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Evaluation of intensity modulated radiation therapy dose painting for localized prostate cancer using 68Ga-HBED-CC PSMA-PET/CT: A planning study based on histopathology reference

  • Constantinos Zamboglou
    Correspondence
    Corresponding author at: Department of Radiation Oncology, Robert-Koch Straße 3, 79106 Freiburg, Germany.
    Affiliations
    Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Ilias Sachpazidis
    Affiliations
    Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Khodor Koubar
    Affiliations
    Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Vanessa Drendel
    Affiliations
    Department of Pathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Rolf Wiehle
    Affiliations
    Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Simon Kirste
    Affiliations
    Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Michael Mix
    Affiliations
    Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Florian Schiller
    Affiliations
    Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Panayiotis Mavroidis
    Affiliations
    Department of Radiation Oncology, University of North Carolina, Chapel Hill, USA
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  • Philipp T. Meyer
    Affiliations
    Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Martin Werner
    Affiliations
    Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Anca L. Grosu
    Affiliations
    Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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  • Dimos Baltas
    Affiliations
    Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    German Cancer Consortium (DKTK), Partner Site Freiburg, Germany
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      Abstract

      Purpose

      To demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of IMRT dose painting using 68Ga-HBED-CC PSMA PET/CT for target delineation in prostate cancer (PCa).

      Methods and materials

      10 patients had PSMA PET/CT scans prior to prostatectomy. GTV-PET was generated on the basis of an intraprostatic SUVmax of 30%. Two IMRT plans were generated for each patient: Plan77 which consisted of whole-prostate IMRT to 77 Gy, and Plan95 which consisted of whole-prostate IMRT to 77 Gy and a simultaneous integrated boost to the GTV-PET up to 95 Gy (35 fractions). The feasibility of these plans was judged by their ability to adhere to the FLAME trial protocol. TCP-histo/-PET were calculated on co-registered histology (GTV-histo) and GTV-PET, respectively. NTCPs for rectum and bladder were calculated.

      Results

      All plans reached prescription doses whilst adhering to dose constraints. In Plan77 and Plan95 mean doses in GTV-histo were 75.8 ± 0.3 Gy and 96.9 ± 1 Gy, respectively. Average TCP-histo values for Plan77 and Plan95 were 70% (range: 15–97%), and 96% (range: 78–100%, p < 0.0001). Average TCP-PET values for Plan77 and Plan95 were 55% (range: 27–82%), and 100% (range: 99–100%, p < 0.0001). There was no significant difference between TCP-PET and TCP-histo in Plan95 (p = 0.25). There were no significant differences in rectal (p = 0.563) and bladder (p = 0.3) NTCPs.

      Conclusions

      IMRT dose painting using PSMA PET/CT was technically feasible and resulted in significantly higher TCPs without higher NTCPs.

      Keywords

      For radiotherapy (RT) of primary prostate cancer (PCa) a dose–response relationship between RT dose and tumour control rates is described. A meta-analysis postulated that the total dose of RT reduces the risk of biochemical failure by approximately 1.8% per Gy increase [
      • Viani G.A.
      • Stefano E.J.
      • Afonso S.L.
      Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized controlled trials.
      ]. However, due to the proximity to rectum and bladder an unlimited dose escalation to the whole prostatic gland with external beam RT would entail an unacceptably high risk of severe toxicity [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ]. Previous planning studies simulated the use of focal dose escalation on a sub-volume within the prostate, which was defined by dynamic contrast-enhanced magnetic resonance imaging (MRI), MR spectroscopy [
      • van Lin E.N.J.T.
      • Futterer J.J.
      • Heumink S.W.T.P.J.
      • et al.
      IMRT boost dose planning on dominant intraprostatic lesions: Gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and H-1-spectroscopic MRI.
      ] or 11C–choline PET/CT [
      • Chang J.H.
      • Joon D.L.
      • Lee S.T.
      • et al.
      Intensity modulated radiation therapy dose painting for localized prostate cancer using C-11-choline positron emission tomography scans.
      ]. The latter study reported a tumour control probability (TCP) of 97% when an IMRT boost of 90 Gy was delivered to a gross tumour volume (GTV) based on 70% of SUVmax [
      • Chang J.H.
      • Joon D.L.
      • Lee S.T.
      • et al.
      Intensity modulated radiation therapy dose painting for localized prostate cancer using C-11-choline positron emission tomography scans.
      ]. However, two more recent studies reported poor performance for choline PET/CT in PCa detection and delineation [
      • Grosu A.L.
      • Weirich G.
      • Wendl C.
      • et al.
      11C-choline PET/pathology image coregistration in primary localized prostate cancer.
      ,
      • Bundschuh R.A.
      • Wendl C.M.
      • Weirich G.
      • et al.
      Tumour volume delineation in prostate cancer assessed by [11C]choline PET/CT: validation with surgical specimens.
      ]. A multicentre, randomized trial (FLAME-trial) defined the intraprostatic boost volume by multiparametric MRI (mpMRI) [
      • Lips I.M.
      • van der Heide U.A.
      • Haustermans K.
      • et al.
      Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.
      ]. The control group received 77 Gy in 35 fractions to the whole prostate. The experimental group received 77 Gy to the whole prostate with an additional integrated boost to the MRI-defined macroscopic tumour to a total dose of 95 Gy. The suspected benefit on five-year freedom from biochemical failure was at least 10% for the experimental group.
      Radioactive-labelled tracers targeting the prostate specific membrane antigen (PSMA) have gained interest. PSMA is a membrane-bound enzyme and has a higher expression in malignant prostate tissue compared to benign prostate tissue [
      • Mhawech-Fauceglia P.
      • Zhang S.
      • Terracciano L.
      • et al.
      Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using mutiple tumour tissue microarray technique.
      ,
      • Silver D.A.
      • Pellicer I.
      • Fair W.R.
      • Heston W.D.
      • Cordon-Cardo C.
      Prostate-specific membrane antigen expression in normal and malignant human tissues.
      ]. Preliminary studies have illustrated the potential for PSMA PET/CT in the detection of primary PCa based on histology reference [
      • Zamboglou C.
      • Schiller F.
      • Fechter T.
      • et al.
      (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.
      ,
      • Rahbar K.
      • Weckesser M.
      • Huss S.
      • et al.
      Correlation of intraprostatic tumor extent with 68Ga-PSMA distribution in patients with prostate cancer.
      ]. Our group compared mpMRI with PSMA PET/CT for GTV delineation in patients with primary PCa. In half of the patients discrepant results were observed [
      • Zamboglou C.
      • Wieser G.
      • Hennies S.
      • et al.
      MRI versus (68)Ga-PSMA PET/CT for gross tumour volume delineation in radiation treatment planning of primary prostate cancer.
      ]. Three studies compared mpMRI and PSMA PET/CT with histology after prostatectomy in patients with primary PCa. PSMA PET/CT outperformed mpMRI for PCa detection in all three studies [
      • Rhee H.
      • Thomas P.
      • Shepherd B.
      • et al.
      Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer as confirmed by whole mount histopathology.
      ,
      • Eiber M.
      • Weirich G.
      • Holzapfel K.
      • et al.
      Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer.
      ,
      • Zamboglou C.
      • Drendel V.
      • Jilg C.A.
      • et al.
      Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
      ].
      Two studies compared the volumes of mpMRI and PSMA PET derived GTVs [
      • Zamboglou C.
      • Wieser G.
      • Hennies S.
      • et al.
      MRI versus (68)Ga-PSMA PET/CT for gross tumour volume delineation in radiation treatment planning of primary prostate cancer.
      ,
      • Thorwarth D.
      • Notohamiprodjo M.
      • Zips D.
      • Muller A.C.
      Personalized precision radiotherapy by integration of multi-parametric functional and biological imaging in prostate cancer: A feasibility study.
      ]. Both studies observed that PET based GTVs were larger than GTVs based on mpMRI. A focal dose escalation on larger GTVs implies a potential increase in toxicity for rectum and bladder.
      The aim of this RT planning study was to demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) focal dose escalation on 68Ga-HBED-CC PSMA PET/CT derived GTVs (GTV-PET) in patients with primary PCa. Furthermore, we calculated TCPs and the normal tissue complication probability (NTCP) for rectum and bladder.

      Methods and materials

      Patients

      The study cohort consisted of 10 patients with intermediate (3 patients) to high-risk (7 patients) PCa [
      • Mohler J.
      • Bahnson R.R.
      • Boston B.
      • et al.
      NCCN clinical practice guidelines in oncology: prostate cancer.
      ] who had PSMA PET/CT scans prior to radical prostatectomy. In a previous study [
      • Zamboglou C.
      • Schiller F.
      • Fechter T.
      • et al.
      (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.
      ] a voxel-level comparison between PSMA PET and histology was performed in 9 of the 10 patients. Their characteristics are described in Supplementary Table 1. Written informed consent was obtained from each patient, and the institutional review board approved this study.

      PET/CT imaging

      A detailed description of our 68Ga-HBED-CC-PSMA PET/CT imaging protocol can be found in Zamboglou et al. [
      • Zamboglou C.
      • Wieser G.
      • Hennies S.
      • et al.
      MRI versus (68)Ga-PSMA PET/CT for gross tumour volume delineation in radiation treatment planning of primary prostate cancer.
      ] for PSMA PET/CT scans using the ligand 68Ga-HBED-CC-PSMA [
      • Eder M.
      • Neels O.
      • Muller M.
      • et al.
      Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer.
      ] were either performed with a 64-slice GEMINI TF PET/CT or a 16-slice GEMINI TF BIG BORE PET/CT (both Philips Healthcare, USA). The scanners were cross-calibrated to ensure the compatability of the quantitative measurements. Patients underwent a whole body PET scan 1 h post injection. The uptake of 68Ga-PSMA-HBED-CC was quantified by standardized uptake values (SUV, regional tracer concentration normalized by injected dose per body weight).

      Image co-registration

      After fixation, the resected prostate underwent an ex-vivo CT scan in a customized localizer (according to our protocol [
      • Zamboglou C.
      • Drendel V.
      • Jilg C.A.
      • et al.
      Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
      ]). Subsequently, whole-mount step sections were cut every 4 mm using an in–house cutting device and processed by an experienced pathologist (VD). The sections obtained had the same cutting angle and position as the corresponding ex-vivo CT slices. Histology sections were registered on ex-vivo CT images and PCa contours were transferred onto the CT images. The contours were expanded by 2 mm in both Z-axis directions to create GTV-histo. Taking into account the non-linear shrinkage and distortion of the prostatic gland after resection, ex-vivo CT (including GTV-histo) was registered on in vivo CT (from PSMA PET/CT scans) by careful manual coregistration with additional non-rigid deformation (Fig. 1). The alignment of in vivo CT and PET scan was already given by the hardware coregistration of the combined PET/CT scanners.
      Figure thumbnail gr1
      Fig. 1Co-registration and planning procedures. (A) shows one H&E stained prostatectomy specimen of patient 1. PCa tissue was delineated with black ink. (B) shows an axial CT slice (PSMA PET/CT scan) including digitalized and registered histological information (GTV-histo, green contour). The prostate contour is marked in red. (C) shows the fused 68Ga-HBED-CC-PSMA PET/CT scan, indicating PCa in the right lobe. In (D) the colourwash representation for Plan95 is presented. The GTV delineated with PSMA PET was expanded in all directions with a 4 mm margin to create PC3, which is marked in red.

      Generation of contours

      According to our previous work [
      • Zamboglou C.
      • Schiller F.
      • Fechter T.
      • et al.
      (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.
      ], GTV-PET was created semi-automatically using a threshold of 30% of SUVmax within the prostate in the RT planning system iPLAN RT image 4.1 (BrainLAB, Germany). Subsequently, in vivo CT (including GTV-histo and GTV-PET) was transferred in RT planning system Oncentra v4.3 (Nucletron, The Netherlands) and contours for the prostate, seminal vesicles, and surrounding organs at risk were generated. Clinical target volume 1 (CTV1) was defined as the prostate and the seminal vesicles. CTV2 was defined as the prostate and half of the seminal vesicles (high risk patients) or the basis of the seminal vesicles (intermediate risk patients). CTV1/2 and GTV-PET were enlarged by an isotropic margin of 4 mm to create the planning target volumes (PTVs): PC1, PC2 and PC3, respectively.

      IMRT planning

      All CT images and contours were imported into Eclipse v13.5 (Varian, USA) and Rapid Arc IMRT treatment plans were created. The two arms of the FLAME trial [
      • Lips I.M.
      • van der Heide U.A.
      • Haustermans K.
      • et al.
      Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.
      ] were simulated for each patient. The standard arm received 52.8 Gy in 24 fractions on PC1 and 24.3 Gy in 11 fractions on PC2 (Plan77). The experimental arm received a concomitant boost to the PC3 with a dose of 95 Gy in 35 fractions (Plan95). At least 70 Gy had to be delivered to 99% of PC2 in both arms. The D2% of PC3 had to be ≤105% of the prescribed dose (99.75 Gy) [
      • Andrzejewski P.
      • Kuess P.
      • Knausl B.
      • et al.
      Feasibility of dominant intraprostatic lesion boosting using advanced photon-, proton- or brachytherapy.
      ]. However, a D2% >99.75 Gy was accepted as a minor deviation.
      Dose constraints for rectum and bladder were taken from the FLAME protocol [
      • Lips I.M.
      • van der Heide U.A.
      • Haustermans K.
      • et al.
      Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.
      ]. Penile bulb, small bowel and sigma dose constraints were taken from the QUANTEC review [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ,
      • Fowler J.F.
      The radiobiology of prostate cancer including new aspects of fractionated radiotherapy.
      ,
      • McDonald A.M.
      • Baker C.B.
      • Shekar K.
      • et al.
      Reduced radiation tolerance of penile structures associated with dose-escalated hypofractionated prostate radiotherapy.
      ] and have been adapted to the FLAME-trial fractionation schemes. For detailed restriction doses please see Supplementary Table 2. Adherence to the dose constraints for the organs at risk had the highest priority.

      Radiobiological treatment plan evaluation

      The calculations were performed in the research version of BIOTOP/BIOSPOT available in our department (provided by Pi-medical, Greece). For this purpose all DICOM RT data (images, structures, plans and doses) have been transferred from Eclipse to BIOSPOT. The summation of 3D dose distributions and EQD2 values as well as TCP and NTCP calculations were performed at the voxel level.
      For Plan77 and Plan95 the differential dose-volume histogram (DDVH) for GTV-histo was generated and the corresponding average dose defined as the volume-weighted average dose (D¯) was calculated.
      For TCP modelling a radiobiological model based on the linear quadratic (LQ) Poisson model [
      • Munro T.R.
      • Gilbert C.W.
      The relation between tumour lethal doses and the radiosensitivity of tumour cells.
      ,
      • Brahme A.
      • Agren A.K.
      Optimal dose distribution for eradication of heterogeneous tumours.
      ,
      • Lind B.K.
      • Mavroidis P.
      • Hyodynmaa S.
      • Kappas C.
      Optimization of the dose level for a given treatment plan to maximize the complication-free tumor cure.
      ,
      • Wheldon T.E.
      • Deehan C.
      • Wheldon E.G.
      • Barrett A.
      The linear-quadratic transformation of dose-volume histograms in fractionated radiotherapy.
      ,
      • Yorke E.D.
      Modeling the effects of inhomogeneous dose distributions in normal tissues.
      ,
      • Tucker S.L.
      • Taylor J.M.
      Improved models of tumour cure.
      ,
      • Zaider M.
      • Minerbo G.N.
      Tumour control probability: a formulation applicable to any temporal protocol of dose delivery.
      ,
      • Kauweloa K.I.
      • Gutierrez A.N.
      • Bergamo A.
      • Stathakis S.
      • Papanikolaou N.
      • Mavroidis P.
      Practical aspects and uncertainty analysis of biological effective dose (BED) regarding its three-dimensional calculation in multiphase radiotherapy treatment plans.
      ] was used (see Supplementary Material A). TCP calculations were performed for both Plan77 and Plan95 based on GTV-histo (TCP-histo) under the assumption that GTV-histo represents the true target and true clinical response, respectively.
      To account for the diversity of parameters which were used for TCP calculations in current literature, we performed our TCP-histo calculation using 15 different parameter value sets (see Supplementary Material A). The following parameter ranges were used: α/β = 1.2–4 Gy, [
      • Vogelius I.R.
      • Bentzen S.M.
      Meta-analysis of the alpha/beta ratio for prostate cancer in the presence of an overall time factor: bad news, good news, or no news?.
      ]; and tumour cell density ρ = 105–2.8 × 108 cells/cm3 for intermediate and high-risk patients according to [
      • Chang J.H.
      • Joon D.L.
      • Lee S.T.
      • et al.
      Intensity modulated radiation therapy dose painting for localized prostate cancer using C-11-choline positron emission tomography scans.
      ,
      • Casares-Magaz O.
      • van der Heide U.A.
      • Rorvik J.
      • Steenbergen P.
      • Muren L.P.
      A tumour control probability model for radiotherapy of prostate cancer using magnetic resonance imaging-based apparent diffusion coefficient maps.
      ,
      • Ghobadi G.
      • de Jong J.
      • Hollmann B.G.
      • et al.
      Histopathology-derived modeling of prostate cancer tumor control probability: implications for the dose to the tumor and the gland.
      ]. Similar to [
      • Casares-Magaz O.
      • van der Heide U.A.
      • Rorvik J.
      • Steenbergen P.
      • Muren L.P.
      A tumour control probability model for radiotherapy of prostate cancer using magnetic resonance imaging-based apparent diffusion coefficient maps.
      ] for each parameter value combination the value of α was chosen in order to achieve an average TCP-histo value of 70% across all patients when Plan77 was used. Additionally, TCP-PET was calculated by taking GTV-PET as the tumour volume. For the calculation of TCP-PET solely parameter value set 1 was used: α/β = 1.93 Gy, α = 0.1335 Gy−1, ρ = 2.8 × 108 cells/cm3.
      To calculate NTCP from non-uniform dose distributions the relative seriality model was used [
      • Lind B.K.
      • Mavroidis P.
      • Hyodynmaa S.
      • Kappas C.
      Optimization of the dose level for a given treatment plan to maximize the complication-free tumor cure.
      ,
      • Kallman P.
      • Agren A.
      • Brahme A.
      Tumour and normal tissue responses to fractionated non-uniform dose delivery.
      ,
      • Lyman J.T.
      Complication probability as assessed from dose-volume histograms.
      ,
      • Kutcher G.J.
      • Burman C.
      Calculation of complication probability factors for non-uniform normal tissue irradiation: the effective volume method.
      ,
      • Adamus-Gorka M.
      • Mavroidis P.
      • Lind B.K.
      • Brahme A.
      Comparison of dose response models for predicting normal tissue complications from cancer radiotherapy: application in rat spinal cord.
      ,
      • Niemierko A.
      • Goitein M.
      Calculation of normal tissue complication probability and dose-volume histogram reduction schemes for tissues with a critical element architecture.
      ,
      • Schultheiss T.E.
      • Orton C.G.
      • Peck R.A.
      Models in radiotherapy: volume effects.
      ,
      • Mavroidis P.
      • Laurell G.
      • Kraepelien T.
      • Fernberg J.O.
      • Lind B.K.
      • Brahme A.
      Determination and clinical verification of dose-response parameters for esophageal stricture from head and neck radiotherapy.
      ] (see Supplementary Material B). For bladder a D50 = 80 Gy as EQD2 (symptomatic contracture and volume loss), s = 1.3 and γ = 2.59 were chosen in accordance to [
      • Takam R.
      • Bezak E.
      • Yeoh E.E.
      • Marcu L.
      Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models.
      ]. For rectum a D50 = 80 Gy as EQD2 (for severe proctitis/necrosis/stenosis/fistula, average of D50 values in [
      • Takam R.
      • Bezak E.
      • Yeoh E.E.
      • Marcu L.
      Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models.
      ,
      • Kuang Y.
      • Wu L.
      • Hirata E.
      • Miyazaki K.
      • Sato M.
      • Kwee S.A.
      Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.
      ,
      • Liu M.
      • Moiseenko V.
      • Agranovich A.
      • et al.
      Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: a test of the QUANTEC-recommended NTCP model.
      ,
      • Peeters S.T.
      • Hoogeman M.S.
      • Heemsbergen W.D.
      • Hart A.A.
      • Koper P.C.
      • Lebesque J.V.
      Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling.
      ,
      • Michalski J.M.
      • Gay H.
      • Jackson A.
      • Tucker S.L.
      • Deasy J.O.
      Radiation dose-volume effects in radiation-induced rectal injury.
      ]), s = 0.75 were chosen according to [
      • Takam R.
      • Bezak E.
      • Yeoh E.E.
      • Marcu L.
      Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models.
      ]. The γ-values (γ = 2.59 for bladder and γ = 1.79 for rectum) were calculated based on the listed k-values [
      • Adamus-Gorka M.
      • Mavroidis P.
      • Lind B.K.
      • Brahme A.
      Comparison of dose response models for predicting normal tissue complications from cancer radiotherapy: application in rat spinal cord.
      ,
      • Niemierko A.
      • Goitein M.
      Calculation of normal tissue complication probability and dose-volume histogram reduction schemes for tissues with a critical element architecture.
      ,
      • Schultheiss T.E.
      • Orton C.G.
      • Peck R.A.
      Models in radiotherapy: volume effects.
      ] (see Supplementary Material B). For both organs an α/β of 3 Gy was assumed according to a recent study [
      • Kuang Y.
      • Wu L.
      • Hirata E.
      • Miyazaki K.
      • Sato M.
      • Kwee S.A.
      Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.
      ].

      Statistical analysis

      Statistical analysis was performed with MATLAB (MATLAB R2014a, The MathWorks, USA) and Microsoft Excel 2010 (Microsoft, Redmond, USA). The Wilcoxon matched pairs signed-rank test was used with a threshold for statistical significance of <0.05.

      Results

      Mean volumes of GTV-PET and GTV-histo were 7.5 ± 4.8 ml and 5.4 ± 6.9 ml, respectively. This difference was not significant in paired comparison (p = 0.2). In all 10 patients, the target volume objectives as well as the OAR dose constraints were met with the exception of a minor deviation (D2% in PC3 > 99.75 Gy) in Plan95 in 7 patients.
      For Plan77 and Plan95 the volume weighted average doses in GTV-histo were 76.8 ± 3 Gy and 96.9 ± 1 Gy, respectively. Fig. 2 shows the averaged dose volume histograms (DVHs) for the relevant volumes and Supplementary Fig. 1 shows for each patient the DVHs for Plan95 in GTV-histo and GTV-PET.
      Figure thumbnail gr2
      Fig. 2Averaged DVHs. An averaged DVH, over all 10 cases, for GTV-histo, GTV-PET, bladder and rectum is shown. The dashed line represents Plan95 and the continuous line Plan77.
      Average TCP-PET were 55% (range: 27–82%) for Plan77 and 100% (range: 99–100%) for Plan95. Average TCP-histo values for all parameter value sets were 70% (range: 15–97%) and 96% (range: 78–100%) for Plan77 and Plan95, respectively. TCP-histo and TCP-PET were significantly higher for Plan95 compared to Plan77 (p < 0.0001), respectively. Supplementary Tables 3 and 4 show a detailed presentation of the TCP-values. Mean NTCPs for bladder in Plan77 and Plan95 were 3 ± 1.2% and 2.9 ± 0.9%, respectively. The average NTCPs for rectum in Plan77 and Plan95 were 0.9 ± 0.4% and 1 ± 0.6%, respectively. No significant differences in rectal (p = 0.563) and bladder (p = 0.3) NTCPs were observed between the 2 plans.

      Discussion

      In the current study we examined the technical feasibility of PSMA PET/CT guided dose painting using the prescription doses and dose constraints of the FLAME trial (experimental and standard arm). TCP calculation was performed on PET information (GTV-PET) as well as on the registered histological information after prostatectomy (GTV-histo). The latter should demonstrate the actual tumour location and likewise should predict the true response.
      Several RT planning studies demonstrated an increased therapeutic ratio when an intraprostatic boost was delivered to MRI or choline PET/CT based GTVs [
      • Chang J.H.
      • Joon D.L.
      • Lee S.T.
      • et al.
      Intensity modulated radiation therapy dose painting for localized prostate cancer using C-11-choline positron emission tomography scans.
      ,
      • Kuang Y.
      • Wu L.
      • Hirata E.
      • Miyazaki K.
      • Sato M.
      • Kwee S.A.
      Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.
      ,
      • van Lin E.N.
      • Futterer J.J.
      • Heijmink S.W.
      • et al.
      IMRT boost dose planning on dominant intraprostatic lesions: gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI.
      ]. Two, multi-institutional trials included GTV boosts based on mpMRI (FLAME [
      • Lips I.M.
      • van der Heide U.A.
      • Haustermans K.
      • et al.
      Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.
      ] and HEIGHT (clinicialtrials.gov NCT0141132)). Both studies delivered a GTV boost of 95 Gy with whole prostate doses in the range of 76–77 Gy. However, three studies compared mpMRI with PSMA PET/CT for detection of primary PCa based on histology Refs. [
      • Rhee H.
      • Thomas P.
      • Shepherd B.
      • et al.
      Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer as confirmed by whole mount histopathology.
      ,
      • Eiber M.
      • Weirich G.
      • Holzapfel K.
      • et al.
      Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer.
      ,
      • Zamboglou C.
      • Drendel V.
      • Jilg C.A.
      • et al.
      Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
      ] and reported higher sensitivities (49–75%) and specificities (87–95%) for PSMA PET/CT.
      Our group showed that PSMA PET-based volumes (mean 11 ml) were significantly larger compared to MRI-defined volumes (mean 6 ml) [
      • Zamboglou C.
      • Wieser G.
      • Hennies S.
      • et al.
      MRI versus (68)Ga-PSMA PET/CT for gross tumour volume delineation in radiation treatment planning of primary prostate cancer.
      ]. This observation was also reported by Thorwarth et al. [
      • Thorwarth D.
      • Notohamiprodjo M.
      • Zips D.
      • Muller A.C.
      Personalized precision radiotherapy by integration of multi-parametric functional and biological imaging in prostate cancer: A feasibility study.
      ]. Thus, boosting of PSMA PET-defined targets may become more challenging than boosting on MRI-defined GTVs. In the present study, mean GTV-PET was larger than mean GTV-histo (7.5 ml vs. 5.4 ml), although this difference was not significant in paired analysis. This finding may be explained by the specificity of 65% when GTV-PET is delineated using a threshold of an intraprostatic SUVmax of 30% [
      • Zamboglou C.
      • Drendel V.
      • Jilg C.A.
      • et al.
      Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
      ]. This threshold was derived from a voxel-wise correlation between PSMA PET/CT and PCa in histology using receiver operating characteristic analysis demanding a sensitivity ≥0.9 [
      • Zamboglou C.
      • Schiller F.
      • Fechter T.
      • et al.
      (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.
      ].
      However, in this study the dose constraints and prescription doses of the FLAME trial [
      • Lips I.M.
      • van der Heide U.A.
      • Haustermans K.
      • et al.
      Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.
      ] were applied and maintained for all patients. For Plan95 a D2% > 99.75 Gy (EQD2 = 121.3 Gy, α/β = 1.93 Gy) in PC3 [
      • Andrzejewski P.
      • Kuess P.
      • Knausl B.
      • et al.
      Feasibility of dominant intraprostatic lesion boosting using advanced photon-, proton- or brachytherapy.
      ] was accepted as a minor deviation in 7 patients. A recent study [
      • Gomez-Iturriaga A.
      • Casquero F.
      • Urresola A.
      • et al.
      Dose escalation to dominant intraprostatic lesions with MRI-transrectal ultrasound fusion High-Dose-Rate prostate brachytherapy. Prospective phase II trial.
      ], applied a cumulative dose of EQD2 = 140.9 Gy (α/β = 1.93 Gy) to GTV defined by mpMRI using 1 fraction HDR-brachytherapy in combination with hypo-fractionated external beam radiation therapy. With a median follow-up of 18 months none of the patients experienced acute urinary retention and only three patients (20%) experienced acute grade 2 GU toxicity. Further studies with longer follow-up are necessary to assess whether the delivery of increasing doses leads to increased genitourinary toxicity (e.g. urethral stricture). In the current study, NTCPs for bladder and rectum did not differ between dose escalation and standard RT plans using the relative seriality model. These results have been confirmed using the Lyman-Kutcher-Burman model [
      • Michalski J.M.
      • Gay H.
      • Jackson A.
      • Tucker S.L.
      • Deasy J.O.
      Radiation dose-volume effects in radiation-induced rectal injury.
      ] with the same α/β and D50 values. For the parameters m (slope) and n (volume) the values of 0.13 and 0.12 for bladder and 0.14 and 0.105 rectum have been used, respectively.
      Niyazi et al., simulated a dose escalation based on cholin PET defined GTVs and found a dependence of different parameter values (α/β, γ50) on TCP [
      • Niyazi M.
      • Bartenstein P.
      • Belka C.
      • Ganswindt U.
      Choline PET based dose-painting in prostate cancer–modelling of dose effects.
      ]. To account for this issue, we used 15 parameter sets which included a combination of suggested values from current literature. The observed variance between the TCP-histo values for the different parameter value sets was low in our study. The average standard deviation over all datasets was 0.5% and 0.2% for Plan77 and Plan95, respectively.
      Fig. 1 shows an exemplary case where PSMA PET failed to detect three small PCa lesions (<5 mm) in the left lobe. The lack of detection of small PCa lesions may lead to sensitivities <75% [
      • Rhee H.
      • Thomas P.
      • Shepherd B.
      • et al.
      Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer as confirmed by whole mount histopathology.
      ,
      • Eiber M.
      • Weirich G.
      • Holzapfel K.
      • et al.
      Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer.
      ,
      • Zamboglou C.
      • Drendel V.
      • Jilg C.A.
      • et al.
      Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
      ] and may be explained by PET resolution limitation [
      • Souvatzoglou M.
      • Weirich G.
      • Schwarzenboeck S.
      • et al.
      The sensitivity of [11C]choline PET/CT to localize prostate cancer depends on the tumor configuration.
      ]. In a previous study, our group performed a voxel-level correlation between PSMA PET/CT and PCa in histology [
      • Zamboglou C.
      • Schiller F.
      • Fechter T.
      • et al.
      (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.
      ]. A moderate correlation (R2 ≤ 50%) was reported in 44% of the patients. Consequently, the present study addressed the question whether a lack in PCa detection has an influence in TCP-histo. A moderate correlation between PSMA PET/CT and PCa may explain the difference between GTV-histo and GTV-PET in the DVHs of patient 6 and 8–10 (see Supplementary Fig. 1). Despite this, we could show high TCP-histo values for Plan95 (in mean 96%). Moreover, there was no significant difference observed when TCP was calculated on PET (TCP-PET) or histology information (TCP-histo). However, patient 9 and 10 had lower TCP-histo values compared to the other patients in Plan95. This observation can be explained by the low coverage of GTV-histo by PSMA PET, since 76% and 88% of GTV-histo overlapped with PC3 in patient 9 and 10, respectively. On the other hand, 74% and 85% of GTV-histo overlapped with PC3 in patient 6 and 8. Both had an average TCP-histo value of 100%. The total volume of GTV-histo in patient 6 (2.7 ml), 8 (3.1 ml), 9 (40.5 ml) and 10 (31.4 ml) could explain the difference in TCP-histo values, as TCP decreases with the absolute volume of GTV-histo which is not boosted. Our findings showed the feasibility of PSMA PET/CT as a guidance tool for dose painting in primary PCa. Future studies should assess whether the additional usage of mpMRI information can lead to a further improvement of TCP, especially in patients with large tumours.
      Ikeda et al. simulated the effect of intrafraction prostate motion on dose coverage of the boost volume during simultaneous boost intensity-modulated RT [
      • Ikeda I.
      • Mizowaki T.
      • Ono T.
      • et al.
      Effect of intrafractional prostate motion on simultaneous boost intensity-modulated radiotherapy to the prostate: a simulation study based on intrafractional motion in the prone position.
      ]. Since the majority of published planning studies did not investigate this effect it remains generally unknown how sensitive the coverage of GTV-histo is for dose painted PTVs to intrafractional motion. Recently, Rowe et al. defined a dominant intraprostatic lesion (DIL) as the lesion with the highest Gleason score [
      • Rowe S.P.
      • Gage K.L.
      • Faraj S.F.
      • et al.
      18F-DCFBC PET/CT for PSMA-based detection and characterization of primary prostate cancer.
      ]. Since data regarding the parameters to define a potential DIL are inconclusive [
      • Ravery V.
      • Chastang C.
      • Toublanc M.
      • Boccon-Gibod L.
      • Delmas V.
      • Boccon-Gibod L.
      Percentage of cancer on biopsy cores accurately predicts extracapsular extension and biochemical relapse after radical prostatectomy for T1–T2 prostate cancer.
      ,
      • Haffner M.C.
      • Mosbruger T.
      • Esopi D.M.
      • et al.
      Tracking the clonal origin of lethal prostate cancer.
      ], no separate analysis of boosting only the DIL was performed in our study. An important issue of our study is the uncertainty in the correlation of PET/CT and histopathology (e.g. manual registration between ex-vivo and in vivo CT to account for non-linear shrinkage of the prostate after prostatectomy). Thus, it could not be excluded that moderate coverage of GTV-histo by GTV-PET is partly a consequence of mismatch in coregistration or incomplete histopathological coverage instead of poor tracer performance.

      Conclusion

      In patients with primary PCa, IMRT dose escalation to PSMA PET/CT defined GTVs is technically feasible, achieving significantly higher TCPs based on co-registered histology without higher NTCPs compared to normal fractionation.

      Funding sources

      This study had no founding sources.

      Conflict of interest statement

      Author PTM received research grants from Piramal and GE . Author MM received research grants from Philips Medical Systems . All the other authors declare that they have no conflict of interest.

      Acknowledgement

      We would like to thank Colin Nolden and Mark Gainey for proof reading.

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