Impact of non-regional lymph node metastases accurately revealed on ¹⁸F-PSMA-1007 PET/CT in the clinical management of metastatic hormone-sensitive prostate cancer

Prostate cancer (PCa) is the second most common cancer in men worldwide, and approximately 68% of primary patients present with metastatic hormone-sensitive PCa (mHSPC) in China [1, 2]. Androgen deprivation therapy (ADT) is the mainstay therapy for primary mHSPC, while the durability of response to ADT and time to castration resistance is variable owing to the significant heterogeneity of mHSPC [3‐5]. In the past few years, the treatment paradigm of mHSPC has tremendously changed, and docetaxel, abiraterone and enzalutamide have been sequentially approved as first-line treatment options for primary mHSPC [6].

As proposed in the CHAARTED trials, the localization and number of metastases are widely used to categorize mHSPC into low- or high-volume disease for risk stratification and treatment selection purposes [7]. As we all know, the common sites of metastasis from PCa, in order of decreasing frequency, are the bone (84%), distant lymph nodes (10.6%), liver (10.2%) and thorax (9.1%) [8]. However, this classification only focused on the status of bone and visceral metastases and did not include non-regional lymph node (NRLN) metastases. Emerging evidence suggests that NRLN metastases is an important prognostic factor for mHSPC, especially concomitant with bone metastases [9, 10]. Furthermore, a study conducted by Shiota et al. showed that NRLN metastases were associated with worse progression-free survival (PFS) than bone metastases, especially in patients with low-volume diseases [11]. Thus, in addition to bone or visceral metastases, NRLN metastases should be included as another risk factor to classify low- or high-volume disease, but the clinical application value of NRLN metastases is limited by its detection rate, which is as low as 9–12% [12, 13].

Currently, conventional imaging (CI) modalities, including computerized tomography (CT) or magnetic resonance imaging (MRI), are recommended to evaluate metastatic spread to lymph nodes, and morphological changes in lymph nodes are the main diagnostic criterion [14, 15]. However, morphologic changes frequently lag behind functional changes, making it difficult for CI to identify small metastatic lesions and distinguish metastases from inflammation, which leads to the low sensitivity and specificity of CI in detecting NRLN metastases [16]. Prostate-specific membrane antigen (PSMA) is expressed on PCa cells and often shows marked overexpression in metastatic PCa tissue [17, 18]. Therefore, PSMA PET/CT may be a more promising technique for accurately detecting NRLN metastases than CI. Furthermore, the definition of low- and high-volume disease in the CHAARETED trial was based upon CI, and studies exploring the concordance rates between PSMA PET/CT and CI in terms of tumor volume evaluation are limited. To address this void, we analyzed a consecutive cohort of patients with primary mHSPC who received PSMA PET/CT or CI before initial treatment. We hypothesized that PSMA PET/CT could detect more NRLN metastases, which might affect tumor volume evaluation and treatment selection.

Tumor volume is a critical factor for treatment decision-making in primary mHSPC. In addition to bone and visceral metastases, NRLN metastases may be an important additional factor for distinguishing between low- and high-volume diseases. In the current study, we focused on the cohort of primary mHSPC and found that the concordance rates of ¹⁸F-PSMA-1007 PET/CT and CI in detecting bone and visceral metastases were 82.83% and 86.87%, respectively, while the concordance rate in detecting NRLN metastases was only 61.62%. Among 94 patients without NRLN metastases on CI, NRLN metastases were detected by ¹⁸F-PSMA-1007 PET/CT in 37 patients (39.4%). Thus, we deduced that ¹⁸F-PSMA-1007 PET/CT had a higher sensitivity and specificity in detecting NRLN metastases than CI, which provided new insight into the clinical management of mHSPC.

Recently, PSMA PET/CT has shown increasing importance in the comprehensive management of PCa, including presurgical staging [22], biochemical recurrence prediction [23], and lymph node metastasis detection [24]. The diagnosis of lymph node metastases on CI mainly depends on the morphological size. However, the majority of metastatic nodes from PCa are < 8 mm [25], which does not satisfy the CI morphological size of lymph node metastases. Thus, tiny lymph node metastases of < 8 mm were inevitably missed by CI. Several studies have demonstrated that ⁶⁸Ga-PSMA-11 PET/CT can provide a pattern of metastatic spread of lymph node metastases with higher sensitivity and specificity than CI and detect more NRLN metastases [26, 27]. Furthermore, a study conducted by Lenis et al. noted that the non-concordance rate between CI and ⁶⁸Ga-PSMA-11 PET/CT was nearly 30%, and ⁶⁸Ga-PSMA-11 PET/CT identified 20% of pelvic nodal disease and up to 10% of distant metastatic disease that was negative on CI [28]. To the best of our knowledge, this is the first study to evaluate the concordance rates between ¹⁸F-PSMA-1007 PET/CT and CI in terms of tumor volume evaluation and TNM classification. In the subset of patients who received ¹⁸F-PSMA-1007 PET/CT and CI before initial treatment, we found that ¹⁸F-PSMA-1007 PET/CT could detect more bone and visceral metastases that were negative on CI, but the effects of these additional findings on tumor volume evaluation were limited, as the concordance rate of tumor volume evaluation was 90.91%, and only 9 patients upgraded from low-volume to high-volume disease. Furthermore, Barbato et al. also noted that PSMA-PET criteria with volume quantification deliver comparable with CHAARTED criteria, with only 13% misalignment [29]. However, ¹⁸F-PSMA-1007 PET/CT detected an additional 37 of 94 (39.4%) patients with positive NRLNs who were negative on CI. Among 94 patients without NRLN metastases on CI, the median PFS of 37 patients with NRLN metastases on ¹⁸F-PSMA-1007 PET/CT was 18.0 months, which was significantly shorter than that of patients without NLRN metastases both on CI and ¹⁸F-PSMA-1007 PET/CT (18.0 vs. 25.0 months, P = 0.01) (Additional file 1: Fig. S1). In addition, 55 patients (58.5%) had diseases progression during the period of follow-up. Univariate Cox regression revealed that primary treatment modality, NRLN metastases detected by ¹⁸F-PSMA-1007 PET/CT were associated with PFS (Additional file 2: Table S1). Subsequently, the multivariate Cox analysis including all the above two variables suggested that ADT, NRLN metastases detected by ¹⁸F-PSMA-1007 PET/CT were also associated with worse PFS (all P < 0.05).

Furthermore, among 224 patients with primary mHSPC, we also found that NRLN metastases was an independent prognostic factor, and the progression risk of disease increased by twofold in patients with NLRN metastases. Ali et al. identified 17,167 patients who were diagnosed with mHSPC in the Surveillance, Epidemiology, and End Results database and noted that patients with bone and NRLN metastases had a significantly higher risk of all-cause mortality and prostate cancer-specific mortality [13]. Recently, Heesterman et al. also found that the presence of concomitant NRLNs and bone metastases was a poor prognostic sign, especially in patients with low-volume mHSPC [12]. Subsequently, a study also demonstrated that increased metastatic burden of 5 or more nodal metastases was associated with worse outcomes in patients with mHSPC either treated with ADT combined with docetaxel or ADT alone [30]. Moreover, our study further identified a special population with low-volume disease but with NRLN metastases. The PFS of these patients was 19.5 months, which was similar to that of high-volume disease but significantly shorter than that of patients with low-volume disease without NRLN metastases. This phenomenon warned that NRLN metastases, especially synchronous with bone metastases, should be considered a high-risk feature with metastatic volume stratification definitions to improve the accuracy of disease volume-based treatment decisions.

The management of NRLN metastases remains a challenge for urologists, and metastatic volume evaluation might be helpful. Tumor volume classification, as proposed in the CHAARTED trials, is universally accepted for use in clinical practice or clinical trial conduct. For primary mHSPC synchronous with NRLN metastases, several studies have shown that local treatment combined with systemic therapy could improve the prognosis compared with systemic therapy alone [31]. However, we should pay more attention to interpreting these results, as the potential benefit of local treatment depends largely on the characteristics of the primary tumor and the number of suspicious nodes [32]. Prospective data from arm H of the STAMPEDE trial showed that the survival benefit of prostate radiotherapy decreased continuously as the number of bone metastases increased, with the benefit most pronounced with up to three bone metastases [33]. Furthermore, they also noted that the magnitude of benefit from the addition of prostate radiation therapy was greater in patients with only NRLN metastases, which indicated that only patients with very low metastatic burden (only NRLN metastases) or oligometastatic status (three or fewer bone metastases without visceral metastasis) might benefit more from local treatment. Previously, the CHAARTED trial showed that docetaxel could improve the prognosis for mHSPC patients with high-volume disease, but the benefit of docetaxel was not observed for patients with low-volume disease [7]. As mentioned above, coexisting NRLNs and bone metastases represented a high metastatic burden, even in patients with low-volume disease. Recently, the 2023 EAU guidelines recommended that all men with mHSPC should receive intensified ADT + androgen receptor signaling inhibitors (ARSI) or triple therapy (ADT + ARSI + docetaxel) [15]. However, the most suitable population for triple therapy is still unknown, and multi-drug combination therapy might result in more toxicity events. Thus, ADT combined with docetaxel or ARSI was still first-line treatment option for patients with primary mHSPC in clinical practice. Previously, several studies demonstrated that ADT combined docetaxel could improve the prognosis for mHSPC patients with high-volume disease, but the benefit of docetaxel was not observed for patients with low-volume disease. In the present study, we found that patients with low-volume plus NRLN metastases had a poor prognosis and could benefit more from docetaxel than ADT alone. Herein, we suggested that the metastatic burden of patients with low-volume plus NRLN metastases was remarkably higher than that of patients with low-volume without NRLN metastases but similar to that of patients with high-volume disease, and early intensive treatments, such as docetaxel, should be performed for these patients.

Despite these positive results in this real-world retrospective study, there also had several limitations. First, the retrospective nature of the present study and the small sample size from a single center might cause selection bias. Second, a part of patients only received CI examination, might indicate insufficient metastatic screening and tumor volume evaluation. Moreover, due to the short follow-up time, the impact of NRLN metastases on overall survival was not analyzed, and a longer follow-up duration might produce more positive findings. Lastly, only less of half the patients in our study had both received ¹⁸F-PSMA-1007 PET/CT and CI before treatment and there was no standard of reference for the assessment of diagnostic performance in our study. Hence, further prospective multicenter studies are needed to support our findings.

In the present study, we found that the concordance rates between ¹⁸F-PSMA-1007 PET/CT and CI in terms of tumor volume evaluation were comparable. However, the concordance rate between ¹⁸F-PSMA-1007 PET/CT and CI in detecting NRLN metastases was very low, as ¹⁸F-PSMA-1007 PET/CT could reveal more NRLN metastases, which was an important prognostic factor for primary mHSPC. Furthermore, in patients with low-volume disease, the presence of concomitant NRLN metastases is a poor prognostic sign compared to patients without NRLN metastases, and more intensive treatment, such as early docetaxel chemotherapy, may be more suitable for these patients.