Chemotherapy After Prostatectomy (CAP) For High Risk Prostate Carcinoma

VA Cooperative Study #553 is designed to prospectively evaluate the efficacy of early
adjuvant chemotherapy using docetaxel and prednisone added to the standard of care for
patients who are potentially cured by radical prostatectomy but who are at high risk for
relapse. The standard of care is surveillance, with the addition of androgen deprivation at
the time of biochemical relapse. This study will assess the effect of adding early
chemotherapy to the standard of care on progression free survival in Veterans at high risk
for progression after prostatectomy.

The ability of radical prostatectomy to cure prostate cancer and to therefore prevent the
morbidity and mortality associated with progression to metastatic disease depends on
effectively treating both local and potential systemic disease. In the United States alone,
over 80,000 men per year are treated with prostatectomy to cure their disease. Because 20% of
these men will be found to have locally advanced or high-grade disease, they will be at risk
for relapse and morbidity from their prostate cancer. Although androgen deprivation,
radiation therapy, and chemotherapy have been considered potentially effective adjuvant
modalities for localized prostate cancer, there are no randomized studies that support the
utility of any of these treatments as a standard of care. Ultimately, it is androgen
independent prostate cancer, which causes morbidity for these patients. Docetaxel based
chemotherapy has been shown to prolong survival and induce responses in up to 80% of patients
with androgen independent disease, generating enthusiasm for the use of chemotherapy early in
the treatment of prostate cancer. This study is designed to test the value of adjuvant
chemotherapy in improving progression free survival, which is critical in preventing
morbidity and mortality from relapse in patients with clinically localized, but high risk,
prostate cancer.

After patients are stratified for PSA, Gleason score, tumor stage, the presence of positive
margins, and the planned use of adjuvant radiation therapy, this study will randomized 300
patients from 30 VA sites, after prostatectomy, to the standard of care or to docetaxel and
prednisone administered every 3 weeks for 18 weeks. Patients would then be observed with PSA
for a minimum of one and a maximum of five years. The study is designed with 90% power to
detect a reduction in the 5-year progression rate from 60% to 45% (15% absolute difference,
25% relative difference).

At the end of the study period (October 31, 2012), the patients in the study will continue to
be passively followed for three more years. The follow-up study involved centralized remote
access of the participants' medical records to obtain information on PSA levels and study
endpoints.

Prostate cancer is the leading cause of malignancy for Veterans, and the second leading cause
of death. Patients with high risk, localized disease account for 70% of all cancer deaths in
patients treated for cure with radical prostatectomy. Effective adjuvant therapy is critical
to reducing suffering and death from prostate cancer. The VA Cooperative Studies Program is
uniquely placed to address this question. The VA has a longstanding history of important
studies in prostate cancer, which have significantly changed the way urologic oncologists
treat patients with this disease. The incidence of prostate cancer in our older, male
population is substantial, the number of Veterans treated with prostatectomy continues to
rise, and the incidence of high risk prostate cancer in Veterans is greater than that
typically found in the community. For all of these reasons, carrying out this study within
the VA through the VA Cooperative Studies Program is the optimal way to determine whether
adjuvant chemotherapy will benefit men with high risk prostate cancer.

Inclusion Criteria:

- A histologic diagnosis of cT1-T2 primary adenocarcinoma of the prostate prior to
prostatectomy, with lymph node dissection at time of radical prostatectomy

- One or more of the following poor prognostic features:

- tumor extension to seminal vesicle (pT3b) or bladder neck (T4)

- established extracapsular extension (pT3a) and Gleason Score >= 7

- organ confined (pT2) with positive surgical margin and Gleason 8-10

- preoperative PSA > 20

- SWOG performance status 0-1

- PSA nadir of <= 0.1 ng/ml up to 30 days prior to randomization. Patients must be
randomized within 120 days after prostatectomy.

- Laboratory values (no more than 30 days before randomization) must be as follows:

- Absolute granulocyte count: >= 1,500/mm3

- Platelets: >= 100,000/mm3

- Hemoglobin: >= 10 g/dL

- Serum Creatinine: <= 1.5 x ULN

- AST: <= 1.5 x ULN

- ALT: <= 1.5 x ULN

- Serum Calcium: <= ULN

- Total Bilirubin: <=ULN

- Plasma Phosphorus Level: <= 6 mg/dl

- Patients with preoperative PSA > 20 ng/mL must have a negative bone scan within 120
days of randomization

- A valid, signed, and witnessed informed consent by the patient

Exclusion Criteria:

- Small cell histology

- N1 disease or M1 disease

- Clinical T3 disease prior to prostatectomy

- Any other investigational therapy

- An active serious infection or other serious underlying medical condition that would
otherwise impair their ability to receive protocol treatment

- A history of cancer related hypercalcemia

- Uncontrolled heart failure

- Prior malignancy other than curatively treated squamous cell or basal cell carcinoma
of the skin. If another malignancy has been treated and there is no evidence of
relapse > 5 years from the time of treatment, patients are eligible

- Androgen deprivation, chemotherapy, or radiation therapy to treat prostate carcinoma

- Current peripheral neuropathy of any etiology that is greater than Grade I