HDR Brachytherapy as Monotherapy for Low and Intermediate Risk Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional

Summary: 
      The purpose of this study is to evaluate High-dose rate (HDR) brachytherapy (1 vs 2 fractions
      on single implant) as monotherapy for the treatment of low risk and intermediate risk
      prostate cancer
    

Detailed description: 
      INTRODUCTION:

      Several modalities of radiotherapy treatments are available for low and intermediate risk of
      prostate cancer, all avec similar results on biochemical control and toxicities. Among them,
      the brachytherapy consist in the implantation of radioactive sources directly in the
      prostate. Due to the fast dose shot/application of brachytherapy, the irradiation dose is
      less damaging to neighbor organs. This specific brachytherapy behavior can enhance the
      control over cancer while reducing toxicities.

      Brachytherapy treatment can be delivered by high-dose-rate (HDR) while, at this time,
      catheters are implanted in the prostate and retrieved right after treatment (10-15 minutes).
      HDR brachytherapy dose is more coherent than LDR brachytherapy, because it is not under the
      risk of loss or migration of its source, neither the variations of prostate size due to
      swelling or shrinkage after the implantation. A more precise and reproducible dose coverage
      is accomplished with better preserving of the urethra, bladder, and rectum.

      Several authors are investigating HDR brachytherapy and comparing doses and the number of
      fractions of the different treatment plans.

      Morton et al. researched the use of one single fraction of 15 Gray HDR with External Beam
      Radiation Therapy (EBRT) for the treatment of intermediate risk. The investigators found a
      progression free survival rate higher than 95% at 5 years follow-up, making this the more
      used treatment plan at this time.

      Since investigators already have good control rates with LDR brachytherapy for low and
      intermediate risk cancers with lower toxicity rates, investigators began to question the need
      of adjunct external radiotherapy. Besides those rates, HDR brachytherapy has other advantages
      such as: Medical staff is not subjected to radiation, no radiation source is left on the
      patient's body, treatment time is decreased from several months to few minutes, and the dose
      distribution is better used because of the capacity to precisely control the source position
      during treatment.

      HDR brachytherapy is usually given is small fraction number, but the optimal fraction number
      for HDR monotherapy is unknown. Most researchers prescribe 4 to 6 fractions, with a 6 hours
      interval between fractions. Catheters are left in place and treatment lasts from two to
      several days, unavoidably needing patient's hospitalisation. Another possible inconvenience
      is the possible catheters displacement between fractions, leading to verifications and
      corrections before each fraction is delivered. Trying to reduce the number of fractions and
      give enough dose is being studied in several institutions. The dose is not only related to
      the efficacy of the treatment, but also to the toxicities related to it.

      The purpose of this study is to evaluate High-dose rate (HDR) brachytherapy (1 vs 2 fractions
      on single implant) as monotherapy for the treatment of low risk and intermediate risk
      prostate cancer. One fraction HDR brachytherapy will be delivered in one 19.5 Gy dose, while
      the two fractions will be delivered in two fractions of 14.5 Gy (total dose of 29Gy), both on
      single implant procedure. This evaluation will be carried under a single institution as a
      phase II randomized clinical trial (RTC) design.

      Hypothesis:

      The HDR brachytherapy as monotherapy given in one or two fractions (one fraction of 19.5 Gy
      or two fractions of 14.5Gy) is well tolerated and effective for the treatment of low and
      intermediate risk prostate cancers.

      Objectives:

      Primary Objective:

      The aim of this study is to evaluate acute (early) toxicities (genitourinary and
      gastrointestinal) of HDR brachytherapy (1 vs 2 fractions on single implant) as monotherapy
      for low and intermediate risk prostate cancer.

      Secondary Objectives:

        -  Measure overall survival and progression free survival rate

        -  Evaluate the evolution of the International Prostate Symptom Score (IPSS) and its time
           to return to baseline.

        -  Evaluate late genitourinary and gastrointestinal toxicities changes measured by RTOG and
           CTCAE v4 score

        -  Evaluate biochemical failure

        -  Evaluate erectile dysfunction rates

        -  Investigate associations between dosimetric parameters and toxicity

        -  Investigate associations between iUrethra parameters and toxicity

        -  Assess changes in the quality of life of patients - EORTC QLQ-C30

      METHODS:

      Patient's selection and randomization:

      Inclusion and exclusion criteria are described elsewhere. Once patients fullfil all selection
      criteria they will be randomized between one of the 2 arms of the study (1 or 2 fractions) by
      sealed envelope system.

      Treatment:

      Patients will undergo preoperative standard care conditions. The procedure will be taken
      under regional anesthesia with sterile conditions; Foley urinary catheter will be inserted
      and will aid the urethra delimitation. The bladder will be emptied and the catheter will be
      clamped. Transrectal ultrasound (TRUS) will guide the placement of the transperineal
      catheters. The number of temporary interstitial catheters will be based on the size and shape
      of the prostate (at least 16 catheters will be implanted).

      Optimization of treatment plan will be done with Oncentra (Elekta) based on MRI imaging done
      post-implant. The following contours will be delimited: the prostate, the urinary catheter
      (urethra), the urethra as seen on the MRI (iUrethra), the rectum and the bladder. Catheters
      will be rebuilt on the planning system. The dose calculations will be done by reverse
      planning. After treatment, catheters will be removed and the patient will be transferred to
      the recovery room. Patient will be sent home after recovery with urinary catheter. Urinary
      catheter will be retrieved the day after.

      Patients receiving two fractions will undergo CT scan before the second fraction, if the
      catheters have to be repositioned, appropriate adjustments will be made to optimize the dose
      distribution and correct any changes in dosimetry of the implant.

      Patient's evaluation:

      After the end of treatment, patients will be seen at 1, 3 and 6 weeks, 3 months, 6 months, 12
      months and then every 6 months until year 5. PSA, IPSS, IIEF5 and EORTC QLQ-C30 will be
      fulfilled during follow-up appointments.

      Procedures for biochemical recurrence will be at the discretion of the attending physician.

      New biopsies will not be performed if local recurrence is suspected and that the metastatic
      work-up (abdominopelvic CT scan, bone scintigraphy) is positive. Nevertheless, in cases of
      suspicion of local or remote recccurence investigation will take place.

      Statistics:

      The assumption is that for each arm the probability of a standard deviation difference will
      be higher than 0.5 of the urinary toxicities at one year compared to the baseline will be
      lower than or equal to our current standards.

      Sample size:

      To detect this difference, the test of proportions was used with the NCSS / PASS software.
      The sample size was estimated at 180 patients (90 per arm) calculated with 99% power and a
      0.05 significance level (one-tail test). Considering 10% ineligibility, the required sample
      size is 200 patients (100 per arm).

      Statistical analysis:

      Statistical analysis will be performed at SAS 9.3 software package. Anova repeated measures
      (Mixed Models) and regression logistic regression models (GEE: Generalized Estimation
      Equations) will be used.

      These multivariate models will allow us to determine the potential associations between our
      dependent variables while controlling as much for socio-demographic factors and especially
      for potentially confounding clinical variables.
    

Intervention name(s): HDR brachytherapy as monotherapy
Intervention type(s): Radiation
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Radiation: HDR brachytherapy monotherapy (1 vs 2 fractions on single implant)
Brachytherapy in this study consists of treatment with a single interstitial HDR brachytherapy procedures with temporary interstitial catheters. The number of temporary interstitial catheters will be based on the size and shape of the prostate (at least 16 catheters will be implanted).
In one arm patient will received a single fraction of 19.5 Gray (Gy), in the other arm patient will received 29 Gy/ 2 fractions of 14.5 Gy separated by 6 hours on a single implant.
Implant will be done with transperineal insertion of interstitial catheters under sterile conditions guided by transrectal ultrasounds.
Optimization of treatment plan will be done with Oncentra (Elekta) based on MRI imaging done post-implant.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Brachytherapy; Monotherapy; HDR Brachytherapy; Toxicity; Quality of Life; Progression Free Survival