Background: Focal radiation therapy has gained of interest in treatment of patients with primary prostate cancer (PCa). The question of how to define the intraprostatic boost volume is still open. Previous studies showed that multiparametric MRI (mpMRI) or PSMA PET alone could be used for boost volume definition. However, other studies proposed that the combined usage of both has the highest sensitivity in detection of intraprostatic lesions. The aim of this study was to demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of radiation therapy dose painting using Ga-HBED-CC PSMA PET/CT, mpMRI or the combination of both in primary PCa. Methods: Ten patients underwent PSMA PET/CT and mpMRI followed by prostatectomy. Three gross tumour volumes (GTVs) were created based on PET (GTV-PET), mpMRI (GTV-MRI) and the union of both (GTV-union). Two plans were generated for each GTV. Plan95 consisted of whole-prostate IMRT to 77 Gy in 35 fractions and a simultaneous boost PET MRI union to 95 Gy (Plan95 /Plan95 /Plan95 ). Plan80 consisted of whole-prostate IMRT to 76 Gy in 38 fractions and a PET MRI union simultaneous boost to 80 Gy (Plan80 /Plan80 /Plan80 ). TCPs were calculated for GTV-histo (TCP-histo), which was delineated based on PCa distribution in co-registered histology slices. NTCPs were assessed for bladder and rectum. Results: Dose constraints of published protocols were reached in every treatment plan. Mean TCP-histo were 99.7% union union union (range: 97%–100%) and 75.5% (range: 33%–95%) for Plan95 and Plan80 , respectively. Plan95 had significantly MRI PET union higher TCP-histo values than Plan95 (p =0.008) and Plan95 (p = 0.008). Plan80 had significantly higher TCP-histo MRI PET values than Plan80 (p = 0.012), but not than Plan80 (p = 0.472). MRI union Plan95 had significantly lower NTCP-rectum than Plan95 (p = 0.012). No significant differences in NTCP-rectum and NTCP-bladder were observed for all other plans (p > 0.05). Conclusions: IMRT dose escalation on GTVs based on mpMRI, PSMA PET/CT and the combination of both was feasible. Boosting GTV-union resulted in significantly higher TCP-histo with no or minimal increase of NTCPs compared to the other plans. Keywords: Prostate cancer, Focal therapy, MRI, PSMA PET/CT * Correspondence: email@example.com Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, Robert-Koch Straße 3, 79106 Freiburg, Germany German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zamboglou et al. Radiation Oncology (2018) 13:81 Page 2 of 9 Background that the TCP calculation is based on the histological data, Radiation therapy dose escalation for primary prostate while the radiation treatment planning is done based on cancer (PCa) can lower the risk of biochemical relapse . multimodal imaging derived GTVs. The normal tissue Although toxicity from intensity modulated radiation complication probabilities (NTCPs) for bladder and rec- therapy (IMRT) is manageable even at whole-prostate tum were calculated. doses up to 86 Gy , recurrent PCa at the original tumour volume was still reported at this dose magnitude Methods . Therefore, further increase in dose escalation may be Patients necessary to improve local tumour control . In the last The study cohort consisted of 10 patients with primary years, focal radiation therapy strategies evolved which PCa (intermediate and high risk according to NCCN- limit normal tissue toxicity while enabling a further dose guidelines) who had PSMA PET/CT and mpMRI scans escalation to the tumour . prior to radical prostatectomy. Their characteristics are The exact delineation of the intraprostatic tumour mass described in Additional file 1: Table S1. Written informed is crucial for focal therapy strategies since the PCa volume consent was obtained from each patient, and the institu- should be covered by the imaging defined target region. tional review board approved this study. Recently, two phase III trials (FLAME trial and HEIGHT trial) defined the intraprostatic boost volume by multi- PET/CT imaging parametric MRI (mpMRI) . However, first studies PET/CT scans using the ligand Ga-HBED-CC-PSMA showed that PSMA PET/CT has a potential both in pri-  were either performed with a 64-slice GEMINI TF mary PCa detection and delineation [7, 8]. We examined PET/CT or a 16-slice GEMINI TF BIG BORE PET/CT the value of IMRT dose escalation on PSMA PET/CT-de- (both Philips Healthcare. USA). A detailed description of fined gross tumour volumes (GTVs) in a planning study. our Ga-HBED-CC-PSMA PET/CT imaging protocol is A boost of up to 95 Gy in 35 fractions resulted in signifi- given in our previous publication . To ensure the cantly higher tumour control probability (TCP) values comparability of the quantitative measurements, both than a standard fractionation to the whole prostatic gland imaging systems were cross-calibrated. Patients under- with 77 Gy in 35 fractions (96% vs. 70%). However, in 20% went the whole-body PET scan starting 1 h after injection. of the patients the dose escalation plans reached TCP The uptake of Ga-PSMA-HBED-CC was quantified by values of around 80% . standardized uptake values (SUV). In a comparison of PSMA PET and mpMRI for PCa detection, Eiber et al.  reported better area under the MR imaging curve (AUC) values when PSMA PET and MRI informa- MR images were acquired either on a 3 Tesla system (Trio tion were combined, which we could confirm by perform- Tim, Siemens, Germany / 7 patients) or on a 1.5 Tesla sys- ing a slice-by-slice comparison between mpMRI, PSMA tem (Aera and Avanto, Siemens, Germany / 3 patients). All PET/CT and histopathology after prostatectomy . systems were equipped with a surface phased array (Body Sensitivities of 75%, 70% and 82% for PSMA PET, mpMRI Matrix) in combination with an integrated spine array coil. and combined information were reported. No endo-rectal coil was used. Essentially, T2-weighted fast Furthermore, both studies pointed out that mpMRI spin echo (T2W-TSE) images, diffusion weighted images and PSMA PET offer complementary information. How- (DWI) and dynamic contrast-enhanced (DCE) perfusion ever, there was a specificity of 67% for combined PSMA images were acquired. A detailed description of the MR PET and mpMRI information , indicating that the imaging protocol is given in . combination may overestimate the true PCa amount within the prostate. Whether the increase in sensitivity Image co-registration and the decrease in specificity could be transferred to in- After formalin-fixation, the resected prostate was placed in creased tumour control and normal tissue toxicity could a special holder and a CT scan was performed. Subse- not yet be answered. quently, whole-mount step sections were cut using an in- The aim of this radiation therapy planning study was to house cutting device and processed by a board-certified demonstrate the technical feasibility of IMRT boosting pathologist. According to our previous study , histo- based on GTVs derived from PSMA PET/CT, mpMRI or pathological information was digitalized to create GTV- combined (PSMA PET and mpMRI) information in histo and registered on in-vivo CT (PSMA PET/CT scans), patients with primary PCa. Additionally, we compared the taking into account the non-linear shrinkage and distortion value of mpMRI, PSMA PET/CT and their combination of theresectedprostate tissue(Fig. 1). Subsequently, in-vivo for IMRT dose escalation guidance by calculating the PET/CT datasets (including GTV-histo) were imported TCPs based on the dose distribution in PCa within co- into iPlan (iPLAN RT image 4.1, BrainLAB. Germany). registered histology. The strength of this planning study is AxialTSE-, DWI- ADCmapsand DCE-MRIimageswere Zamboglou et al. Radiation Oncology (2018) 13:81 Page 3 of 9 Fig. 1 Transverse T2-weighted image (a) shows a hypointense signal in the left lobe. (b) shows a PSMA PET image with intense focal uptake located in the left lobe. Haematoxylin and eosin gross section histopathology shows a large tumour focus in the left lobe (c). (d)shows atransverse CTimage (from PSMA PET/CT scan) with projected GTVs (green: GTV-histo, yellow: GTV-PET, red: GTV-MRI) for patient 9. In (e) the colourwash representation for 95union Plan is presented. The PTV of the boost volume is marked in red matched with in-vivo CT images using mutual information IMRT planning registration. If visual assessment showed an anatomical Rapid Arc IMRT treatment plans were created in Eclipse mismatch, a manual adjustment was performed based on v13.5 (Varian, USA). For each patient two different focal anatomical markers. For alignment between PET and CT radiation therapy regiments were simulated. A moderate images the pre-set registration was used. Thus, CT/PET/ dose escalation was planned according to Pinkawa et al. MRI and histopathology data were registered in the same  and a more intense dose escalation was planned in reference frame. analogy to the experimental arm of the Flame trial . The simultaneous integrated boost was delivered based Generation of contours on PET (PTV-PET), MRI (PTV-MRI) or combined Contours of the GTVs were generated in iPLAN. Based PSMA PET and mpMRI information (PTV-union). on our recent results, GTV-PET was created semi- automatically using a threshold of 30% of SUVmax within 1.) FLAME trial protocol the prostate . Two board-certified radiologists delin- To simulate the experimental arm of the FLAME trial we eated GTV-MRI in consensus using T2W, DWI and planned 52.8 Gy in 24 fractions on PTV1 and 24.2 Gy in DCE-sequences to characterize each lesion. Lesions with 11 fractions on PTV2 (EQD2 = 80 Gy) with a α/β=3Gy MRI visually determined PI-RADs v2 score 4or higher concomitant boost to PTV-MRI (Plan95 ), PTV-PET PET union were included in the analysis. With respect to PI-RADs v2 (Plan95 ), PTV-union (Plan95 ) with a dose of criteria, T2W-TSE and DWI images were primarily used 95 Gy in 35 fractions (EQD2 = 109 Gy). Dose α/β=3Gy for delineation of transition zone and peripheral zone constraints for bladder and rectum were taken from the lesions, respectively. The addition of GTV-PET and GTV- FLAME protocol . MRI was classified as GTV-union. Subsequently, the in- vivo CT including all above described GTVs was trans- 2.) Pinkawa et al. protocol ferred to the RT planning system Eclipse v13.5 (Varian, Treatment planning was performed according to . We USA) and contours for the prostate, seminal vesicles, and planned 54 Gy in 27 fractions on PTV1 and 22 Gy in 11 surrounding Organs at risk were generated. Clinical target fractions on PTV2 (EQD2 = 76 Gy) with a simul- α/β=3Gy MRI volume 1 (CTV1) was defined as the prostate and the taneous dose escalation to PTV-MRI (Plan80 ), PTV- PET union seminal vesicles. CTV2 was defined as the prostate and PET (Plan80 ), PTV-union (Plan80 ) with a dose of half of the seminal vesicles (high risk patients) or the basis 80 Gy in 38 fractions (EQD2 =80 Gy). Dose α/β=3Gy of the seminal vesicles (intermediate risk patients). CTV1, constraints for bladder and rectum were taken from the CTV2, GTV-MRI, GTV-PET and GTV-union were study protocol . In case of an overlap between the enlarged by an isotropic margin of 4 mm to create the boost volumes and the rectal wall a maximum dose to the respective PTVs. rectum of up to 80 Gy was defined as a minor deviation. Zamboglou et al. Radiation Oncology (2018) 13:81 Page 4 of 9 During planning, dose constraints for the organs at risk stenosis/fistula. EQD2), s = 0.75 and γ =1.79 were chosen. had the highest priority. In order to achieve comparable The γ-values were calculated based on the listed k-values plans for the different boost volumes the dose distribution . For both organs, an α/β ratio of 3 Gy was assumed within the corresponding PTVs was optimized to be as according to a recent study . homogeneous as possible (see Additional file 2: Table S2a and 2b). Statistical analysis Statistical analyses were performed with Prism 7 (Graph- Radiobiological treatment plan evaluation Pad, USA) and Microsoft Excel 2010 (Microsoft, USA). The TCP and NTCP calculations were performed using The Wilcoxon matched pairs signed-rank test was used the research version of BIOTOP/BIOSPOT (Pi-medical, with a threshold for statistical significance of < 0.05. Greece) and MATLAB R2017a (The MathWorks, USA). The summation of 3D dose distributions, EQD2 as well as Results TCP and NTCP calculations were performed at voxel GTV-histo, GTV-PET, GTV-MRI and GTV-union in level. For TCP calculations, a radiobiological model based average amounted to 15 ± 12%, 17 ± 13%, 10 ± 9% and 20 on the linear quadratic (LQ) Poisson model [16–20] was ± 14% of the total intraprostatic volume (mean 54.17 ± 24. used. TCP calculations were performed based on GTV- 35 ml), respectively (Table 1). histo (TCP-histo), assuming it to represent the true clin- In average, 86 ± 10%, 74 ± 17% and 93 ± 5% of GTV-histo ical response. overlapped with PTV-PET, PTV-MRI and PTV-union, For the TCP calculations, we used the parameter α/β = respectively (Fig. 2). 1.93  and the tumor cell density ρ =2.8 × 10 cells For all patients the target volume objectives as well as the 3 PET MRI /cm for intermediate and high-risk patients [22–24]. The OAR dose constraints were met. For Plan95 ,Plan95 − 1 union value for α (α =0.1335 Gy ) was chosen in order to and Plan95 the mean doses for GTV-histo were 95.3 ± achieve an average TCP-histo value of 70% over all 2.6 Gy, 93.3 ± 2.6 Gy and 96.3 ± 1.5 Gy, respectively. For PET MRI union patients for the standard arm fractionation of the FLAME Plan80 ,Plan80 and Plan80 the mean doses for trial (77 Gy in 35 fractions) . For a detailed description GTV-histo were 80.7 ± 0.4 Gy, 79.9 ± 0.8 Gy and 80.8 ± 0. of the TCP calculation methodology performed in this 5 Gy, respectively. Additional file 4:FigureS1shows dose study, please see Additional file 3 and our previous publi- volume histograms (DVHs) for GTV-histo, averaged for all cation . plans and all patients. To calculate NTCPs of non-uniform dose distributions TCP-histo values are listed in Table 2. union the relative seriality model was used [18, 25–27]. The fol- Plan95 had significantly higher TCP-histo values MRI PET lowing parameters were selected for bladder and rectum than Plan95 (p = 0.008) and Plan95 (p = 0.008). union according to . For bladder D50 = 80 Gy (symptomatic Plan80 had significantly higher TCP-histo values MRI contracture and volume loss. EQD2), s = 1.3 and γ =2.59 than Plan80 (p = 0.012). There were no significant PET and for rectum D50 = 80 Gy (severe proctitis/necrosis/ differences in TCP-histo values between Plan80 and Table 1 GTV volumes for each patient % of prostatic volume Patient GTV-Histo GTV-PET GTV-MRI GTV-union Volume prostate (ml) 1 17% 39% 8% 41% 31.9 2 10% 23% 8% 24% 31.4 3 32% 25% 25% 36% 61.8 4 25% 9% 19% 22% 53.6 5 2% 2% 1% 2% 110.2 6 3% 4% 3% 5% 48.7 72% 3% 1% 4% 70 8 4% 10% 4% 11% 60 9 19% 24% 22% 33% 26.5 10 33% 26% 10% 26% 47.6 Mean 15% 17% 10% 20% 54.2 SD ± 12% 13% 9% 14% 24.4 GTV-histo was not significantly smaller than GTV-union (p = 0.1) and GTV-PET (p = 0.715) but significant larger than GTV-MRI (p = 0.047) in Wilcoxon matched pairs signed-rank test. Mean prostatic volume (delineated in CT) was 54.2 ± 24.4 ml Zamboglou et al. Radiation Oncology (2018) 13:81 Page 5 of 9 combined mpMRI and PSMA PET information, than with PTV-PET or PTV-MRI alone. Furthermore, mean GTV- union was slightly larger than mean GTV-PET (p >0.05) and mean GTV-histo (p > 0.05) and it was significantly larger than GTV-MRI (p < 0.05). The main questions for this study were whether a focal dose escalation, which is guided by combined PSMA PET and mpMRI information, is technically feasible and if an increase in TCP values is achieved compared to boosting GTVs based on PSMA PET or mpMRI alone. We performed TCP-histo calculations based on registered histological information after prostatectomy, which should correlate with the real PCa distribution and should also predict the true clinical outcome. This study confirmed the technical feasibility for pre- Fig. 2 The middle horizontal bars represent the mean values and scription doses and dose constraints of the FLAME trial the upper and lower bars the standard deviations. In Wilcoxon  and Pinkawa et al. . These two clinical protocols matched pairs signed-rank test, GTV-histo overlapped significantly were chosen since they applied different prescription higher with PTV-union than with PTV-PET (p = 0.016) and PTV-MRI doses for the prostate (EQD2 =76 Gy and α/β=3Gy (p = 0.002), respectively 80 Gy ) and the boost volume (EQD2 =80 Gy α/β=3Gy and 109Gy ) using similar fractions. NTCP values union Plan80 (p = 0.472). Whether the dose escalation was for rectum and bladder were identical for all plans, except MRI delivered based on PET or mpMRI information had of a slight decrease in NTCP-rectum values for Plan95 MRI no impact on TCP-histo values for both protocols (mean NTCP-rectum was 1.09 for Plan95 ,1.41 for PET union (p > 0.05, Fig. 3). Plan95 and 1.42 for Plan95 ). union NTCP calculations for bladder and rectum revealed no TCP-histo values were significantly higher for Plan95 union significant differences for all plans (p > 0.05, Fig. 4), with and Plan80 compared to the plans in which the boost MRI the exception that Plan95 had significantly lower volume was derived from mpMRI or PSMA PET/CT alone. union NTCP-rectum values than Plan95 (p = 0.012) and This observation can most likely be ascribed to the high PET Plan95 (p = 0.047), respectively. overlap between PTV-union and GTV-histo. In average 86%, 74% and 93% of GTV-histo overlapped with PTV- Discussion MRI, PTV-PET and PTV-union, respectively. For Plan80, A reliable delineation of the intraprostatic tumor burden the assumed correlation between GTV-histo coverage and is a prerequisite for implementation of focal therapy resulting TCP-histo was confirmed as the mean TCP-histo PET MRI approaches in treatment of primary PCa. Most of the pub- was indeed higher for Plan80 than it was for Plan80 . MRI lished studies used mpMRI to define the target for focal Interestingly though, for Plan95 the mean TCP-histo PET therapy guidance . Our group  and others [8, 30] was higher than for Plan95 . A good coverage of the illustrated a great potential for PSMA PET/CT based main PCa mass by PTV-MRI serves as an explanation for delineation of primary PCa. However, two recent studies this observation. Since the FLAME protocol deliveres a examined the role of combined PSMA PET and mpMRI higher dose to theentireprostatethanthe Pinkawa proto- information for primary PCa localization based on hist- col (difference of EQD2 = 4 Gy), missing small PCa α/β=3Gy ology reference. Both reported higher sensitivities when lesions with the boost volume has a lower impact on the the combined information was used compared to PSMA TCP for the FLAME protocol than it has for the Pinkawa PET or mpMRI alone [10, 11]. Accordingly, we could protocol. For ultra-focal therapyapproacheslikehighinten- show in this study that GTV-histo overlapped significantly sity focused ultrasound (HIFU) , or focal low−/high- higher with PTV-union, which was generated based on dose rate brachytherapy [32, 33] the treatment is focused Table 2 TCP-histo values PET MRI union PET MRI union Plan95 Plan95 Plan95 Plan80 Plan80 Plan80 Mean (%) 94.7 96.9 99.7 73.0 70.8 75.5 Maximum (%) 100.0 100.0 100.0 94.0 94.0 95.2 Minimum (%) 69.6 86.4 97.4 25.1 30.2 33.0 Mean, maximum and minimum TCP-histo values over all patients for all plans are listed Zamboglou et al. Radiation Oncology (2018) 13:81 Page 6 of 9 Fig. 3 The middle horizontal bars represent the mean values and the upper and lower bars the respective maximum and minimum values. union MRI PET Wilcoxon matched pairs signed-rank test showed that Plan95 had significantly higher TCP values than both Plan95 and Plan95 , union MRI PET respectively (p < 0.05). Plan80 only had significantly higher TCP values than Plan80 (p < 0.05) but not than Plan80 (p = 0.5). There MRI PET were no significant differences in TCP-histo values between Plan80/95 and Plan80/95 (p = 0.371 for Plan80 and p = 0.844 for Plan95) solely within the imaging defined target or region. Thus, a in detection of primary PCa [10, 11, 13]. 22% to 32% high coverage of the PCa mass may be even more  of prostatic areas were classified as positive by one crucial than for the two IMRT protocols which were modality and negative by the other. Furthermore, we used in this study. found very little to no differences in NTCP values for As expected, TCP-histo values for Plan95 had a much bladder and rectum between the plans. Future studies are union lower range than TCP-histo values for Plan80 (Fig. 3 needed to characterize those patient populations (e.g. by and Table 2), indicating that the intensity of dose Gleason score or PSA serum levels) in which a combined escalation has a higher impact than the modality which usage of PSMA PET and mpMRI is necessary and to was chosen for boost-volume delineation. Dose escalation differentiate them from the remaining majority of cases up to 95 Gy on PTV-PET and PTV-MRI alone reached where only a single imaging modality is sufficient. Until excellent results (TCP-histo > 95%) in 8 of 10 patients. this question is finally answered, the combined usage of Furthermore, only a small difference in mean TCP-histo PET and mpMRI for GTV-delineation ensures the best PET union values between Plan80 and Plan80 was measured therapeutic ratio. (73% vs. 76). This might be seen as an indicator that a Beyond GTV-delineation for dose escalation guidance, single imaging modality (PSMA PET or mpMRI) is the combined usage of mpMRI and PSMA PET/CT sufficient for GTV-delineation, particularly when consid- offers further advantages in the clinical workflow of ering the overutilization of diagnostic imaging in current patients with primary PCa. MRI provides a better soft health systems . However, several studies showed that tissue contrast than CT images and is likewise superior PSMA PET and mpMRI offer complementary information for prostatic gland delineation . On the other hand, Fig. 4 For all patients NTCP values for bladder and rectum were presented for all plans. The middle bars represent the mean values and the upper and lower bars the standard deviations. Wilcoxon matched pairs signed-rank test showed that no significant differences in NTCP values for the different Plans when dose was delivered in analogy to the Pinkawa protocol (p > 0.05). When dose was delivered in analogy to the Flame trial MRI union PET a significant reduction in NTCP-rectum values was observed for Plan95 compared to Plan95 (p = 0.012) and Plan95 (p = 0.047). There were no significant differences in NTCP-bladder values for Plan95 (p > 0.05) Zamboglou et al. Radiation Oncology (2018) 13:81 Page 7 of 9 PSMA PET/CT is superior in lymph node  and skel- in this study have not been validated through prospective etal  staging compared to conventional imaging, in- clinical trials. To account for this issue a previous dicating that PSMA PET/CT may also be used as a planning study used 15 different parameter value combi- “one-stop shop staging” modality for patients with inter- nations for TCP calculations. The observed variance mediate and high-risk PCa. between the TCP-histo values for the different parameter An important issue of this study is the uncertainty in value sets was low , which justifies the approach in this registration of PET/CT, mpMRI and histopathology (e.g. study. non-linear shrinkage of the prostate after prostatectomy In summary, we could show in 10 patients that the con- or different rectum and bladder fillings during imaging) cept of a focal dose escalation is feasible on GTVs delin- . The usage of hybrid PET/MRI systems  might eated by combined PSMA PET and mpMRI information. account for the registration uncertainties between the High TCPs were achieved with acceptable NTCPs. These PET and mpMRI, but these systems are currently not findings need to be further validated in a prospective dose widely available. A second issue of this study is the mar- escalation trial for patients with primary PCa. gin used for PTV generation since the PTV affects the NTCP (dose to rectum and bladder) as well as the TCP Conclusion (potential shifts of GTV-histo out of the dose escalation In patients with primary PCa IMRT dose escalation is area). The FLAME trial (5–8 mm)  and the Pinkawa feasible using GTVs defined on multimodal image data protocol (3–8 mm)  used larger PTV margins (mpMRI and PSMA PET/CT). It achieves significantly around the prostate than our study. On the other hand, higher TCP-histo values with minimal to no increase of the Pinkawa protocol  applied a margin of 3–4mm NTCP values compared to IMRT dose escalation on to create the intraprostatic dose escalation volume and GTVs derived solely based on one imaging modality. the FLAME trial  used no margin for this at all. In the current study we expanded both the prostate and Additional files the intraprostatic GTVs with an isotropic margin of 4 mm to create the respective PTVs. At our department Additional file 1: Table S1. Patient characteristics. (PDF 106 kb) the patients with primary PCa receive daily fiducial Additional file 2: Tables S2a + b. 1. FLAME protocol / 2. Pinkawa marker-based position verification to account for inter- protocol. Dose characteristics after IMRT planning based on different protocols (PDF 82 kb) fractional movements. Additionally, an adaptive radio- Additional file 3: A. Additional information on TCP calculation / B. therapy  protocol based on repeated cone-beam CT Additional information on NTCP calculation. (PDF 278 kb) scans was established in order to calculate the average Additional file 4: Figure S1. Dose volume histograms (DVHs) for GTV- position of the targets and the organs at risk. Therefore, histo, averaged for all plans and all patients. (PDF 169 kb) at our department the PTV mainly accounts for the intrafractional movement during IMRT (maximum Abbreviations movement of 2 mm in > 85% of datasets after 6 min of approx: Approximately; AUC: Area under the curve; CT: Computer RT ) and possible registration errors between CT tomography; CTV1: Clinical target volume; DCE: Dynamic contrast-enhanced images; DWI : Diffusion weighted images; EQD2: Equivalent dose in 2 Gy per and MRI information (approx. 2 mm ). The usage of fraction; GTV: Gross tumour volume; Gy: Gray; IMRT: Intensity modulated 4 mm margins around the prostate in our study could radiation therapy; MRI: Magnetic resonance imaging; NTCP: Normal tissue be considered as a possible reason for keeping the dose complication probability; PCa: Prostate cancer; PET: Positron emission tomography; PTV: Planning target volume; SUV: Standardized uptake value; constraints for rectum and bladder. However, a planning T2W-TSE : T2-weighted fast spin echo images; TCP: Tumour control study by Lips et al.  simulated an intraprostatic dose probability escalation and analyzed the effect of different margins (2–8 mm) around the prostate on the dose distributions Funding The study was funded from house internal budget. for bladder and rectum. The authors observed that the dose constraints for both organs were met for all mar- Availability of data and materials gins. Our group simulated intrafractional movement The datasets used and/or analyses during the current study are available during PSMA PET guided simultaneous integrated boost from the corresponding author on reasonable request. IMRT for patients with primary PCa . By using the same PTV margins as the current study we showed that Authors’ contributions CZ and BT analysed and CZ, BT and ALG interpreted the data. CZ, ALG and intrafractional movement in average does not have any BT performed the statistical analysis and were contributors in writing the significant effect on the TCP and can even increase the manuscript. HCR, PTM and TK helped generating the GTVs (data acquisition). TCP if the boost volume is surrounded by a sufficiently MB was concerned with the MRI sequences. KR and CAJ performed the prostatectomies. PB, VD and MW performed the histopathological high dose plateau. preparation of the data. KK and BT did the IMRT planning. IS and DB were Another potential limitation of this study is that the responsible for biological modelling. ALG supervised the whole project. All clinically derived parameters of the biological model used authors read and approved the final manuscript. Zamboglou et al. Radiation Oncology (2018) 13:81 Page 8 of 9 Ethics approval and consent to participate journal of the European Society for Therapeutic Radiology and Oncology. The University of Freiburg ethics committee approved the study and written 2017;123(3):472–7. informed consent was obtained from all participants. 10. Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate Cancer. Eur Urol. 2016;70:829–36. Consent for publication 11. Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze- Written informed consent for publication was obtained from all participants. Seemann W, et al. Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients Competing interests with primary prostate cancer based on slice by slice comparison with The authors declare that they have no competing interests. histopathology. Theranostics. 2017;7(1):228–37. 12. Eder M, Neels O, Muller M, Bauder-Wust U, Remde Y, Schafer M, et al. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA- Publisher’sNote HBED-CC: a new PET tracer for imaging of prostate Cancer. Springer Nature remains neutral with regard to jurisdictional claims in Pharmaceuticals. 2014;7(7):779–96. published maps and institutional affiliations. 13. Zamboglou C, Wieser G, Hennies S, Rempel I, Kirste S, Soschynski M, et al. MRI versus (68)Ga-PSMA PET/CT for gross tumour volume delineation in Author details radiation treatment planning of primary prostate cancer. Eur J Nucl Med Department of Radiation Oncology, Medical Center – University of Freiburg, Mol Imaging. 2016;43(5):889–97. Faculty of Medicine, Robert-Koch Straße 3, 79106 Freiburg, Germany. 14. Weinreb JC, Barentsz JO, Choyke PL, Cornud F, Haider MA, Macura KJ, et al. Division of Medical Physics, Department of Radiation Oncology, Medical PI-RADS prostate imaging - reporting and data system: 2015, version 2. Eur Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany. Urol. 2016;69(1):16–40. Department of Pathology, Medical Center – University of Freiburg, Faculty 15. Pinkawa M, Piroth MD, Holy R, Klotz J, Djukic V, Corral NE, et al. Dose- of Medicine, Freiburg, Germany. Department of Nuclear Medicine, Medical escalation using intensity-modulated radiotherapy for prostate cancer - Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany. evaluation of quality of life with and without (18)F-choline PET-CT detected Department of Radiology, Medical Center – University of Freiburg, Faculty of simultaneous integrated boost. Radiat Oncol. 2012;7:14. Medicine, Freiburg, Germany. Department of Urology, Medical Center – 16. Munro TR, Gilbert CW. The relation between tumour lethal doses and the University of Freiburg, Faculty of Medicine, Freiburg, Germany. Division of radiosensitivity of tumour cells. Br J Radiol. 1961;34:246–51. Medical Physics, Department of Radiology, Medical Center – University of 17. Brahme A, Agren AK. Optimal dose distribution for eradication of Freiburg, Faculty of Medicine, Freiburg, Germany. German Cancer heterogeneous tumours. Acta Oncol. 1987;26(5):377–85. Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. 18. Lind BK, Mavroidis P, Hyodynmaa S, Kappas C. Optimization of the dose Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, level for a given treatment plan to maximize the complication-free tumor Freiburg, Germany. cure. Acta Oncol. 1999;38(6):787–98. 19. Wheldon TE, Deehan C, Wheldon EG, Barrett A. The linear-quadratic Received: 7 March 2018 Accepted: 26 April 2018 transformation of dose-volume histograms in fractionated radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 1998;46(3):285–95. References 20. Yorke ED. Modeling the effects of inhomogeneous dose distributions in 1. Kupelian PA, Ciezki J, Reddy CA, Klein EA, Mahadevan A. Effect of increasing normal tissues. Seminars In Radiation Oncology. 2001;11(3):197–209. radiation doses on local and distant failures in patients with localized 21. Vogelius IR, Bentzen SM. Meta-analysis of the alpha/Beta ratio for prostate prostate cancer. Int J Radiat Oncol Biol Phys. 2008;71(1):16–22. Cancer in the presence of an overall time factor: bad news, good news, or 2. Spratt DE, Pei X, Yamada J, Kollmeier MA, Cox B, Zelefsky MJ. Long- no news? Int J Radiat Oncol. 2013;85(1):89–94. term survival and toxicity in patients treated with high-dose intensity 22. Casares-Magaz O, van der Heide UA, Rorvik J, Steenbergen P, Muren LP. A modulated radiation therapy for localized prostate cancer. Int J Radiat tumour control probability model for radiotherapy of prostate cancer using Oncol Biol Phys. 2013;85(3):686–92. magnetic resonance imaging-based apparent diffusion coefficient maps. 3. Cellini N, Morganti AG, Mattiucci GC, Valentini V, Leone M, Luzi S, et al. Radiother Oncol. 2016;119(1):111–6. Analysis of intraprostatic failures in patients treated with hormonal therapy 23. Chang JH, Joon DL, Lee ST, Gong SJ, Anderson NJ, Scott AM, et al. Intensity and radiotherapy: implications for conformal therapy planning. Int J Radiat modulated radiation therapy dose painting for localized prostate Cancer Oncol Biol Phys. 2002;53(3):595–9. using C-11-choline positron emission tomography scans. Int J Radiat Oncol. 4. Martinez AA, Gonzalez J, Ye H, Ghilezan M, Shetty S, Kernen K, et al. 2012;83(5):E691–E6. Dose escalation improves Cancer-related events at 10 years for 24. Ghobadi G, de Jong J, Hollmann BG, van Triest B, van der Poel HG, Vens C, intermediate- and high-risk prostate Cancer patients treated with et al. Histopathology-derived modeling of prostate cancer tumor control Hypofractionated high-dose-rate boost and external beam radiotherapy. probability: implications for the dose to the tumor and the gland. Int J Radiat Oncol. 2011;79(2):363–70. Radiotherapy and oncology : journal of the European Society for 5. Bauman G, Haider M, Van der Heide UA, Menard C. Boosting imaging Therapeutic Radiology and Oncology. 2016;119(1):97–103. defined dominant prostatic tumors: a systematic review. Radiotherapy and 25. Kallman P, Agren A, Brahme A. Tumour and normal tissue responses to oncology : journal of the European Society for Therapeutic Radiology and fractionated non-uniform dose delivery. Int J Radiat Biol. 1992;62(2):249–62. Oncology. 2013;107(3):274–81. 26. Lyman JT. Complication probability as assessed from dose-volume 6. Lips IM, van der Heide UA, Haustermans K, van Lin EN, Pos F, Franken SP, et histograms. Radiat Res Suppl. 1985;8:S13–9. al. Single blind randomized phase III trial to investigate the benefit of a 27. Kutcher GJ, Burman C. Calculation of complication probability factors for focal lesion ablative microboost in prostate cancer (FLAME-trial): study non-uniform normal tissue irradiation: the effective volume method. Int J protocol for a randomized controlled trial. Trials. 2011;12:255. Radiat Oncol Biol Phys. 1989;16(6):1623–30. 7. Zamboglou C, Schiller F, Fechter T, Wieser G, Jilg CA, Chirindel A, et al. 28. Takam R, Bezak E, Yeoh EE, Marcu L. Assessment of normal tissue (68)Ga-HBED-CC-PSMA PET/CT versus histopathology in primary localized complications following prostate cancer irradiation: comparison of radiation prostate Cancer: a voxel-wise comparison. Theranostics. 2016;6(10):1619–28. treatment modalities using NTCP models. Med Phys. 2010;37(9):5126–37. 8. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic tumor extent with 68Ga-PSMA distribution in 29. Kuang Y, Wu L, Hirata E, Miyazaki K, Sato M, Kwee SA. Volumetric modulated patients with prostate Cancer. Journal of nuclear medicine : official arc therapy planning for primary prostate cancer with selective publication, Society of Nuclear Medicine. 2016;57(4):563–7. intraprostatic boost determined by 18F-choline PET/CT. Int J Radiat Oncol 9. Zamboglou C, Sachpazidis I, Koubar K, Drendel V, Wiehle R, Kirste S, et al. Biol Phys. 2015;91(5):1017–25. Evaluation of intensity modulated radiation therapy dose painting for 30. Rhee H, Thomas P, Shepherd B, Greenslade S, Vela I, Russell PJ, et al. localized prostate cancer using 68Ga-HBED-CC PSMA-PET/CT: a planning Prostate specific membrane antigen positron emission tomography may study based on histopathology reference. Radiotherapy and oncology : improve the diagnostic accuracy of multiparametric magnetic resonance Zamboglou et al. Radiation Oncology (2018) 13:81 Page 9 of 9 imaging in localized prostate Cancer as confirmed by whole mount histopathology. J Urol. 2016;196(4):1261–7. 31. Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology. 2004;63(2):297–300. 32. Zamboglou C, Rischke HC, Meyer PT, Knobe S, Volgeova-Neher N, Kollefrath M, et al. Single fraction multimodal image guided focal salvage high-dose- rate brachytherapy for recurrent prostate cancer. Journal of contemporary brachytherapy. 2016;8(3):241–8. 33. Langley S, Ahmed HU, Al-Qaisieh B, Bostwick D, Dickinson L, Veiga FG, et al. Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer. BJU Int. 2012;109(Suppl 1):7–16. 34. Hendee WR, Becker GJ, Borgstede JP, Bosma J, Casarella WJ, Erickson BA, et al. Addressing overutilization in medical imaging. Radiology. 2010;257(1):240–5. 35. Rasch C, Barillot I, Remeijer P, Touw A, van Herk M, Lebesque JV. Definition of the prostate in CT and MRI: a multi-observer study. Int J Radiat Oncol. 1999;43(1):57–66. 36. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic efficacy of (68)gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate Cancer. J Urol. 2016;195(5):1436–43. 37. Pyka T, Okamoto S, Dahlbender M, Tauber R, Retz M, Heck M, et al. Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43:2114–21. 38. Schiller F, Fechter T, Zamboglou C, Chirindel A, Salman N, Jilg CA, et al. Comparison of PET/CT and whole-mount histopathology sections of the human prostate: a new strategy for voxel-wise evaluation. EJNMMI physics. 2017;4(1):21. 39. Monninkhof EM, van Loon JWL, van Vulpen M, Kerkmeijer LGW, Pos FJ, Haustermans K, et al. Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: toxicity in the FLAME randomized controlled trial. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2018. 40. Ghilezan M, Yan D, Martinez A. Adaptive radiation therapy for prostate cancer. Semin Radiat Oncol. 2010;20(2):130–7. 41. Xie Y, Djajaputra D, King CR, Hossain S, Ma L, Xing L. Intrafractional motion of the prostate during hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72(1):236–46. 42. Dean CJ, Sykes JR, Cooper RA, Hatfield P, Carey B, Swift S, et al. An evaluation of four CT-MRI co-registration techniques for radiotherapy treatment planning of prone rectal cancer patients. Brit J Radiol. 2012; 85(1009):61–8. 43. Lips IM, van der Heide UA, Kotte AN, van Vulpen M, Bel A. Effect of translational and rotational errors on complex dose distributions with off-line and on-line position verification. Int J Radiat Oncol Biol Phys. 2009;74(5):1600–8. 44. Thomann B, Sachpazidis I, Koubar K, Zamboglou C, Mavroidis P, Wiehle R, et al. Influence of inhomogeneous radiosensitivity distributions and intrafractional organ movement on the tumour control probability of focused IMRT in prostate cancer. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2018.
Radiation Oncology – Springer Journals
Published: May 2, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera