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Brachytherapy focal dose escalation using ultrasound based tissue characterization by patients with non-metastatic prostate cancer: Five-year results from single-center phase 2 trial

Open AccessPublished:April 06, 2022DOI:https://doi.org/10.1016/j.brachy.2022.02.003

      ABSTRACT

      PURPOSE

      This prospective trial investigates side effects and efficacy of focal dose escalation with brachytherapy for patients with prostate cancer.

      METHODS AND MATERIALS

      In the Phase II, monocentric prospective trial 101 patients with low-/intermediate- and high-risk prostate cancer were enrolled between 2011 and 2013. Patients received either PDR-/HDR-brachytherapy alone with 86–90 Gy (EQD2, α/β = 3 Gy) or PDR-/HDR-brachytherapy as boost after external beam radiation therapy up to a total dose of 91–96 Gy (EQD2, α/β = 3 Gy). Taking place brachytherapy all patients received the simultaneous integrated focal boost to the intra-prostatic tumor lesions visible in computer-aided ultrasonography (HistoScanning™) - up to a total dose of 108–119 Gy (EQD2, α/β = 3 Gy). The primary endpoint was toxicity. Secondary endpoints were cumulative freedom from local recurrence, PSA-free survival, distant metastases-free survival, and overall survival. This trial is registered with ClinicalTrials.gov, number NCT01409876.

      Results

      Median follow-up was 65 months. Late toxicity was generally low with only four patients scoring urinary grade 3 toxicity (4/101, 4%). Occurrence of any grade of late rectal toxicities was very low. We did not register any grade ≥2 of late rectal toxicities. The cumulative 5 years local recurrence rate (LRR) for all patients was 1%. Five years- biochemical disease-free survival estimates according Kaplan-Meier were 98,1% and 81,3% for low-/intermediate-risk and high-risk patients, respectively. Five years metastases-free survival estimates according Kaplan-Meier were 98,0% and 83,3% for all patients, low-/intermediate-risk and high-risk patients, respectively.

      Conclusions

      The 5 years-results from this Phase II Trial show that focal dose escalation with computer-aided ultrasonography and brachytherapy for patients with non-metastatic prostate cancer is safe and effective.

      Keywords

      Introduction

      Patients with non-metastatic prostate cancer can be treated with brachytherapy, external beam radiation therapy or radical prostatectomy. For low- and low-intermediate risk prostate cancer the results of external beam radiation therapy (EBRT) and sole brachytherapy treatment are comparable to radical prostatectomy with freedom from biochemical failure rates of approximately 95% after 5−10-years follow-up (
      • Kishan A.U.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason Score 9-10 prostate cancer.
      ,
      • Pollack A.
      • Zagars G.K.
      • Starkschall G
      • et al.
      Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial.
      ,
      • Rosenthal S.A.
      • Bittner N.H.
      • Beyer D.C.
      • et al.
      American Society for Radiation Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the transperineal permanent brachytherapy of prostate cancer.
      ,
      • Tselis N.
      • Tunn U.W.
      • Chatzikonstantinou G.
      • et al.
      High dose rate brachytherapy as monotherapy for localised prostate cancer: a hypofractionated two-implant approach in 351 consecutive patients.
      ,
      • Zamboglou N.
      • Tselis N.
      • Baltas D.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results.
      ,
      • Kee D.L.C.
      • Gal J.
      • Falk A.T.
      • et al.
      Brachytherapy versus external beam radiotherapy boost for prostate cancer: systematic review with meta-analysis of randomized trials.
      ,
      • Hoskin P.
      • Rojas A.
      • Lowe G.
      • et al.
      High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence.
      ,
      • Franzese C.
      • Badalamenti M.
      • Di Brina L.
      • et al.
      Linac-based stereotactic body radiation therapy for low and intermediate-risk prostate cancer: long-term results and factors predictive for outcome and toxicity.
      ,
      • Moll M.
      • Paschen C.
      • Zaharie A.
      • et al.
      Treatment of low-risk prostate cancer: a retrospective study with 477 patients comparing external beam radiotherapy and I-125 seeds brachytherapy in terms of biochemical control and late side effects.
      ). For high-intermediate and high risk patients, EBRT followed by brachytherapy as boost is probably the best treatment approach with freedom from biochemical failure ranging between 70% and 86% after 5−10-years follow-up (
      • Shilkrut M.
      • Merrick G.S.
      • McLaughlin P.W.
      • et al.
      The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.
      ,
      • Sandler K.A.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Prostate-only versus whole-pelvis radiation with or without a brachytherapy boost for Gleason Grade Group 5 prostate cancer: a retrospective analysis.
      ,
      • Kishan A.U.
      • Shaikh T.
      • Wang P.C.
      • et al.
      Clinical outcomes for patients with Gleason Score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis.
      ,
      • Joseph D.
      • Denham J.W.
      • Steigler A.
      • et al.
      Radiation dose escalation or longer androgen suppression to prevent distant progression in men with locally advanced prostate cancer: 10-year data from the TROG 03.04 RADAR trial.
      ,
      • Dayes I.S.
      • Parpia S.
      • Gilbert J.
      • et al.
      Long-term results of a randomized trial comparing iridium implant plus external beam radiation therapy with external beam radiation therapy alone in node-negative locally advanced cancer of the prostate.
      ).
      Several randomized controlled trials and reports have demonstrated that dose escalation of up to 80 Gy using EBRT techniques significantly improves the biochemical disease free survival (
      • Pollack A.
      • Zagars G.K.
      • Starkschall G
      • et al.
      Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial.
      ,
      • Widmark A.
      • Klepp O.
      • Solberg A.
      • et al.
      Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.
      ,
      • Peeters S.T.
      • Heemsbergen W.D.
      • Koper P.C.
      • et al.
      Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy.
      ,
      • Zietman A.L.
      • DeSilvio M.L.
      • Slater J.D.
      • et al.
      Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial.
      ,
      • Dearnaley D.P.
      • Sydes M.R.
      • Graham J.D.
      • et al.
      Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial.
      ,
      • Beckendorf V.
      • Guerif S.
      • Le Prise E.
      • et al.
      70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial.
      ,
      • Dearnaley D.P.
      • Jovic G.
      • Syndikus I.
      • et al.
      Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial.
      ). Further increase in dose is considered to improve the treatment results even further (
      • Pollack A.
      • Zagars G.K.
      • Starkschall G
      • et al.
      Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial.
      ,
      • Kishan A.U.
      • Shaikh T.
      • Wang P.C.
      • et al.
      Clinical outcomes for patients with Gleason Score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis.
      ,
      • Peeters S.T.
      • Heemsbergen W.D.
      • Koper P.C.
      • et al.
      Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy.
      ,
      • Zelefsky M.J.
      • Fuks Z.
      • Hunt M.
      • et al.
      High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients.
      ). Interestingly, some dose response analyses suggest that local recurrences after radiation therapy preferably occur at the site of the primary macroscopic tumor (
      • Cellini N.
      • Morganti A.G.
      • Mattiucci G.C.
      • et al.
      Analysis of intraprostatic failures in patients treated with hormonal therapy and radiotherapy: implications for conformal therapy planning.
      ,
      • Pucar D.
      • Hricak H.
      • Shukla-Dave A.
      • et al.
      Clinically significant prostate cancer local recurrence after radiation therapy occurs at the site of primary tumor: magnetic resonance imaging and step-section pathology evidence.
      ). Moreover, it is evident that the improvement of local control is associated with an improvement in terms of a reduction in the rate of distant metastases and of survival. Local failure is associated with an increase of distant metastases and mortality (
      • Kishan A.U.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason Score 9-10 prostate cancer.
      ,
      • Sandler K.A.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Prostate-only versus whole-pelvis radiation with or without a brachytherapy boost for Gleason Grade Group 5 prostate cancer: a retrospective analysis.
      ,
      • Kishan A.U.
      • Shaikh T.
      • Wang P.C.
      • et al.
      Clinical outcomes for patients with Gleason Score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis.
      ,
      • Joseph D.
      • Denham J.W.
      • Steigler A.
      • et al.
      Radiation dose escalation or longer androgen suppression to prevent distant progression in men with locally advanced prostate cancer: 10-year data from the TROG 03.04 RADAR trial.
      ,
      • Coen J.J.
      • Zietman A.L.
      • Thakral H.
      • Shipley W.U.
      Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases.
      ,
      • Jacob R.
      • Hanlon A.L.
      • Horwitz E.M.
      • et al.
      The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer.
      ,
      • Kupelian P.A.
      • Ciezki J.
      • Reddy C.A.
      • et al.
      Effect of increasing radiation doses on local and distant failures in patients with localized prostate cancer.
      ). As a consequence, a radiation dose escalation selectively to the intra-prostatic macroscopic tumor hold at least a potential to increase local control and survival while at the same time being able to respect normal tissue constraints. However, an appropriate visualization / appropriate imaging method should be considered a prerequisite for such a kind of microboost allowing a dose escalation to intra-prostatic tumor lesions. A number of recent studies have demonstrated the capability and high efficacy of multiparametric MRI to identify intra-prostatic tumor lesions and its consistency and reproducibility (
      • Rischke H.C.
      • Nestle U.
      • Fechter T.
      • et al.
      3 Tesla multiparametric MRI for GTV-definition of Dominant Intraprostatic Lesions in patients with Prostate Cancer – an interobserver variability study.
      ,
      • Dickinson L.
      • Ahmed H.U.
      • Allen C.
      • et al.
      Magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a European consensus meeting.
      ,
      • van Schie M.A.
      • Dinh C.V.
      • PJv Houdt
      • et al.
      Contouring of prostate tumors on multiparametric MRI: evaluation of clinical delineations in a multicenter radiotherapy trial.
      ,
      • Lunacek A.
      • Simon J.
      • Bernt R.
      • et al.
      Increased rate of positive biopsies using a combination of MR-Tomography, spectroscopy and diffusion-weighted magnetic resonance imaging prior to prostate biopsies in patients with persistent elevated prostate-specific antigen values: a retrospective analysis.
      ,
      • Tamihardja J.
      • Zenk M.
      • Flentje M.
      MRI-guided localization of the dominant intraprostatic lesion and dose analysis of volumetric modulated arc therapy planning for prostate cancer.
      ). On the other hand, image guidance with modern transrectal ultrasound (TRUS) provides a cost-effective and efficient method to delineate prostate boundaries particularly when using brachytherapy techniques. Unfortunately, current TRUS technology does not reliably differentiate between benign and malignant prostate tissue (
      • Bjurlin M.A.
      • Wysock J.S.
      • Taneja S.S.
      Optimization of prostate biopsy: review of technique and complications.
      ,
      • Ukimura O.
      • Coleman J.A.
      • de la Taille A.
      • et al.
      Contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care.
      ). Efforts to increase TRUS diagnostic performance include contrast-enhanced ultrasound, computer-assisted TRUS (C-TRUS), elastography, and computer-aided ultrasonography studies (HistoScanningTM, Advanced Medical Diagnostics, Waterloo, Belgium) (
      • Pummer K.
      • Rieken M.
      • Augustin H.
      • et al.
      Innovations in diagnostic imaging of localized prostate cancer.
      ,
      • Wysock J.S.
      • Xu A.
      • Orczyk C.
      • Taneja S.S.
      HistoScanning(TM) to detect and characterize prostate cancer-a review of existing literature.
      ). Based on early HistoScanning, studies that reported sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) of up to 100%, 82%, and up to 100%, respectively (
      • Braeckman J.
      • Autier P.
      • Soviany C.
      • et al.
      The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers.
      ,
      • Braeckman J.
      • Autier P.
      • Garbar C.
      • et al.
      Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer.
      ,
      • Simmons L.A.
      • Autier P.
      • Zat'ura F.
      • et al.
      Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(.
      ), in 2011 we initiated a prospective Phase 2 trial (NCT01409876) to assess the value of HistoScanning-based “Image-guided dose-painting brachytherapy for localized prostate cancer”. In this paper we report the long-term results of this Phase 2 trial.

      Methods

      Study design and participants

      We analyzed the long-term results from this monocentric, phase 2, non-randomized prospective trial. The trial was undertaken at University Hospital Erlangen. The corresponding ethics committee approved the protocol.
      Patients treated from 2011 were considered eligible for the trial if they were aged 18 years or older, had cT1–3 prostate cancer, no distant metastases and a prostate volume smaller 70 cm³. All eligible patients were included in our analyses. Patients were excluded if they had T4 prostate cancer, metastatic disease, or if International Prostate Symptom Score (IPSS) was higher than 20, general or regional anesthesia was not possible or if there were pathological blood coagulation parameters. We obtained written informed consent according to Good Clinical Practice guidelines and the local rules of our institute. All eligible patients were stratified into low-risk, intermediate-risk, and high-risk groups according to pretreatment PSA level, Gleason score, and clinical cancer stage (
      • D'Amico A.V.
      • Whittington R.
      • Malkowicz S.B.
      • et al.
      Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.
      ,
      • D'Amico A.V.
      • Schultz D.
      • Silver B.
      • et al.
      The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer.
      ). The most important patient characteristics are listed in Table 1.
      Table 1Patient characteristics.
      VariableValue
      Age (year)
      (median, range)63 (41 – 76y.)
      T stage
      T134/101 (33.7%)
      T259/101 (58.4%)
      T38/101 (7.9%)
      Gleason
      ≤644/101 (43.6%)
      735/101 (34.7%)
      >722/101 (21.8%)
      Pretreatment PSA level (ng/mL)
      ≤1059/101 (58.4%)
      10–2025/101 (24.8%)
      >2017/101 (16.8%)
      D´Amico risk group
      Low risk22/101 (21.8%)
      Intermediate risk31/101 (30.7%)
      High risk48/101 (47.5%)
      Treatment modality
      Brachytherapy alone Low risk

      Intermediate risk

      High risk
      22/22 pts.

      (2/22 HDR-BT, 20/22 PDR-BT)
      5/31 (PDR-BT)
      0/48
      EBRT+Brachytherapy Low risk

      Intermediate risk

      High risk
      0/22 pts.
      26/31

      (5/31 HDR-BT, 21/31 PDR-BT)
      48/48 (PDR-BT)
      EBRT = external beam radiation therapy, HDR-BT = high-dose rate brachytherapy, PDR-BT = pulsed-dose rate brachytherapy.

      Procedures

      Before the start of the radiation therapy, all patients received a transrectal ultrasound sonography (TRUS) examination. As a special part of this examination additional 3-D ultrasound raw data was acquired performing a standardized three-dimensional (3D) examination of the prostate using motorized TRUS in the sagittal plane of a dedicated ultrasound device (B-K Medical, Copenhagen, Denmark; equipped with an 8658 probe) (
      • Braeckman J.
      • Autier P.
      • Soviany C.
      • et al.
      The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers.
      ,
      • Braeckman J.
      • Autier P.
      • Garbar C.
      • et al.
      Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer.
      ). The data was subsequently analyzed, possible suspicious foci of prostate cancer visualized and tumor foci volumes (cut-off threshold volume of >0.5 cm3, the typical threshold used for attribution of significant foci of prostate cancer) calculated (
      • Wise A.M.
      • Stamey T.A.
      • McNeal J.E.
      • Clayton J.L.
      Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens.
      ). With the HistoScanning- algorithm of the special use software, each labelled unit was categorized as suspicious or non-suspicious, generating a red overlay for areas suspicious for prostate cancer (
      • Hamann M.J.K
      How to Make TRUS better: HistoScanning-guided biopsies For Identification of Cancer Within the prostate. In: Focal therapy of Prostate cancer: an Emerging Strategy For Minimally invasive, Staged Treatment.
      ).
      The radiation therapy concept was either brachytherapy alone or a combination of external beam radiation therapy (EBRT) and brachytherapy as boost. Patients with low risk prostate cancer (cT1 or cT2, Gleason score ≤6 and PSA value ≤10) got sole brachytherapy. Patients with intermediate- and high-risk prostate cancer were treated with EBRT followed by interstitial brachytherapy as boost.

      External beam radiation therapy

      External beam radiation therapy (EBRT) was performed to prostate and seminal vesicles only with an additional safety margin in the range of 5–10 mm in all directions for patients with a risk of lymph node metastasis below 20%, calculated according the Yale formula (
      • Yu J.B.
      • Makarov D.V.
      • Gross C.
      A new formula for prostate cancer lymph node risk.
      ). In patients with a probability of lymph node affection of more than 20%, the internal and common iliac nodes were also included up to the level of the lower border of L5 with safety margins of 10–15 mm in all directions. The EBRT was administered using the IMRT-technique in single daily fractions of 1.8 Gy at the reference point in line with ICRU 50 recommendations five times per week up to a total reference dose of 50.4 Gy.

      Brachytherapy

      The brachytherapy technique we used is already described in detail elsewhere (
      • Lettmaier S.
      • Lotter M.
      • Kreppner S.
      • et al.
      Long term results of a prospective dose escalation phase-II trial: interstitial pulsed-dose-rate brachytherapy as boost for intermediate- and high-risk prostate cancer.
      ). In brief: under transrectal ultrasound guidance, stainless steel or titanium needles (length 20 cm) were placed through a transperineal approach in the entire prostate. For this special therapy PDR-brachytherapy was preferred, although HDR-brachytherapy was also performed. For sole PDR-brachytherapy a total dose of 70 Gy was administered in two sessions of 35 Gy with a pulse dose of 0,7 Gy given every hour for 24 h per day. On average, there was a time gap of 3–4 weeks between sessions. Assuming a value of 3 Gy for the fractionation sensitivity α/β and a repair half-time of 1.9 h, the biologically equivalent dose (EQD2) for this PDR schedule is calculated to be 90.2 Gy (
      • Lettmaier S.
      • Lotter M.
      • Kreppner S.
      • et al.
      Long term results of a prospective dose escalation phase-II trial: interstitial pulsed-dose-rate brachytherapy as boost for intermediate- and high-risk prostate cancer.
      ). For PDR-brachytherapy as boost after EBRT, the total dose of 35 Gy was administered in one session – 35 Gy / 0.7 Gy/h, 24 h (EQD2 = 45,1 Gy, α/β= 3 Gy, T1/2 = 1,9 h). As an alternative to PDR-brachytherapy, part of the patients were treated with a HDR regime. For sole HDR-brachytherapy the dose was 4 × 9 Gy in two sessions (EQD2=86,4 Gy, α/β= 3 Gy). In case of HDR-brachytherapy as boost after EBRT, the dose was given in one session with two fractions of 9 or 9.5 Gy (EQD2=43,2–47,5 Gy, α/β= 3 Gy) (Table 2 and 3). For brachytherapy procedures, the clinical target volume (CTV) consisted of the entire prostate gland without any added safety margins. In addition, all intra-prostatic tumor areas, as detected with HistoScanning-based analysis, were demarcated as HR-CTV (high-risk CTV) without any added safety margin). Furthermore, we delineated the urethra and rectal mucosa as organs at risk. Because of the fact that it is impossible to perform HistoScanning imaging during brachytherapy and to the inability to perform an exact fusion of HistoScanning-images with online-images of brachytherapy, we manually converted as accurately as possible the size, shape and volume of tumor foci visible by the HistoScanning–examination into TRUS sets of images made during brachytherapy and in cases of discrepancy between HistoScanning- and brachytherapy-images of the prostate we delineated the tumor foci in the brachytherapy-images stretched. As a consequence of this the final size, shape and volume of tumor foci in the brachytherapy TRUS imaging data set was nearly always slightly overestimated, as compared to the one generated by HistoScanning-based analysis. The dose specification was done based on DVH values with V100>95% and D90>100% as the optimum while keeping the doses to OAR below the tolerance doses (see below). Furthermore the final dose optimization for all intra-prostatic tumor areas detected with HistoScanning (high-risk clinical target volume, HR-CTV) was adapted in such way, that for HR-CTV the value of VHR-CTV120 was more than 90% and DHR-CTV90 > 120%. Beyond that for HR-CTV we documented also values of VHR-CTV130, VHR-CTV140, VHR-CTV150, and DHR-CTV100. Simultaneously we payed attention to the dose constraints for the organs at-risk - D2cc < 85 Gy for bladder and D2cc < 75 Gy for rectum (these doses are total doses, i.e., brachytherapy doses and the sum of EBRT, if applicable) and D0.1cc <130% for the urethra. Using the radiobiological values (T1/2 and α/β) mentioned above, we reached EQD2-dose values in the HR-CTV of around 119 Gy for brachytherapy alone and in the range of 108–114 Gy if brachytherapy was applied as boost after 50.4 Gy of EBRT. The corresponding details are summarized in Table 3.
      Table 2Brachytherapy and dosimetric characteristics
      ParameterMedian (range)
      Prostate (CTV) ultrasound volume23.8 cc (11.4–59.1)
      CTV: D90 (% prescription dose)111.3 (99.8–111.9)
      CTV: V100 (%)97.4 (89.7–99.9)
      Intra-prostatic tumor areas (HR-CTV) volume1.39 cc (0.4–7.1)
      HR-CTV: D90 (% prescription dose)125.0 (101.3–149.9)
      HR-CTV: V120 (%)94.3 (64.2–99.9)
      HR-CTV: V130 (%)85.4 (50.6–99.9)
      HR-CTV: V140 (%)74.5 (39.6–99.9)
      HR-CTV: V150 (%)60.2 (28.1–98.4)
      Organ at risk
      Rectum: D2cc (% prescription dose)70.5 (29.0–86.4)
      Urethra: D0.1cc (% prescription dose)125.9 (94.4–144.0)
      CTV = clinical target volume, HR-CTV = high-risk clinical target volume, cc = cubic centimeter, V = volume, D = dosis.
      Table 3Summary of different total doses of PDR- and HDR-brachytherapy ± EBRT in prostate and intra-prostatic tumor foci (HR-CTV) according to study protocol
      Treatment modalityProstate (CTV)HR-CTV
      Dose(Gy)EQD2 [α/β = 3](Gy)Dose (120%)(Gy)EQD2 [α/β = 3](Gy)
      PDR-brachytherapy alone

      (2x 35 Gy)
      70,090,3
      for pulsed dose 0,7 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time);.
      84,0119,9
      for pulsed dose 0,84 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time).
      HDR-brachytherapy alone

      (4x 9 Gy)
      36,086,443,2119,2
      EBRT +

      PDR-brachytherapy

      (50,4 Gy + 35 Gy)
      85,493,5

      (48,4
      for EBRT with single dose 1,8 Gy/day;.
       + 45,1
      for pulsed dose 0,7 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time);.
      )
      90,4

      (50,4 + 42,0)
      108,3

      (48,4
      for EBRT with single dose 1,8 Gy/day;.
       + 59,9
      for pulsed dose 0,84 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time).
      )
      EBRT  + 

      HDR-brachytherapy

      (50,4 Gy + 2x 9–9,5 Gy)
      68,4–69,491,2 - 95,5

      (48,4
      for EBRT with single dose 1,8 Gy/day;.
       + 

      43,2–47,5)
      72,0 - 73,2

      (50,4 +

      21,6–22,8)
      108,0–114,1

      (48,4
      for EBRT with single dose 1,8 Gy/day;.
      +

      59,6–65,7)
      CTV = clinical target volume, HR-CTV = high-risk clinical target volume, EBRT = external beam radiation therapy, HDR = high-dose rate, PDR = pulsed-dose rate, EQD2 = biologically equivalent doses in 2-Gy fractions.
      a for pulsed dose 0,7 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time);.
      b for EBRT with single dose 1,8 Gy/day;.
      c for pulsed dose 0,84 Gy/h/24 h and assumed T1/2 = 1,9 h (repair half-time).

      Antihormonal therapy

      A total of 69 of 101 patients (68%) did not receive any additional antihormonal treatment. At the time of brachytherapy 4 of 31 patients (13%) with intermediate risk prostate cancer and 26 of 48 patients (54%) with high risk cancer disease received adjuvant antihormonal therapy of different duration – mostly for 1–2 years. No patient with low risk prostate cancer received any antihormonal treatment.

      Outcomes

      The primary aim of the study was to evaluate the feasibility and safety of HistoScanning-based focal dose escalation with image-guided dose-painting brachytherapy for localized prostate cancer by recording serious adverse events. Urinary and rectal toxicities were assessed according to the Common Toxicity Criteria Adverse Events Versions 4 (

      National Cancer Institute-Common Toxicity Criteria Adverse Events Versions 3 and 4. 2022 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-614_QuickReference_8.5x11.pdf. Accessed December 1, 2021.

      ). Adverse events were scored weekly during treatment every 3 months for the first 2 years and half- yearly thereafter. Against this background, as well as for pragmatic reasons, we considered that the total number of 100 patients was sufficient (dropout included). A secondary objective was to analyze the effectiveness of our treatment in terms of cumulative 5 year local recurrence-free rate (LRR), biochemical disease-free survival, distant metastases-free survival (DMFS) and overall survival rates. Biochemical recurrence was defined as the lowest prostate-specific antigen (PSA) value after treatment (PSA nadir) plus 2 ng/mL, according to the Phoenix criteria (
      • Roach M.
      • 3rd, Hanks G.
      • Thames H.
      • et al.
      Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference.
      ). Local recurrence and distant metastases-free survival were defined as evidence of recurrent disease on imaging and time to clinically evident local recurrence or to the first distant metastasis. Patients treated at our institution between 2011 and 2014 were included in the study. The study had approval from the ethics committee of the Erlangen University hospital and prior to enrollment we obtained informed consent from all patients. This trial is registered with ClinicalTrials.gov, number NCT01409876.

      Statistical analysis

      For statistical analysis, the IBM SPSS Statistics 24 software package was used. We used the Kaplan-Meier method to calculate the probability of local control and survival, and a log rank test to compare the subgroups. All events (cumulative local recurrence rate, biochemical disease-free (biochemical no evidence of disease) survival, overall survival) were defined for the time period from the beginning of radiation therapy to the time of the event or death. The biochemical disease-free survival was defined for the period from the start of salvage brachytherapy to a PSA increase of > 2 ng/mL above nadir (Phoenix definition).

      Results

      Dosimetry

      Using brachytherapy the median coverage index (V100) for prostate (CTV) was 97.4% and the corresponding median value of D90 was 111.3%. The median value of V120 for all intra-prostatic tumor areas detected (HR-CTV) was 94.3%. For intra-prostatic tumor areas detected with HistoScanning (HR-CTV) the median values of V120, V130, and V150 were 94.3%. 85.4%, and 60.2%, respectively. For detailed information on the dose parameters please see Tables 2 and 3 and an example of a typical dose distribution in Fig. 1.
      Fig 1
      Fig. 1Clinical example: (a) HistoScanning-based visualization of prostate and intra-prostatic tumor foci in selected slices of prostate. (b) Prostate (clinical target volume, CTV) and delineated intra-prostatic tumor lesions (high-risk clinical target volume, HR-CTV) with brachytherapy needles in situ, typical dose distribution and corresponding dosimetric parameters with focal dose escalation according protocol (Fig.1b(1)) or without focal dose escalation (Fig.1b(2)). For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.

      Clinical outcomes

      The median follow-up was 65 months. The cumulative 5 year local recurrence rate (LRR) for all patients was 1%. When subdivided by risk categories, 5 year-LRR estimates were 0%, and 2% for low-/intermediate- and high risk patients, respectivel 5year-biochemical disease-free survival estimates according Kaplan-Meier were 98.1% and 81.3% for low-/intermediate-risk and high-risk patients (Fig. 2). Five year metastases-free survival estimates according Kaplan-Meier was 98.0% and 83.3% for low-/intermediate-risk and high-risk patients (Fig. 3), respectively 5 year-overall survival was 60.4% and 47.9% for low-/intermediate-risk and high-risk patients, respectively.
      Fig 2
      Fig. 2The 5-years. biochemical disease-free survival for low-/intermediate (green line) and high-risk (red line) patient population. For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.
      Fig 3
      Fig. 3The 5-years. metastases-free survival for low-/intermediate (green line) and high-risk (red line) patient population. For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.
      Late toxicity was generally low with only four patients scoring a grade 3 toxicity (4/101, 4%). All these patients had grade 3 urinary late side effects requiring surgical intervention such as stricture dilatation or transurethral resection. Furthermore, 5 patients (5/101, 5%) experienced grade 2 late urinary toxicity – persistent urinary symptoms such as nycturia, polakisuria requiring medication (anticholinergics, alpha antagonists, no-steroid anti-inflammatory drugs) or pads for urinary incontinence. Grade 1 urinary toxicity was observed in 35 of 101 patients (34%). We did not identify any correlation between late urinary symptoms and urethral dose. No grade 4 toxicity was seen. Occurrence of any grade of late rectal toxicities was very low – only 3 of 101 of patients (3%) experienced Grade 1 rectal toxicity. We did not register any grade ≥2 of late rectal toxicities.

      Discussion

      In this prospective Phase 2 trial, we report outcomes of computer-aided ultrasonography (HistoScanning)-based focal dose escalation with image-guided dose-painting brachytherapy for non-metastatic prostate cancer. In all patients, in the HistoScanning-positive tumor areas, an adequate coverage with doses greater than 120% (V120median= 94%) maintaining appropriate coverage of whole prostate gland (V100median= 97%) and comparatively low doses to the urethra and rectum could be achieved. As clinical justification of these parameters, we registered a high 5 years-tumor control probability (99%) and 5year-biochemical disease-free survival (90%) while simultaneously finding a very low incidence of serious late side effects – in the low single-digit range.
      Other authors reported results of focal dose escalation with brachytherapy or external beam radiation therapy particularly using magnetic resonance spectroscopic imaging (MRSI) (
      • King M.T.
      • Nasser N.J.
      • Mathur N.
      • et al.
      Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.
      ,
      • DiBiase S.J.
      • Hosseinzadeh K.
      • Gullapalli R.P.
      • et al.
      Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostate cancer.
      ,
      • Pouliot J.
      • Kim Y.
      • Lessard E.
      • et al.
      Inverse planning for HDR prostate brachytherapy used to boost dominant intraprostatic lesions defined by magnetic resonance spectroscopy imaging.
      ), multiparametric-MRI(
      • Crook J.
      • Ots A.
      • Gaztanaga M.
      • et al.
      Ultrasound-planned high-dose-rate prostate brachytherapy: dose painting to the dominant intraprostatic lesion.
      • van Schie M.A.
      • Janssen T.M.
      • Eekhout D.
      • et al.
      Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.
      ) or combination of MRSI and MRI(55). All these authors reported a very low rate of late side effects as a results of focused dose escalation without increasing dose to surrounding organs at risk for a relatively small number of patients ranging from 5 to 47 (
      • King M.T.
      • Nasser N.J.
      • Mathur N.
      • et al.
      Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.
      ,
      • DiBiase S.J.
      • Hosseinzadeh K.
      • Gullapalli R.P.
      • et al.
      Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostate cancer.
      ,
      • Pouliot J.
      • Kim Y.
      • Lessard E.
      • et al.
      Inverse planning for HDR prostate brachytherapy used to boost dominant intraprostatic lesions defined by magnetic resonance spectroscopy imaging.
      ,
      • Crook J.
      • Ots A.
      • Gaztanaga M.
      • et al.
      Ultrasound-planned high-dose-rate prostate brachytherapy: dose painting to the dominant intraprostatic lesion.
      ,
      • Mason J.
      • Al-Qaisieh B.
      • Bownes P.
      • et al.
      Multi-parametric MRI-guided focal tumor boost using HDR prostate brachytherapy: a feasibility study.
      ,
      • Maggio A.
      • Fiorino C.
      • Mangili P.
      • et al.
      Feasibility of safe ultra-high (EQD(2)>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy.
      ,
      • Wang T.
      • Zhou J.
      • Tian S.
      • et al.
      A planning study of focal dose escalations to multiparametric MRI-defined dominant intraprostatic lesions in prostate proton radiation therapy.
      ,
      • 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.
      ,
      • Ennis R.D.
      • Quinn S.A.
      • Trichter F.
      • et al.
      Phase I/II prospective trial of cancer-specific imaging using ultrasound spectrum analysis tissue-type imaging to guide dose-painting prostate brachytherapy.
      ,
      • Tissaverasinghe S.
      • Crook J.
      • Bachand F.
      • et al.
      Dose to the dominant intraprostatic lesion using HDR vs. LDR monotherapy: a Phase II randomized trial.
      ,
      • Smith C.W.
      • Hoover D.
      • Surry K.
      • et al.
      A multiobserver study investigating the effectiveness of prostatic multiparametric magnetic resonance imaging to dose escalate corresponding histologic lesions using high-dose-rate brachytherapy.
      ,
      • Vigneault E.
      • Mbodji K.
      • Racine Ll-G
      • et al.
      Image-guided high-dose-rate brachytherapy boost to the dominant intraprostatic lesion using multiparametric magnetic resonance imaging including spectroscopy: results of a prospective study.
      ). Typically, the authors report focal dose escalation to approximately 125%−150% of the prescribed dose to the whole prostate gland (
      • Wang T.
      • Zhou J.
      • Tian S.
      • et al.
      A planning study of focal dose escalations to multiparametric MRI-defined dominant intraprostatic lesions in prostate proton radiation therapy.
      ). In the largest study dedicated focal dose escalation to the tumor foci in prostate cancer, the multicenter randomized Focal Lesion Ablative Microboost in prostate cancer (FLAME) trial, patients in the dose-escalated arm received an escalated dose up to 95 Gy to the visible tumor and 77 Gy to the whole gland(
      • van Schie M.A.
      • Janssen T.M.
      • Eekhout D.
      • et al.
      Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.
      ,
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ). Within a 5 years follow-up the authors did not observe a significant increase in GU and GI toxicity when compared to the standard treatment. The cumulative incidence of late genitourinary and GI toxicity grade ≥2 was 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively (
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ,
      • Monninkhof E.M.
      • van Loon J.W.L.
      • van Vulpen M.
      • et al.
      Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: toxicity in the FLAME randomized controlled trial.
      ). It is important to mention that the 5 years-biochemical disease-free survival was significantly higher in the focal boost arm when compared to the standard arm at 92% and 85% (p < 0.001), respectively (
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ). Contrary to this fact the 5 years metastasis free survival was in the range of 90%, but did not show any statistically significant difference between treatment arms (p = 0.27)(
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ).
      In comparison to these excellent data in our phase two trial we observed very similar efficacy – both 5 years biochemical disease-free-survival rates and 5 years metastasis free survival values are in the range of 90% in both trials. We think that these very similar efficacy results mirror similar doses in visible tumor foci used in both trials – in FLAME-trial the reported EQD2 was 108.3 Gy (α/β = 3 Gy) in our phase 2 trial the total EQD2-doses were in range of 108–119 Gy (α/β = 3 Gy). Small differences between the two trials are recognizable only in regard to late side effects. In the FLAME trial cumulative serious late GU toxicity grade ≥3 was reported in 5.6% patients and cumulative serious late GI toxicity grade ≥3 in 1.4% patients, respectively (
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ). In our present analysis, we observed serious late GU toxicity in 4% and no GI toxicity grade ≥3. Whether these very small differences are simply by chance or a consequence of the steep dose gradient characteristic for the brachytherapy used in our trial remains speculative. In any case both trials congruently demonstrated outstanding oncological results with negligible late side effects.
      A key strength of our analysis is the fact, that we report data of a prospective trial with appropriate follow-up and a rather large number of patients. To the best of our knowledge, alongside the FLAME-trial our Phase 2 trial with 101 patients encompasses the largest patient cohort of any series involving intra-prostatic focal dose escalation. In comparison to some other reports (
      • King M.T.
      • Nasser N.J.
      • Mathur N.
      • et al.
      Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.
      ) our dose escalation in tumor areas seems to be moderate – with a median V120 = 94%. Nevertheless, the clinical results surpass our expectations. It seems that the focal dose escalation of up to 120% of the prescribed dose, which corresponds to biologically equivalent doses EQD2 >100 Gy (α/β = 3 Gy) in identifiable tumor areas, is entirely adequate. As a consequence, our clinical results allow us to hypothesize that further significant intra-prostatic dose escalation of more than 120% of the prescription dose, corresponding to values of EQD2 > 100 Gy, is probably not beneficial. A definitive statement on this will, however, only be possible with an appropriate phase 3 trial.
      The key limitation of our trial is in the sensitivity, specificity and spacial resolution of the HistoScanning-based analysis. In early pilot studies, authors reported a 100% sensitivity and 81% specificity of HistoScanning-based analysis (
      • Braeckman J.
      • Autier P.
      • Soviany C.
      • et al.
      The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers.
      ), but in later investigations the sensitivity and specificity varied substantially and ranged from 60 to 90% and 50–94% (
      • Wysock J.S.
      • Xu A.
      • Orczyk C.
      • Taneja S.S.
      HistoScanning(TM) to detect and characterize prostate cancer-a review of existing literature.
      ,
      • Simmons L.A.
      • Autier P.
      • Zat'ura F.
      • et al.
      Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(.
      ,
      • Porres D.
      • Kuru T.H.
      • Epplen R.
      • et al.
      Sextant-specific analysis of detection and tumor volume by HistoScanning.
      ,
      • Macek P.
      • Barret E.
      • Sanchez-Salas R.
      • et al.
      Prostate histoscanning in clinically localized biopsy proven prostate cancer: an accuracy study.
      ,
      • Orczyk C.
      • Rosenkrantz A.B.
      • Deng F.M.
      • et al.
      A prospective comparative analysis of the accuracy of HistoScanning and multiparametric magnetic resonance imaging in the localization of prostate cancer among men undergoing radical prostatectomy.
      ). In conclusion, despite the fact that both the sensitivity and the specificity of HistoScanning-based analysis include some degree of uncertainty, in all our patients the whole prostate gland was treated with sufficient dose and the intra-prostatic focal dose escalation was generous concerning the size and borders of intra-prostatic lesions (see Fig. 1). We believe that the consequence of this treatment strategy – adequate dose to the whole prostate gland and generous definition of intra-prostatic tumor lesion – is the main reason reasonable clinical results reported despite all the uncertainties of the HistoScanning-based definition of intra-prostatic lesions. Unfortunately, the current standard of care – multiparametric MRI including diffusion-weighted and dynamic contrast-enhanced MRI – was not routinely available at the time of the initiation of our trial. It stands to reason that the objective of local cancer therapy is to eradicate all local disease foci and as a consequence, the definitive evidence will be available with longer follow-up ideally including assessment of tissue biopsies (
      • Stone N.N.
      • Stock R.G.
      • Cesaretti J.A.
      • Unger P.
      Local control following permanent prostate brachytherapy: effect of high biologically effective dose on biopsy results and oncologic outcomes.
      ).
      Finally we conclude that the presented prospective results confirm the results of the Phase 3 FLAME-trial (
      • Kerkmeijer L.G.W.
      • Groen V.H.
      • Pos F.J.
      • Haustermans K.
      • et al.
      Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME Randomized Phase III Trial.
      ) as well as those of numerous other investigations (
      • Pouliot J.
      • Kim Y.
      • Lessard E.
      • et al.
      Inverse planning for HDR prostate brachytherapy used to boost dominant intraprostatic lesions defined by magnetic resonance spectroscopy imaging.
      ,
      • Crook J.
      • Ots A.
      • Gaztanaga M.
      • et al.
      Ultrasound-planned high-dose-rate prostate brachytherapy: dose painting to the dominant intraprostatic lesion.
      ,
      • Mason J.
      • Al-Qaisieh B.
      • Bownes P.
      • et al.
      Multi-parametric MRI-guided focal tumor boost using HDR prostate brachytherapy: a feasibility study.
      ,
      • Maggio A.
      • Fiorino C.
      • Mangili P.
      • et al.
      Feasibility of safe ultra-high (EQD(2)>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy.
      ,
      • Wang T.
      • Zhou J.
      • Tian S.
      • et al.
      A planning study of focal dose escalations to multiparametric MRI-defined dominant intraprostatic lesions in prostate proton radiation therapy.
      ,
      • van Schie M.A.
      • Janssen T.M.
      • Eekhout D.
      • et al.
      Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.
      ,
      • 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.
      ), suggesting that the focal tumor boost to intra-prostatic tumor lesions is effective and safe at the same time as yielding excellent oncological results. As a consequence, we are convinced that the clinical benefit of focal intra-prostatic dose escalation is already duly validated, very clearly defined and should be considered in determining the optimal treatment strategy when treating patients with non-metastatic prostate cancer with radiotherapy.

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