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Paclitaxel Couplets With Cyclophosphamide or Cisplatin in Metastatic Breast Cancer
Anthony W. Tolcher
Determining active combinations containing paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to treat metastatic breast cancer has been the focus of recent clinical development. Paclitaxel combined with eithe r cyclophosphamide or cisplatin has several potential advantages: cisplatin and cyclophosphamide are active single agents against previously untreated meta· static breast cancer, colony-stimulating factors can modulate overlapping toxicities like myelosuppression, and no mechanisms of cross-resistance between paclitaxel and these agents are yet known. Major questions include the optimal schedule of administration and the sequence dependence of toxicities with these combinat ions. Paclitaxel schedules with cisplatin include either two dose levels using the 24.hour infusion o r a novel biweekly l·hour infusion. The sequence in the three available studies was paclitaxel followed by cisplatin. Hematologic toxicities were dose limiting with the biweekly and low-dose 24-hour pacl itaxel/cisplatin com· binations; with granulocyte colony-stimulating factor, neurotoxicity became a prominent cumulative toxicity of the high-dose paclit axel/cisplatin combination. Re· sponse rates in the first-line treatment of metastatic breast cancer ranged from 49% to 85%. In the three completed studies with cyclophosphamide, paclitaxel has been administered over e ithe r 72, 24, or 3 hours. Paclitaxel followed by cyclophosphamide had greater he matologic toxicity than the opposite schedule or concurrent administration. Pharmacokinetic factors do not see m to account for this sequence-dependent toxic· ity. As expected, dose-limiting toxicity in all studies has been hematologic. However, granulocyte colony-stimulating factor has ameliorated myelosuppression and allowed considerable dose escalation of cyclophospha· mide. This combination has demonstrated activity in previously treated patients with m etastatic breast cancer, including the anthracycline-refractory subpopula· t ion that will be reviewed. Copyright © 1996 by W.B. Saunders Company
PACUTAXEL (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an active single
agent in the treatment of metastatic breast cancer with reported response rates up to 62% in first-line therapy and up to 30% in extensively pretreated patients. H The logical progression for the clinical development of this agent includes combination studies of paclitaxel and other drugs that possess proven activity against breast cancer. Cyclophosphamide and cisplatin are two such agents: both have proven activity in rhe treatment of breast cancer and neither has any known mechanisms of cross-resistance with paclitaxel.
Seminors in Oncology, Vol 23. No I. Suppl I (February). 1996: pp 37-43
A lthough seldom used in treating breast cancer, cisplatin is active, with single-agent response rates of 47% to 54%5
·6 as first-line therapy for metastatic
breast cancer. A paclitaxcl/cisplatin combination has several potential advantages: patients generally have nor received adjuvanr cisplatin and, with the exception of peripheral neuropathy, overlapping toxicities for the two drugs are uncommon and are not usually hematologic.
Cyclophosphamide is the standard alkylating agent used in both the adjuvant and palliative treatment of breast cancer. Considerable cl inical experience has been ga ined from its past 30 years of use against this disease. Single-agent activity, reported from the earliest clinica l trials, ranged from 25% to 45% in patients with advanced disease.7
'8 Myelosup
pression, particularly neutropenia, is the major overlapping toxicity of cyclophosphamide and paclitaxel; this can now be diminished with the use of colony-stimulating factors.
Combining two chemotherapy agems with distinctly different mechanisms of action and characteristics into a couplet represents a challenge. The optimal dose and schedule of both agents in combination needs to be determined, which requires balancing the combined, and at times unexpected, clinical toxicities against the need for maximum cytotoxicity from each agent. Similarly, the optimal sequence of administration may need tO be determined. Potential sequence-dependent toxicities and cytotoxic activity have been associated with other chemotherapy combinations in clinical oncology.9·t0 If sequence dependence is clinically significant, phase I evaluation must determine whether pharmacokinetic or biologic factors are responsible.
PACLITAXEL/CISPLATIN COUPLET
Preclinical and Clinical Sequence Rationale
Paclitaxel/cisplatin combinations have demonstrated additive and synergistic cytotoxicity in
From rhe British Columbia Cancer Agency, Uni••ersity of British Columbia, Vancouver, BC, Canada.
Addre.1.1 reprint r~quests co Anthony W. Tolcher, MD , FRCPC, Bricish Columbia Cancer Agi'llC)', University of British Columbia, 600 \~ 10th Ave, Vancouver, BC V7C IY4 , Canada.
Copyright© 1996 by W .B. Saunders Company 0093-7754196/2301-0113$05.0010
37
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Table I. Paclitaxel/Clsplatin In Breast Cancer:
Dose and Schedules
Investigator Dose (mg/m'}nnfusioo Length
Low dose BU Paclicaxel I 35121 hr
Cfsplatin 75
High dose NYU Paclicaxel 200121 hr
Cisplatin 75
I G·CSF
Biweekly BCCA Paclicaxel 90/3 hr
Cispladn 60
Abbreviations: BU. Brown University; NYU. New York Uni-
versity: BCCA. British Columbia Cancer Agency.
some cell lines in vitro.it.i i Sequence analysis of this combination has been studied in vitro by many investigators. n·14 Paclitaxel followed by cisplatin appears to produce maximal cytotoxicity in many cell lines, whereas the reverse sequence has demonstrated antagonism_ l).l 4 Paclitaxel is a cell cycle phase-specific agent, and perturbations of the cell cycle by cisplatin have been hypothesized as a biologic explanation for this sequence-dependent antagonism.14·1 5
In an elegant phase I and pharmacokinetic study, Rowinsky et al examined the sequence-dependent clinical toxicities of the paclitaxel/cisplarin combination. In this study, cisplatin administered before a 24-hour paclitaxel infusion was associated with significantly increased granu locyte toxicity compared with the reverse sequence of paclitaxel fol lowed by c isplatin .16 Pharmacokinetic analysis of these sequences suggested that administering cisplatin first significantly delayed clearance of the myelosuppressive agent paclitaxel compared with the alternate sequence and that the delayed clearance was responsible for the increased granulocyre toxicity. Based on this compelling laboratory and clinical evidence, paclitaxel followed by cisplatin has become the standard sequence of administration in clinical investigation.
Clinical Scudies
Interim results from three phase 11 studies are available for analysis. Table 1 lists the doses and schedules, which are illustrated in Fig 1.
New York University Medical Cencer trial. Wasserheit et al studied paclitaxd 200 mg/m2 by 24-hour infusion followed immediately by cisplatin
ANTHONY W. TOLCHER
P200mg/m2 ,
G-CSF 22 NYU - ---------------+- -C 75mg/m2
t t , 22 BU P135mg/m2 - -C7Smgtm2 t t , 15 BCCA P90mg/m2 • • C60mg/m2 t t
Fig I. The schedule and sequence of the three phase II stud
ies of paclitaxel (P) in combination with cisplatin (C). N YU,
New York University; BU, Brown University; BCCA, British
Columbia Cancer Agency; G·CSF, granulocyt e colony-stimulatlng factor.
75 mg/m2 every 3 weeks (C. Wasserheit, MD, principal investigator, unpublished data, July 1995). Based on previous clinical trial experience with paclitaxel in ovarian cancer and, as a single agent, in breast cancer, neutropenia was anticipated to
be dose limiting. Thus, granulocyte colony-stimulating facror (G-CSF) was administered to all patients following chemotherapy.
Open to women with metastatic breast cancer the study has treated 44 patients. Prior adjuvan; chemotherapy was permitred and three patients had received prior chemotherapy for metastatic disease. Twenty-three patients had prior adjuvanr chemotherapy and 19 had received anchracyclines. Tahle 2 summarizes patient characteristics.
Although G-CSF modified hematologic toxicity, instances of febrile neutropenia and one toxic death were recorded. Neuropathy was a prominent nonhemaLOlogic and dose-limitingcumulacive toxicity in chis study. Peripheral neuropathy grade 2 o r greater occurred in 88% of patients over a median of five cycles. Periphera l neuropathy was dose limiting in the phase I study of pacliraxel/cisplatin and G-CSF due to rhe G-CSF-relaced ameliorat ion of the usually dose-limiting neutropenia and
Table 2. PaclitaxeVClsplatln in Breast Cancer:
Patient Characteristics
NYU BU BCCA
No. of patients 44 16 29 Median age (yr) 49 53 47
Median no. of disease siles 2 2 2
No. of patients with prior chemotherapy 23 13 27 Anthracycline containing 19 12 23
Abbreviations- NYU. New York University: BU. Brown Uni-
versity; BCCA, British Columbia Cancer Agency.
I
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PACUTAXEL W ITH CJSPlATIN OR CYCLOPHOSPHAMIDE
the consequent increased dose delivery of these two neurotoxic agents. 17
This schedule of paclitaxel/cisplatin at these doses was active, with five complete responses (CRs) and 15 partial responses (PRs) of 41 evaluable patients, for an overall response rate of 49%.
Brown University Hospitals study. Browne and colleagues initiated a phase II study of paclitaxel 135 mg/m2 by 24-hour infusion followed immediately by cisplatin 75 mg/m2 in women with metastatic breast cancer (M. Browne, MD, principal investigator, unpublished data, July 1995). The doses and schedule were derived from phase I studies in ovarian cancer. Granulocyte colony-stimulating factor was used only as indicated clinically. Only patients with untreated metastatic breast cancer were eligible, although prior adjuvant chemotherapy was allowed. Sixteen patients have been entered to date, 13 of whom had received prior adjuvant chemotherapy.Twelve patients' adjuvant therapy contained anthracycline. Table 2 summarizes patient characteristics. The largely hematologic clinical toxicities have been tolerable. Nonhematologic toxicities have included alopecia, rash, nausea and vomiting, and fatigue, a ll which were anticipated in a cisplatin-containing regimen. Peripheral neuropathy has been tolerable and consistent in frequency with the incidence reported in ovarian cancer trials.
Two CRs and six PRs have been observed with this pacliraxel/cisplarin dose and schedule in 15 patients evaluable for response, for an interim response rare of 53%. This level of activity is encouraging considering that most of the women had received anthracyclines.
British Columbia Cancer Agency trial. This phase I/II study (K. Gelmon, MD, principal investigator, unpublished data, Ju ly 1995) was planned to deliver biweekly pacliraxel by 3-hour infusion followed immediately by cisplatin. The biweekly schedule of paclitaxel combined wirh cisplatin was based on the results of the European and Canadian study of single-agent paclitaxel in refractory ovarian carcinoma, which compared the 3- and 24-hour infusion schedules at dose levels of 135 and 175 mg/m2•
18 In this comparative study, the majority of patients who received paclitaxel by the 3-hour infusion at both dose levels had neutrophil recovery to greater than 1,500/ µL by day 15, suggesting that biweekly administration of a 3-hour paclitaxel infusion was possible. The paclitaxel/
39
cisplatin combination in a biweekly schedule was hypothesized to be tolerable due to the modest myelosuppression associated with cisplatin. The schedules and sequence of the agents are demonstrated in Fig l.
The starting dose level in the phase I portion of the study in metastatic breast cancer cou ld not be escalated, however, because the patients' granulocyte counts had not recovered to greater than 750/µL by day 14. The phase !I dose level was thus determined to be paclitaxel 90 mg/m2 by 3-hour infusion followed by cisplatin 60 mg/m2 administered every 2 weeks. The use of G-CSF was not permitted. The study was open to patients with chemotherapy-naive metastatic breast cancer, although prior adjuvant chemotherapy was permissible. Twenty-nine patients were entered, 27 of whom were evaluable for response in the phase II portion. Twenty-seven patients had received prior adjuvant chemotherapy, 23 with anthracyclinecontaining regimens. Table 2 summarizes patient characteristics.
Hematologic toxicity was common, although brief grade 4 neutropenia, median 2 days' duration (range, 0 to 7), was observed in only 34% of patients. One patient was admitted for febrile neutropenia and bacteremia was documented. During the septic episode, which responded to antibiotic management, this same patient experienced the only case of grade 4 thrombocytopenia.
Mild nonhematologic toxicities were common. Alopecia, nausea and vomiting, and fatigue, although frequent with this combination, were generally not dose limiting. Arthralgia and myalgia occurred in 41 % of patients but were dose limiting in only one. Mild sensory changes were observed, but only one patient experienced grade 3/4 peripheral neuropathy with this schedu le.
This combination and schedule have been associated with a provocative level of activity. Three patients have achieved CRs and 20 achieved PRs, for an overall response rate of 85% in a patient population exposed to prior adjuvant, mostly anthracycline-based, chemotherapy. A confirmatory phase II study is presently being performed.
Summary of Paclitaxel/Cisplatin Couplet Trials
The pacliraxel/cisplarin combination has demonstrated an encouraging level of antitumor activity in women with metastatic breast cancer and has an acceptable level of toxicity. These response
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rates occurred despite previous adjuvant chemotherapy, in many cases with anchracyclines. The use of G-CSF permits higher doses of the drugs to be delivered, but peripheral neuropathy then becomes a prominent dose-limiting toxicity.
The differenc response rates in these phase II trials should be interpreted with caution. Results with the biweekly schedule generate several ques· tions. Is the antitumor activity schedule dependent? A phase I/II study of biweekly paclitaxel alone is presently under way to determine whether frequent dosing of the 3-hour paclitaxel infusion alone is associated with a high level of activity. An alternate explanation for the high level of anti· tumor response includes the different cisplatin dose intensity. Nonetheless, the actual difference in cisplatin dose intensity between the studies is quite small (30 v 25 mg/m2/wk). The biweekly schedule also allowed treatment on day 15 if the granulocyte count was at least 750/µL and the platelets had recovered to at least 75,000/ µL. Given this same level of hematologic recovery, would a similar level of activity be observed with the other regimens if treatment was also initiated earlier than day 21? It is hoped that some of these questions will be answered should results of the confirmatory study support the biweekly paclitaxel/ cisplatin schedule.
PACLIT AXEU CYCLOPHOSPHAMIDE COUPLET
Preclinical RatioTlllle
Combinations of paclitaxel and alkylating agents have demonstrated additive but also antagonistic cyrotoxicity in vitro. Preclinical pacl itaxel/ cyclophosphamide sequence data were not available before phase l tria ls of this combination began. Recently, however, in vitro results with some cell lines have demonstrated that the sequence of an alkylating agent before paclitaxel is associated with reduced cell kill compared with the reverse sequence, much like the in vi tro results with the cisplatin/paclitaxel combination. 14 This finding was not universal, however; other cell lines did not demonstrate sequence dependence. 14
•19
Phase I Clinical Studies
Results of three phase l stud ies are mature. The dose and schedules used in each of these studies
ANTHONY W. TOLCHER
are summarized in Table 3 and illustrated in Fig 2.
Johns Hopkins Oncology Center trial. Kennedy et al initiated a phase I study of paclitaxel/cyclophosphamide with G-CSF in patients with anthracycline-refractory metastatic breast carcinoma. 1
'.I
Table 4 briefly summarizes the patient characteristics.
Paclitaxel was administered by a 24-hour infusion with intravenous bolus cyclophosphamide (Fig 2). The elegant clinical trial design incorporated sequence analysis of toxicity for al l dose levels when possible. All patients received both drug administration sequences. The use of G-CSF permitted considerable dose escalation of this combination, with nine dose levels (paclitaxel l35 to 200 mg/m2 and cyclophosphamide 750 to 2,000 mg/m2
). Dose-limiting toxicity was neutropenia (one patient) and typhlitis (one patient) in two of four patients. The ma,'<imum tolerated dose was considered to be paclitaxel 200 mg/m2 and cyclophosphamide 1,600 mg/m2 while the recommended doses for phase II investigation were 200 and 1,250 mg/m2
, respectively. Dose-limiting thrombocytopenia was uncommon, occurring in on ly two patients. Myalgias and neuropachy were uncommon nonhemarologic dose-limiting toxicities, occurring in only five patients. The dose-limiting toxicity of typhlitis with this combination and schedule had been observed in a phase l study of the paclitaxel/doxorubicin combination and
Table 3. Padit:axel/Cyclophosphamide in Breast Canc,er
Dose (mg/m'}/lnfusion Length
NCI
Pacliaxel 160172 hr
Cyclophosphamide 2,700 (divided dose)
G-CSF
JHOC
Pacliaxel 200124 hr
Cyclophosphamide 1,600
G-CSF
Bell inzona
Pacliaxel 20013 hr
Cyclophosphamide 1,250
Abbreviations: NCI, National Cancer Institute: JHOC, Johns
Hopkins Oncology Center. Bellinzona, Ospedale San Giovanni.
Bellinzona, Switzerland.
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PACLITAXEL WITH CISPLATIN OR CYCLOPHOSPHAMIDE
may represent a unique, albeit an uncommon, toxicity for paclitaxel combinations.20
Sequence-dependent toxicities were observed. Paclitaxel fo llowed by cyclophosphamide was associated with greater neutrophil and platelet tox icity compared with the alternate sequence, as confirmed by the rates of admission for febrile neutropenia (27% v 11 %, respectively). The pharmacology of these agents did not differ significantly with either sequence. Therefore, and in contrast to the paclitaxel/cisplatin data, a ltered pharmacokinetics does not explain the observed d ifference in hematologic toxicity, and a biologic explanation for sequence-dependent cytotoxicity may apply.
ln this phase I study of heavily pretreated, doxorubicin-refractory patients, the overall response rate of 28% demonstrated encouraging activity. Phase 11 data will clarify the true activity of this schedule and combination .
Currently, the Johns Hopkins group is evaluating the same combination using the 3-hour paclitaxel infusion schedu le with G-CSF.
Ospedale San Giovanni, Bellinzona, phase I trial. Sessa and Pagani (0. Pagani, MD, principa l investigator, unpublished data, July 1995) and their colleagues initiated a phase I study of pacliraxel by 3-hour infusion combined with cyclophosphamide. The characteristics of the 43 patients are summarized in Table 4. Dose levels of paclitaxel 175 to
200 mg/m2 and cyclophosphamide 750 to 1,250 mg/m2 without G-CSF were explored. Further dose escalation ro 1,750 mg/m2 cyclophosphamide was possible with the use of G-CSF. Grade 4 neutropenia for greater than 7 days limited further dose escalation. Nonhemarologic toxicities were nor dose limiting, and ryphlit is was not observed. Sequence-dependent toxicity analysis is planned but nor yet avai lable. However, caution is warranted
1 2 3 NCI P 160 mgfm2 72 hr G-CSF
C 2,700 mg/m2 t ---------.-
t t
P 200 mg/m2 24 hr 1 G-CSF JHOC --------------·
C 1,600 mg/m2
t
Bellinzona P 200 mgtm2 3 hr • G-CSF -------------· C 1,250 mg/m2
t
Fig 2. T he schedule and sequence of the three phase I studies of paclitaxel (P) in combination with cyclophosphamide (C). N CI, N ational Cancer Institute; )HOC, Johns H opkins Oncology Cente,r.
41
Table 4. Paclitaxel/Cyclophosphamlde In Breast
Cancer: Patient Characterist ics
NCI JHOC Bell
No. of patients 55 37 43
Median age (yr) 45 so 5 1 Median no. of disease sites 2 2 2
No. of patients with prior chemotherapy 53 37 36
Median no. o f prior chemotherapy
regimens 2 2 -Anthracycline-containing 47 37 26
Anthracycline-resistant 19 29 14
in interpreting the existence of sequence effects for the shorter paclitaxel infusion schedule. Sequence dependence may be less apparent with concurrent or near-concurrent administration of paclitaxel and cyclophosphamide. With such schedu les, the actual toxicities observed may reflect not the order of administration but, rather, the relatively different pharmacokinetic half-lives of the two drugs and the sequence that this engenders.
Preliminary activity data demonstrate objective responses including CRs at multiple dose levels in th is phase I study.
Medicine Branch, National Cancer lnscicute phase I study. This phase I study (A. T olcher, MD, principal investigator, unpublished data, July 1995) was initiated to determine the tolerability of administering paclitaxel by 72-hour continuous infusion (CIVI) in combination with high-dose cyclophosphamide and G-CSF in the ambulatory setting. In vitro data suggest that paclitaxel is a cell cycle phase-specific cytotoxic agent. Cytotoxicity in cell lines in vitro reaches a plateau at a threshold paclitaxel concentration beyond which increased pacliraxel concentrations do nor yield greater cell kill; however, prolonging the duration of drug exposure over multiple drug concentrations to a maximum of 72 hours has increased cell kill further in some assays.2
1.22 In the clinical setting,
prolonged infusions of paclitaxel can theoretica lly increase the number of cancer cells exposed to pacliraxel during the G 2/M phase of the cell cycle, in which cells are most vulnerable to this agent's cytotoxic effects. Alkylating agents like cyclophosphamide are associated with steep dose-response relationships in vitro and considerable dose escalation of this agent can be achieved clinically with the use of G-CSF. Divided-dose cyclophosphamide
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theoretically permits ambulatory administration of high doses of this agent, while reducing urotoxicity, emesis, and the risk of cardiotoxicity. The schedule of administration for this study appears in Fig 2. This phase I study included 55 patients, 54 of whom are evaluable for toxicity. The patient characteristics are summarized in Table 4. Fortyseven patients had already received doxorubicin and 52 had received cyclophosphamide. The study was open to patients with metastatic breast cancer who had received up to two prior chemotherapy regimens (one adjuvant, one for metastasis) and the median number of prior regimens was two. Dose escalation was completed over 10 levels from a starting dose of paclitaxel 135 mg/m1 C IVl and cyclophosphamide 600 mg/m2 to paclitaxel 160 mg/m2 C IVI and cyclophosphamide 3,300 mg/m2
•
Dose-limiting toxicity was reached at the latter dose level, with two patients experiencing grade 4 neutropenia for more than 5 days and one patient experiencing both this level of grade 4 neutropenia and platelets less than 20,000/ µL. The maximum tolerated dose was therefore paclitaxel 160 mg/m1
C IVI over 72 hours and cyclophosphamide 2,700 mg/m1 in three divided doses. Febrile neutropenia commonly complicated this dose-intense regimen, causing at least one hospitalization in 86% of patients; one patient died of a septic complication.
Dose-limiting nonhematologic toxicities were uncommon. Diarrhea was a cumu lative toxicity, occurring in six patients, and may have been related to the use of broad-spectrum antibiotics for febrile neutropenia; in three patients with Clostridium difficile, toxin was detected. Six patients developed gross hematuria requiring dose reduction and increased hydration. In those patients whose hematuria recurred, oral mesna prevented further bleeding and permitted ambulatory treatment to be continued. Despite a premedication regimen of dexamethasone, diphenhydramine, and cimetidine, five patients experienced grade 1 or 2 acute hypersensitivity reactions to paclitaxel. Four of these patients cou ld be re-treated; the o ther refused further therapy. No episodes of typhlitis were observed with this paclitaxel/cyclophosphamide schedule.
A pilot study of the sequence of paclitaxel by 72-hour CIVI followed by a single bolus dose of cyclophosphamide was initiated to determine whether the sequential schedule was tolerable and comparable with the concurrenc schedule (A.
ANTHONY W. TOLCHER
Tolcher, MD, principal investigator, unpublished data, July 1995). Dose-limiting toxicity was observed in three patients at the first dose level of paclitaxel 160 mg/m2 C IVJ followed by cyclophosphamide 1,600 mg/m2 and G-CSF. The sequential schedule was associated with intolerable hematologic and gastrointestinal toxicity (grade 4 mucositis), despite a cyclophosphamide dose that was only 60% of the previous maximum tolerated dose. These results suggested that the sequence of paclitaxel fo llowed by cyclophosphamide was more toxic than the concurrent schedule of paclitaxel and divided-dose cyclophosphamide. Since data from Kennedy at al 19 demonstrated a similar finding and no alterations in pharmacology were observed with these two agencs, one can hypothesize that a perturbation of paclitaxel's cell cycle-dependent cytotoxicity may occur to the hematologic and gastrointestinal progenitor cells with the concurrent schedule, which is not seen when paclitaxel is fo llowed by cyclophosphamide. The preclinical data suggest that this reduction in normal tissue toxicity may result from a reduction in the number of progenitor cells in the G 2/M phase, where paclitaxel exerts its greatest cytotoxic ity. 14
The question remains whether the schedu le and sequence of cyclophosphamide also a lter rumor responsiveness to this couplet.
In this phase I study using a spectrum of dose levels, the responses of 44 patients with measurable disease were assessed: 23 patients achieved a PR and one patient a CR, for an overall response rate of 55%. In the doxorubicin-refractory subset, seven (54%) of 13 patients evaluable for response obtained an objective response (one CR and six PRs). In this heavily pretreated popu lation, this response rate is encouraging.
Summary of Pacliraxel/Cyclophosphamide Couplet Trials
In these three phase I studies, the paclitaxel/ cyclophosphamide combination has demonstrated both an acceptable level of toxicity and encouraging anritumor activity in metastatic breast cancer patients previously treated with doxorubicin and/ or cyclophosphamide. Sequence analysis suggests that paclitaxel followed by cyclophosphamide is associated with greater hematologic toxicity compared with either the opposite sequence or with concurrent adm inistration. Based on the Johns Hopkins data, 19 altered pharmacokinetics do not
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PACLITAXEL WITH CISPLATIN OR CYCLOPHOSPHAMIDE
cause this sequence dependence. Whether the administration sequence of paclitaxel/cyclophosphamide wi ll affect amitumor activity, as it does normal organ toxicity, has yet to be determined. Phase 11 assessments of the role of this couplet, and the schedule and sequence effects, are necessary to determine the place of this combination in the treatment of both early and advanced breast cancer.
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14. Liebmann]£, Fisher J, Teaugue D. et al: Sequence dependence of paclitaxel (Taxol) combined with cisplatin or alkylators in human cancer cells. Oneal Res 6:25-31, 1994
15. Vanhoefer U, Hamrick A, Wilke H, er al: Scheduledependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer 31A:92-97, 1995
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17. Rowinsky EK. Chaudhry V, Forastiere AA, et al: Phase I and pham1acokinetic srudy of paclitaxel and cisplatin with granulocyre colony-stimulating factor: Neuromuscular toxicity is dose-limiting. J C lin Oncol 11:2010-2020. 1993
18. Eisenhauer EA, ten Bokkel Huinink WW, Swenerron KD, et al: Europc.an-Omadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654-2666, 1994
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21. Lopes NM, Adams EG, Pitts TW. ct al: Cell kill kinetics and cell cycle effects of T axol on human and hamster ovarian cell lines. C',ancer Chcmother Pharmacol .32:235-242, 1993
22. Liebmann JE. Cook JA, Lipschultz C, et al: Cytotoxic studies of paclitaxcl (T axol) in human tumour cell lines. Br J Cancer 68:1104-1109, 1993
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