Molecular Imaging and PET-Guided Dose Escalation Revolutionize Salvage Radiotherapy: Insights from EMPIRE-1 and EMPIRE-2

Introduction: The Evolution of Postprostatectomy Management

Biochemical recurrence (BCR) after radical prostatectomy remains a significant clinical challenge, affecting approximately 30% to 40% of patients. For these individuals, salvage radiotherapy (SRT) offers a potential for cure. Historically, SRT was administered based on conventional imaging—computed tomography (CT) and bone scans—which frequently failed to detect the exact site of recurrence at low prostate-specific antigen (PSA) levels. This often led to ‘blind’ treatment of the prostate bed, potentially missing extra-prostatic disease or under-treating localized foci. The EMPIRE (Enlarging the Molecular Imaging Role in Prostate Radiation Therapy) trials, led by researchers at Emory University, have fundamentally shifted this paradigm by demonstrating the clinical utility of molecular imaging in guiding treatment decisions and dose escalation.

EMPIRE-1: Establishing the Value of Molecular Imaging

Study Rationale and Design

EMPIRE-1 was a landmark phase 2/3 randomized controlled trial designed to determine whether [18F]-fluciclovine PET/CT could improve cancer control compared to conventional imaging alone. The study enrolled 165 patients with detectable PSA after prostatectomy and negative conventional imaging. Participants were randomized to either radiotherapy guided by conventional imaging (the control group) or radiotherapy guided by conventional imaging plus [18F]-fluciclovine PET/CT.

A unique aspect of EMPIRE-1 was the rigid adherence to PET findings. In the PET group, the imaging results were used not only to decide whether to proceed with radiotherapy but also to delineate the target volumes. If PET showed disease outside the standard radiation fields, the treatment plan was adjusted accordingly.

Key Findings of EMPIRE-1

The primary endpoint was 3-year event-free survival (EFS), defined as the absence of biochemical or clinical recurrence, or the initiation of systemic therapy. The results, published in The Lancet, were transformative:

• The 3-year EFS was 75.5% in the [18F]-fluciclovine PET group compared to 63.0% in the conventional imaging group (p=0.0028).
• The integration of PET imaging provided a significant absolute improvement of 12.5% in 3-year EFS.
• Toxicity profiles were similar between the two groups, confirming that more precise, PET-guided targeting did not increase the burden of adverse effects such as urinary frequency or diarrhea.

EMPIRE-1 provided the first level-1 evidence that molecular imaging-guided SRT improves oncological outcomes, setting the stage for more advanced applications of PET technology.

EMPIRE-2: Pushing the Boundaries with Dose Escalation and PSMA-PET

The Shift to Dose Escalation

Building on the success of EMPIRE-1, the EMPIRE-2 trial sought to answer two critical questions: First, can dose escalation to PET-positive sites further improve outcomes? Second, how does the newer [68Ga]-PSMA-11 tracer compare to [18F]-fluciclovine?

While [18F]-fluciclovine targets increased amino acid transport in cancer cells, [68Ga]-PSMA-11 targets the prostate-specific membrane antigen, which is highly overexpressed in most prostate cancers. EMPIRE-2 randomized 140 patients to receive SRT guided by either [18F]-fluciclovine or [68Ga]-PSMA-11. Crucially, both arms employed dose escalation to PET-detected sites, with doses up to 76.0 Gy to the prostate bed and 56.0 Gy to pelvic nodes.

Results and Comparative Efficacy

The primary endpoint of EMPIRE-2 compared the 2-year EFS of the new cohort against the fluciclovine arm from EMPIRE-1 (which did not receive dose escalation). The results showed a clear benefit for the escalated approach:

• The overall 2-year EFS for EMPIRE-2 was 87%, significantly higher than the 80% observed in the EMPIRE-1 comparison cohort (p=0.01).
• After propensity score weighting to ensure a fair comparison, the EFS remained superior (84% vs 73%, p=0.01).
• When comparing the two tracers within EMPIRE-2, the 2-year EFS was nearly identical: 87% for [18F]-fluciclovine and 88% for [68Ga]-PSMA-11 (p > 0.9).

These findings suggest that while the choice of tracer (PSMA vs. Fluciclovine) may not drastically alter short-term EFS when used for dose escalation, the act of intensifying the radiation dose based on molecular localization is a powerful driver of improved survival.

Comparative Analysis: Fluciclovine vs. PSMA-11

The equivalence of [18F]-fluciclovine and [68Ga]-PSMA-11 in the context of EMPIRE-2 is a subject of significant clinical interest. PSMA-PET is widely regarded as having higher sensitivity and specificity, particularly at very low PSA levels (<0.5 ng/mL). However, EMPIRE-2 indicates that both tracers are highly effective at identifying targets for salvage therapy.

Clinicians might choose one over the other based on availability, patient-specific factors (such as the presence of PSMA-negative disease), or institutional expertise. The EMPIRE trials emphasize that the value of the ‘map’ provided by PET is maximized when the ‘intervention’ (radiotherapy) is intensified at the identified hotspots.

Clinical Implications and Expert Commentary

The transition from EMPIRE-1 to EMPIRE-2 represents a logical progression in precision oncology. EMPIRE-1 proved that seeing the disease matters; EMPIRE-2 proved that hitting the visible disease harder matters even more.

Expert consensus suggests that molecular imaging should now be considered the standard of care for planning salvage radiotherapy. The ability to escalate the dose to 76 Gy in the prostate bed based on PET uptake allows for better local control without necessarily increasing the radiation dose to the surrounding healthy tissues (rectum and bladder), provided that modern techniques like Intensity-Modulated Radiation Therapy (IMRT) are used.

However, limitations remain. Both trials were conducted at a single high-volume center (Emory University), which may affect generalizability. Furthermore, while 2-year and 3-year EFS are strong intermediate endpoints, long-term data on metastasis-free survival and overall survival are still needed to fully confirm the curative potential of these strategies.

Conclusion: A New Standard for Salvage Radiotherapy

The EMPIRE-1 and EMPIRE-2 trials provide a robust evidentiary framework for the integration of molecular imaging into the management of recurrent prostate cancer. By moving away from standardized ‘one-size-fits-all’ radiation fields and toward personalized, PET-guided plans, clinicians can significantly improve the chances of achieving long-term biochemical control. The evidence strongly supports the use of PET imaging for target delineation and justifies the use of dose escalation to PET-positive sites in the prostate bed and pelvis.

Funding and Clinical Trial Information

EMPIRE-1 was registered under NCT01666808 and funded by the National Institutes of Health (NIH), Blue Earth Diagnostics, and the Winship Cancer Institute. EMPIRE-2 was registered under NCT03762759 (and related protocols) and continues the investigation into optimized molecular imaging applications in radiation oncology.

References

1. Jani AB, et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial. Lancet. 2021 May 22;397(10288):1895-1904.

2. Jani AB, et al. [18F]-Fluciclovine or [68Ga]-PSMA-11 Molecular Imaging To Guide Dose Escalation of Salvage Radiotherapy After Radical Prostatectomy for Prostate Cancer: The EMPIRE-2 Trial. Eur Urol. 2025 Dec 17:S0302-2838(25)04857-2.