Outcomes of Radiotherapy With or Without Dose Escalation to Lymph Node Metastases Detected by PET PSMA or Conventional Imaging in Node-Positive Prostate Cancer

Abstract

Purpose:

To evaluate the impact of PSMA PET versus conventional imaging for staging, and the effect of dose escalation (DE) to metastatic lymph nodes in cN1 prostate cancer patients treated with EBRT and ADT.

Methods:

A retrospective multicenter analysis included 197 propensity score-matched patients (77 staged with PSMA PET, 120 with conventional imaging) treated with EBRT and ADT, with or without DE to lymph node metastases. Matching criteria were T stage, nodal involvement, imaging modality, Gleason score, and ADT duration. Primary endpoint was metastasis-free survival (MFS); secondary endpoints included overall survival (OS), locoregional control (LRC), and toxicity.

Results:

Median follow-up was 42 months (IQR: 25–59). Median EQD2 (alpha/beta=1.5) to elective nodes was 46 Gy, and to metastatic nodes, 66 Gy (PSMA PET) and 63 Gy (conventional imaging). The 3-year MFS was 80.5% (95% CI: 71.3–90.8%) for PSMA PET and 77.2% (95% CI: 69.5–85.8%) for conventional imaging; 5-year MFS was 59.3% versus 65.8% (P=0.57). OS at 5 years was 82.2% (PSMA PET) and 77.4% (conventional imaging) (P=0.72). On multivariable analysis, ISUP grade group 3–5 predicted earlier metastasis (HR: 4.03, 95% CI: 1.61–10.06; P=0.003); higher prostate dose (EQD2 ≥113 Gy) improved MFS (HR: 0.53, 95% CI: 0.30–0.95; P=0.033); long-term ADT (≥24 mo) improved OS (HR: 0.38, 95% CI: 0.19–0.78; P=0.009). No significant difference in toxicity was observed between groups.

Conclusions:

PSMA PET staging and nodal dose escalation >60 Gy were safe but did not improve MFS, OS, or LRC. ISUP grade group 3–5 and higher prostate dose significantly influenced outcomes.

Prostate cancer (PC) is the most common cancer in men, aside from skin cancers, with nearly 1.5 million new cases diagnosed worldwide in 2020. In the same year, 380,000 patients died from PC worldwide. Every year, since 2014, there has been a steady increase of about 5% in the incidence rate of the disease.^1,2 Traditional imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), have historically indicated that ~5%–13% of patients with newly diagnosed prostate cancer present with synchronous nodal metastases.^3–5 However, these estimates are likely conservative. More sensitive imaging techniques, particularly prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), have shown that the incidence may be as high as 30% among high-risk populations.⁵ The postoperative findings indicate that 15% of patients with conventional imaging N0 disease have regional lymph node metastases.⁶ This rate is even higher among patients with high and very high-risk prostate cancer, potentially reaching 25%.⁷ Furthermore, research has demonstrated that extended lymphadenectomy, as recommended by EAU guidelines for high-risk and intermediate-risk prostate cancer patients, results in a linear increase in the likelihood of detecting lymph node metastases.^8,9 According to international guidelines, given the high incidence of regional node metastases in high-risk populations, especially when the risk of nodal involvement is >20% according to the Roach formula, it is advisable to strongly consider elective nodal irradiation when radiotherapy is chosen as the primary treatment modality¹⁰ (https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf). In randomized controlled trials, this approach has been shown to prolong biochemical progression-free survival (bPFS) and disease-free survival (DFS). However, it does not benefit overall survival (OS).^11–13 The absence of clear benefit from nodal irradiation for micrometastases and small positive nodes (<1 cm) in high-risk patients remains uncertain. This prompts the question of whether treatment outcomes differ between conventional imaging and PSMA PET staging. Is it justifiable to escalate the dose for clinically detected regional node metastasis, and what dose should be used? Are there any differences regarding toxicity when the dose is escalated to metastatic lymph nodes?

There is a notable absence of randomized controlled trials providing evidence for the effectiveness of dose escalation to metastatic regional lymph nodes diagnosed in the primary setting. Although small retrospective studies, primarily from single institutions or incorporating postoperative data,^14–17 provide some insights, international guidelines encourage the practice of escalating radiation doses to the highest achievable levels while carefully adhering to dose constraints for organs at risk (OARs) (https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf).^10,18

The primary aim of this study was to analyze the differences in treatment outcomes in patients with node-positive (cN1) prostate cancer treated with radiotherapy and androgen deprivation therapy (ADT) and staged with PET PSMA or conventional imaging. The secondary aims were to define the potential benefits of dose escalation to metastatic regional lymph nodes and the toxicity profile when treated concomitantly with the prostate region.

METHODS

This multicentric retrospective cohort study included patients diagnosed with prostate cancer and regional lymph nodes involvement treated with EBRT with or without dose escalation to metastatic lymph nodes and with short-term or long-term ADT. Data were collected from 9 European institutions. Clinical data, including demographic, clinical, pathologic, and treatment-related variables, were extracted from institutional databases and electronic medical records using case report forms. Radiotherapy dose parameters were converted to equivalent dose in 2 Gy fractions [EQD2], and alpha/beta equal to 1.5 Gy was adopted. Details of radiotherapy doses and nodal boost are provided in Table 1 and Supplementary Table S1, Supplemental Digital Content 1, http://links.lww.com/CNM/A604. The selection of staging modality was determined by the availability of PSMA PET and institutional protocols at the time of diagnosis.

TABLE 1.

Baseline Clinical, Pathologic, and Treatment Characteristics of the Propensity Score-Matched Cohort, Stratified by Imaging Modality Used for Staging (Conventional Imaging vs. PSMA PET)

		Imaging for Staging
Characteristic	Overall N=197	Conventional Imaging N=120	PSMA PET N=77	P
Age (y)	69 (64, 73)	68 (63, 72)	70 (66, 73)	0.1
PSA level (ng/mL)				0.9
<10	31 (16)	19 (16)	12 (16)
≥20	119 (60)	74 (62)	45 (58)
10–20	47 (24)	27 (23)	20 (26)
ISUP grade group				0.8
ISUP 1–2	43 (22)	27 (23)	16 (21)
ISUP 3–5	154 (78)	93 (78)	61 (79)
ISUP grade				0.15
1	22 (11)	17 (14)	5 (6.5)
2	21 (11)	10 (8.3)	11 (14)
3	53 (27)	27 (23)	26 (34)
4	65 (33)	41 (34)	24 (31)
5	35 (18)	24 (20)	11 (14)
NA	1 (0.5)	1 (0.8)	0
T stage 3–4				>0.9
0	84 (43)	51 (43)	33 (43)
1	113 (57)	69 (58)	44 (57)
Lymph node categories				0.9
0	106 (54)	64 (53)	42 (55)
1	91 (46)	56 (47)	35 (45)
Lymph node count				0.9
1	106 (54)	64 (53)	42 (55)
>1	91 (46)	56 (47)	35 (45)
No. involved lymph nodes				0.6
1	106 (54)	64 (53)	42 (55)
2	49 (25)	34 (28)	15 (19)
3	16 (8.1)	8 (6.7)	8 (10)
4	11 (5.6)	6 (5.0)	5 (6.5)
5	6 (3.0)	3 (2.5)	3 (3.9)
6	4 (2.0)	3 (2.5)	1 (1.3)
7	4 (2.0)	1 (0.8)	3 (3.9)
9	1 (0.5)	1 (0.8)	0
Nodal volume				0.4
0–3 cm3	140 (77)	81 (74)	59 (80)
>3 cm3	43 (23)	28 (26)	15 (20)
Unknown	14	11	3
Metastatic node volume (cm3)	1.7 (0.7, 3.0)	1.6 (0.6, 3.2)	1.8 (1.0, 2.7)	0.5
Unknown	14	11	3
Long-term ADT (≥24 mo)				0.8
0	54 (27)	32 (27)	22 (29)
1	143 (73)	88 (73)	55 (71)
Nodal boost				0.7
0	67 (34)	42 (35)	25 (32)
1	130 (66)	78 (65)	52 (68)
Elective nodal EQD2 (Gy)	46.00 (44.00, 50.00)	46.00 (44.50, 50.00)	46.00 (44.00, 50.00)	0.3
Total EQD2 (Gy)	82 (78, 117)	80 (77, 121)	82 (78, 117)	0.4
Metastatic nodal EQD2 (Gy)	65 (50, 67)	66 (50, 67)	63 (50, 67)	0.7

n (%); Median (Q1, Q3).

Pearson χ² test; Wilcoxon rank-sum test; Fisher exact test.

The primary exposure variable was the use of Ga-68-PSMA PET imaging versus conventional imaging (CT, bone scintigraphy, and pelvic MRI) for staging at the time of curative treatment. The primary endpoint was metastasis-free survival (MFS), defined as the time from the initiation of radiotherapy until the diagnosis of metastases and/or death.¹⁹ Diagnosis of metastasis was based on findings from clinically indicated imaging performed during routine follow-up, independent of the baseline staging modality. The secondary endpoints included overall survival (OS), defined as the time from the initiation of radiotherapy until death and locoregional control (LRC), the time from initiation of radiotherapy to radiographic recurrence within the irradiation field.

Acute (≤6 mo from the beginning of radiotherapy) and late toxicities (>6 mo) were evaluated according to the Radiation Therapy Oncology Group (RTOG)/ European Organization for Research and Treatment of Cancer (EORTC) criteria.²⁰ Toxicities were compared between the treatment schedules using the 2-sided Fisher exact test.

Propensity Score Matching

To reduce confounding, propensity score matching was performed using nearest neighbor matching with a caliper of 0.2 based on a logistic regression model. The matching variables included ISUP group (1–2 vs. 3–5), T stage (binary), PSA group (<10, 10–20, ≥20 ng/mL), nodal boost, ADT duration (long-term ≥24 mo vs. short-term), lymph node count category (1 vs. >1), and nodal EQD2 doses for both elective nodal regions and metastatic lymph nodes. Patients staged with and without PSMA PET were matched with a ratio of up to 1:2, to maximize statistical power and precision given the larger availability of conventionally staged patients, meaning that for every patient in the PSMA PET group, up to 2 comparable patients without PSMA PET were included in the analysis. Covariate balance was assessed using standardized mean differences (SMD) with a threshold of <0.1 indicating adequate balance and statistical tests were performed to evaluate between-group differences.

Statistical Analysis

Descriptive statistics were generated for baseline characteristics, stratified by the employment of PET PSMA. Continuous variables were summarized as means and SDs, and categorical variables as frequencies and percentages. Between-group differences were assessed using t tests or χ² tests as appropriate. Interaction terms were tested to assess effect modification.

Survival analyses for MFS, OS, and LRC were conducted using the Kaplan-Meier method, with differences between groups compared using log-rank tests. Cox proportional hazards regression models were fitted to estimate hazard ratios (HRs) and 95% CIs for the association between PET PSMA use and outcomes. Variables with a P-value <0.10 were considered for the multivariate analysis.

Group comparisons were performed using Pearson χ² test for categorical variables, Wilcoxon rank-sum test for continuous variables, and Fisher exact test. All statistical analyses were conducted using R. A 2-sided P-value <0.05 was considered statistically significant. Forest plots were generated to visualize hazard ratios from multivariable Cox models across outcomes.

The bioethics committee of the Regional Chamber of Medicine approved this study (IRB approval No 209/2024/KB/IX), with a waiver of informed consent due to the retrospective nature of the analysis. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE, Supplemental Digital Content 1, http://links.lww.com/CNM/A604) checklist was used in the preparation of this manuscript.

RESULTS

Patient Characteristics

A total of 308 patients met the inclusion criteria from 2010, and after matching, 197 patients were retained in the study, with 77 staged by PSMA PET and 120 by conventional imaging. Initial cohort characteristics are available in Table S1 is Supplementary Materials, Supplemental Digital Content 1, http://links.lww.com/CNM/A604. A sub-analysis of the co-occurrence of the different imaging modalities is available in Figure S1, Supplemental Digital Content 1, http://links.lww.com/CNM/A604.

The matched-pair analysis confirmed successful alignment of baseline variables between the 2 imaging cohorts. The standardized mean differences for all matched covariates were below 0.1, indicating excellent balance (Figure S2, Supplemental Digital Content 1, http://links.lww.com/CNM/A604). After matching, no significant differences in patient or tumor characteristics remained between the PSMA PET and conventional staging groups (Table 1), eliminating the baseline imbalances observed in the unmatched cohort and creating comparable groups suitable for outcome analyses.

The majority of patients in both groups had high-risk disease, with ISUP grade group 3–5 tumors comprising 78% and 79% of the conventional imaging and PSMA PET groups, respectively (P=0.8). Tumor stage T3–T4, as determined by diagnostic imaging, was present in 58% versus 57% of patients (P >0.9), and PSA ≥20 ng/mL was observed in 62% versus 58% of patients (P=0.9) in the conventional imaging and PSMA PET groups, respectively.

Treatment characteristics were comparable between the conventional imaging and PSMA PET groups. In the conventional imaging group, nodal boost radiation therapy was administered to 65% of patients, long-term androgen deprivation therapy (≥24 mo) was used in 73%, and the median elective nodal EQD2 dose was 46 Gy. The median metastatic nodal EQD2 dose was 66 Gy, and multiple lymph node involvement (>1 node) was observed in 47% of cases. The median age was 68 years (IQR: 63–72).

In the PSMA PET group, nodal boost was delivered to 68% of patients, 71% received long-term androgen deprivation therapy, and the median elective nodal EQD2 dose was 46 Gy. The median metastatic nodal EQD2 dose was 63 Gy, and multiple lymph node involvement was present in 45% of patients. The median age was 70 years (IQR: 66–73).

Seminal vesicle invasion patterns, the distribution of involved lymph nodes, and metastatic node volumes on planning CT (median: 1.6 vs. 1.8 cm³, P=0.5) were also similar between groups. All differences were statistically nonsignificant.

Clinical Outcomes

With a median follow-up of 42 months (IQR: 25–59), oncologic outcomes were tracked for all 197 patients in the matched cohort. A total of 62 patients (31%) developed distant metastases, 17 (9%) experienced locoregional recurrence, and 38 (19%) died during the follow-up period. Kaplan-Meier analysis demonstrated no significant difference in MFS between the PSMA PET and conventional imaging cohorts (P=0.57). The 3-year MFS rate was 80.5% (95% CI: 71.3–90.8%) in the PSMA PET group versus 77.2% (95% CI: 69.5–85.8%) in the conventional imaging group. At 5 years, MFS rates remained comparable between groups, with 59.3% (95% CI: 42.9–82%) for PSMA PET versus 65.8% (95% CI: 56.5–76.7%) for conventional imaging (Fig. 1A).

FIGURE 1.

Kaplan-Meier curves for metastasis-free survival (A), overall survival (B), and locoregional control (C) according to staging method (PSMA PET vs. conventional imaging) in the propensity score-matched cohort.

OS showed no significant difference by staging modality (Fig. 1B). The estimated 3-year OS was 93.3% (95% CI: 87–99.9%) for patients staged with PSMA PET versus 90.4% (95% CI: 84.9–96.3%) for those with conventional imaging, not reaching statistical significance (log-rank P=0.72). Five-year OS rates were 82.2% (95% CI: 74.4–90.8%) for PSMA PET and 77.4% (95% CI: 64.4–93%) for conventional imaging (Fig. 1B).

Locoregional control (LRC) remained excellent in both groups. Only 17 patients (9% of the cohort) experienced a locoregional relapse. At 3 years, freedom from locoregional failure was 93% (95% CI: 87.2–99.1%) in the conventional imaging group and 94.4% (95% CI, 89.3–99.9%) in the PSMA PET arm. At 5 years, LRC rates were 90.5% (95% CI: 83.7–97.8%) for conventional imaging and 89.8% (95% CI: 81.7–98.6%) for PSMA PET. The 2 cohorts showed no significant difference in locoregional control (P=0.84) (Fig. 1C).

Nodal Boost Analysis

A dedicated analysis of nodal boost therapy was performed to evaluate its impact on oncologic outcomes per imaging modality. All patients received elective nodal irradiation encompassing the nodal volume up to the aortic bifurcation. Among the 197 patients, 130 (66%) received nodal boost to metastatic lymph nodes, whereas 67 (34%) received elective nodal irradiation without boost. A boost was delivered using the simultaneous integrated boost (SIB) technique. In patients staged with conventional imaging, those receiving nodal boost demonstrated inferior MFS compared with those without boost, with median MFS of 67.1 months versus 77.3 months in the no-boost group (P=0.026) as shown in Figure 2. However, in patients staged with PSMA PET, no statistical difference was present when comparing the nodal boost group versus the no-boost group (P=0.29) as shown in Figure 3.

FIGURE 2.

Kaplan-Meier curves for metastasis-free survival (MFS) in patients staged with conventional imaging, stratified by the use of nodal boost therapy.

FIGURE 3.

Kaplan-Meier curves for metastasis-free survival (MFS) in patients staged with prostate-specific membrane antigen positron emission tomography (PSMA PET), stratified by the use of nodal boost therapy.

Cox Regression Analysis

In multivariable Cox regression analysis for MFS, ISUP grade group 3–5 emerged as the strongest independent predictor of earlier metastasis (HR: 4.03, 95% CI: 1.61–10.06; P=0.003) (Table 2). Higher total EQD2 dose (≥113 Gy) was associated with improved MFS (HR: 0.53, 95% CI: 0.30–0.95; P=0.033) (Table 2). Notably, the imaging modality used for staging (PSMA PET versus conventional imaging) was not associated with any difference in MFS (HR: 0.85, 95% CI: 0.50–1.47; P=0.566) (Table 2). A secondary analysis was performed to identify the significant dose thresholds linked to MFS events, showing a significant impact of 50 Gy (HR: 2.04, 95% CI: 1.12–3.7, P=0.019) and 55 Gy (HR: 1.83, 95% CI: 1.03–3.24, P=0.038).

TABLE 2.

Univariate and Multivariate Cox Regression Analysis for Metastasis-Free Survival (MFS) in the Matched Cohort

Variable	Univariate HR (95% CI)	Univariate P	Multivariate HR (95% CI)	Multivariate P
ISUP grade group 3–5	3.94 (1.58–9.84)	0.003	4.03 (1.61–10.06)	0.003
T stage binary (T3–T4)	0.95 (0.57–1.57)	0.832	—	—
PSA group (10–20 ng/mL)	0.96 (0.48–1.93)	0.905	—	—
PSA group (≥20 ng/mL)	1.10 (0.49–2.45)	0.817	—	—
PET PSMA	0.85 (0.50–1.47)	0.566	—	—
Long-term ADT (≥24 mo)	0.66 (0.36–1.18)	0.158	—	—
LN count category (>1)	0.84 (0.51–1.39)	0.493	—	—
Nodal dose category (>60 Gy)	1.22 (0.74–2.03)	0.431	—	—
EQD2 ≥113 Gy prostate	0.55 (0.31–0.98)	0.042	0.53 (0.30–0.95)	0.033
Nodal volume category (>3cc)	1.08 (0.61–1.91)	0.794	—	—
Elective nodal dose (>44 Gy)	0.81 (0.48–1.35)	0.416	—	—

In the OS analysis, ISUP grade group 3–5 remained a significant independent predictor of worse outcome (HR: 4.40, 95% CI: 1.34–14.42; P=0.015) (Table 3). Long-term ADT (≥24 mo) was associated with improved survival (HR: 0.38, 95% CI: 0.19–0.78; P=0.009). However, staging with PSMA PET imaging had no significant impact on OS (HR: 0.88, 95% CI: 0.42–1.83; P=0.724) (Table 3).

TABLE 3.

Univariate and Multivariate Cox Regression Analysis for Overall Survival (OS) in the Matched Cohort

Variable	Univariate HR (95% CI)	Univariate P	Multivariate HR (95% CI)	Multivariate P
ISUP grade group 3–5	3.91 (1.20–12.73)	0.023	4.40 (1.34–14.42)	0.015
T stage binary (T3–T4)	0.83 (0.43–1.59)	0.567	—	—
PSA group (10–20 ng/mL)	1.07 (0.40–2.83)	0.897	—	—
PSA group (≥20 ng/mL)	1.42 (0.48–4.16)	0.522	—	—
PET PSMA	0.88 (0.42–1.83)	0.724	—	—
Long-term ADT (≥24 mo)	0.44 (0.22–0.89)	0.023	0.38 (0.19–0.78)	0.009
LN count category (>1)	0.69 (0.36–1.33)	0.267	—	—
Nodal dose category (>60 Gy)	1.06 (0.56–2.02)	0.852	—	—
High EQD2 (≥113 Gy)	0.59 (0.28–1.26)	0.175	—	—
Nodal volume category (>3cc)	0.84 (0.38–1.85)	0.668	—	—
Elective nodal dose (>44 Gy)	0.82 (0.43–1.57)	0.551	—	—

The Cox model for locoregional control identified advanced T stage (T3–T4) as the sole significant predictor of locoregional failure (HR: 0.34, 95% CI: 0.12–0.97; P=0.044) (Table 4). The choice of PSMA PET versus conventional imaging for staging showed no influence on LRC outcomes (HR: 1.11, 95% CI: 0.41–3.01; P=0.845) (Table 4).

TABLE 4.

Univariate Cox Regression Analysis for Locoregional Control (LRC) in the Matched Cohort

Variable	Univariate HR (95% CI)	Univariate P
ISUP grade group 3–5	1.02 (0.33–3.14)	0.968
T stage binary (T3–T4)	0.34 (0.12–0.97)	0.044
PSA group (10–20 ng/mL)	0.17 (0.02–1.54)	0.115
PSA group (≥20 ng/mL)	0.71 (0.23–2.25)	0.565
PET PSMA	1.11 (0.41–3.01)	0.845
Long-term ADT (≥24 mo)	0.45 (0.15–1.30)	0.139
LN count category (>1)	0.46 (0.16–1.32)	0.148
Nodal dose category (>60 Gy)	1.76 (0.65–4.77)	0.269
High EQD2 (≥113 Gy)	0.97 (0.36–2.62)	0.945
Nodal volume category (>3cc)	1.08 (0.35–3.35)	0.896
Elective nodal dose (>44 Gy)	0.96 (0.35–2.61)	0.941

Toxicity Data

Treatment-related toxicity was assessed in 308 patients (whole cohort) with complete toxicity data and is shown in Table 5. Overall, radiation therapy was well-tolerated with low rates of severe toxicity across all categories. Acute genitourinary toxicity up to grade 2 occurred in 129 patients (41.9%), whereas severe acute GU toxicity (≥G3) was rare, affecting only 1 patient (0.3%). Late GU toxicity up to grade 2 was observed in 69 patients (22.4%), with late severe GU toxicity occurring in 6 patients (1.9%). Acute gastrointestinal toxicity up to grade 2 developed in 45 patients (14.6%), with only 1 patient (0.3%) experiencing severe acute GI toxicity. Late GI toxicity up to grade 2 affected 36 patients (11.7%), whereas severe late GI toxicity was documented in 4 patients (1.3%).

TABLE 5.

Treatment-Related Genitourinary (GU) and Gastrointestinal (GI) Toxicity in the Whole Cohort and According to Use of Nodal Boost Therapy

Variable	N	Grade	Whole Group Count	Whole group %	Nodal Boost Count	Nodal Boost %	No Nodal Boost Count	No Nodal Boost %	P
Acute GU toxicity	308	Up to G2	129	41.90	85	43.60	44	38.90	0.473
		≥ G3	1	0.30	1	0.50	0	0.00	1
Late GU toxicity	308	Up to G2	69	22.40	42	21.50	27	23.90	0.672
		≥ G3	6	1.90	4	2.10	2	1.80	1
Acute GI toxicity	308	Up to G2	45	14.60	34	17.40	11	9.70	0.068
		≥ G3	1	0.30	0	0.00	1	0.90	0.367
Late GI toxicity	308	Up to G2	36	11.70	25	12.80	11	9.70	0.466
		≥ G3	4	1.30	1	0.50	3	2.70	0.142

When comparing patients who received nodal boost therapy versus those who received elective nodal irradiation without boost, no statistically significant differences in toxicity rates were observed across any category. Acute GU toxicity up to grade 2 occurred in 43.6% of nodal boost patients versus 38.9% of no-boost patients (P=0.473). Acute GI toxicity up to grade 2 showed a trend toward higher rates in the nodal boost group (17.4% vs. 9.7%, P=0.068), although this did not reach statistical significance. Late toxicity rates were similar between groups, with late GU toxicity up to grade 2 occurring in 21.5% of nodal boost patients versus 23.9% of no-boost patients (P=0.672), and late GI toxicity up to grade 2 in 12.8% versus 9.7%, respectively, (P=0.466).

DISCUSSION

In this multi-institutional cohort, survival outcomes were comparable irrespective of staging modality, whereas dose escalation to metastatic nodes did not provide a consistent benefit. These results indicate that the higher accuracy of PSMA PET did not translate into improved survival, and that nodal dose intensification may not be universally advantageous. Instead, established prognostic factors, such as ISUP grade group and prostate dose, remained the primary determinants of outcome.

With the increasing use of advanced diagnostic tests, particularly those utilizing PET PSMA, more patients are likely to receive a diagnosis of regional nodal metastasis.^21,22 Prospective randomized trials and a recent meta-analysis have demonstrated that PET PSMA offers superior sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in detecting lymph node and visceral metastases compared with conventional diagnostic methods.^21,23 In addition, the proPSMA study revealed that PET PSMA imaging provides a significant advantage over traditional imaging techniques (such as CT and bone scans), with a reduction in radiation exposure of 10-9 mSv.²¹

The benefit of advanced diagnostic imaging for improving treatment outcomes remains uncertain. Spatial heterogeneity among tumor clones leads to variable aggressiveness by anatomic location.^24,25 Selective pressures in the prostate drive expansion of more aggressive subclones,^26,27 whereas regional lymph node metastases are typically monoclonal and may be less aggressive.^28,29 Early micrometastatic lymph node lesions often have reduced proliferative and invasive capacity compared with the primary tumor.³⁰ Given that the tumor cells found in lymph nodes may exhibit lower aggressiveness, the standard radiation doses typically used in pelvic elective irradiation could be sufficient to control the disease, without the need to escalate the dose in these metastatic niches. However, this concept has been challenged recently, with the emergence of publications supporting dose intensification. Importantly, higher radiation doses to the pelvic bone marrow may contribute to radiation-induced lymphopenia, which has been associated with inferior clinical outcomes.³¹ Spatial differences in clonal behavior highlight the need to consider molecular characteristics of both primary and metastatic lesions for precise risk stratification and treatment planning.^32–34 It should be emphasized that our findings regarding worse MFS with dose escalation to metastatic nodes in conventionally staged patients may be influenced by chance, given the retrospective design and inherent limitations of comparative subgroup analyses. Therefore, these results should be interpreted with caution. The debate on the optimal radiation dose to metastatic nodes remains open, underscoring the need for further prospective studies to clarify the impact of dose escalation in different clinical and imaging contexts.

Previous multicenter analyses in this clinical context have demonstrated significantly higher 5-year prostate cancer-specific survival (PCSS) rates for patients staged with PET PSMA compared with those assessed with conventional imaging (95.1% vs. 76.9%; P=0.01), whereas there was no notable difference in 5-year progression-free survival (PFS) (63.8% vs. 63.4%; P=0.98).⁴ Similarly, Leow et al⁴ recently reported superior biochemical control and survival for PSMA-detected node-positive disease compared with conventional staging. Patients staged with conventional imaging presented with significantly higher baseline PSA levels (26 vs. 11 ng/mL) and higher-grade disease compared with the PSMA group.⁴ However, unlike our analysis, these previous studies did not use propensity score matching. The observed survival advantage may be largely driven by the “Will Rogers phenomenon” (stage migration) and selection bias rather than the imaging modality itself. Furthermore, the regional lymph nodes of metastatic patients were prescribed doses ranging from 46 to 54 Gy, which methodologically differs from our study, wherein doses up to 50 Gy were considered elective, permitting a more direct comparison of results.³⁵ As noted, we did not find improved outcomes regarding metastasis-free survival (MFS), overall survival (OS), and local recurrence control (LRC) when dose escalation beyond 60 Gy to metastatic lymph nodes was implemented. This may indicate that exceeding this dose level might be unnecessary in this particular scenario.

The total lymph node count, with a cutoff of one or more, and total metastatic lymph node volume categorized as lower or above 3 cm³, did not serve as predictive factors for outcome. However, no specific assessments of lymph node sizes or their volumes were conducted at distinct dosage levels.

Recent analysis by Martell et al³⁶ suggests that the volume of nodal metastases may play a significant role, with larger lymph nodes identified by PET PSMA potentially requiring higher doses to achieve 95% and 99% tumor control probability. In this regard, it is important to consider that lymph nodes visible on conventional imaging need to be larger to be detected, which may explain why the observed differences between PSMA PET-detected lymph nodes—which can often be identified at smaller sizes—did not yield variations in outcomes across staging modalities.

A retrospective analysis by Francolini et al indicated that dose escalation beyond 60 Gy to metastatic lymph nodes significantly improved biochemical relapse-free survival (bRFS) (HR=3.59, 95% CI: 1.3245–9.741, P=0.01); however, data concerning OS were not reported.¹⁴ Another study, which focused on bRFS and escalated doses to 60–66 Gy for metastatic lymph nodes, demonstrated a notable difference compared with standard elective nodal doses.³⁷ We opted not to utilize bRFS as an endpoint, aligning with prior evidence suggesting it is not a reliable surrogate for OS.¹⁹ In contrast, Tsuchida et al found that dose escalation to 60 Gy or more for metastatic lymph nodes significantly enhanced MFS, with 4-year MFS rates of 90.6% versus 82.1% and 7-year MFS rates of 90.6% versus 62.8% (P=0.023), although no significant differences in OS or cancer-specific survival (CSS) were observed.¹⁷ The non-randomized prospective Platin-2 study treated 40 patients with dose escalation to metastatic lymph nodes (61.2 Gy in 34 fractions, EQD2 of 57.12 with α/β=1.5), which is below our established threshold of EQD2 60 Gy. Notably, a median OS of 107 months was achieved, and initial staging with PET/CT correlated with a reduced risk of post-treatment progression—primarily systemic—when compared with conventional imaging modalities (P=0.04). However, only 10% of patients were staged using PET PSMA.¹⁷ Similar to our findings, the number of involved lymph nodes did not significantly predict treatment outcomes.³⁸ Yap and colleagues proposed a more aggressive strategy, implementing dose escalation to regional lymph nodes identified by PET PSMA, delivering 81 Gy in 45 fractions (EQD2 of 75.6 Gy). With a median follow-up of 60 months, the study reported OS and MFS rates of 91.5% and 95.8%, respectively.¹⁶ Future investigations should consider the specific volumes of lymph nodes and the tailored doses applied when evaluating the impact of exceeding 60 Gy on treatment outcomes.

Although upfront PSMA PET staging did not translate into improved MFS, OS, or LRC in this cohort, this finding should not be interpreted as a lack of clinical value of PSMA PET for initial staging. Robust prospective evidence, including the proPSMA trial,²¹ has consistently demonstrated the superior diagnostic accuracy of PSMA PET compared with conventional imaging, with clinically meaningful implications for stage migration and treatment selection. The present analysis addresses a distinct clinical question: namely, whether the choice of staging modality impacts long-term outcomes among patients ultimately selected for definitive radiotherapy and androgen deprivation therapy for clinically node-positive disease.

Within this real-world, multicenter cohort, once patients were managed with curative-intent cN1 treatment, the increased sensitivity of PSMA PET did not result in superior survival outcomes. Importantly, any earlier detection of distant metastases during follow-up due to the increased use of sensitive imaging would be expected to bias MFS against PSMA PET-staged patients (surveillance bias), rendering the observed absence of difference a conservative finding. Consequently, our results suggest that although PSMA PET remains essential for accurate staging and optimal treatment allocation, its diagnostic superiority does not necessarily translate into improved outcomes within a matched cN1 population treated with contemporary definitive radiotherapy and systemic therapy.

Limitations

Our study has several limitations. Its retrospective, multi-institutional design introduces selection bias and the possibility of residual confounding, even after propensity score matching. The modest sample size and low event rates limit statistical power, resulting in wide confidence intervals. Short median follow-up, due to recent PSMA PET adoption, restricts assessment of late outcomes. Stage migration from the higher sensitivity of PSMA PET may have led to reclassification of some patients, reducing observable benefits. In addition, follow-up imaging was not standardized across participating centers, which may introduce detection bias regarding the precise timing of metastatic events; however, this heterogeneity reflects the real-world nature of the study. Moreover, findings may not generalize to surgical patients or those receiving less intensive therapy. Finally, current SoC Abiraterone plus ADT in N+ patients as it improves MFS and OS, as shown in the STAMPEDE trial and recommended by current guidelines.(https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf) These issues underscore the need for adequately powered, prospective trials with longer follow-up to define the clinical utility of PSMA PET staging in node-positive prostate cancer.

CONCLUSIONS

The clinical outcome analysis indicates that upfront PSMA PET staging did not lead to statistically significant improvements in metastasis-free survival, overall survival, or locoregional recurrence-free survival when compared with conventional imaging. Although local dose escalation to regional metastatic lymph nodes above 60 Gy is deemed safe, it did not result in more favorable outcomes in terms of metastasis-free survival, overall survival, and locoregional recurrence-free survival for patients with clinically node-positive prostate cancer treated with androgen deprivation therapy and definitive external beam radiotherapy. These findings need further validation through longer follow-up periods and prospective trials with randomization.