Dose Escalation Using Fiducial Markers in Image Guided Volumetric Modulated Arc Therapy to the Focal Lesion Micro Boost of Localized Prostate Cancer
Condition: Prostatic Adenocarcinoma
MeSH terms: Adenocarcinoma
Study type: Interventional
Phase: Phase 2

Summary: 
      Gold markers implanted in the prostate are used frequently for position verification of the
      prostate during external-beam radiotherapy. By using the markers as a surrogate for the
      prostate itself, not only set-up errors, but also the internal motion of the prostate
      relative to the bony anatomy can be identified.

      It is thus believed that escalated dose marker guided radiotherapy should result in better
      biochemical control compared to conventional external beam radiotherapy, with a similar or
      lower incidence of toxicity. However, clinical data to support this is still limited. The
      purpose of this study is to directly compare late toxicity as well as biochemical control
      between patients treated with dose escalated marker guided radiotherapy versus conventional
      dose non-marker guided radiotherapy who has otherwise been treated with similar radiotherapy
      planning techniques and equipment.

      Prostate magnetic resonance imaging has undergone several technical improvements and shows
      promises for prostate tumor detection and localization. In addition to morphological
      information, magnetic resonance imaging allows an estimation of physiological properties of
      tissues. Diffusion-weighted magnetic resonance imaging is sensitive to restriction of
      diffusion of water molecules, and dynamic contrast enhanced magnetic resonance imaging can
      analyze tissue micro vascular properties. Multi para metric magnetic resonance imaging
      combining Diffusion-weighted and Dynamic contrast enhanced has demonstrated its value in
      distinguishing malignant from benign prostate tissue.

      Higher radiation dose levels were consistently associated with improved biochemical control
      outcomes and reduction in distant metastases. Radiation dose was one of the important
      predictors of long-term biochemical tumor control. Dose levels < 70.2 Grey and 70.2-79.2 Grey
      were associated with 2.3 and 1.3-fold increased risks of pro static specific antigen relapse
      compared with higher doses. However, further dose escalation to the whole gland is limited
      due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences
      often originate at the location of the macroscopic tumor, so boosting the radiation dose at
      the macroscopic tumor within the prostate might increase local control. A reduction of
      distant metastases and improved survival can be expected by reducing local failure. Treating
      the dominant focus or boosting the dose to this area while reducing the dose to as much
      healthy tissue as possible has significant potential for improving treatment.
    

Detailed description: 
      Thirty consecuative loclized prostate cancer patients will be recruited according to
      inclusion & exclusion criteria. Once the patient meets the selection criteria stratification
      will be done according to the following risk group classification:

      Stage Gleason score PSA Low risk T1-T2a 2-6 < 10 ng/mL Intermediate risk T2b-T2c 7 10-20
      ng/mL High risk T3a 8-10 > 20 ng/mL

      The patient will receive 2-6 months of neo adjuvant hormonal treatment, followed with
      concomitant hormonal treatment during the radiation course for intermediate and high risk
      groups then adjuvant hormonal for 2-3 years in the high risk group.

      For each patient the radio-opaque marker (used for treatment verification) will be inserted
      by ultrasound guidance & local anesthetic with an 17 GA x 30 cm brachy therapy needle that
      has 1.2 mm x 3 mm one gold marker. The ultrasound probe (as used for trans rectal biopsy)
      will be introduced rectally with the patient in the left lateral position. After measuring
      the volume of the prostate and determining the desired position (preferably in the corpus of
      prostate), three gold markers will be inserted as follows: one into right side, one into left
      side of the base and the third in the apex of the prostate. All patients will receive a
      course of preventive antibiotic treatment that consists of ciprofloxacine 500 mg BID, 1 day
      before implantation and 4 consecutive days. Patients under anti-platelet therapy will be told
      to stop the medication 5 days before implantation.

      CT images will be done within 5 days of markers insertion in the same treatment supine
      position with Knee & ankle support. CT images will be taken in 1.25 mm slice thickness from
      the top of the 4th lumbar vertebrae to ischial tuberosities. Patients will be asked to
      evacuate bowels prior to scanning, and bladder will be kept comfortably full by drinking two
      glasses of water (250-500 ml) 30 min prior to the scan.

      The reference marks, one mid line and two lateral, will be placed at the level of the upper
      border of the symphysis pubis or iliac crest. No contrast will be used so as to avoid the
      dose artifact by it during treatment planning and dose calculation.

      Multi parametric magnetic resonance imaging combing Diffusion-weighted & Dynamic contrast
      enhanced with intravenous contrast will be done prior to Marker insertion with the sequence
      of: axial T1 & T2, coronal T2 & spare, post contrast dynamic axial & sagittal and diffusion
      with ADC. The views of MRI images will be in 1.25 mm thickness with 0 gap. Fusion of both CT
      images & MRI images will be done using manual registration guided by bony landmarks.

      Delineation of clinical target volumes & risk organs will be done on CT images guided with
      MRI fused images according to Radiation therapy oncology group criteria. MRI T2 weighted
      images will guide the pro static delineation from base to apex, with more accurate
      identification of the apex compared to CT. Also Diffusion-weighted with Dynamic contrast
      enhanced magnetic resonant imaging will be of value for identification of dominant focal
      lesion of the prostate.

      The patient will be treated with radical radiotherapy to prostate 78 Gray/35# (2.2 Gray/#)
      with simultaneous integrated boost to focal lesion 87.5 Grey/35# (2.5 Gray/#). Lymph node 60
      Grey if positively involved. Seminal vesicle will receive 78 Gray if involved & 54 Gray if
      not. Roche formula will be used to estimate lymph node & seminal vesicle involvement if more
      than 15%:

        -  Seminal vesicle involvement (%) = PSA + [10× (Gleason-6)]

        -  Pelvic lymph node involvement = 2/3 × PSA + [10× (Gleason score -6)]

      Constrains for organs at risk will be followed according to QUANTEC. Plan acceptance for
      Planning target volume of the targets will be done as follows:

        -  D 95(95% of the prescribed dose) must be received by at least 95% of the planning target
           volume.

        -  D max (dose received by 2% of the volume) should not exceed 107% and should be inside
           the clinical target volume.

        -  D min (dose received by 98% of the volume) should not be less than 90% and should be
           outside the clinical target volume.

      In addition to the standard quality assurance procedures carried out for any radiation
      technique, such as dose output calibration, ISO-center and Multi-leaf collimator
      verification, V MAT patients will undergo specific pretreatment quality assurance measures to
      check ISO-center absolute dose (using ionization chamber and slap phantom) and dose (using
      portal image and portal dosimeter module on the planning system).

      Position verification will be done guided with implanted gold markers with daily portal
      imaging (AP & lateral) correction protocol in mediolateral, superior-inferior &
      inward-outward directions. The portal correction images will be verified daily to detect
      average shifts in the three directions using 2D-2D match & Marker Match. Random or
      inter-fraction errors which are deviations between different fractions will be taken weekly
      during a treatment series. Systematic errors Which are deviations between the planned patient
      position and the average patient position of a course of fractional therapy will be taken in
      the first three settings. The mean and standard deviation (SD) of the systematic error and SD
      of random errors will be analyzed. To represent true magnitude of errors, the absolute value
      of the deviations will be also considered. These means will be used in calculations of the
      off-line treated Dose-Volume Histogram versus Planned Dose-Volume Histogram and in
      measurement of systemic & random error to define reasonable planning target volume.

      Follow up of the patients will be done with mean of 12 months to detect biochemical control &
      disease free survival. PSA & pelvic ultrasound will be done every 3 months for first 2 years
      then every 6 months for 3-5 years. Genito-urinary, gastro-intestinal & hematological toxicity
      will be assessed using Radiation Therapy Oncology Group toxicity score & patient reported out
      coming will be assessed using questionnaire (validated Arabic translation) every 3 months.
    

Intervention name(s): Dose escalation to prostate focal lesion
Intervention type(s): Radiation
Intervention description(s): For each patient the radio-opaque marker (used for treatment verification) will be inserted by ultrasound guidance & local anaesthetic with an 17ga x 30cm brachytherapy needle that has 1.2mm x 3mm one gold marker. The ultrasound probe (as used for transrectal biopsy) will be introduced rectally with the patient in the left lateral position. After measuring the volume of the prostate and determining the desired position (preferably in the corpus of prostate), three gold markers will be inserted as follows: one into right side, one into left side of the base and the third in the apex of the prostate
Intervention model: Single Group Assignment
Intervention model description: VMAT dose escalation protocol with image guided fiducial markers
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Localized Prostate; VMAT; Dose escalation; Fiducial marker; Focal Lesion; Random error during dose escalation radiotherapy; fiducial marker image guided technique