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Phase I Trial of High Dose Rate Brachytherapy Combined With Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients

Phase 1
18 Years
Open (Enrolling)
Prostate Cancer, Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer

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Trial Information

Phase I Trial of High Dose Rate Brachytherapy Combined With Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients

Prostate cancer is the most common non cutaneous malignancy diagnosed in the United States.
Men with newly diagnosed disease are currently stratified based on their PSA, Gleason score,
and DRE into one of three groups: low risk, intermediate risk, or high risk. Low risk is
defined as either Gleason score 6 or below, PSA <10, and T1-T2a. Intermediate risk is
defined as T2b-T2c or Gleason score 7 or PSA 10-20 ng/ml. High-risk disease is defined as
PSA >20 or Gleason >7 or T2c or greater. The current standard non-surgical treatment for men
with intermediate risk prostate cancer is radiation therapy.

Recently, there have been multiple phase III trials demonstrating the benefit of radiation
dose escalation in the treatment of both low risk, intermediate risk, and high risk prostate
cancer. These trials have all used external beam radiation therapy and have set a new
standard dose for radiation treatment for men with prostate cancer that has been endorsed by
the NCCN.

In addition to increasing the total dose delivered by EBRT, dose escalation can be achieved
using brachytherapy. The radiation can be delivered either with low activity radioactive
seed sources (termed low dose rate or LDR brachytherapy) or using a temporary implant with a
higher activity source (high dose rate or HDR brachytherapy). HDR brachytherapy is a
standard of care in the United States and Europe to deliver a radiation boost to the
prostate when combined with external beam radiation. Three large studies including over 500
men received a combination of EBRT and HDR. All reported excellent outcome with PSA
progression free survival between 70-90% for men with both intermediate and high-risk

Further, the rate of late GI/GU toxicity was quite low as well with late grade 3 GU toxicity
ranging from 2.1-6.7%, late grade 4 GU toxicity of 0-1%, late grade 3 GI toxicity of 0-1%
and late grade 4 GI toxicity of 0-0.5%.

In addition, a phase III randomized trial compared EBRT alone or EBRT combined with an HDR
boost. This trial demonstrated a significant improvement in actuarial biochemical
relapse-free survival is seen in favor of the combined brachytherapy schedule. However, this
trial was criticized that the EBRT alone arm had a lower biologic radiation dose than the
combined arm. A retrospective study from Memorial Sloan Kettering Cancer Center compared
patients who received EBRT alone to 86.4 Gy with those who underwent HDR brachytherapy
combined with EBRT. Dose escalation by adding HDR brachytherapy provided improved PSA
relapse-free survival in the treatment of prostate cancer compared with ultra-high-dose
EBRT, independent of risk group on multivariate analysis, with the most significant benefit
for intermediate-risk patients. Finally, a systemic review of the literature compared
results from EBRT alone, EBRT combined with LDR, and EBRT combined with HDR. This study
concluded that combination of external beam radiotherapy and HDR brachytherapy results in a
superior biochemical control and overall survival.

Radiation effects in prostate cancer cells have been typically studied using clonogenic cell
survival curves, which allow cell death to be modeled using a linear quadratic equation. The
dose response of tumors and normal tissues to fractionated radiation therapy can be
predicted according to a formula: S= e^(-D-D2), where and are the linear and quadratic
components of the model. Based upon this model, an alpha/beta ratio can be calculated which
allows various dose and fractionation schemes to be compared. The alpha-beta ratio is
generally >10 Gy for early-responding tissue such as skin, mucosa, and most tumors and <5 Gy
for late responding tissue such as connective tissues and muscles. Recent evidence reveals
that prostate cancer has a low alpha/beta ratio, implying that those cells are more
sensitive to doses delivered in larger fraction size. Further, given the lower alpha-beta
ratio for prostate cancer than bladder and rectal mucosa (where the most significant late
toxicity occurs) creates the potential for therapeutic gain with larger fraction sizes.
Based upon this, there is an increasing trend to reduce the total treatment time by
administering higher dose/fraction.

There have been a number of phase I trials reporting the use of hypofractionated regimens
for the treatment of low and intermediate risk prostate cancer in the (primary) definitive
setting. These trials show excellent biochemical control and toxicity profiles. A five
institutional cooperative phase I/II trial that explored the tolerance and efficacy of 3
increasingly hypofractionated radiation regimens with equivalent predicted late toxicity was
recently reported in abstract form. A total of 307 men were enrolled and biochemical
progression free survival was 95% at 5 years. At 2 years, actuarial rectal bleeding was 8%
with all cases resolving either spontaneously or after minor intervention.

One caveat with dose escalation to doses between 74-80 Gy is that current radiation therapy
treatment is given in daily fractions of sizes of 2 Gy/day and treatments last for
approximately 2 months. The prolonged nature of the radiation treatment course has been
cited by prostate cancer patients as a primary reason for not choosing RT.

The combination of high dose rate brachytherapy and external beam radiation therapy has been
recently published. The protocol used a single HDR treatment of 15 Gy followed by EBRT to a
dose of 37.5 Gy in 15 fractions. One hundred and twenty three patients were followed for a
median of 45 months. Biochemical disease-free survival was 95% and the two year prostate
biopsy was positive in only 4% of men. Further, acute grade 3 or higher GU toxicity was
experienced by only 2 patients and 1 patient developed a grade 3 late GU toxicity. The grade
3 toxicity was hemorrhagic cystitis that required cysto-prostatectomy; however the patient
was also diagnosed with scleroderma and telangiectasia (CREST) syndrome, which is generally
a contraindication to radiation therapy and may have been a contributing factor to his
toxicity. There was 4% grade 2 GI toxicity consisting of proctitis. Patient reported
toxicity using the EPIC tool was notable for decrease in urinary, bowel and sexual domain
scores in the first 2 years following treatment, but median urinary and bowel domain scores
were not significantly different from baseline at 3 and 4 years.

Inclusion Criteria:

- Adenocarcinoma of the prostate with intermediate risk disease T2b-T2c or Gleason
score 7 or prostate specific antigen (PSA) 10-20 ng/ml, without metastatic disease

- To rule out metastatic disease, patients must have the following tests:

- Bone scan within 60 days prior to registration

- Computed tomography (CT) of abdomen/pelvis within 60 days prior to registration

- Karnofsky performance status > 70

- Age > 18

- PSA blood test within 60 days prior to registration

- Prostate biopsy within 180 days prior to registration

- Within 60 days prior to registration, hematologic minimal values:

- Absolute neutrophil count > 1,500/mm^3

- Hemoglobin > 8.0 g/dl

- Platelet count > 100,000/mm^3

- Men of childbearing potential must be willing to consent to using effective
contraception while on treatment and for at least 3 months thereafter

- No history of previous pelvic irradiation

Exclusion Criteria:

- History of urological surgery or procedures predisposing to GU complications after
radiation, i.e., anastomoses, stricture repair, etc. (will be determined by radiation

- History of prior pelvic irradiation

- Documented distant metastatic disease

- Prior radical prostatectomy or cryosurgery for prostate cancer

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose limiting toxicities (DLT) graded according to the National Cancer Institute, Common Toxicity Criteria (NCI, CTC), v 4.0

Outcome Description:

Data analysis of phase I studies is descriptive. All estimates of dose-specific rates (e.g., response and toxicity) will be presented with corresponding confidence intervals using the exact method.

Outcome Time Frame:

Up to 3 months

Safety Issue:


Principal Investigator

Robert Den, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University


United States: Institutional Review Board

Study ID:




Start Date:

October 2012

Completion Date:

September 2019

Related Keywords:

  • Prostate Cancer
  • Adenocarcinoma of the Prostate
  • Recurrent Prostate Cancer
  • Stage IIA Prostate Cancer
  • Stage IIB Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms



Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541