Exploring new frontiers: Outcomes and feasibility of a third radiotherapy course in recurrent prostate cancer

Abstract

Background and purpose:

Re-irradiation is increasingly recognized as a viable and safe treatment option for prostate cancer (PCa) local recurrence. The aim of this study is to present the safety profile, feasibility, and efficacy of a third radiation therapy (RT) course with stereotactic image-guided technique for PCa local relapse through a retrospective analysis of a tertiary centre experience.

Materials and methods:

Inclusion criteria for the third RT course were as follows: (1) histologically confirmed PCa initial diagnosis; (2) history of two prior courses of RT targeting the prostate gland or the prostate bed; (3) no evidence of greater than grade 2 genitourinary (GU) or gastrointestinal (GI) late events from previous treatments; (4) diagnosis of local recurrence at the restaging imaging in hormone sensitive patients performed after second RT biochemical recurrence. Primary endpoint was incidence of adverse events (AEs) and secondary endpoints included biochemical recurrence-free survival (BRFS) and clinical progression-free survival (CPFS).

Results:

From 2013 to 2024, 18 and five patients received a third RT course to a radiologicaly-detectable intraprostatic or prostate-bed recurrence, respectively. Androgen deprivation therapy (ADT) was not routinely used and only seven patients received concurrent ADT. Five patients had follow-up of less than 12 months. Of the remaining 18 patients, five were considered disease-free at a median follow-up of 48.5 months. Median BRFS following third RT was 22.6 months in patients with intraprostatic recurrence and 27.0 months in patients with prostate bed recurrence, while median CPFS was 30.9 months and 33.8 months, respectively. Three grade 3 acute GU events, two grade 3 late GU events, one grade 4 late GU event, and one grade 3 late GI event were recorded. No grade 5 events were observed.

Conclusions:

This unique series shows that a third RT can be proposed to highly selected patients as a salvage therapy in experienced centers with an acceptable safety profile, potentially prolonging relapse-free survival and ADT-free interval. Further studies are necessary to fully evaluate the most suitable patients population, optimal dose prescription, and dosimetric constraints to organs at risk.

Keywords

Radiotherapy prostate cancer reirradiation re-RT prostate cancer local recurrence prostate cancer local relapse

Introduction

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men worldwide.¹ Localized disease is treatable with radical prostatectomy (RP) and radiation therapy (RT),^2,3 yet after primary treatment 5% to 60% of men experience biochemical recurrence (BCR).^4–6 Radiorecurrent prostate cancer is the 4th most common urogenital malignancy in men after primary prostate cancer, bladder, and kidney cancer.⁷

One of the most common sites of recurrence is locally in the prostate gland or seminal vesicles (~55%)⁸ in case of RT as primary treatment, and in the prostate bed –more specifically at the vesicourethral anastomosis (~79%)⁹ – in case of surgery as primary treatment. Detecting the location and extent of recurrence is critical for guiding salvage therapies. Traditional imaging modalities like computed tomography (CT) and bone scans have limited sensitivity for detecting low-volume disease, particularly at low prostate-specific antigen (PSA) levels.¹⁰ However, advanced imaging techniques, such as prostate-specific membrane antigen (PSMA) positron emission tomography with co-registered CT (PET/CT) and magnetic resonance imaging (MRI), have significantly improved the detection of local recurrences, even at low PSA values.^11,12

After disease progression has been confirmed either via BCR and/or radiographic progression, androgen deprivation therapy (ADT) is often the treatment of choice,¹³ with a negative impact on patients quality of life due to the wide range of associated side effects.¹⁴ Since ADT is a fundamentally non-curative treatment that primarily aims to postpone disease progression,¹⁵ in the setting of an isolated local recurrence, a local salvage therapy as a potentially curative option should be proposed instead.

Managing locally recurrent prostate cancer after primary RT is complex. Guidelines recommend various approaches—from observation to local therapy (e.g., surgery, high-intensity focused ultrasound, cryotherapy, re-irradiation) or lifelong castration, i.e. ADT. While salvage prostatectomy has been the traditional curative approach, its high morbidity has driven exploration of alternatives like re-irradiation to improve control and reduce adverse events (AEs). Stereotactic body radiation therapy (SBRT) has emerged as a promising, curative, non-invasive salvage option, offering precise re-irradiation with minimal AEs.

In their systematic review and meta‑analysis, Ingrosso et al.¹⁶ showed that nonsurgical salvage local therapies, like BT and SBRT, can achieve meaningful biochemical control rates with an acceptable safety profile in carefully selected patients with radiorecurrent PCa. Valle et al.’s¹⁷ meta-analysis reported no significant differences in 5-year recurrence-free survival among RP, high-intensity focused ultrasound, cryotherapy, and re-irradiation (re-RT) techniques via brachytherapy (BT) and SBRT. However, re-RT with SBRT was associated with significantly lower genitourinary (GU) AEs compared to RP, suggesting equivalent efficacy but potentially higher safety profile with re-RT. Similarly, a systematic review on re-RT for local failure after a prior RT showed a safe level of AEs and promising overall mortality and biochemical control rates.¹⁸

Despite encouraging results with SBRT, some patients experience subsequent relapse after their salvage re-RT treatment.¹⁹ While many patients develop distant metastatic disease that requires systemic therapies as treatment of choice, a notable proportion have a confirmed tendency to recur locally. The management of such second local relapses remains a complex and significant unexplored clinical challenge.

The aim of the present study is to retrospectively analyze a cohort of patients who received a third course of RT for local relapse of prostate cancer, assessing safety profile, feasibility, and clinical outcomes of this approach in a real-world setting.

Patients and methods

The study was approved by the ethical committee of the IEO, European Institute of Oncology, IRCCS, in Milan, Italy (under a notification Nr: 79). Patients were considered eligible for the third RT if they met the following criteria: (1) histologically confirmed PCa initial diagnosis; (2) history of two prior courses of RT (or BT) targeting the prostate gland or the prostate bed; (3) no evidence of late GU or gastrointestinal (GI) AEs greater than grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE)²⁰ from previous treatments; (4) restaging after second RT BCR performed by imaging studies, i.e. whole-body diffusion-weighted MRI including multiparametric MRI of the prostate and/or [11C]-choline PET/CT and/or [68Ga]-PSMA PET/CT; (5) diagnosis of local recurrence at the restaging imaging in hormone sensitive patients; (6) written informed consent for the third RT course.

Histopathological confirmation of recurrence after second RT was not mandatory if clinical and radiologic evidence was conclusive, as stated in Jereczek-Fossa et al.’s Delphi consensus.²¹ All cases were discussed in the institutional multidisciplinary uro-oncology tumor board.

Concurrent ADT with Anti-Androgens or Luteinizing Hormone-Releasing Hormone (LHRH) agonists was allowed for castration-sensitive patients alongside RT courses. Short-course ADT was defined as hormone therapy lasting six months, long-course ADT as hormone therapy lasting from 12 to 24 months, and lifelong ADT as hormone therapy taken continuously without interruptions. Prescription was at the treating radiation oncologist’s discretion. In clinical practice, ADT was predominantly prescribed in patients presenting with higher‑risk characteristics at recurrence, including elevated PSA levels, a short PSA doubling time consistent with high‑risk biochemical recurrence as per European Association of Urology (EAU) criteria²² (i.e. PSA‑DT ⩽ 12 months), or adverse pathological features such as a high Gleason score (⩾ 8) or cribriform growth patterns.

Radiation therapy planning and dosimetric evaluation

All salvage RT courses (i.e., first and second re-RT) were delivered via image-guided radiation therapy (IGRT) with SBRT to ensure precise dose delivery and high biologically effective dose. To ensure optimal treatment delivery, preparation guidelines for empty rectum and full bladder was given to each patient and requested to be closely followed for the simulation CT scan and each RT fraction.

For patients who were restaged with PET, a dedicated fusion multiparametric MRI was scheduled on the day of simulation CT to support accurate delineation of the gross tumor volume (GTV). RT was exclusively delivered to the site of relapse (i.e. focal SBRT), with no margins given for subclinical disease (Figure 1). Planning target volume (PTV) was obtained expanding the GTV of 5 mm except posteriorly, where the expansion was 3 mm. Conversely, a 3 mm expansion was given to all margins except posteriorly (1 mm) in all cases treated with Cyberknife (Accuray Inc., Sunnyvale, California). Biodegradable spacers were not used in our cohorts.

Figure 1.

Illustrative example of sequential intraprostatic relapses treated with focal radiation therapy on a patient in the prostate gland cohort. (A) First re-irradiation plan for local relapse on the left lobe of the prostate gland; (B) Second re-irradiation plan for a subsequent local relapse in the contralateral (right) lobe; (C) Shows the overlapping of the two plans. In light blue there is the 25% isodose curve, in green the 50% isodose curve, in pink the 100% isodose curve, in red the planning target volume.

Since standardized dose constraints for multiple RT courses are not yet established, we referred to prior institutional findings specifically addressing safe dose-volume cumulative constraints for prostate cancer re-RT (see Online Supplementary Material 1). Augugliaro et al.²³ conducted a retrospective analysis evaluating 26 patients undergoing SBRT for intraprostatic recurrence. Their research identified specific cumulative dose-volume constraints to OARs in equivalent dose in 2 Gy fractions (EQD2), determined through correlation with the occurrence of clinically significant AEs. On top of the cumulative report, for the third RT plan we also employed our Institutional Pelvic re-RT Dosimetric Report for OARs, further implementing a conservative approach by applying a 20% reduction to the recommended constraints (see Online Supplementary Material 2).

Cumulative maximum doses (Dmax) to the rectum and bladder were calculated in EQD2 using an α/β ratio of 3 Gy. When available, the actual Dmax received from prior RT courses by each organ was used. If earlier treatment plans were not retrievable, the entire prescription dose was used as in a worst-case scenario approach.

Study endpoints

The primary endpoint of this study was safety and feasibility, in terms of incidence of CTCAE grade ⩾ 3 treatment-related AEs. Secondary endpoints included biochemical recurrence-free survival (BRFS) and clinical progression-free survival (CPFS).

Follow-up procedure

Follow-up was conducted through annual medical visits, which included systematic assessment of GU and GI AEs according to CTCAE. Follow-up visits were to be brought forward if the PSA level exceeded the BCR threshold (documented on an initial assay and confirmed by a second determination after 30 days), or if the patient developed new-onset, persistent GU or GI AEs. For patients who underwent RT courses on the prostate gland (PG cohort), BCR was defined as PSA nadir +2 ng/mL, according to the Phoenix consensus.²⁴ For patients who underwent RT courses on prostate bed (PB cohort), BCR was defined as a PSA ⩾ 0.5 ng/mL if the pre-RT PSA was < 0.5 ng/mL, or as an increase of ⩾10% from the pre-RT PSA value if it was ⩾ 0.5 ng/mL. Following BCR, patients underwent restaging with whole-body diffusion-weighted MRI including multiparametric MRI of the prostate or [68Ga]-PSMA PET/CT.

BRFS was defined as the time from the end of third RT course to the date of BCR, or date of the last clinical visit without recurrence, or death. CPFS was defined as the time from the end of third RT course to the occurrence of clinical progression (detected via imaging studies or physical findings), or date of the last clinical visit without recurrence, or death from any cause. Follow-up was calculated from the end of third RT course to date of the last clinical visit, or death from any cause. OS1 was calculated as the time from first RT course to date of the last clinical visit, or death from any cause.

Results

Study population

From May 2013 to Jan 2024, 18 and five patients received a third RT course at IEO, respectively on the radiologically detectable intraprostatic disease and on the radiologically detectable prostatic bed disease.

For patients undergoing third RT course for intraprostatic recurrence (PG cohort), median age was 75.5 years (IQR: 70.5 – 77.7) and median PSA before third RT-course was 3.9 ng/mL (IQR: 3.2 – 5.9). Four patients (4/18, 22.2%) initiated concurrent short- or long-course hormone therapy during their third treatment.

For patients undergoing third RT course for prostate bed recurrence (PB cohort), median age was 71.8 years (IQR: 66.2 – 74.9) and median PSA before third RT-course was 2.7 ng/mL (IQR: 0.9 – 3.2). Three patients (3/5, 60%) initiated concurrent short- or long-course hormone therapy during their third treatment.

Patients’ initial clinical and pathological features are illustrated in Table 1. RT treatments characteristics are illustrated in detail in Table 2.

Table 1.

Patients’ initial clinical and pathological features.

	Prostate gland (n=18)		Prostate bed (n=5)
iPSA, median (IQR) [ng/mL]	12.0 (6.9 – 15.1)		9.1 (8.7 – 17.6)
1-month post-op PSA, median (IQR) [ng/mL]			0.5 (0.3 – 0.9)
Tumor stage, number (%)	cT1	5 (27.8%)
	cT2	8 (44.4%)	pT2	3 (60%)
	cT3	3 (16.7%)	pT3	2 (40%)
	cT4	0	pT4	0
	cTx	2 (11.1%)
Nodal stage, number (%)	cN0	18 (100%)	pN0	5 (100%)
Nodal stage, number (%)	cN1	0	pN1	0
M stage, number (%)	cM0	18 (100%)	cM0	5 (100%)
M stage, number (%)	cM1	0	cM1	0
ISUP grade group, number (%)	1	11 (61.1%)	1	0
	2	4 (22.2%)	2	1 (20%)
	3	1 (5.6%)	3	4 (80%)
	4	1 (5.6%)	4	0
	5	0	5	0
	na	1 (5.6%)	na	0

iPSA, initial (pretreatment) prostate-specific antigen; IQR, interquartile range; ISUP, International Society of Urological Pathology; PSA, prostate-specific antigen.

Table 2.

Radiotherapy treatment characteristics.

	Prostate gland (n=18)		Prostate bed (n=5)
First RT course
Age, median (IQR) [years]	64.0 (56.3 – 67.3)		60.3 (56.3 – 61.1)
PSA before first irradiation, median (IQR) [ng/mL]	12.0 (6.9 – 15.1)		1.1 (0.9 – 1.3)
Concurrent ADT, number (%)	7/18 (38.9%), 1/18 na (5.6%)		2/5 (40%)
Fractionation [Gy/fractions], number (%)	35/5	1 (5.6%)	73.6/32	1 (20%)
	70.2/26	3 (16.7%)	72/36	1 (20%)
	70/30	1 (5.6%)	70/35	2 (40%)
	76/38	5 (27.8%)	66/33	1 (20%)
	45/25 + 30/15	1 (5.6%)
	50.4/28 + 28/14	1 (5.6%)
	50/25 + 100/1*	2 (11.1%)
	145/1*	2 (11.1%)
	na	2 (11.1%)
Second RT course
Age, median (IQR) [years]	70.8 (66.9 – 75.0)		67.9 (61.8 – 69.1)
PSA before second irradiation, median (IQR) [ng/mL]	4.4 (3.1 – 7.1)		2.0 (1.2 – 3.0)
Concurrent ADT, number (%)	3/18 (16.7%)		1/5 (20%)
Fractionation [Gy/fractions], number (%)	20/2	1 (5.6%)	25/5	2 (40%)
	30/10	1 (5.6%)	30/5	3 (60%)
	25/5	3 (16.7%)
	30/5	9 (50%)
	32.5/5	1 (5.6%)
	35/5	3 (16.7%)
Third RT course
Age, median (IQR) [years]	75.5 (70.5 – 77.7)		71.8 (66.2 – 74.9)
PSA before third irradiation, median (IQR) [ng/mL]	3.9 (3.2 – 5.9)		2.7 (0.9 – 3.2)
Concurrent ADT, number (%)	4/18 (22.2%)		3/5 (60%)
Duration of ADT, number (%)	short-course long-course lifelong	03 (75%)1 (25%)	short-course long-course lifelong	1 (33.3%)1 (33.3%)1 (33.3%)
Fractionation [Gy/fractions], number (%)	24/4	1 (5.6%)	25/5	4 (80%)
	25/5	6 (33.3%)	35/5	1 (20%)
	30/5	4 (22.2%)
	32/4	1 (5.6%)
	32.5/5	2 (11.1%)
	35/5	4 (22.2%)

Brachytherapy schedule via permanent implant (ultra-low dose rate). ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate-specific antigen; RT, radiation therapy.

Oncological outcomes

In the PG cohort, one patient was lost at first follow-up, one was lost after the first 3-months follow-up visit, and two had follow-up < 12 months. Of the remaining 14 patients, four (28.6%) are considered disease-free, while 10 (71.4%) experienced BCR. Median follow-up was 50.6 months (IQR: 33.5 – 69.5), median BRFS was 22.6 months (IQR: 18.6 – 31.9), and median CPFS was 30.9 months (IQR: 27.1 – 39.8). Among the 10 patients who developed BCR, nine relapsed locally and one started ADT without undergoing a radiological restaging. No patients developed regional or distant metastasis. Two non-cancer-related deaths and one cancer-related death due to PCa progression were recorded in this cohort during the follow-up period.

In the PB cohort, one patient was lost at first follow-up. Of the remaining four patients, one (25%) is considered disease-free, while three (75%) experienced BCR. Median follow-up was 52.2 months (IQR: 48.5 – 61.3), median BRFS was 27.0 months (IQR: 24.2 – 33.6), and median CPFS was 33.8 months (IQR: 26.8 – 43.3). Among the three patients who developed BCR, two relapsed locally and one started ADT without undergoing a radiological restaging. No patients developed regional or distant metastasis. No deaths were recorded in this cohort during the follow-up period.

Oncological outcomes are illustrated in detail in Table 3.

Table 3.

Oncological outcomes.

	Prostate gland (n=18)	Prostate bed (n=5)
First RT course
BRFS, median (IQR) [months]	57.1 (40.3 – 78.3)	27.6 (22.1 – 58.7)
Second RT course
BRFS, median (IQR) [months]	30.6 (16.7 – 48.2)	17.6 (15.7 – 27.1)
Third RT course
Patients with FUP >12 months, number (%)	14/18 (77.8%)	4/5 (80%)
FUP >12 months, median (IQR) [months]	50.6 (33.5 – 69.5)	52.2 (48.5 – 61.3)
Biochemical relapse, number (%)	10/14 (71.4%)	3/4 (75%)
BRFS, median (IQR) [months]	22.6 (18.6 – 31.9)	27.0 (24.2 – 33.6)
CPFS, median (IQR) [months]	30.9 (27.1 – 39.8)	33.8 (26.8 – 43.3)

BRFS, biochemical recurrence-free survival; CPFS, clinical progression-free survival; FUP, follow-up; IQR, interquartile range; RT, radiation therapy.

Safety profiles

For patients in the PG cohort, one CTCAE acute grade 3 GU event (i.e. gross hematuria) was recorded. Concerning the maximum late AEs observed, one grade 3 GU event (i.e. acute urinary retention) and one grade 3 GI event (i.e. rectal bleeding) were reported. No grade > 3 AEs were observed in this cohort.

For patients in the PB cohort, two CTCAE acute grade 3 GU events (i.e. two cases of gross hematuria) were recorded. Concerning the maximum late AEs observed, one grade 3 GU event (i.e. gross hematuria) and one grade 4 GU event (i.e. severe hematuria requiring placement of a suprapubic catheter) were reported. No grade 5 events were observed in this cohort.

At last follow-up, persistent AEs were observed only in the PB cohort patient who experienced the grade 4 GU event. All other patients from both cohorts showed an overall improvement in treatment-related AEs, with no CTCAE grade > 2 GU or GI events reported.

Third RT treatment AEs are illustrated in detail in Table 4.

Table 4.

Safety profile of the third course of radiation therapy.

Third RT acute AEs	Prostate gland (n=18)		Prostate bed (n=5)
GU acute AEs, number (%)	G1 G2 G3 G4	2 (11.1%) 1 (5.6%) 1 (5.6%): 1 hematuria 0	G1 G2 G3 G4	0 0 2 (40%): 2 hematuria 0
GI acute AEs, number (%)	G1 G2 G3 G4	1 (5.6%) 0 0 0	G1 G2 G3 G4	1 (20%) 0 0 0
Third RT maximum late AEs
GU late AEs, number (%)	G1 G2 G3 G4	4 (22.2%) 3 (16.7%) 1 (5.6%): 1 acute urinary retention 0	G1 G2 G3 G4	0 0 1 (20%): 1 hematuria 1 (20%): 1 vesical fistula
GI late AEs, number (%)	G1 G2 G3 G4	1 (5.6%) 1 (5.6%) 1 (5.6%): 1 rectal bleeding 0	G1 G2 G3 G4	0 1 (20%) 0 0
AEs at last FUP
GU AEs at last FUP, number (%)	G1 G2 G3 G4	3 (16.7%) 2 (11.1%) 0 0	G1 G2 G3 G4	0 1 (20%) 0 1 (20%): 1 vesical fistula
GI AEs at last FUP, number (%)	G1 G2 G3 G4	0 1 (5.6%) 0 0	G1 G2 G3 G4	1 (20%) 0 0 0

AE, adverse event; G1-4, Common Terminology Criteria for Adverse Events grade 1-4; GI, genitourinary; GU, gastrointestinal; RT, radiation therapy.

Dosimetric OARs evaluation

For patients in the PG cohort, the median Dmax to rectum at third RT was 41.7 Gy (IQR: 39.7 – 42.8) and the median mean dose was 2.8 Gy (IQR: 2.7 – 2.8). The median Dmax to bladder at third RT was 42.8 Gy (IQR: 41.7 – 45.0) and the median mean dose was 0.8 Gy (IQR: 0.7 – 2.5). The median cumulative Dmax to the rectum was 168.8 Gy (IQR: 152.3–170.1) while the median cumulative Dmax to the bladder was 173.0 Gy (IQR: 171.6–174.6).

For patients in the PB cohort, the median Dmax to rectum at third RT was 52.6 Gy (IQR: 37.7 – 56.1) and the median mean dose was 3.5 Gy (IQR: 3.1 – 5.7). The median Dmax to bladder at third RT was 40.7 Gy (IQR: 9.5 – 56.8) and the median mean dose was 1.1 Gy (IQR: 0.3 – 2.4). The median cumulative Dmax to the rectum was 170.6 Gy (IQR: 150.3–194.7) while the median cumulative Dmax to the bladder was 171.5 Gy (IQR: 136.3–174.6).

Doses to organs at risk are illustrated in detail in Table 5.

Table 5.

Doses to organs at risk.

	Prostate gland (n=18)	Prostate bed (n=5)
Third RT doses to OARs
Rectum Dmean, median (IQR) [Gy]	3.5 (3.1 – 5.7)	2.8 (2.7 – 2.8)
Rectum Dmax, median (IQR) [Gy]	52.6 (37.7 – 56.1)	41.7 (39.7 – 42.8)
Bladder Dmean, median (IQR) [Gy]	1.1 (0.3 – 2.4)	0.8 (0.7 – 2.5)
Bladder Dmax, median (IQR) [Gy]	40.7 (9.5 – 56.8)	42.8 (41.7 – 45.0)
Cumulative doses to OARs
Cumulative Rectum Dmax, median (IQR) [Gy]	170.6 (150.3 – 195.7)	168.8 (152.3 – 170.1)
Cumulative Bladder Dmax, median (IQR) [Gy]	171.5 (136.3 – 174.6)	173.0 (171.6 – 174.6)

Dmax, maximum dose; Dmean, mean dose; IQR, interquartile range; OAR, organ at risk; RT, radiotherapy.

Discussion

In this retrospective study –the largest in this clinical setting– we analyzed a unique cohort of PCa patients treated with a third course of RT for local recurrence after two prior RT treatments. The results demonstrate that carefully selected patients can undergo multiple courses of image-guided, high-precision RT with acceptable safety profiles and promising oncological outcomes within highly experienced centers, as emphasized by recent expert consensus guidelines.^21,25

Advances in imaging and precision delivery have made SBRT feasible to achieve local tumor control even after multiple prior RT courses. Recent series have reported that salvage SBRT for locally radiorecurrent PCa after a prior definitive RT can yield durable biochemical control with limited AEs, with 2-year biochemical control rates of 50–80%.²⁶ Mariucci et al.²⁷ reported a 2‑year BRFS of 55% after a first re-RT in patients with radiorecurrent PCa within the prostate gland or the prostate bed. The MASTER meta-analysis¹⁷ reported approximately a 60% five-year relapse-free survival after salvage re-RT on the prostate gland –comparable to salvage prostatectomy– but with significantly lower rates of GU AEs. In our study, the observed cancer control rates are encouraging, with 27.8% of patients considered disease-free at last follow-up. In the PG cohort, median BRFS declined from 30.6 months after the second RT course to 22.6 months after the third, suggesting that tumor biology and acquired radioresistance could play a relevant role; nonetheless, a roughly 2-year disease-free interval gained by a third RT is quite significant for patients who might otherwise have started lifelong ADT. Conversely, in the PB cohort, median BRFS increased from 17.6 months after the second RT course to 27.0 months after the third, suggesting that, in the setting of local relapse after prostatectomy, highly focused irradiation targeting only the macroscopic recurrence could offer improved disease control and may represent a viable treatment strategy.

As the tolerance of OARs can be stretched by multiple radiation courses, a key consideration for any re-RT regimen is safety profile. The cumulative burden of previous irradiations increases the risk of severe AEs, particularly in anatomically altered tissues. This aligns with findings from a recent prospective study by Ekanger et al.,²⁸ which reported long-term outcomes of salvage re-irradiation for locally recurrent prostate cancer. One patient in their cohort experienced a severe complication after the second RT course, underscoring the potential risks associated with cumulative radiation exposure. These findings emphasize that a third course of RT should be only reserved to fit patients without significant AEs from prior treatments.

In our protocol, we mitigated this risk through meticulous patient selection and dose planning. Only patients without pre-existing grade ⩾ 2 late AEs from prior treatments were offered a third RT course, and we used a conservative approach to OARs dose constraints. Specifically, we employed our Institutional Pelvic re-RT Dosimetric Report for OARs, maintaining third RT treatment plan values at approximately 80% of the recommended constraints. By implementing these precautions, we observed manageable GU and GI AEs, considering the particular context of a third local treatment. This must be contextualized within the broader spectrum of AEs associated with alternative salvage therapies, such as prostatectomy or the early initiation of lifelong ADT, both of which are known to carry significant risks of local and systemic toxicities.

GU AEs were predominantly low-grade, however, a limited number of higher-grade events were observed, including three grade 3 acute AEs (i.e. gross hematuria), two grade 3 late AEs (i.e. one case of acute urinary retention, and one case of gross hematuria), and a single grade 4 late AE requiring urethrectomy. It is noteworthy that the grade 4 late GU event occurred in a PB cohort patient who received the highest cumulative maximum dose to bladder (192.34 Gy, EQD2 α/β 3 Gy). GI AEs were also predominantly low-grade, except for one grade 3 late AE (i.e. rectal bleeding). Notably, at last follow-up visit, persistent AEs were observed only in the patient who had experienced the grade 4 late GU event. All other patients across both cohorts showed no CTCAE GU or GI AEs greater than grade 2.

As expected, we observed a higher incidence of recurrent late AEs among patients in the PB cohort, likely reflecting the greater vulnerability of altered pelvic anatomy and tissue integrity to cumulative radiation exposure. While any AE is cause for caution, the incidence in our series remains within a clinically acceptable range given the complexity of repeated treatments. In fact, reported rates of grade ⩾ 3 GU and GI AEs after a single salvage SBRT are generally around 3–10% and <5%, respectively.^17,29

The optimal target volume in the setting of locally recurrent prostate cancer is an area of active debate. Treating only the visible lesion can minimize AEs to OARs, whereas expanding the target volume might address occult microscopic disease and possibly improve tumor control. Emerging evidence favors a tailored approach: for example, Lewin et al.²⁹ reported a 93% in-field local control rate using primarily focal SBRT directed by PSMA PET imaging, with failures predominantly in patients who had systemic progression. In our series, modern imaging was integral to patient selection – all patients underwent advanced restaging ensuring that we were treating only a localized disease.

The question of combining hormonal therapy with salvage radiation in this context remains open.^30,31 In our cohort, ADT was not routinely used – only seven out of 23 patients received any hormonal therapy as an adjunct to their third RT. In an era where most patients with PCa local recurrence receive lifelong ADT as salvage therapy,³² our findings highlight a potential path that can prolong the ADT-free interval. Given the significant metabolic, cardiovascular, and quality-of-life impacts of ADT,¹⁴ any strategy that safely postpones or avoids its use could be of considerable clinical value and impactful for quality of life, especially for older patients or those with comorbidities.

In the extended follow-up of a large SBRT re-RT cohort, Francolini et al.³³ reported that concomitant ADT use was associated with worse BRFS, presumably due to higher-risk disease profiles. Published after completion of our data collection, the EMBARK trial³⁴ demonstrated that patients presenting more aggressive disease characteristics, such as higher PSA value at recurrence (e.g., PSA > 5 ng/mL), might benefit from combination therapy strategies. Specifically, the study reported improved oncological outcomes in patients with high-risk biochemical recurrence with the combination of enzalutamide plus leuprolide compared to leuprolide alone, significantly prolonging metastasis-free survival and PSA progression-free survival.

Considering the elevated PSA levels prior to re-RT observed in some patients of our study, integrating an intensified systemic approach in selected high-risk cases could potentially optimize clinical outcomes. The role of concurrent ADT with salvage SBRT has to be investigated in prospective trials, in order to delineate the subpopulations that could benefit enough to justify the added AEs of a combined treatment.

Another important consideration is whether further dose escalation or novel fractionation could improve outcomes in the salvage setting. Many patients in our series ultimately experienced a subsequent BCR after the third RT, in some cases pointing to the need for even more potent local therapy. Prostate cancer has a very low α/β (~1.5 Gy),³⁵ indicating a high sensitivity to higher dose per fraction. Ultra-hypofractionated regimens confer a radiobiological advantage on tumoricidal efficacy without significantly increasing late normal tissue AEs. In this setting, proton therapy can significantly reduce incidental dose to tissues beyond target volume. In pelvic re-RT scenarios, this dosimetric advantage translates to better sparing of OARs compared to conventional RT.³⁶ Likewise, MRI-guided adaptive RT represents an evolving strategy that could enhance the safety and precision of multiple-course re-RT.³⁷

Some limitations of this study must be acknowledged. Firstly, the retrospective nature of the analysis introduces inherent selection bias, as patients selected for a third RT course were those who experienced only local relapse and recovered from previous treatments with minimal AEs. This likely enriched our population with more radio-tolerant patients and possibly those with more indolent tumor biology. Patients were not prospectively enrolled according to predefined criteria but were selected through multidisciplinary clinical judgment in a highly individualized setting. As a result, clinical decision-making may have varied over time and across cases. Secondly, the sample size is relatively small, and this inevitably limits the statistical robustness and generalizability of our findings. Given the limited cohort sizes, particularly when considering subgroup analyses (such as PG versus PB oncological outcomes), our study was not adequately powered to detect meaningful differences. Additionally, heterogeneity in prior treatments, disease characteristics, and timing of recurrences further complicates the interpretation of outcomes. However, this limitation primarily reflects the rarity of this clinical scenario. Thirdly, in an era increasingly oriented toward precision oncology, our work does not incorporate histological subtyping and biomarker‑driven selection. Patient candidacy was determined exclusively on the basis of clinical factors, without integration of prognostic biomarkers able to stratify patients and monitor treatment response, such as circulating tumor cells and circulating tumor DNA. As tumor histology appears to play a relevant role in clinical outcomes,³⁸ aggressive variants may significantly influence response to local therapies and could potentially benefit from treatment intensification. In the future, the incorporation of histological subtyping and molecular biomarkers into decision‑making frameworks could improve discrimination between patients whose disease will remain predominantly local and truly amenable to further focal treatments, and those who might instead benefit from systemic intensification. Overall, these limitations underscore the exploratory nature of our study, which represents, to the best of our knowledge, the first reported study in literature in this particular clinical setting.

Conclusions

This unique series provides preliminary evidence supporting the concept that a third course of RT can be a feasible and effective salvage option for locally recurrent prostate cancer in selected patients. This approach, made possible by modern SBRT techniques, has the potential clinical benefit of prolonging relapse-free survival and avoiding, or delaying, the start of ADT. Importantly, half of the patients remain progression-free at two years from their third RT course, and AEs appear acceptable when adhering to conservative dose constraints. However, our findings should be interpreted cautiously and considered hypothesis-generating, warranting confirmation in larger, prospective investigations to fully evaluate the most suitable patient population, dose prescription and cumulative constraints to OARs.

Supplemental Material

sj-docx-1-tmj-10.1177_03008916261445263 – Supplemental material for Exploring new frontiers: Outcomes and feasibility of a third radiotherapy course in recurrent prostate cancer

Supplemental material, sj-docx-1-tmj-10.1177_03008916261445263 for Exploring new frontiers: Outcomes and feasibility of a third radiotherapy course in recurrent prostate cancer by Costantino Putzu, Federico Mastroleo, Mattia Zaffaroni, Maria Giulia Vincini, Dario Zerini, Giovanni Carlo Mazzola, Chiara Lorubbio, Sabrina Clobiaco, Karl Amin, Francesca Emiro, Federica Cattani, Stefano Luzzago, Francesco Alessandro Mistretta, Ottavio De Cobelli, Gennaro Musi, Giuseppe Petralia, Marcin Miszczyk, Giulia Marvaso and Barbara Alicja Jereczek-Fossa in Tumori Journal

Supplemental Material

sj-docx-2-tmj-10.1177_03008916261445263 – Supplemental material for Exploring new frontiers: Outcomes and feasibility of a third radiotherapy course in recurrent prostate cancer

Supplemental material, sj-docx-2-tmj-10.1177_03008916261445263 for Exploring new frontiers: Outcomes and feasibility of a third radiotherapy course in recurrent prostate cancer by Costantino Putzu, Federico Mastroleo, Mattia Zaffaroni, Maria Giulia Vincini, Dario Zerini, Giovanni Carlo Mazzola, Chiara Lorubbio, Sabrina Clobiaco, Karl Amin, Francesca Emiro, Federica Cattani, Stefano Luzzago, Francesco Alessandro Mistretta, Ottavio De Cobelli, Gennaro Musi, Giuseppe Petralia, Marcin Miszczyk, Giulia Marvaso and Barbara Alicja Jereczek-Fossa in Tumori Journal

Footnotes

Acknowledgements

The IEO (European Institute of Oncology, IRCCS, Milan, Italy) is partially supported by the Italian Ministry of Health (with “Ricerca Corrente” and “5x1000” funds). The IEO Division of Radiation Oncology received research funding from AIRC (Italian Association for Cancer Research) and Fondazione IEO-CCM (Istituto Europeo di Oncologia-Centro Cardiologico Monzino), and is partially supported by institutional grants from Accuray Inc. (Sunnyvale, California). The sponsors had no role in the study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit the manuscript for publication.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BAJ-F received speakers fees from Accuray, Astellas, Astra Zeneca, Bayer, Carl Zeiss, Elekta, IBA, Ipsen, and Janssen, all outside the current project. MM was supported by the European Urological Scholarship Programme (EUSP) Scholarship of the European Association of Urology (EAU). The remaining authors declare no conflicts of interest that are relevant to the content of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics approval and consent to participate

All procedures performed in the present study involving human participants will be in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients provided written informed consent for treatment and research participation.

ORCID iDs

Costantino Putzu

Mattia Zaffaroni

Maria Giulia Vincini

Dario Zerini

Karl Amin

Marcin Miszczyk

Supplemental material

Supplemental material for this article is available online.

References

Zhou

Check

Lortet-Tieulent

, et al. Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group. Int J Cancer 2016; 138: 1388-1400.

Lane

Donovan

Davis

, et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol 2014; 15: 1109-1118.

Hamdy

Donovan

Lane

, et al. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2023; 388: 1547-1558.

Catton

. Post-operative radiotherapy following radical prostatectomy. EAU Update Ser 2005; 3: 107-116.

Isharwal

Stephenson

. Post-prostatectomy radiation therapy for locally recurrent prostate cancer. Expert Rev Anticancer Ther 2017; 17: 1003-1012.

Makarewicz

Reszke

. Biochemical failure in prostate cancer following radiation therapy. Contemp Oncol Onkol 2006; 10: 152-155.

Jones

. Radiorecurrent prostate cancer: an emerging and largely mismanaged epidemic. Eur Urol 2011; 60: 411-412.

Zumsteg

Spratt

Romesser

, et al. Anatomical patterns of recurrence following biochemical relapse in the dose escalation era of external beam radiotherapy for prostate cancer. J Urol 2015; 194: 1624-1630.

Park

Pyo

, et al. Suggestion for the prostatic fossa clinical target volume in adjuvant or salvage radiotherapy after a radical prostatectomy. Radiother Oncol 2014; 110: 240-244.

10.

Uemura

Watabe

Hoshi

, et al. The current status of prostate cancer treatment and PSMA theranostics. Ther Adv Med Oncol 2023; 15: 17588359231182293.

11.

Mattana

Muraglia

Rajwa

, et al. Metastatic sites’ location and impact on patient management after the introduction of prostate-specific membrane antigen positron emission tomography in newly diagnosed and biochemically recurrent prostate cancer: a critical review. Eur Urol Oncol 2023; 6: 128-136.

12.

Zhang-Yin

Montravers

Montagne

, et al. Diagnosis of early biochemical recurrence after radical prostatectomy or radiation therapy in patients with prostate cancer: State of the art. Diagn Interv Imaging 2022; 103: 191-199.

13.

NCCN. NCCN Guidelines Version 1.2025 Prostate Cancer, 2025. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459 (accessed 8 August 2025).

14.

Schwandt

Garcia

. Complications of androgen deprivation therapy in prostate cancer: Curr Opin Urol 2009; 19: 322-326.

15.

Abouassaly

Paciorek

Ryan

, et al. Predictors of clinical metastasis in prostate cancer patients receiving androgen deprivation therapy: Results from CaPSURE. Cancer 2009; 115: 4470-4476.

16.

Ingrosso

Becherini

Lancia

, et al. Nonsurgical salvage local therapies for radiorecurrent prostate cancer: a systematic review and meta-analysis. Eur Urol Oncol 2020; 3: 183-197.

17.

Valle

Lehrer

Markovic

, et al. A systematic review and meta-analysis of local salvage therapies after radiotherapy for prostate cancer (MASTER). Eur Urol 2021; 80: 280-292.

18.

Munoz

Fiorica

Caravatta

, et al. Outcomes and toxicities of re-irradiation for prostate cancer: A systematic review on behalf of the Re-Irradiation Working Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO). Cancer Treat Rev 2021; 95: 102176.

19.

Volpe

Jereczek-Fossa

Zerini

, et al. Case series on multiple prostate re-irradiation for locally recurrent prostate cancer: something ventured, something gained. Neoplasma. 2019;66(02):308-314.

20.

National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v6, 2025. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (accessed 8 August 2025).

21.

Jereczek-Fossa

Marvaso

Zaffaroni

, et al. Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus. Cancer Treat Rev 2021; 98: 102206.

22.

Scilipoti

Barletta

Stabile

, et al. A0609 – Systematic assessment of the prognostic role of PSA doubling time in predicting the risk of subsequent metastases in patients who experienced biochemical recurrence. Eur Urol 2025; 87: S1433.

23.

Augugliaro

Marvaso

Cambria

, et al. Finding safe dose-volume constraints for re-irradiation with SBRT of patients with prostate cancer relapse: The IEO experience. Phys Med 2021; 92: 62-68.

24.

Roach

Hanks

Thames

, 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 2006; 65: 965-974.

25.

Slevin

Aitken

Alongi

, et al. An international Delphi consensus for pelvic stereotactic ablative radiotherapy re-irradiation. Radiother Oncol 2021; 164: 104-114.

26.

Zhong

Slevin

Scarsbrook

, et al. Salvage reirradiation options for locally recurrent prostate cancer: a systematic review. Front Oncol 2021; 11: 681448.

27.

Mariucci

Ingrosso

Bini

, et al. Helical tomotherapy re-irradiation for patients affected by local radiorecurrent prostate cancer. Rep Pract Oncol Radiother 2020; 25: 157-162.

28.

Ekanger

Helle

Reisæter

, et al. Salvage reirradiation for locally recurrent prostate cancer: results from a prospective study with 7.2 years of follow-up. J Clin Oncol 2024; 42: 1934-1942.

29.

Lewin

Amit

Laufer

, et al. Salvage re-irradiation using stereotactic body radiation therapy for locally recurrent prostate cancer: the impact of castration sensitivity on treatment outcomes. Radiat Oncol 2021; 16: 114.

30.

Carrie

Hasbini

De Laroche

, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 2016; 17: 747-756.

31.

Jereczek-Fossa

Marvaso

Zaffaroni

, et al. Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus. Cancer Treat Rev 2021; 98: 102206.

32.

Agarwal

Sadetsky

Konety

, et al. Treatment failure after primary and salvage therapy for prostate cancer: Likelihood, patterns of care, and outcomes. Cancer 2008; 112: 307-314.

33.

Francolini

Loi

Di Cataldo

, et al. Stereotactic re-irradiation in recurrent prostate cancer after previous postoperative or definitive radiotherapy: long-term results after a median follow-up of 4 years. Clin Onco. 2022; 34: 50-56.

34.

Freedland

De Almeida Luz

De Giorgi

, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2023; 389: 1453-1465.

35.

Brenner

Hall

. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol 1999; 43: 1095-1101.

36.

Simone

Plastaras

Jabbour

, et al. Proton reirradiation: expert recommendations for reducing toxicities and offering new chances of cure in patients with challenging recurrence malignancies. Semin Radiat Oncol 2020; 30: 253-261.

37.

Alongi

Rigo

Figlia

, et al. 1.5T MR-guided daily-adaptive SBRT for prostate cancer: preliminary report of toxicity and quality of life of the first 100 patients. J Pers Med 2022; 12: 1982.

38.

Marra

Van Leenders

GJLH

Zattoni

, et al. Impact of epithelial histological types, subtypes, and growth patterns on oncological outcomes for patients with nonmetastatic prostate cancer treated with curative intent: a systematic review. Eur Urol 2023; 84: 65-85.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.05 MB

0.00 MB

0.04 MB