The dose distribution in dominant intraprostatic tumour lesions defined by multiparametric MRI and PSMA PET/CT correlates with the outcome in patients treated with primary radiation therapy for prostate cancer

Prostate cancer (PCa) is known to be a multifocal disease [1]. Likewise, conventional external beam radiation therapy (EBRT) for patients with primary PCa aims at delivering a homogeneous dose to the entire prostatic gland. However, there is growing evidence that dominant intraprostatic lesions (DIL) within the gland may be responsible for metastatic and recurrent disease. Haffner et al. tracked the clonal origin in a patient who died of metastases from PCa and proved that all metastases arose from a single prostatic lesion [2]. Three studies examined whether the local recurrences of PCa after primary radiation therapy (RT) occur at the site of primary lesion using pre and post treatment magnetic resonance imaging (MRI) in a limited number of patients, respectively. All of them concluded that local recurrence after RT occurs mostly at the side of the primary tumour [3‐5]. However, our group and others performed comparison studies between MRI, prostate-specific membran antigen positron emission tomography/computed tomography (PSMA PET/CT) and PCa in surgery specimen. Sensitivities of 52–85% for MRI [6] and 64–75% for PSMA PET/CT [7‐9] were reported, suggesting, that not the entire PCa amount is identified by these techniques mainly because of non-detectable microscopic lesions.

A dose-response relationship between RT dose to the entire prostatic gland and PCa control rates has been reported. A meta-analysis demonstrated, that the total RT dose on the prostatic gland reduces the risk of biochemical failure in patients with primary PCa by approximately 1.8% for each 1-Gray (Gy) increase [10]. Martinez et al. reported a significant decrease in biochemical failures when a biological equivalent dose BED_{α/β = 1.2 Gy} > 268 Gy was delivered to the prostate by a combination of EBRT and high-dose rate brachytherapy [11]. There is limited evidence [12] if the RT dose delivered to the imaging defined PCa has an impact on the tumour control.

In this analysis we hypothesized that the DIL could be depictured by multimodal imaging techniques: multiparametric MRI (mpMRI) and/or PSMA PET/CT. Likewise, we tested whether the RT doses delivered to the DILs may influence the patients’ outcome.

Several studies proposed the existence of a DIL as a driver of the metastatic and recurrent PCa post EBRT and concepts to detect and escalate RT dose to the DIL are under investigation [19, 20]. In this retrospective analysis we hypothesized that PSMA PET/CT and mpMRI are appropriate to localize the DIL (DIL-imaging) and that consequently, the dose parameters for DIL-imaging should correlate with the outcome in patients with PCa after EBRT. Our patients underwent conventional EBRT which aims at delivering a homogeneous dose to the entire prostatic gland without considering the localization of DIL-imaging. This explains why no significant differences between the Dmean values for all three volumes were observed and why Dmax was located only in 8% of the patients in DIL-imaging in in our study.

Dmin (cut-off: 70.6 Gy) in DIL-imaging influenced BRFS in multivariate analysis, whereas Dmin (range: 70–75.2 Gy) in PG and SPG had no impact on BRFS. Furthermore, median Dmin in DIL-imaging was significantly lower in patients with BR than in patients without BR. These findings support the theory of DIL since only an under dosage of clinically significant areas may lead to BR, whereas lower doses in non-DIL tissue had no impact on BRFS. Multivariate Cox regression showed a significant influence of Dmax within all three considered volumes for BRFS. The influence of Dmax in DIL-imaging may be explained by an increased killing of radio resistant PCa cells which may comprise tumour initiating features [21] or by possibly enhanced activation of the immune system [22]. The influence of Dmax in non-DIL-imaging tissue may be explained by the very high correlation between Dmax values in all three volumes. Furthermore, 92% of the patients with Dmin ≥70.6 Gy in DIL-imaging also had a Dmax ≥76 Gy in SPG.

In our study the binarized Dmean values (range: 73.5–77.3 Gy) in the respective three volumes had no significant impact on BRFS. However, several studies proved that the RT dose delivered on the entire prostatic gland has an impact on BRFS after primary EBRT for PCa [23, 24]. It should be mentioned, that no separate analysis of the dose distribution within DIL-imaging was performed in these studies. In our collective high correlations (rho> 0.7, p < 0.01) between Dmean values in PG and Dmax/Dmin values within DIL-imaging were calculated. What appears to be a significant influence of Dmean and Dmax in SPG/PG might therefore again be proof of the significance of Dmin and Dmax in DIL-imaging on BRFS.

Surely our observations need validation by future studies including more patients, longer follow-up and more dose parameters (e.g. D2%, D98% or Dmedian) for their analyses. However, our data provide evidence, that the delineation of the intraprostatic tumour using PSMA PET and mpMRI information should be performed routinely prior to RT of PCa in order to avoid under dosage and to possibly escalate the RT dose in these areas. Since there is no evidence of how to define patient populations in which one of the two imaging modalities performs better, the DIL-definition should preferably be performed based on combined PSMA PET and mpMRI information. Future work may also address which RT doses should be given to SPG since it still remains unclear if a dose ≥76 Gy on SPG is really needed in all patients. Keeping in mind that not the entire intraprostatic PCa amount is visible on mpMRI and PSMA PET dose de-escalation may possibly increase the risk for BR. On the other hand previous analyses [3‐5] and this study showed that local recurrent disease after EBRT mostly occurred at the side of the primary tumour. Furthermore, our study indicated that the RT dose within the imaging defined DIL may be more crucial for the outcome after EBRT than the dose applied to SPG. To address this important question, RT planning studies should simulate de-escalation strategies while considering the dose distribution within the co-registered histological information [20].

This retrospective study has several limitations. The treatment protocols (e.g. ADT duration, RT technique) and the follow-up procedure are not identical for all patients. Thus, our results need validation, preferably by a prospective trial. A further shortcoming is the relatively short period of follow-up. Persistent testosterone suppression after adjuvant ADT might have an impact on PSA levels [25]. However, the median ADT duration in our cohort was 7 months. A longer follow-up would also enable the evaluation of other relevant endpoints like PCa-specific survival or overall survival. Eiber et al. [8] and our group [7] published on comparing mpMRI and PSMA PET/CT with histopathology after prostatectomy, both reporting a good sensitivity and specificity for mpMRI and PSMA PET/C, individually. However, the combined usage of both modalities achieved the highest sensitivity, indicating that they may offer complementary information. Most of the patients in our cohort (74%) had mpMRI only, thus an underestimation of the total PCa amount may have occured. On the other hand, several studies postulated that even if mpMRI may not detect the entire PCa tissue, it is able to detect a clinically sufficient amount of the tumour [26, 27]. For this study we supposed that mpMRI and PSMA PET/CT are equivalent in DIL-definition and we did not analyse them separately.

Another issue of this study is the uncertainty in registration of PET/CT, mpMRI and planning CT images (e.g. due different rectum and bladder fillings during imaging). To minimize geometrical errors we used automatic 3D matching tools and performed a manual re-adjustment if necessary. The insertion of intraprostatic fiducial markers visible in MRI and CT images would facilitate this process by enabling landmark based registration techniques. In this study the implantation of intraprostatic fiducial markers (94% of the patients) was performed 2–3 weeks before the planning CT and mostly after the MRI and PET scans. However, using daily image-guidance based on the markers we accounted for inter-fractional movement. Nevertheless, we were not able to account for intra-fractional movement and possible shifts of the target regions during RT. By implementing real-time tracking systems [28] or by using brachytherapy [29, 30] possible strategies to solve this problem have already been proposed.

This study showed that the dose distribution within DILs defined by mpMRI and/or PSMA PET imaging are independent risk factors for biochemical failure after primary EBRT in patients with PCa. These findings support the implementation of modern imaging for DIL detection and may be considered in RT treatment planning to avoid an under dosage or to escalate the RT dose in these areas. Further validation in larger patient cohorts with longer follow-up should be warranted.