SRT is the last curative option for patients with recurrent or persistent PCa after surgery, but heterogeneous responses demonstrate the need for improved and differentiated risk stratification and subsequently appropriate adaptions in disease management. Whilst implementation of PSMA-PET led to relevant improvements in disease localization, with results of prospective trials pending it is not yet clear whether the sole spatial information of tumor burden and the accompanying changes in treatment management have a relevant impact on progression rates. Considering that PSMA-PET positive findings might only represent the "tip of the iceberg" the additional biological information provided by this molecular imaging bears great potential. To our knowledge, this is the first large multicenter retrospective study to evaluate the potential of SUVmax values in PSMA-PET as a new biomarker in patients with PCa persistence/recurrence. The findings from this study suggest that SUVmax values may significantly contribute to identify patients who are at higher risk for progression after sRT and therefore might benefit from treatment intensification, guiding personalized treatment approaches.
In contrary to prospective trials investigating sRT, most of the patients included in our study are likely to be at advanced recurrent disease stages with 70% having a PSA ³ 0.5ng/ml prior to sRT and 59% having nodal recurrence. Therefore, the comparison with data of recently published randomized controlled trials 25-27 is limited. Nevertheless, sRT in fossa-confined patients yielded BRFS in 71% after 4 years. Considering slightly different definitions of endpoints these results are comparable to freedom from biochemical failure in approximately 50%-70% for patients with a pre-sRT PSA between 0.2 and 2.0 ng/ml in a large retrospective study of conventionally staged patients 5,28. BRFS rates for patients with node-positive PSMA-PET findings dropped dramatically to 42% after 4 years, which is in line with findings from a prospective trial, reporting 3-year BRFS rates of 45% with PSMA-PET-positive disease outside the prostatic fossa 29. Our results thereby confirm, that PSMA-PET findings are highly prognostic for BRFS.
In our retrospective analysis presence of PSMA-PET positive local and nodal recurrence positive on PSMA-PET were prognosticators for BRFS after sRT, whereas classical pathological and clinical parameters were not. Since Emmet et al. prospectively demonstrated the prognostic value of PET-positive findings, it is likely that they dominate established parameters in our cohort, since we included only patients with PSMA-PET positive lesions. The improved BRFS associated with the presence of LR (HR 0.5, p=0.016) is explainable by the dose escalation of PET-positive LRs yielding sufficient RT dose coverage, which was previously reported to beneficial 10. Despite favorable outcomes, still nearly one third of patients suffered from progression after sRT. In multivariate analysis our results demonstrate a significant association of SUVmax ³ 75% quartile (HR 2.3, p=0.022) with unfavorable BRFS in this subgroup.
Sensitivity analysis confirmed these results with a HR of 3.9 in patients with LR only and FU of >12 months. These findings are in line with the biological understanding of PSMA, with high PSMA-expression being associated with more aggressive disease 30 and SUVmax correlating with PSMA-expression 31. Therefore, patients with LR and high SUVmax values might represent a subgroup with more aggressive PCa, potentially suffering from micro metastases outside the prostatic bed at the time of imaging and therefore benefiting from intensified treatments. Cox-regression and ROC analysis furthermore suggest, that SUVmax in LR might be a valuable prognosticator in patients with both, LRs and NR. However, these results need to be interpreted carefully, since ADT is administered more often and for a longer period of time in patients with NR (44% in our cohort).
Whether extraction of additional radiomic features from PSMA-PET images enables identification of additional prognosticators 32 needs to be evaluated in future studies. However, implementation of SUVmax offers great potential in this scenario, since it is easily and non-invasively determinable with minimal resources and without additional costs and is not affected by interobserver variability 33. AUC values of the time-dependent ROC analysis showed the best discrimination in patients with >12 months FU and LR only. In an exploratory analysis, we calculated SUVmax cut-off value for optimal discrimination. In all patients, the optimized cut-off value was slightly lower than the 75% quartile (11.8 g/ml vs 12.8 g/ml). In the subgroup with FU > 12 months the cut-off value was, however, more similar (13 g/ml). Thus, a SUVmax threshold of approximately 13.0 g/ml should be validated in future studies in PSMA-PET imaging. This being said, the role of SUVmax in these patient subgroups needs to be evaluated in future studies including new tracers to validate putative cut-off values and design studies, which evaluate treatment intensification such as extension of RT fields to elective nodes or intensified systemic treatments. To define optimal RT fields, patterns of metastases need to be vigorously analyzed. Intensification of systemic treatments in sRT is currently investigated by the FORMULA-059 RCT (NCT03141671). Keeping in mind that sRT should be initiated at low PSA levels, implementation of SUVmax into risk stratification might even be relevant in this scenario, with approximately 50% and 65% of patients having PET-positive findings at PSA values <0.2ng/ml and between 0.2 - 0.5 ng/ml 29. Furthermore, administration of ADT was associated with favorable BRFS in the entire cohort in univariate analysis, but not in multivariate analysis. Additionally ADT was not associated with BRFS in patients with LR only. This suggests, that these patients might rather benefit from local than from systemic treatment intensification.
Interestingly presence of NR was associated with significantly unfavorable BRFS (HR 2.1) but not SUVmax values in NR, suggesting that the additional biologic information provided by SUVmax values do not contribute to this patient subgroup, who already suffer from relevantly poorer prognosis. These patients might benefit from systemic treatment intensification, since despite dose escalation to PET positive nodes, it is likely that sRT might not cover non-visible tumor spread.
Our study has some limitations. First, due to its retrospective design, protocols for PSMA-PET scans, sRT and follow-up varied between centers and are prone to selection bias. Since the tracer kinetics depends on the time between injection and image acquisition we want to point out that all scans were acquired in line with recent guidelines in all centers, but use of different PET scanners might affect comparability. Second, no central review of PET images was performed with potential differences in interpretation between centers. Third, the median FU is relatively short with a median FU of 24 months. Lastly pathological data from RP was missing in up to 27% of patients, likely contributing to inferior Cox-regression results.