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Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

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Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

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Anti-Inflammatory Agents

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Androgens

Dexamethasone

Hormones

Docetaxel

Prednisone

Dexamethasone acetate

Androgen Antagonists

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Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Androgen suppression (AS; LHRH agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of radiation therapy (RT).

Androgen suppression (AS; LHRH agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of RT. Following completion of RT, 6 cycles of docetaxel (premedicated with dexamethasone) and prednisone are delivered concurrently with androgen suppression.

Premedication of dexamethasone prior to docetaxel, per institutional standards.

10 mg orally per day until day 21 of the last cycle of docetaxel, beginning 28 days after the completion of RT.

75 mg/m2 i.v. over 1 hour (on day 1 of each cycle) every 21 days for 6 cycles, beginning 28 days after the completion of RT.

docetaxel

Oral antiandrogen of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy. Treatment is discontinued at the end of radiation therapy.

Oral antiandrogen

46.8 Gy, using either three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT), will be given to the regional lymphatics followed by a 25.2-28.8 Gy boost to the prostate, to bring the total dose to the prostate to 72.0-75.6 Gy. Daily prescription doses will be 1.8 Gy per day, 5 days per week x 8-8.5 weeks, beginning 8 weeks after the initiation of androgen suppression.

Radiation therapy

LHRH agonist of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy, and then until 24 months from initiation of any treatment has been reached.

LHRH agonist

Howard M. Sandler, MD

Seth Rosenthal, MD

Mahul Amin, MD

Leonard G. Gomella, MD

James Purdy, PhD

Jeff Michalski, MD

Mark Garzotto, MD

Oliver Sartor, MD

RATIONALE: Androgens can cause the growth of prostate cancer cells. Hormone therapy using drugs, such as leuprolide, goserelin, flutamide, or bicalutamide, may fight prostate cancer by lowering the amount of androgens the body makes. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving hormone therapy and radiation therapy together with chemotherapy is more effective than giving hormone therapy together with radiation therapy in treating prostate cancer.

PURPOSE: This randomized phase III trial is studying hormone therapy and radiation therapy followed by docetaxel and prednisone to see how well it works compared to hormone therapy and radiation therapy in treating patients with localized prostate cancer.

OBJECTIVES:

Primary

* Compare the relative efficacy, in terms of overall survival, of the combination of androgen suppression and radiotherapy versus androgen suppression and radiotherapy followed by docetaxel and prednisone in patients with localized, high-risk prostate cancer.

Secondary

* Compare the disease-free survival and incidence of adverse events in patients treated with these regimens.
* Compare the biochemical control, local control, and freedom from distant metastases in patients treated with these regimens.
* Determine the validity of prostate-specific antigen (PSA)-defined endpoints as a surrogate for overall survival of patients treated with these regimens.
* Compare the time interval between biochemical failure and distant metastases with respect to testosterone level in patients treated with these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to risk group.

* Arm I: Patients receive androgen suppression therapy comprising luteinizing hormone-releasing hormone (LHRH) agonist (e.g., leuprolide acetate, goserelin, buserelin, or triptorelin) and oral antiandrogen (i.e., oral flutamide 3 times daily for 2 months or oral bicalutamide once daily for 2 months). Beginning at week 8, patients undergo radiotherapy 5 days a week for approximately 8 weeks. Antiandrogen therapy is discontinued at completion of radiotherapy, but LHRH agonist therapy continues for 20 months.
* Arm II: Patients receive androgen suppression therapy and undergo radiotherapy as in arm I. Beginning 4 weeks after completion of radiotherapy, patients receive docetaxel IV over 1 hour on day 1 and oral prednisone daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients continue LHRH agonist therapy as in arm I.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.

Hormone Therapy and Radiation Therapy or Hormone Therapy and Radiation Therapy Followed by Docetaxel and Prednisone in Treating Patients With Localized Prostate Cancer

A Phase III Protocol of Androgen Suppression (AS) and 3DCRT/IMRT Vs AS and 3DCTR/IMRT Followed by Chemotherapy With Docetaxel and Prednisone for Localized, High-Risk, Prostate Cancer

Four-year rates are shown. Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Four-year rates are shown (Kaplan-Meier estimates). Biochemical control is defined as freedom from biochemical failure. Biochemical failure was considered as the first of either prostate-specific antigen (PSA) failure or initiation of salvage hormone therapy. PSA failure was defined as a rise of 2 ng/ml over the nadir PSA. Patients who experienced death without biochemical failure, local failure prior to biochemical failure, or development of distant metastases prior to biochemical failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization.

Local control is defined as the absence of local failure which is the first of either progression or recurrence within the prostate. Progression of the tumor was considered to have occurred when there was a 25% or greater increase in the product of the two largest perpendicular diameters of the prostate. Recurrence was defined as the reappearance of disease after a complete response. Patients who experienced death without local failure, biochemical failure prior to local failure, and development of distant metastases prior to local failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization. Due to an insufficient number of events (2 in each arm), this endpoint was not statistically compared. Local control rates at 4 years were calculated using the Kaplan-Meier method.

Distant failure was considered when there was evidence of metastatic disease. Patients who experienced death without distant failure, local failure prior to distant failure, and biochemical failure prior to distant failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization. Distant failure rates at 4 year were calculated using the Kaplan-Meier method.

A failure for disease-free survival is the first of the following: biochemical failure, local failure, distant metastases, or death due to any cause. The corresponding outcome time was measured from the date of randomization. Disease-free survival rates at 4 years were calculated using the Kaplan-Meier method.

Adverse events are graded using CTCAE v3.0. The worst grade of all adverse events for each patient is counted.

Biochemical failure is defined as the first of either prostate-specific antigen (PSA) failure or the initiation of salvage hormone therapy. PSA failure is defined as a rise in PSA of 2 ng/ml over the nadir PSA. Distant failure is defined as the first occurrence of distant metastasis.

Prentice's operational criteria for determining whether determining whether biochemical failure (surrogate endpoint) is a suitable endpoint for overall survival (true endpoint):

1. Treatment is prognostic for true endpoint
2. Treatment is prognostic for surrogate endpoint
3. Surrogate is prognostic for true endpoint
4. The full effect of the treatment on the true endpoint is explained by the surrogate.

If any of the criteria are not met, it is concluded that biochemical failure is not a suitable surrogate for overall survival. Therefore, if any of the criteria are met, the other criteria do not do not need to be evaluated.

National Cancer Institute (NCI)

NRG Oncology

Radiation Therapy Oncology Group

Participants who started protocol treatment.

Androgen suppression (AS; LHRH agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of RT.

Androgen Suppression + Radiation Therapy

Androgen Suppression + Radiation Therapy + Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Eligible patients who have not withdrawn consent.

Due to insufficient number of events, local control analysis was not conducted.

Wendy Seiferheld, M.S.

The study was designed to detect an improvement in the 4-year overall survival rate from 86% (AS+RT) to 93% (AS+RT+CT). Assuming an exponential survival distribution for each arm, then an absolute improvement of 7% in the 4-year overall survival rate translates to a 51% relative reduction (hazard ratio 0.49) in the yearly death rate. Under a 1-sided significance level of 0.05 and 90% power, at least 78 deaths and 486 cases were required to perform the primary endpoint analysis.

Eligible patients who did not withdraw consent.

Overall Survival

Biochemical control rates at 4 years were calculated using the Kaplan-Meier method and compared by a two-sided log-rank test with a significance level of 0.05.

Biochemical Control

Eligible patients who did not withdraw consent

Local Control

Distant failure rates at 4 years were calculated using the Kaplan-Meier method and compared by a two-side log-rank test at the 0.05 significance level.

Distant Metastasis

Disease-free survival rates were compared by a two-sided log-rank test at a significance level of 0.05.

Disease-free Survival

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Eligible patients who started protocol treatment and did not withdraw consent

Incidence of Adverse Events

The analysis will not be done because testosterone measurement dates were not collected.

The Time Interval Between Biochemical Failure and Distant Failure Respect to Testosterone Level

Because the second criterion is not met, further analysis was not performed.

Validity of PSA Endpoint as a Surrogate for Overall Survival

Androgen suppression (AS; luteinizing hormone-releasing hormone (LHRH) agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of RT.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Hormone Therapy and Radiation Therapy or Hormone Therapy and Radiation Therapy Followed by Docetaxel and Prednisone in Treating Patients With Localized Prostate Cancer	NCT00288080	Prostate Cancer	Dexamethasone Prednisone docetaxel Oral antiandrog... Radiation thera... LHRH agonist	18 Years - 120 Years	Radiation Therapy Oncology Group
Hormone Therapy and Radiation Therapy or Hormone Therapy and Radiation Therapy Followed by Docetaxel and Prednisone in Treating Patients With Localized Prostate Cancer	NCT00288080	Prostate Cancer	Dexamethasone Prednisone docetaxel Oral antiandrog... Radiation thera... LHRH agonist	18 Years - 120 Years	Radiation Therapy Oncology Group
Hormone Therapy and Radiation Therapy or Hormone Therapy and Radiation Therapy Followed by Docetaxel and Prednisone in Treating Patients With Localized Prostate Cancer	NCT00288080	Prostate Cancer	Dexamethasone Prednisone docetaxel Oral antiandrog... Radiation thera... LHRH agonist	18 Years - 120 Years	Radiation Therapy Oncology Group

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