A Phase I/II study of weekly paclitaxel and 3 days of high dose oral ...

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2042 CANCER June 1, 2001 / Volume 91 / Number 11TABLE 2Distribution of Toxicity Events by Type and GradeToxicityGrade1 2 3 4Neuropathy 2 1 0 0Musculoskeletal 1 0 0 0Alopecia 3 2 0 0Neutropenia 0 0 1 0Phlebitis a 0 4 0 0Edema 0 0 1 0Thrombosis/embolism 0 0 0 1Nausea 3 3 1 0Emesis 2 0 0 0Diarrhea 0 0 1 0a Phlebitis refers to induration and erythema at the site of intravenous infusion.mg/m 2 with estramustine 900 mg/m 2 . One patient waslost to follow-up after 5 weeks of treatment. Two patientscompleted two cycles. For Cohort III, six patientswere enrolled to receive paclitaxel 75 mg/m 2with estramustine 900 mg/m 2 . The cohort was expanded,because one patient developed Grade 3 nauseaand diarrhea, requiring treatment interruption.Five patients completed two cycles. In Cohort IV, sixpatients were enrolled to receive paclitaxel 90 mg/m 2with estramustine 900 mg/m 2 . The cohort also wasexpanded, because 1 patient developed Grade 3edema with pulmonary embolism during the secondweek of the first cycle and was removed from protocol.One patient discontinued therapy after 4 weeks, andone patient developed Grade 3 neutropenia. Four patientscompleted two cycles.According to the MTD criteria, no further escalationswere made after Cohort IV. In summary, 14patients completed two cycles of therapy, and 4 patientsdid not complete the first cycle.Toxicity AssessmentToxicity could be evaluated in all patients enrolled inthe study, because the discontinuation of treatment infour patients occurred after they had started treatment.Overall, there were no therapy-related deaths. Adetailed account of the spectrum of toxicity and thenumber of patients for each grade of toxicity are listedin Table 2. Grade 1 and 2 paresthesias were observedin three patients, and Grade 1 musculoskeletal symptomswere documented in another patient. Partial lossof hair was seen in five patients. There was only onepatient with Grade 3 neutropenia without febrile complications.At the time of enrollment, 17 patients hadGrade 1 and 2 anemia secondary to prolonged androgenablation and chronic disease. There were no newTABLE 3Distribution of Grade 3 and 4 Toxicity Events among CohortsIII and IVToxicity Cohort III Cohort IVNeutropenia 0 1Edema 0 1Thrombosis/embolism 0 1Nausea 1 0Emesis 0 0Diarrhea 1 0patients with Grade 1 or 2 anemia or progression ofanemia during therapy. Four patients had superficialphlebitis with erythema at the site of intravenous injectionwithout evidence of deep vein thrombosis,which resolved with local therapy. One patient hadGrade 3 lower extremity edema and subsequently developeda pulmonary embolism with pleuritic chestpain and shortness of breath without hemodynamiccomplications. Symptoms improved rapidly with standardanticoagulation treatment with heparin and warfarin,and the patient was removed from study. Nauseawas the most common gastrointestinal symptomand was experienced by six of seven patients as Grade1–2 and by one patient as Grade 3. Grade 2 emesis wasseen in two patients, and Grade 3 diarrhea was experiencedby one patient.Overall, there were four events of Grade 3 toxicityand one event of Grade 4 toxicity. Table 3 summarizedthe number of Grade 3– 4 toxicity events by cohort.There was one patient with Grade 3 nausea and diarrheain Cohort III, and one patient with Grade 3 neutropeniaand one patient with edema and pulmonaryembolism in Cohort IV.PSA ResponseTable 4 summarizes the clinical responses for eachcohort according to PSA criteria and intent-to-treatanalysis results. Cohort I had one patient with stablePSA levels and two patients with PSA progression.Cohort II had one patient who was lost to follow upafter 5 weeks of treatment, one patient had PSA progression,and one had PSA decline 75%. In CohortIII, one patient was removed early, one patient hadstable PSA, one patient had PSA decline 50%, andthree patients had PSA decline 75%. In Cohort IV,two patients were removed early, one patient had PSAdecline 50%, and three patients had PSA decline 75%.The PSA response rate estimated on the basis ofthe intent-to-treat analysis showed that 9 of 18 patients(50%) enrolled in the study had a PSA decline
Weekly Paclitaxel/Estramustine in HRPC/Ferrari et al. 2043TABLE 4Prostate Specific Antigen Response by CohortCohort Paclitaxel Estramustine No.Treatmentdiscontinued Progressed StablePSA decline> 50%Intent to treatresponse (%)I 40 600 3 0 3 0 0 0 of 3II 60 900 3 1 1 0 1 1 of 3IIII 75 900 6 1 0 1 4 4 of 6IV 90 900 6 2 0 0 4 4 of 6Total — — 18 4 4 1 9 9 of 18 (50)PSA: prostate specific antigen. 50%. Because the group of patients in Cohorts II–IVreceived a dose of estramustine 1.5 times greater thanCohort I, and this alone may have affected the PSAresponse irrespective of the dose of paclitaxel, we alsoanalyzed them as a group. The intent-to-treat analysisshowed that 9 of 15 patients (60%) had a PSA decline 50%; in 7 patients, the decline was 75%. Themedian duration of response (n 9 patients) was 16.7weeks, with a range from 3 weeks to 48.6 weeks.Fifteen of 18 patients (83%) had metastatic diseaselimited to bone, including 12 patients in Cohorts II–IV.Seven of these patients (58%) experienced PSA decline 50% from baseline. Stabilization with mild improvementwas reported in two patients. Three patients hadmeasurable disease to lymph nodes, one patient had ameasurable response with a PSA decline 75%, anotherpatient had no response with a PSA decline 50%, and one patient did not complete therapy.Bone scan abnormalities persisted in all patients.DISCUSSIONIn this report, we present the toxicity profile and responseof patients with hormone-refractory prostatecarcinoma to a new schedule and dose range of paclitaxeland oral estramustine. This regimen was basedon previous experience with other tumors suggestingthat more frequent 24,25 and lower doses of paclitaxel, 17,26as well as intermittent but higher doses of estramustine,19 could improve the toxicity profile of each drugwithout compromising their synergistic activity.Therefore, weekly 1-hour infusions of paclitaxel weregiven in escalating doses of 40 mg/m 2 , 60 mg/m 2 ,75mg/m 2 , and 90 mg/m 2 combined with 3 days of oralestramustine. The dose of estramustine, which wasestablished at 600 mg/m 2 in the original design andwas received by patients in Cohort I along with 40mg/m 2 of paclitaxel, was increased subsequently to900 mg/m 2 and fixed at that level for all subsequentpaclitaxel dose levels.The results of this trial indicate that the grade andspectrum of toxicity associated with taxanes in previousstudies of this combination 7,15 can be improvedmarkedly. Compared with the 20% and 53% incidencerates of Grade 3– 4 granulocytopenia, there was onlyone patient without febrile complications in our series.Similarly, there were no new incidents of anemiaor worsening of preexisting anemia compared with the18% and 59% incidence rates reported in the previousstudies, and there were no incidents of thrombocytopenia.Neurologic and musculoskeletal symptoms alsowere infrequent and predominantly were Grade 1.Hypersensitivity reactions, arrhythmia, or hypotensionwere not reported during the infusions. The incidenceof peripheral edema also was reduced markedly.Gastrointestinal complications commonly associatedwith oral estramustine 27 were ameliorated butnot eliminated with the brief and intermittent schedulethat was used. Despite the high dose of estramustine,the frequency and severity of nausea, emesis, anddiarrhea was low 7,28 and was limited to the days oftreatment. This may explain why, compared withother regimens using lower doses of estramustine forprolonged periods of time, 28 anorexia and weight losswere rare.This treatment schedule did not appear to preventthe development of thromboembolic events previouslyreported with regimens containing estramustine,27 as illustrated by the patient who developed apulmonary embolism in the second week of therapy.Given the proximity of the episode to the initiation oftherapy, the possibility cannot be excluded that it mayhave been related to the advanced stage of the diseaserather than the treatment. Also, because we did notobserve other patients with deep vein thrombosis, andrecent studies quote 8 –10% thromboembolic eventswith lower 28 and intermittent 7 dosing of estramustine,we do not have evidence that the higher dose used inthis trial played a role. In recognizing this risk, prophylaxisof thrombosis using low doses of warfarinand aspirin currently are included in the treatmentplan of new trials containing estramustine. Based on
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