Radiation Therapy With or Without Androgen-Deprivation Therapy in Treating Patients With Prostate Cancer

Study Description

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Brief Summary:

RATIONALE: Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Androgens can cause the growth of prostate cancer cells. Androgen-deprivation therapy may lessen the amount of androgens made by the body. It is not yet known whether radiation therapy is more effective with or without androgen-deprivation therapy in treating patients with prostate cancer.

PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with androgen-deprivation therapy in treating patients with prostate cancer.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Drug: bicalutamide; Drug: buserelin; Drug: flutamide; Drug: goserelin acetate; Drug: leuprolide acetate; Drug: triptorelin; Radiation: 3-dimensional conformal radiation therapy; Radiation: intensity-modulated radiation therapy	Phase 3

Detailed Description:

OBJECTIVES:

Primary

• Demonstrate an overall survival (OS) advantage in patients with intermediate-risk prostate cancer treated with dose-escalated radiotherapy (RT) with versus without short-term androgen-deprivation therapy (ADT).

Secondary

• Determine whether the addition of ADT to dose-escalated RT versus RT alone improves clinical failures, biochemical failure by the "nadir +2", freedom from failure, rate of salvage ADT, and prostate cancer-specific mortality in these patients.
• Estimate the magnitude of benefit of ADT with respect to OS in patients treated with different RT modalities (i.e., external-beam radiation therapy alone vs low-dose rate brachytherapy boost vs high-dose rate brachytherapy boost).
• Compare acute and late treatment adverse events of these regimens and correlate these events with the presence or absence of pre-existing comorbidity as documented by the Adult Comorbidity Evaluation 27 assessment.

OUTLINE: This is a multicenter, dose-escalation study of radiotherapy. Patients are stratified according to number of risk factors (1 vs 2-3), comorbidity (ACE-27 grade ≥ 2 vs < 2), and radiotherapy (RT) modality (dose-escalated external-beam RT [EBRT] vs EBRT and low-dose rate brachytherapy boost vs EBRT and high-dose rate brachytherapy boost). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo EBRT* once daily on days 1-5 for about 9 weeks (44 treatments). Some patients instead receive EBRT with high-dose rate or low-dose rate brachytherapy implant on days 1-5 for about 5 weeks (25 treatments). NOTE: *Type of RT is at discretion of treating physician and may include either 3D-conformal RT or intensity-modulated RT.
• Arm II: Patients receive androgen-deprivation therapy comprising luteinizing-hormone releasing-hormone (LHRH) agonist (leuprolide, goserelin, buserelin, or triptorelin) subcutaneously or as an injection every 1 to 3 months AND an oral antiandrogen therapy (flutamide 3 times daily or bicalutamide once daily) for 6 months. Beginning 8 weeks after the first LHRH injection, patients undergo radiotherapy as in arm I.

After completion of study therapy, patients are followed up periodically.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1538 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer
Study Start Date :	September 2009
Estimated Primary Completion Date :	May 2022
Estimated Study Completion Date :	May 2027

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Arm I; Patients undergo external-beam radiation therapy (EBRT) once daily on days 1-5. Some patients instead receive EBRT with high-dose rate or low-dose rate brachytherapy implant.	Radiation: 3-dimensional conformal radiation therapy; Given as external-beam radiation therapy Radiation: intensity-modulated radiation therapy; Given as external-beam radiation therapy
Experimental: Arm II; Patients receive androgen-deprivation therapy comprising luteinizing-hormone releasing-hormone (LHRH) agonist (leuprolide, goserelin, buserelin, or triptorelin) subcutaneously or as an injection every 1 to 3 months AND an oral antiandrogen therapy (flutamide 3 times daily or bicalutamide once daily) for 6 months. Beginning 8 weeks after the first LHRH injection, patients undergo radiotherapy as in arm I.	Drug: bicalutamide; Given orally Drug: buserelin; Given subcutaneously or as an injection Drug: flutamide; Given orally Drug: goserelin acetate; Given subcutaneously or as an injection Drug: leuprolide acetate; Given subcutaneously or as an injection Drug: triptorelin; Given subcutaneously or as an injection Radiation: 3-dimensional conformal radiation therapy; Given as external-beam radiation therapy Radiation: intensity-modulated radiation therapy; Given as external-beam radiation therapy

Outcome Measures

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Primary Outcome Measures :

1. Overall survival (OS) [ Time Frame: From the date of randomization to the date of death due to any cause. ]

Secondary Outcome Measures :

1. Biochemical failure according to the Phoenix (nadir + 2) definition [ Time Frame: From the date of randomization to the date of first documented rise in PSA of 2 ng/ml above the post treatment nadir value. ]
2. Local recurrence [ Time Frame: From the date of randomization to the date of first palpable progression or pathologic confirmation of local progression or to the date of first biochemical failure (nadir +2ng/ml) once the possibility of distant metastasis is ruled out. ]
3. Regional recurrence [ Time Frame: From the date of randomization to the date of first documented progression in pelvic lymph nodes or the date of first documented biochemical failure (BCF) if the CT of the pelvis was prompted by a BCF. ]
4. Distant metastasis [ Time Frame: From the date of randomization to the date of first documented metastatic disease by any measure or to the date of first documented biochemical failure if diagnostic imaging is prompted by BCF. ]
5. Prostate cancer-specific mortality [ Time Frame: From the date of randomization to the date of death due to prostate cancer/complication of treatment. ]
6. Non-prostate cancer-specific mortality [ Time Frame: From the date of randomization to the date of death without the evidence of prostate cancer/complication of treatment. ]
7. Rate of salvage androgen-deprivation therapy [ Time Frame: From the end of treatment to the date of first administration of ADT. ]
8. Rates of OS for patients treated with the 3 different radiotherapy modalities in each arm [ Time Frame: From the date of randomization to the date of death due to any cause. ]
9. Incidence of "acute" adverse events as assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v. 4.0 [ Time Frame: From the start of radiation therapy (RT) to first occurrence of worse severity of adverse event within 30 days after the completion of RT. ]
10. Time to "late" grade 3+ adverse events as assessed by NCI CTCAE v. 4.0 [ Time Frame: From the date of completion of RT to the date of first grade 3 or above adverse event occurring 30 days after the completion of RT. ]
11. Freedom from Failure [ Time Frame: From date of randomization to the date of first event of biochemical failure or local recurrence or regional reccurrence or distant metastasis. ]
12. Comparison of prostate cancer-specific health related quality of life (HRQOL) change as measured by EPIC [ Time Frame: From date of randomization to the following times: last week of RT, 6 months, 1 year and 5 years post RT. ]
13. Comparison of fatigue status as measured by the Patient Reported Outcome Measurement Information System (PROMIS) fatigue domain [ Time Frame: From date of randomization to the following times: last week of RT, 6 months, 1 year and 5 years post RT. ]
14. Assessment and comparison of Quality Adjusted Life Years (QALYs) [ Time Frame: From date of randomization to the following times: last week of RT, 6 months, 1 year and 5 years post RT. ]
15. Correlation between the fatigue PROMIS score change and plasma cytokine change [ Time Frame: From date of randomization to 3 weeks from start of RT. ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate diagnosed within the past 180 days and at intermediate-risk for recurrence by meeting 1 or more of the following criteria:

  • Gleason score = 7

  • Prostate Specific Antigen (PSA) > 10 and ≤ 20 ng/mL

    • Baseline serum PSA value performed within 60 days with an FDA-approved assay (e.g., Abbott, Hybritech)
    • Baseline PSA must not be obtained during any of the following time frames:10-day period after prostate biopsy, after initiation of androgen-deprivation therapy, or within the past 30 days after discontinuation of finasteride (90 days for dutasteride)
  • Clinical stage T2b or T2c disease
  • Patients previously diagnosed with low-risk (Gleason score < 6, clinical stage < T2a, and PSA < 10 ng/mL) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate-risk disease according to the protocol criteria are eligible for enrollment within 6 months of the repeat biopsy procedure

• Patients with Gleason Score ≥ 8, PSA > 20 ng/mL, OR clinical stage ≥ T3 are ineligible for this trial

  • If findings of extracapsular extension or seminal vesicle invasion are noted on prostate MRI, this study, if used, will not render patients ineligible for accrual to this protocol
  • Primary tumor staging for eligibility purposes is to be based on palpable or core biopsy evidence only with respect to extracapsular extension or seminal vesicle involvement

• No patients with all 3 intermediate-risk factors who also have ≥ 50% of the number of their biopsy cores positive for cancer

  • The percentage of biopsy cores involved will only be considered with respect to eligibility for those patients with all 3 of the above risk factors (i.e., patients with one or two of the above risk factors are eligible irrespective of the percentage of biopsy cores involved)

• Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal CT scan or MRI), nodal sampling, or dissection within the past 60 days (required for patients with 2-3 risk factors)

  • Abdominal imaging not required for a single intermediate-risk factor (these studies may be obtained at the discretion of the treating physician)
  • Lymph nodes that are equivocal or questionable by imaging allowed without biopsy if nodes ≤ 1.5 cm
  • Any node > 1.5 cm on imaging requires a negative biopsy

• No evidence of bone metastases on bone scan within the past 60 days

  • Bone scan not required for patients with a single intermediate-risk factor (scan may be obtained at the discretion of the treating physician)
  • Equivocal bone scan findings allowed if plain film x-rays negative for metastasis

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) ≥ 1,800/mm^3*
• Platelet count ≥ 100,000/mm^3*
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve level allowed)*
• NOTE: *For patients undergoing brachytherapy only.
• Fertile patients must use effective contraception during and for the 3 months after cessation of protocol treatment

• No invasive malignancy or hematological malignancy (e.g., leukemia, lymphoma, myeloma) within the past 5 years except adequately treated non-melanomatous skin cancer

  • Prior diagnoses of carcinoma in situ allowed

• No severe or active co-morbidity with any of the following:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
  • Transmural myocardial infarction within the past 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy, within the past 30 days

  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

    • Laboratory tests for liver function and coagulation parameters not required for entry into this protocol

  • AIDS based upon current Centers for Disease Control (CDC) definition

    • HIV testing not required for entry into this protocol
    • HIV-seropositive patients who do not meet criteria for diagnosis of AIDS allowed

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior radical surgery (prostatectomy), high-intensity focused ultrasound, or cryosurgery for prostate cancer
• No prior hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), antiandrogens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or bilateral orchiectomy
• No finasteride within past 30 days (90 days for dutasteride)

• No prior or concurrent cytotoxic chemotherapy for prostate cancer

  • Prior chemotherapy for a different cancer allowed

• No prior radiotherapy (RT), including brachytherapy, to the region of the study cancer that would result in overlap of RT fields

  • Patients undergoing brachytherapy must have transrectal ultrasound confirmation of prostate volume < 60 cc, American Urological Association (AUA) score ≤ 15 within the past 60 days of registration, and no history of prior transurethral resection of the prostate (TURP)
  • TURP allowed for patients who receive external-beam radiation therapy only

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

  Show 518 Study Locations

Sponsors and Collaborators

Radiation Therapy Oncology Group

National Cancer Institute (NCI)

NRG Oncology

Investigators

Study Chair:	Alvaro A. Martinez, MD, FACR	21st Century Oncology - Michigan Institute for Radiation Oncology

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:	NCT00936390 History of Changes
Other Study ID Numbers:	RTOG 0815; CDR0000648194; NCI-2011-01948 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted:	July 10, 2009
Last Update Posted:	December 26, 2017
Last Verified:	December 2017

Keywords provided by Radiation Therapy Oncology Group:

adenocarcinoma of the prostate; stage IIB prostate cancer; stage IIA prostate cancer

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Androgens; Leuprolide; Buserelin; Goserelin; Triptorelin Pamoate; Flutamide; Bicalutamide	Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Fertility Agents, Female; Fertility Agents; Reproductive Control Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Androgen Antagonists; Hormone Antagonists; Luteolytic Agents; Contraceptive Agents, Female; Contraceptive Agents