Paclitaxel for Breast Cancer: The Memorial Sloan-Kettering Cancer Center Experience

ABSTRACT: The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer. [ONCOLOGY 11(Suppl):20-28, 1997]

Introduction

In the management of patients with metastatic breast cancer, paclitaxel(Taxol) has demonstrated safety and significant antitumor activity.[1-5]To fully characterize the drug's potential in the treatment of advancedbreast cancer, we have conducted a series of phase II clinical trials evaluatingits efficacy and tolerability as single-agent therapy (Table1).

Paclitaxel has been studied in various doses and schedules among patientswith metastases who have not received previous chemotherapy for advanceddisease, as well as among those who have had moderate and extensive priortherapy.[1,3-5] In heavily pretreated patients, we have conducted a formalparallel investigation of quality-of-life (QOL) parameters to better assessthe palliative potential of paclitaxel among patients who receive thisagent with the primary intent of symptom control.[6] We are presently incorporatingthese variables into a prospective study that addresses economic (charges/costs)and QOL outcomes, in addition to classic tumor response and toxicity assessments,in patients receiving single-agent paclitaxel.[7]

Our studies were influenced by preclinical data demonstrating schedule-dependentcytokinetic variability in resistance profiles to the taxanes,[8-10] aswell as clinical documentation of the efficacy and safety of a 96-hourinfusion schedule against anthracycline-refractory breast cancer.[11] Theseinvestigations led us to perform a phase II and pharmacologic trial assessingthe activity and toxicity profile of this prolonged infusion schedule inpatients with documented progression of disease during shorter taxane exposure.[12]

Data supporting the feasibility and efficacy of more frequent, shorter-durationtaxane infusions[13] has motivated our ongoing trial, which is evaluatinga weekly 1-hour infusion paclitaxel schedule in patients who have receivedone or two prior regimens for breast cancer (including adjuvant therapy).[14]Collaborative laboratory investigations aimed at characterizing clinicallyrelevant mechanisms of resistance to paclitaxel are well underway in studiesinvolving biopsied human breast cancer tissue.

Combinations of paclitaxel and other cytotoxic agents are being studied.A variety of two- and three-drug paclitaxel-containing regimens are inclinical trials to define possible synergism, as well as to illuminatesafety profiles. At Memorial Sloan-Kettering Cancer Center (MSKCC), wehave investigated the combination of paclitaxel and edatrexate, a dihydrofolatereductase inhibitor with preclinical advantages over methotrexate[15] andproven single-agent activity against metastatic breast cancer.[16-17] Thetrial design derives from schedule-dependent synergy observed in vitroin mammary carcinoma cells.[18,19]

A promising avenue of translational research pertains to the observedsynergy between paclitaxel and monoclonal antibodies (MoAbs) directed atvarious growth factor receptors in human breast carcinoma xenografts.[20,21]While laboratory studies addressing possible cellular mechanisms for thiseffect are ongoing, we are conducting a clinical trial combining paclitaxelwith a MoAb directed against the epidermal growth factor.

The preserved activity of paclitaxel after anthracycline threapy hasstimulated its evaluation as a component of an adjuvant sequential chemotherapyregimen for node-positive stage II-III resectable breast cancer.[22] Werecently evaluated the optimal integration of paclitaxel into doxorubicin/cyclophosphamide(Cytoxan, Neosar)-based adjuvant therapy in a randomized clinical trial.[23]

This article will review 6 years of experience with paclitaxel in thetreatment of breast cancer at MSKCC and describe ongoing and planned studies.

Single-Agent Paclitaxel

First-Line Therapy

Subsequent to the M. D. Anderson Cancer Center report of the promisingantitumor activity of paclitaxel against metastatic breast cancer,[2] weperformed a confirmatory phase II trial of the agent as first-line chemotherapyfor stage IV disease.[3] In this study, 28 patients who had not receivedprior chemotherapy for metastatic disease were treated with paclitaxel,250 mg/m² via a 24-hour infusion every 3 weeks. Because the firsttwo patients we treated on this protocol experienced significant myelosuppression(which was dose-limiting in the previous trial[2]), the protocol was amendedso that all subsequent patients received prophylactic granulocyte colony-stimulatingfactor (G-CSF [Neupogen]), 5 µg/kg/d subcutaneously, on days 3 to10 of each cycle.

A 62% response rate (95% confidence interval [CI], 41% to 80%) was noted,including three complete responses.[3] Responses were as common among womenwho had received prior adjuvant therapy, including doxorubicin-containingregimens, as among those who had not. Treatment was well tolerate; adverseeffects included generalized alopecia in all patients, and grade 3 or 4nonhematologic toxicities were uncommon. Of 178 cycles administered, therewere 8 admissions (4%) for febrile neutropenia, involving 6 (21%) of 28patients.

Administration of recombinant human granulocyte colony stimulating factor(rh-G-CSF) resulted in a median duration with an absolute neutrophil countless than 500 cells/µL of 2 days, which was shorter than that previouslyreported (7 days)[1] without concomitant growth factor support. Fifty-eightpercent of cycles were delivered at modestly reduced doses, primarily dueto significant neutropenia or febrile neutropenia. Because drug supplywas a consideration at this time in the agent's development, the clinicaltrial design specified the length of treatment to be two cycles beyondthe best response, with a maximum of 10 cycles per patient. Thus, responseduration was not a valid end point of this trial.

After Prior Chemotherapy

Following this confirmation of paclitaxel's marked antitumor activityin patients with minimal prior therapy, we evaluated patients who had receivedextensive prior chemotherapy for metastatic breast cancer.[4] Fifty-onepatients who had previously received two or more prior chemotherapy regimensfor metastatic disease (median number of regimens, three; range, two tosix; all with prior anthracycline therapy) entered our second phase IItrial.

The median Karnofsky performance score (KPS) for these patients was70% (range, 60% to 90%). Fourteen percent had received prior high-dosechemotherapy regimens sufficiently myelotoxic as to require the reinfusionof autologous bone marrow and/or peripheral blood progenitor cells; two-thirdsof these patients had received radiotherapy for metastatic disease. Paclitaxelwas administered at 200 mg/m² (a lower starting dose was chosen inanticipation of significant toxicity in these more heavily pretreated patients)via a 24-hour infusion every 3 weeks with G-CSF, as previously described.

Partial responses were observed in 14 patients (27.5%; 95% CI, 16% to42%), with a median response duration of 7 months. Hospitalization forfebrile neutropenia occurred in 24 (8%) of the first 312 cycles and in9 (18%) of 51 patients. No patient was removed from the trial due to toxicity.

Our next trial evaluated the higher 250-mg/m² dose, again via a24 hour infusion every 3 weeks, in patients who had received only one priorchemotherapy regimen for metastatic disease (with or without prior adjuvanttherapy).[4] Nine partial and two complete responses were noted among 25evaluable patients (44%; 95% CI, 24% to 65%).

Significantly, in this and the previous trial, prior demonstrated sensitivityor resistance to an anthracycline did not predict the likelihood of subsequentresponse to paclitaxel. This lack of significant clinical cross-resistancebetween paclitaxel and doxorubicin, an observation corroborated by others,was particularly gratifying because preclinical data suggest significantin vitro cross-resistance between paclitaxel and other agents for whichp-glycoprotein-mediated multidrug resistance is considered relevant.[24,25]

These observations have motivated our ongoing studies characterizingpre- and post-paclitaxel human tumor tissue biopsies for mdr expression,tubulin alterations, and genomic changes. It is hoped that such studieswill expand the understanding of clinically relevant mechanisms of taxaneresistance, which may then guide the development of efficient strategiesto overcome resistance and, potentially, the development of superior analogs.

Shorter Infusion Schedule

Renewed interest in the shorter, more convenient 3-hour infusion schedulecoincided with our next two phase II trials, which addressed the safetyand efficacy of this schedule as salvage chemotherapy in heavily treatedpatients and as initial chemotherapy for stage IV disease. In the previouslytreated patients (two or more prior regimens for metastatic disease, includingan anthracycline), paclitaxel was administered at a starting dose of 175mg/m² via a 3-hour infusion every 3 weeks. Since 3-hour infusionsare associated with less significant myelosuppression than 24-hour infusions,G-CSF was not administered prophylactically.

Sixty-four percent of the patients had predominantly visceral disease,and the median KPS was 70%. After the 111 cycles were delivered (median,3; range, 1 to 8), five partial responses were observed in 24 evaluablepatients (20.8%; 95% CI, 7% to 42%),[5] with a median response durationof 4 months (range, 2 to 11 months).

Paclitaxel treatment was well tolerated; the only grade 3 or 4 nonhematologictoxicities noted were myalgia (4%) and mucositis (4%). Grade 3 or 4 neutropeniawas seen in one-third of patients, grade 3 or 4 thrombocytopenia in 8%,and grade 3 or 4 anemia in 13%. Dose reduction was required in 21% of patients,and dose escalation was possible in only 4%.

We then evaluated a 250-mg/m² dose administered via a 3-hour infusion,again without prophylactic G-CSF, as first-line chemotherapy for metastaticbreast cancer. Among 25 evaluable patients,1 complete and 7 partial responseswere noted (32%; 95% CI, 15% to 53%).[5]

Myalgias, arthralgias, and neuropathy appeared to be more significantthan in our prior experience with this dose delivered over 24 hours toa similar group of patients. Several patients experienced photopsia[26]at paclitaxel doses of 250 mg/m² or more over 3 hours, a phenomenonthat may represent an optic neuropathy.[27] These trials provided pilotdata for the design of ongoing randomized trials by the Cancer and LeukemiaGroup B (CALGB) and National Surgical Adjuvant Breast and Bowel Project(NSABP).

Additional Effects of Prolonged Treatment

In the course of these trials, it became obvious to us that many patientsexperiencing symptomatic relief of bone pain and radiographic healing ofosteolytic metastases on plain x-rays, CT, or MRI had transient worseningon nuclear scintigraphic evaluation of the skeleton.[28] This radiographic"flare" on bone scan was followed by further clinical improvementin skeletal pain and recalcification of destructive bone lesions in one-thirdof patients.

Another phenomenon became apparent with prolonged paclitaxel treatment(in some cases, beyond 20 courses). Among a series of 52 patients experiencingcontinued response of visceral, osseous, and soft-tissue metastases duringpaclitaxel treatment, 6 experienced disease progression in the centralnervous system in the absence of other evidence of treatment failure. Thismanifested as both parenchymal brain metastases and leptomeningeal disease.Thus, the central nervous system does appear to be a sanctuary site inmany women receiving paclitaxel for the management of metastatic breastcancer.[29]

Schedule-Dependent Activity

Our next phase II clinical and pharmacologic trial was motivated byin vitro data showing less resistance to paclitaxel in p-glycoprotein-overexpressingMCF-7 breast cancer cells with longer drug exposure time.[8] Further supportof this phenomenon came from other preclinical studies[9,10,30,31] andencouraging clinical experience with prolonged paclitaxel infusion in patientswith anthracycline-resistant breast cancer.[11]

In this study, we evaluated the possibility of schedule-dependent activityby administering paclitaxel via a 96-hour continuous infusion specificallyto patients with disease that had demonstrated clinical resistance to shorttaxane exposure.[12] A total of 27 such patients with disease progressionhad recently received 3-hour paclitaxel (N = 24), 1-hour docetaxel (Taxotere;N = 2), or both (N = 1). Per protocol, all patients received paclitaxelvia a 96-hour infusion at 140 mg/m² (35 mg/m²/d ×4), witha starting dose of 120 mg/m²/d for patients with impaired hepaticfunction. Because early data had suggested that the omission of steroidand H1- and H2-receptor antagonist premedication was not associated withsignificant hypersensitivity-like reactions with this dose and schedule,[11]these drugs were not given in our study.

With 195 cycles administered, seven partial responses were noted in26 evaluable patients (26.9%; 95% CI, 11.6% to 47.8%), with acceptablehematologic and nonhematologic toxicity. Despite the omission of standardpremedication, no cases of hypersensitivity-like reactions occurred. Thissuggests that the slower rate of exposure to paclitaxel--and possibly tothe polyoxyethylated castor oil (Cremophor EL) formulation--may not precipitatemast-cell degranulation and other cellular phenomena associated with hypersensitivityreactions.

Serum paclitaxel concentrations were assayed in 23 patients by high-performanceliquid chromatography at 24, 48, 72, and 96 hours of the infusion. Themedian steady-state paclitaxel concentration (Css) was .047 µM (range,.023 to .176 µM). For 11 patients experiencing grade 4 neutropenia,median Css was .068 µM (range, .032 to .176 µM), as comparedwith .039 µM (.023 to .098 µM) in 12 patients with less severeneutropenia (P less than .05). Median Css and absolute neutrophil count(ANC) nadirs were .094 µM (range, .074 to .176 µM) and 300cells/mm³, respectively, in four patients with baseline elevationof hepatic transaminases vs .041 µM (.023 to .102 µM) and 800cells/mm³ in 19 patients with normal transaminases (Css, P less than.01; ANC, not significant).[12]

No relationship between steady-state level and tumor response was notedwith this limited sample size. To further define the significance of infusionduration for paclitaxel, a recently completed multi-institution trial ledby the M. D. Anderson Cancer Center randomized patients with refractorymetastatic breast cancer to receive paclitaxel via either a 3- or 96-hourinfusion schedule. It is noteworthy that there are greater pharmacologicdifferences between the 3- and 96-hour infusion schedules than betweenthe 3- and 24-hour schedules, and many preclinical data suggest the importanceof paclitaxel exposure duration in breast carcinoma cells. Thus, this trialshould provide the most definitive information about the impact of paclitaxelinfusion duration on efficacy and toxicity.

Weekly1-Hour Paclitaxel in Metastatic Breast Cancer

Experience With Shorter Infusions

Although paclitaxel exposure duration seems to be an important determinantof cell kill, many oncologists perceive prolonged continuous infusionsto be cumbersome and inconvenient. Theoretically, one might approximatethe pharmacokinetics of prolonged paclitaxel infusion by more frequentadministration of the agent, which can also increase the delivered dosedensity. Pharmacodynamic studies have linked pharmacologic parameters,such as time above a specific threshold plasma paclitaxel concentrationand neutropenia, with toxicity. However, little is known about pharmacologiccorrelates of antitumor activity.

Recently, several investigators have begun to explore short 1-hour infusionsof paclitaxel. Hainsworth et al[32] compared a triweekly 1-hour infusionvs split-dose paclitaxel for three consecutive daily 1-hour infusions every3 weeks in 164 patients with advanced refractory cancers. In this study,no serious hypersensitivity reactions occurred, and activity in varioussolid tumor types was noted.

Loeffler et al [33] studied a weekly paclitaxel 1-hour infusion in 50patients, all of whom had previously received chemotherapy. Initial dosesof 40 mg/m² weekly for six cycles, followed by a 3-week off-treatmentinterval, were escalated up to 90 mg/m² weekly, without grade 3 or4 neutropenia. Responses were seen in 20 (40%) of the 50 patients, includingpartial responses in 3 of 6 patients with breast cancer.

The tolerability of a weekly 1-hour schedule has been confirmed in furtherstudies by Klaassen et al[13] and in ovarian cancer at our institution.[34]

An Active, Tolerable Regimen

Motivated by these experiences, in addition to preclinical data demonstratingthat paclitaxel can inhibit basic fibroblast growth factor and vascularendothelial growth factor-induced angiogenesis,[35] we recently initiateda phase II and pharmacologic study of paclitaxel, 100 mg/m² via a1-hour weekly infusion, in patients with metastatic breast cancer. Patientswho have not received extensive prior therapy (one or two prior regimensthat may include anthracyclines in the metastatic or adjuvant setting)are eligible for inclusion. Intrapatient dose escalation or reduction accordingto tolerance is addressed in the trial design.

To date, 16 patients have received 215 weekly infusions of paclitaxel(median, 13 per patient; range, 7 to 22). The initial dose was 100 mg/m²;actual median delivered dose intensity is 95 mg/m²/wk thus far. Granulocytecolony-stimulating factor was not given prophylactically, nor was its administrationnecessary to maintain weekly dosing.

Preliminary data suggest that this is both an active and tolerable regimen.No episodes of febrile neutropenia have been encountered. In the absenceof dose-limiting or cumulative myelosuppression, paclitaxel doses wereincreased to 110 to 120 mg/m²wk in the first nine patients. Unfortunately,this strategy resulted in grade 3 neurosensory and neuromotor toxicityin five of nine patients; hence subsequent escalation above 100 mg/m²was abandoned. Other grade 3 or 4 toxicities that have been observed areneutropenia (14%) and headache (7%).

Thus far, responses have been noted in 6 of 15 evaluable patients (40%;95% CI, 16% to 68%), including one complete response (cutaneous chest walldisease) and five partial responses (liver, lung, lymph nodes, and skin).Plasma paclitaxel concentration assayed by high-performance liquid chromatographyin 14 patients reveal a median peak concentration (Cmax) of 4.75 µM(range, 2.73 to 6.76 µM), median area under the curve of 17.23 µM-h(9.34 to 22.35 µM-h), and t½beta of 12.35 h (8.3 to 25.0 h).

Patient accrual continues to better estimate the proportion of responsesto this promising schedule of paclitaxel administration.

QOL and Outcome Assessment

The therapeutic goals in the management of metastatic breast cancerare being extended beyond classic bidimensional measurement of tumor responseto include relief of tumor-related symptoms and maintenance or enhancementof QOL. With this in mind, we performed a parallel prospective and comprehensiveassessment of these parameters in conjunction with our clinical trialsof the 24-hour paclitaxel infusion with G-CSF in previously treated patients.

Patients completed a series of validated instruments designed to capturethe many dimensions that contribute to global QOL. Questionnaires werecompleted prior to paclitaxel therapy and at 9-week (three-cycle) intervalsduring therapy. We found QOL assessment to be feasible in patients withadvanced cancer receiving investigational therapy in a phase II clinicaltrial setting.[6]

Although limited by sample sizes, our single-institution experiencesuggests a potential palliative benefit afforded by paclitaxel in patientswith responsive disease (complete or partial response) or minor response.[6]Multivariate analysis, using logistic regression models, also demonstratesthe independent prognostic value of baseline scores of two QOL instrumentsin predicting survival.[6] These instruments are the Global Distress Index,a 10-item subscale of the recently validated Memorial Symptom AssessmentScale (MSAS),[36] and the Functional Living Index-Cancer (FLIC).[37]

Since chemotherapy-related symptoms (eg, myalgia and arthralgia) areoften transient, we have obtained frequent prospective measurements ofpain in parallel with paclitaxel/G-CSF therapy of metastatic breast cancer.[38]This exploratory analysis demonstrated the ability to capture short-livedepisodic symptoms--in this case, attributable to paclitaxel and/or G-CSF--thatwould not have been captured with less frequent assessment. We are encouragedby ongoing investigations addressing these important issues in parallelwith ongoing randomized phase III trials of paclitaxel alone and in combination(eg, Eastern Cooperative Oncology Group [ECOG] protocol 1193).

We are presently addressing the issue of cost/charges of medical carerelative to the standard outcome measurements of response, survival, toxicity,and QOL.[7] Consenting patients receiving single-agent paclitaxel for metastaticbreast cancer are followed prospectively, with classic assessment of tumorresponse and toxicity. In addition, patients complete the MSAS and FunctionalAssessment of Cancer Therapy-Breast (FACT-B)[39] instruments at regularintervals to capture parallel longitudinal QOL changes. Health-care expendituresincurred during the treatment period are evaluated prospectively by administrativecollaborators within our institution, using existing computerized datasystems. This nonrandomized effort is designed to examine the relationshipbetween tumor response, palliation, and costs in the treatment of advancedbreast cancer.

Combination Therapy

Doxorubicin/Cisplatin

Several studies have shown impressive antitumor activity of combinationsof paclitaxel with doxorubicin[40-45] and cisplatin (Platinol)[46,47] againstmetastatic breast cancer and have begun to elucidate the potential toxicitiesof these combinations. It has become apparent in these trials that dose,duration of infusion, and sequence of administration are all importantdeterminants of toxicity. Randomized trials, such as the intergroup studyof paclitaxel vs doxorubicin vs the combination of the two agents withG-CSF support, are critical to gauge the relative value of such combinationsover single-agent paclitaxel.

Edatrexate

Edatrexate is an analog of methotrexate that competes for the folate-bindingsite of the enzyme dihydrofolate reductase, and thus, indirectly blocksthe synthesis of nucleotides. It possesses potential preclinical advantagesover methotrexate in that it demonstrates greater selective entry and intracellularconversion to polyglutamate forms in neoplastic cells compared to otherantifolates.[15] In addition, edatrexate has shown promising single-agentactivity against metastatic breast cancer in previous clinical trials.[15-17]

In vitro data from our center have demonstrated that the sequence ofedatrexate followed by paclitaxel showed marked synergism in inhibitingthe growth of SKBR-3 human breast adenocarcinoma cells,[18,19] while thereverse schedule showed antagonism. We therefore evaluated the sequentialcombination of edatrexate and paclitaxel in a phase I-II clinical trialin patients with stage IV breast cancer.[48] Edatrexate doses of up to350 mg/m² were well tolerated in combination with paclitaxel at 175mg/m² via a 3-hour infusion without hematopoietic growth factor support,with both agents recycled every 21 days. Preliminary data show eight responses(three complete, five partial) among the first 12 evaluable patients (edatrexatedose range, 180 to 270 mg/m²).

Cyclophosphamide

For chemoresponsive metastatic breast cancer, single-cycle, conventionalhigh-dose chemotherapy regimens requiring autologous stem-cell supporthave produced complete responses in up to 50% of patients, and yet themajority of these patients ultimately develop recurrent disease. Motivatedby the apparent failure of a single high-dose application of chemotherapyto eradicate all viable malignant cells in prior clinical trials, we appliedthe concepts of the Norton-Simon hypothesis and the Gompertzian model ofbreast cancer kinetics[49] in a series of studies. We evaluated the deliveryof multiple courses of high-dose alkylating agents at short intertreatmentintervals in patients with responsive metastatic breast cancer.[50]

Notably, our group has demonstrated that the addition of paclitaxel(250 mg/m²) to high-dose cyclophosphamide (3 g/m²) does not compromisethe mobilization of CD34+ peripheral blood progenitor cells (median, 16.22E⁶/kg/leukapheresis), as compared with 3 g/m² of cyclophosphamidealone (2.64 E⁶/kg/leukapheresis).[51] Hence, we are presentlyevaluating the incorporation of paclitaxel into a high-dose sequentialregimen in chemosensitive metastatic breast cancer. This regimen consistsof tandem cycles of high-dose cyclophosphamide plus paclitaxel followedby tandem cycles of high-dose thiotepa plus paclitaxel with peripheralblood progenitor cells for hematologic rescue (MSKCC IRB protocol 94-77).

Monoclonal Antibodies

There has recently been an expansion of knowledge about the role thatcertain oncogenes, growth factors, and growth factor receptors play inbreast cancer.[52] One of the best-studied growth factor receptor systemsin breast cancer includes the epidermal growth factor receptor (EGFR) andthe closely related HER-2/neu receptor, both of which possess intrinsictyrosine kinase activity. When directed against both these receptors, MoAbsinhibit the growth of breast cancer cells overexpressing the target receptor.[52,53]Over the past several years, compelling experimental data have suggestedthat combining certain chemotherapeutic agents with MoAb-mediated blockadeof either EGFR or HER-2/neu receptors can eradicate well-establishedhuman tumor xenografts resistant to either treatment given singly.[20,21,54]

Significant antineoplastic effects are observed when human breast cancerxenografts are exposed to paclitaxel in combination with either anti-EGFRor anti-HER-2/neu MoAb.[21] This strong synergy is achieved withno increased toxicity in the animal model. Although the mechanisms forthe apparent supra-additive effects of certain chemotherapeutic agentsand MoAbs are still being investigated,[55] these data provide a lead fortranslation into the clinic. Recent data indicate that downstream eventsin the signal transduction pathway may be involved in paclitaxel-inducedapoptotic cell death.[56] We are presently evaluating the human-murinechimeric anti-EGFR MoAb C225 in combination with paclitaxel in a phaseI trial in patients with metastatic breast cancer.

Growth Factor Receptors and Clinical Paclitaxel Sensitivity

There is a growing body of predominantly preclinical information suggestinga relationship between growth factor receptor expression and chemosensitivityor resistance.[57] Among patients receiving higher doses of anthracycline-basedadjuvant therapy, those with primary breast cancers overexpressing theHER-2/neu receptor had improved disease-free and overall survivalcompared with those that lacked overexpression.[58] To better define thisrelationship for paclitaxel, we conducted a multivariate analysis of immunohistochem-ical HER-2/neu expression and clinical taxane sensitivity in patientsreceiving single-agent paclitaxel (and docetaxel) in clinical trials overthe last 5 years at MSKCC.[59]

Preliminary analysis showed that 51 (40.5%) of 126 patients treatedwith either single-agent paclitaxel or docetaxel had tumor overexpressionof HER-2. The overall response rate for all patients was 46.8% (59/126).The response proportion was 58.8% (30/51) if HER-2 was overexpressed, comparedwith 38.7% (29/75) if HER-2 was negative (Mantel-Haenszel test, P = .027).

Among the factors assessed in conjunction with tumor response, visceral-dominantdisease, low KPS, and extensive prior therapy correlated with a poor clinicalresponse. Among these, HER-2 overexpression was positively correlated witha low KPS, and a low KPS with extensive prior therapy. It appears, thereforethat HER-2 overexpression in metastatic breast cancer seems to confer sensitivityrather than resistance to taxanes, despite a positive correlation of HER-2positivity with poor prognostic features. We are presently expanding ouranalysis to address other relevant oncogene modulators of paclitaxel cytotoxicity,including regulators of apoptotic cell death.[56,60]

Adjuvant Therapy of Early-Stage Breast Cancer

The significant activity and safety of paclitaxel noted among patientswith advanced disease has motivated us to incorporate the agent into apostoperative adjuvant chemotherapy regimen. We sequence the schedulingof active therapeutic components in the adjuvant setting, as suggestedby mathematical models of tumor kinetics[49] and substantiated by a clinicaltrial.[61] We have previously demonstrated the feasibility of sequentialadministration of doxorubicin and high-dose cyclophosphamide as adjuvanttherapy for patients with resectable stage II-III breast cancer with fouror more involved axillary lymph nodes.[62] The recurrence-free survivalcurve noted thus far is encouraging; with a median follow-up time of 895days, a 65% recurrence-free survival rate has been noted among 60 patientswith a median of nine involved axillary nodes.

This experience, coupled with paclitaxel's activity and partial non-cross-resistancewith doxorubicin, led us to incorporate it into an adjuvant chemotherapyregimen for women of the same risk category.[23] Forty-two patients with4 or more positive axillary lymph nodes (median, 8 nodes; range, 4 to 25)have received the regimen of rapidly sequenced doxorubicin (90 mg/m²),paclitaxel (250 mg/m², 24-hour schedule), and high-dose cyclophosphamide(3,000 mg/m²), all administered with G-CSF support, as shown in Figure1.[22] The median delivered dose intensity for each component of thisregimen has been 100% of planned intensity.

Approximately two-thirds of patients had to be hospitalized at leastonce during the regimen, most commonly for febrile neutropenia. A similarproportion of patients required red blood cell transfusion, and 10% requiredplatelet transfusion. The more frequent grade 3 nonhematologic toxicitiesincluded fatigue (24%), bone pain (24%), stomatitis (17%), dermatologicreactions (17%) neurosensory effects (15%), nausea (12%), and diarrhea(7%). Serial gated radionuclide heart scans showed no decline in cardiacejection fraction, and no clinical cardiotoxicity was noted.

At a median follow-up of 448 days from surgery (range, 82 to 632 days),7% of patients have relapsed (Figure 2).In an effort to optimally integrate paclitaxel into adjuvant systemic therapy,we performed a study randomizing patients to receive either a slightlymodified version of the above sequential regimen or single-agent doxorubicin×3 followed by concomitant paclitaxel and high-dose cyclophosphamide.[23]The median number of positive lymph nodes was 8 (range, 1 to 35), and themedian tumor size was 2.3 cm (range, 0.4 to 8.0 cm). All patients receivedG-CSF. A total of 41 patients were enrolled; 21 were randomized to receivesequential paclitaxel and cyclophosphamide (arm A) after dose-dense doxorubicin,and 20 patients received paclitaxel and cyclophosphamide concomitantly(arm B).

At a median follow-up of 10 months (range, 6 to 15 months), there havebeen no relapses, deaths, or instances of cardiac toxicity. The concomitantadministration of paclitaxel and cyclophosphamide was associated with greatertoxicity, with 16 of 20 patients (89%) hospitalized for toxicity comparedwith 4 (19%) of 21 patients on the sequential arm. The concomitant regimenrequired greater dose-reduction and delay after doxorubicin, while offeringno known advantage over sequential administration.

Therefore, the appropriate regimen for phase III testing is sequentialdoxorubicin, paclitaxel, and cyclophosphamide, and a trial testing thisregimen is ongoing (Figure 3). This trialcompares sequential dose-dense chemotherapy with doxorubicin, paclitaxel,and high-dose cyclophosphamide with G-CSF support to a more standard doxorubicin/cyclophosphamidedoublet followed by high-dose chemotherapy (STAMP I or V) requiring peripheralblood progenitor cell (and G-CSF) support.

This study should complement the information being obtained from theimportant intergroup randomized trial (Figure4), which is evaluating the value of four cycles of paclitaxel, administeredvia a 3-hour infusion, after delivery of one of three dose levels of doxorubicin/cyclophosphamide(60/600, 75/600, or 90/600 mg/m², respectively) for four courses asadjuvant chemotherapy for node-positive early-stage breast cancer. It ishoped that these results will be further augmented by those of the NSABPB-28 trial, which is using four courses of paclitaxel or no further therapyafter four courses of standard doxorubicin/cyclophosphamide adjuvant therapy.

Conclusions

By the end of the 1990s, a number of large multicenter trials will haveprovided the answers to important questions regarding the optimal applicationof single-agent paclitaxel (dose and schedule), its role in relation toother active agents and regimens, its comparative impact on QOL (ie, therapeuticindex), and the potential benefits of combination regimens. Importantly,the potential contribution of paclitaxel to improving our ability to cureearly-stage breast cancer will begin to be appreciated when survival curvesfrom ongoing and soon-to-be-completed adjuvant trials mature.

Studies at MSKCC and elsewhere are attempting to characterize in vivoresistance mechanisms to taxanes--efforts that may result in mechanism-directedstrategies to overcome resistance and/or to guide the development of analogs.Translational research involving growth factors and their receptors promisesto exploit an expanding knowledge of autocrine and paracrine pathways.In both the laboratory and the clinic, there are numerous reasons for optimismregarding the future contribution of paclitaxel to the fight against breastcancer.

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