2044 CANCER June 1, 2001 / Volume 91 / Number 11the fact that Cohort IV required expansion becausethere were two patients with Grade 3 <strong>and</strong> 4 toxicity, weconcluded that the MTD for this regimen had beenreached.A second objective <strong>of</strong> this <strong>study</strong> was to evaluatethe efficacy <strong>of</strong> the combination by PSA response <strong>and</strong>,whenever possible, by measurable disease parameters.The intent-to-treat analysis by PSA response criteriashowed an overall response rate <strong>of</strong> 50%, because9 <strong>of</strong> 18 patients enrolled in the <strong>study</strong> had a PSA decline 50% from baseline. When looking at PSA responserates by cohort, it appears that a <strong>dose</strong> <strong>of</strong> <strong>paclitaxel</strong>between 75 mg/m 2 <strong>and</strong> 90 mg/m 2 was required toachieve synergism with 900 mg/m 2 <strong>of</strong> estramustine.These PSA response rates are <strong>high</strong>er than the 23%rate reported with 24-hour infusions <strong>of</strong> <strong>paclitaxel</strong> at135–170 mg/m 2 every 3 weeks 29 or <strong>weekly</strong> 1-hour infusions<strong>of</strong> <strong>paclitaxel</strong> at 150 mg/m 2 . 30 They also aresuperior to the 14% rate observed with continuousestramustine at 560 – 840 mg daily. 31We took into consideration the facts that the 15patients enrolled in Cohorts <strong>II</strong>–IV had received a 1.5times larger <strong>dose</strong> <strong>of</strong> estramustine compared with patientsin Cohort I <strong>and</strong> that this alone may have influencedtheir response independent <strong>of</strong> the <strong>dose</strong> <strong>of</strong> <strong>paclitaxel</strong>.The 60% response rate observed in the intentto-treatanalysis reflects the fact that the 9 responderswere among the 15 patients in this group. It is noteworthythat seven <strong>of</strong> these responders had a PSA decline 75% from baseline <strong>and</strong> that the drop in PSAlevels for eight <strong>of</strong> these patients occurred within theinitial 6 weeks <strong>of</strong> treatment, which may have affectedthe median PSA response duration determination 23 <strong>of</strong>16.7 weeks, because, at the time <strong>of</strong> first evaluation <strong>of</strong>response, PSA levels had decreased beyond 50%.Although they were limited because <strong>of</strong> the nature<strong>of</strong> the <strong>study</strong>, the PSA response rates observed in theintent-to-treat analysis were within the 53% <strong>and</strong> 63%response rates reported previously with either <strong>paclitaxel</strong>or docetaxel every 3 weeks <strong>and</strong> continuous orintermittent lower <strong>dose</strong>s <strong>of</strong> estramustine. 7,28 The timeto response <strong>and</strong> duration <strong>of</strong> response also were withinthe 8 weeks <strong>and</strong> 20 –22 weeks observed, respectively,in those studies.We also evaluated whether there was any evidence<strong>of</strong> response in bone metastasis or measurabledisease. Like what is seen frequently with metastaticbone disease in patients with hormone-refractoryprostate carcinoma, we observed decreased intensity<strong>of</strong> bony lesions in two patients, but no decrease in thenumber <strong>of</strong> bone lesions was observed. We did observea partial response in one patient with measurabledisease to the lymph nodes, whereas the PSA level haddeclined more than 75%. These preliminary observationssuggest that measurable responses also may beexpected with this schedule after a decline in the PSAlevel 50%. 15This <strong>study</strong> supports the finding that the MTD <strong>of</strong><strong>paclitaxel</strong> in a <strong>weekly</strong> 1-hour infusion schedule is 90mg/m 2 with intermittent estramustine at 900 mg/m 2for 3 <strong>days</strong>. The current schedule had markedly improvedhematologic <strong>and</strong> neurotoxicity pr<strong>of</strong>ile <strong>and</strong>milder gastrointestinal side effects compared with<strong>high</strong>er <strong>dose</strong>s <strong>of</strong> <strong>paclitaxel</strong> at 3-week intervals <strong>and</strong> continuousestramustine in patients with hormone-refractoryprostate carcinoma. In terms <strong>of</strong> efficacy, biochemicalresponses were similar for either 75 mg/m 2or 90 mg/m 2 <strong>of</strong> <strong>paclitaxel</strong>, <strong>and</strong> the response ratespromise to be within the 50 – 60% range expected forthese agents. Therefore, the improved toxicity pr<strong>of</strong>ile<strong>and</strong> potential efficacy <strong>of</strong> this schedule supports a<strong>Phase</strong> <strong>II</strong> <strong>study</strong> incorporating prophylactic measures todecrease the incidence <strong>of</strong> thromboembolic complications.REFERENCES1. 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