vesico-ureteral anastomosis biopsy, magnetic resonance imaging and positron emission tomography before sRt were not mandatory, but in general they were performed in case of palpable disease at DRe or rapid Psa Doubling time (Psa Dt <6 months, whenever available). Patients’ clinical–pathological characteristics are shown in table 1.

Radiotherapy treatment

all patients were treated with external beam radiotherapy (eBRt), administered with high-energy photons (10–18 MV). eBRt was delivered via 5-fields 3D conformal tech-nique (coplanar beam angles: 0°, 90°, 45°, 270°, 315°) (Oncentra MasterPlan v.3.0). Weekly electronic portal images were used to verify treatment accuracy. Median radiation dose was 72 gy (range 64–78 gy), delivered with conventional fractionation schedule (2 gy daily fractions, 5 days per week), with 159 patients (94.6 %) receiving doses ≥70 gy.

Clinical target volume (CtV) consisted of the prostate bed and the vesico-ureteral anastomosis. In case of patholog-ical involvement of the seminal vesicles at RP, the original position and/or the remnants, if present, were also included in the CtV. elective pelvic nodal irradiation was not per-formed. a planning target volume (PtV) was generated by adding a 12-mm isotropic margin (except posteriorly, where a 10-mm margin was added, to limit the high-dose region to the rectal wall) to CtV (Oncentra MasterPlan v.3.0).

late radiation side effects were assessed at each follow-up visit using radiation therapy oncology group/euro-pean organization for research and treatment for cancer (RtOg/eORtC) bladder (gU) and bowel (gI) toxicity score.

Follow-up protocol, endpoints and statistics

all patients were evaluated every 3 months for the first 2 years and every 6 months thereafter, with Psa monitor-ing and digital rectal examination. Metastatic workup was performed only when clinically indicated (biochemical recurrence or onset of new symptoms suggesting disease progression).

Median follow-up time was estimated by reverse Kaplan–Meier method.

Biochemical relapse-free survival (bRFs), clinical relapse-free survival (cRFs), cancer-specific survival (Css) and overall survival (Os) were chosen as endpoints. BF after sRt was defined as a serum Psa value of 0.2 ng/ml greater than the post-radiation nadir Psa (nPsa) followed by a second Psa level higher than the first by any amount or by a continuous increase in Psa level after treatment greater than the pre-sRt Psa level or by the initiation of salvage aDt (stephenson et al. 2007). Biochemical RFs,

Table 1 Relevant patients’ characteristics

n (%)

total number of patients 168

Pre-prostatectomy median age (range), years 65 (48–78)

Pre-sRt median age (range), years 68 (52–81)

Interval between RP and sRt, years

Median (range) 35.9 (2–194)

Mean (sD) 45.44 (35.6)

Psa pre-Rt (ng/ml)

Median (range) 0.56 (0.2–14.6)

Mean (sD) 1.14 (2.4)

Psa at diagnosis (ng/ml)

Median (range) 7.97 (3.2–26)

Mean (sD) 12.5 (15.52)

Pathological stage

pt2 118 (70.2 %)

pt3a 34 (20.2 %)

pt3b 16 (9.6 %)

gleason score

≤6 50 (29.8 %)

7 96 (57.1 %)

≥8 22 (13.1 %)

Follow-up after RP, median (range), months 92.6 (23.7–238.9)

Follow-up after sRt, median (range), months 54 (6–118.2)

Persistently detectable Psa levels after RP 24 (14.3 %)

surgical margins

negative 94 (55.95 %)

Positive 74 (44.1 %)

Rt dose

Median (range) 72 (64–78)

Mean (sD) 71.4 (1.9)

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cRFs, Css and Os were depicted using Kaplan–Meier method. Comparison between groups was carried out with the log-rank test. Univariate (UV) and multivariate (MV) analyses were conducted for bRFs, cRFs, Css and Os (for MV prediction, Cox proportional hazards regression was used). Only factors that were significant at UV analysis were entered into the MV model. all p values reported are two-sided, and a p value <0.05 is considered significant.

statistical analyses were performed with stata/MP, ver-sion 11 (stataCorp, College station, tX).

Results

Median follow-up after sRt was 54 months (range 6–118.2 months). Median interval between RP and sRt was 35.9 months (range 2–194 months). nearly 30 % of patients presented with a pt3 disease and 44.1 % with positive margins at surgical specimens. twenty-four (14.1 %) patients presented with persistently detectable Psa after RP. In 115 (68.45 %) patients, a lymph node dissection was performed (all pn0), while the remaining 53 (31.54 %) underwent RP only, and they were therefore staged as cn0.

Median and mean Psa levels pre-sRt were 0.56 ng/ml (range 0.2–14.6 ng/ml) and 1.14 ng/ml (stand-ard deviation-sD 2.4 ng/ml), respectively. In particu-lar, in 36 (21.42 %) patients, pre-sRt Psa was ≥0.2 and <0.3 ng/ml, in 18 (10.71 %) was ≥0.3 and <0.4 ng/ml, in 16 (9.52 %) ≥0.4 and <0.5 ng/ml, in 45 (26.8 %) ≥0.5 and <1 ng/ml and in 48 (31.55 %) ≥1 ng/ml.

after the completion of sRt, 116 patients (116/168, 69.1 %) achieved Psa levels of <0.2 ng/ml, 88 patients (88/168, 52.4 %) of <0.1 ng/ml and 60 patients (60/168, 35.7 %) of <0.05 ng/ml.

Median and mean nPsa after sRt were, respectively, 0.12 ng/ml and 0.05 (range 0.000–1.6, sD 0.21), with a median time to nPsa of 10 months (range 1–74 months).

Biochemical relapse-free survival

Fifty-five out of 168 patients (32.7 %) developed BF after sRt (in 35 patients only a BF was documented, while we observed isolated pelvic lymph node relapse in five patients, prostatic bed relapse in two, prostatic bed and pel-vic lymph node relapse in two cases, distant relapse in five patients, distant disease together with pelvic nodal relapse in five patients). salvage therapies were as follows: aDt in 51 patients, chemotherapy and aDt in three patients and hIFU at the vesico-ureteral anastomosis in one patient.

Mean and median times to BF were, respectively, 27 and 21 months (range 1–93.2; sD 21.9). three- and five-year bRFs were 72.9 % [95 % confidence interval (CI) 64.8–79.4] and 64 % (95 % CI 54.8–71.8), respectively.

Mean nPsa was 0.25 ng/ml (sD 0.15) in patients who developed BF and 0.08 ng/ml (sD 0.07) in patients who remained disease-free.

On univariate analysis, pre-sRt Psa (linear correla-tion and with a cut-off at 0.3 ng/ml, p < 0.05), nPsa after sRt (p < 0.05) and t stage at RP (p < 0.05) were associ-ated with biochemical recurrence. On multivariate analy-sis, nPsa after sRt (linear correlation; hR 15, p = 0.001) remained independent predictor of biochemical recurrence (table 2), while pre-sRt Psa of <0.3 vs. ≥0.3 ng/ml was not significant (p = 0.07).

Clinical relapse-free survival

nineteen out of 168 patients (11.3 %) developed clini-cal failure (for the detailed pattern of failure of these

Table 2 Biochemical relapse-free survival (bRFs), clinical relapse-free survival (cRFs), cancer-specific survival (Css) and overall survival (Os): summary of univariate and multivariate analysis results

the bold values are ones that are statistically significant at the multivariate analysis

bRFs cRFs Css Os

UV MV UV MV UV MV UV MV

gs ns – <0.05 ns ns – ns –

t stage 0.05 ns ns – ns – ns –

Margin status ns – ns – ns – ns –

zPsa pre-Rt (linear correlation) ns – ns – ns – <0.05 0.023 (HR 1.1)

zPsa pre-Rt (<1.5 vs. ≥1.5 ng/ml) ns – ns – <0.05 0.008 (HR 1.3) ns –

zPsa pre-Rt (<0.3 vs. ≥0.3 ng/ml) 0.05 ns ns – ns – ns –

surgery-Rt interval ns – ns – ns – ns –

Rt dose (<72 vs. ≥72 gy) ns – <0.05 ns <0.05 0.023 (HR 1.9) <0.05 ns

nadir Psa <0.05 0.001 (HR 15) <0.05 0.001 (HR 9.1) ns – ns –

age (<75 vs. ≥75 years) ns – ns – <0.05 0.012 (HR 1.3) <0.05 0.026 (HR 1.1)

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patients see above), at a mean and median time of 27.2 and 22.6 months, respectively (range 1–76.6; sD 19.2).

three- and five-year cRFs were 92.9 % (95 % CI 84.9–96.8) and 86.2 % (95 % CI 75.4–92.4), respectively.

Mean nPsa in patients who developed clinical failure was 0.35 ng/ml (sD 0.30), while in patients who remained disease-free was 0.11 ng/ml (sD 0.7).

On univariate analysis, clinical, treatment-related and pathological factors associated with the onset of clinical failure were nPsa after sRt (p < 0.05), gs (p = 0.02) and sRt dose (<72 gy vs. ≥72; p = 0.027). On multivariate analysis, only nPsa after sRt remained statistically signif-icant (linear correlation; hR 9.1, p = 0.02) (table 2).

Cancer-specific survival

six patients (6/168: 3.6 %) died as a consequence of pros-tate cancer progression.

three- and five-year Css were 97.9 % (95 % CI 93.8–99.3) and 94.5 % (95 % CI 87.8–97.6 %), respectively.

On univariate and multivariate analysis, pre-sRt Psa (<1.5 vs. ≥1.5 ng/ml; UV: p < 0.5; MV: hR 1.3, p = 0.008), sRt dose (<72 gy vs. ≥72 gy; UV: p < 0.05; MV: hR 1.9, p = 0.023) and age (<75 vs. ≥75 years; UV: p < 0.05; MV: hR 1.3, p = 0.012) significantly affected Css (table 2).

Overall survival

Overall, eight patients died (six of prostate cancer, two of other causes; 8/168: 4.8 %).

three- and five-year Os were 98.6 % (95 % CI 94.3–99.6) and 96.6 % (95 % CI 90.2–98.6 %), respectively.

On univariate analysis, pre-sRt Psa (linear correlation, p < 0.05), age (<75 vs. ≥75 years; UV: p < 0.5) and sRt dose (<72 vs. ≥72 gy, p = 0.03). On multivariate analysis, pre-sRt Psa (linear correlation; hR 1.1, p = 0.023) and age (<75 vs. ≥75 years; hR 1.1, p = 0.026) retained statis-tical significance for Os (table 2).

toxicity

the crude rates of late grade g2 genito-urinary (gU) and gastro-intestinal (gI) toxicity were 21 and 13 %, respec-tively. More severe toxicity was quite rare, with, late g3 and g4 gU toxicity rates of 4.2 and 1.8 %, respectively, and late g3 gI toxicity rates of 0.6 % (no patients pre-sented with late g4 gI toxicity).

Discussion

We retrospectively analyzed the outcomes of 168 node-negative, hormone-naïve patients who underwent high-dose

sRt (median Rt dose 72 gy) for biochemical recurrence after RP for prostate cancer. at 5 years, bRFs, cRFs and Css were, respectively, 64, 84 and 94.5 %. nadir Psa was identified as the most predictive factor for bRFs and cRFs, while sRt dose, pre-sRt Psa and age for Css.

In the adjuvant/salvage setting, lower eBRt doses (com-pared to definitive eBRt) have traditionally been admin-istered and dose-escalation has never been prospectively tested, mainly due to the presumption that the tumor burden in the prostate fossa is microscopic and that postoperative patients are believed to be less tolerant to escalated doses. therefore, median dose administered in observational stud-ies in sRt setting is nearly 65 gy (King 2012), and bio-chemical outcomes are far from being satisfactory (average 5-year bRFs of all published sRt studies is <50 %, with a median follow-up of 50 months (King 2012; Ohri et al. 2012). as confirmed by a secondary analysis of the sWOg 8,794 trial, disease recurrence in the observation arm was more likely to be within the prostatic fossa (swanson et al. 2007), and, therefore, strategies to improve local control (which appears to have a key role in clinical outcome) in the salvage setting (i.e., dose-escalation) are likely to result in improved outcomes. Indeed, emerging evidence from retrospective studies (Bernard et al. 2010; Cozzarini et al. 2004; King and spiotto 2008; siegmann et al. 2011; Ost et al. 2012; goenka et al. 2012) and systematic reviews (King 2012; Ohri et al. 2012; King and Kapp 2008) is promisingly suggesting that Rt doses above 70–72 gy can be safely delivered also in sRt setting, with an acceptable rate of acute and late toxicity and a significant increase in biochemical control.

In two systematic reviews, King et al. (2008, 2012) showed that the dose–response relationship for sRt is remarkably close to the dose–response relationship for radical radiotherapy for localized prostate cancer, confirm-ing its intrinsic radioresistant nature and thus providing the radiobiological rationale for escalating the dose also in postoperative setting. the authors estimated a tD50 of (67.8 vs. 66 gy for definitive Rt for prostate cancer) and calculated a proportional gain in bRFs rates of 2 % per incremental gy (King 2012). sRt doses in the range of 60–70 gy lie in the middle-steep part of the sigmoidal dose–response curve, with doses of 70 gy achieving a bRFs of 54 versus 34 % for Rt dose of 60 gy. the same authors described the importance of pre-sRt Psa values on bio-chemical outcomes, with an estimated 2.6 % loss of bRFs for each incremental 0.1 ng/ml in a Psa range of 0–1 ng/ml (King 2012). these estimates compare favorably well with our cohort: with a median Rt dose of 72 gy and a median pre-sRt Psa of 0.53 ng/ml, observed 5-year bRFs was 64 %. Previously published retrospective high-dose sRt studies (median sRt dose ≥66–70 gy) show similar bRFs rates, generally ranging from 50 to 70 % at

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5 years (Bernard et al. 2010; King and spiotto 2008; Ost et al. 2012; goenka et al. 2012). Direct comparison of bio-chemical outcomes in such reports (with local recurrence/distant metastases/overall survival underreported) is ham-pered by the heterogeneity of patients’ characteristics, and median pre-Rt Psa certainly plays an important role. In the report of Ost et al. (2012) (median sRt dose: 76 gy), reported 5-year bRFs was 56 %, with a median pre-sRt Psa of 0.8 ng/ml. When selecting patients with pre-sRt values of <0.5 ng/ml, the same authors reported a 5-year bRFs of 73 %, which was similar to the 61 % reported by Bernard et al. 2010 (sRt dose >66.6, median pre-sRt Psa 0.5 ng/ml), to the 58 % reported by King and spio-tto (2008) (sRt dose 70 gy, median pre-sRt Psa 0.5 ng/ml) and to the 70 % reported by goenka et al. (2012) (sRt dose ≥70 gy, pre-sRt Psa values <0.4 ng/ml and favora-ble pathologic characteristics).

nadir Psa after sRt was identified as the only inde-pendent predictor of biochemical and clinical outcome (loco-regional recurrence and distant metastases); pre-sRt Psa and t stage were significant only at univariate anal-ysis, probably due to the interference from the very high statistical significance of nPsa (hR 15, p = 0.001). nadir Psa after eBRt or brachytherapy for definitive treatment for prostate cancer has been well established as predictor of biochemical and clinical outcome (Ray et al. 2006; Ko et al. 2012). similarly, Wiegel et al. (2009) report a corre-lation between achieving an undetectable Psa (defined as Psa <0.1 ng/ml) and biochemical outcome, with a calcu-lated 3.5-year bRFs of 75 versus 18 % for the patients with undetectable Psa versus detectable Psa. In our cohort, such a stratification would have been hampered by the dif-ferent Psa assays used during the follow-up (ultra-sensi-tive assays were not used in all patients).

sRt was generally well tolerated, with a very good safety profile and with a very low incidence of late severe toxicity.

Major limitations of our study are its retrospective design (which can hamper a correct results interpretation with unforeseen bias), the 54-month follow-up that may be insufficient for a reliable evaluation of distant metastases and survival, and the lack of information about Psa kinet-ics before sRt, in particular on Psa doubling time, that has been showed to be an important prognostic factor in sRt patients (stephenson et al. 2007). however, at the best of our knowledge, our cohort is one of the largest in which high-dose sRt has been used as monotherapy (thus avoid-ing a potential confounding effect of aDt on outcome). In fact, the role of aDt in sRt context remains unclear and currently under investigation by randomized clinical trials: several retrospective reports and only one randomized trial have been published and they reach different conclusions (thompson et al. 2013). although most of them suggested

better outcomes for patients who underwent combined modality treatment, they differed in aDt type, timing (neo-adjuvant, concomitant and/or adjuvant) and duration. Moreover, studies varied in patient risk factors, sRt dose and follow-up durations (thompson et al. 2013).

Conclusions

although a significant proportion of our patients may still have the chance of a durable response after sRt, some of them may present with poorer outcome, with 36 % of BF and 14 % of distant metastases at 5 years. Patients with higher nPsa values after sRt, higher pre-Rt Psa values and treated with lower sRt doses have a higher rate of clinical and biochemical failure and lower prostate cancer survival. More aggressive and tailored treatment strategies for such patients (i.e., concomitant use of aDt or other systemic treatments, earlier sRt) should be tested in pro-spective trials.

Acknowledgments none.

Conflict of interest We declare that we have no conflict of interest.

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