Background In an open-label, randomized, phase 3 trial, we comparedthe efficacy and safety of paclitaxel with that of paclitaxelplus bevacizumab, a monoclonal antibody against vascular endothelialgrowth factor, as initial treatment for metastatic breast cancer.
Methods We randomly assigned patients to receive 90 mg of paclitaxelper square meter of body-surface area on days 1, 8, and 15 every4 weeks, either alone or with 10 mg of bevacizumab per kilogramof body weight on days 1 and 15. The primary end point was progression-freesurvival; overall survival was a secondary end point.
Results From December 2001 through May 2004, a total of 722patients were enrolled. Paclitaxel plus bevacizumab significantlyprolonged progression-free survival as compared with paclitaxelalone (median, 11.8 vs. 5.9 months; hazard ratio for progression,0.60; P<0.001) and increased the objective response rate(36.9% vs. 21.2%, P<0.001). The overall survival rate, however,was similar in the two groups (median, 26.7 vs. 25.2 months;hazard ratio, 0.88; P=0.16). Grade 3 or 4 hypertension (14.8%vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001),headache (2.2% vs. 0.0%, P=0.008), and cerebrovascular ischemia(1.9% vs. 0.0%, P=0.02) were more frequent in patients receivingpaclitaxel plus bevacizumab. Infection was more common in patientsreceiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001),but febrile neutropenia was uncommon (<1% overall).
Conclusions Initial therapy of metastatic breast cancer withpaclitaxel plus bevacizumab prolongs progression-free survival,but not overall survival, as compared with paclitaxel alone.(ClinicalTrials.gov number, NCT00028990
[ClinicalTrials.gov]
.)
Laboratory and clinical evidence supports the central role ofangiogenesis in the progression of breast cancer.1,2 Multipleangiogenic factors are commonly expressed by invasive breastcancers; the 121-amino-acid isoform of vascular endothelialgrowth factor (VEGF) predominates.3 VEGF stimulates endothelialproliferation and migration, inhibits endothelial apoptosis,induces proteinases that remodel the extracellular matrix, increasesvascular permeability and vasodilatation, and inhibits antigen-presentingdendritic cells.4 Differences in function among the variousVEGF isoforms are not well defined, though VEGF-C has a predominantrole in lymphangiogenesis, whereas VEGF-A is more potent ininducing vasodilatation and pathologic angiogenesis.5,6
Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibodydirected against all isoforms of VEGF-A. In a phase 1 and phase2 study that tested three different doses of bevacizumab monotherapy(3, 10, or 20 mg per kilogram of body weight every 2 weeks)in 75 patients with previously treated metastatic breast cancer,the objective response rate was 9.3%, and 17% of patients hada response or were stable at 22 weeks. The dose of 10 mg perkilogram was suggested for further trials.7 In a phase 3 trial,the addition of bevacizumab to capecitabine in patients previouslytreated with anthracyclines and taxanes significantly increasedthe objective response rate (9.1% vs. 19.8%, P=0.001) but notprogression-free survival (4.2 vs. 4.9 months; hazard ratiofor disease progression, 0.98) or overall survival (15.1 vs.14.5 months).8 The present trial (E2100) compared paclitaxelalone with paclitaxel plus bevacizumab as initial therapy forpatients with metastatic breast cancer.
Methods
Patient Eligibility
Patients with histologically or cytologically confirmed metastaticbreast cancer were eligible if they had not received previouscytotoxic therapy for metastatic disease. Previous hormonaltherapy for metastatic breast cancer or cytotoxic adjuvant chemotherapywas allowed. Patients who had received taxane-based adjuvanttherapy were required to have had a disease-free interval ofat least 12 months after completion of taxane therapy. Thosewith human epidermal growth factor receptor type 2 (HER2)–positivebreast cancer (graded as 3+ according to immunohistochemicalanalysis or gene amplification by fluorescence in situ hybridization)were eligible only if they had received trastuzumab. Additionalinclusion criteria included Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1 and adequate renal, hepatic,and hematologic function. The presence of measurable tumor wasnot required for inclusion in the trial.
Patients were excluded if they had a history of or radiographicevidence of central nervous system disease; imaging of the centralnervous system was required as a screening test. Patients werealso excluded if they had had another cancer except basal-cellcarcinoma of the skin or in situ cervical cancer within theprevious 5 years, major surgery within the previous 4 weeks,or other antitumor therapy within the previous 21 days, or ifthey currently had a nonhealing wound or fracture, an infectionrequiring parenteral antibiotics, or clinically significantcardiovascular disease. Patients were excluded if they werecurrently taking therapeutic anticoagulant agents, nonsteroidalantiinflammatory agents, or more than 325 mg of aspirin daily,but prophylactic low-dose anticoagulant agents were permitted.Concurrent administration of bisphosphonates was allowed.
Local institutional review boards approved the protocol. Writteninformed consent was required from each patient before screening.
Treatment Plan
All patients received 90 mg of paclitaxel per square meter ofbody-surface area on days 1, 8, and 15 of every 28-day cycle.The dose was transiently reduced to 65 mg per square meter ifany of the following toxic effects occurred: 1000 to 1499 granulocytesper cubic millimeter, 75,000 to 99,999 platelets per cubic millimeter,aspartate transaminase more than 5 but not more than 10 timesthe upper limit of normal, or 1.6 to 2.5 mg of bilirubin perdeciliter (27 to 43 µmol per liter). The dose was permanentlyreduced to 65 mg per square meter in cases of prolonged granulocytopenia,fever associated with granulocytopenia, bleeding associatedwith 40,000 or fewer platelets per cubic millimeter, and anyplatelet count of 20,000 or fewer per cubic millimeter. Paclitaxelwas withheld in cases of grade 3 neuropathy and resumed at areduced dose on resolution to grade 0 or 1. It was permanentlydiscontinued for severe hypersensitivity reactions or for grade3 or 4 neuropathy lasting more than 3 weeks or recurring afterdose reduction.
Patients assigned to combined therapy received 10 mg of bevacizumabper kilogram intravenously on days 1 and 15. Initially, bevacizumabwas infused for 90 minutes; subsequent infusions were reducedto 60 minutes and then to 30 minutes, as tolerated. Premedicationwas optional. Treatment was interrupted for proteinuria (urinaryprotein excretion, 2000 mg per 24 hours). Antihypertensive therapywas administered at the discretion of the investigator. Bevacizumabtherapy was not withheld or discontinued for paclitaxel-relatedtoxic effects.
The patients continued therapy until disease progression orprohibitive toxic effects occurred. Patients assigned to combinationtherapy who discontinued paclitaxel without disease progression(i.e., because of toxic effects or at the discretion of thepatient or investigator) could continue bevacizumab monotherapyuntil disease progression or unacceptable toxic effects occurred.Patients assigned to paclitaxel monotherapy could not receivebevacizumab at any time.
Safety and Efficacy
Clinical status, liver function, and serum creatinine levelswere assessed before each cycle. A complete blood count wasobtained before each paclitaxel infusion. Dipstick urinalysiswas performed before each bevacizumab infusion; a 24-hour urinesample was obtained for 1+ protein on dipstick testing. Toxiceffects were graded according to the National Cancer InstituteCommon Toxicity Criteria (NCI-CTC), version 2.0. Disease statuswas assessed according to the Response Evaluation Criteria inSolid Tumors (RECIST)9 at baseline and every 12 weeks untilprogression. Quality of life was assessed with the use of theFunctional Assessment of Cancer Therapy–Breast (FACT-B)questionnaire at baseline, week 17, and week 33.
Role of the Sponsor
The E2100 trial was conducted under a corporate research anddevelopment agreement between Genentech and the National CancerInstitute. Genentech provided bevacizumab and partial fundingbut did not participate in the design of the study or data collection.Analysis was conducted by the ECOG. The lead author made thedecision to publish and wrote the manuscript, which was reviewedby all authors and submitted to Genentech for comment. The authorsvouch for the completeness and accuracy of the data.
Statistical Analysis
The primary end point was progression-free survival, definedas the time from randomization to disease progression or deathfrom any cause. In patients with measurable disease, progressionwas determined by RECIST. In patients without measurable lesions,progression was defined as development of new lesions or "unequivocalprogression" of existing lesions. Secondary end points includedobjective response rate, toxic effects, overall survival, andquality of life.
The study design required enrollment of 685 patients to givefull information at 546 progression-free survival events. Thedesign yielded an 85% power to detect a 33% improvement in medianprogression-free survival (from 6 months to 8 months). The trialincluded prespecified stopping rules based on toxic effects,a prespecified stopping rule based on evaluation of efficacyafter 171 progression-free survival events (at 31% information),and two additional planned interim efficacy analyses, at 50%and 78% information. Stopping rules in favor of the alternativehypotheses were obtained by the one-sided Lan–DeMets errorspending rate function corresponding to the O'Brien–Flemingboundary10 with a one-sided type I error of 2.7%; those in favorof the null hypothesis were based on repeated-confidence-intervalsmethods.11 With the futility stopping rules taken into account,the overall type I error was expected to be 2.5% or less. Withthe use of survival data through June 7, 2007, we report thefinal analysis of progression-free survival and overall survival.
Treatment assignments were determined with the use of permutedblocks within strata. Stratification factors included disease-freeinterval (24 months vs. 24 months), number of metastatic sites(<3 vs. 3), previous adjuvant chemotherapy (yes vs. no),and estrogen-receptor status (positive vs. negative vs. unknown).All eligible patients were included in the efficacy analysisaccording to their treatment assignment. The primary prespecifiedanalysis for progression-free survival and overall survivalwas stratified with the use of the log-rank test according toprevious adjuvant therapy and disease-free interval. All treatedpatients were included in the analyses of toxic effects (analyzedas treated), regardless of eligibility.
Time-to-event distributions were estimated by Kaplan–Meieranalysis. Cox proportional-hazards methods, with data stratifiedaccording to previous adjuvant therapy and disease-free interval,were used to estimate hazard ratios and test for the significanceof time-to-event variables. The proportionality assumption wastested by the method of Grambsch and Therneau.12 Both the objectiveresponse rate and toxic effects were compared with the use ofFisher's exact test. Change in quality of life was comparedwith the use of the Wilcoxon rank-sum test. A pattern-mixturemodel analysis for longitudinal data with nonignorable missingdata was also conducted.13 All P values are two-sided; confidenceintervals are at the 95% level.
Results
Patient Population
We randomly assigned 722 patients to treatment between December2001 and May 2004. All 711 treated patients were evaluated fortoxic effects (Figure 1A). Forty-nine enrolled patients (6.8%)did not meet all the eligibility criteria and were excludedfrom efficacy analyses (Figure 1B). Six eligible patients assignedto paclitaxel and two assigned to combination therapy were nottreated but are included in the efficacy analysis accordingto their assignment. The two groups of patients were similarat baseline with respect to demographic and tumor characteristics,except that more patients assigned to paclitaxel alone had eithermeasurable disease or visceral involvement (Table 1).
All treated patients were included in the analyses of toxic effects (Panel A), irrespective of eligibility. All patients meeting eligibility criteria were included in the efficacy analyses (Panel B) according to their randomized treatment assignment. Two eligible patients assigned to paclitaxel plus bevacizumab and six patients assigned to paclitaxel alone never started treatment. Progression-free survival data were censored for patients initiating nonprotocol therapy. CNS denotes central nervous system.
Table 1. Demographic and Disease Characteristics of Eligible Patients.
Efficacy
There were 624 reported events, and paclitaxel plus bevacizumabsignificantly prolonged progression-free survival as comparedwith paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratiofor disease progression, 0.60; P<0.001) (Figure 2A). A Coxregression model including treatment (P<0.001) and the interactionbetween treatment and time (P<0.001) showed that the effectof treatment declined with time. The addition of bevacizumabto paclitaxel significantly improved the objective responserate in all eligible patients (36.9% vs. 21.2%, P<0.001)and in the subgroup of patients with measurable disease at baseline(49.2% vs. 25.2%, P<0.001). At data cutoff, 483 patientshad died, the majority (88.8%) from progressive disease. Combinedtherapy increased the 1-year survival rate (81.2% vs. 73.4%,P=0.01); however, the median overall survival was similar inthe group receiving combined therapy and in the group receivingpaclitaxel alone (26.7 months and 25.2 months, respectively;hazard ratio, 0.88; P=0.16) (Figure 2B).
Progression-free survival (Panel A) and overall survival (Panel B) in all eligible patients were analyzed with the use of the Kaplan–Meier method. Analyses including all patients assigned to treatment yielded similar results (data not shown).
Proportional-hazards models stratified according to disease-freeinterval and adjuvant chemotherapy were fitted to investigatethe effect of bevacizumab on progression-free survival in clinicallyrelevant subgroups of patients (Figure 3). The hazard ratiosfavored combined therapy in all subgroups but did not reachstatistical significance in some of the smaller subgroups. Theaddition of bevacizumab prolonged progression-free survivalfrom 3.0 to 12.0 months (hazard ratio, 0.46; P<0.001) inpatients who had received taxane-based adjuvant therapy. Theeffect of bevacizumab declined significantly with age treatedas a continuous variable (P=0.04). There was no significantinteraction between treatment and any other patient characteristic.
Hazard ratios favor the addition of bevacizumab in all clinically relevant patient subgroups. Only the interaction between treatment assignment and age (treated as a continuous variable) was significant (P=0.04), a result indicating that the effect of bevacizumab declined with age. There was no significant interaction between treatment and any other patient characteristic, suggesting that benefit was not limited to any particular subgroup of patients. The size of the squares is proportional to the size of the subgroup. CI denotes confidence interval, ER estrogen-receptor status (positive or negative), and PR progesterone-receptor status (positive or negative).
Slightly more patients with visceral involvement or measurabledisease were assigned to paclitaxel monotherapy than to combinationtherapy. To investigate the influence of this imbalance andother potential prognostic factors on our results, we conducteda multivariate analysis using the proportional-hazards model,with data stratified according to disease-free interval andadjuvant chemotherapy. We considered the following covariates:treatment assignment, measurable disease, number of diseasesites, estrogen-receptor status, location of disease (visceralonly vs. bone only), age (as a continuous variable), race (whitevs. other), progesterone-receptor status, menopausal status,and the interactions between treatment assignment and age andtime. The final model, which satisfied the Cox model assumption,included treatment assignment (P<0.001), measurable disease(P=0.03), number of disease sites (P=0.003), estrogen-receptorstatus (P<0.001), age (P=0.02), the interaction between treatmentassignment and age (P=0.02), and the interaction between treatmentassignment and time (P<0.001).
To investigate the influence of patient- or investigator-drivenascertainment bias, we compared the distribution of the intervalfrom the last negative disease assessment with the time of documentedprogression. The median was 2.8 months in both groups (P=0.94by the Wilcoxon two-sample test). Similarly, we found no differencein the proportion of patients with an interval less than 2.5months (30.1% vs. 31.7%). Finally, we moved all progression-freesurvival times forward to the next scheduled assessment andrecalculated progression-free survival. The results were similarto those of our original analysis (12.8 vs. 6.2 months; hazardratio, 0.61; P<0.001).
Toxic Effects
The addition of bevacizumab had little effect on the frequencyor severity of expected paclitaxel-related toxic effects (Table 2).Hematologic, gastrointestinal, and musculoskeletal toxic effectswere minimal and similar in both groups. Grade 3 or 4 neuropathy(23.6% vs. 17.6%, P=0.03), infection (9.3% vs. 2.9%, P<0.001)and fatigue (8.5% vs. 4.9%, P=0.04) were more frequent in thecombination group. Paclitaxel was discontinued at least 3 weeksbefore disease progression (or before the last disease assessmentfor patients without progression) in 117 patients treated withpaclitaxel (35.9%) and 178 patients treated with paclitaxelplus bevacizumab (51.3%), most commonly because of cumulativetoxic effects. The median duration of paclitaxel treatment was5.1 months in patients treated with paclitaxel alone and 7.1months in patients treated with combined therapy. Of the patientsin the combination group, 74 (21.3%) continued bevacizumab monotherapyfor a median of 3.7 months. The Supplementary Appendix (availablewith the full text of this article at www.nejm.org) lists thereasons for discontinuation of treatment in both groups.
Hypertension was more common in patients receiving bevacizumaband was managed with medical therapy; grade 4 hypertension developedin only one patient, resulting in discontinuation of bevacizumab.Proteinuria was rarely clinically significant. Grade 3 hemorrhagewas uncommon and its frequency did not differ between treatmentgroups; grade 4 hemorrhage was not reported. Thromboembolicevents were infrequent overall, but there was a significantincrease in cerebrovascular ischemia among patients receivingcombined therapy (1.9% vs. 0.0%, P=0.02). Patients receivingcombined therapy were also more likely to report grade 3 or4 headaches (2.2% vs. 0.0%, P=0.008).
Quality of Life
The FACT-B questionnaire was completed by 631 patients at baseline,488 at 17 weeks, and 368 at 33 weeks. There were no significantdifferences in the mean change in scores from baseline for theFACT-B, the FACT-B subscale, or the Trial Outcome Index14,15(the sum of the physical well-being, functional well-being,and breast cancer–specific questions in the FACT-B) (Figure 4).
The graphs show the mean changes in the scores on the Functional Assessment of Cancer Therapy–Breast (FACT-B) questionnaire (Panel A), the FACT-B subscale (Panel B), and the Trial Outcome Index (Panel C) during treatment. Error bars indicate standard deviations. A decrease in score denotes a decline in health-related quality of life; no significant differences were identified.
Discussion
In this phase 3 trial of paclitaxel plus bevacizumab as theinitial treatment of metastatic breast cancer, the safety profileof the combination was similar to profiles reported in previousrandomized trials.8,16,17,18 Most toxic effects were minimal,rarely limited therapy, and did not have a detrimental effecton overall quality of life.15
We enrolled patients with predominantly HER2-negative breastcancer; no patient received concurrent trastuzumab. Furtherstudies are needed to assess the efficacy of bevacizumab inpatients with HER2-positive metastatic breast cancer.19,20 Inour trial, bevacizumab was not given to patients who had a tumorwith a specific molecular phenotype. Although benefit was seenacross a number of clinically important subgroups, our resultswould be strengthened by the ability to identify patients mostlikely to benefit from VEGF-directed therapies.
In a previous phase 3 study, the addition of bevacizumab tocapecitabine significantly increased the objective responserate but not progression-free survival or overall survival.8What might account for the different results in these trials?It seems unlikely that chance could account for the improvementin progression-free survival found in our trial. Investigatoror patient bias, always a consideration in open-label studies,is unlikely to explain our results. If such biases had a largerole, we would have expected to see a greater improvement inpatients with nonmeasurable lesions, where disease assessmentis necessarily subjective. Actually, the hazard ratio was morefavorable in patients with measurable disease than in thosewith nonmeasurable disease (0.55 vs. 0.68).
Substantial differences between the patient populations of thesestudies may account for the disparate results. All patientsin the earlier study had received previous anthracycline andtaxane therapy, and most (more than 85%) had received chemotherapyfor metastatic disease.8 In contrast, 35.2% of our patientshad not received any previous chemotherapy, and only 13.2% hadreceived both an anthracycline and a taxane as adjuvant therapy.
A recent phase 2 trial found a median time to disease progressionof only 5.7 months (95% confidence interval, 4.9 to 8.4) withcapecitabine plus bevacizumab as initial chemotherapy.21 Perhapspaclitaxel is uniquely synergistic with bevacizumab. Indeed,the taxanes have distinct antiangiogenic activity.22 In preclinicalstudies, VEGF protected endothelial cells from the antiangiogenicproperties of docetaxel; bevacizumab overcame this protectiveeffect in vitro and in vivo.23
Despite a striking improvement in progression-free survival,the addition of bevacizumab did not prolong overall survivalin this study. Patients with metastatic breast cancer frequentlyreceive multiple therapies during the course of their disease.Data on treatment administered after progression were not collectedin this trial, precluding an exploratory analysis of the influenceof subsequent therapy on overall survival. Though the mechanismsof resistance to bevacizumab are not well defined,24,25 it ispossible that resistance to bevacizumab results in relativeresistance to subsequent therapies. Alternatively, rebound increasesin VEGF on discontinuation of bevacizumab could result in moreaggressive disease. Resistance to paclitaxel, whether mediatedby increased expression of the multidrug resistance protein26or by microtubule mutations,27 could also cause resistance tosubsequent chemotherapy.
We found that treatment with bevacizumab early in the courseof metastatic breast cancer, when angiogenic pathways are lessredundant, improved progression-free survival and the objectiveresponse rate. Although our patients were receiving their firsttreatment for metastatic breast cancer, only a third had neverreceived any chemotherapy. More than 80% had overt visceralinvolvement, presumably with an established vasculature. Inshort, first-line therapy for metastatic breast cancer is not"early" in the natural history of breast cancer. Recent laboratorystudies suggest that the initial events in the development ofmetastasis are VEGF-dependent.28,29 If this is true, the mostsuccessful clinical application of angiogenesis inhibitors islikely to be in patients with micrometastatic disease in theadjuvant setting.
Supported in part by Public Health Service Grants CA23318, CA66636,CA21115, CA49883, and CA16116 from the National Cancer Institute,National Institutes of Health, Department of Health and HumanServices, and by Genentech.
Dr. Miller reports receiving lecture fees and consulting feesfor service on breast cancer advisory boards from Roche. Dr.Gralow reports receiving lecture fees and consulting fees forservice on breast cancer advisory boards from Genentech andRoche. Dr. Dickler and Dr. Cobleigh report receiving consultingfees from Genentech for service on breast cancer advisory boards.Dr. Cobleigh reports receiving lecture fees from Genentech.Dr. Perez reports receiving consulting fees from Genentech,GlaxoSmithKline, Bristol-Myers Squibb, and Sanofi-Aventis forservice on breast cancer advisory boards, as well as grant supportfor clinical translational studies from Genentech. No otherpotential conflict of interest relevant to this article wasreported.
The views expressed are those of the authors and do not necessarilyrepresent the official views of the National Cancer Institute.
We thank Dr. George Sledge and Dr. Robert Gray for helpful discussionsand Carol Chami for providing technical assistance in preparingthe manuscript.
Source Information
From Indiana University Cancer Center, Indianapolis (K.M.); Dana–Farber Cancer Institute, Boston (M.W.); Puget Sound Oncology Consortium, Seattle (J.G.); Memorial Sloan-Kettering Cancer Center, New York (M.D.); Rush–Presbyterian–St. Luke's Medical Center, Chicago (M.C.); Mayo Clinic, Jacksonville, FL (E.A.P.); British Columbia Cancer Agency–Vancouver Cancer Center, Vancouver, BC, Canada (T.S.); Evanston Northwestern Healthcare and Robert H. Lurie Comprehensive Cancer Center of Northwestern University — both in Evanston, IL (D.C.); and Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore (N.E.D.).
Address reprint requests to Dr. Miller at the Indiana Cancer Pavilion, 535 Barnhill Dr., RT473, Indianapolis, IN 46202, or at kathmill{at}iupui.edu.
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2000 mg per 24 hours). Antihypertensive therapy was administered at the discretion of the investigator. Bevacizumab therapy was not withheld or discontinued for paclitaxel-related toxic effects. 
24 months vs. 
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