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Variability of radiotherapy volume delineation: PSMA PET/MRI and MRI based clinical target volume and lymph node target volume for high-risk prostate cancer

Variability of radiotherapy volume delineation: PSMA PET/MRI and MRI based clinical target volume... Purpose: A comparative retrospective study to assess the impact of PSMA Ligand PET/MRI ([68 Ga]‑ Ga‑PSMA‑11 and [18F]‑F‑PSMA‑1007 PET/MRI) as a new method of target delineation compared to conventional imaging on whole ‑ pelvis radiotherapy for high‑risk prostate cancer (PCa). Patients and methods: Forty‑nine patients with primary high‑risk PCa completed the whole ‑pelvis radiotherapy plan based on PSMA PET/MRI and MRI. The primary endpoint compared the size and overlap of clinical target volume (CTV ) and nodal gross tumour volume (GTVn) based on PSMA PET/MRI and MRI. The diagnostic performance of two methods for pelvic lymph node metastasis (PLNM) was evaluated. Results: In the radiotherapy planning for high‑risk PCa patients, there was a significant correlation between MRI‑ CTV and PET/MRI‑ CTV (P = 0.005), as well as between MRI‑ GTVn and PET/MRI‑ GTVn (P < 0.001). There are non‑significant differences in the CTV and GTVn based on MRI and PET/MRI images (P = 0.660, P = 0.650, respectively). The conformity index (CI), lesion coverage factor (LCF) and Dice similarity coefficient (DSC) of CTVs were 0.999, 0.953 and 0.954. The CI, LCF and DSC of GTVns were 0.927, 0.284, and 0.32. Based on pathological lymph node analysis of 463 lymph nodes from 37 patients, the sensitivity, specificity of PET/MRI in the diagnosis of PLNM were 77.78% and 99.76%, respectively, which were higher than those of MRI (P = 0.011). Eight high‑risk PCa patients who finished PSMA PET/MRI changed their N or M stage. Conclusion: The CTV delineated based on PET/MRI and MRI differ little. The GTVn delineated based on PET/MRI encompasses metastatic pelvic lymph nodes more accurately than MRI and avoids covering pelvic lymph nodes with‑ out metastasis. We emphasize the utility of PET/MRI fusion images in GTVn delineation in whole pelvic radiotherapy for PCa. The use of PSMA PET/MRI aids in the realization of more individual and precise radiotherapy for PCa. Keywords: Prostate cancer, PET/MRI, PSMA, Radiotherapy, CTV, GTVn Introduction Prostate cancer (PCa) is a common malignancy in men, Lin‑Lin Liu and Lei‑Lei Zhu contributed equally to this work. accounting for 27% (233,000) of cancer incidence in the *Correspondence: 446720864@qq.com; xiangzuolinmd@hotmail.com United States [1]. In recent years, the incidence of pros- Department of Radiation Oncology, Shanghai East Hospital, School tate cancer in China has significantly increased, seriously of Medicine, Tongji University, Shanghai 200120, China affecting men’s health; the most common pathologi - Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China cal type of PCa is adenocarcinoma [2]. Lymphatic and Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Cancer Imaging (2023) 23:1 Page 2 of 12 haematogenous metastasis are the two common meta- MRI in diagnosing prostate cancer [14–18]. PET/MRI static pathways of prostate cancer, and the metastasis of combines the advantages of PET and MRI, providing pelvic lymph nodes (PLN) is strongly associated with the anatomical images in a single imaging session, detailed prognosis of prostate cancer [3]. functional and cellular metabolism and other molecular PCa cases are stratified into low/intermediate-risk and information of the lesion, while the anatomical structure high-risk groups according to the definition of the Euro - of the lesion can be accurately displayed, providing more pean Association of Urology (EAU) based on the serum clinical information compared to PET/CT. However, prostate specific antigen (PSA) level, Gleason score and there is a lack of evaluation of the value of PSMA PET/ clinical stage of prostate cancer patients. Among them, MRI in the clinical radiotherapy of prostate cancer. high-risk localized prostate cancer includes patients with The aim of this study was indeed to evaluate the differ - prostate-specific antigen (PSA) > 20  ng/ml or Gleason ence in CTV and GTVn outlined by MRI and PET/MRI score > 7 (Gleason Grade Group 4/5) or cT2c [4]. fusion images to investigate the value of PSMA PET/MRI Radical prostatectomy, radiation therapy (with or with- in high-risk prostate cancer radiotherapy. out androgen deprivation therapy), androgen depriva- tion therapy, deferred treatment (active surveillance) Methods or watchful waiting are the current treatment strategies Data collection for prostate cancer [5, 6]. Among them, radiotherapy is From May 2020 to December 2021, we retrospectively one of the main treatment methods for organ-confined enrolled 70 patients with definitive prostate cancer by and locally advanced prostate cancer, along with hor- pathological biopsy who presented to our hospital for mone therapy and surgery. And it has an irreplaceable PSMA PET/MRI. The patient enrollment process is role in improving the survival rate, prolonging the sur- summarized in Fig.  1. All patients had received no other vival time and reducing complaints of patients with treatment prior to this date, and no patients had con- prostate cancer [7–9]. For high-risk prostate cancer traindications to MR or PET imaging. Of the 70 patients, (clinical T1-4N0-1M0), radical radiotherapy combined 55 cases were defined as having high-risk prostate cancer with endocrine therapy can achieve the same efficacy according to the European Association of Urology guide- as surgery [10]. Schaeffer E confirmed that prophylactic lines. 4 cases were excluded due to incomplete clini- whole-pelvis radiation improves disease-free survival and cal data or images, 1 case was excluded due to excessive biochemical-failure-free survival compared with prostate image motion artefacts and 1 case was excluded due to radiotherapy alone for high-risk, locally advanced pros- its prostate cancer metastasis exceeding the upper bound tate cancer [11]. Whole-pelvis radiation is essential in of the CTV. 49 patients were finally included in this high-risk prostate cancer treatment and is closely associ- study, 39 of whom underwent [18F]-F-PSMA-1007 PET/ ated with actual survival and prognosis. MRI imaging, and the other 10 underwent [68  Ga]-Ga- Accurate outlining of the target area is the corner- PSMA-11 imaging. The study was approved by our ethi - stone to ensure radiotherapy efficacy. Precise external cal review committee. radiotherapy improves in-field tumour control while reducing the incidence of toxic side effects. Currently, PET/MRI Image Acquisition computed tomography (CT) and magnetic resonance Patients should be encouraged to drink sufficient imaging (MRI) are widely used for target volume deline- amounts of water and to empty their bladders prior to ation [12], and MRI has the advantage of better soft tis- and after the PET/MRI examination. 0.1  mCi/kg body sue resolution, multidirectional imaging techniques and weight of 18F-PSMA-1007 or 68  Ga-PSMA-11 was no ionizing radiation compared to CT. However, CT or injected intravenously. Then, whole-body PET scans were MRI can show the anatomical features of the tumour but performed, covering 5 bed positions with an acquisition provide little information regarding the tumour’s bio- time of 3  min per bed position (15  min at the prostate logical behavior. The introduction of positron emission bed position). Hybrid PET/MRI images were acquired tomography (PET) tracers targeting prostate-specific in 3D mode on a 3-Tesla PET/MR scanner (uPMR790 membrane antigen (PSMA) has filled this gap. PSMA, as TOF, United Imaging, China). PET images were recon- an important biomarker, is a type II transmembrane gly- structed by the ordered subset expectation maximization coprotein that is expressed at 100–1000-fold higher levels (OSEM) algorithm (including 2 iterations, 20 subsets, a in prostate cancer cells than in normal cells [13]. Several 4  mm full-width half-maximum (FWHM) Gaussian fil - studies have shown that PSMA-targeted PET is supe- ter, and a 150 × 150 image matrix). The device uses the rior to conventional imaging (CT, MRI and 18F-FDG) in tissue segmentation method for attenuation correction, detecting metastases, and some articles have confirmed acquiring images with a 2-point Dioxon sequence and that PSMA PET/MRI is superior to multiparametric dividing the images into air, lung, fat, and soft tissue for Liu  et al. Cancer Imaging (2023) 23:1 Page 3 of 12 Fig. 1 Patient enrollment process attenuation correction. Diagnostic MRI scans included course of illness and written reports from the radiolo- T1-weighted high-resolution isotropic volume acquisi- gist and nuclear medicine physician were also provided, tion, T2-weighted (T2W) 3D volumetric fast spin-echo and the imaging could be viewed simultaneously in the (FSE) imaging in the axial, sagittal, and coronal direc- Radiology Information System (RIS) and Hospital Infor- tions. T1 sequence parameters: repetition time (TR)/ mation System (HIS) system. Regarding the determina- echo time (TE) = 5.04/2.24 ms, 4 mm slice thickness, 20% tion of lymph nodes, increased local uptake of pelvic and interslice gap, 350  mm × Ax FSE T2 sequence param- retroperitoneal lymph nodes was thought to be metasta- eters: TR/TE = 3998/88.74 ms, 6 mm slice thickness, 20% sis, while in MRI, a threshold of 1.0  cm short-axis node interslice gap, 300 mm × 300 mm field of view, 320 × 320 diameter for oval nodes and 0.8  cm for round nodes matrix. Delayed pelvic PET/MRI scans were performed was used as a criterion for lymph node metastasis [19]. if clinically indicated. Image analysis was performed to GTV includes definite primary prostate foci based on the confirm the MRI and PET/MRI images of each patient abovementioned imaging basis; if accompanied by pelvic separately, which was performed by 2 radiologists, one lymph node metastases, GTVn is outlined. CTV includes working in radiology and the other in nuclear medi- the prostatic + seminal vesicle bed (proximal 1–2.5  cm cine, both board-certified and with more than 5  years of seminal vesicle) and pelvic lymph nodes area. The of experience. The three radiation oncologists further pelvic lymphatic drainage area was outlined accord- performed target area outlining independently based ing to the NRG Oncology consensus contour atlas [20]. on the above, including the patient’s tumour target vol- The above target areas were outlined manually on MRI ume (GTV) and clinical target volume (CTV). None of and PET/MR fusion images based on axial T2-weighted the three physicians had any prior medical involvement, MRI. The method of image acquisition and the sequence knowledge of patients’ medical history, or had previ- selected for target delineation is similar to a previous ously seen any images of them. A medical report of the research project done by our group, which was based Liu et al. Cancer Imaging (2023) 23:1 Page 4 of 12 on assessing the clinical value of 18F-PSMA-1007 and The sensitivity and specificity of both MRI and PET/ 68  Ga-PSMA-11 PET/MRI in the gross tumour volume MRI imaging methods were evaluated for PLN, which (GTV) delineation of radiotherapy for prostate cancer were determined using pathological results as refer- [21]. ence. The confusion matrix was presented. The paired sample Wilcoxon signed-rank tests were performed to compare the differences between the two groups of Patient information CTV and GTVn delineated by different methods (PET/ The individuals in this study had all been diagnosed MRI and MRI). The correlation between the two groups with high-risk PCa. Basic and clinical information was of CTV and GTVn was presented by scatter plot. Cor- collected for each patient, including age, TNM stag- relations were assessed using Pearson analysis. The ing, Gleason score, preoperative PSA and pathology McNemar test was used to compare the sensitivity and of surgical specimens. We considered the pathologic specificity of MRI and PET/MRI in detecting positive TNM (pTNM) classification or, when absent, the clini - lymph nodes. 95% confidence intervals (95% CI) for sen - cal TNM (cTNM) classification. The pathological results sitivity and specificity were calculated using Wilson score of all high-risk prostate pelvic lymph nodes obtained method [22]. SPSS 24.0 (IBM Corp, Armonk, NY, USA) in our organization include both the number of posi- was used for statistical analysis, and the ggplot, rms and tive lymph nodes and the total number of lymph nodes foreign packages in R 3.4.3 (https:// www.r- proje ct. org/) extracted. The surgical specimens of the pelvic lymph were also used for statistical analysis. All statistical tests nodes are divided into seven groups to be submitted as were 2-tailed, and P < 0.05 was considered statistically packets. Including, common iliac nodes, left-internal iliac significant. nodes, right-internal iliac nodes, left-external iliac nodes, right-external iliac nodes, obturator nodes, and presa- cral nodes. We divided lymph nodes into five groups for Results evaluation, including common iliac nodes, internal iliac Patient information nodes, external iliac nodes, obturator nodes, and presa- A total of 49 patients with high-risk prostate cancer cral nodes. underwent MRI and PSMA PET/MRI detection at East- ern Hospital between May 2020 and December 2021. Statistical analysis The demographics of the patients are shown in Table  1. The data of CTV and GTVn volumes based on MRI and Patients had a median age of 72  years, of whom 14%, PET/MRI outlined by three observers and the conform- 70%, and 16% were at T2, T3, and T4 stages, respectively, ity index (CI), the lesion coverage factor (LCF), and the and 27% of patients were at N1 stage. The mean value of Dice similarity coefficient (DSC) are presented as the PSA was approximately 16.81 ng/ml, and the majority of mean ± standard deviation. Three methods of volu - patients (47%) had a Gleason score of eight. All patients metric analysis, CI, LCF and DSC, were used to com- had adenocarcinoma confirmed by pathological biopsy. pare the correspondence between PET/MRI-CTV with Thirty-seven patients had pathological examination of MRI-CTV and PET/MRI-GTVn with MRI-GTVn. CI, PLN. used to determine the relative concordance between the two different modalities, was defined as A/B, where Volume measurements A and B represent two volumes delineated on MRI and Figures  2 and 3 shows examples of delineation of CTV PET/MRI, respectively (the same below). LCF, used and GTVn of whole-pelvic radiotherapy measured under to determine the percentage of overlap between the PSMA PET/MRI and MRI conditions. In our study, when two volumes, was defined as (A ∩ B)/B, where A ∩ B each observer used MRI or PET/MRI to delineate the represents the overlap between the two volumes (the patient’s target area, there would be a group of observa- same below). DSC, used to determine the similarities tion data and the recorded relevant parameters, includ- between the two datasets regarding both volumet- ing CI, LCF, and DSC. The mean values of CTV, GTVn, ric and spatial agreement, was defined as 2 × (A ∩ B)/ CI, DSC, and LCF based on MRI and PET/MRI meas- (A + B), where (A + B) represents the sum of the abso- urements by three observers are shown in Supplement lute value of their volumes. The closer the CI result is to Tables  1 and 2. The Bland–Altman analysis between 1, the more similar the two volumes are. The closer the MRI and PET/MRI values for CTV and GTVn indicated LCF and DSC result are to 1, the higher the degree of mean differences of -1.98 and -0.34, respectively. The overlap between the two volumes. The Bland–Altman 95% CI for the difference was from -42.34 to 38.37, and analysis between volumes delineated on PET/MRI and from -4.87 to 4.19, respectively, as shown in Fig.  4. For MRI was conducted. CTV, the ordinates of 93.9% of the measured values were Liu  et al. Cancer Imaging (2023) 23:1 Page 5 of 12 Fig. 2 Target volume delineation for a 68‑ year‑ old man with high‑risk PCa who was assumed three lymph node metastases based on PSMA Ligand PET/MRI ( T2‑ weighted) leading to three GTVs (green line)(A). Target volume delineation based on MRI ( T2‑ weighted) assuming two lymph node metastases leading to two GTVs (pink line) (B) within the 95% CI, and for GTVn, the ordinates of 83.3% were analysed (Table  2). The mean CTV for MRI-based of the measured data were within the 95% CI, indicating contouring was 579.3 c m , and the value of PET/MRI that the data of the two groups had a good level of con- was 580.3 cm . The CI was 0.999 ± 0.036, the LCF was sistency. In addition, for CTV, the Bland–Altman analysis 0.953 ± 0.024, and the DSC was 0.954 ± 0.021. Regarding demonstrated that the data consistency was constant and volume and CI values, CTV-PET/MRI is comparable to would not change with the x-axis value (volume value). CTV-MRI. The values of LCF and DSC were 0.953 and For GTVn, when the measured value of the x-axis was 0.954, respectively, indicating a high spatial overlap of the large, the data presented a large discrete type with a poor CTV based on the two imaging methods. level of consistency. For the target area of positive lymph nodes in whole- The descriptive statistics of the target area, including pelvis radiation (GTVn), we observed pelvic lymph node the metrics of CTV, CI, DSC, and LCF, for the 49 patients metastasis in 12 of 49 cases based on MRI and PET/ Fig. 3 Target volume delineation for a 68‑ year‑ old man with high‑risk PCa who was assumed two lymph node metastases based on PET/MRI ( T2‑ weighted), leading to two GTVs (green line), resulting CTV in blue line (A). Target volume delineation based on MRI ( T2‑ weighted) assuming two lymph node metastases leading to two GTVs (pink line), resulting CTV in pink line (B). Target volume delineation for a 67‑ year‑ old man with high‑risk PCa who was assumed one lymph node metastasis based on PET/MRI ( T2‑ weighted), leading to one GTV (green line), resulting CTV in blue line (C). Target volume delineation based on MRI ( T2‑ weighted) assuming no lymph node metastasis, resulting CTV in pink line (D) Liu et al. Cancer Imaging (2023) 23:1 Page 6 of 12 Diagnostic sensitivity and specificity for the detection Table 1 Patient demographics of pelvic lymph node Characteristic Value Of the 49 patients included in the study, 463 lymph nodes N 49 from 37 patients had pathological examination of PLN, Age(y) and the demographic and clinical characteristics of the Median (range) 72(42–89) above patients are described in Supplement Table  3. All T Stage of these patients underwent radical prostatectomy (RP) T2 7(14%) and pelvic lymph node dissection (PLND). Extended pel- T3 34(70%) vic lymph node dissection (EPLND) was chosen in 27 of T4 8(16%) these patients. In Fig. 6, we present a confusion matrix of N Stage the final detection results. In the lymph node-based anal - N0 36(73%) ysis, a total of 28/36 (77.8%) positive lymph nodes were N1 13(27%) detected by PET/MRI, while 8 lymph nodes were classi- M Stage fied as false negatives (22.2% of abnormal lymph nodes M0 40(82%) were missed). A total of 23/36 (63.9%) positive lymph M1 9(18%) nodes were correctly detected by MRI, while 13 lymph PSA (ng/ml) nodes were classified as false negatives (36.1% of abnor - Mean (std dev) 16.81 (19.11) mal lymph nodes were missed). In the patient-based analysis, among 37 patients, neither MRI nor PET/MRI Gleason Score detected positive lymph nodes in 25 patients without pel- 6 2(4%) vic lymph node metastasis (PLNM), and for 12 patients 7 9(18%) with definite pelvic lymph node pathology biopsies, PET/ 8 23(47%) MRI identified 11/12 (91.7%) patients with PLNM, while 9 11(23%) MRI identified 10/12 (83.3%) patients with PLNM. The 10 4(8%) sensitivity and specificity of PET/MRI vs. MRI for lymph node detection at two levels of analysis are shown in Table  4. A comparison of the efficacy of PET/MRI and MRI for PLNM revealed a significant difference between MRI, as described in Table  3 and Supplement Table  2. the two methods (P = 0.011). In Supplement Table  4, the The average value of GTVn based on MRI and PET/MRI 3 3 relationship between imaging diagnosis and pathology of was 2.775 cm and 3.167 c m , respectively. The mean pelvic lymph nodes (divided into five groups, including CI, LCF, and DSC were 0.927 ± 0.621, 0.284 ± 0.272, and common iliac nodes, internal iliac nodes, external iliac 0.321 ± 0.235, respectively. Regarding volume size, the nodes, obturator nodes, and presacral nodes) is reflected. mean value of MRI-based GTVn was slightly smaller than that based on PET/MRI, with a CI of 0.927. The Discussion heterogeneity of MRI- and PET/MRI-based lymph node For high-risk prostate cancer patients, this is the first profiles was high according to the value of LCF and DSC. study to examine PSMA PET/MRI-based target volumes The results of the paired sample Wilcoxon signed-rank (TVs) for whole-pelvis radiation. This is also the first tests showed non-significant differences in the CTV and study comparing PSMA PET/MRI and MRI-based radio- GTVn based on MRI and PET/MRI images (P = 0.660, therapy target  volumes. We found that the GTVn based P = 0.650). According to the results of the correlation on PSMA PET/MRI differs from that based on MRI, with analysis, there was a statistically significant link between existing spatial heterogeneity between them. PSMA PET/ the MRI-CTV volume and PET/MRI-CTV volume MRI can identify more lymph node metastasis or even (P = 0.005), as well as between MRI-GTVn volume and change the tumour stage of some patients, and it also PET/MRI-GTVn volume (P < 0.001) (Fig. 5). reduces the probability of false-positive lymph nodes and Table 2 Clinical target volume measurement and parameter statistics Characteristic MRI-CTV (cc) PET/MRI-CTV (cc) Overlap volume (cc) CI LCF DSC (n = 49) Mean 579.3 580.3 552.8 0.999 0.953 0.954 SD 56.4 62.7 55.85 0.036 0.024 0.021 CI Conformity index, LCF Lesion-coverage factor, DSC Dice similarity coefficient, CTV Clinical target volume Liu  et al. Cancer Imaging (2023) 23:1 Page 7 of 12 Fig. 4 Bland–Altman analysis between volumes delineated on the two modalities for CTV(A) and for GTVn (B) Liu et al. Cancer Imaging (2023) 23:1 Page 8 of 12 Table 3 Nodal gross tumor volume measurement and parameter statistics Characteristic MRI-GTVn(cc) PET/MRI-GTVn(cc) Overlap volume (cc) CI LCF DSC (n = 12) Mean 2.775 3.167 1.433 0.927 0.284 0.295 SD 5.047 4.118 2.854 0.621 0.272 0.242 CI Conformity index, LCF Lesion-coverage factor, DSC Dice similarity coefficient, GTVn  Nodal gross tumor volume changes the TVs in radiotherapy planning (RTP) to pro- PSMA-targeted PET provides better detection of tect normal tissues. The difference between CTVs based metastases than conventional imaging (i.e., CT, mul- on PSMA PET/MRI and MRI was not significant, indi - tiparametric MRI, and 18F-based PET-CT [flucil - cating that the ability to identify the tissue structure of loflox and choline]). Several studies have confirmed the pelvic drainage area was similar for PSMA PET/MRI that 68  Ga-PSMA PET-CT has higher sensitivity and and MRI. specificity in identifying pelvic nodes and/or distant More than 30–40% of high-risk PCa patients present metastases with biopsy-proven high-risk PCa than with PLNM during pelvic lymph node dissection and CT or bone scans. Sawicki et  al. found that 68  Ga- staging [23]. The treatment of PLN with external beam PSMA PET-CT detected lesions missed by WB-MRI radiation therapy (RT) is a frequent component of the in patients with biochemical failure after radical management of patients with prostate cancer. Whole pel- prostate cancer surgery [27–31]. Another study of a vic radiation therapy (WPRT) is a common practice for high-risk prostate cancer group showed that PSMA men receiving prostate radiotherapy for high-risk disease, PET-CT resulted in improved overall staging in 23.9% clinical lymph node-positive disease, and postprostatec- of patients with negative conventional imaging (CT or tomy [5, 24, 25].The consensus atlas for pelvic nodal con - MRI) [32]. Even in the diagnosis of small lymph nodes, touring in the clinical target area for WPRT was newly PSMA PET also had a specificity of 95% for diagnosis revised in 2021. In our research, CTV was contoured [33, 34]. An article evaluating the use of [68  Ga] Ga- based on MRI and PET/MRI according to the above prin- PSMA-11 PET (PSMA-PET)/MRI in the staging of ciples. No statistically significant differences were found primary tumour-node-metastasis in prostate cancer when comparing the results, no matter the volume size or affirmed its excellent accuracy (93% accuracy at N1 spatial coincidence. Based on the Bland–Altman analysis, stage) and found that it could change the treatment strategy in 28.7% of patients [16]. In this paper, com the MRI-CTV and PET/MRI-CTV had good consistency - without changing with the size of the CTV. This shows pared to MRI, PSMA PET/MR had high sensitivity and that the CTV delineated based on the two methods of specificity, with significant differences between the two whole pelvic radiotherapy for prostate cancer is compara- methods (P = 0.011). Of the 49 high-risk prostate can- ble. Although the boundary of CTV may differ due to the cer patients, 21 patients (42.9%) had N1/M1 disease, of difference in GTVn (as depicted in Fig.  3), the range of whom 1 patient was previously N0 and 7 patients had CTV was much larger than GTVn, so that the difference bone metastases on PSMA PET/MRI. Similar results caused by GTVn cannot be clearly reflected. In a word, were confirmed in other articles. The high sensitivity the results reflect the high similarity of the CTV obtained and specificity of PSMA PET/MRI changes the clinical by the two methods. Ingrid White et  al. noted that MRI stage of patients, which may affect the treatment plan provides superior soft tissue contrast compared to CT of patients [35]. in RTP for rectal cancer, resulting in a clearer delinea- Integration of PET/CT in radiotherapy planning is com- tion of the boundaries of the target areas and reducing mon in many cancer types [10], and PET/MRI is now the volume due to observer uncertainty, as demonstrated increasingly being used in RTP [36–41]. In prostate can- by the reduced margins of both CTV and PTV in the cer, several studies have also evaluated the use of PSMA corresponding adapted radiotherapy [26]. Based on our PET/MRI in the radiotherapy of primary and recurrent research results, the CTVs of PET/MRI and MRI are sim- prostate cancer [16, 42, 43]. We are the first to investi - ilar. Therefore, despite the lack of research comparing the gate the application of PSMA PET/MRI in the GTVn of difference between targets delineated based on CT and radiotherapy, and we discovered that when compared to PET/MRI, we believe that PET/MRI has advantages simi- MRI, PSMA PET/MRI has altered the RTP. The spatial lar to those of MRI in target delineation for radiotherapy, analysis index indicated that the overlap between the two namely, based on the excellent soft tissue resolution it GTVn was low, and when combined with the analysis of provides, doctors could delineate the boundary of the sensitivity and specificity for lymph nodes, we confidently target areas more clearly. concluded that the GTVn contouring on PSMA PET/ Liu  et al. Cancer Imaging (2023) 23:1 Page 9 of 12 Fig. 5 PSMA PET/MRI‑ CTV versus MRI‑ CTV (A); PSMA PET/MRI‑ GTVn versus MRI‑ GTVn (B) Liu et al. Cancer Imaging (2023) 23:1 Page 10 of 12 Fig. 6 Confusion matrix results of MRI and PET/MRI for lymph node‑based analysis (A) and for patient ‑based analysis (B) MRI is more accurate and may help to reduce lymph node Therefore, we have emphasized the utility of PET/MRI recurrence. In combination with a recent research effort fusion images in delineating prostate cancer radiotherapy. conducted by our group, which showed that it was feasi- It is necessary to acknowledge some limitations. The ble to visually delineate GTV on PSMA PET/MRI in PCa nature of retrospective studies may have introduced radiotherapy [21]. Our investigation has shown that it is unnoticed statistical bias in adherence. CT is the most feasible to delineate GTVn and CTV on PSMA PET/MRI. commonly used imaging technique in radiotherapy treat- ment planning. This paper only compares PET/MRI and MRI, leaving CT out of the equation. It is basically Table 4 PSMA PET/MRI has higher sensitivity and specificity for impossible to obtain the results of node-to-node rad path detecting pelvic lymph node metastasis when compared to MRI. correlation, so we grouped pelvic lymph nodes into five (A: lymph node‑based analysis; B: patient ‑based analysis) groups for a matching analysis between pathology and Parameter Sensitivity % (95% CI) Specificity % (95% CI) imaging, which may bias the results of the diagnosing efficacy of imaging methods (PET/MRI or MRI). In addi - A PET/MRI 77.78 (61.91 to 88.28) 99.76 (98.68 to 99.96) tion, we only analysed a small sample size, specifically, MRI 63.89 (75.03 to 97.78) 99.53 (98.31 to 99.87) the CTV of 49 patients and the GTVn of 12 patients. As a B PET/MRI 91.67 (64.61 to 98.51) 100.00 (86.68 to 100.00) result, the practical application value of PSMA PET/MRI MRI 83.33 (55.20 to 95.30) 100.00 (86.68 to 100.00) requires further investigation in large, well-designed, randomized, controlled trials. The 95% CI for the sensitivity and specificity estimates were calculated using Wilson’s score method Liu  et al. Cancer Imaging (2023) 23:1 Page 11 of 12 Consent for publication Conclusion Written informed consent was obtained from the patient for publication of PSMA PET/MRI-GTVn is more accurate in whole pel- this case report and any accompanying images. A copy of the written consent vic radiotherapy for high-risk prostate cancer patients is available for review by the Editor‑in‑ Chief of this journal. because PSMA PET/MRI has higher sensitivity, speci- Competing interests ficity and diagnostic accuracy than MRI in identifying The authors declare that there are no conflicts of interest regarding the publi‑ PLNM. The CTV of whole pelvic radiotherapy deter - cation of this article. mined by PSMA PET/MRI and MRI is comparable. Eight Author details high-risk prostate cancer patients who finished PSMA Department of Radiation Oncology, Shanghai East Hospital, School of Medi‑ PET/MRI changed their N or M stage. The use of PSMA cine, Tongji University, Shanghai 200120, China. Department of Nuclear Medicine, Shanghai East Hospital, School of Medicine, Tongji University, PER/MRI aids in the realization of more individualized Shanghai 200120, China. Department of Urology, Shanghai East Hospital, and precise radiotherapy. School of Medicine, Tongji University, Shanghai 200120, China. Depar tment of Radiation Oncology, Shanghai East Hospital Ji’an hostipal, Ji’an City, Jiangxi Province 343000, China. Abbreviations PCa: Prostate cancer; RTP: Radiotherapy planning; PSMA: Prostate‑specific Received: 1 August 2022 Accepted: 25 December 2022 membrane antigen; CTV: Clinical target volume; GTVn: Nodal gross tumour volume; WPRT: Whole pelvic radiation therapy; PLNM: Pelvic lymph node metastasis; RP: Radical prostatectomy; PLN: Pelvic lymph node; PLND: Pelvic lymph node dissection; EPLND: Extended pelvic lymph node dissection; CI: Conformity index; LCF: Lesion coverage factor; DSC: Dice similarity coefficient; References EAU: European Association of Urology. 1. Sita TL, Petras KG, Wafford QE, Berendsen MA, Kruser TJ. Radiotherapy for cranial and brain metastases from prostate cancer: a systematic review. J Neurooncol. 2017;133(3):531–8. Supplementary Information 2. Fine SW. Variants and unusual patterns of prostate cancer: clinico‑ The online version contains supplementary material available at https:// doi. pathologic and differential diagnostic considerations. Adv Anat Pathol. org/ 10. 1186/ s40644‑ 022‑ 00518‑7. 2012;19(4):204–16. 3. Cai T, Nesi G, Tinacci G, Giubilei G, Gavazzi A, Mondaini N, et al. Clinical importance of lymph node density in predicting outcome of prostate Additional file 1. cancer patients. J Surg Res. 2011;167(2):267–72. 4. Chughtai B, Mian BM. High risk prostate cancer: evolving definition and Acknowledgements approach to management. Can J Urol. 2008;15(6):4375–80. The authors would like to thank the the National Natural Science Founda‑ 5. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, tion of China (Grant No.81960525 and 82160591), Science and Technology et al. EAU guidelines on prostate cancer. part 1: screening, diagno‑ Commission of Shanghai Municipality (Grant No.19DZ1930900), Key Project sis, and local treatment with curative intent‑update 2013. Eur Urol. of Clinical Research of Shanghai East Hospital, Tongji University (Grant No. 2014;65(1):124–37. https:// doi. org/ 10. 1016/j. eururo. 2013. 09. 046. Epub DFLC2022012) and Key Specialty Construction Project of Shanghai Pudong 2013 Oct 6. New Area Health Commission (Grant No. PWZzk2022‑02). 6. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: Treatment of Author contributions advanced, relapsing, and castration‑resistant prostate cancer. Eur Urol. ZLX: Study design, contouring, data analysis, manuscript preparation and 2014;65(2):467–79. https:// doi. org/ 10. 1016/j. eururo. 2013. 11. 002. Epub editing. LLL: Study design, data collection, image analysis, data analysis, manu‑ 2013 Nov 12. script editing. LLZ: Contouring, data collection, data analysis. ZGL: Contouring, 7. Cho Y, Chang JS, Rha KH, Hong SJ, Choi YD, Ham WS, et al. Does Radio‑ data collection. JDS: Contouring, data collection. 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Variability of radiotherapy volume delineation: PSMA PET/MRI and MRI based clinical target volume and lymph node target volume for high-risk prostate cancer

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Abstract

Purpose: A comparative retrospective study to assess the impact of PSMA Ligand PET/MRI ([68 Ga]‑ Ga‑PSMA‑11 and [18F]‑F‑PSMA‑1007 PET/MRI) as a new method of target delineation compared to conventional imaging on whole ‑ pelvis radiotherapy for high‑risk prostate cancer (PCa). Patients and methods: Forty‑nine patients with primary high‑risk PCa completed the whole ‑pelvis radiotherapy plan based on PSMA PET/MRI and MRI. The primary endpoint compared the size and overlap of clinical target volume (CTV ) and nodal gross tumour volume (GTVn) based on PSMA PET/MRI and MRI. The diagnostic performance of two methods for pelvic lymph node metastasis (PLNM) was evaluated. Results: In the radiotherapy planning for high‑risk PCa patients, there was a significant correlation between MRI‑ CTV and PET/MRI‑ CTV (P = 0.005), as well as between MRI‑ GTVn and PET/MRI‑ GTVn (P < 0.001). There are non‑significant differences in the CTV and GTVn based on MRI and PET/MRI images (P = 0.660, P = 0.650, respectively). The conformity index (CI), lesion coverage factor (LCF) and Dice similarity coefficient (DSC) of CTVs were 0.999, 0.953 and 0.954. The CI, LCF and DSC of GTVns were 0.927, 0.284, and 0.32. Based on pathological lymph node analysis of 463 lymph nodes from 37 patients, the sensitivity, specificity of PET/MRI in the diagnosis of PLNM were 77.78% and 99.76%, respectively, which were higher than those of MRI (P = 0.011). Eight high‑risk PCa patients who finished PSMA PET/MRI changed their N or M stage. Conclusion: The CTV delineated based on PET/MRI and MRI differ little. The GTVn delineated based on PET/MRI encompasses metastatic pelvic lymph nodes more accurately than MRI and avoids covering pelvic lymph nodes with‑ out metastasis. We emphasize the utility of PET/MRI fusion images in GTVn delineation in whole pelvic radiotherapy for PCa. The use of PSMA PET/MRI aids in the realization of more individual and precise radiotherapy for PCa. Keywords: Prostate cancer, PET/MRI, PSMA, Radiotherapy, CTV, GTVn Introduction Prostate cancer (PCa) is a common malignancy in men, Lin‑Lin Liu and Lei‑Lei Zhu contributed equally to this work. accounting for 27% (233,000) of cancer incidence in the *Correspondence: 446720864@qq.com; xiangzuolinmd@hotmail.com United States [1]. In recent years, the incidence of pros- Department of Radiation Oncology, Shanghai East Hospital, School tate cancer in China has significantly increased, seriously of Medicine, Tongji University, Shanghai 200120, China affecting men’s health; the most common pathologi - Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China cal type of PCa is adenocarcinoma [2]. Lymphatic and Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Cancer Imaging (2023) 23:1 Page 2 of 12 haematogenous metastasis are the two common meta- MRI in diagnosing prostate cancer [14–18]. PET/MRI static pathways of prostate cancer, and the metastasis of combines the advantages of PET and MRI, providing pelvic lymph nodes (PLN) is strongly associated with the anatomical images in a single imaging session, detailed prognosis of prostate cancer [3]. functional and cellular metabolism and other molecular PCa cases are stratified into low/intermediate-risk and information of the lesion, while the anatomical structure high-risk groups according to the definition of the Euro - of the lesion can be accurately displayed, providing more pean Association of Urology (EAU) based on the serum clinical information compared to PET/CT. However, prostate specific antigen (PSA) level, Gleason score and there is a lack of evaluation of the value of PSMA PET/ clinical stage of prostate cancer patients. Among them, MRI in the clinical radiotherapy of prostate cancer. high-risk localized prostate cancer includes patients with The aim of this study was indeed to evaluate the differ - prostate-specific antigen (PSA) > 20  ng/ml or Gleason ence in CTV and GTVn outlined by MRI and PET/MRI score > 7 (Gleason Grade Group 4/5) or cT2c [4]. fusion images to investigate the value of PSMA PET/MRI Radical prostatectomy, radiation therapy (with or with- in high-risk prostate cancer radiotherapy. out androgen deprivation therapy), androgen depriva- tion therapy, deferred treatment (active surveillance) Methods or watchful waiting are the current treatment strategies Data collection for prostate cancer [5, 6]. Among them, radiotherapy is From May 2020 to December 2021, we retrospectively one of the main treatment methods for organ-confined enrolled 70 patients with definitive prostate cancer by and locally advanced prostate cancer, along with hor- pathological biopsy who presented to our hospital for mone therapy and surgery. And it has an irreplaceable PSMA PET/MRI. The patient enrollment process is role in improving the survival rate, prolonging the sur- summarized in Fig.  1. All patients had received no other vival time and reducing complaints of patients with treatment prior to this date, and no patients had con- prostate cancer [7–9]. For high-risk prostate cancer traindications to MR or PET imaging. Of the 70 patients, (clinical T1-4N0-1M0), radical radiotherapy combined 55 cases were defined as having high-risk prostate cancer with endocrine therapy can achieve the same efficacy according to the European Association of Urology guide- as surgery [10]. Schaeffer E confirmed that prophylactic lines. 4 cases were excluded due to incomplete clini- whole-pelvis radiation improves disease-free survival and cal data or images, 1 case was excluded due to excessive biochemical-failure-free survival compared with prostate image motion artefacts and 1 case was excluded due to radiotherapy alone for high-risk, locally advanced pros- its prostate cancer metastasis exceeding the upper bound tate cancer [11]. Whole-pelvis radiation is essential in of the CTV. 49 patients were finally included in this high-risk prostate cancer treatment and is closely associ- study, 39 of whom underwent [18F]-F-PSMA-1007 PET/ ated with actual survival and prognosis. MRI imaging, and the other 10 underwent [68  Ga]-Ga- Accurate outlining of the target area is the corner- PSMA-11 imaging. The study was approved by our ethi - stone to ensure radiotherapy efficacy. Precise external cal review committee. radiotherapy improves in-field tumour control while reducing the incidence of toxic side effects. Currently, PET/MRI Image Acquisition computed tomography (CT) and magnetic resonance Patients should be encouraged to drink sufficient imaging (MRI) are widely used for target volume deline- amounts of water and to empty their bladders prior to ation [12], and MRI has the advantage of better soft tis- and after the PET/MRI examination. 0.1  mCi/kg body sue resolution, multidirectional imaging techniques and weight of 18F-PSMA-1007 or 68  Ga-PSMA-11 was no ionizing radiation compared to CT. However, CT or injected intravenously. Then, whole-body PET scans were MRI can show the anatomical features of the tumour but performed, covering 5 bed positions with an acquisition provide little information regarding the tumour’s bio- time of 3  min per bed position (15  min at the prostate logical behavior. The introduction of positron emission bed position). Hybrid PET/MRI images were acquired tomography (PET) tracers targeting prostate-specific in 3D mode on a 3-Tesla PET/MR scanner (uPMR790 membrane antigen (PSMA) has filled this gap. PSMA, as TOF, United Imaging, China). PET images were recon- an important biomarker, is a type II transmembrane gly- structed by the ordered subset expectation maximization coprotein that is expressed at 100–1000-fold higher levels (OSEM) algorithm (including 2 iterations, 20 subsets, a in prostate cancer cells than in normal cells [13]. Several 4  mm full-width half-maximum (FWHM) Gaussian fil - studies have shown that PSMA-targeted PET is supe- ter, and a 150 × 150 image matrix). The device uses the rior to conventional imaging (CT, MRI and 18F-FDG) in tissue segmentation method for attenuation correction, detecting metastases, and some articles have confirmed acquiring images with a 2-point Dioxon sequence and that PSMA PET/MRI is superior to multiparametric dividing the images into air, lung, fat, and soft tissue for Liu  et al. Cancer Imaging (2023) 23:1 Page 3 of 12 Fig. 1 Patient enrollment process attenuation correction. Diagnostic MRI scans included course of illness and written reports from the radiolo- T1-weighted high-resolution isotropic volume acquisi- gist and nuclear medicine physician were also provided, tion, T2-weighted (T2W) 3D volumetric fast spin-echo and the imaging could be viewed simultaneously in the (FSE) imaging in the axial, sagittal, and coronal direc- Radiology Information System (RIS) and Hospital Infor- tions. T1 sequence parameters: repetition time (TR)/ mation System (HIS) system. Regarding the determina- echo time (TE) = 5.04/2.24 ms, 4 mm slice thickness, 20% tion of lymph nodes, increased local uptake of pelvic and interslice gap, 350  mm × Ax FSE T2 sequence param- retroperitoneal lymph nodes was thought to be metasta- eters: TR/TE = 3998/88.74 ms, 6 mm slice thickness, 20% sis, while in MRI, a threshold of 1.0  cm short-axis node interslice gap, 300 mm × 300 mm field of view, 320 × 320 diameter for oval nodes and 0.8  cm for round nodes matrix. Delayed pelvic PET/MRI scans were performed was used as a criterion for lymph node metastasis [19]. if clinically indicated. Image analysis was performed to GTV includes definite primary prostate foci based on the confirm the MRI and PET/MRI images of each patient abovementioned imaging basis; if accompanied by pelvic separately, which was performed by 2 radiologists, one lymph node metastases, GTVn is outlined. CTV includes working in radiology and the other in nuclear medi- the prostatic + seminal vesicle bed (proximal 1–2.5  cm cine, both board-certified and with more than 5  years of seminal vesicle) and pelvic lymph nodes area. The of experience. The three radiation oncologists further pelvic lymphatic drainage area was outlined accord- performed target area outlining independently based ing to the NRG Oncology consensus contour atlas [20]. on the above, including the patient’s tumour target vol- The above target areas were outlined manually on MRI ume (GTV) and clinical target volume (CTV). None of and PET/MR fusion images based on axial T2-weighted the three physicians had any prior medical involvement, MRI. The method of image acquisition and the sequence knowledge of patients’ medical history, or had previ- selected for target delineation is similar to a previous ously seen any images of them. A medical report of the research project done by our group, which was based Liu et al. Cancer Imaging (2023) 23:1 Page 4 of 12 on assessing the clinical value of 18F-PSMA-1007 and The sensitivity and specificity of both MRI and PET/ 68  Ga-PSMA-11 PET/MRI in the gross tumour volume MRI imaging methods were evaluated for PLN, which (GTV) delineation of radiotherapy for prostate cancer were determined using pathological results as refer- [21]. ence. The confusion matrix was presented. The paired sample Wilcoxon signed-rank tests were performed to compare the differences between the two groups of Patient information CTV and GTVn delineated by different methods (PET/ The individuals in this study had all been diagnosed MRI and MRI). The correlation between the two groups with high-risk PCa. Basic and clinical information was of CTV and GTVn was presented by scatter plot. Cor- collected for each patient, including age, TNM stag- relations were assessed using Pearson analysis. The ing, Gleason score, preoperative PSA and pathology McNemar test was used to compare the sensitivity and of surgical specimens. We considered the pathologic specificity of MRI and PET/MRI in detecting positive TNM (pTNM) classification or, when absent, the clini - lymph nodes. 95% confidence intervals (95% CI) for sen - cal TNM (cTNM) classification. The pathological results sitivity and specificity were calculated using Wilson score of all high-risk prostate pelvic lymph nodes obtained method [22]. SPSS 24.0 (IBM Corp, Armonk, NY, USA) in our organization include both the number of posi- was used for statistical analysis, and the ggplot, rms and tive lymph nodes and the total number of lymph nodes foreign packages in R 3.4.3 (https:// www.r- proje ct. org/) extracted. The surgical specimens of the pelvic lymph were also used for statistical analysis. All statistical tests nodes are divided into seven groups to be submitted as were 2-tailed, and P < 0.05 was considered statistically packets. Including, common iliac nodes, left-internal iliac significant. nodes, right-internal iliac nodes, left-external iliac nodes, right-external iliac nodes, obturator nodes, and presa- cral nodes. We divided lymph nodes into five groups for Results evaluation, including common iliac nodes, internal iliac Patient information nodes, external iliac nodes, obturator nodes, and presa- A total of 49 patients with high-risk prostate cancer cral nodes. underwent MRI and PSMA PET/MRI detection at East- ern Hospital between May 2020 and December 2021. Statistical analysis The demographics of the patients are shown in Table  1. The data of CTV and GTVn volumes based on MRI and Patients had a median age of 72  years, of whom 14%, PET/MRI outlined by three observers and the conform- 70%, and 16% were at T2, T3, and T4 stages, respectively, ity index (CI), the lesion coverage factor (LCF), and the and 27% of patients were at N1 stage. The mean value of Dice similarity coefficient (DSC) are presented as the PSA was approximately 16.81 ng/ml, and the majority of mean ± standard deviation. Three methods of volu - patients (47%) had a Gleason score of eight. All patients metric analysis, CI, LCF and DSC, were used to com- had adenocarcinoma confirmed by pathological biopsy. pare the correspondence between PET/MRI-CTV with Thirty-seven patients had pathological examination of MRI-CTV and PET/MRI-GTVn with MRI-GTVn. CI, PLN. used to determine the relative concordance between the two different modalities, was defined as A/B, where Volume measurements A and B represent two volumes delineated on MRI and Figures  2 and 3 shows examples of delineation of CTV PET/MRI, respectively (the same below). LCF, used and GTVn of whole-pelvic radiotherapy measured under to determine the percentage of overlap between the PSMA PET/MRI and MRI conditions. In our study, when two volumes, was defined as (A ∩ B)/B, where A ∩ B each observer used MRI or PET/MRI to delineate the represents the overlap between the two volumes (the patient’s target area, there would be a group of observa- same below). DSC, used to determine the similarities tion data and the recorded relevant parameters, includ- between the two datasets regarding both volumet- ing CI, LCF, and DSC. The mean values of CTV, GTVn, ric and spatial agreement, was defined as 2 × (A ∩ B)/ CI, DSC, and LCF based on MRI and PET/MRI meas- (A + B), where (A + B) represents the sum of the abso- urements by three observers are shown in Supplement lute value of their volumes. The closer the CI result is to Tables  1 and 2. The Bland–Altman analysis between 1, the more similar the two volumes are. The closer the MRI and PET/MRI values for CTV and GTVn indicated LCF and DSC result are to 1, the higher the degree of mean differences of -1.98 and -0.34, respectively. The overlap between the two volumes. The Bland–Altman 95% CI for the difference was from -42.34 to 38.37, and analysis between volumes delineated on PET/MRI and from -4.87 to 4.19, respectively, as shown in Fig.  4. For MRI was conducted. CTV, the ordinates of 93.9% of the measured values were Liu  et al. Cancer Imaging (2023) 23:1 Page 5 of 12 Fig. 2 Target volume delineation for a 68‑ year‑ old man with high‑risk PCa who was assumed three lymph node metastases based on PSMA Ligand PET/MRI ( T2‑ weighted) leading to three GTVs (green line)(A). Target volume delineation based on MRI ( T2‑ weighted) assuming two lymph node metastases leading to two GTVs (pink line) (B) within the 95% CI, and for GTVn, the ordinates of 83.3% were analysed (Table  2). The mean CTV for MRI-based of the measured data were within the 95% CI, indicating contouring was 579.3 c m , and the value of PET/MRI that the data of the two groups had a good level of con- was 580.3 cm . The CI was 0.999 ± 0.036, the LCF was sistency. In addition, for CTV, the Bland–Altman analysis 0.953 ± 0.024, and the DSC was 0.954 ± 0.021. Regarding demonstrated that the data consistency was constant and volume and CI values, CTV-PET/MRI is comparable to would not change with the x-axis value (volume value). CTV-MRI. The values of LCF and DSC were 0.953 and For GTVn, when the measured value of the x-axis was 0.954, respectively, indicating a high spatial overlap of the large, the data presented a large discrete type with a poor CTV based on the two imaging methods. level of consistency. For the target area of positive lymph nodes in whole- The descriptive statistics of the target area, including pelvis radiation (GTVn), we observed pelvic lymph node the metrics of CTV, CI, DSC, and LCF, for the 49 patients metastasis in 12 of 49 cases based on MRI and PET/ Fig. 3 Target volume delineation for a 68‑ year‑ old man with high‑risk PCa who was assumed two lymph node metastases based on PET/MRI ( T2‑ weighted), leading to two GTVs (green line), resulting CTV in blue line (A). Target volume delineation based on MRI ( T2‑ weighted) assuming two lymph node metastases leading to two GTVs (pink line), resulting CTV in pink line (B). Target volume delineation for a 67‑ year‑ old man with high‑risk PCa who was assumed one lymph node metastasis based on PET/MRI ( T2‑ weighted), leading to one GTV (green line), resulting CTV in blue line (C). Target volume delineation based on MRI ( T2‑ weighted) assuming no lymph node metastasis, resulting CTV in pink line (D) Liu et al. Cancer Imaging (2023) 23:1 Page 6 of 12 Diagnostic sensitivity and specificity for the detection Table 1 Patient demographics of pelvic lymph node Characteristic Value Of the 49 patients included in the study, 463 lymph nodes N 49 from 37 patients had pathological examination of PLN, Age(y) and the demographic and clinical characteristics of the Median (range) 72(42–89) above patients are described in Supplement Table  3. All T Stage of these patients underwent radical prostatectomy (RP) T2 7(14%) and pelvic lymph node dissection (PLND). Extended pel- T3 34(70%) vic lymph node dissection (EPLND) was chosen in 27 of T4 8(16%) these patients. In Fig. 6, we present a confusion matrix of N Stage the final detection results. In the lymph node-based anal - N0 36(73%) ysis, a total of 28/36 (77.8%) positive lymph nodes were N1 13(27%) detected by PET/MRI, while 8 lymph nodes were classi- M Stage fied as false negatives (22.2% of abnormal lymph nodes M0 40(82%) were missed). A total of 23/36 (63.9%) positive lymph M1 9(18%) nodes were correctly detected by MRI, while 13 lymph PSA (ng/ml) nodes were classified as false negatives (36.1% of abnor - Mean (std dev) 16.81 (19.11) mal lymph nodes were missed). In the patient-based analysis, among 37 patients, neither MRI nor PET/MRI Gleason Score detected positive lymph nodes in 25 patients without pel- 6 2(4%) vic lymph node metastasis (PLNM), and for 12 patients 7 9(18%) with definite pelvic lymph node pathology biopsies, PET/ 8 23(47%) MRI identified 11/12 (91.7%) patients with PLNM, while 9 11(23%) MRI identified 10/12 (83.3%) patients with PLNM. The 10 4(8%) sensitivity and specificity of PET/MRI vs. MRI for lymph node detection at two levels of analysis are shown in Table  4. A comparison of the efficacy of PET/MRI and MRI for PLNM revealed a significant difference between MRI, as described in Table  3 and Supplement Table  2. the two methods (P = 0.011). In Supplement Table  4, the The average value of GTVn based on MRI and PET/MRI 3 3 relationship between imaging diagnosis and pathology of was 2.775 cm and 3.167 c m , respectively. The mean pelvic lymph nodes (divided into five groups, including CI, LCF, and DSC were 0.927 ± 0.621, 0.284 ± 0.272, and common iliac nodes, internal iliac nodes, external iliac 0.321 ± 0.235, respectively. Regarding volume size, the nodes, obturator nodes, and presacral nodes) is reflected. mean value of MRI-based GTVn was slightly smaller than that based on PET/MRI, with a CI of 0.927. The Discussion heterogeneity of MRI- and PET/MRI-based lymph node For high-risk prostate cancer patients, this is the first profiles was high according to the value of LCF and DSC. study to examine PSMA PET/MRI-based target volumes The results of the paired sample Wilcoxon signed-rank (TVs) for whole-pelvis radiation. This is also the first tests showed non-significant differences in the CTV and study comparing PSMA PET/MRI and MRI-based radio- GTVn based on MRI and PET/MRI images (P = 0.660, therapy target  volumes. We found that the GTVn based P = 0.650). According to the results of the correlation on PSMA PET/MRI differs from that based on MRI, with analysis, there was a statistically significant link between existing spatial heterogeneity between them. PSMA PET/ the MRI-CTV volume and PET/MRI-CTV volume MRI can identify more lymph node metastasis or even (P = 0.005), as well as between MRI-GTVn volume and change the tumour stage of some patients, and it also PET/MRI-GTVn volume (P < 0.001) (Fig. 5). reduces the probability of false-positive lymph nodes and Table 2 Clinical target volume measurement and parameter statistics Characteristic MRI-CTV (cc) PET/MRI-CTV (cc) Overlap volume (cc) CI LCF DSC (n = 49) Mean 579.3 580.3 552.8 0.999 0.953 0.954 SD 56.4 62.7 55.85 0.036 0.024 0.021 CI Conformity index, LCF Lesion-coverage factor, DSC Dice similarity coefficient, CTV Clinical target volume Liu  et al. Cancer Imaging (2023) 23:1 Page 7 of 12 Fig. 4 Bland–Altman analysis between volumes delineated on the two modalities for CTV(A) and for GTVn (B) Liu et al. Cancer Imaging (2023) 23:1 Page 8 of 12 Table 3 Nodal gross tumor volume measurement and parameter statistics Characteristic MRI-GTVn(cc) PET/MRI-GTVn(cc) Overlap volume (cc) CI LCF DSC (n = 12) Mean 2.775 3.167 1.433 0.927 0.284 0.295 SD 5.047 4.118 2.854 0.621 0.272 0.242 CI Conformity index, LCF Lesion-coverage factor, DSC Dice similarity coefficient, GTVn  Nodal gross tumor volume changes the TVs in radiotherapy planning (RTP) to pro- PSMA-targeted PET provides better detection of tect normal tissues. The difference between CTVs based metastases than conventional imaging (i.e., CT, mul- on PSMA PET/MRI and MRI was not significant, indi - tiparametric MRI, and 18F-based PET-CT [flucil - cating that the ability to identify the tissue structure of loflox and choline]). Several studies have confirmed the pelvic drainage area was similar for PSMA PET/MRI that 68  Ga-PSMA PET-CT has higher sensitivity and and MRI. specificity in identifying pelvic nodes and/or distant More than 30–40% of high-risk PCa patients present metastases with biopsy-proven high-risk PCa than with PLNM during pelvic lymph node dissection and CT or bone scans. Sawicki et  al. found that 68  Ga- staging [23]. The treatment of PLN with external beam PSMA PET-CT detected lesions missed by WB-MRI radiation therapy (RT) is a frequent component of the in patients with biochemical failure after radical management of patients with prostate cancer. Whole pel- prostate cancer surgery [27–31]. Another study of a vic radiation therapy (WPRT) is a common practice for high-risk prostate cancer group showed that PSMA men receiving prostate radiotherapy for high-risk disease, PET-CT resulted in improved overall staging in 23.9% clinical lymph node-positive disease, and postprostatec- of patients with negative conventional imaging (CT or tomy [5, 24, 25].The consensus atlas for pelvic nodal con - MRI) [32]. Even in the diagnosis of small lymph nodes, touring in the clinical target area for WPRT was newly PSMA PET also had a specificity of 95% for diagnosis revised in 2021. In our research, CTV was contoured [33, 34]. An article evaluating the use of [68  Ga] Ga- based on MRI and PET/MRI according to the above prin- PSMA-11 PET (PSMA-PET)/MRI in the staging of ciples. No statistically significant differences were found primary tumour-node-metastasis in prostate cancer when comparing the results, no matter the volume size or affirmed its excellent accuracy (93% accuracy at N1 spatial coincidence. Based on the Bland–Altman analysis, stage) and found that it could change the treatment strategy in 28.7% of patients [16]. In this paper, com the MRI-CTV and PET/MRI-CTV had good consistency - without changing with the size of the CTV. This shows pared to MRI, PSMA PET/MR had high sensitivity and that the CTV delineated based on the two methods of specificity, with significant differences between the two whole pelvic radiotherapy for prostate cancer is compara- methods (P = 0.011). Of the 49 high-risk prostate can- ble. Although the boundary of CTV may differ due to the cer patients, 21 patients (42.9%) had N1/M1 disease, of difference in GTVn (as depicted in Fig.  3), the range of whom 1 patient was previously N0 and 7 patients had CTV was much larger than GTVn, so that the difference bone metastases on PSMA PET/MRI. Similar results caused by GTVn cannot be clearly reflected. In a word, were confirmed in other articles. The high sensitivity the results reflect the high similarity of the CTV obtained and specificity of PSMA PET/MRI changes the clinical by the two methods. Ingrid White et  al. noted that MRI stage of patients, which may affect the treatment plan provides superior soft tissue contrast compared to CT of patients [35]. in RTP for rectal cancer, resulting in a clearer delinea- Integration of PET/CT in radiotherapy planning is com- tion of the boundaries of the target areas and reducing mon in many cancer types [10], and PET/MRI is now the volume due to observer uncertainty, as demonstrated increasingly being used in RTP [36–41]. In prostate can- by the reduced margins of both CTV and PTV in the cer, several studies have also evaluated the use of PSMA corresponding adapted radiotherapy [26]. Based on our PET/MRI in the radiotherapy of primary and recurrent research results, the CTVs of PET/MRI and MRI are sim- prostate cancer [16, 42, 43]. We are the first to investi - ilar. Therefore, despite the lack of research comparing the gate the application of PSMA PET/MRI in the GTVn of difference between targets delineated based on CT and radiotherapy, and we discovered that when compared to PET/MRI, we believe that PET/MRI has advantages simi- MRI, PSMA PET/MRI has altered the RTP. The spatial lar to those of MRI in target delineation for radiotherapy, analysis index indicated that the overlap between the two namely, based on the excellent soft tissue resolution it GTVn was low, and when combined with the analysis of provides, doctors could delineate the boundary of the sensitivity and specificity for lymph nodes, we confidently target areas more clearly. concluded that the GTVn contouring on PSMA PET/ Liu  et al. Cancer Imaging (2023) 23:1 Page 9 of 12 Fig. 5 PSMA PET/MRI‑ CTV versus MRI‑ CTV (A); PSMA PET/MRI‑ GTVn versus MRI‑ GTVn (B) Liu et al. Cancer Imaging (2023) 23:1 Page 10 of 12 Fig. 6 Confusion matrix results of MRI and PET/MRI for lymph node‑based analysis (A) and for patient ‑based analysis (B) MRI is more accurate and may help to reduce lymph node Therefore, we have emphasized the utility of PET/MRI recurrence. In combination with a recent research effort fusion images in delineating prostate cancer radiotherapy. conducted by our group, which showed that it was feasi- It is necessary to acknowledge some limitations. The ble to visually delineate GTV on PSMA PET/MRI in PCa nature of retrospective studies may have introduced radiotherapy [21]. Our investigation has shown that it is unnoticed statistical bias in adherence. CT is the most feasible to delineate GTVn and CTV on PSMA PET/MRI. commonly used imaging technique in radiotherapy treat- ment planning. This paper only compares PET/MRI and MRI, leaving CT out of the equation. It is basically Table 4 PSMA PET/MRI has higher sensitivity and specificity for impossible to obtain the results of node-to-node rad path detecting pelvic lymph node metastasis when compared to MRI. correlation, so we grouped pelvic lymph nodes into five (A: lymph node‑based analysis; B: patient ‑based analysis) groups for a matching analysis between pathology and Parameter Sensitivity % (95% CI) Specificity % (95% CI) imaging, which may bias the results of the diagnosing efficacy of imaging methods (PET/MRI or MRI). In addi - A PET/MRI 77.78 (61.91 to 88.28) 99.76 (98.68 to 99.96) tion, we only analysed a small sample size, specifically, MRI 63.89 (75.03 to 97.78) 99.53 (98.31 to 99.87) the CTV of 49 patients and the GTVn of 12 patients. As a B PET/MRI 91.67 (64.61 to 98.51) 100.00 (86.68 to 100.00) result, the practical application value of PSMA PET/MRI MRI 83.33 (55.20 to 95.30) 100.00 (86.68 to 100.00) requires further investigation in large, well-designed, randomized, controlled trials. The 95% CI for the sensitivity and specificity estimates were calculated using Wilson’s score method Liu  et al. Cancer Imaging (2023) 23:1 Page 11 of 12 Consent for publication Conclusion Written informed consent was obtained from the patient for publication of PSMA PET/MRI-GTVn is more accurate in whole pel- this case report and any accompanying images. A copy of the written consent vic radiotherapy for high-risk prostate cancer patients is available for review by the Editor‑in‑ Chief of this journal. because PSMA PET/MRI has higher sensitivity, speci- Competing interests ficity and diagnostic accuracy than MRI in identifying The authors declare that there are no conflicts of interest regarding the publi‑ PLNM. The CTV of whole pelvic radiotherapy deter - cation of this article. mined by PSMA PET/MRI and MRI is comparable. Eight Author details high-risk prostate cancer patients who finished PSMA Department of Radiation Oncology, Shanghai East Hospital, School of Medi‑ PET/MRI changed their N or M stage. The use of PSMA cine, Tongji University, Shanghai 200120, China. Department of Nuclear Medicine, Shanghai East Hospital, School of Medicine, Tongji University, PER/MRI aids in the realization of more individualized Shanghai 200120, China. Department of Urology, Shanghai East Hospital, and precise radiotherapy. School of Medicine, Tongji University, Shanghai 200120, China. Depar tment of Radiation Oncology, Shanghai East Hospital Ji’an hostipal, Ji’an City, Jiangxi Province 343000, China. Abbreviations PCa: Prostate cancer; RTP: Radiotherapy planning; PSMA: Prostate‑specific Received: 1 August 2022 Accepted: 25 December 2022 membrane antigen; CTV: Clinical target volume; GTVn: Nodal gross tumour volume; WPRT: Whole pelvic radiation therapy; PLNM: Pelvic lymph node metastasis; RP: Radical prostatectomy; PLN: Pelvic lymph node; PLND: Pelvic lymph node dissection; EPLND: Extended pelvic lymph node dissection; CI: Conformity index; LCF: Lesion coverage factor; DSC: Dice similarity coefficient; References EAU: European Association of Urology. 1. Sita TL, Petras KG, Wafford QE, Berendsen MA, Kruser TJ. Radiotherapy for cranial and brain metastases from prostate cancer: a systematic review. J Neurooncol. 2017;133(3):531–8. Supplementary Information 2. Fine SW. Variants and unusual patterns of prostate cancer: clinico‑ The online version contains supplementary material available at https:// doi. pathologic and differential diagnostic considerations. 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Journal

Cancer Imaging – Springer Journals

Published: Jan 4, 2023

Keywords: Prostate cancer; PET/MRI; PSMA; Radiotherapy; CTV; GTVn

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