carboplatin-etoposide combination in hormone-resistant prostate cancers

Conditions: Prostate Cancer

Summary: the aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. eligible patients are treated with the combination of carboplatin auc4 on day 1 and etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles. efficacy endpoints include prostate specific antigen (psa) and neuro-endocrine marker response (defined as a 50% or greater decrease from baseline serum values), objective response rate (according to recist criteria), and toxicity.

neuro-endocrine differentiation is observed in the evolution of hormone-resistant prostate cancer. the aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. to be eligible, patients must have either circulating neuro-endocrine markers (chromogranin a: cga, neuron specific enolase: nse)and/or visceral metastases. eligible patients are treated with the combination of carboplatin auc4 administered on day 1 and etoposide 100 mg/m2 given on day 1, day 2 and day 3 and repeated every 3 weeks for a maximum of 6 cycles. the primary objective of the study is to assess objective response to the carboplatin - etoposide combination (according to recist criteria for lesions and defined as a 50% or greater decrease from baseline serum values for psa and neuro-endocrine markers). secondary objectives include evaluation of toxicity, duration of response, progression-free-survival and overall survival.

Eligibility criteria:
inclusion criteria: * histological evidence of prostate adenocarcinoma * metastatic disease, either measurable (lymph nodes, hepatic lesion, pulmonary lesions with longest diameter \> or = 1 cm on spiral scan), or non measurable (bone metastasis) * patients must: * have received hormonal therapy via surgical or chemical castration (lh-rh agonist) with or without anti-androgens. anti-androgen withdrawal is recommended before inclusion, with an off-treatment period of at least 4 weeks. lh-rh agonist treatment must be continued. * have a relapse or disease refractory to hormonal treatment (defined by a testosterone level \< 0.5 µg/ml) * have neuroendocrine progression defined, whatever the psa level, as: * nse and/or chromogranin a \> 1.5 x upper limit of normal (uln) with or without visceral metastases (liver, lung, lymph node) * no increase of nse or chromogranin a, but visceral metastases (either hepatic, pleuro-pulmonary, or nodal) with cytological or histological confirmation of the presence of an undifferentiated or neuro-endocrine component of prostatic origin * prior treatment by radiotherapy is allowed but radiation therapy must have been completed for at least 4 weeks before inclusion and irradiated areas must not represent more than 25% of marrow reserves * prior treatment by estramustine is allowed but must have been stopped at least 4 weeks before inclusion * age\> or = 18 years * life expectancy\> or = 3 months * karnofsky index\> or = 50% * adequate haematological function: neutrophils\> or = 1.5 g/l, platelets\> or = 100 g/l, haemoglobin\> or = 8 g/dl. use of erythropoietin is allowed. * adequate liver function: bilirubin level within the institution's normal range, ast and alt\< or = 1.5 uln * adequate renal function: creatinine clearance\> or = 40 ml/min (gault and cockroft method) * signed written informed consent. exclusion criteria: * patients having no\> 1.5 x uln increase of at least one neuro-endocrine marker (nse or chromogranin a) and no cytological or histological (undifferentiated or neuro-endocrine type) evidence of visceral metastasis (hepatic, pleuro-pulmonary, or nodal) * history of other malignancies, other than curatively treated basal cell skin carcinoma or any other curatively treated cancer with no sign of recurrence within 5 years * symptomatically uncontrolled brain metastasis * interstitial radiation therapy (using strontium or samarium) within the previous 3 months * prior treatment with platinum salts or etoposide. other chemotherapy regimens are allowed provided that the last dose has been administered\> or = 4 weeks prior to inclusion. * concomitant treatment with other anti-cancer drugs, except corticoid or lh-rh agonist injections * peripheral neuropathy\> or = 2 (nci-ctcae) * uncontrolled progressive thrombo-embolic disease * uncontrolled infection * medical history of acute myocardial infection or uncontrolled angina pectoris, or hypertension or uncontrolled arrythmia * inclusion in another clinical trial * impaired follow-up for social, geographical, familial or psychological reasons * any other unstable disease.

Keywords: hormone resistant prostate cancer neuro-endocrine marker carboplatin-etoposide combination neuro-endocrine differentiation