Boosting imaging defined dominant prostatic tumors: A systematic review

Open AccessPublished:June 24, 2013DOI:https://doi.org/10.1016/j.radonc.2013.04.027

      Abstract

      Introduction

      Dominant cancer foci within the prostate are associated with sites of local recurrence post radiotherapy. In this systematic review we sought to address the question: “what is the clinical evidence to support differential boosting to an imaging defined GTV volume within the prostate when delivered by external beam or brachytherapy”.

      Materials and methods

      A systematic review was conducted to identify clinical series reporting the use of radiation boosts to imaging defined GTVs.

      Results

      Thirteen papers describing 11 unique patient series and 833 patients in total were identified. Methods and details of GTV definition and treatment varied substantially between series. GTV boosts were on average 8 Gy (range 3–35 Gy) for external beam, or 150% for brachytherapy (range 130–155%) and GTV volumes were small (<10 ml). Reported toxicity rates were low and may reflect the modest boost doses, small volumes and conservative DVH constraints employed in most studies. Variability in patient populations, study methodologies and outcomes reporting precluded conclusions regarding efficacy.

      Conclusions

      Despite a large cohort of patients treated differential boosts to imaging defined intra-prostatic targets, conclusions regarding optimal techniques and/or efficacy of this approach are elusive, and this approach cannot be considered standard of care. There is a need to build consensus and evidence. Ongoing prospective randomized trials are underway and will help to better define the role of differential prostate boosts based on imaging defined GTVs.

      Keywords

      Prostate cancer is a multi-focal disease and conventional therapies address this by treating the whole gland. In the case of radiation, such an approach however, may be limiting to the efficacy of radiotherapy as escalation of dose to improve tumor control may be limited by adjacent organ at risk tolerance [
      • 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.
      ]. Whole mount prostate pathology studies suggest in many cases a dominant cancer focus exists within the gland and may be a driver of the aggressiveness of the cancer and the epicenter of recurrence post treatment [
      • Mouraviev V.
      • Villers A.
      • Bostwick D.G.
      • et al.
      Understanding the pathological features of focality, grade and tumor volume of early-stage prostate cancer as a foundation for parenchyma-sparing prostate cancer therapies: active surveillance and focal targeted therapy.
      ,
      • 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.
      ]. Thus strategies to identify and intensify treatment to dominant prostate foci (Gross Tumor Volume/GTV) are under active investigation. Advances in Positron Emission Tomography (PET), Single Positron Emission Tomography (SPECT) and magnetic resonance imaging (MRI) show promise in identifying prostate GTVs and advances in precision radiotherapy enable dose intensification [
      • 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.
      ,
      • Pinkawa M.
      • Eble M.J.
      • Mottaghy F.M.
      PET and PET/CT in radiation treatment planning for prostate cancer.
      ,
      • Bauman G.
      • Belhocine T.
      • Kovacs M.
      • et al.
      18F-fluorocholine for prostate cancer imaging: a systematic review of the literature.
      ,
      • Pickett B.
      • Vigneault E.
      • Kurhanewicz J.
      • et al.
      Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy.
      ,
      • Ling C.C.
      • Humm J.
      • Larson S.
      • et al.
      Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality.
      ]. In this systematic review we sought to address the question: “is there clinical evidence to support differential boosting to an imaging defined GTV boost within the prostate when delivered by external beam or brachytherapy (low dose or high dose rate)”. In particular we were interested in techniques used for GTV definition on imaging for boosting and clinical endpoints of toxicity (both acute and late) and efficacy (biochemical and clinical control) among men so treated.

      Materials and methods

      Formulation of the research question, search strategy and data extraction elements were agreed upon by the lead authors (GB,CM) in advance of the literature review. A search of the PubMed database for the years January 1, 2000–June 30, 2012 was conducted using the following search strategy “(intraprostatic[tw] OR intra-prostatic[tw] OR DIL[tw] OR ipl[tw]) AND (radiation[tw] OR radiotherapy[tw] OR brachytherapy[tw]) AND prostate[tw]”. Papers describing focal salvage treatment (e.g. Nguyen [
      • Nguyen P.L.
      • Chen M.H.
      • D’Amico A.V.
      • et al.
      Magnetic resonance image-guided salvage brachytherapy after radiation in select men who initially presented with favorable-risk prostate cancer: a prospective phase 2 study.
      ] image guidance for whole gland therapy (e.g. Menard [
      • Menard C.
      • Susil R.C.
      • Choyke P.
      • et al.
      MRI-guided HDR prostate brachytherapy in standard 1.5T scanner.
      ]) or partial gland therapy based on anatomically defined (not lesion defined) targets (e.g. Nguyen [
      • Nguyen P.L.
      • Chen M.H.
      • Zhang Y.
      • et al.
      Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy.
      ]) or where a focal boost was based exclusively on biopsy results (e.g. Gaudet [
      • Gaudet M.
      • Vigneault E.
      • Aubin S.
      • et al.
      Dose escalation to the dominant intraprostatic lesion defined by sextant biopsy in a permanent prostate I-125 implant: a prospective comparative toxicity analysis.
      ]) rather than lesion imaging were excluded. Papers included needed to available as full published manuscripts, available in English and reporting at least one clinical outcome (toxicity or efficacy) among treated patients (papers reporting planning studies without actual patient treatment and single case reports were not included), Full text versions of the eligible papers were retrieved and reviewed including manual searching of the bibliographies for other applicable papers. In the case of one paper [
      • Pinkawa M.
      • Attieh C.
      • Piroth M.D.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of the dose distribution with and without 18F-choline PET-CT detected simultaneous integrated boost.
      ] the corresponding author was contacted for additional information regarding clinical outcomes and this lead to the identification of a companion paper [
      • Pinkawa M.
      • Piroth M.D.
      • Holy R.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of quality of life with and without (18)F-choline PET-CT detected simultaneous integrated boost.
      ] with this information. For the review, data extracted for each series included year of report, number of patients treated, proportion of low, intermediate and high risk patients (NCCN criteria) included in the series, median PSA among the patient population, methods used for GTV imaging and GTV delineation criteria, PTV1 delineation criteria, boost technique used and dose of the boost, use of supplementary pelvic nodal or androgen deprivation therapy, acute and late toxicity observed (along with toxicity scale used) clinical outcomes (clinical and/or biochemical control) and series specific observations were extracted. Nomenclature regarding intra-prostatic lesion definition differed significantly between patient series; for the purposes of this systematic review, GTV refers to imaging defined intra-prostatic lesions; PTV1 refers to the volumetric expansion on the GTV for the boost and PTV2 refers to the volumetric expansion of the whole prostate volume to account for setup and delivery uncertainty. Initial data extraction was undertaken by one author (GB) with review by a second author (CM). The remaining authors (MH, UVH) contributed to the analysis and interpretation of the extracted results and the manuscript. Given the heterogeneous nature of the patient series reported, no formal attempt at a quantitation of bias or analysis of pooled results was attempted however qualitative appraisal of the relative strengths and weaknesses of the individual series was made and qualitative statements are included in the results and discussion of the papers. The primary outcomes of interest were safety (toxicity reported), efficacy (clinical and biochemical control) as well as method of lesion delineation.

      Results

      In total, thirteen papers describing eleven unique patient series with a total of 833 patients were identified for data extraction. A flow diagram of the search results is available in Fig. 1. As outlined in Table 1, the analyzed literature [
      • Pinkawa M.
      • Attieh C.
      • Piroth M.D.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of the dose distribution with and without 18F-choline PET-CT detected simultaneous integrated boost.
      ,
      • Pinkawa M.
      • Piroth M.D.
      • Holy R.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of quality of life with and without (18)F-choline PET-CT detected simultaneous integrated boost.
      ,
      • De Meerleer G.
      • Villeirs G.
      • Bral S.
      • et al.
      The magnetic resonance detected intraprostatic lesion in prostate cancer: planning and delivery of intensity-modulated radiotherapy.
      ,
      • DiBiase S.J.
      • Hosseinzadeh K.
      • Gullapalli R.P.
      • et al.
      Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostate cancer.
      ,
      • Ellis R.J.
      • Zhou H.
      • Kaminsky D.A.
      • et al.
      Rectal morbidity after permanent prostate brachytherapy with dose escalation to biologic target volumes identified by SPECT/CT fusion.
      ,
      • Ellis R.J.
      • Zhou H.
      • Kim E.Y.
      • et al.
      Biochemical disease-free survival rates following definitive low-dose-rate prostate brachytherapy with dose escalation to biologic target volumes identified with SPECT/CT capromab pendetide.
      ,
      • Ippolito E.
      • Mantini G.
      • Morganti A.G.
      • et al.
      Intensity-modulated radiotherapy with simultaneous integrated boost to dominant intraprostatic lesion: preliminary report on toxicity.
      ,
      • Wong W.W.
      • Schild S.E.
      • Vora S.A.
      • et al.
      Image-guided radiotherapy for prostate cancer: a prospective trial of concomitant boost using indium-111-capromab pendetide (ProstaScint) imaging.
      ,
      • Zelefsky M.J.
      • Cohen G.
      • Zakian K.L.
      • et al.
      Intraoperative conformal optimization for transperineal prostate implantation using magnetic resonance spectroscopic imaging.
      ,
      • Miralbell R.
      • Molla M.
      • Rouzaud M.
      • et al.
      Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.
      ,
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      ,
      • Fonteyne V.
      • Villeirs G.
      • Speleers B.
      • et al.
      Intensity-modulated radiotherapy as primary therapy for prostate cancer: report on acute toxicity after dose escalation with simultaneous integrated boost to intraprostatic lesion.
      ,
      • Singh A.K.
      • Guion P.
      • Sears-Crouse N.
      • et al.
      Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study.
      ] included patients treated with external beam (EBXRT) focal boost (n = 5 with simultaneous boost; n = 1 with sequential boost) as well as low dose rate brachytherapy (LDR, n = 4) and high dose rate brachytherapy (HDR, n = 1). Heterogeneity between the series restricted analyses to qualitative descriptions and pooling of results of data was not possible. The majority of series were prospective series examining relatively small numbers of patients. The largest external beam series (Fontenye et al. [
      • Fonteyne V.
      • Villeirs G.
      • Speleers B.
      • et al.
      Intensity-modulated radiotherapy as primary therapy for prostate cancer: report on acute toxicity after dose escalation with simultaneous integrated boost to intraprostatic lesion.
      ,
      • Singh A.K.
      • Guion P.
      • Sears-Crouse N.
      • et al.
      Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study.
      ,
      • Barentsz J.O.
      • Richenberg J.
      • Clements R.
      • et al.
      ESUR prostate MR guidelines 2012.
      ]) was limited by its retrospective nature and lack of an MRI panel confirming to current standards [
      • 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.
      ]. The largest brachytherapy series (Ellis et al. [
      • Ellis R.J.
      • Kaminsky D.A.
      • Zhou E.H.
      • et al.
      Ten-year outcomes: the clinical utility of single photon emission computed tomography/computed tomography capromab pendetide (Prostascint) in a cohort diagnosed with localized prostate cancer.
      ]) utilized an imaging modality with recognized technical challenges in interpretation and limited histopathologic validation. Approximately one quarter of the patients described met the NCCN criteria [
      • Mohler J.
      • Bahnson R.R.
      • Boston B.
      • et al.
      NCCN clinical practice guidelines in oncology: prostate cancer.
      ] for low risk. Androgen deprivation therapy varied among series as did the use of nodal radiation. Techniques for GTV definition used Standard Uptake Value (SUV) thresholds on 111In-Capromab SPECT (n = 2) or 18F-Fluorocholine PET imaging (n = 1). MRI based series (8) generally used a 1.5T magnet with endorectal (ERC) and pelvic coils. The T2W sequence was most commonly used (GTV = decreased intensity with a mass like appearance) with Dynamic Contrast Enhanced (DCE, GTV = increased enhancement); Diffusion Weighted derived apparent diffusion coefficient maps (DWI/ADC, GTV = regions of decreased ADC values) or magnetic resonance spectroscopy (MRSI, GTV = increased choline + creatinine:citrate ratio) used less often. Only one series [
      • Singh A.K.
      • Guion P.
      • Sears-Crouse N.
      • et al.
      Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study.
      ] utilized T2W + DWI + DCE which reflects the current consensus guidelines for prostate imaging [
      • Barentsz J.O.
      • Richenberg J.
      • Clements R.
      • et al.
      ESUR prostate MR guidelines 2012.
      ,
      • Dickinson L.
      • Ahmed H.U.
      • Allen C.
      • et al.
      Scoring systems used for the interpretation and reporting of multiparametric MRI for prostate cancer detection, localization, and characterization: could standardization lead to improved utilization of imaging within the diagnostic pathway?.
      ]. Imaging defined GTVs were transferred to planning images (Computed Tomography/CT or Ultrasound/US) through image registration (n = 6) or manual transfer/”cognitive fusion” (n = 5). Where reported, GTV volumes ranged from 3.5–6.8 ml; multiple GTVs were defined in 10% of patients and close GTV proximity (<3–5 mm) to Organs at Risk (OAR) was noted. Most series defined a PTV1 (most commonly 3–4 mm, excluding OAR) for the GTV. For EBXRT series, PTV2 doses ranged from 64–78 Gy; PTV1 doses from 80–94.5 Gy. The average differential dose (PTV2–PTV1) was 8 Gy (BED2, a/b = 3 Gy, range 3–35 Gy). The most common EBXRT rectal dose constraints was V70 <15–30% with rectal Dmax of 76–80 Gy; bladder constraints were V70 <15–30% and Dmax of 80 Gy. For the brachytherapy series, 125I LDR was most commonly used with a PTV2 dose of 145 Gy, a PTV1 dose of 217 Gy (150%) and Dmax to urethra of <130–150%. Median follow-up ranged from 3–66 months. Outcomes reported included biochemical control in 4 series and toxicity in 10. Grade 4 toxicity was reported in 4 patients (3 rectovesical fistula, 1 hematuria) [
      • Ellis R.J.
      • Zhou H.
      • Kaminsky D.A.
      • et al.
      Rectal morbidity after permanent prostate brachytherapy with dose escalation to biologic target volumes identified by SPECT/CT fusion.
      ,
      • Wong W.W.
      • Schild S.E.
      • Vora S.A.
      • et al.
      Image-guided radiotherapy for prostate cancer: a prospective trial of concomitant boost using indium-111-capromab pendetide (ProstaScint) imaging.
      ,
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      ]. The series with the highest boost differentials [
      • Miralbell R.
      • Molla M.
      • Rouzaud M.
      • et al.
      Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.
      ,
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      ] included 66 patients with reported late Grade 3 or greater toxicities that ranged from 0 to 10% including one patient with fistula formation.
      Figure thumbnail gr1
      Fig. 1PRISMA diagram of systematic review results.
      Figure thumbnail gr2
      Fig. 2An example of the dose distribution of a patient enrolled on the FLAME randomized controlled trial. Left- A standard dose of 77 Gy in 35 fractions is delivered to the prostate and seminal vesicles. Right- An illustration of an integrated boost of 95 Gy delivered to the GTV with compromised posterior coverage adjacent to the rectum.
      Table 1Literature summary.
      ReferencePatient populationTumor volume delineationTreatmentOutcomes
      Ippolito Ref.
      • Ippolito E.
      • Mantini G.
      • Morganti A.G.
      • et al.
      Intensity-modulated radiotherapy with simultaneous integrated boost to dominant intraprostatic lesion: preliminary report on toxicity.
      N = 40

      Median PSA: 7
      1.5 TMRI + ERC; sequences not specified; fusion; GTV ‘defined on MRI, consistent with biopsy findings’5 field IMRT; 6MVSurvival

      No biochemical failures
      LR: 4

      IR: 17

      HR: 19
      PTV2 = prostate + SV + 1 cm

      PTV1 = GTV + 5 mm
      PTV2: 72 Gy

      PTV1: 80 Gy (84 Gy a/b = 3)
      GI toxicity (RTOG/EORTC)

      Acute: 15% Grade 2; 5% Grade 3

      Late: 5% Grade 2; 2.5% Grade 3
      Prospective feasibility study; IRB approvedMedian follow-up 19 monthsMedian PTV1 volume 55 mlAdditional treatments

      100% ADT
      GU toxicity (RTOG/EORTC)

      Acute: 30% Grade 2; 2.5% Grade 3

      Late: 5% Grade 2; 2.5% (1/40) Grade 4
      2 year actuarial risk of toxicity >Grade 2 was 13% (GU); 9.5% (GI)
      Pinkawa Ref.
      • Pinkawa M.
      • Attieh C.
      • Piroth M.D.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of the dose distribution with and without 18F-choline PET-CT detected simultaneous integrated boost.
      ,
      • Pinkawa M.
      • Piroth M.D.
      • Holy R.
      • et al.
      Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of quality of life with and without (18)F-choline PET-CT detected simultaneous integrated boost.
      N = 66

      Median PSA: 14

      LR: 23

      IR: 21

      HR: 22
      18F-Fluorocholine PET; fusion; GTV SUV >2 times background5 field, 15 MV IMRTSurvival

      NR
      Prospective quality of life study; IRB not specifiedMedian follow-up 19 monthsPTV2 = prostate + SV + 4–8 mm

      PTV1 = GTV + 3–4 mm
      PTV2 = 76 Gy

      PTV1 = 80 Gy (83 Gy a/b = 3)
      GI/GU Toxicity (EPIC)

      10% deterioration in brother and function scores at median of 2 months post radiation; return to baseline by median of 19 months. No difference between patients who received an SIB (n = 46) vs. no SIB(n = 21)
      Extra-prostatic disease was detected in 1/66mean GTV 6.2 ml; 22 had 2 GTV; 7 had 3 GTV defined; 36 GTV had involvement of central gland; 36 GTV were within 3 mm of rectum;Additional treatments

      16% ADT
      Wong Ref.
      • Wong W.W.
      • Schild S.E.
      • Vora S.A.
      • et al.
      Image-guided radiotherapy for prostate cancer: a prospective trial of concomitant boost using indium-111-capromab pendetide (ProstaScint) imaging.


      Prospective feasibility study, IRB approved
      N = 71

      Median PSA: 6.1

      LR: 28

      IR: 40

      HR: 3
      111In-Capromab SPECT; fusion; GTV = SUV 3× muscle SUV5 field IMRT; 6MVSurvival

      94% 5 year BDFS; 93% 5 year OS (Phoenix)
      Median follow-up

      66 months
      PTV2 = prostate + SV + 6 mm

      PTV1 = GTV
      PTV2: 75.6 Gy

      PTV1: 82 Gy (85 Gy a/b = 3)
      GI Toxicity (Modified RTOG)

      Acute: 45% Grade 2

      Late: 15% Grade 2
      Median GTV = 7% of PTV2Additional treatments

      60% ADT
      GU Toxicity (Modified RTOG)

      Acute: 54% Grade 2; 1% Grade 3

      Late: 39% Grade 2; 3% Grade 3; 1% Grade 4
      Ellis Ref.
      • Ellis R.J.
      • Zhou H.
      • Kaminsky D.A.
      • et al.
      Rectal morbidity after permanent prostate brachytherapy with dose escalation to biologic target volumes identified by SPECT/CT fusion.
      ,
      • Ellis R.J.
      • Zhou H.
      • Kim E.Y.
      • et al.
      Biochemical disease-free survival rates following definitive low-dose-rate prostate brachytherapy with dose escalation to biologic target volumes identified with SPECT/CT capromab pendetide.
      ,
      • Ellis R.J.
      • Kaminsky D.A.
      • Zhou E.H.
      • et al.
      Ten-year outcomes: the clinical utility of single photon emission computed tomography/computed tomography capromab pendetide (Prostascint) in a cohort diagnosed with localized prostate cancer.
      N = 239

      Median PSA: 7.6

      LR: 116

      IR: 72

      HR: 51
      111In-Capromab SPECT gamma contrast uptake “dialed in” to correlate with biopsy. No fusionLDR prostate brachytherapySurvival

      85% 10 year BDFS; 85% OS (Phoenix)
      Prospective study, IRB approved111In-Capromab SPECT suggested metastatic disease in 9.2%PTV2 = prostate + 2–5 mm

      PTV1 = GTV + 5 mm
      PTV2 = 108–144 Gy (I125) = 100–125 Gy (P103)

      PTV1 = 150% of PTV2
      GI Toxicity (RTOG)

      Acute: 4% Grade 2; 0% Grade 3

      Late: 2% Grade 2; 1% Grade 4
      Median follow-up

      NR
      Additional treatments

      37%: EBXRT

      21%: ADT

      27%: Node dissection
      GU Toxicity

      NR

      Survival was worse for patients with extra-prostatic disease on SPECT. 2 patients had Grade 4 toxicity (fistula) at 18 and 30 months
      Schick Ref.
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      N = 77

      Median PSA: NR

      LR: 7

      IR: 9

      HR: 61
      A hemi-prostate (n = 20) or bilateral (n = 57) prostate GTV was defined by correlation of DRE, biopsy results and ERC MRI; if T2W changes and biopsy involvement confined to same lobe, unilateral boost otherwise bilateral boost; catheter + 3–5 mm used to define urethra PRV; no fusionHDR prostate brachytherapy

      PTV2 = 64.4 Gy

      PTV1 = 88–104 Gy (a/b = 3)
      Survival

      78% 5 yr BDFS (Phoenix)
      Prospective study; IRB not specifiedMedian follow-up

      62–67 months
      PTV2 = Prostate + SV

      PTV1 = GTV
      Patients treated with an HDR boost after completing prostate EBXRTGI Toxicity (RTOG/EORTC)

      Acute: 3% Grade 2; 0% Grade 3/4

      Late: 9% Grade 2; 4% Grade ¾
      N = 19: 2 × 6 Gy

      N = 21: 2 × 7 Gy

      N = 37: 2 × 8 Gy

      Additional treatments

      81% ADT

      36% PLN
      GU Toxicity (RTOG/EORTC)

      Acute: 3% Grade 2; 3% Grade3/4

      Late: 10% Grade 2; 9% Grade 3/4



      Higher acute and late GU toxicity was noted for bilateral vs. unilateral boost; one patient (unilateral 2 × 8 Gy) developed a fistula requiring pelvic exenteration
      Miralbell Ref.
      • Miralbell R.
      • Molla M.
      • Rouzaud M.
      • et al.
      Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.
      N = 50

      Median PSA: NR

      LR: 5

      IR: 12

      HR: 33
      GTV defined on ERC MRI (T2 + DCE) correlated with biopsy; fusion (ERC used for planning CT to facilitate); bilateral gland in 48;3DCRT (n = 39) or IMRT (n = 11)

      PTV2 = 64 Gy

      PTV1 = 80–99 Gy (a/b = 3)
      Survival

      98% 5 year BDFS (Phoenix)

      GI Toxicity(RTOG/EORTC)

      Acute: 8% Grade 2; 0% Grade 3

      Late: 10% Grade 2; 10% Grade 3
      Prospective study; IRB not specifiedPTV2 = prostate + SV+?

      PTV1 = GTV + 3 mm
      stereotactic boost after completing prostate EBXRTN = 5: 2 × 5 Gy

      N = 8: 2 × 6 Gy

      N = 8: 2 × 7 Gy

      N = 29: 2 × 8 Gy
      GU Toxicity(RTOG/EORTC)

      Acute:46% Grade 2; 4% Grade 3

      Late: 12% Grade 2; 0% Grade 3
      Additional treatments

      56% PLN

      66% ADT
      No statistically significant toxicity difference between high dose arm (8 Gy × 2) vs. lower dose arms; actuarial risk of >Grade 2 toxicity was 18% GU; 28% GI
      Fonteyne Ref.
      • Fonteyne V.
      • Villeirs G.
      • Speleers B.
      • et al.
      Intensity-modulated radiotherapy as primary therapy for prostate cancer: report on acute toxicity after dose escalation with simultaneous integrated boost to intraprostatic lesion.
      N = 230

      Median PSA: 11.2

      LR: 17

      IR: 97

      HR: 116
      GTV defined on 1.5T ERC MRI T2W or MRSI by consensus; 118/230 had MRI defined GTV; 4/118 were defined on MRSI; 8/118 had more than one GTV defined. Fusion3–6 field IMRT; daily U/S guidanceSurvival

      NR
      Retrospective review; IRB not specifiedPTV2 = prostate+/− SV + 4 mm

      PTV1 = GTV + 8 mm
      PTV2: 78 Gy

      PTV1: 80 Gy (81 Gy a/b = 3)
      GI Toxicity (modified RTOG)

      Acute: 11% Grade 2; 0% Grade 3

      Late: NR
      GU Toxicity (modified RTOG)

      Acute: 41% Grade 2; 7% Grade 3

      Late: NR

      50% had boost to GTV; no difference in toxicity boost vs. no boost
      Singh Ref.
      • Singh A.K.
      • Guion P.
      • Sears-Crouse N.
      • et al.
      Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study.
      N = 3GTV defined on 3T ERC MRI by T2W + DCE + DWI with biopsy confirmation; gold seed fiducials were used for fusion. 1 patient had 2 GTVIMRT with daily image guidanceSurvival

      NR
      Prospective, phase I, IRB approvedFollow-up of 3–18 monthsPTV2 = prostate + 7 mm

      PTV1 = GTV + 3 mm
      PTV2 = 75.6 Gy

      PTV1 = 94.5 Gy
      GI Toxicity (RTOG)

      Acute: 0/3 Grade >2

      Late: NR
      GU Toxicity (RTOG)

      Acute: 2/3 Grade 2

      Late: NR

      First cohort of a Phase I study that seeks to dose escalate the GTV to 152 Gy
      DeMeerleer Ref.
      • De Meerleer G.
      • Villeirs G.
      • Bral S.
      • et al.
      The magnetic resonance detected intraprostatic lesion in prostate cancer: planning and delivery of intensity-modulated radiotherapy.
      N = 38

      Median PSA: 10.2
      Three physician consensus read of 1.5T ERC MRI; GTV delineated on T2W (15/38 patients imaged had GTV defined); median volume was 4 cc; 13/15 were <5 mm from rectal wall; no fusion3 Field IMRTSurvival

      NR
      Retrospective review, IRB not specifiedLR: 3

      IR: 8

      HR: 5
      PTV2 = prostate + 7–10 mm

      PTV1 = GTV + 0 mm
      PTV2 = 78 Gy

      PTV1 = 80 Gy
      GI Toxicity

      Acute: 20% Grade 2; 0% Grade 3

      Late: NR
      GU Toxicity

      Acute: 40% Grade 2; 7% Grade 3

      Late: NR
      Dibase Ref.
      • DiBiase S.J.
      • Hosseinzadeh K.
      • Gullapalli R.P.
      • et al.
      Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostate cancer.
      Prospective feasibility, IRB approved
      N = 15

      Median PSA: 7.1
      1.5T ERC MRI spectroscopy used to manually map voxels with citrate: choline + creatinine ratio <1.4 onto axial USLDR prostate brachytherapySurvival

      NR
      LR: 15/15PTV2 = prostate + 0–2 mm

      PTV1 = GTV
      PTV2 = 145 Gy (I125)

      PTV1 = 188 Gy
      GI Toxicity

      Acute: “No rectal morbidity”

      Late: NR
      Median follow-up

      NR

      1/14 not implanted
      GU Toxicity (modified RTOG)

      Acute: 53% Grade 2

      Late: NR
      Zelefsky Ref.
      • Zelefsky M.J.
      • Cohen G.
      • Zakian K.L.
      • et al.
      Intraoperative conformal optimization for transperineal prostate implantation using magnetic resonance spectroscopic imaging.


      Prospective feasibility; IRB not specified
      N = 4

      Median PSA: 4.5

      LR: 2

      IR: 2
      1.5T ERC MRI spectroscopy to identify voxels with high choline + creatinine: choline ratio; mapped to ultrasound as GTV using deformable registration

      PTV2 = prostate

      PTV1 = GTV
      LDR prostate brachytherapySurvival

      NR
      PTV2 = 100–145 Gy (I125)

      PTV1 = 150% of PTV2
      GI Toxicity

      NR
      GU Toxicity (modified RTOG)

      NR
      LR, low risk; IR, intermediate risk; HR, high risk; ERC, endorectal coil; MRSI, magnetic spectroscopy imaging; BDFS, biochemical disease free survival; NR, not reported; ADT, androgen deprivation therapy; PLN, pelvic lymph node radiation.

      Discussion

      Histopathologic studies and patterns of recurrence after external beam radiotherapy suggest that many men may have a dominant focus of disease in the prostate that is a key driver of cancer biology and treatment success [
      • Mouraviev V.
      • Villers A.
      • Bostwick D.G.
      • et al.
      Understanding the pathological features of focality, grade and tumor volume of early-stage prostate cancer as a foundation for parenchyma-sparing prostate cancer therapies: active surveillance and focal targeted therapy.
      ,
      • Karavitakis M.
      • Ahmed H.U.
      • Abel P.D.
      • et al.
      Tumor focality in prostate cancer: implications for focal therapy.
      ]. Evolution of prostate cancer imaging [
      • 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.
      ,
      • Pinkawa M.
      • Eble M.J.
      • Mottaghy F.M.
      PET and PET/CT in radiation treatment planning for prostate cancer.
      ,
      • Bauman G.
      • Belhocine T.
      • Kovacs M.
      • et al.
      18F-fluorocholine for prostate cancer imaging: a systematic review of the literature.
      ] and radiation treatment [
      • Pickett B.
      • Vigneault E.
      • Kurhanewicz J.
      • et al.
      Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy.
      ] has driven the exploration of focal intra-prostatic dose escalation. Consensus statements and prospective trials regarding the implementation of therapies based on the identification of focal intra-prostatic lesions are emerging [
      • Ahmed H.U.
      • Akin O.
      • Coleman J.A.
      • et al.
      Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer.
      ,
      • Ahmed H.U.
      • Hindley R.G.
      • Dickinson L.
      • et al.
      Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study.
      ,
      • Langley S.
      • Ahmed H.U.
      • Al-Qaisieh B.
      • et al.
      Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer.
      ]. Concerns regarding therapies addressing the focal lesion only are the difficulty in identifying men with truly focal disease [
      • Mouraviev V.
      • Villers A.
      • Bostwick D.G.
      • et al.
      Understanding the pathological features of focality, grade and tumor volume of early-stage prostate cancer as a foundation for parenchyma-sparing prostate cancer therapies: active surveillance and focal targeted therapy.
      ] and the high risk of recurrence noted to date when less than whole gland treatment is attempted based on strategies without explicit lesion targeting [
      • Nguyen P.L.
      • Chen M.H.
      • Zhang Y.
      • et al.
      Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy.
      ,
      • Vainshtein J.
      • Abu-Isa E.
      • Olson K.B.
      • et al.
      Randomized phase II trial of urethral sparing intensity modulated radiation therapy in low-risk prostate cancer: implications for focal therapy.
      ]. For this reason, differential boosting of the prostate with dose escalation to imaging defined intra-prostatic GTV volumes is attractive. In this systematic review, a variety of approaches attempting to exploit this strategy were identified. The variability in approaches reflects the lack of consensus around key issues that need to be addressed in order to rigorously assess the efficacy and safety of this approach.

       Optimal intra-prostatic GTV boost dose

      There have been numerous studies modeling the benefit and safety of incorporating a boost of dominant intra-prostatic GTV(s) with whole prostate treatment (see Supplementary References) and an example is illustrated in Fig. 2. The majority of studies modeling GTV boosts used MRI for GTV delineation with fewer using PET or SPECT. Anatomy dependence is noted with boosts more achievable if GTVs are located more than 3 mm from OAR. Like the clinical data reported here, modeling studies suffer from lack of consistent methodology for GTV delineation and deformable mapping onto planning images. The series by Huisman and Van Lin are notable in that they describe planning workflow in detail and use intra-prostatic fiducial markers to assist in image fusion as well as image guidance for treatment [
      • Huisman H.J.
      • Futterer J.J.
      • van Lin E.N.
      • et al.
      Prostate cancer: precision of integrating functional MR imaging with radiation therapy treatment by using fiducial gold markers.
      ,
      • 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.
      ]. In general, planning studies suggest that GTV dose escalation up to 95 Gy with external beam radiotherapy should be feasible for most patients with a resulting absolute increase in TCP of 2–15%. The ideal GTV dose remains to be determined however and higher doses that respect OAR tolerances may be difficult to achieve for all patients depending on the anatomic location of the dominant lesion and plateaus in TCP beyond doses of 84–90 Gy have been suggested [
      • Seppala J.
      • Seppanen M.
      • Arponen E.
      • et al.
      Carbon-11 acetate PET/CT based dose escalated IMRT in prostate cancer.
      ,
      • Housri N.
      • Ning H.
      • Ondos J.
      • et al.
      Parameters favorable to intraprostatic radiation dose escalation in men with localized prostate cancer.
      ]. Achieving a high boost dose at the expense of a lower (<70–75 Gy) whole prostate dose may be a counter-productive strategy as increased intraprostatic recurrences have been noted with this approach [
      • Nguyen P.L.
      • Chen M.H.
      • Zhang Y.
      • et al.
      Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy.
      ,
      • Vainshtein J.
      • Abu-Isa E.
      • Olson K.B.
      • et al.
      Randomized phase II trial of urethral sparing intensity modulated radiation therapy in low-risk prostate cancer: implications for focal therapy.
      ,
      • van der Heide U.A.
      • Houweling A.C.
      • Groenendaal G.
      • et al.
      Functional MRI for radiotherapy dose painting.
      ]. For example, D’Amico reported on a series of patients where MRI was used to define the peripheral zone as an “anatomic” GTV for dose escalated partial prostate brachytherapy and noted relatively high failure rates compared to whole gland brachytherapy series [
      • Nguyen P.L.
      • Chen M.H.
      • Zhang Y.
      • et al.
      Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy.
      ]. Clinically, both Schick and Miralbell [
      • Miralbell R.
      • Molla M.
      • Rouzaud M.
      • et al.
      Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.
      ,
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      ] described series using relatively low (60 Gy) whole gland treatment with external beam radiotherapy followed by an intra-prostatic boost with HDR or stereotactic external beam boost. In both cases, boost volumes were generous and encompassed the majority of the gland (typically a horseshoe shaped boost with urethral sparing) which may have contributed to the relatively favorable control rates seen (78% and 98% 5 year bDFS respectively).

       Standards for GTV delineation

      The potential benefits of intra-prostatic boosts are dependent on the performance of the imaging techniques used for GTV delineation [
      • Niyazi M.
      • Bartenstein P.
      • Belka C.
      • et al.
      Choline PET based dose-painting in prostate cancer – modelling of dose effects.
      ]. Within the series reviewed imaging used for GTV definition including single parameter MRI, multi-parametric MRI, SPECT and PET imaging. Of these imaging modalities, MRI has the strongest evidence base validating MRI against pathology gold standards (see Supplementary References) but even then considerable variability in methodology between these reports exist. Most MRI validation studies used 1.5T with pelvic and ERCs and evaluated mainly intermediate and high risk patients. T2W was routinely used with variable incorporation of other sequences (DCE, DWI, and MRSI). Criteria for lesion identification differed considerably between series with some series using qualitative “suspicion scales” to score sectors or regions “benign” to “definitely malignant” based on combinations of imaging traits to more quantitative measures based on perfusion or spectroscopy parameters. In general, test performance (as measured by sensitivity/specificity or ROC analysis) is worst for single sequence MRI (performance around 0.6–0.7) with performance improving for multi-parametric MRI (performance 0.8–0.9) and this is reflected in current consensus guidelines recommending T2W + DWI + DCE for lesion detection [
      • Barentsz J.O.
      • Richenberg J.
      • Clements R.
      • et al.
      ESUR prostate MR guidelines 2012.
      ,
      • Dickinson L.
      • Ahmed H.U.
      • Allen C.
      • et al.
      Scoring systems used for the interpretation and reporting of multiparametric MRI for prostate cancer detection, localization, and characterization: could standardization lead to improved utilization of imaging within the diagnostic pathway?.
      ]. As an example, Futterer [
      • Futterer J.J.
      • Scheenen T.W.
      • Heijmink S.W.
      • et al.
      Standardized threshold approach using three-dimensional proton magnetic resonance spectroscopic imaging in prostate cancer localization of the entire prostate.
      ] reported on 34 patients, intermediate risk, imaged with 1.5T, T2W, DCE and MRSI and noted that a multi-parametric score of MPKS (mean score of DCE parameters) + spectroscopy provided the best performance (ROC Az = 0.94). There is less information regarding performance of MRI in defining boundaries of lesions compared with pathology (as opposed to identifying the presence of cancer on a quadrant or sextant basis). Variations in malignant gland density and sparse tumor distribution can affect visibility of prostate cancer with MRI and confound lesion delineation [
      • Langer D.L.
      • van der Kwast T.H.
      • Evans A.J.
      • et al.
      Intermixed normal tissue within prostate cancer: effect on MR imaging measurements of apparent diffusion coefficient and T2 – sparse versus dense cancers.
      ]. Where reported, modest concordance levels lesion boundaries on imaging and pathology are noted (0.6–0.7) with expansions of imaging boundaries by 2–5 mm to account for imaging and registration uncertainties improving concordance indices [
      • Mazaheri Y.
      • Shukla-Dave A.
      • Hricak H.
      • et al.
      Prostate cancer: identification with combined diffusion-weighted MR imaging and 3D 1H MR spectroscopic imaging – correlation with pathologic findings.
      ,
      • Groenendaal G.
      • Borren A.
      • Moman M.R.
      • et al.
      Pathologic validation of a model based on diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for tumor delineation in the prostate peripheral zone.
      ,
      • Groenendaal G.
      • Moman M.R.
      • Korporaal J.G.
      • et al.
      Validation of functional imaging with pathology for tumor delineation in the prostate.
      ,
      • Scheidler J.
      • Hricak H.
      • Vigneron D.B.
      • et al.
      Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging – clinicopathologic study.
      ]. Probability maps generated by statistical models have demonstrated excellent concordance with pathology defined GTVs in the peripheral zone [
      • Groenendaal G.
      • Borren A.
      • Moman M.R.
      • et al.
      Pathologic validation of a model based on diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for tumor delineation in the prostate peripheral zone.
      ,
      • Moradi M.
      • Salcudean S.E.
      • Chang S.D.
      • et al.
      Multiparametric MRI maps for detection and grading of dominant prostate tumors.
      ,
      • Shah V.
      • Turkbey B.
      • Mani H.
      • et al.
      Decision support system for localizing prostate cancer based on multiparametric magnetic resonance imaging.
      ] and could be incorporated into radiation “dose painting” treatment planning [
      • van der Heide U.A.
      • Houweling A.C.
      • Groenendaal G.
      • et al.
      Functional MRI for radiotherapy dose painting.
      ] but still require validation in larger patient cohorts and across institutions. Finally, biopsy confirmation of suspicious targets identified on imaging may be considered in order to exclude a subset of patients with false-positive imaging findings [
      • Singh A.K.
      • Guion P.
      • Sears-Crouse N.
      • et al.
      Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study.
      ]. Such image guided biopsies may address the uncertainty associated with the planning of boost therapies based on random systematic biopsies of the prostate alone [
      • Gaudet M.
      • Vigneault E.
      • Aubin S.
      • et al.
      Dose escalation to the dominant intraprostatic lesion defined by sextant biopsy in a permanent prostate I-125 implant: a prospective comparative toxicity analysis.
      ] by allowing precision localization of involved biopsies while avoiding the cost and potential morbidity of intensive biopsy correlations through template or saturation biopsies either alone or with imaging as implemented by some investigators for GTV identification [
      • Ahmed H.U.
      • Hindley R.G.
      • Dickinson L.
      • et al.
      Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study.
      ].
      There are fewer studies of histopathologic validation of SPECT and PET. (see Supplemental References) In our review, two large series with long term follow-up reviewed defined GTVs using 111In Capromab SPECT imaging. Ellis demonstrated a PPV/NPV of 0.68/0.88 using 111In Capromab correlated with biopsy positive sectors among 7 patients [
      • Ellis R.J.
      • Kim E.Y.
      • Conant R.
      • et al.
      Radioimmunoguided imaging of prostate cancer foci with histopathological correlation.
      ]. Mouraviev [
      • Mouraviev V.
      • Madden J.F.
      • Broadwater G.
      • et al.
      Use of 111in-capromab pendetide immunoscintigraphy to image localized prostate cancer foci within the prostate gland.
      ], however, noted no correlation between 111In Capromab uptake and the presence of cancer on whole mount pathology in 25 patients. Thus, continued use of 111In Capromab for GTV delineation would seem ill advised unless there is further work to validating this imaging against histopathology. Kwee [
      • Kwee S.A.
      • Thibault G.P.
      • Stack R.S.
      • et al.
      Use of step-section histopathology to evaluate 18F-fluorocholine PET sextant localization of prostate cancer.
      ] compared 18F-Fluorocholine PET imaging with whole mount pathology on a sextant basis. They found SUVmax correlated with sextant involvement and identified involved sextants with an overall accuracy of 0.72. When comparing 11C-Choline to MRI among 23 patients Vandenbergh [
      • Van den Bergh L.
      • Koole M.
      • Isebaert S.
      • et al.
      Is there an additional value of (11)C-choline PET-CT to T2-weighted MRI images in the localization of intraprostatic tumor nodules?.
      ] noted 11C-Choline had similar performance to T2W with an overall accuracy of 0.6–0.7 but PET approached MRI accuracy only for lesions >0.9 cm3. Like MRI, automated thresholding techniques based on relative SUV may improve concordance with pathology and can be exploited for “dose painting” [
      • Chang J.H.
      • Joon D.L.
      • Lee S.T.
      • et al.
      Histopathological correlation of (11)C-choline PET scans for target volume definition in radical prostate radiotherapy.
      ,
      • Wang H.
      • Vees H.
      • Miralbell R.
      • et al.
      18F-fluorocholine PET-guided target volume delineation techniques for partial prostate re-irradiation in local recurrent prostate cancer.
      ,
      • Chang J.H.
      • Lim Joon D.
      • Lee S.T.
      • et al.
      Intensity modulated radiation therapy dose painting for localized prostate cancer using (11)C-choline positron emission tomography scans.
      ] however the limited histopathology correlative studies suggest caution in using PET as the sole modality for GTV definition.

       Patient selection and outcomes reporting

      In our review of the literature we were able to identify eleven unique patient series (833 patients) ranging from small preliminary experiences of 3–4 patients to large institutional series of over 200 patients. The EBXRT series reported were comprised of primarily intermediate to high risk patients; the brachytherapy series included a higher proportion of low risk patients. Among all series there was variability in patient populations, use of androgen deprivation (which may affect GTV definition [
      • Groenendaal G.
      • van Vulpen M.
      • Pereboom S.R.
      • et al.
      The effect of hormonal treatment on conspicuity of prostate cancer: implications for focal boosting radiotherapy.
      ]) use of nodal irradiation, length of follow-up and outcomes reporting that preclude definitive statements regarding efficacy of the boost techniques reported to date. While reported toxicity was generally noted to be low, many (56%) EBXRT patients had a very modest differential boost of 3 Gy and many of the brachytherapy patients had boosts which redirected expected “hot spots” into GTV regions. Furthermore, PTV1 coverage was sometimes compromised in order to respect conservative rectal dose constraints. Thus the toxicity profile noted in this review may not accurately reflect risks associated with more significant differential boosts (>10 Gy). It is perhaps somewhat reassuring that the series with highest boost ranges did not report dramatically different toxicity than the other series [
      • Miralbell R.
      • Molla M.
      • Rouzaud M.
      • et al.
      Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.
      ,
      • Schick U.
      • Popowski Y.
      • Nouet P.
      • et al.
      High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer.
      ]. However, these series used relatively low whole prostate doses of 64 Gy and generous (hemi prostate or bilateral prostate GTV) volumes with relatively high HDR or stereotactic dose of 5–8 Gy × 2; complicating extrapolation to other treatment situations. Efficacy data are limited to reports of biochemical control at early (5 year) endpoints. No series reported on histopathologic outcomes (i.e. post treatment biopsies) as an early endpoint and this may be an opportunity for future clinical trials.

      Recommendations

      Despite a large cohort of patients treated with the use of imaging for delineating and delivering a GTV boost in prostate cancer conclusions regarding optimal techniques and/or efficacy of this approach are elusive, and the use of intra-prostatic GTV boost cannot be considered standard of care. The fact that dominant intra-prostatic foci appear to be important drivers of cancer outcomes justifies continued exploration of strategies for differential dose escalation however significant issues need to be addressed in order to rigorously evaluate the validity of this approach. Key issues identified through our review include the need for standardized, reproducible and accurate intra-prostatic GTV definition guidelines based on standardized imaging protocols using clinically validated tools for deformable registration of GTVs onto planning scans. In this regard PET/CT and SPECT/CT techniques carry the advantage of potentially simplified integration into clinical radiation planning workflow but the absence of rigorous histopathology validation of these modalities argues against these techniques. Multi-parametric T2W + DCE + DWI has the strongest histopathologic validation however the fusion of these images with planning CT scans for GTV definition is technically more challenging and subject to error especially when endorectal coil is used for imaging due to gland deformation. Robust motion management strategies to decrease the chance of geographic miss of the GTV are required. In this regard use of fiducial markers may be a preferred strategy as they may assist in the image fusion process and also facilitate daily image guidance. Appropriate clinical trial design for evaluating a strategy of GTV boosting need to be identified including stratification or otherwise controlling for variability in other treatment elements such as the use of pelvic nodal irradiation, hormone therapy use and patient selection (low vs. intermediate vs. high risk). Clinical trial endpoints of early and late toxicity are clearly needed with reporting by standardized toxicity scales (CTCAE or RTOG/LENT). Traditional clinical endpoints of biochemical control and disease free survival pose challenges for the efficient evaluation of new technologies in this disease. Prostate biopsies pre- and at 1–3 years post-treatment directed at both the “uninvolved” prostate as well as the imaging defined GTVs may be an appropriate surrogate endpoint and have been proposed as primary endpoints for trials of focal therapy [
      • Ahmed H.U.
      • Akin O.
      • Coleman J.A.
      • et al.
      Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer.
      ]. Such biopsies could help validate GTV definition as well as characterize response in both the boosted and unboosted areas of the prostate although the use of biopsies as an endpoint needs to consider issues of timing and the challenge of interpreting histologic response post radiation [
      • Crook J.
      • Malone S.
      • Perry G.
      • et al.
      Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients.
      ] which may be more problematic compared to physical ablative therapies such as high intensity focused ultrasound, cryotherapy or focal laser ablation which produce well defined tissue effects [
      • Lindner U.
      • Lawrentschuk N.
      • Weersink R.A.
      • et al.
      Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy.
      ]. Other proposed endpoints to be considered include toxicity and clinical efficacy. For example, a recent trial of focal therapy based on imaging and template biopsy targeting used erectile function as a primary endpoint with disease control and biopsy control [
      • Ahmed H.U.
      • Hindley R.G.
      • Dickinson L.
      • et al.
      Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study.
      ]. Another unresolved issue in designing trials is the best technology for GTV boosting. At this time, both brachytherapy and external beam boosting strategies appear worthy of investigation. Both LDR and HDR are inherently inhomogenous in their dose distribution and “strategic placement” of expected hotspots (150%) in the imaging defined GTV regions should be feasible and reduces the potential for inter and intra fraction variation in delivery when external beam techniques are used for GTV boosting. Fusion of pre-treatment imaging with the ultrasound imaging used for brachytherapy remains a challenge however commercial solutions for MRI-ultrasound fusion for needle guidance are becoming available [
      • Natarajan S.
      • Marks L.S.
      • Margolis D.J.
      • et al.
      Clinical application of a 3D ultrasound-guided prostate biopsy system.
      ]. For external beam, there are many technologies available that can deliver differential boosting and the availability of in-room image guidance can potentially reduce errors due to inter or intra fraction motion [
      • Abdellatif A.
      • Craig J.
      • Jensen M.
      • et al.
      Experimental assessments of intrafractional prostate motion on sequential and simultaneous boost to a dominant intraprostatic lesion.
      ]. An optimal GTV boost dose and fractionation has yet to be determined for external beam and several lines of investigation are underway. Current multi-institutional trials of GTV boosts based on multi-parametric MRI are underway including 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) are evaluating a GTV boosts equivalent to 95 Gy with whole prostate doses in the range of 76–77 Gy. A phase II trial (clinicialtrials.gov NCT01409473) is examining a hypofractionated strategy with whole prostate doses in the range of 40–45 Gy/5 fractions with simultaneous boost of the GTV of 50 Gy/5. DELINEATE is a Phase II study examining the toxicity and feasibility of a dose escalated boost to magnetic resonance imaging identified tumor nodule(s) in localized prostate cancer [http://www.controlled-trials.com/ISRCTN04483921].

      Conclusions

      Available literature describes patients treated with modest boosts to intra-prostatic GTVs although standards for imaging, GTV delineation, treatment planning and dose remain to be determined and the available clinical series do not permit conclusions regarding the safety or efficacy of this approach. At the current time, this approach cannot be considered standard of care. Ongoing prospective trials are underway and will help to better define the role of differential prostate boosts based on imaging defined GTVs.

      Acknowledgements

      The authors wish to thank Dr. Martin Pomper for his helpful review of the manuscript. This work supported by the Ontario Institute for Cancer Research, Smarter Imaging Program and the Canadian Institute for Health Research Team in Image Guidance for Prostate Cancer . The funding agencies had no role in the conduct of the systematic review itself.

      Appendix A. Supplementary data

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