Sequence-Dependent Hematological Toxicity Associated with the 3-Hour Paclitaxel/Cyclophosphamide Doublet’

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 chemotherapy 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.

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 h, we Squibb Pharmaceuticals, Princeton, NJ) was supplied by the performed the study reported here. The goals of the study were Division of Cancer Treatment, National Cancer Institute (Be- to determine the MTD of paclitaxel (3-h infusion) and cyclo- thesda, MD) as a concentrated sterile solution with 6 mg/mI in phosphamide administered every 3 weeks with G-CSF support, a 5-mi ampule in 50% polyoxyethylated castor oil (Cremophor to seek evidence of impact of drug administration sequence on EL) and 50% dehydrated alcohol, USP 50%. The total dose was the toxicity associated with this drug combination, and to eval- administered over 3 h after dilution in 1,000 ml of 5% dextrose uate the potential pharmacokinetic interaction between pacli- injection, USP. Glass infusion bottles and nitroglycerin tubing taxel and cycbophosphamide. were used for administration. Cyclophosphamide (Neosar; Ad- ria Laboratories, Columbus, OH) was supplied in 100-, 200-, PATIENTS AND METHODS 500-, 1,000-, and 2,000-mg vials and dissolved in bacteriostatic Patient Eligibility. Women with histologically docu- water for injection, USP. The required dose was diluted in 500 mented breast cancer that was metastatic who were 1 8 years of ml of 5% dextrose water and administered over 1 h. The age or older were eligible to participate in the study. An ECOG following premedications were administered to all patients: (a) performance status of 2 or better and a life expectancy of at beast dexamethasone (20 mg), iv. or orally, 14 and 7 h before 3 months were required. Prior chemotherapy for metastatic paclitaxel; and (b) diphenhydramine (50 mg) iv. and famotidine disease, with the exception of high-dose therapy with autolo- (20 mg) iv. 30 mm before paclitaxel. Patients who received less gous stem cell support or prior taxane treatment, was allowed. than 1,500 mg/m2 cycbophosphamide received hydration with Adequate hematopoietic (WBC count 4,000 cells/pA with neu- 1,000 ml of 0.9% sodium chloride solution over 3 h following trophils (ANC) 1,500 cells/pA and platelets 100,000 cells/ chemotherapy. Patients who received more than 1 ,500 mg/m2 p.1), hepatic (total bilirubin 1 .5 mg/dl), and renal (creatinine cyclophosphamide received 0.9% sodium chloride solution at 4 1 .5 mg/dl) function was required. All patients gave written mI/kg/h for 6 h before and 12 h after treatment with cycbophos- informed consent according to institutional and federal guide- phamide. All patients were treated with recombinant human lines. G-CSF (Filgrastim; Amgen, Thousand Oaks, CA; S p.g/kg/day) Dosage. In a prior study that evaluated the feasibility of s.c. beginning no sooner than 24 h after the end of chemother- administering the combination of paclitaxel given by 24-h in- apy. G-CSF was continued until the ANC exceeded 1,500 fusion with cyclophosphamide over 1 h and G-CSF, the MTD cells/pA on two consecutive determinations. Chemotherapy was was found to be 200 mg/m2 paclitaxel and 1250 mg/m2 cyclo- administered every 2 1 days, unless the ANC or platelet count phosphamide. Because paclitaxel administered over 3 h results was less than 1,500 or 100,000 cells/pA, respectively.

Drug Sequence. The initial sequence of drug adminis- Table I Patient Characteristics tration was alternated in each successive patient entered on Characteristic No. study and with subsequent courses of therapy administered to Patients 15 each individual patient. The first patient received cyclophosph- Assessable for sequence dependence 14 amide immediately before paclitaxel, and the second patient Age (yr) received paclitaxel immediately before cyclophosphamide dur- Median 49 ing the first course. Thereafter, the sequence of drug adminis- Range 35-68 ECOG performance status tration for the first course alternated with each additional new 0 ., patient entered on study. In each individual patient, the sequence 10 of drug administration was also alternated with each successive 2 3 course. Therefore, all patients were treated with both sequences. Disease sites The major statistical endpoint of the study was the ratio of Liver 3 Lung 6 pre- and posttreatment ANC and platelet count. which were Bone 3 assessed according to treatment sequence, i.e. cyclophospha- Nodal 4 mide and then paclitaxel or paclitaxel and then cycbophospha- Local 4 mide. The ANC and platelet ratios were regressed on treatment Disease sites Median sequence, adjusted for patient identification number. Thus, the Range 1-3 effects of sequence on hematological toxicity could be deter- Prior therapy mined by performing a paired analysis, with each patient acting Prior anthracyclines as her own control. Hospital admission for fever associated with Adjuvant 11 severe neutropenia was also considered a statistical endpoint, Metastatic 4 Both 0 and conditional logistic regression was used to determiner whether treatment sequence was an independent determinant of this event. Pretreatment and Follow-Up Evaluations. History and Table 2 Dose escalation scheme physical examination were performed, and routine laboratory Paclitaxel/cycbophosphamide Patients Courses studies were obtained on the first day of each course. Toxicity Level (mg/m2) (new/total) (new/total) was evaluated weekly during therapy. Routine laboratory tests - I” 200/1 250 0/1 0/5 included complete blood count with WBC count differential, I 200/1600 4/4 27/27 electrolytes, urea, creatinine, total protein, albumin, calcium, 2 250/1600 7/95 25/32” glucose, phosphate, uric acid, alkaline phosphatase, total and 3 250/2000 4/4 13/13 direct bilirubin, aspartate aminotransferase, alanine aminotrans- “ One patient treated at the first dose level (200/1600) had doses ferase, amylase. prothrombin time, and urinalysis. All patients reduced to 200/1250 because of neutropenia-associated fever on more had an electrocardiogram before entry on study. Complete blood than one course of therapy. h Two additional patients received seven extra courses after dose- counts were obtained three times weekly until the ANC cx- reduction from dose level 3. ceeded 1500/pA on two consecutive occasions. Assessment of tumor response was performed after every two courses of therapy, and treatment continued as long as there was no evidence of disease progression and toxicity permitted. values was calculated to determine whether there was an effect Pharmacokinetic Studies. An analysis of plasma con- of drug sequence on AUC. centrations of both paclitaxel and cycbophosphamide was performed with each sequence of drug administration in patients RESULTS who received two or more courses of therapy. Blood samples Patient characteristics are outlined Table 1 . Fifteen patients were drawn for assay of paclitaxel concentrations, according to were entered on study, all of whom were assessable for toxicity. a limited sampling scheme: pre-infusion; 1 h into infusion; and One patient treated at dose level 2 developed progressive dis- 1 mm, 3 h, and 24 h after infusion. Plasma paclitaxel concen- ease during course 1 ; thus, 14 patients received at least 2 courses trations were measured by high-performance liquid chromatog- and are evaluable for assessments of sequence-dependent ef- raphy using the method described previously (10). Paclitaxel fects. Median age was 45 years (range, 35-68 yeas), and

AUC was measured by the mixed linear-bog trapezoidal rube. median ECOG performance status was 1 . The median number of The 95% CI for the ratio of paired values was calculated to disease sites was 1, (range, 1-3). All patients had received prior determine whether there was an effect of drug sequence on anthracyclines, 1 1 in the adjuvant setting and 4 for metastatic AUC. disease. Patients were treated in the dose escalation scheme as Blood samples to assess the pharmacokinetic behavior of outlined in Table 2. Fifteen patients received a total of 77 cycbophosphamide were collected preinfusion, at 45 mm into the courses of treatment at 4 dose levels. The median number of infusion, and at 5, 20, and 40 mm and 1, 1.5, 2, 3, 6, and 24 h courses per patient was S (range, 1-14). after the infusion. Plasma cyclophosphamide concentrations The DLTs are summarized in Table 3. Whereas no DLTs were measured by gas chromatography, as described previously were observed at dose level 1 (paclitaxel/cyclophosphamide. (14). Cycbophosphamide AUC was measured by the mixed 200/1600 mg/m2), one of four patients did develop neutropenia- linear-log trapezoidal rule. The 95% CI for the ratio of paired associated fevers on more than one occasion and required a dose

Table 3 DLTs at each dose level

Dose No. of patients with DLT Paclitaxel/ cycbophosphamide Dose reduction due Level (mg/m2) New patients New courses DLT to recurrent NP’

1 200/1600 4 27 0 1/4 2 250/1600 7 25 2/7” on 3 250/2000 4 13 0 2/4

“ NF, neutropenia-associated fever.

“ One malaise, one syncope.

Table 4 Hematobogical toxicity

Paclitaxel/ cycbophosamide Total Total Fever with Grade 3/4 Dose j.__i___ (mg/m2) patients courses Grade 4 ANC” neutropenia platelets” reductionc

- I 200/1 250 1 5 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/1 1 200/1 600 4 27 24/27 (88%) 4/27 ( 15%) 0/27 (0%) 1/4 2 250/1600 9 32 15/32(47%) 3/32(9%) 2/32(6%) 0/9 3 250/2000 4 13 11/13(85%) 6/13(45%) 1/13(8%) 2/4

‘, Neutrophil nadir count less than 500 cells/bib.

“ Platelet nadir count less than 50,000 cells/bib.

( Dose reductions, per patient treated, due to repeated episodes of neutropenia-associated fever.

reduction to dose level - I (paclitaxel/cycbophosphamide, 200/ mg/rn2 (9%)] but occurred in 45% of courses at dose level 3 1250 mg/m2). Treatment at this dose level was subsequently (paclitaxel/cyclophosphamide, 250/2,000 mg/m2). Recurrent well tolerated for five courses. Only 1 of 24 courses of therapy neutropenia-associated fevers in each of the first two courses administered to the other 3 patients treated at dose level 1 was mandated dose reductions in two of four patients treated at this complicated by a fever associated with severe neutropenia. One dose level. Severe platelet toxicity was uncommon, with platelet other patient developed cumulative grade 2 malaise that con- nadir counts of less than 50,000 cells/pA occurring in fewer than tributed to the decision to discontinue therapy after six courses. 10% of courses at all dose levels. Seven new patients were treated at dose level 2 (paclitaxell The sequence of drug administration had an impact on the cyclophosphamide, 250/1600 mg/m2). One patient developed severity of hematobogical toxicity observed (Table 5). There was progressive disease and was taken off study after one course of no difference in mean ANC before therapy with either sequence treatment. One patient developed syncope with two courses of (data not shown). As shown in Table 6, the posttreatment therapy at the end of the paclitaxel infusion and was taken off average ANC for paclitaxel-first courses (P/C) was 661 cells/pA protocol because of this DLT. A second patient at dose level 2 and was not significantly different from the posttreatment aver- developed dose-limiting malaise and was taken off protocol age of 1 .007 cells/pA for the cycbophosphamide-first (C/P)

after two courses of therapy. At dose level 3 (paclitaxel/cyclo- courses (P = 0.08). However, paired analysis of the ratio of phosphamide, 250/2000 mg/m2), two of four patients were nadir count to pretreatment ANC indicates a borderline signif- hospitalized for treatment of fevers associated with severe neu- icantly lower ratio for P/C courses (0. 1 2) than for C/P courses

tropenia on more than one occasion and received further therapy (0.19; P = 0.05). Conditional logistic regression analysis dem- after course 2 at dose level 2 (paclitaxel/cycbophosphamide, onstrated that the odds ratio for developing a neutropenia- 250/1600 mg/m2). In retrospect, therefore, recurrent episodes of associated fever on P/C courses was 1.7 times that for C/P neutropenia-associated fevers were treated as DLTs, and dose courses. However, this was not statistically significantly in- modifications were made in patients who suffered these toxic- creased for P/C courses as the 95% bound of the CI crossed 1 ities. Because DLTs occurred in two of seven patients treated at (95% CI, 0.5-5.7). An effect of sequence of drug administration dose level 2 (paclitaxel/cyclophosphamide, 250/1600 mg/m2), was observed on platelet toxicity. Again, the mean pretreatment and because two of four patients treated at dose level 3 (pacli- platelet count was similar for both sequences of therapy (data taxel/cyclophosphamide, 250/2000 mg/m2) required dose reduc- not shown). Platelet nadir were significantly lower in P/C tions due to recurrent neutropenia-associated fevers, the MTD courses ( I 27,000 cells/p.l) than in C/P courses ( 1 50,000 cells/pA;

for the paclitaxel/cyclophosphamide combination on this sched- P = 0.01). Also, the ratio of paired nadir platelet count to ule with G-CSF support is 200/1600 mg/m2. pretreatment platelet count was also lower for P/C (0.43) than

Hematobogical Toxicity and Sequence Dependence. for C/P courses (0.51; P = 0.02). These effects were not Substantial hematological toxicity was observed at all dose clinically significant. levels (as outlined in Table 4). Fevers associated with severe Nonhematobogical Toxicity. Neuropathy, myalgias, and neutropenia were uncommon at dose levels 1 and 2 [paclitaxel/ malaise were the most common nonhematobogical toxicities. cyclophosphamide, 200/I ,600 mg/m2 ( I 5%) and 250/1,600 Grade 2 neuropathy was observed in three of four patients at

Table 5 Impact of sequence of drug administration on hematobogical toxicity: average absolute neutrophil and platelet nadirs and the ratios of nadir counts to pretreatment values for each sequence

Neutrophils Platelets Neutropenia- sequence no. Nadir Ratio” Nadir Ratio” associated fevers

C/V 38 1007 19% 150 51% 13% P/C” 39 661 12% 127 43% 15% P 0.08 0.05 0.01 0.02 OW 1.7 (95% CI, 0.5-5.7

a Paired analysis of the ratio of the nadir neutrophib count to the pretreatment count. b Paired analysis of the ratio of the nadir platelet count to the pretreatment count.

C Cycbophosphamide followed by paclitaxeb.

a Paclitaxel followed by cycbophosphamide. e OR, odds ratio.

Table 6 Impact of sequence of drug administration on hematobogicab toxicity: comparison of nadir counts for each sequence of drug administration in the current study (3-h pacbitaxeb) and in the historical control population (24-h paclitaxel A. 3-h paclitaxel with cycbophosphamide

Drug sequence Course no. Nadir ANC (mean) Nadir platelets (rnean

C/I” 38 1007 150 P/C5 39 661 127 P 0.08 0.01

B. 24- h paclitaxeb with cycbophosphamide

Drug sequence Course no. Nadir ANC (mean) Nadir platebets(mean)

C/P 108 1283 112 P/C 98 546 96 P 0.001 0.04 a Cyclophosphamide followed by paclitaxel.

b Paclitaxel followed by cyclophosphamide.

dose level 1 , four of seven patients at dose level 2, and three of and four patients, respectively. The effect of drug administration four patients at dose-level 3. One patient at dose level 1 who was sequence on the cycbophosphamide AUC was evaluated by treated with a total 14 courses of therapy received treatment on calculating the 95% CI for the ratio of the paired values. The a 4-week schedule after course 1 1 because of cumulative neu- mean ratio AUC,1:AUC, was 0.93 (95% CI: 0.79-I .08) for ropathy. In two other patients who received six and eight cyclophosphamide. The effect of drug sequencing on paclitaxel courses of therapy at dose level 1 , cumulative sensory neurop- AUC was estimated calculating the 95% CI for the ratio of the athy contributed to the decision to discontinue therapy after paired values. The mean ratio of AUCC/P:AUCP,(. was I .09 maximal response had been achieved. Two patients (one each at (95% CI, 0.58-2.08) for paclitaxeb. dose levels 1 and 2) were treated with tricyclic antidepressants Response to Therapy. Four of 1 5 patients had responses to ameliorate neurosensory neuropathy. Myalgias were corn- to therapy. Partial responses were observed in two patients with monly observed at all dose levels and treated with nonsteroidal soft tissue disease and in one patient with liver metastases. One anti-inflammatory drugs and narcotic analgesics as required. additional patient had a complete response in recurrent axibbary Myalgias were never dose-limiting. Severe malaise that required nodal disease. discontinuation of therapy was observed in one patient treated at dose level 2, and a second patient at that dose level discontinued therapy because of episodes of syncope at the end of her DISCUSSION paclitaxel infusion. Gastrointestinal toxicities were uncommon. The activity of paclitaxel in the treatment of advanced Grade 1 or 2 nausea, vomiting, mucositis, or diarrhea was chemotherapy-naive and -resistant breast cancer has been well observed on one or more occasions in three of four patients at dose level 1, four of seven patients at dose level 2, and three of documented, and this agent is currently undergoing evaluation four patients at dose level 3. Gastrointestinal toxicity was never in the adjuvant setting. Combination chemotherapy regimens. dose-limiting. comprising paclitaxel and a variety of other active cytotoxics. Pharmacokinetics. Pharmacokinetic data are summa- notably doxorubicin. cisplatin, and cycbophosphamide. have rized in Table 7. Paired plasma samples were analyzed to previously been evaluated in Phase I and Phase II trials. Al- evaluate the possibility of sequence-dependent pharmacological though these drug combinations have been shown to be active. interactions between cycbophosphamide and paclitaxel in nine it remains unclear whether there are advantages to combination

Table 7 Mean AUC for cycbophosphamide and paclitaxel in those patients for whom data from both sequences of drug administration was available

Mean AUC (p.moblhlbiter) ._2!’. P/C” Mean AUC ratio 95% Cl Patient no. Cycbophosphamide (mg/m2) 1600 2739 2783 0.99 0.77-1.27 5 2000 2673 3078 0.85 0.63-1.16 4 1600 and 2000 combined 0.93 0.79-1.08 9 Paclitaxel (mg/m2) 250 48.9 44.7 1.09 0.58-2.08 4

“ C/P. cycbophosphamide followed by paclitaxeb. h P/C. paclitaxeb followed by cycbophosphamide.

over single-agent therapy in the treatment of women with ad- first. Further evaluation of the paclitaxel/doxorubicin doublet vanced disease. has been performed by Gianni et a!. and by Gehl et a!. in two In vitro and in vito evaluations have demonstrated that separate studies (12, 19). Gianni et a!. evaluated the combina- complex drug interactions occur when paclitaxel and certain tion of doxorubicin as a 5-mm bolus and paclitaxel as a 3-h other cytotoxics are combined. This was first observed in a infusion in a Phase II study of 35 women with advanced breast Phase I study of paclitaxel (given over 24 h) and cisplatin (15). cancer. The infusions were separated by 15 mm. Gehl et a!. Patients were treated with both sequences of drug administra- treated 30 women with the paclitaxel/doxorubicin combination, tion, i.e., C/P and P/C. The hematological toxicity of therapy also administering paclitaxel over 3 h. Although the response was more severe in those courses in which cisplatin was admin- rates to therapy were high in both studies, cardiac toxicity istered first. Pharmacological analysis indicated that this was complicated treatment to a significant extent. Gianni reported due to a 25% lower paclitaxel clearance rate in those courses. cardiac failure in 18% of patients after a median 480 mg/m2 One possible hypothesis offered was that cisplatin may inhibit doxorubicin. Gehl et a!. observed congestive cardiac failure in paclitaxel-metabolizing P450 mixed-function oxidases, thus in- 20% of 30 patients. In 15 patients treated by Gehl, the left creasing drug exposure and hematological toxicity when cispla- ventricular ejection fraction dropped below normal, and signif- tin is administered before paclitaxel (16). However, the icant reductions were noted after only 360 rng/m2 cumulative sequence-dependent interaction of paclitaxel and alkylating dose of doxorubicin. Sequences of drug administration were agents is quite different in in vitro models. The cytotoxicity of evaluated only in the study by Gianni, and no evidence of the cisplatin/paclitaxel combination against Li 210 leukemia sequence-dependent toxicity was observed. However, Gianni et cells was documented to be significantly greater when the cells a!. have recently reported on detailed pharmacological studies of were exposed to paclitaxel for 24 h before exposure to cisplatin the influence of sequence of drug administration, interval be- when compared to the other sequence of administration (17). tween drugs, drug dosing, and duration of doxorubicin infusion Additional similar in vitro studies by Cook ci a!. ( 1 8) have on the plasma disposition of doxorubicin and paclitaxel (admin- evaluated the sequence-specific effects of paclitaxel in combi- istered over 3 h; Ref. 13). These studies have in fact indicated nation with a variety of alkylating agents in A549 cells. In their that paclitaxel administered over 3 h before doxorubicin can studies, clonogenic cell survival assays have demonstrated increase the doxorubicin peak level and reduce both the peak subadditive toxicity for the combinations of paclitaxel with level and AUC of the main metabolite of doxorubicin, doxoru- thiotepa, melphalan, or cisplatin when the alkylating agents bicinol. Studies of the interval between drug infusions indicated were administered first. In contrast, toxicity was additive when a rebound in the concentration of both doxorubicin and the the cells were exposed to paclitaxel first. From cell cycle anal- metabolite doxorubicinol as soon as paclitaxel infusions were yses of these interactions in A549 cells, Cook et a!. have begun. This rebound lasted about 6 h, and the effect was greater suggested that the alkylator-first sequence is less toxic, because with higher doses of paclitaxel. Additional studies evaluating the initial exposure to alkylators induces G2 arrest, thereby doxorubicin administered as a 3-h and IS-mm infusion con- inhibiting the progression ofcells into mitosis, in which phase of firmed that these effects are also dependent on anthracycline the cell cycle cells may be most sensitive to the cytotoxic effects concentration. These data clearly indicate a pharmacokinetic of paclitaxel. Therefore, less toxicity is observed with the alky- interaction between paclitaxel (by 3-h infusion) and doxorubicin lator-first sequence. that may be responsible for both the cardiac toxicity and sub- Pharmacological interactions have also had a profound stantial antitumor activity observed by Gianni for this combi- impact on the toxicity of combination chemotherapy with pa- nation administered on this schedule. Gianni has postulated that clitaxel and doxorubicin. Holmes et a!. (1 1) evaluated paclitaxel these interactions may result from competition between doxo- by 24-h infusion and doxorubicin by 48-h infusion and found rubicin and paclitaxel, formulated in cremophor EL, for P- that doxorubicin clearance was reduced by 33% (from 51.6 to glycoprotein-mediated biliary excretion. 34.3 liters/h/m2) when paclitaxel was administered before doxo- We have previously evaluated the combination of cyclo- rubicin. The altered pharmacokinetics of doxorubicin resulted in phosphamide with paclitaxel administered as a 24-h infusion in more profound neutropenia in patients who received paclitaxel women with advanced breast cancer ( 10). The MTD for this

combination on this schedule was 200 mg/m2 paclitaxel and Gianni et a!. have proposed that sequence did not have an 1250 mg/rn2 cycbophosphamide. Both sequences of drug admin- impact on toxicity in their initial study, because the pharmaco- istration were evaluated in all patients, and the hematological kinetic differences did not lead to significantly different AUCs toxicity of therapy was more severe in courses in which pacli- of either drug between the two sequences. taxel was administered first. However, unlike the interaction Many issues rebated to the use of taxanes in the treatment between paclitaxel and doxorubicin noted by Holmes and by of metastatic breast cancer are still unclear. For patients with Gianni, in which paclitaxel reduces the clearance of doxorubi- previously treated disease, the optimal duration of infusion, dose cm, no effect of drug sequencing was noted on drug clearance of paclitaxel, and relative merits of single-agent or combination for either cycbophosphamide or paclitaxel, although a full eval- therapy remain the focus of clinical investigation. For uation of the pharmacology of metabolites of both drugs was not paclitaxel-containing combinations, it is clear, however, that attempted. Preclinical data, as reported by Cook et a!. (see complex interactions between the drugs can have a significant above) suggest that the interaction between paclitaxel and cy- impact on toxicity. and that these effects can occur when pacli- cbophosphamide is due to intrinsic effects of the drugs on cell taxel is infused over 3 h. It remains uncertain whether these cycle progression rather than on pharmacokinetics. This is con- differences in toxicity will be reflected in differences in activity gruent with the observation that cycbophosphamide is not a against breast cancer, and this possibility is currently being target of P-glycoprotein-mediated biliary excretion. In the cur- tested in clinical trials. rent study, the impact of drug sequencing on hematological toxicity was evaluated in patients treated with cyclophospha- ACKNOWLEDGMENTS mide and paclitaxeb administered as a 3-h infusion. The hema- We thank Susan B. Kiraly for technical expertise. The excellent tobogical toxicity of therapy was again observed to be sequence nursing care provided by the nurses of the Johns Hopkins Oncology specific with this briefer infusion duration. Both neutrophil and Center is gratefully acknowledged. platelet nadir counts, expressed as a proportion of pretreatment values, were lower in courses in which pacbitaxel was administered first. These effects are similar to those observed in the REFERENCES prior study of 24-h paclitaxel with cycbophosphamide. The I. Reichman, B. S., Seidman, A. D., Crown, J. P. A., Heeban, R., Hakcs, phamacokinetic analysis in the current report is very limited T. B., Lebwohl, D. E., Gilewski, T. A., Surbone, A., Curie. V.. Hudis, C. A., Yae, T. J., Klecker, R.. Jamis-Dow, C., Collins, J., Quinlivan, S., and has only focused on the parent compounds cyclophospha- Berkery, R., Toomasi, F., Canetta, R., Fisherman, J.. Arbuck, S., and mide and paclitaxel. AUC of paclitaxel could only be analyzed Norton, L. Paclitaxel and recombinant human granubocyte colony-stim- in four patients with both sequences of drug administration, ubating factor as initial chemotherapy for metastatic breast cancer. because in several patients, the 24-h sample was not drawn or J. Clin. Oncob., 11: 1943-1951, 1993. was zero. Accordingly, because of the small numbers analyzed. 2. Abrams. J. S., Vena, D. A., Babtz, J., Adams, J.. Montebbo, M., the available data from this study do not rule out the possibility Christian, M., Onetto, N., Sesmond-Hellmann, S., Canetta, R., Fried- man, M. A., and Arbuck, S. G. Pacbitaxel activity in heavily pretreated of a pharmacokinetic interaction between paclitaxel and cyclo- breast cancer: a National Cancer Institute treatment referral center trial. phosphamide. J. Clin. Oncob., 13: 2056-2065, 1995. Why is sequence-specific toxicity observed with both 3- 3. Seidman, A. D., Reichman, B. S., Crown, J. P. A., Yae, T-J., Cume, and 24-h paclitaxel in combination with cycbophosphamide, but V., Hakes, T. B., Hudis, C. A., Gilewski. T. A.. Baselga. J., Forsythe, P.. only with the 24-h paclitaxel in the paclitaxel/doxorubicin corn- Lepore. J.. Marks. L., Fain, K., Souhrade, M.. Onetto, N., Arbuck, S., and Norton, L. Paclitaxeb as second and subsequent therapy for meta- bination? The answer probably lies with the different causes of static breast cancer: activity independent of prior anthracycline re- sequence-specific toxicity for these doublets. The available cv- sponse. J. Cbin. Oncol., 13: 1152-1159, 1995. idence suggests that for the paclitaxel/cycbophosphamide dou- 4. Sledge, G. W., Neuberg, D., Ingle, J., Martino, S.. and Wood, W. blet, sequence-specific interactions are not due to alterations in Phase III trial of doxorubicin (A) versus paclitaxel (T) versus doxoru- drug disposition, but to effects on cell cycle progression of bicin + paclitaxel (A + T) as first-line therapy for metastatic breast cancer (MBC): an intergroup trial. Proc. Am. Soc. Cbin. Oncol.. 16: 2. target tissues (18). Initial administration of cycbophosphamide 1997. delays cell cycle progression into G,-M, phase. thus reducing 5. Gelmon, K. A., O’Reilly, S. E., Tolcher, A. W., Campbell. C.. Bryce, cytotoxicity due to paclitaxeb and ameliorating hematobogical C., Ragaz, J.. Coppin, C., Plenderleith, I. H., Ayers, D., McDermott, B., toxicity. This effect is due to the initial administration of cycbo- Nakashima, L., Healey, D., and Onetto, N. Phase I/Il trial of biweekly phosphamide and occurs independent of whether paclitaxel is paclitaxeb and cisplatin in the treatment of metastatic breast cancer. subsequently administered over a 3- or 24-h infusion. However, J. Clin. Oncol., 14: 1185-1191, 1996. the mechanism of sequence-specific toxicity is quite different 6. Sparano. J. A., Neuberg, D., Glick, J. H., Robert, N. J., Goldstein. L. J., Sledge. G. W., and Wood, W. Phase II trial of biweekly paclitaxel when paclitaxel is administered with doxorubicin. For this com- and cisplatin in advanced breast carcinoma: an Eastern Cooperative bination, the evidence from the studies of Holmes and of Gianni Oncology Group study. J. Clin. Oncol.. 15: 1880-1884, 1997. suggests that paclitaxel reduces the clearance of doxorubicin, 7. Wasserheit, C.. Frazien, A.. Oratz, R., Sorich, J., and Downey, A., resulting in increased toxicity when paclitaxel as a 24-h infusion Hochster, H., Chachoua, A., Wernz, J., Zebeniuch-Jacquotte. A., Bbum, is administered first. Gianni et a!. did not observe clinical R., and Speyer, J. Phase II trial of paclitaxel and cisplatin in women with evidence of sequence-dependent effects on toxicity in their advanced breast cancer: an active regimen with limiting neurotoxicity. J. Clin. Oncol.. 14: 1993-1999, 1996. study of 3-h paclitaxel and doxorubicin. Their pharmacological 8. Tobcher, A. W., Cowan, K. H., Noone, M. H., Denicoff, A. M., studies, however, do indicate that the initial administration of Kohler, D. R., Goldspiel, B. R., Barnes, C. S., McCabe, M., Gossard, paclitaxel over 3 h can interfere with the disposition of subse- M. R., Zujewski, J., and O’Shaughnessy, J. A. Phase I study of pacbi- quently administered doxorubicin as well as its metabolites. taxel in combination with cycbophosphamide and granulocyte colony-

stimulating factor in metastatic breast cancer patients. J. Clin. Oncol., 13. Gianni, L., Vigan#{246},L., Locatelli, A., Capri, G., Giani, A., Tarenzi, 14: 95-102, 1996. E., and Bonadonna, G. Human pharmacokinetic characterization and in 9. Fennelly, D., Schneider, J., Spriggs, D., Bengala, C., Hakes, T., vitro study of the interaction between doxorubicin and paclitaxel in Reich, L., Barakat, R., Curtin, J., Moore, M. A. S., Hoskins, W., Norton, patients with breast cancer. J. Clin. Oncol., 15: 1906-1915, 1997. L., and Crown, J. Dose escalation of paclitaxel with high-dose cyclo- 14. Chen, T-L., Passos-Coclho, J-L., Noe, D. A., Kennedy, M. J., phosphamide. with analysis of progenitor cell mobilization and hema- Black, K. C., Colvin, 0. M., and Grochow, L. B. Nonlinear pharmaco- tobogic support of advanced ovarian cancer patients receiving rapidly kinetics of cycbophosphamide in patients with metastatic breast cancer sequenced high-dose carboplatin/cyclophosphamide courses. J. Clin. receiving high-dose chemotherapy followed by autologous bone marrow Oncol., 13: 1160-1166, 1995. transplant. Cancer Res., 55: 810-816, 1995. 10. Kennedy, M. J., Zahurak, M. L., Donehower, R. C., Noe, D. A., 15. Rowinsky, E. K., Gilbert, M., McGuire, W. P., Noc, D. A., Gro- Sartorius, S., Chen, T-L., Bowling, K., and Rowinsky, E. K. Phase I and chow, L. B., Forastiere, A. A., Ettinger, D. S.. Lubejko, B. G.. Clark. B., pharmacologic study of sequences of paclitaxel and cyclophosphamide Sartorius, S. E., Cornblath, D. R., Hendricks, C. B., and Donehower, supported by granulocyte colony stimulating factor in women with R. C. Sequences of Taxol and cisplatin: a Phase I and pharmacologic study. J. Clin. Oncol., 9: 1692-1703, 1991. previously treated metastatic breast cancer. J. Clin. Oncob., 14: 783-79 1, 1996. 16. LeBlanc, 0. A., Sundseth, S. S., Weber, G. F., and Waxman, D. J. Platinum anticancer drugs modulate p.450 mRNA levels and differen- 1 1. Holmes, F. A., Madden, T., Newman, R. A., Valero, V., Theriault, tially alter hepatic drug and steroid hormone metabolism in male and R. L., Fraschini, G., Walters, R. S., Booser, D. J., Buzdar, A. U., Willey, female rats. Cancer Res., 54: 540-547, 1992. J., and Hortobagyi, G. N. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a Phase I study of pacbitaxel and 17. Rowinsky, E. K., Citardi, M. J., Noc, D. A., and Donehower, R. C. doxorubicin inpatients with metastatic breast cancer. J. Clin. Oncol., 14: Sequence-dependent cytotoxic effects due to combinations of cisplatin 2713-2721. 1996. and the antimicrotubule agents Taxol and vincristine J. Cancer Res. Clin. Oncol., 119: 727-733, 1993. 12. Gianni, L., Munzone, E., Capri, G., Fulfaro, F., Tarenzi, E., Villani, F.. Spreadfico, C., Laffranchi, A., Caraceni, A., Martini, C., Stefanelli, 18. Liebmann, J. E., Fisher, J., Teague, D., and Cook, J. A. Sequence M., Vabagussa, P., and Bonadonna, G. Paclitaxel by 3-hour infusion in dependence of paclitaxel (Taxol) combined with cisplatin or alkylators combination with bobus doxorubicin in women with untreated metastatic in human cancer cells. Oncol. Res., 6: 25-31, 1994. breast cancer: high antitumor efficacy and cardiac effects in a dose- 19. Gehl, J., Boesgaard, M.. Paaske, T., Vittrup Jenson, B., and finding and sequence-finding study. J. Clin. Oncol., 13: 2688-2699, Dombcrnowsky, P. Combined doxorubicin and pacbitaxel in advanced 1995. breast cancer: effective and cardiotoxic. Ann. Oncol., 7: 687-693, 1996.

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M J Kennedy, M L Zahurak, R C Donehower, et al.

Clin Cancer Res 1998;4:349-356.

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