(cid:22)(cid:26)(cid:22)373
`
`Paclitaxel in Breast Cancer
`
`EDITH A. PEREZ
`
`Mayo Foundation and Mayo Clinic Jacksonville, Jacksonville, Florida, USA
`
`
`
`Kay Words. Paclitaxel ~Antineoplastic agents ~Breas! neoplasms ' Clinical trials
`
`ABSTRACT
`
`Paclitaxel has emerged as an important agent in the
`of paclitaxel and doxorubicin has been the most exten-
`treatment of breast cancer. The efficacy and tolerability of
`sively studied, with the role of this regimen continuing to
`this agent, as well as its lack of cross-resistance with
`evolve. Other combination regimens that appear to hold
`substantial promise as first-line metastatic treatment
`anthracyclines, have spurred intensive clinical investiga-
`tion worldwide. Optimization of paclitaxel dose and sched-
`are paclitaxel with carboplatin and paclitaxel with
`trastuzumab (anti-HERZ antibody). The favorable
`uling and evaluation of the drug in combination regimens
`are a central focus of investigations. Recent clinical evi-
`results obtained in the metastatic setting have prompted
`dence suggests that optimal dose of single-agent paclitaxel
`phase II and phase III investigations of paclitaxel in the
`by 3-h infusion is 175 mg/m‘. Trials evaluating adminis-
`adjuvant and neoadjuvant settings. In the adjuvant set-
`tration schedule have not found either a 24-h or 96-h
`ting, a recent phase III study has indicated that the addi-
`infusion to be superior to a 3-h infusion. Weekly moderate-
`tion of sequential paclitaxel to standard therapy affords
`both disease-free and overall survival benefits.
`dose paclitaxel administration is also generating much
`interest, given the high relative dose intensity and dose
`Current investigations with paclitaxel will con-
`density delivered, yet very modest myelosuppression and
`tinue to optimize the role of this agent in the treatment
`manageable neurotoxicity observed.
`of early- and advanced-stage breast cancer, address-
`As first-line therapy in metastatic disease, multiple
`ing not only response rates but also survival and qual-
`studies have documented overall response rates in the
`ity-of-life issues. The use of paclitaxel on a weekly
`range of 30%—60%. As second-line or salvage single-
`schedule or with new therapeutic modalities, such as
`agent therapy in metastatic patients, paclitaxel generally
`monoclonal antibodies, is also receiving much atten-
`affords an overall response rate of 20%40%, even in
`tion. While it is clear that paclitaxel is a very active
`anthracycline—resistant patients.
`agent in the treatment of breast cancer, it is hoped
`that these innovative trials will further maximize the
`The novel mechanism of action and manageable tox-
`icity of paclitaxel has led to successful incorporation into
`potential of this agent in patients with breast cancer.
`
`combination chemotherapy regimens. The combination The Oncologist 1998;3.'373—389
`
`INTRODUCTION
`
`The role of paclitaxel is being investigated in settings
`ranging from first-line, second-line, and salvage therapy for
`metastatic disease, as well as adjuvant and neoadjuvant
`treatment. Paclitaxel’s place in combination chemotherapy,
`as well as optimal dosing and scheduling, are among the
`critical issues being addressed in clinical trials worldwide.
`A number of large-scale, randomized phase in clinical trials
`have been initiated, and recently several have had preliminary
`results reported.
`Paclitaxel is classified as a taxane, an antimicrotubulin
`agent with a unique mechanism of action and potent activity
`
`against several tumor types, including breast cancer. Unlike
`other antimicrotubulin agents, paclitaxel achieves its antim-
`mor effect by promoting tubulin dimerization and inhibiting
`depolymerization of the microtubules [1].
`Paclitaxel is active in the treatment of metastatic breast
`
`cancer as first-line therapy [2—4], as well as in heavily pre-
`treated patients [3, 5-7]. Especially encouraging is its activ-
`ity in anthracycline-resistant disease [7, 8]. Recognition of
`the activity of this agent in advanced breast cancer has led
`to its study in earlier stages of the disease. Several phase Ill
`randomized trials are evaluating the efficacy ofpaclitaxel in
`the adjuvant and neoadjuvant settings.
`
`Conespandence: Edith A. Perez, MD, Division ofHematology/Oncology. Mayo Clinic Jacksonville, 4500 San Pablo Road.
`Jacksonville. Florida 32224. USA. Telephone: 904-953-2000; Fax: 904—953-2315; e-mail: perez.edith@maya.edu Accepted
`for publication September 2, I998. GAlphaMed Press 1083- 7159/98/35.00f0
`
`
`
`1.10:‘05JOunDAONuotsanBKqfilo‘ssoadpouqupnsifio[muoamrfzduqLuogpopeolumoa
`
`
`
`
`
`The Oncologist 1998;31373-389
`
`% a...
`2060
`§__,____
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`IPR2017-00805
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`Genentech Exhibit 2030
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`

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`374
`
`Paclitaxel in Breast Cancer
`
`Paclitaxel use is generally associated with manageable
`toxicity. Neutropenia and peripheral neuropathy are common
`clinical side effects ofpaclitaxel [l 1. The most common dose-
`limiting toxicity of paclitaxel, neutropenia, is both dose- and
`schedule-dependent Severe neutropenia is typically of short
`duration and rarely associated with other hematologic toxici-
`ties. Cumulative peripheral neurotoxicity is typically mild and
`often reversible. Hypersensitivity reactions are almost com-
`pletely prevented by the use of a premedication regimen
`consisting of corticosteroids, cimetidine or ranitidine, and
`diphenhydramine.
`Paclitaxel infusion schedules of l h, 3 h, 24 h, and 96 h
`have been studied in the treatment of breast cancer patients.
`Because of its convenience in the outpatient setting, a 3-h
`infusion is currently the most widely used. Today, clinical
`studies are typically employing a 3-h infusion at a dose
`range of 135-250 mg/m2 every three weeks. Dosing and
`scheduling issues have been investigated in a number of
`clinical trials, summarized in Table l. The results of several
`recently reported trials have provided much insight into
`optimal dosing and scheduling [9-12]. This review will
`describe completed and ongoing clinical trials of paclitaxel
`in breast cancer. Promising avenues of further investigation
`will also be highlighted.
`
`METASTATIC BREAST CANCER
`
`Single-Agent Therapy
`Since chemotherapy in metastatic breast cancer patients
`remains palliative, both response and tolerability are important
`considerations in evaluating new agents. Paclitaxel has been
`shown to achieve comparatively high response rates with an
`acceptable toxicity profile.
`
`The single-agent activity of paclitaxel in metastatic breast
`cancer was established in seminal phase II studies. As fust- or
`second-line treatment, a 24—h infusion of 250 mg/m2 paclitaxel
`every 21 days displayed high levels of antitumor activity, with
`overall response rates of 56% and 62%, as reported by inves-
`tigators at the MD Anderson Cancer Center (MDACC) and the
`Memorial Sloan-Kettering Cancer Center (MSKCC), respec-
`tively [13, 14]. These studies provided the first evidence that
`paclitaxel was very active as single-agent therapy for metasta-
`tic breast cancer. Phase I studies have indicated that the maxi-
`
`mum tolerated dose ofpaclitaxel given by 24-h infusion every
`three weeks is 175-200 mg/m2 without G-CSF support and
`200-250 mg/m2 with G-CSF support [15, 16].
`
`Phase II Trials ofShort Infusion Schedules
`Following these early studies, the use of shorter infusion
`schedules of paclitaxel was investigated. Studies in ovarian
`cancer patients indicated that a 3-h infusion of paclitaxel every
`three weeks was safe and was associated with significantly less
`myelosuppression than a 24 h-infusion [17]. The shorter
`infusion schedule also allowed for outpatient administration.
`Phase 11 studies with single-agent paclitaxel produced
`overall response rates of 21%—60% at doses of 135 mg/m2 to
`225 mg/m2 administered by 3-h infusion [3, 4, 8,
`l8, 19].
`Treatment was generally well tolerated, and prophylactic use
`of hematopoietic growth factors was not required.
`As first-line therapy for metastatic disease, overall response
`rates of43% and 32% have been reported in two studies admin-
`istering paclitaxel 250 mg/m2 every three weeks [2, 3], and a
`third study administering 225 mg/m2 on the same schedule
`reported an overall response rate of 60% [4]. Neutropenia was
`the most common toxicity encountered in these studies. These
`response rates are comparable to the 29%-43% rates obtained
`with doxombicin in first-line regimens [20].
`
`Table 1. Paclitaxel doses and schedules in selected randomized clinical trials
`
`
`
`
`
`
`
`“oz‘05.roqurvoNuoisonfi.(qfim‘ssmdpoureqd[easrfimoouoaqufiduqLUOJJpopcorn/mg
`
`Study
`
`Nabho/rz [9]
`
`Paclitaxel dose
`(mg/m’)/schedule
`135/3 h
`175/3 h
`
`Pererz [33]
`
`175 to MTD/3 h
`175 to MTD/24 h
`
`CALGB 9342 [10]
`
`NSABP B-26 [11]
`
`MDACC [12]
`
`175/3 h
`210/3 h
`250/3 h
`
`250/3 h
`250/24 h
`
`Evaluable patients Overall
`response (%)
`
`Comments
`
`227
`223
`
`521,,
`
`325’
`
`516‘
`
`22
`29
`
`29
`32
`
`2|
`28
`22
`
`40
`50
`
`No difference in overall response; median time to
`progression favored higher dose.
`
`No difference in overall response, survival, or time
`to progression when adjusted for prognostic factors.
`
`No difference in overall response or overall survival.
`Improved time to treatment failure with highest dose.
`Toxicity profile favored lower dose.
`
`Significant difference in overall response, but no difference
`in overall survival. Toxicity profile favored shorter infirsion.
`
`MDACC = MD Anderson Cancer Center.
`
`No difference in response or survival. Toxicity profile
`23
`88
`250/3 h
`30
`91
`140/96 h
`and feasibility favored shorter schedule.
`
`*All arms combined. CALCB = Cancer and Leukemia Group B; NSABP = National Surgical Adjuvant Breast and Bowel Program;
`
`

`

`Perez
`
`375
`
`Response in Anthracycline-Resistanr Patients
`Heavily pretreated breast cancer patients usually have a
`very poor prognosis, and few treatment options are available.
`Most will have failed anthracycline therapy, and anthracy-
`cline resistance is an indicator of very poor prognosis. In the
`pre-taxane era, patients with anthracycline-resistant metasta-
`tic breast cancer faced a median survival of about four
`
`months. Responses to all other treatment regimens, whether
`single-agent or combination, were less than 15% [21].
`In the phase II setting, response rates of approximately
`20%-40% were obtained with single-agent paclitaxel
`in
`patients who failed prior anthracycline therapy (Table 2) [3, 7,
`8, 18, 19]. In heavily pretreated patients, response rates of
`up to 22% were achieved [19]; however, in patients who
`had received 22 prior chemotherapy regimens containing
`doxorubicin or epirubicin, response rates were lower, at
`6% [22]. Phase III studies have confirmed the activity of
`paclitaxel
`in anthracycline-resistant patients. An overall
`response rate of 25% was observed in anthracycline-pre-
`treated patients who received paclitaxel 135 or 175 mg/m2
`over 3 h [9]. In addition, the intergroup trial 15-1193, a
`phase III study in which patients randomized to received
`single-agent doxorubicin could be crossed over to receive
`paclitaxel
`(24-h infusion) upon disease progression,
`
`reported a 22% overall response rate to paclitaxel following
`anthracycline failure [23, 24].
`
`Weekly PacIiraer
`Another area of considerable interest is the administra-
`
`tion of weekly cycles of paclitaxel. With weekly adminis-
`tration of moderate doses of paclitaxel, higher cumulative
`doses can be achieved than with an every-three-weeks
`schedule, yet myelosuppression is generally modest [25-29].
`Seidman et 0]. administered paclitaxel 100 mg/m2 weekly
`via l-h infiision to patients with previously treated metastatic
`breast cancer and observed a 53% overall response rate, with
`10% complete responses [25]. In the subgroup with anthracy-
`cline-resistant disease, the response rate was 50%. Therapy
`was well tolerated, with a lack of cumulative neutropenia and
`manageable neurotoxicity.
`Neurotoxicity, which can be cumulative with paclitaxel
`treatment, is generally not a problem with weekly paclitaxel
`doses up to 80 mg/m2 [26]. Perez et a]. at the Mayo Clinic
`Jacksonville are currently conducting a multicenter phase
`II
`trial of continuous, weekly paclitaxel 80 mgim2 in
`patients with metastatic breast cancer and to date have
`not encountered difficulty with cumulative neurotoxicity
`or myelosuppression.
`
`Table 2. Single-agent paclitaxel therapy in anthracycline-treated or anthracycline-resistant breast cancer
`Dose/schedule
`Evaluable
`Overall
`patients
`response (%)
`
`Trial
`design
`
`Study
`
`Phase II Trials
`
`Seidman [3]
`
`Phase II
`
`Seidman [7]
`
`Phase II
`
`125 mg/m2 i.v., 3-h infusion
`Cycles repeated q 3 wk
`
`200-250 mg/mZ i.v., 24-h infusion
`Cycles repeated q 3 wk
`
`Abrams [6]
`
`NC] treatment
`referral
`
`135 or 175 mg/m2 i.v., 24-h infusion
`Cycles repeated q 3 wk
`
`Comments
`
`Two or more prior regimens for
`metastatic disease.
`
`At least one prior therapy for
`metastatic disease.
`
`Patients had progressed either while
`on doxorubicin or within 6 months
`after doxorubicin.
`
`Anthracycline resistant.
`
`Up to two prior regimens, one
`adjuvant and one metastatic.
`
`Two to five prior therapies for
`advanced disease.
`
`Two or more prior anthracycline-
`containing regimens.
`
`and metastatic.
`
`[75 mg/m2 i.v., 3-h infusion
`Cycles repeated q 3 wk
`
`175 or 225 mg/m1 i.v., 3-h infusion
`Cycles repeated q 3 wk
`
`135 or 175 mg/m2 i.v., 3-h infusion
`Cycles repeated q 3 wk
`
`250-300 mg/m2 i.v., 3-h infusion
`Cycles repeated q 3 wk
`
`Fountzilas [8]
`
`Phase 11
`
`Gianni [18]
`
`Phase II
`
`Vici [19]
`
`Phase II
`
`Vermorken [22]. European
`Cancer Center
`Trial
`
`Phase III Trials
`
`Nabholtz [9]
`
`Multicenter
`
`I35 or 175 mg/m2 i.v., 3 h infusion
`Cycles repeated q 3 wk
`
`One prior regimen, adjuvant or
`metastatic, or one each adjuvant
`
`
`
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`

`376
`
`Paclitaxel in Breast Cancer
`
`it appears that a dose and schedule of 175 mg/m2 by 3-h infir-
`sion every 21 days is both effective and well tolerated, and a
`reasonable therapeutic choice.
`
`Phase [1! Trials: Infusion Schedule
`Two phase III trials have addressed the issue of com-
`parative efficacy and safety of 3-h versus 24-h paclitaxel
`infusions in patients with advanced breast cancer. A pre-
`liminary report by Peretz et al. of the results of a
`European phase III trial evaluating 3-h versus 24-h pacli-
`taxel infusion, each at 175 mg/mz, did not show either
`schedule superior [33]. Patients were stratified according
`to no prior chemotherapy, adjuvant chemotherapy, or
`chemotherapy for advanced disease. Overall, there were
`no differences in cumu-
`
`A higher-dose weekly paclitaxel regimen, 175 mg/m2 by
`3-h infusion for six weeks of an eight-week cycle, is under
`investigation by the Brown University Oncology Group
`as first-line treatment for locally advanced or metastatic
`breast cancer. The overall response rate was 78%, with 16%
`complete responses; however, most patients required dose
`modification secondary to cumulative toxicities [30, 31).
`
`Phase III Trials: Dose Response
`Phase III trials have confirmed the high, single-agent
`activity of paclitaxel in advanced breast cancer. Issues of
`paclitaxel dose have recently been studied by Nabholtz et
`al. [9] and CALGB trial 9342 [10]. The trial reported by
`Nabhollz et al., which compared doses of paclitaxel 135
`and 175 mg/m2 deliv-
`ered by 3-h infusion
`every
`three weeks,
`reported
`overall
`response rates of 22%
`and 29%,
`respectively,
`and complete response
`rates of 5% and 2%, for
`each
`of
`the
`doses,
`
`It appears that a dose and
`
`schedule of I 75 mg/m2 by 3-h
`
`infusion every 21 days is both
`
`eflective and well tolerated,
`
`rates,
`response
`lative
`median progression-free
`survival, or overall sur-
`vival between the two
`
`groups when adjusted
`for prognostic factors. In
`the salvage setting,
`the
`24-h infusion had some
`
`respectively [9]. These
`differences were not sta-
`
`tistically
`however,
`
`significant;
`there was a
`
`and a reasonable therapeutic
`
`choice.
`
`efficacy advantage, but
`did not confer a signifi-
`cantly greater patient
`benefit when compared
`with 3-h infusion. More grade 3 and 4 neutropenia was
`reported in patients receiving the 24-h infusion, while
`peripheral neuropathy was more common in the 3-h
`schedule.
`
`significant difference in time to progression, with the
`higher dose producing a median time to disease progres-
`sion of 4.2 months, compared with 3.0 months for the
`lower dose.
`
`Preliminary results of CALGB 9342 have recently been
`reported [10, 32]. In this phase III trial, single-agent paclitaxel
`doses of 175, 2l0, and 250 mg/m2 were administered as a 3-
`h infusion every three weeks to patients who had received up
`to one prior therapy for metastatic disease. In updated results
`presented at the 1998 American Society of Clinical Oncology
`(ASCO) annual meeting in Los Angeles, response rates and
`overall survival were not statistically different among the
`three arms; however, time to treatment failure was statisti-
`cally longer
`for patients receiving the highest dose.
`Although all dose levels were well tolerated and overall
`quality of life was not different among the three arms of the
`trial, grade III neurosensory toxicity and grade IV hemato~
`logic toxicity were more frequent with the 250 mg/m2 dose
`than with either 175 or 210 mg/mz.
`These studies have not shown a clear-cut dose-response
`relationship for paclitaxel in the treatment of metastatic breast
`cancer. Although time to treatment failure may favor higher
`doses, there have been no differences in overall response or
`survival between arms of the studies. Given this information,
`
`Preliminary results of NSABP B-26, which compared a
`3-h versus 24-h infusion of paclitaxel 250 mg/m2 have
`recently been reported [1 l], with updated data presented at
`the 1998 ASCO meeting [34]. Patients enrolled had stage
`IIIB or
`IV breast cancer, and only prior adjuvant
`chemotherapy was allowed. The overall response rate for all
`patients was significantly higher in the 24-h infusion group
`(50%) than in the 3-h group (40%) [11]. For the subset of
`patients with stage IV disease,
`the overall response rates
`were 48% and 36% for the 24-h and 3-h infusions, respec-
`tively. The median time to progression was 7.1 months for
`the 24-h arm, and 6.4 months for the 3-h arm [34]. Despite
`the difference in response, there was no difference in overall
`survival between the 24-h infusion (21 months) and the 3-h
`infusion (20.7 months). Although the median overall survival
`for the subset ofpatients with stage IIIB disease had not been
`reached at the time of presentation in May 1998, the median
`overall survival for stage IV patients was 18.2 months for the
`24-h infiasion and 20.3 months for the 3-h infusion arm. As
`
`with the European phase III trial, the 24-h schedule was
`
`
`
`
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`

`Perez
`
`377
`
`associated with more severe hematologic toxicity, and severe
`neurotoxicity was more common with 3-h infusions. The
`authors concluded that although the 24-h schedule offered a
`higher overall response rate,
`this did not translate to an
`increase in event-free or overall survival as compared with
`the 3-h arm. Because of the increased toxicity and costs asso-
`ciated with the 24—h infusion, the authors concluded that the
`3-h infiasion was generally preferable.
`A third phase III multicenter trial, coordinated by
`MDACC, evaluated 3-h versus 96-h infusions of paclitaxel in
`metastatic breast cancer [12]. Doses of 250 mg/m2 by 3-h
`infusion and 140 mg/m2 for the 96-h infusion were adminis-
`tered every three weeks. There were no differences in overall
`response, response duration, or overall survival between study
`arms. The investigators concluded that the extra logistical
`support required for 96-h
`infusion was not justified.
`
`200 mg/m2 by 3-h infusion, which demonstrated a 25% over-
`all response rate and 4.0 months progression-free survival.
`However, the doxorubicin arm was associated with greater
`hematologic, gastrointestinal, and cardiac toxicities, sug-
`gesting that the drugs were not compared in equitoxic doses.
`In contrast to the EORTC study, U.S. Intergroup Study E-
`1193, a randomized Phase III trial, failed to reveal any differ-
`ence between doxorubicin and paclitaxel as single agents in
`overall response rate, time to disease progression, or overall
`survival [23, 24]. This three-arm study compared doxorubicin
`60 mg/m2 with paclitaxel 175 mg/m2 by 24-h infusion versus
`a combination of doxorubicin 50 mg/ml and paclitaxel 150
`m m2 by 24-h infusion. In the preliminary report, overall
`response rates prior to any crossover therapy were 36% for
`single-agent doxorubicin, 34% for single-agent paclitaxel,
`and 47% for the combina-
`tion. The combination had
`
`Paclitaxel has demonstrated
`
`Phase III Trials:
`
`Comparison Studies
`
`Paclitaxel versus CMFP
`
`significant activity in patients with
`
`anthracycline-resistant breast cancer.
`
`superior
`statistically
`a
`response; however,
`there
`was no statistical differ-
`ence in response between
`the two single-agent arms.
`
`Preliminary results of a phase III study from New
`Zealand and Australia reported by Bishop et a1. indicate
`that single-agent paclitaxel yields response rates equivalent
`to standard combination cyclophosphamidetmethotrex-
`atet5-fluorouracil
`(5-FU)tprednisolone (CMFP) at equi-
`toxic doses in patients with previously untreated metastatic
`breast cancer [35-37]. In their preliminary report, the over-
`all response rate was 30% with paclitaxel and 36% with
`CMFP [35]. Median time to progression was 5.3 months for
`paclitaxel and 6.5 months for CMFP. Paclitaxel was associ-
`ated with significantly less severe leukopenia, thrombocy-
`topenia, mucositis,
`infections, and nauseatvomiting.
`Alopecia, peripheral neuropathy, and myalgia/arthralgia
`were more frequent with paclitaxel. Patient assessment of
`quality of life appeared to improve with paclitaxel, but
`deteriorate with CMFP. The investigators concluded that
`single-agent paclitaxel is well tolerated, has efficacy com-
`parable to CMFP, and may have additional benefits with
`respect to quality of life.
`
`Paclitaxel versus Doxorubicin
`
`Results were recently reported from another multi-
`institutional phase III trial comparing paclitaxel with dox-
`orubicin, each as single agents, as first-line treatment of
`metastatic breast cancer [38]. In this European Organiza-
`tion for Research and Treatment of Cancer (EORTC) trial
`of 331 anthracycline-naive patients, doxorubicin 75 mg/m2
`produced a higher response rate, 41%, and longer progres-
`sion-free survival, 7.3 months, as compared with paclitaxel
`
`Paclitaxel versus Docetaxel
`
`An ongoing U.S. multicenter trial is comparing pacli-
`taxel 175 mg/m2 by 3-h infusion with docetaxel 100 mg/m2
`by l-h infusion as first- or second-line therapy of advanced
`breast cancer [39]. The question of an equitoxic dose com-
`parison arises, as the maximum tolerated dose for docetaxel
`is 100 mg/mz, while paclitaxel has been shown to be well
`tolerated up to 250 mg/mz. While the paclitaxel dose
`appears reasonable based on current information, the opti-
`mal dose of docetaxel, in terms of efficacy and toxicity, is
`not yet defined and awaits the results of a separate trial
`evaluating docetaxel
`60 mg/m2 versus
`75 mgx’m2
`versus 100 mg/mz.
`In summary, paclitaxel has substantial activity as a sin-
`gle agent in the treatment of metastatic breast cancer. While
`
`response rates are highest in the first-line setting, single-
`agent paclitaxel maintains very good activity as second-line
`and salvage therapy. The response rate to single-agent pacli-
`taxel is reasonably comparable to that of single-agent dox-
`orubicin. Of importance, paclitaxel has demonstrated
`significant activity in patients with anthracycline-resistant
`breast cancer. Although a well-defined dose-response rela-
`tionship has not been established for 3-h infiisions of pacli-
`taxel on an every-three-weeks schedule, a dose of 175 mymZ
`appears to offer the best balance of efficacy and tolerability.
`With regard to infusion schedule, when overall survival is
`considered, neither 24—h nor 96-h schedules appear to offer
`survival benefits over a 3-h schedule. Although the 24-h
`
`
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`LIOZ‘ogJOqLuaAONuoisons.(qfiio'ssasdpomnqdln'rs[Soloauooqwzduqmoi;papac|umoa
`
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`

`378
`
`Paclitaxel in Breast Cancer
`
`schedule has been associated with a higher overall response
`rate, this did not translate into a survival difference. Overall,
`a 3-h schedule of paclitaxel 175 mg/m2 every three weeks
`appears to be a reasonable option for the treatment of breast
`cancer. Weekly studies with moderate-dose, single-agent
`paclitaxel appear very promising in terms of both efficacy
`and tolerability. A relatively high rate of dose delivery com-
`bined with a remarkably tolerable toxicity profile has been
`observed, encouraging continued investigation.
`
`Combination Chemotherapy
`Combination chemotherapy is the standard approach to
`the treatment ofbreast cancer. Multidmg regimens have gen-
`erally resulted in higher complete and overall response rates,
`with improvements in response durations. The novel mecha-
`nism of action of paclitaxel, its demonstrated single-agent
`activity, and its manageable toxicity profile make it an attrac-
`tive candidate for inclusion in combination chemotherapy
`regimens.
`Paclitaxel has been studied in combination with a number
`
`of other agents effective in breast cancer. The largest number
`of studies have been conducted with the paclitaxelidoxoru-
`bicin combination as first-line therapy in advanced breast can-
`cer [24, 40-48]. Other combinations for both first-line and
`salvage therapy have included paclitaxel and 5-fluorouracil
`(5-FU) [49, 50], paclitaxel and cyclophosphamide [51—55],
`and paclitaxel with a platinum compound [56-65].
`New insights in molecular biology have led to combination
`chemotherapy and antibody studies. With respect to breast
`cancer in particular, the investigation of combination pacli-
`taxel or anthracycline/cyclophosphamide with anti-HERZ anti-
`body has generated much interest.
`
`Paclitaxel/Anthracycline or Anthracenedione Combinations
`
`Paclitaxel and Doxorubicin
`
`The high individual activity of doxorubicin and paclitaxel
`in breast cancer and their incomplete clinical cross-resistance
`make combination therapy with these two agents an attractive
`option for first-line treatment of metastatic breast cancer. This
`combination has been extensively evaluated in phase II trials
`of breast cancer patients worldwide. Response rates—among
`the highest reported for first—line metastatic treatment—have
`been encouraging (Table 3).
`The first two trials of combination doxorubicin and pacli-
`taxel
`involved administration of both drugs as prolonged
`infusions. In a National Cancer Institute study, paclitaxel and
`doxorubicin were administered concurrently as a 72-h infu-
`sion. The overall response rate was 72% [66]. An MDACC
`trial of paclitaxel by 24-h infusion and doxorubicin by 48-h
`infusion also investigated the effect of drug sequencing. As
`
`the overall response rate was
`reported by Holmes e! (11.,
`higher (80%) when paclitaxel preceded doxorubicin versus
`57% when the order was reversed, but tolerability was clearly
`lower [67]. Mucositis, fever, neutropenia, and diarrhea were
`dose-limiting in the above trials. A phannacokinetic study
`revealed that when paclitaxel administration preceded that of
`doxorubicin, the clearance of doxorubicin was decreased by
`32% [68]. An Eastern Cooperative Oncology Group (ECOG)
`study also observed substantially more mucositis when pacli-
`taxel by 24-h infitsion preceded a doxorubicin bolus than
`when the drugs were administered in the reverse order [69].
`Moreover, preclinical studies had shown that doxorubicin
`followed by paclitaxel has a synergistic or additive effect in
`primary breast cancer cell cultures or breast cancer cell
`lines [70]. Consequently, the sequence of doxorubicin fol-
`lowed by paclitaxel has been preferred in subsequent trials.
`The desire to deliver paclitaxel and doxorubicin in
`combination on an outpatient basis led to studies of shorter
`administration times [40-44, 48]. These short-infusion stud-
`ies provided evidence of high overall and complete response
`rates (Table 3).
`In all trials conducted to date, the paclitaxelfdoxorubicin
`combination has resulted in high rates of response. However,
`in trials reported by Gianni et a]. [40] and Gehl et a]. [41], high
`response rates were accompanied by an increased incidence of
`congestive heart failure (CHF), an incidence much higher than
`expected in light of the cumulative doses of doxorubicin
`administered. A pharrnacokinetic analysis revealed apparent
`interference by paclitaxel in the elimination of doxorubicin,
`resulting in increased concentrations of both doxorubicin and
`its major metabolite, doxorubicinol [71]. Other investigations
`have also documented a phannacokinetic interaction between
`paclitaxel and doxorubicin [68, 72].
`Recently, the international experience with combination
`paclitaxel and doxorubicin therapy in patients with advanced
`breast cancer has been analyzed with respect to cardiac tox-
`icity [73]. Of the total of 656 patients treated on a combi-
`nation of 10 different trials, 3l patients (5%) developed
`CHF. In patients receiving a cumulative doxorubicin dose
`of up to 380 mymz, the incidence of CHF was less than 5%,
`similar to that expected with doxorubicin alone. Above this
`dose, an increase in CHF was apparent. Therefore, the cur-
`rent recommendation for combination doxorubicin/pacli-
`taxel therapy is to limit the maximum cumulative doses of
`doxorubicin to 380 mg/mz, with a maximum single dose of
`50-60 mg/mz.
`Data from the only phase III trial of combination pacli-
`laxel and doxorubicin, the Intergroup study E-l 193, were
`included in the above analysis [23, 24]. As has been noted,
`this trial allowed for comparison of efficacy and toxicity of
`paclitaxel and doxorubicin, each as single agents,
`to the
`
`
`
`
`
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`
`

`

`Perez
`
`379
`
`Table 3. Doxorubicin/paclitaxel as first-line therapy in metastatic breast cancer
`
`Study
`
`Dose/schedule
`
`Evaluable
`patients
`
`Response
`(%)
`
`Comments
`
`Phase [III or H trials
`
`Gianni [40]
`
`Gehl [41]
`
`Amadari [42]
`
`Schwansmann [43]
`
`Sparano [48]
`
`Jovtis [44]
`
`Lararre [45]
`
`Phase [[I trials
`
`Sledge [24]
`
`T 200 mg/m2 i.v., 3-h infusion
`A 60 mg/m2 iv. bolus
`Cycles repeated q3 wk, maximum
`8 cycles
`
`T 155-200 mym2 i.v., 2-3-h infusion
`A 30 mg/m2 iv. bolus, d 1 and 8
`
`A 50 mg/m2 iv. bolus 16 h before T
`T 130-250 mg/m2 i.v. 3-h infusion
`Cycles repeated q 3 wk
`
`T 250 mg/m2 i.v., 2-3-h infusion
`A 60 mglm2 iv. bolus
`Cycles repeated q 3 wk, maximum
`6 cycles
`
`A 60 mg/m2 iv. bolus
`T 200 mg/m2 i.v., 3-h infusion 15 min
`afier A
`Cycles repeated q 3 wk, maximum
`6 cycles
`
`A 50 mg/m2 i.v. short infusion
`T 200 mg/m2 i.v., l-h infusion afier A
`Cycles repeated q 3 wk, maximum
`10 cycles
`
`A 50 mg/m2 iv. bolus l d before T
`T 130-250 mg/m2 i.v., 3-h infusion
`Cycles repeated q3 wk
`
`A 60 mg/m2 or
`T 175 mg/m2/24 h or
`A+T, 50 mg/m2 and 150 mg/m2/24 h
`
`
`
`CR
`
`4]
`
`PR
`
`53
`
`No prior chemotherapy.
`
`51 prior adjuvant regimen;
`no prior anthracycline.
`
`No prior chemotherapy for
`metastatic disease; adjuvant
`chemotherapy allowed.
`
`No prior chemotherapy for
`metastatic disease; adjuvant
`chemotherapy allowed.
`
`No prior chemotherapy for
`metastatic disease; adjuvant
`chemotherapy allowed other
`than A or T.
`
`No prior chemotherapy for
`metastatic disease; adjuvant
`chemotherapy (without
`anthracyclines) allowed.
`
`No prior chemotherapy for
`metastatic disease; adjuvant
`chemotherapy allowed.
`
`First-line therapy; adjuvant
`chemotherapy allowed other
`than A or T.
`
`
`
`
`
`“oz‘05JoqLuaAONuorsanfiKq[Sm'ssaadpamaqdlu'rs[Soloauooqwzduq[110.13popaolumog
`
`Abbreviations: T = paclitaxel; A = doxorubicin; NR = not reported; CR = complete response; PR = partial response; OR = overall response.
`
`combination of the two. For patients enrolled on either sin-
`gle-agent arm, crossover to the other agent was allowed at
`disease progression. In this trial, the concurrent administra-
`tion of paclitaxel and doxorubicin was not associated with
`any greater cardiac toxicity than that observed with single-
`agent doxorubicin. With respect to response, the combina-
`tion had an overall response rate of 47%, statistically higher
`than either paclitaxel (34%) or doxorubicin (36%) as single
`agents. The crossover design resulted in a similar survival
`rate in the three study arms, independent of randomization
`assignment [24]. Also, analysis of the crossover responses
`revealed that 22% of patients res