Beer Tomasz M, Garzotto Mark, Lowe Bruce A, Ellis William J, Montalto Michelle A, Lange Paul H, Higano Celestia S
Divisions of Hematology and Medical Oncology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
Clin Cancer Res. 2004 Feb 15;10(4):1306-11. doi: 10.1158/1078-0432.ccr-1021-03.
The purpose is to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of mitoxantrone and docetaxel administered weekly before prostatectomy in men with localized prostate cancer at high risk for recurrence.
Twenty-two patients were treated with four cycles of docetaxel 35 mg/m(2) and increasing doses of mitoxantrone starting at 2 mg/m(2) repeated weekly for 3 weeks of a 4-week cycle before prostatectomy. The MTD was defined as that dose at which fewer than one-third of patients experienced a DLT (>or=grade 4 hematological or >or=>grade 3 nonhematological toxicity). Changes in serum prostate-specific antigen and serum testosterone, and pathological outcome with surgery were secondary endpoints.
The MTD for mitoxantrone in combination with this dose of docetaxel was 4 mg/m(2). Neutropenia was the DLT for the combination. Ten of 12 patients treated at the MTD completed the planned 16 weeks of chemotherapy, whereas 2 discontinued therapy early because of toxicity. The median reduction in PSA was 41% (range, 4-88%). Serum testosterone levels remained constant postchemotherapy.
In this patient population, the planned Phase II regimen is 4 mg/m(2) mitoxantrone and 35 mg/m(2) docetaxel weekly for 3 of every 4 weeks. Delivery of this regimen before prostatectomy is feasible with acceptable toxicity. Additional studies are needed to determine whether this combined modality approach will reduce cancer recurrence rates in this high-risk population. Because extent of disease and exposure to prior therapy may impact treatment tolerance these safety data may not be applicable to patients with advanced prostate cancer.
确定米托蒽醌和多西他赛每周给药的剂量限制性毒性（DLT）和最大耐受剂量（MTD），这两种药物在前列腺切除术前用于复发风险高的局限性前列腺癌男性患者。
22例患者接受四个周期的多西他赛35mg/m²治疗，并从2mg/m²开始递增剂量的米托蒽醌，在前列腺切除术前，每4周为一个周期，每周重复给药3周。MTD定义为少于三分之一的患者出现DLT（≥4级血液学毒性或≥3级非血液学毒性）时的剂量。血清前列腺特异性抗原和血清睾酮的变化以及手术病理结果为次要终点。
米托蒽醌与该剂量多西他赛联合使用时的MTD为4mg/m²。中性粒细胞减少是联合用药的DLT。在MTD剂量下接受治疗的12例患者中有10例完成了计划的16周化疗，而2例因毒性反应提前停药。前列腺特异性抗原（PSA）的中位降低率为41%（范围4%-88%）。化疗后血清睾酮水平保持稳定。
在该患者群体中，计划的II期治疗方案为米托蒽醌4mg/m²和多西他赛35mg/m²，每4周中的3周每周给药一次。在前列腺切除术前实施该方案是可行的，毒性可接受。需要进一步研究以确定这种联合治疗方法是否会降低该高危人群的癌症复发率。由于疾病范围和既往治疗暴露情况可能影响治疗耐受性，这些安全性数据可能不适用于晚期前列腺癌患者。
