Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy

doi:10.1016/j.eururo.2017.11.012

European Urology

Volume 73, Issue 6, June 2018, Pages 879-887

https://doi.org/10.1016/j.eururo.2017.11.012 Get rights and content

Abstract

Background

The Stephenson nomogram is widely used to estimate the success of salvage radiotherapy (sXRT) for prostate cancer (PCa) recurrence after radical prostatectomy (RP).

Objective

To determine whether multiparametric pelvic magnetic resonance imaging (mpMRI) performed for biochemical recurrence after RP improves prognostication of sXRT relative to the Stephenson nomogram.

Design, setting, and participants

Men undergoing RP at our institution from 2003 to 2012 who had biochemical recurrence evaluated by mpMRI within 12 mo of sXRT were retrospectively reviewed. Exclusion criteria included PCa treatment prior to RP, adjuvant XRT after RP, salvage cryotherapy before sXRT, and hormone refractory disease prior to sXRT.

Outcome measurements and statistical analysis

Multivariable Cox regression analyses (adjusting for Stephenson nomogram covariates) associated mpMRI findings with prostate-specific antigen (PSA) recurrence and metastasis after sXRT. The mpMR images were compared in a binary fashion: no lesion versus vesicourethral/seminal vesical bed/prostate fossa lesions.

Results and limitations

Among 473 sXRT patients, 57%(204) had lesions on mpMRI: 26%(124) vesicourethral, 28%(135) seminal vesical bed/prostatic fossa, 7%(34) nodal, and 1%(3) bone. Median PSA at mpMRI with lesions was 0.46 versus 0.40 ng/ml without lesions. After excluding nodal/bone lesions, 29% of men developed PSA recurrence and 14% metastasis (median follow-up 45 mo after sXRT). For patients with a pre-sXRT PSA of ≤0.5 ng/ml, negative mpMRI was associated with increased PSA recurrence (39% vs 12%, p < 0.01) and metastasis (16% vs 2%, p < 0.01) at 4 yr after sXRT. For patients with a PSA of ≤0.5 ng/ml, the addition of mpMRI to the propensity score (created using variables from the original Stephenson nomogram) improved the c-statistic from 0.71 to 0.77 for PSA recurrence (hazard ratio [HR] 3.60, p < 0.01) and from 0.66 to 0.77 for metastasis (HR 6.68, p < 0.01). Limitations include evolutions in MRI technique and lack of a cohort of men undergoing mpMRI electing against sXRT.

Conclusions

Pre-sXRT mpMRI improves clinicopathologic variables to estimate sXRT success, particularly in the early sXRT setting.

Patient summary

Men who have biochemically recurrent prostate cancer after radical prostatectomy often receive salvage radiotherapy. In our study, multiparametric pelvic magnetic resonance imaging prior to salvage radiotherapy was a significant predictor of prostate-specific antigen failure and metastasis after radiotherapy.

Introduction

Approximately 70 000 radical prostatectomies (RPs) are performed for prostate cancer (PCa) annually in the USA [1], [2], and ∼30% of these men experience biochemical recurrence (BCR) [3]. At 10 yr, only 10% of men with BCR will die of PCa [4]. Salvage radiotherapy (sXRT) may achieve durable prostate-specific antigen (PSA) remissions, and Stephenson nomograms are widely used in this setting to estimate the success of sXRT [5], [6]. On this basis, the “early” delivery of sXRT at PSA ≤0.5 ng/ml has been advocated due to improved PSA recurrence and metastasis rates [7].

However, some patients may not benefit from sXRT, particularly those who harbor distant disease at the time of sXRT. Indeed, 50% of men undergoing sXRT with a PSA between 0.2 and 0.5 ng/ml experience a PSA recurrence at 10 yr [6]. Accordingly, the updated Stephenson nomogram's concordance index for PSA recurrence is only 0.68 [6], supporting the need for further research to identify the optimal sXRT candidate. Moreover, minimizing overtreatment with sXRT may improve quality of life for patients, considering the toxicities [8], [9] associated with sXRT.

Advanced PCa imaging may become sensitive enough to identify patients with distant metastases, and improve upon existing clinical and pathologic predictors of sXRT success. Nevertheless, a median PSA value of ∼2 ng/ml per positive scan limits the utility of C11-choline [10] and prostate specific membrane antigen [11] positron emission tomography (PET) and computed tomography (CT) scans in the early sXRT setting. Instead, multiparametric pelvic magnetic resonance imaging (mpMRI) has sensitivity of >90% at PSA levels of ∼1 ng/ml with an area under the curve of 0.93 [12] and 0.91 [13] for identifying local recurrences after BCR.

Herein, we evaluate the utility of mpMRI to predict PSA recurrence and metastasis after sXRT, and improve upon the clinical and pathologic variables of the original [5] and updated [6] Stephenson nomograms. We hypothesize that patients with negative mpMRI may be more prone to sXRT failure due to an increased risk of distant disease.

Section snippets

Patient population

In this Institutional Review Board–approved study, men undergoing RP from January 2003 to December 2012 who had BCR (defined as PSA ≥ 0.2 or rising PSA before 0.2) and received sXRT (N = 1111) were identified using a prospectively maintained institutional prostatectomy registry. A retrospective chart review identified patients who received mpMRI for BCR after RP. The mpMRI was performed within 12 mo prior to sXRT. Exclusion criteria were as follows: PCa treatment prior to RP (radiotherapy,

Baseline characteristics

A total of 473 patients undergoing sXRT received mpMRI prior to sXRT, with a median of 1 mo (interquartile range [IQR]: 0–3) between mpMRI and sXRT. Overall, 56.9% (204) of mpMR images had a lesion. The median PSA at mpMRI for patients without visible lesions was 0.40 ng/ml (IQR: 0.27–0.55) versus 0.46 ng/ml (IQR: 0.34–1.15) for patients with visible lesions. Fifty-four percent of patients with a PSA of 0.2–0.5 ng/ml had an identifiable lesion on mpMRI. Figure 1 depicts the univariable logistic

Discussion

In a cohort of 473 patients undergoing mpMRI prior to sXRT, we found that approximately 50% of patients will have mpMRI lesions even at PSA levels of 0.2–0.5 ng/ml. Furthermore, mpMRI was most useful in the early sXRT setting, improving the c-statistic of the original Stephenson nomogram from 0.71 to 0.77 for PSA recurrence and 0.66 to 0.77 for metastasis. Decision curve analysis further supported that mpMRI may have a role in evaluating patients prior to sXRT. Our hypothesis was validated in

Conclusions

Pre-sXRT mpMRI is a valuable adjunct to current clinicopathologic variables used to estimate the success of sXRT. Approximately 50% of patients will have mpMRI lesions even at PSA levels of 0.2–0.5 ng/ml. Negative mpMRI was an independent risk factor for PSA recurrence and metastasis for patients undergoing sXRT with a PSA level of <0.5 ng/ml. Furthermore, rigorous studies are warranted to verify the benefits and limitations of mpMRI in the early sXRT setting.

References (27)

M.D. Tyson et al.
Radical prostatectomy trends in the United States: 1998 to 2011
Mayo Clin Proc
(2016)
V. Sharma et al.
Open conversion during minimally invasive radical prostatectomy: impact on perioperative complications and predictors from national data
J Urol
(2014)
A. Toussi et al.
Standardizing the definition of biochemical recurrence after radical prostatectomy—what prostate specific antigen cut point best predicts a durable increase and subsequent systemic progression?
J Urol
(2016)
S.A. Boorjian et al.
Long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence
Eur Urol
(2011)
E. Zaffuto et al.
Early postoperative radiotherapy is associated with worse functional outcomes in patients with prostate cancer
J Urol
(2017)
I. Sobol et al.
Contemporary mapping of post-prostatectomy prostate cancer relapse with (11)C-choline positron emission tomography and multiparametric magnetic resonance imaging
J Urol
(2017)
A.J. Vickers et al.
European Urology guidelines for reporting of statistics in European Urology
Eur Urol
(2015)
H.C. Rischke et al.
PET/CT and MRI directed extended salvage radiotherapy in recurrent prostate cancer with lymph node metastases
Adv Med Sci
(2016)
S. Johnson et al.
A comprehensive assessment of the prognostic utility of the Stephenson nomogram for salvage radiation therapy postprostatectomy
Pract Radiat Oncol
(2014)
A.J. Stephenson et al.
Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy
J Clin Oncol
(2007)

R.D. Tendulkar et al.

Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy

J Clin Oncol

(2016)

B.J. Stish et al.

Improved metastasis-free and survival outcomes with early salvage radiotherapy in men with detectable prostate-specific antigen after prostatectomy for prostate cancer

J Clin Oncol

(2016)

P. Ghadjar et al.

Acute toxicity and quality of life after dose-intensified salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: first results of the randomized trial SAKK 09/10

J Clin Oncol

(2015)

Cited by (26)

Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Based Clinical Target Volume Delineation Guideline for Postprostatectomy Salvage Radiation Therapy: The PERYTON Guideline
2024, International Journal of Radiation Oncology Biology Physics
Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT–detected local recurrences (LRs).
Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC).
After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT–detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83).
This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.
ESTRO ACROP consensus recommendation on the target volume definition for radiation therapy of macroscopic prostate cancer recurrences after radical prostatectomy
2023, Clinical and Translational Radiation Oncology
The European Society for Radiotherapy & Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) panel on prostate bed delineation reflected on macroscopic local recurrences in patients referred for postoperative radiotherapy (PORT), a challenging situation without standardized approach, and decided to propose a consensus recommendation on target volume selection and definition.
An ESTRO ACROP contouring consensus panel consisting of 12 radiation oncologists and one radiologist, all with subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in two separate clinically relevant scenarios: a local recurrence at the seminal vesicle bed and one apically at the level of the anastomosis. Both recurrences were prostate-specific membrane antigen (PSMA)-avid and had an anatomical correlate on magnetic resonance imaging (MRI). Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed.
Contouring of the two cases confirmed considerable variation among the panelists. Finally, however, a consensus recommendation could be agreed upon. Firstly, it was proposed to always delineate the entire prostate bed as clinical target volume and not the local recurrence alone. The panel judged the risk of further microscopic disease outside of the visible recurrence too high to safely exclude the rest of the prostate bed from the CTV. A focused, “stereotactic” approach should be reserved for re-irradiation after previous PORT. Secondly, the option of a focal boost on the recurrence was discussed.
Radiation oncologists are increasingly confronted with macroscopic local recurrences visible on imaging in patients referred for postoperative radiotherapy. It was recommended to always delineate and irradiate the entire prostate bed, and not the local recurrence alone, whatever the exact location of that recurrence. Secondly, specific dose-escalation on the macroscopic recurrence should only be considered if an anatomic correlate is visible. Such a focal boost is probably feasible, provided that OAR constraints are prioritized. Possible dose is also dependent on the location of the recurrence. Its potential benefit should urgently be investigated in prospective clinical trials.
Mapping of Local Recurrences After Radical Prostatectomy Using 68-Gallium–Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: Implications for Postprostatectomy Radiation Therapy Clinical Target Volumes
2023, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Given the frequent use of PPRT, the patterns of failure data that underlie the delineation of the CTV are poorly described. Several transrectal ultrasound3 or magnetic resonance imaging (MRI) studies4-16 have attempted to categorize the location of recurrences within the prostate bed, generally in 1 dimension only (eg, along the superior/inferior axis). Most of these studies were not sufficiently granular to inform radiation therapy treatment volumes.
Our objective is to describe the distribution of local recurrences after radical prostatectomy (RP) as delineated using 68-Gallium–prostate-specific membrane antigen positron emission tomography/computed tomography (⁶⁸Ga-PSMA PET/CT) to identify areas where current consensus guideline clinical target volumes (CTVs) are insufficient or excessive and to identify predictors of recurrence location within the fossa.
Retrospective review of databases from 2 tertiary referral centers was performed to identify patients who underwent ⁶⁸Ga-PSMA PET/CT for biochemical recurrence after RP. Those with a component of local recurrence were included for further analysis. The epicenter of each recurrence was defined relative to reference points in 3 axes, categorized into 1 of 7 levels in the superior/inferior axis relative to the vesicourethral anastomosis, and recorded as within or outside the Faculty of Radiation Oncology Genito-urinary Group (FROGG) and Radiation Therapy Oncology Group consensus CTVs. Univariate and multivariate analysis was performed to identify predictors of recurrence location based on clinical and histopathologic variables.
One thousand forty-nine ⁶⁸Ga-PSMA PET/CT scans were reviewed. One hundred forty sites of local recurrence were identified on 132 scans. Relative to the vesicourethral anastomosis, 13 (9%), 31 (22%), 17 (12%), 24 (17%), 27 (19%), 20 (14%), and 8 (6%) recurrences occurred >5 mm inferior; within 5 mm above or below; and 6 to 15 mm, 16 to 25 mm, 26 to 35 mm, 36 to 45 mm, and >45 mm superiorly, respectively. Thirteen (9%) and 2 (1.4%) recurrences occurred beyond the FROGG and Radiation Therapy Oncology Group consensus CTVs, respectively, with all below the inferior CTV margin.
In the largest study to date mapping local recurrences after RP in 3-dimensions, we provide several insights to inform future contouring guidelines; in particular, 9% of recurrences occurred inferior to the FROGG CTV.
A prospective study assessing the pattern of response of local disease at DCE-MRI after salvage radiotherapy for prostate cancer
2022, Clinical and Translational Radiation Oncology
Citation Excerpt :
However, even if sRT is started at PSA levels below 0.5 ng/ml, up to 50% of patients harbor one or more visible lesions in the prostatic bed at high resolution DCE-MRI [9,16,17]. Though a minority of the detected lesions may be falsely positives [8,18,19] and the detection of a local lesion per se is a favorable prognostic factor [12,16,20], there are concerns on the appropriateness of such limited dosages of radiation. Indeed, in a recent randomized trial comparing two dose levels of sRT, local recurrence alone or in combination with other sites represented 21.6% of all first events of clinical progression after 64 Gy [1].
To assess the pattern of response of presumed local lesions at dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) after salvage radiotherapy (sRT).
This is a prospective study conducted at a single Institution accruing patients with one or more local failures at DCE-MRI after radical prostatectomy between August 2017 and June 2020. Patients underwent exclusive sRT delivering 66–69 Gy and 73.5 Gy in 30 fractions to the whole prostatic fossa and to the local failure(s) seen at DCE-MRI, respectively.
Patients were offered DCE-MRI at 3 months intervals after sRT until complete disappearance (CR) of the lesion(s) or up to a maximum of 4 revaluations.
62 patients with 72 nodules were enrolled. All patients underwent the 1st revaluation, and 33 patients (53.2%) showed a CR. The median time to CR was 4.7 months. Four patients did not undergo further testing before achieving a CR and even considering these patients as no responses, the vast majority (87.1%, 95%CI: 78.5–94.4%) of lesions would have completely disappeared by 12 months from the end of sRT.
The volume of the lesion at pre-sRT DCE-MRI was an independent predictor of CR at the 1st revaluation (OR: 0.076, 95%CI: 0.009–0.667; p = 0.020) along with time elapsed from sRT (OR: 3.399, 95% CI: 1.156–9.993, p = 0.026).
The present study documents the complete disappearance of the vast majority of local lesions after dose-escalated sRT though this requires several months after sRT; timing of CR is at least in part predictable based on the volume of the lesion.
Trial registration: Clinicaltrials.gov NCT04703543, registered July 15 2020, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04703543.
Can Pre-treatment Quantitative Multi-parametric MRI Predict the Outcome of Radiotherapy in Patients with Prostate Cancer?
2022, Academic Radiology
Citation Excerpt :
Moreover, PSA is not a definitive indicator of disease status, and it does not provide information about location of cancer. A heightened anticipation of local failure can lead to earlier diagnosis and improve the selection and outcome of second‐line treatment including salvage local therapies (5). Multiparametric magnetic resonance imaging (mpMRI) is increasingly being used in the detection, local staging and risk stratification of PCa.
To investigate whether pre-treatment quantitative multiparametric MRI can predict biochemical outcome of prostate cancer (PCa) patients treated with primary radiotherapy (RT).
Fifty-one patients with biopsy confirmed PCa underwent prostate multiparametric MRI on 3T MR scanner prior to RT. Thirty-seven men (73%) were treated with external beam RT alone, 12 men (24%) were treated with brachytherapy monotherapy, and two men (4%) were treated with external beam RT with brachytherapy boost. The index lesion was outlined by a radiologist and quantitative apparent diffusion coefficient (ADC), T2 and DCE parameters were measured. Biochemical failure was defined using the Phoenix criteria.
After a median follow-up of 65 months, seven patients had biochemical failure. ADC had an area under the receiver operating characteristic curve of 0.71 for predicting RT outcome with significantly lower ADC (0.78 ± 0.17 vs 0.96 ± 0.26 µm²/ms, p = 0.04) of the index lesion in men with biochemical failure. Ideal ADC cutoff point (Youdens index) was 0.96 µm²/ms which had a sensitivity of 100% and specificity of 48% for predicting biochemical failure. Kaplan-Meier analysis showed that lower ADC values were associated with significantly lower freedom from biochemical failure (FFBF, p = 0.03, no failures out of 20 men if ADC ≥ 0.96 µm²/ms; seven of 31 with failures if ADC < 0.96 µm²/ms). On multivariable analysis, ADC was associated with FFBF (HR 0.96 per increase in ADC of 0.01 um²/ms [95% CI, 0.92-1.00]; p = 0.042) after accounting for National Comprehensive Cancer Network risk category (p = 0.064) and receipt of androgen deprivation therapy (p = 0.141). Quantitative T2 and DCE parameters were not associated with biochemical outcome.
Our results suggest that quantitative ADC values of the index lesion may predict biochemical failure following primary radiotherapy in patients with PCa. Lower ADC values were associated with inferior biochemical control.
The prognostic value, sensitivity, and specificity of multiparametric magnetic resonance imaging before salvage radiotherapy for prostate cancer
2021, Radiotherapy and Oncology
Citation Excerpt :
Our findings demonstrated that either a T2 hyperintense lesion or focal contrast enhancement was associated with better outcomes after SRT. This is consistent with the study by Sharma et al, who also observed that negative MRI was associated with increased risk of subsequent BCR following SRT [23]. Sharma et al. demonstrated that adding MRI findings to an established nomogram improved its performance to predict BCR following SRT [6].
To determine the operational characteristics of pelvic magnetic resonance imaging (MRI) prior to salvage radiation therapy (SRT) for biochemically recurrent prostate cancer following radical prostatectomy.
We reviewed the medical records of 386 patients who underwent MRI prior to SRT. We assessed associations of pre-SRT MRI findings with biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and salvage androgen deprivation therapy (ADT) use following SRT. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI for detecting local recurrence were also calculated.
Pre-SRT MRI was positive for local recurrence in 216 patients (56%), indeterminate in 46 (12%), and negative in 124 (32%). On univariate analysis, BCR following SRT was significantly less likely for patients with positive (HR: 0.58, 95% CI: 0.42–0.8) or indeterminate (HR: 0.6: 0.36–1) MRI findings, compared to patients with negative imaging (p = 0.003). These associations remained significant on multivariate analysis (p < 0.05) and across pre-SRT PSA groups.
For the entire cohort, the sensitivity of MRI for local recurrence was 61.0% (53.5–68.1%), specificity 60.0% (44.3–73.0%), PPV 86.1% (78.9–91.5%) and NPV 27.6% (19.0–37.5%). Sensitivity of MRI was better in men with higher pre-SRT PSA (80.0% for PSA > 1.0), and specificity was improved with lower pre-SRT PSA (73.9% for PSA 0.1–0.5).
Positive or indeterminate MRI findings prior to SRT were associated with improved biochemical control following SRT, across PSA levels. The sensitivity and specificity of MRI for local recurrence were 61% and 58.7%, respectively.

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Platinum Priority – Prostate CancerEditorial by Martin Spahn and Jean-Luc Fehr on pp. 888–889 of this issueMultiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Patient population

Baseline characteristics

Discussion

Conclusions

Mayo Clin Proc

J Urol

J Urol

Eur Urol

J Urol

J Urol

Eur Urol

Adv Med Sci

Pract Radiat Oncol

Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy

J Clin Oncol

Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy

J Clin Oncol

Improved metastasis-free and survival outcomes with early salvage radiotherapy in men with detectable prostate-specific antigen after prostatectomy for prostate cancer

J Clin Oncol

Acute toxicity and quality of life after dose-intensified salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: first results of the randomized trial SAKK 09/10

J Clin Oncol

Platinum Priority – Prostate Cancer
Editorial by Martin Spahn and Jean-Luc Fehr on pp. 888–889 of this issue
Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy