A Phase I Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy

A Phase I Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy - ScienceDirect

INTRODUCTION

Isolated local failure (LF) after definitive radiotherapy for prostate cancer has the potential to significantly impact long-term disease-specific survival [1, 2]. Prior prospective trials have reported heterogeneous long-term rates of LF from approximately 1% [3] to 30%[4]. In part, this heterogeneity is explained by both the poor sensitivity of clinical examination and the poor specificity of a post-treatment biopsy to diagnose local failure, especially at early post-treatment timepoints[5]. In addition, treatment factors such as the receipt of androgen deprivation therapy (ADT)[6] and radiation dose[4, 7] have also been shown to substantially impact the rate of LF.

As a result of rapid dose fall off, brachytherapy allows for the delivery of higher integral doses of radiation than external beam radiotherapy (EBRT), while simultaneously maintaining an acceptable safety profile. Prostate brachytherapy can be highly effective with a low prevalence of local recurrence[8]. In the subset of patients with biochemical recurrence (BCR), LF in the anterior prostate and/or seminal vesicle is often identified [9].

There is no universally accepted standard of care for the optimal management of LF after brachytherapy. Recent analyses have identified salvage stereotactic body radiotherapy (SBRT) as a viable treatment option for patients with a local recurrence after prior EBRT, but the optimal SBRT dose and corresponding toxicity profile for salvage SBRT after brachytherapy remains unknown. Here, we report a phase I, dose escalation trial with the primary intention to identify the maximum tolerable dose (MTD) of salvage SBRT after prior brachytherapy with key secondary objectives to profile objective toxicity and treatment efficacy.

METHODS AND MATERIALS

NCT03253744 was a phase I trial designed to identify the MTD of image-guided, dose-escalated, salvage SBRT for isolated local radiorecurrence. All participants provided informed consent, and the trial was conducted with approval from the institutional review board of the **************************. The trial included two parallel cohorts. The first, reported previously [***], enrolled patients with local recurrence after EBRT, and the second, reported here, enrolled patients after prior brachytherapy.

Eligible patients had BCR prostate cancer (defined by the Phoenix criteria [10]) and a biopsy-verified, intraprostatic recurrence with or without seminal vesicle (SV) invasion. Additional eligibility criteria included age ≥18 and ECOG performance status ≤1. Exclusion criteria included ongoing grade 3 or higher toxicities from prior RT, prior prostatectomy, distant metastases, or recurrence within one year of prior brachytherapy. All patients underwent staging with a multiparametric MRI (mpMRI), ¹⁸F-NaF PET/CT or ^99mTc-MDP bone scan, and ¹⁸F-DCFPyL PET/CT.

TREATMENT PROTOCOL

The protocol was designed to treat patients on one of three dose levels: 40Gy (DL1), 42.5Gy (DL2), and 45Gy (DL3) in 5 fractions delivered over 10-12 days (Supplemental Table 1) while simultaneously delivering a dose of 30 Gy in 5 fractions to the whole prostate. Due to excellent biochemical control on DL1 and DL2 accompanied by a high incidence of late Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade (G) 2 (i.e., non-dose limiting toxicity [non-DLT]) genitourinary (GU) toxicities, the trial was amended to halt escalation at DL2.

The gross tumor volume (GTV) was defined using simulation CT, multiparametric MRI (mpMRI), which included T2-weighted MRI (T2W), diffusion weighted imaging (DWI)/ apparent diffusion coefficient (ADC), and dynamic contrast enhanced (DCE) sequences, ¹⁸F-DCFPyL PET/CT (i.e., a PSMA-based PET/CT), and systematic and targeted biopsy mapping. The GTVs were contoured collaboratively by the treating radiation oncologist and a GU-specialized radiologist to include the union of the volumes identified on ¹⁸F-DCFPyL PET/CT and MRI that were all pathologically confirmed with targeted biopsy. The planning target volume (PTV_Tumor) was a 3mm expansion beyond the GTV posteriorly and superiorly and up to 5mm in all other directions. ADT was utilized in a single instance due to a COVID 19-related treatment delay. Additional details are provided in Supplemental Table 2. The V_110% of the PTV_Tumor (PTV_Tumor receiving ≥110% of the prescription dose) was limited to <5%. Planning constraints per protocol included a maximum dose (D_max) less than 100%, 105%, and 105% of the prescription dose for the rectal wall outside of the PTV_Prostate, bladder wall, and urethra, respectively (Supplemental Table 3).

ASSESSMENTS

Subjects were followed for 24 months after completion of SBRT on trial with serial PSA measurements. BCR was defined by the Phoenix criteria [10]. Adverse events (AEs) were classified using the CTCAE v5.0 and were scored weekly during treatment through 1 month, and thereafter at 3-month intervals for 24 months and PSA measurements for disease monitoring were conducted on the same schedule. Post-treatment imaging (MRI and ¹⁸F-DCFPyL PET/CT) was obtained at 6 months for exploratory response assessment.

STATISTICAL DESIGN

The primary objective was to determine the MTD for mpMRI- and ¹⁸F-DCFPyL PET/CT-guided salvage SBRT. Dose escalation followed a 3+3 design[11, 12]. Dose limiting toxicities (DLTs) were defined: (1) treatment delays of ≥1 week due to toxicity, (2) persistent (>4 days) acute ≥G3 gastrointestinal (GI) or GU toxicity or other in-field toxicity occurring during or within 3 weeks of treatment completion, or (3) ≥G3 GU or ≥G4 GI toxicity thereafter. Secondary objectives included a characterization of biochemical progression free survival (bPFS). Exploratory objectives included descriptions of (1) dosimetric predictors of toxicity, (2) PSA kinetics, (3) baseline imaging (mpMRI and ¹⁸F-DCFPyL PET/CT), and (4) 6-month post-treatment imaging response. A full description of these objectives is included in the Supplemental Methods.

All radiologic assessments were made by nuclear medicine physicians and radiologists with expertise in ¹⁸F-DCFPyL PET/CT and prostate MRI interpretation, respectively. Paired Wilcoxon testing was conducted to compare baseline and 6-month post-treatment imaging. P-values<0.05 were considered statistically significant for all reported hypothesis testing. As these analyses were exploratory in nature, no adjustment for multiple comparisons was made.

RESULTS

Patient Characteristics

Nine patients with BCR at a median of 8.2 years (min-max: 3.7-11.0 years) after prior brachytherapy were enrolled. At initial diagnosis, all patients had low (56%) or intermediate-risk (44%) prostate cancer. Most were treated with low dose rate (LDR) brachytherapy (¹⁰³Pd [n=5/9], ¹²⁵I [n=2/9],¹³¹Cs [n=1/9]) and most without EBRT (n=8/9). Additional patient characteristics are summarized in Table 1.

Table 1. Baseline Characteristics

Category	n (%)
Race
Black	1 (11.1%)
White	8 (88.9%)
Age at Initial Diagnosis
Mean (SD)	60.9 (5.57)
Median [Min, Max]	63.8 [52.1, 68.4]
Time from Diagnosis to Study Entry
Mean (SD)	7.29 (2.69)
Median [Min, Max]	8.15 [3.67, 11.0]
T-stage at Initial Diagnosis
T1c	8 (88.9%)
T2a	1 (11.1%)
PSA Prior to Initial Brachytherapy
Mean (SD)	7.55 (4.18)
Median [Min, Max]	5.40 [4.10, 15.2]
ISUP Grade at Diagnosis
GG1	5 (55.6%)
GG2	3 (33.3%)
GG3	1 (11.1%)
GG4	0 (0%)
GG5	0 (0%)
NCCN Risk Group at Diagnosis
Low Risk	5 (55.6%)
Favorable Intermediate Risk	2 (22.2%)
Unfavorable Intermediate Risk	2 (22.2%)
High Risk	0 (0%)
Isotope Utilized During Initial Brachytherapy
¹³¹Cs	1 (11.1%)
¹²⁵I	2 (22.2%)
¹⁹²Ir	1 (11.1%)
¹⁰³Pd	4 (44.4%)
¹⁰³Pd + EBRT	1 (11.1%)
Absorbed Dose (Gy) of Initial Treatment
Mean (SD)	116 (36.2)
Median [Min, Max]	125 [27.0, 145]
RT Volume of Initial Treatment
Prostate Only	8 (88.9%)
Prostate and Seminal Vesicles	0 (0%)
Prostate, Seminal Vesicles, and Pelvic LNs	1 (11.1%)
Age at Study Entry
Mean (SD)	68.2 (5.33)
Median [Min, Max]	68.8 [59.9, 77.1]
PSA Prior to Salvage SBRT
Mean (SD)	6.03 (5.52)
Median [Min, Max]	3.10 [2.10, 19.5]
Baseline AUA International Prostate Symptom Score
Mean (SD)	8.78 (6.53)
Median [Min, Max]	7 [2, 20]
ISUP Grade at Relapse
GG1	0 (0%)
GG2	3 (33.3%)
GG3	1 (11.1%)
GG4	0 (0%)
GG5	2 (22.2%)
Recurrent Adenocarcinoma with Treatment Effect	3 (33.3%)
Salvage Treatment Included Seminal Vesicles
No	6 (66.7%)
Yes	3 (33.3%)
ADT with Salvage SBRT
None	8 (88.9%)
Short Term	1 (11.1%)

Abbreviations: SD, Standard deviation; ISUP, International Society of Urological Pathology; RT, radiotherapy; GG, Grade Group; NCCN, National Comprehensive Cancer Network; EBRT, External beam radiation therapy; PSA, Prostate-specific antigen; ADT, Androgen deprivation therapy; NOS, Not otherwise specified; SBRT, Stereotactic body radiation therapy; AUA, American Urological Association

Treatment Volumes

Eleven MRI-defined, biopsy-confirmed, GTVs were treated in the 9 patients. Approximately half of GTVs arose from the peripheral zone (PZ, 58%), and the remainder arose from the transition zone (TZ, 25%) or the SV (17%). Half of the lesions involved the base and one-third of lesions involved the mid-gland and apex each. Eight of nine patients were treated with a single boost volume due to overlap of the tumor PTVs in patients with more than one lesion. The median GTV was 8.3cc (min-max: 0.2-16.4cc), and the median PTV_Tumor was 19.0cc (min-max: 1.3-32.9cc).

Primary Objective, Toxicity, and Quality of Life

The MTD was considered to be 42.5Gy in 5 fractions (DL2). No grade 3-5 AEs related to study treatment were observed, and, thus, no DLTs occurred during the trial observation period (median: 21 months, IQR: 16-24 months). Overall, GU toxicities were more common than GI toxicities with a 100% cumulative incidence of G2 GU toxicities and 22% (95% confidence interval [CI], 55%-100%) cumulative incidence of G2 GI at 24 months (Figure 1A,C). This corresponded to all patients on DL1 and DL2 encountering a maximum of G2 GU toxicity and 67% and 17% of patients on DL1 and DL2 encountering a maximum of G1 and G2 GI toxicity (Supplemental Table 4), which is further detailed by adverse event in Supplemental Table 5. Furthermore, GU toxicities were longer in duration than GI toxicities with a median duration of 289 days (min-max:144-614) versus 6 days (min-max: 1-165) (Figure 1B,D). The most common GU toxicities were urinary tract pain/dysuria (G1), noninfective cystitis (G2), and urinary frequency (G2), occurring in 6 (67%), 6 (67%), and 4 (44%) of patients, respectively. These objective toxicities translated into a numerical worsening in urinary quality of life with a peak at approximately 9-12 months post-salvage (Supplemental Figure 1).

Contradicting the hypothesis that dose exposure from salvage SBRT to the rectum was related to GI toxicity, patients without ≥G2 GI toxicity had higher median rectal exposure on the metrics studied (D_Max, D_1cc, D_2cc, D_15%, and D_20%) than did patients who did (Supplemental Figure 2). Given that all patients in this trial cohort had the same maximum GU toxicity, the hypothesis that radiation exposure of the urethra or bladder related to the severity of GU toxicity was inevaluable.

Disease Control

Patients were followed for a median of 22 months (IQR, 20-43 months) after enrollment for biochemical progression free survival (bPFS). The 12-month and 24-month bPFS were 100% and 86% (95% CI, 63%-100%), respectively. A single BCR event was observed at 20 months post treatment. Radiologic assessment suggested an isolated regional recurrence with subtle abnormalities in a perirectal lymph node. No clinical evidence of local failure was noted with a negative mpMRI and PSMA-based PET/CT demonstrating only an area of mild intraprostatic ¹⁸F-DCFPyL avidity which corresponded to benign prostate on pre-salvage biopsy.

PSA Kinetics

The PSA nadir was ≤0.2ng/mL in 7 of 8 of the patients who achieved a PSA nadir during the observation period. The median time-to-nadir was 12 months (95% confidence interval [CI]: 6 months – not reached). The single patient with BCR after treatment had the highest nadir PSA (1.8ng/mL) which was reached at 12 months. The median time-to-nadir was numerically shorter for subjects who did not receive a complete response (CR) ¹⁸F-DCFPyL PET/CT than those who did (9.1 vs 12.3 months, log-rank p-value=0.6). No transient rises (i.e.,“PSA bounces”) were observed. PSA kinetics are detailed in Figure 2.

MRI Outcomes

At baseline, the median maximum axial dimension (MRI_Max) was 1.7cm(min-max: 0.7-3.5cm) and median GTV_MRI was 1.5cc(min-max: 0.3-6.3cc). A significant reduction in both metrics was observed between baseline and 6 months post-salvage (p-values <0.01; Figure 3A-B). A qualitative analysis of each lesion on a binary (positive or negative) or ternary scale (positive, slightly positive, or negative) showed a decrease in imaging signature in 50% (6/12), 92% (11/12), and 82% (9/11) for T2W (Figure 3C), DWI/ADC (Figure 3D), and DCE (Figure 3E), respectively. The single patient with BCR (Figure 3; box icon) was observed to have treatment response in all size (MRI_Max and GTV_MRI) and qualitative metrics studied.

PET/CT Response

Amongst treated lesions there was a wide variability in SUV_Max (median 15.7, min-max: 3.8-30.3; Figure 4A), and SUV_Mean (median: 10.9, min-max: 2.8 to 16.2; Figure 4B) at baseline. Similarly, the Total Lesion PSMA and GTV_PSMA are summarized in Figure 4C-D. The distribution of each PET metric was observed to have a significant reduction at 6 months from baseline (all p<0.01), as all but one lesion demonstrated response on all parameters (Figure 4A-D). This lesion was noted to have slight growth of the GTV_PSMA at 6-month PET/CT (0.24 to 0.36cc; Figure 4D). Exploratory analyses confirmed that this trend was replicated independent of contour technique (gradient edge-based vs. 40% isocontour) and reconstruction technique (attenuation corrected [AC] vs. Q.Clear) for each metric with the exception of GTV response when utilizing a gradient edge-based contour technique on a Q.Clear reconstruction (p=0.05).

MRI and PET/CT Comparison at Baseline and 6 months

All lesions were identified on both modalities. Overall, the GTV_PSMA underestimated the radiographic extent of disease relative to MRI at baseline. At baseline, there was a positive correlation of GTV_MRI with GTV_PSMA for all methods of GTV_PSMA contour; however, this relationship only reached statistical significance for GTV_PSMA contoured via the gradient edge method on the attenuation corrected (AC) PET reconstruction (Supplemental Figure 3A). In contrast, the GTV_MRI was poorly representative of the GTV_PSMA at the 6-month timepoint with GTV_MRI explaining less than 15% of the variance in GTV_PSMA, which was due in part to the differential rate of complete radiographic response noted between these two modalities (Supplemental Figure 3B).

DISCUSSION

The optimal management for patients with isolated local failure (LF) after definitive brachytherapy remains unknown. Several options have been proposed for the management of local radiorecurrence including a variety of curative options – salvage prostatectomy [13], focal therapy [14], and curative re-irradiation with EBRT[15, 16], brachytherapy[17, 18], or SBRT[19-22] – or surveillance with ADT at the time of rapid biochemical or clinical progression[23]. A recent meta-analysis has suggested that salvage re-irradiation may provide the best therapeutic index of these options in patients with local radiorecurrence [24], thus driving enthusiasm for this curative strategy. These conclusions are drawn mainly from the study of post-EBRT failures, and to our knowledge, while a single retrospective report exists [25], no prospective trials specific to post-brachytherapy salvage SBRT have been reported. Here we report the first such trial in patients with post-brachytherapy LF with the primary objective to identify the maximum tolerable re-irradiation dose via focally-dose-escalated SBRT.

Since no DLTs were observed at the treated dose levels, the maximum tolerated focal boost dose was considered 42.5Gy in 5 fractions (DL2) delivered to the PTV_Tumor (GTV_{MRI ⋃ PSMA}+3-5mm) with the simultaneous integrated delivery of 30Gy in 5 fractions to the whole prostate. Further dose escalation was halted via a trial amendment due to the observed prevalence and duration of G2 GU toxicities in the setting of reassuring early biochemical control, as it was felt that the risk for further dose escalation far outweighed the potential benefit. Overall, the toxicity profile of this treatment was biased towards a higher incidence and longer duration GU AEs compared to GI AEs. Broadly speaking, this reflects the trend observed in several prior studies of salvage whole gland [19, 20] and focal RT[21, 22] treatments for radiorecurrence, in which GU toxicities predominated. In first line EBRT approaches, the rectum is a dose limiting structure across fractionation schedules [26, 27], suggesting the possibility that the rectum would be dose limiting in salvage SBRT treatments. Although this may highlight challenges extrapolating observations from the first-line to the re-irradiation setting, it may also highlight concerns unique to this cohort of patients who having undergone initial management with brachytherapy may be differentially sensitive to further GU toxicities.

As no G3-5 toxicities were observed, G2 GU AEs represent the most severe toxicities in this trial. While only G2 in nature, these toxicities were often extended, persistent, and clinically significant. The lack of ≥G3 GU and GI toxicities observed was representative of prior reports of salvage SBRT for radiorecurrence as summarized in a recent meta-analysis[24]. The absolute rate of ≥G2 GU AEs was higher in this trial than in several prior reports of salvage re-irradiation[19-22]. This may have been due to several factors including (1) the focal “boost” dose utilized, (2) the simultaneous delivery of a whole gland dose, and (3) the specific cohort under study (e.g., post-brachytherapy). The focal boost dose utilized in this trial corresponds to the highest equivalent dose in 2Gy fractions (EQD2) of all published, prospective reports of prostate re-irradiation. In fact, the whole gland dose alone was similar to the treatment employed in prior reports of salvage RT[19, 28], and thus, the observed incidence of toxicity may be related to total exposure to both the prostate and regional organs-at-risk resultant from the simultaneous treatment of the two dose volumes. It is possible that focal treatment alone, as previously recommended [29], may have decreased toxicity in this series, although it is possible that this may also have lowered the observed efficacy of the treatment regimen.

The rationale of focal dose-escalation in this study was based on the known relationship between dose-escalation and biochemical control for prostate cancer[7, 30-32] and the hypothesis that dose escalation would be important to sterilize radiorecurrent prostate cancer. While the aforementioned re-irradiation studies[19-22] had maximum prescription doses of ≤70Gy₃ EQD2 delivered to the whole gland or tumor-bearing subregion, the lowest dose level in the present trial corresponded to a higher dose of 88Gy₃ EQD2 delivered to the PTV_Tumor with a whole gland dose of 54Gy₃ EQD2. This suggests the possibility that the observed rate of toxicity may be related to focal dose-escalation. While in some cases a focal boost may be delivered without an increase in toxicity as observed in the first-line treatment setting[33], it may have the potential to increase toxicity in the salvage setting.

Similar to prior studies[28], no clear predictors of toxicity were detected in part based on the size of this trial cohort. Further investigation is required to identify the predictors of toxicity in this setting for the unique patient population under study (post-brachytherapy). Patient selection via the exclusion of candidates who exceed a pre-defined threshold of baseline symptom burden, as previously utilized[18, 19, 34], remains an important element of selecting optimal candidates for re-irradiation. Further, the location and size of the local recurrence and proximity to organs-at-risk may also impact the capacity to safely deliver SBRT in the post-brachytherapy setting.

Patients were carefully selected not only by baseline symptom burden, but also by strict imaging criteria. All patients enrolled were required to have one or more imaging-defined recurrence verified by targeted biopsy. While patients were required to have an imaging-detected focus of recurrence, the two dose level treatment paradigm utilized here was devised to deliver a prophylactic dose to the whole gland to account for the possibility of any additional foci of recurrent disease not detected on imaging. This consideration was especially pertinent for this patient population given the possibility of MRI artifact related to indwelling brachytherapy seeds[35]. Prior studies have found that mpMRI alone may have suboptimal reliability and moderate positive predictive value in the evaluation of local recurrence after radiotherapy[36] due to artifacts caused by brachytherapy seeds and changes in the signal characteristics of the gland post-irradiation[37]. The utility of MR imaging may be improved by radiologist expertise[35], and thus, all imaging studies were interpreted by an expert, GU-specialized radiologist. Further, both mpMRI and PSMA-based PET/CT were utilized, and while all lesions were identified on both studies, mutual information was often required for accurate detection. PSMA-based PET/CT while helpful in many cases was not universally diagnostic with only 6 of 11 lesions (54%) having a signal-to-background ratio (i.e., SUV_Max ratio of lesion to normal prostate) >2.

Finally, this study showed promising efficacy for salvage SBRT in the post-brachytherapy population. A single patient developed BCR during the follow-up period without evidence of local failure, and all other patients continued to have a deep PSA nadir (≤0.2 ng/mL) during the trial observation period. The biochemical control for this cohort was favorable as compared to recent meta-analytic estimates[24], despite the inclusion of patients with SV recurrences (n=3/9) which is a high-risk feature and has previously been suggested as an exclusionary criterion[38]. These favorable oncologic outcomes are likely a result of the superior in-field control resulting from the dose-escalated regimen administered as well as the careful selection of patients with without evidence of metastasis or out-of-field recurrence assessed by mpMRI, PSMA-based PET/CT, and biopsy mapping. The observation of early imaging response on MRI and PSMA-based PET/CT suggests the potential promise of these techniques for response assessment, although, given the lack of local failures observed, further study is needed to validate these imaging biomarkers of treatment efficacy.

CONCLUSIONS

The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 42.5Gy in 5 fractions when delivered in combination with a 30Gy whole gland dose, producing an 86% 24-month bPFS, with one biochemical failure at 19 months post salvage SBRT. The most frequent clinically significant toxicity was late ≥G2 GU toxicity, and minimal GI toxicity was observed. Multimodal radiologic assessment (PET/CT and mpMRI) was an important element of patient selection and target delineation given the difficulty of image interpretation after brachytherapy. Early response assessment at 6 months appeared to be feasible; however, further study is required to validate this early imaging biomarker of treatment response against long term outcomes.

References

1. Stone, N.N., et al., Factors associated with late local failure and its influence on survival in men undergoing prostate brachytherapy. Brachytherapy, 2022. 21(4): p. 460-467.

2. Ma, T.M., et al., Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN). Eur Urol, 2022.

3. Nabid, A., et al., Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. European Urology, 2018. 74(4): p. 432-441.

4. Zietman, A.L., et al., Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate. JAMA, 2005. 294(10): p. 1233.

5. Crook, J., et al., Postradiotherapy prostate biopsies: what do they really mean? results for 498 patients. International Journal of Radiation Oncology*Biology*Physics, 2000. 48(2): p. 355-367.

6. Bolla, M., et al., Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet, 2002. 360(9327): p. 103-6.

7. Michalski, J.M., et al., Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial. JAMA Oncol, 2018. 4(6): p. e180039.

8. Stone, N.N., et al., Local control following permanent prostate brachytherapy: effect of high biologically effective dose on biopsy results and oncologic outcomes. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 355-60.

9. Salerno, K.E., et al., Detection of Failure Patterns Using Advanced Imaging in Patients With Biochemical Recurrence Following Low Dose Rate Brachytherapy for Prostate Cancer. International Journal of Radiation Oncology*Biology*Physics, 2021. 111(3): p. S134-S135.

10. Roach, M., 3rd, et al., Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys, 2006. 65(4): p. 965-74.

11. Le Tourneau, C., J.J. Lee, and L.L. Siu, Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst, 2009. 101(10): p. 708-20.

12. Storer, B.E., Design and analysis of phase I clinical trials. Biometrics, 1989. 45(3): p. 925-937.

13. Mohler, J.L., et al., Management of recurrent prostate cancer after radiotherapy: long-term results from CALGB 9687 (Alliance), a prospective multi-institutional salvage prostatectomy series. Prostate Cancer Prostatic Dis, 2019. 22(2): p. 309-316.

14. Shah, T.T., et al., Magnetic Resonance Imaging and Targeted Biopsies Compared to Transperineal Mapping Biopsies Before Focal Ablation in Localised and Metastatic Recurrent Prostate Cancer After Radiotherapy. Eur Urol, 2022. 81(6): p. 598-605.

15. Dipasquale, G., et al., Salvage reirradiation for local failure of prostate cancer after curative radiation therapy: Association of rectal toxicity with dose distribution and normal-tissue complication probability models. Advances in radiation oncology, 2018. 3(4): p. 673-681.

16. Kaplan, I., D.S. Kapp, and M.A. Bagshaw, Secondary external-beam radiotherapy and hyperthermia for local recurrence after 125-iodine implantation in adenocarcinoma of the prostate. International Journal of Radiation Oncology* Biology* Physics, 1991. 20(3): p. 551-554.

17. Kaljouw, E., et al., A Delphi consensus study on salvage brachytherapy for prostate cancer relapse after radiotherapy, a Uro-GEC study. Radiother Oncol, 2016. 118(1): p. 122-30.

18. Crook, J.M., et al., A prospective phase 2 trial of transperineal ultrasound-guided brachytherapy for locally recurrent prostate cancer after external beam radiation therapy (NRG Oncology/RTOG-0526). International Journal of Radiation Oncology* Biology* Physics, 2019. 103(2): p. 335-343.

19. D'Agostino, G.R., et al., Reirradiation of Locally Recurrent Prostate Cancer With Volumetric Modulated Arc Therapy. Int J Radiat Oncol Biol Phys, 2019. 104(3): p. 614-621.

20. Jereczek-Fossa, B.A., et al., Reirradiation for isolated local recurrence of prostate cancer: Mono-institutional series of 64 patients treated with salvage stereotactic body radiotherapy (SBRT). The British Journal of Radiology, 2019. 92(1094): p. 20180494.

21. Scher, N., et al., Stereotactic prostate focal reirradiation therapy for local recurrence: preliminary results of Hartmann Oncology Radiotherapy Group. BJR Open, 2019. 1(1): p. 20180027.

22. Pasquier, D., et al., Salvage Stereotactic Body Radiation Therapy for Local Prostate Cancer Recurrence After Radiation Therapy: A Retrospective Multicenter Study of the GETUG. Int J Radiat Oncol Biol Phys, 2019. 105(4): p. 727-734.

23. Network., N.C.C. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer (version 2.2023). 2023; Available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

24. Valle, L.F., et al., A systematic review and meta-analysis of local salvage therapies after radiotherapy for prostate cancer (MASTER). European urology, 2021. 80(3): p. 280-292.

25. Nikitas, J., et al., Early Safety and Efficacy Profile of Homogeneously Dosed Salvage Stereotactic Body Radiotherapy (SBRT) for Intraprostatic Recurrences After Low Dose Rate (LDR) Brachytherapy. Clin Genitourin Cancer, 2023. 21(2): p. 208-212.

26. Zelefsky, M.J., et al., High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys, 2002. 53(5): p. 1111-6.

27. Kim, D.W.N., et al., Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer. International Journal of Radiation Oncology*Biology*Physics, 2014. 89(3): p. 509-517.

28. Loi, M., et al., Robotic Stereotactic Retreatment for Biochemical Control in Previously Irradiated Patients Affected by Recurrent Prostate Cancer. Clin Oncol (R Coll Radiol), 2018. 30(2): p. 93-100.

29. Jereczek-Fossa, B.A., et al., Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus. Cancer treatment reviews, 2021. 98: p. 102206.

30. Peeters, S.T.H., et al., Dose-Response in Radiotherapy for Localized Prostate Cancer: Results of the Dutch Multicenter Randomized Phase III Trial Comparing 68 Gy of Radiotherapy With 78 Gy. Journal of Clinical Oncology, 2006. 24(13): p. 1990-1996.

31. Pasalic, D., et al., Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the Outcomes of a Phase 3, Single Institution Randomized Clinical Trial. International Journal of Radiation Oncology*Biology*Physics, 2019. 104(4): p. 790-797.

32. Dearnaley, D.P., et al., Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial. The Lancet Oncology, 2014. 15(4): p. 464-473.

33. Kerkmeijer, L.G.W., et al., Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial. Journal of Clinical Oncology, 2021. 39(7): p. 787-796.

34. Lewin, R., et al., Salvage re-irradiation using stereotactic body radiation therapy for locally recurrent prostate cancer: the impact of castration sensitivity on treatment outcomes. Radiation Oncology, 2021. 16(1).

35. Valle, L.F., et al., Multiparametric MRI for the detection of local recurrence of prostate cancer in the setting of biochemical recurrence after low dose rate brachytherapy. Diagn Interv Radiol, 2018. 24(1): p. 46-53.

36. Arumainayagam, N., et al., Accuracy of multiparametric magnetic resonance imaging in detecting recurrent prostate cancer after radiotherapy. BJU Int, 2010. 106(7): p. 991-7.

37. Moman, M.R., et al., Focal salvage guided by T2-weighted and dynamic contrast-enhanced magnetic resonance imaging for prostate cancer recurrences. Int J Radiat Oncol Biol Phys, 2010. 76(3): p. 741-6.

38. Créhange, G., et al., Salvage reirradiation for locoregional failure after radiation therapy for prostate cancer: Who, when, where and how? Cancer/Radiothérapie, 2014. 18(5): p. 524-534.

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