Practical Radiation OncologyÒ (2023) 13, 540−550

www.practicalradonc.org

Basic Original Report

A Phase 1 Trial of Focal Salvage Stereotactic

Body Radiation Therapy for Radiorecurrent
Prostate Cancer
Krishnan R. Patel, MD,a,* Nicholas R. Rydzewski, MD, MPH,a
Erica Schott, CRNP,a Theresa Cooley-Zgela, RN,a Holly Ning, PhD,a
Jason Cheng, PhD,a Kilian Salerno, MD,a Erich P. Huang, PhD,b
Peter A. Pinto, MD,c Liza Lindenberg, MD,d Esther Mena, MD,d
Peter Choyke, MD,d Baris Turkbey, MD,d and Deborah E. Citrin, MDa
a
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland;
b
Biometric Research Branch, National Cancer Institute, NIH, Rockville, Maryland; cUrologic Oncology Branch, National
Cancer Institute, NIH, Bethesda, Maryland; and dMolecular Imaging Branch, National Cancer Institute, NIH, Bethesda,
Maryland

Received 28 March 2023; accepted 6 May 2023

Purpose: NCT03253744 was a phase 1 trial to identify the maximum tolerated dose (MTD) of image-guided, focal, salvage stereotactic
body radiation therapy (SBRT) for patients with locally radiorecurrent prostate cancer. Additional objectives included biochemical con-
trol and imaging response.
Methods and Materials: The trial design included 3 dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions
delivered ≥48 hours apart. The prescription dose was delivered to the magnetic resonance− and prostate-specific membrane antigen
imaging−defined tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored
until 2 years after completion of SBRT using Common Terminology Criteria for Adverse Events, version 5.0, criteria. Escalation was
halted if 2 dose-limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after
SBRT and any grade 3 genitourinary (GU) or grade 4 gastrointestinal (GI) toxicity thereafter.
Results: Between August 2018 and May 2022, 8 patients underwent salvage focal SBRT, with a median follow-up of 35 months. No dose-lim-
iting toxic effects were observed on DL1. Two patients were enrolled in DL2 and experienced grade 3 GU toxicities, prompting de-escalation
and expansion (n = 6) at the MTD (DL1). The most common toxicities observed were grade ≥2 GU toxicities, with only a single grade 2 GI
toxicity and no grade ≥3 GI toxicities. One patient experienced biochemical failure (prostate-specific antigen nadir + 2.0) at 33 months.
Conclusions: The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 40 Gy in 5 fractions, producing a 100%
24-month biochemical progression free survival, with 1 poststudy failure at 33 months. The most frequent clinically significant toxicity
was late grade ≥2 GU toxicity.
Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Research data are stored in an institutional repository and will be shared upon request to the senior author. This trial is registered with ClinicalTrials.
gov at https://classic.clinicaltrials.gov/ct2/show/NCT03253744.
Sources of support: This research was supported by the Intramural Research Program of the National Institutes of Health (NIH). Funding was pro-
vided by grant ZIA BC 011552, awarded by the NIH Clinical Center for Research.
* Corresponding author: Krishnan R. Patel, MD; E-mail: Krishnan.Patel@nih.gov

https://doi.org/10.1016/j.prro.2023.05.012
1879-8500/Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Practical Radiation Oncology: November/December 2023
Introduction
Advances in medical imaging, fusion biopsy techniques,
and local salvage options with favorable toxicity profiles have
led to increasing ability to localize the origin of biochemically
recurrent prostate cancer after definitive radiation therapy,
defined by an increase in prostate-specific antigen (PSA) lev-
els of 2.0 ng/mL above the posttreatment nadir. Imaging
techniques such as magnetic resonance imaging (MRI) and
prostate-specific membrane antigen (PSMA)−based positron
emission tomography−computed tomography (PET-CT)
have been shown to have excellent sensitivity and specificity
in the identification of local and distant recurrence of prostate
cancer in the setting of biochemical recurrence,1 an advance-
ment that has enhanced the confidence in patient selection
for local salvage therapies.2,3
Several forms of local salvage treatments have been
reported, and reirradiation with external beam radiation
therapy (EBRT) is increasingly recognized as a viable
option due to the favorable efficacy and toxicity profile.4
Stereotactic body radiation therapy (SBRT) has become of
widespread interest in the setting of reirradiation owing to
its capacity to deliver highly conformal, ablative doses to
tumors with reduced biologically equivalent dose exposure
to normal tissues. The optimal dose regimen and treatment
volume for salvage SBRT remain unknown. Focal salvage
reirradiation approaches may allow escalation of dose
beyond that achievable with whole-gland exposures, but
the resulting efficacy and toxicity of this approach is uncer-
tain. Herein, we report the results of the first phase 1 trial
designed to define the maximum tolerable dose (MTD) for
salvage, focal SBRT guided by MRI and PSMA-based PET-
CT in patients with local recurrence after prior EBRT,
which is termed “radiorecurrence” hereafter.
Methods and Materials
NCT03253744 was a single-institution, phase 1 trial
designed to identify the MTD of image-guided, focal, dose-
escalated, salvage SBRT for isolated local radiorecurrence.
The trial was conducted with approval from the institutional
review board of the National Cancer Institute, and all study
participants provided informed consent. The trial included
2 parallel cohorts. The first, reported here, consisted of par-
ticipants with local recurrence after EBRT. The second
included participants with local recurrence after brachyther-
apy and will be reported upon maturity.
Eligible patients had biochemically recurrent prostate
(defined by the Phoenix criteria5) and biopsy-verified, intra-
prostatic recurrence with or without seminal vesicle inva-
sion. Additional eligibility criteria included age of ≥18 years
and Eastern Cooperative Oncology Group performance sta-
tus score of ≤1. Exclusion criteria included ongoing grade
(G) ≥3 toxicities from prior EBRT, prior prostatectomy,
Phase 1 trial of salvage SBRT 541
distant metastases, or recurrence within 1 year of definitive
EBRT. All patients underwent staging with a multiparamet-
ric MRI (mpMRI), 18F-NaF PET-CT or 99mTc-MDP
(99mTc-methylene diphosphonate) bone scan, and 18F-
DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-car-
bonyl)-amino]-pentyl}-ureido)-pentanedioic acid) PET-CT.
Treatment protocol
Treatment was delivered on 1 of 3 dose levels (DLs): 40
Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions
delivered over 10 to 12 days (Table E1). Patients were main-
tained on pharmacologic therapy for pre-existing urinary
symptoms if previously prescribed (5 of 8 patients); how-
ever, no prophylactic medication was prescribed. The gross
target volume (GTV) was defined using a combination of
simulation CT, mpMRI, 18F-DCFPyL PET-CT, and tar-
geted biopsy mapping. The planning target volume (PTV)
was a 3-mm expansion beyond the GTV posteriorly and
superiorly and 5 mm in all other directions. Androgen dep-
rivation therapy was not used, with exception of a single
instance owing to a COVID-19−related delay in treatment.
Radiation simulation, treatment planning, and delivery are
detailed in the supplemental materials (Table E2).
The specified dose was prescribed to the 100% isodose
line and delivered with volumetric modulated arc therapy.
The V110% of the PTV (PTV receiving ≥110% of the pre-
scription dose) was limited to <5%. Organs at risk were
contoured, and the maximum dose was limited to 100%,
105%, and 105% of the prescription dose for the rectal wall
outside of the PTV, bladder wall, and urethra, respectively
(Table E3). The urethra was delineated on the fused treat-
ment-planning MRI by a genitourinary (GU) specialized
radiologist in collaboration with the treating radiation
oncologist. No foley catheter was used during simulation or
treatment. As detailed in Table E2, interfraction motion was
managed with pretreatment cone beam CT, and intrafrac-
tion motion was managed with cone beam CT between
each volumetric modulated arc therapy arc. All registrations
were conducted via implanted fiducial markers.
Assessments
Patients were followed for 24 months after completion
of SBRT with serial PSA measurements. Adverse events
(AEs) were classified using the Common Terminology
Criteria for Adverse Events, version 5.0, system and were
scored weekly during treatment through 1 month and
thereafter at 3-month intervals for 24 months.
Statistical design
The primary objective was to determine the MTD for
mpMRI- and 18F-DCFPyL PET-CT−guided focal, salvage
542 K.R. Patel et al Practical Radiation Oncology: November/December 2023

SBRT. Dose escalation followed a 3+3 design.6-8 Dose-limit- Table 1 Patient characteristics at initial diagnosis and
ing toxicities were defined as any of the following: (1) treat- salvage SBRT
ment delays of ≥1 week owing to toxicity, (2) persistent (>4
Patients, no. (%) or
days) ≥G3 gastrointestinal (GI) or GU toxicity, (3) other in- Characteristic median (min-max)
field toxicity occurring during or within 3 weeks of treat-
Demographics
ment completion, or (4) ≥G3 GU or ≥G4 GI toxicities
occurring thereafter. Secondary objectives included a char- Race
acterization of biochemical progression-free survival White 4 (50)
(bPFS). Exploratory objectives included descriptions of (1) Black 4 (50)
dosimetric predictors of toxicity, (2) PSA kinetics, (3) base-
Ethnicity
line imaging (mpMRI and 18F-DCFPyL PET-CT), and (4)
6-month posttreatment imaging response. A full description Non-Hispanic 8 (100)
of these objectives is included in Appendix E1. At initial diagnosis
All radiologic assessments were made by dedicated, GU- Age, years 63.8 (52.6-73.0)
specialized radiologists with expertise in the interpretation
PSA level, ng/mL 12.9 (4.7-33.4)
of 18F-DCFPyL PET-CT and prostate MRI. Paired Wil-
coxon testing was conducted to compare baseline and 6- T-stage
month posttreatment imaging, with a P value < .05 consid- T1c 4 (50)
ered statistically significant. Because these analyses were T2a 3 (37.5)
exploratory in nature, no adjustment for multiple compari-
T2c 1 (12.5)
sons was made.
Gleason grade 7 (6-9)

Results 3+3 = 6 3 (37.5)

3+4 = 7 3 (37.5)
Patient characteristics 4+5 = 9 2 (25)
Risk stratum
Eight patients who had experienced biochemical recur- Low 1 (12.5)
rence a median of 9.1 years (min-max, 6.3-16.4 years) after
Intermediate 3 (37.5)
their initial course of EBRT with or without androgen depri-
vation therapy were enrolled between August 2018 and May High 4 (50)
2022. The median dose of prior EBRT was 76.5 Gy (min- EBRT dose (course 1) 76.5 (72.0-79.2)
max, 72.0-79.2 Gy), delivered in 1.8 Gy to 2.0 Gy per frac- <74 Gy 1 (12.5)
tion. Patient characteristics are summarized in Table 1. The
≥74 Gy 7 (87.5)
median follow-up after SBRT reirradiation was 35 months.
EBRT volume (course 1)
Primary objective and toxicity Prostate 1 (12.5)
Prostate + SV 2 (25)
The MTD was found to be 40 Gy in 5 fractions (DL1). Prostate + SV + PLN 5 (62.5)
Two patients were treated on DL2, both of whom experi-
At recurrence
enced self-limited G3 toxicities: hematuria of a 4-day
duration and urge incontinence of a 7-week duration. PSA level 2.92 (2.05-7.92)
Thus, accrual at DL2 was halted, and accrual resumed at Grade 9 (8-10)
DL1. No dose-limiting toxic effects occurred in the 6 4+4 = 8 2 (25)
patients accrued to DL1.
4+5 = 9 4 (50)
Adverse events possibly, probably, or definitely related
to radiation are summarized in Table 2. Most common 5+5 = 10 1 (12.5)
were G1 (n = 6) and G2 (n = 3) GU AEs experienced by Adenocarcinoma with 1 (12.5)
patients treated on DL1. These included dysuria, cystitis, treatment effect
urgency, increased frequency, weak stream, and hematu- Abbreviations: EBRT = external beam radiation therapy;
ria. In DL2, both patients experienced G3 events, hematu- PLN = pelvic lymph nodes; PSA = prostate-specific antigen;
ria and urge incontinence, at 9 weeks and 12.8 months SBRT = stereotactic body radiation therapy; SV = seminal vesicle.
posttreatment, respectively. Representations of the treat-
ment plans of patients with G3 GU toxicity are shown in bladder maximum dose, bladder D1 cc and D5 cc, and ure-
Fig. E5. The exploratory dosimetric analysis was limited thral maximum dose was observed in patients experienc-
owing to sample size; however, a trend toward higher ing ≥G3 GU toxicity.
Practical Radiation Oncology: November/December 2023 Phase 1 trial of salvage SBRT 543

Table 2 CTCAE, version 5.0, adverse events by dose level in NCT03253744 adjudicated to be possibly, probably, or defi-
nitely related to radiation therapy
Latency, indexed Duration
Adverse event G1, no. G2, no. G3, no. from COT on trial
Dose level 1 (n = 6)
Total GU 6 3 0
Urinary urgency 1 1 +3 wk, +1mo 9 d, ≥23 mo
Urinary frequency 1 +1 mo ≥23 mo
Urinary tract pain 2 +5 mo, +1 d 6 wk, 6 wk
Cystitis, noninfective 2 +8 mo, +5mo 10 d, ≥19 mo
Slow urine flow* 1 −3 d 1 mo
Hematuria 1 +2.5 wk 1d
Total GI 2 1 0
Proctitis 1 +3.25 mo 2.5 wk
Hemorrhoidal hemorrhage 1 +9 mo ≥15 mo
Flatulence 1 +3.25 mo 2.5 wk
Total sexual function 0 0 0
Dose level 2 (n = 2)
Total GU 0 2 2
Urinary incontinence 1 +12.8 mo 7.5 wk
Cystitis, noninfective 1 +6.75 mo 6 mo
Urinary tract obstruction 1 +9 d 2 wk
Hematuria 1 +9 wk 4d
Total GI 0 0 0
Total sexual function 1 0 0
Hematospermia 1 −3 d 10 d
(ejaculation disorder)
Dose level 1 and 2 (n = 8)
Total GU 6 5 2
Total GI 2 1 0
Total sexual function 1 0 0
Abbreviations: COT = completion of treatment; CTCAE = Common Terminology Criteria for Adverse Events; G = grade; GI = gastrointestinal;
GU = genitourinary.
*Renal and urinary—other.

Two GI AEs and 1 GU AE were observed: G1 hemor-
rhoidal bleeding with constipation (DL1), G1 flatulence,
and G2 self-limited proctitis (DL1). Both patients with GI
toxicities underwent hydrogel spacer installation. The
patient who developed G2 proctitis experienced rectal
wall infiltration that delayed treatment until hydrogel
resorption. This patient had the highest rectal D1 cc (31.2
Gy) and D2 cc (25.3 Gy).
month and 24-month bPFS were 100%, and 7 of the 8
patients (87.5%) remained free of biochemical progres-
sion at the time of their last follow-up. The 1 patient with
biochemical failure (BF) experienced it at 33 months after
treatment. Restaging showed an equivocal focus in the
right fifth rib, indeterminate for metastatic disease.
PSA

Oncologic outcomes During the reported follow-up, 7 of 8 patients reached

a PSA nadir. The mean PSA nadir was 0.09, with no tran-
Patients were followed up for a median of 27 months sient rises (ie, “PSA bounces”) observed. The median time
(min-max, 6-43 months) after trial enrollment. The 12- to nadir was 12 months (95% CI, 9 months to not
544 K.R. Patel et al Practical Radiation Oncology: November/December 2023

Figure 1 (A) Individual and (D) mean PSA kinetics for the entire population; patients with a CR on (B) 18F-DCFPyL
and (E) PET-CT at 6 months after treatment; and patients with a PR on (C) 18F-DCFPyL and (F) PET-CT at 6 months
after treatment. Abbreviations: 18F-DCFPyL = 2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ure-
ido)-pentanedioic acid; BF = biochemical failure; CR = complete response; PET-CT = positron emission tomography
−computed tomography; PR = partial response; PSA = prostate-specific antigen.

reached). The single patient with BF after treatment had
the highest nadir PSA (0.34). The mean time to nadir was
numerically shorter for patients who achieved only a par-
tial response on 6-month posttreatment 18F-DCFPyL
PET-CT (10.4 months) than those who achieved a com-
plete response (CR) (12.3 months). Prostate-specific anti-
gen kinetics are detailed in Fig. 1A-C for the total
population and for subgroups by PET response; the corre-
sponding means for these subgroups are detailed in
Fig. 1D-F.
Treatment volumes
Eleven intraprostatic GTVs in the 8 patients were
treated. One patient had a 5-mm periprostatic lymph
node detected by 18F-DCFPyL PET-CT that was included
in the target volume in addition to his intraprostatic
recurrence. This patient remained disease free at last fol-
low-up (36 months) and had mild toxicity from treatment
(maximum, G1). Gross target volumes were most
commonly in the peripheral zone (73%), transitional zone
(27%), and posterior gland (82%). The majority (64%) of
lesions involved more than 1 region (apex, 55%; mid,
82%; and base, 36%). The mean GTV was 3.7 cm3 (min-
max, 0.4-10.2 cm3), and the mean PTV was 9.7 cm3 (min-
max, 3.3-25.9 cm3).
MRI outcomes
At baseline, the mean maximum axial dimension
(MRIMax) was 1.3 cm (min-max, 0.5-2.1 cm), and the
mean GTVMRI was 1.3 cm3 (min-max, 0.2-4.15 cm3). A
significant reduction in both the MRIMax and GTVMRI
decreased between pretreatment and 6 months after com-
pletion of treatment (P values < .01) (Fig. 2A-B). On qual-
itative MRI analysis, the majority of lesions showed
decreased imaging signatures on T2-weighted (9 of 11
lesions [81%]), Diffusion-weighted imaging (DWI)/
apparent diffusion coefficient (ADC) (8 of 11 lesions
[82%]), and dynamic contrast enhancement (4 of 8
Practical Radiation Oncology: November/December 2023 Phase 1 trial of salvage SBRT 545

Figure 2 MRI response by (A) MRIMax, (B) GTVMRI, (C) qualitative T2W image score, (D) qualitative DWI/ADC score,
and (E) qualitative DCE score. Qualitative scores were determined by genitourinary-specialized prostate radiology. A ter-
nary scale (negative, slightly positive, and positive) was used for T2W and DWI/ADC images, whereas a binary score (neg-
ative or positive) was used for DCE imaging. The single patient with biochemical failure is shown with a box icon (&).
Abbreviations: DCE = dynamic contrast enhancement; DWI/ADC = diffusion-weighted imaging / apparent diffusion coef-
ficient; GTV = gross target volume; MRI = magnetic resonance imaging; MRIMax = maximum linear measurements;
T2W = T2-weighted.

lesions [50%]) imaging, as shown in Fig. 2C, D, and E, PET-CT response

respectively. Figure 3A and B depict case examples of a
complete and partial response, respectively. The single
patient with BF in our study (Fig. 2; box icon) showed
both MRIMax response (23%) and qualitative response on
T2-weighted, DWI/ADC, and dynamic contrast enhance-
ment sequences on 6-month posttreatment MRI.
Among treated lesions, there was wide variability in
SUVMax (median, 10.7; min-max, 3.9-39.6; Fig. 4A) and
SUVMean (median, 7.4; min-max, 3.2-25.0; Fig. 4B) at
baseline. Similarly, the total lesion PSMA and GTVPSMA
are summarized in Fig. 4C-D. The distribution of each
546 K.R. Patel et al Practical Radiation Oncology: November/December 2023

Figure 3 Imaging response on 6-month MRI and 18F-DCFPyL PET-CT in (A) a patient with complete response on both
imaging modalities and (B) a patient with evidence of persistent disease at 6 months after salvage SBRT. MRIMax are
shown with a line on MRIs, and GTVPSMA are delineated with a dotted circle on PET-CT images. Treatment-planning
MRIs are shown with the treatment-planning GTV, described and delineated in red. The planned dose is shown in color
wash from 20-40 Gy, as noted in the legend. Abbreviations: 18F-DCFPyL = 2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-
carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid; GTV = gross target volume; GTVPSMA = gross target volume on
PSMA imaging; MRI = magnetic resonance imaging; MRIMax = maximum linear measurements; PET-CT = positron emis-
sion tomography−computed tomography; PSMA = prostate-specific membrane antigen; SBRT = stereotactic body radia-
tion therapy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article.)

18
Figure 4 F-DCFPyL PET-CT response at 6 months from baseline on (A) SUVMax, (B) SUVMean, (C) total lesion PSMA
(SUVMean £ GTVPSMA), and (D) GTVPSMA. The single patient with biochemical failure is shown with a box icon (&). All
lesions were noted to produce response on all parameters, with the exception of a single lesion that did not have GTVPSMA
response in a patient who failed to achieve an undetectable prostate-specific antigen (PSA) nadir. Abbreviations:
GTV = gross target volume; PET-CT = positron emission tomography−computed tomography; PSMA = prostate-specific
membrane antigen; SUV = standardized uptake value.
Practical Radiation Oncology: November/December 2023
quantitative PET measurement was observed to have a
significant reduction at 6 months from baseline (all P <
.01), because all but 1 lesion demonstrated response on all
parameters (Fig. 4A-D). This lesion was noted to have
slight growth of the GTVPSMA at 6-month PET-CT (0.37
cm3 at baseline to 0.43 cm3 at 6 months) (Fig. 4D).
Exploratory analyses demonstrated that there were sig-
nificant differences in the SUVMax (P < .01) independent
of contour technique and SUVMean (P < .01) for the 40%
isocontour technique when AC images were compared
with Q.Clear reconstructed images. This change, however,
was not seen in the measurement of total lesion PSMA or
GTVPSMA (all P > .05) (Fig. E3A). There were no signifi-
cant differences observed by contour technique (all P >
.05) (Fig. E3B).
MRI PET-CT comparison at baseline and 6
months
There was good concordance between baseline mpMRI
and baseline PSMA PET-CT in detecting lesions, with all
lesions being identified on both modalities. Overall, the
GTVPSMA underestimated the radiographic extent of dis-
ease on MRI. However, at baseline, GTVMRI was found to
be positively correlated with GTVPSMA for gradient edge-
based contouring methods independent of reconstruction
technique (P < .001) and for the 40% SUVMax threshold
technique for the Q.Clear reconstruction only (P < .05).
In contrast, GTVMRI was not predictive of GTVPSMA at
the 6-month time point, owing to the disparity in the
observed complete response rates between the 2 modali-
ties. These findings are summarized in Fig. E4.
Discussion
Primary endpoint and toxicity
In this prospective phase 1 trial evaluating escalating
dose levels of focal SBRT for the treatment of local,
biopsy-proven, radiorecurrent prostate cancer, we found
that the MTD was 40 Gy in 5 fractions (DL1). Two G3
GU toxicities were observed in patients treated on DL2,
which prompted de-escalation to DL1 for expansion.
As in previous reports,9 no clear dosimetric predictors of
≥G2 or ≥G3 toxicity were identified. However, based on
the trends observed in this trial, the maximum dose to the
bladder and urethra may merit further examination. It is
conceivable that the optimal focal reirradiation dose may be
related to the size and location of the recurrence and prox-
imity to key GU structures. Prior studies of first-line SBRT
have shown an association between GU toxicity and dose.10
One study reported rates of late ≥G2 GU toxicity of 5%
and 48% in patients receiving 35 Gy and 40 Gy, respec-
tively.11 Other studies suggested a relationship between
Phase 1 trial of salvage SBRT 547
toxicity and urethral12,13 and bladder13 exposure. A Euro-
pean Society for Radiotherapy and Oncology consensus
guideline for salvage SBRT recommends dose prescriptions
of >35 Gy in 5 fractions (65 Gy1.5 equivalent dose in 2Gy
fractions [EQD2]) to an isodose line <80%.14 This practice
produces inhomogeneous plans that (1) may result in
higher urethral dose exposure owing to intraobserver differ-
ences in urethral definition and intrafraction motion15,16
and (2) may themselves be associated with higher rates of
toxicity, as reported in the first-line setting.12,17 Our study
achieved good 2-year outcomes prescribing to the 100% iso-
dose line.
Focal, dose-escalated, salvage SBRT was found to have
few GI AEs. Given significant concerns over rectal toxicity
resulting from high cumulative rectal dose exposure, a
previous trial18 excluded patients if their recurrence was
posterior and adjacent to the rectum unless a hydrogel
spacer was used. This may significantly limit eligibility,
because posterior recurrences often include a component
of extraprostatic extension that precludes hydrogel spacer
placement. Despite more permissive inclusion criteria
than this trial and rectal constraints, we observed a simi-
larly low rate of clinically significant GI toxicity. Similar
to other studies,19,20 GU toxicity was more common than
GI toxicity in our study.
Oncologic efficacy
The bPFS rates at 12 and 24 months were 100%, and
during the course of the study, only 1 patient experienced
biochemical failure at 33 months after treatment.
Although the number of treated patients was small, these
rates compare favorably to published results,18-24 possibly
owing to dose escalation, careful patient selection, and the
target volume definition.
This phase 1 trial was designed to define the MTD dose
of focal reirradiation based on the rationale that higher
doses may improve local control. In the first-line setting,
tumor control probability has been shown to be propor-
tional to the dose delivered to gland25-28 and mpMRI-
identified tumor subvolume.29 Although a similar trend
has been suggested in the radiorecurrent setting,30 this
trend has yet to be established, with early, small, prospec-
tive reports instead focusing on feasibility as opposed to
dose response.18,21-23,31 Prior retrospective series24,32,33
have shown significant rates of local recurrence with
lower radiation doses (38.6-77.1 Gy1.5 EQD2) at short-
term follow-up, providing a rationale for dose escalation
to further improve outcomes. In an interim analysis of a
prospective trial, NCT03073278,18 which treated patients
to doses of 36 to 38 Gy in 6 fractions (77.1-85.0 Gy1.5
EQD2), 5 of the 25 patients (20%) had biochemical recur-
rence at a median follow-up of 25 months, with 4 of these
patients having suspicion of local persistence or recur-
rence. In our series, at a dose of ≥40 Gy in 5 fractions
548 K.R. Patel et al
(≥108.6 Gy1.5 EQD2), no clear evidence of second local
failure was observed in our cohort.
Favorable bPFS outcomes may also be explained by other
factors, including careful patient selection and target volume
definition. Patients in our study were selected for focal treat-
ment to ensure the highest likelihood that all tumor was
within treatment volumes. This was accomplished with uni-
versal 18F-DCFPyL PET-CT screening, which ruled out
low-burden metastatic disease and the inclusion of patients
only with biopsy-verified and imaging-concordant local
recurrence. Finally, 18F-DCFPyL PET−augmented treat-
ment planning may have improved our treatment volume
definition. In our study, the GTVPSMA exceeded the
MRIGTV, which subsequently led to a treatment GTV larger
than the MRIGTV for all lesions. Given that prior reports
had no or incomplete PET utilization for GTV
delineation,21,24,34, 35 the use of this new imaging modality
may explain in part the favorable outcomes observed.
Imaging
At baseline, treatment-planning MRI, CT, and 18F-
DCFPyL PET were used for GTV delineation. Although all
lesions were detected on both modalities, there was substan-
tial disagreement in the volume of lesions between the
modalities.35 Although complete pathologic assessment of
the GTV was not available, mpMRI volumes were larger
than the GTVPSMA in most cases, a finding independent of
the PET-CT reconstruction technique or automated thresh-
olding strategy used. Further detailed studies of salvage
prostatectomy specimens with preoperative imaging corre-
lation will be required to better understand the comparative
spatial accuracy of each modality regarding tumor volume
definition. While 18F-DCFPyL PET-CT may be helpful in
staging at ruling out systemic disease, it is unlikely to replace
mpMRI for target volume delineation owing to both volume
underestimation and lower spatial resolution.
In contrast, PET-CT appears to outperform mpMRI at
the evaluation of early treatment response. In our study,
although 9 of 11 treated lesions (82%) had a radiographic
CR on PET-CT imaging at 6 months, only a single tumor
was found to have a CR on mpMRI imaging at 6 months.
This suggests that PET-CT may have an increased sensi-
tivity to detect treatment response at an early stage,
although longer-term outcomes are needed to compare to
eventual local failure patterns. The PSMA-based PET-CT
imaging response was also assessed in NCT03073278,18
using 68Ga-PSMA PET-CT at the 12-month posttreat-
ment time point, although a detailed report of this end-
point is not yet available.
Limitations
Although significant rates of GU toxicity occurred in
patients treated on DL2, both patients had tumor
Practical Radiation Oncology: November/December 2023
geometry that required high-dose exposure to the bladder
and urethra. It is possible that tumors with favorable size
and location may be amenable to further dose escalation.
Additionally, alternative treatment techniques such as the
utilization of an MRI-linear accelerator MRI-LINAC or
high-dose rate (HDR) brachytherapy may also allow for
additional dose escalation. Because this trial tested a focal
method of reirradiation (ie, treatment of the GTV), these
doses should not be generalized to whole-gland reirradia-
tion. Furthermore, although our trial did have a favorable
bPFS at a median follow-up of 35 months in comparison
with prior reports of salvage SBRT,18-20,24,30 it could not
provide a high-precision estimate of oncologic control
given the small sample size. Additionally, although the
study follow-up was limited, these results may be repre-
sentative of future outcomes, because prior studies have
described an early temporal pattern of failure with a
median time to biochemical progression of 9.4 months
and a median time to clinical progression of 13.2 months
for this patient population.35 Larger studies with extended
follow-up will serve to address the question of the interac-
tion between tumor location and objective toxicity as well
as high-precision estimates of long-term local control.
Conclusion
The MTD for focal salvage SBRT for isolated intrapro-
static radiorecurrence was 40 Gy in 5 fractions, producing
a 100% 24-month bPFS, with 1 late failure observed at 33
months. The most frequent clinically significant toxicity
was late grade ≥2 GU toxicity. PSMA-based PET-CT
appeared to improve both target volume delineation and
response assessment at 6 months.
Disclosures
Erich P. Huang reports participation on the American
College of Radiology Imaging Network Data Safety Moni-
toring Board. Peter A. Pinto reports that Philips Inc pays
royalties to the National Institutes of Health (NIH) for a
licensing agreement; the NIH then pays royalties to Dr
Pinto. The NIH has a cooperative research and develop-
ment agreement with Philips; the NIH has intellectual
property in the field, including the patents “System and
Method for Prostate Cancer Detection and Distribution
Mapping” (US Patent number: 8,447,384) and “System
and Method for Computer Aided Cancer Detection Using
T2-Weighted and High-Value Diffusion-Weighted Mag-
netic Resonance Imaging” (US Patent number:
10,215,830). The NIH and Philips (In Vivo Inc) have a
licensing agreement with the authors. The NIH does not
endorse or recommend any commercial products, pro-
cesses, or services. The views and personal opinions of the
authors expressed herein do not necessarily state or reflect
Practical Radiation Oncology: November/December 2023
those of the United States Government or any official rec-
ommendation or opinion of the NIH nor National Cancer
Institute. Baris Turkbey reports receiving royalties from
the NIH, having multiple patents in AI (details available
upon request), and having cooperative research and
development agreements with NVIDIA and Philips. All
other authors have no disclosures to share.
Supplementary materials
Supplementary material associated with this article can
be found in the online version at doi:10.1016/j.
prro.2023.05.012.
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