Clinical trial NCT01655836: High-Dose Rate Brachytherapy and Stereotactic Body Radiation Therapy in Treating Patients With Prostate Cancer
Official title: Phase I Trial of High Dose Rate Brachytherapy Combined With Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Prostate Cancer
Adenocarcinoma of the Prostate
Recurrent Prostate Cancer
Stage IIA Prostate Cancer
Stage IIB Prostate Cancer
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
First posted: 2012-08-02
Enrollment: 42
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The first technology is called high dose rate brachytherapy. Brachytherapy is sometimes called internal radiation therapy. High dose rate brachytherapy is a procedure that involves temporarily placing radioactive material inside the patient's body for about 10-20 minutes. Then, the remainder of the radiation treatment will be given over a 3 week period using stereotactic body radiation therapy (SBRT). SBRT is a novel treatment modality that involves the delivery of very high individual doses of radiation to tumors with high precision. This allows the doctor to deliver the same amount of radiation in a much shorter time. The purpose of this study is to determine the safety of brachytherapy when combined with hypofractionated SBRT.

Detailed description: 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 disease.

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.

Eligibility criteria: 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 oncologist)
* History of prior pelvic irradiation
* Documented distant metastatic disease
* Prior radical prostatectomy or cryosurgery for prostate cancer

Primary outcomes:
measure: Dose limiting toxicities (DLT) graded according to the National Cancer Institute, Common Toxicity Criteria (NCI, CTC), v 4.0
timeFrame: Up to 3 months
Secondary outcomes:
measure: Late nonhematologic toxicity profile
timeFrame: Up to 5 years
measure: Acute and late hematologic toxicity profile of HDR and SBRT combination
timeFrame: Up to 5 years
measure: Correlation of dosimetric parameters, including dose-volume factors for bladder and rectum, with acute toxicity
timeFrame: Up to 5 years
measure: Patient-reported outcomes, assessed by EPIC and AUA symptom score
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
Study officials:
affiliation: Thomas Jefferson University
name: Robert Den, MD
role: PRINCIPAL_INVESTIGATOR
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