Vol. 4, 349-356, February 1998 Clinical Cancer Research 349 Sequence-dependent Hematological Toxicity Associated with the 3-Hour Paclitaxel/Cyclophosphamide Doublet’ M. John Kennedy,2 Marianna L. Zahurak, data using each patient as her own control indicated more Ross C. Donehower, Dennis Noe, severe hematobogical toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence- Louise B. Grochow, Susan Sartorius, dependent effects on the pharmacokinetics of these drugs Tian-Ling Chen, Kathy Bowling, Mary Duerr, that might account for this phenomenon. The impact of drug and Eric K. Rowinsky3 sequencing on toxicity should be considered in the further The Johns Hopkins Oncology Center. Baltimore. Maryland 21287 development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h. ABSTRACT Paclitaxel is active in metastatic breast cancer. Combi- INTRODUCTION nation studies have demonstrated complex interactions A series of Phase II studies has confirmed the clinical between paclitaxel and other cytotoxic agents, including activity of single-agent paclitaxel in the treatment of women sequence-dependent cytotoxic, toxicological, and pharmaco- with both chemotherapy-naive and previously treated metastatic logical effects. The principal objectives of this study were to breast cancer (1-3). However, a variety of issues remain to be determine the maximum tolerated doses of paclitaxel (3-h clarified concerning the optimal use of the drug in this disease. infusion) and cycbophosphamide (1-h infusion) administered These include both the optimal dose and schedule of drug every 3 weeks with granubocyte colony-stimulating factor administration and the role of paclitaxel in the adjuvant treat- (Filgrastim) and to determine if the sequence-dependent ment of high-risk patients with primary breast cancer. In addi- toxicological effects that have previously been observed with tion. it is uncertain whether paclitaxel is best used as a single this combination when paclitaxel was administered over agent or in combination with other active cytotoxics (4). 24 h were evident when paclitaxel was administered over A number of studies have demonstrated the activity of com- 3 h. Fifteen women with metastatic breast cancer were bination chemotherapy with paclitaxel and a variety of alkylating treated. Starting doses were 200 mg/rn2 paclitaxel and 1600 agents in women with metastatic breast cancer. Such regimens may mg/m2 cycbophosphamide, with granulocyte cobony-stimu- be of major clinical utility in patients who have received anthra- bating factor (5 pg/kg/day) given s.c. beginning 24 h after cyclines in the adjuvant setting. A paclitaxel/cisplatin combination chemotherapy. Doses of both drugs were escalated in co- has been shown in one study to have a response rate of 85% when horts of at least four patients. The sequence of drug admin- administered every 2 weeks to 27 women with metastatic breast istration was alternated with each consecutive patient and cancer (5). Subsequent reports suggest that the activity of this with each subsequent course of therapy in each individual combination is likely to be less, and response rates of between 23 patient, enabling the evaluation of sequence-dependent tox- and 60% have been reported (6, 7). Paclitaxel and cyclophospha- icobogical and pharmacological effects. Severe myebosup- mide combinations are also active, and substantial doses of both pression was the principal dose-limiting toxicity for this drugs can be administered before neutropenia is dose-limiting. regimen, precluding dose escalation above 200 mg/m2 pacli- Tolcher ci al. (8) administered paclitaxel by 72-h infusion and taxel and 1600 mg/rn2 cyclophosphamide, the maximum cycbophosphamide by bolus on days I, 2. and 3 every 3 weeks to tolerated dose for this combination on this schedule. As has 55 women with metastatic breast cancer, most of whom had been been previously demonstrated with this combination, when previously exposed to anthracyclines. These authors observed a paclitaxel is administered over 24 h, the hematopoietic tox- response rate of 55%. Fennelly et a!. (9) evaluated this combination icity was sequence dependent. Paired analysis of toxicity for its ability to mobilize peripheral blood progenitor cells for subsequent apheresis to support sequential high-dose chemother- apy in women with ovarian cancer. In a Phase I trial with escalating doses of paclitaxel administered as a 24-h infusion, these authors Received 7/22/97: accepted 10/30/97. reported 300 mg/rn2 paclitaxel could be administered every 2 The costs of publication of this article were defrayed in part by the weeks with 3 g/m2 cycbophosphamide when supported with G- payment of page charges. This article must therefore be hereby marked CSF’ without DLT. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported by National Cancer Institute Contract N0l-CM-07032. and by a clinical research grant from Amgen. 2 To whom requests for reprints should be addressed. at The Johns Hopkins Oncology Center, 600 North Wolfe Street, Room 130, Balti- 4 The abbreviations used are: G-CSF, granulocyte colony-stimulating more, MD 21287. Phone: (410) 614-4192: Fax: (410) 955-0125: E-mail: factor: DLT, dose-limiting toxicity: MTD. maximum tolerated dose: [email protected]. AUC, area under the curve: CI, confidence interval: ANC. absolute 3 Present address: Institute for Drug Development, Cancer Therapy and neutrophil count: ECOG. Eastern Cooperative Oncology Group: USP. Research Center, San Antonio, TX 78229. United States Pharmacopoeia. Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1998 American Association for Cancer Research. 350 3-h Paclitaxel, Cycbophosphamide, G-CSF for Breast Cancer The combination of paclitaxel administered over 24 h with in less myebosuppression than paclitaxel administered over 24 h, bolus cyclophosphamide and G-CSF support has previously the starting doses for the current study were 200 mg/m2 pacli- been evaluated in women with heavily pretreated metastatic taxel given by 3-h infusion and 1600 mg/m2 cycbophosphamide breast cancer (10). Neutropenia was dose-limiting. The MTD given over 1 h. All patients were treated with G-CSF (5 p.g/kg/ for this combination on this schedule was 200 mg/m2 paclitaxel day) s.c. from day 3 until the ANC was 1500 cells/pA. and 1250 mg/m2 cyclophosphamide, and responses were noted Doses of paclitaxel or cycbophosphamide were escalated in 29% of patients with anthracycline-resistant disease. Both sequentially in each successive cohort of new patients. Four new sequences of drug administration (i.e. paclitaxel before cyclo- patients were treated at each dose level in which no DLTs were phosphamide and cyclophosphamide before paclitaxel) were seen, and escalation to the next cohort was not attempted before evaluated in this study. Because as all patients were treated with at least three patients at the prior dose level had completed at both treatment sequences, each patient acted as her own control, least one course of treatment. Intraindividual dose escalation and pairwise comparisons of toxicity with both sequences of was not permitted, but dose reduction by one dose level was drug administration could be performed. Platelet and neutrophil allowed for patients who received at least two courses of therapy toxicities were more severe when paclitaxel was administered and developed DLT or had one or more episodes of grade IV before cycbophosphamide, and the risk of neutropenia-associ- neutropenia (ANC <500 cells/pA) with fever, or grade IV ated fever was four times higher in courses in which paclitaxel thrombocytopenia (platelets <25,000 cells/pA). was administered first. There seemed to be no pharmacokinetic DLT. Toxicity was graded according to the National explanation for this finding. Similar effects of drug sequencing Cancer Institute Common Toxicity Criteria. DLT was defined as on toxicity have been noted in studies of the paclitaxel/doxoru- grade 3/4 nonhematobogical toxicity or the following hemato- bicin doublet. Holmes et a!. (1 1) administered doxorubicin over logical toxicity: (a) ANC <500 cells/pA or platelets <25,000 48 h and paclitaxel over 24 h in both sequences and noted that cells/pA for more than S days; or (b) delay in the initiation of the clearance of doxorubicin was reduced by about 30%, and additional therapy for more than 7 days, due to unresolved toxicity was greater in courses in which paclitaxel was admin- hematobogical toxicity. If DLT occurred in one of the first four istered first. However, in a recently reported study of paclitaxel patients treated at a specific dose level, then two additional administered over 3 h with doxorubicin infused over 15 mm, patients were treated at that dose level. Accrual of additional Gianni et a!. (12) noted no effect of sequence of drug adminis- new patients at the lower dose level was permitted if more than tration on toxicity, although paclitaxel reduced the clearance of two patients had a DLT at the next highest dose level. The MTD both doxorubicin and doxorubicinol in both treatment sequences was defined as the highest dose level at which less than two of ( 1 3). To determine whether sequence of drug administration has six patients experienced a DLT. an impact on the toxicity of the paclitaxel/cyclophosphamide Drug Administration. Paclitaxel (Taxol; Bristol Myers combination when the taxane is administered over 3