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Androgen Deprivation Therapy and High Dose Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized Trial

Phase 3
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

Androgen Deprivation Therapy and High Dose Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized Trial



- Demonstrate that prophylactic, neoadjuvant, androgen-deprivation therapy (NADT) and
whole-pelvic radiation therapy (WPRT) will result in improvement in overall survival
(OS) of patients with "unfavorable" intermediate-risk or "favorable" high-risk prostate
cancer compared to NADT and high-dose prostate (P) and seminal vesicle (SV) radiation
therapy (RT) using intensity-modulated RT (IMRT) or external-beam RT (EBRT) with a
high-dose rate (HDR) or a permanent prostate (radioactive seed) implant (PPI) boost.


- Demonstrate that prophylactic WPRT improves biochemical control.

- Determine the distant metastasis (DM)-free survival.

- Determine the cause-specific survival (CSS).

- Compare acute and late treatment-adverse events between patients receiving NADT and
WPRT versus NADT, P, and SV RT.

- Determine whether health-related quality of life (HRQOL), as measured by the Expanded
Prostate Cancer Index Composite (EPIC), significantly worsens with increasing
aggressiveness of treatment (i.e., Arm 2, NADT + WPRT).

- Determine whether more aggressive treatment (Arm 2, NADT + WPRT) is associated with a
greater increase in fatigue (PROMIS Fatigue Short Form) from baseline to last week of
treatment, and a greater increase in circulating inflammatory markers (IL-1, IL-1ra,
IL-6, TNF-alpha, and C-reactive protein).

- Demonstrate an incremental gain in OS and CSS with more aggressive therapy that
outweighs any detriments in the primary generic domains of HRQOL (i.e., mobility,
self-care, usual activities, pain/discomfort, and anxiety/depression).

- Determine whether changes in fatigue from baseline to the next three time points (week
prior to RT, last week of treatment, and 3 months after treatment) are associated with
changes in circulating cytokines, mood, sleep, and daily activities across the same
time points.

- Collect paraffin-embedded tissue blocks, plasma, whole blood, and urine for planned and
future translational research analyses.

OUTLINE: This is a multicenter study. Patients are stratified according to moderate- to
high-risk groups as listed in the Disease Characteristics of this abstract, type of
radiotherapy boost (IMRT vs brachytherapy [LDR using PPI or HDR]), and duration of
androgen-deprivation therapy (short-term [6 months] vs long-term [32 months]). Patients are
randomized to 1 of 2 treatment arms.

All patients receive neoadjuvant androgen-deprivation therapy comprising bicalutamide orally
(PO) once daily or flutamide PO thrice daily for 6 months, and luteinizing hormone-releasing
hormone (LHRH) agonist/antagonist therapy comprising leuprolide acetate, goserelin acetate,
buserelin, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) every 1 to
3 months beginning 2 months prior to radiotherapy and continuing for 6 or 32 months.

Radiotherapy begins within 8 weeks after beginning LHRH agonist/antagonist injection.

- Arm I: Patients undergo high-dose radiotherapy of the prostate and seminal vesicles
using intensity-modulated radiotherapy (IMRT)* or 3D-conformal radiation therapy
(3D-CRT)* once daily, 5 days a week, for approximately 9 weeks. Patients may also
undergo permanent prostate implant (PPI) brachytherapy or high-dose rate brachytherapy
(iodine I 125 or palladium Pd 103 may be used as the radioisotope).

- Arm II: Patients undergo whole-pelvic radiotherapy (WPRT)* (3D-CRT or IMRT) once daily,
5 days a week, for approximately 9 weeks. Patients may also undergo brachytherapy as in
arm I.

NOTE: * Patients undergoing brachytherapy implant receive 5 weeks of IMRT, 3D-CRT, or WPRT.

Patients may undergo blood and urine sample collection for correlative studies. Primary
tumor tissue samples may also be collected.

Patients may complete the Expanded Prostate Cancer Index Composite (EPIC), the
PROMIS-Fatigue Short Form, and the EuroQol (EQ-5D) quality-of-life (QOL) questionnaires at
baseline and periodically during treatment. Patients who participate in the QOL portion of
the study must also agree to periodic blood collection.

After completion of study therapy, patients are followed up every 3 months for 1 year, every
6 months for 3 years, and then yearly thereafter.

Inclusion Criteria


- Pathologically (histologically or cytologically) proven diagnosis of prostatic
adenocarcinoma within 180 days of registration at moderate- to high-risk for
recurrence as determined by one of the following combinations:

- Gleason score 7-10 + T1c-T2b (palpation) + prostate-specific antigen (PSA) < 50
ng/mL (includes intermediate- and high-risk patients)

- Gleason score 6 + T2c-T4 (palpation) or > 50% (positive) biopsies + PSA < 50

- Gleason score 6 + T1c-T2b (palpation) + PSA > 20 ng/mL

- History and/or physical examination (to include at a minimum digital rectal
examination of the prostate and examination of the skeletal system and abdomen)
within 90 days prior to registration

- Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal CT
or MR), (but not by nodal sampling, or dissection) within 90 days prior to

- Patients with lymph nodes equivocal or questionable by imaging are eligible if
the nodes are ≤ 1.5 cm

- Patients status post a negative lymph node dissection are not eligible

- No evidence of bone metastases (M0) on bone scan within 120 days prior to

- Equivocal bone scan findings are allowed if plain films (or CT or MRI) are
negative for metastasis

- Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott,
Hybritech) within 12 weeks (90 days) prior to registration

- Study entry PSA should not be obtained during the following time frames:

- Ten-day period following prostate biopsy

- Following initiation of hormonal therapy

- Within 30 days after discontinuation of finasteride

- Within 90 days after discontinuation of dutasteride


- Zubrod performance status 0-1

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0
g/dL is acceptable)

- No prior invasive (except non-melanoma skin cancer) malignancy unless disease-free
for a minimum of 3 years (1,095 days) and not in the pelvis

- E.g., carcinoma in situ of the oral cavity is permissible; however, patients
with prior history of bladder cancer are not allowed

- No prior hematological (e.g., leukemia, lymphoma, or myeloma) malignancy

- No severe, active co-morbidity, defined as any of the following:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
or severe liver dysfunction

- Acquired immune deficiency syndrome (AIDS) based upon current CDC definition

- Protocol-specific requirements may also exclude immuno-compromised patients

- HIV testing is not required for entry into this protocol

- No patients who are sexually active and not willing/able to use medically acceptable
forms of contraception

- No prior allergic reaction to the hormones involved in this protocol


- See Disease Characteristics

- No prior radical surgery (prostatectomy) or cryosurgery for prostate cancer

- No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy

- No prior hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH)
agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist
(e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone
acetate), estrogens (e.g., diethylstilbestrol [DES]), or surgical castration

- No prior pharmacologic androgen ablation for prostate cancer unless the onset of
androgen ablation is ≤ 45 days prior to the date of registration

- No finasteride within 30 days prior to registration

- No dutasteride or dutasteride/tamsulosin (Jalyn) within 90 days prior to registration

- No prior or concurrent cytotoxic chemotherapy for prostate cancer

- Prior chemotherapy for a different cancer is allowable

- No prior radiotherapy, including brachytherapy, to the region of the study cancer
that would result in overlap of radiation therapy fields

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival of patients treated with NADT and RT vs NADT and WPRT

Safety Issue:


Principal Investigator

Mack Roach, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco



Study ID:




Start Date:

July 2011

Completion Date:

Related Keywords:

  • Prostate Cancer
  • adenocarcinoma of the prostate
  • stage I prostate cancer
  • stage IIA prostate cancer
  • stage IIB prostate cancer
  • stage III prostate cancer
  • Prostatic Neoplasms



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