Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Herbert Hurwitz, M.D., Louis Fehrenbacher, M.D., William Novotny, M.D., Thomas Cartwright, M.D., John Hainsworth, M.D., William Heim, M.D., Jordan Berlin, M.D., Ari Baron, M.D., Susan Griffing, B.S., Eric Holmgren, Ph.D., Napoleone Ferrara, M.D., Gwen Fyfe, M.D., Beth Rogers, B.S., Robert Ross, M.D., and Fairooz Kabbinavar, M.D.
Background Bevacizumab, a monoclonal antibody against vascularendothelial growth factor, has shown promising preclinical andclinical activity against metastatic colorectal cancer, particularlyin combination with chemotherapy.
Methods Of 813 patients with previously untreated metastaticcolorectal cancer, we randomly assigned 402 to receive irinotecan,bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5mg per kilogram of body weight every two weeks) and 411 to receiveIFL plus placebo. The primary end point was overall survival.Secondary end points were progression-free survival, the responserate, the duration of the response, safety, and the qualityof life.
Results The median duration of survival was 20.3 months in thegroup given IFL plus bevacizumab, as compared with 15.6 monthsin the group given IFL plus placebo, corresponding to a hazardratio for death of 0.66 (P<0.001). The median duration ofprogression-free survival was 10.6 months in the group givenIFL plus bevacizumab, as compared with 6.2 months in the groupgiven IFL plus placebo (hazard ratio for disease progression,0.54; P<0.001); the corresponding rates of response were44.8 percent and 34.8 percent (P=0.004). The median durationof the response was 10.4 months in the group given IFL plusbevacizumab, as compared with 7.1 months in the group givenIFL plus placebo (hazard ratio for progression, 0.62; P=0.001).Grade 3 hypertension was more common during treatment with IFLplus bevacizumab than with IFL plus placebo (11.0 percent vs.2.3 percent) but was easily managed.
Conclusions The addition of bevacizumab to fluorouracil-basedcombination chemotherapy results in statistically significantand clinically meaningful improvement in survival among patientswith metastatic colorectal cancer.
Vascular endothelial growth factor (VEGF), a diffusible glycoproteinproduced by normal and neoplastic cells, is an important regulatorof physiologic and pathologic angiogenesis.1 Preclinical studieshave shown that a murine antihuman monoclonal antibody againstVEGF can inhibit the growth of human tumor xenografts,2 anda humanized variant of this antibody (bevacizumab [Avastin])3is being evaluated in clinical trials as a treatment for variouscancers.
In addition to its direct antiangiogenic effects, bevacizumabmay also improve the delivery of chemotherapy by altering tumorvasculature and decreasing the elevated interstitial pressurein tumors.4,5 In a phase 2 trial of the treatment of colorectalcancer, the addition of bevacizumab to fluorouracil plus leucovorin6increased the response rate, the median time to disease progression,and the median duration of survival. The current phase 3 trialwas designed to determine whether the addition of bevacizumabto a combination of irinotecan, fluorouracil, and leucovorin(IFL)7 improves survival among patients with metastatic colorectalcancer more than does a regimen of IFL plus placebo.
Methods
Patients
Eligible patients had histologically confirmed metastatic colorectalcarcinoma, with bidimensionally measurable disease. Other inclusioncriteria included an age of at least 18 years, an Eastern CooperativeOncology Group (ECOG) performance status8 of 0 or 1, a lifeexpectancy of more than three months, and written informed consent.Adequate hematologic, hepatic, and renal function (includingurinary excretion of no more than 500 mg of protein per day)was also required.
Exclusion criteria included prior chemotherapy or biologic therapyfor metastatic disease (adjuvant or radiosensitizing use offluoropyrimidines with or without leucovorin or levamisole morethan 12 months before study entry was permitted), receipt ofradiotherapy within 14 days before the initiation of study treatment,major surgery within 28 days before the initiation of studytreatment, clinically significant cardiovascular disease, clinicallydetectable ascites, pregnancy or lactation, regular use of aspirin(more than 325 mg per day) or other nonsteroidal antiinflammatoryagents, preexisting bleeding diatheses or coagulopathy or theneed for full-dose anticoagulation, and known central nervoussystem metastases.
The protocol was approved by the institutional review boardsof all participating institutions and carried out in accordancewith the Declaration of Helsinki, current Food and Drug AdministrationGood Clinical Practices, and local ethical and legal requirements.
Study Design
Eligible patients were assigned to treatment with the use ofa dynamic randomization algorithm that was designed to achieveoverall balance between groups; randomization was stratifiedaccording to study center, baseline ECOG performance status(0 vs. 1), site of primary disease (colon vs. rectum), and numberof metastatic sites (one vs. more than one). Initially, patientswere randomly assigned in a 1:1:1 ratio to receive IFL plusplacebo, IFL plus bevacizumab, or fluorouracil and leucovorinplus bevacizumab (Table 1), each of which was to continue untildisease progression or unacceptable adverse effects occurredor for a maximum of 96 weeks.
An interim analysis was scheduled to be performed after 300patients underwent randomization, at which time an unblinded,independent data-monitoring committee was to assess the safetyof IFL plus bevacizumab, on the basis of all the available safetyinformation, including the number of deaths in each group, butin the absence of information related to tumor response. Ifthe data-monitoring committee found no untoward adverse eventsattributable to the addition of bevacizumab to IFL, the enrollmentof patients in the group assigned to receive fluorouracil andleucovorin plus bevacizumab was to be discontinued, and additionalpatients would be randomly assigned in a 1:1 ratio to receiveeither IFL plus placebo or IFL plus bevacizumab. However, ifthe data-monitoring committee concluded that the safety profileof IFL plus bevacizumab was unacceptable, assignment to thattreatment was to be discontinued, and patients would insteadbe randomly assigned in a 1:1 ratio to receive either the combinationof fluorouracil and leucovorin plus bevacizumab or IFL plusplacebo.
Tumor responses and progression were determined with the useof the Response Evaluation Criteria in Solid Tumors.9 At thetime of disease progression, the treatment assignment was revealedand patients could be offered second-line treatment. Such patientsin the group assigned to bevacizumab-containing treatment hadthe option to continue bevacizumab during this second-line treatment.No crossovers were allowed in the group given IFL plus placebo.Patients assigned to a treatment containing bevacizumab whohad no signs of progressive disease at the end of the 96-weekstudy period could continue to receive bevacizumab in a separateextension study. Patients in a group receiving bevacizumab whohad a confirmed complete response or unacceptable adverse effectsfrom chemotherapy could discontinue chemotherapy and receivebevacizumab alone.
Bevacizumab (or placebo) was administered concomitantly withchemotherapy. Doses of bevacizumab and chemotherapy were recalculatedif a patient's weight changed by at least 10 percent duringthe study. Standard intracycle and intercycle dose modificationsof irinotecan and fluorouracil (according to the package insert)10were permitted in patients with treatment-related adverse events.The doses of leucovorin and bevacizumab were not altered.
In the analysis of survival and subsequent treatment, all patientswere followed until death, loss to follow-up, or terminationof the study.
Assessments
After the baseline evaluation, tumor status was assessed every6 weeks for the first 24 weeks of the study and then every 12weeks for the remainder of therapy. All complete and partialresponses9 required confirmation at least four weeks after theywere first noted.
Safety was assessed on the basis of reports of adverse events,laboratory-test results, and vital-sign measurements. Adverseevents were categorized according to the Common Toxicity Criteriaof the National Cancer Institute, version 2, in which a gradeof 1 indicates mild adverse events, a grade of 2 moderate adverseevents, a grade of 3 serious adverse events, and a grade of4 life-threatening adverse events. Prespecified safety measuresincluded the incidence of all adverse events, all serious adverseevents, and adverse events that have been associated with bevacizumab— hypertension, thrombosis, bleeding of grade 3 or 4,and proteinuria — as well as diarrhea of grade 3 or 4,and changes from baseline in various laboratory values and vitalsigns.
To monitor the safety of the regimen of IFL plus placebo andof IFL plus bevacizumab, the incidence of death, serious adverseevents, diarrhea of grade 3 or 4, bleeding of grade 3 or 4 fromany source, and thrombosis was monitored during the study inan unblinded fashion by the data-safety monitoring committeeuntil the completion of recruitment or the time of the interimanalysis of efficacy, whichever came first.
Statistical Analysis
The primary outcome measure was the duration of overall survival;survival was measured without regard to subsequent treatments.There was no crossover between groups, however. Secondary outcomemeasures were progression-free survival, objective responserates (complete and partial responses), the duration of responses,and the quality of life.
For patients who were alive at the time of analysis, data onsurvival were censored at the time of the last contact. Progression-freesurvival was defined as the time from randomization to progressionor death during the study, with death during the study definedas any death that occurred within 30 days after the last doseof bevacizumab or chemotherapy. For patients without diseaseprogression at the time of the final analysis, data on progression-freesurvival were censored at the last assessment of tumor statusor on day 0 if no further assessment was performed after baseline.Patients without adequate follow-up data were categorized ashaving no response.
To detect a hazard ratio of 0.75 for death in the group givenIFL plus bevacizumab as compared with the control group, approximately385 deaths were required. All calculations were performed withthe log-rank test and involved two-sided P values, with an alphavalue of 0.05, a statistical power of 80 percent, and one interimanalysis of efficacy.
Interim analyses were conducted in an unblinded fashion by anindependent data-monitoring committee. An interim analysis ofsafety was conducted after the random assignment of approximately100 patients to each group. A second interim analysis of safetyand efficacy was performed after 193 deaths had occurred (halfthe number of required events). According to the protocol, theseinterim efficacy analyses were governed by a formal group sequentialstopping rule based on an O'Brien–Fleming spending function.
Efficacy analyses were performed according to the intention-to-treatprinciple. Safety analyses included all patients who receivedat least one dose of study medication.
The study was designed by Genentech in collaboration with theinvestigators. Genentech collected and analyzed the data; allauthors had access to the primary data. The decision to publishthe paper was made by all the investigators. The article waswritten by Dr. Hurwitz.
Results
Characteristics of the Patients
Between September 2000 and May 2002, 923 patients underwentrandomization at 164 sites in the United States, Australia,and New Zealand. After 313 patients had been randomly assignedto one of the three groups — 100 to IFL plus placebo,103 to IFL plus bevacizumab, and 110 to fluorouracil, leucovorin,and bevacizumab — assignment to the group given fluorouracil,leucovorin, and bevacizumab was halted (the results in thisgroup are not reported). This step was required by the protocolafter the first formal interim analysis of safety concludedthat the regimen of IFL plus bevacizumab had an acceptable safetyprofile and that assignment to this group could continue.
The intention-to-treat analysis of the primary end point ofoverall survival included 411 patients in the group given IFLplus placebo and 402 patients in the group given IFL plus bevacizumab.Table 2 shows selected demographic and baseline characteristics,which were well balanced between the groups. Similar numbersof patients in each group had previously undergone surgery orreceived radiation therapy or adjuvant chemotherapy for colorectalcancer.
Table 2. Selected Demographic and Baseline Characteristics.
Treatment
The median duration of therapy was 27.6 weeks in the group givenIFL plus placebo and 40.4 weeks in the group given IFL plusbevacizumab. The percentage of the planned dose of irinotecanthat was given was similar in the two groups (78 percent inthe group given IFL plus placebo and 73 percent in the groupgiven IFL plus bevacizumab).
As of April 2003, 33 patients in the group given IFL plus placeboand 71 in the group given IFL plus bevacizumab were still takingtheir assigned initial therapy. The rates of use of second-linetherapies that may have affected survival, such as oxaliplatinor metastasectomy, were well balanced between the two groups.In both groups, approximately 50 percent of patients receivedsome form of second-line therapy; 25 percent of all patientsreceived oxaliplatin, and less than 2 percent of patients underwentmetastasectomy.
Efficacy
The median duration of overall survival, the primary end point,was significantly longer in the group given IFL plus bevacizumabthan in the group given IFL plus placebo (20.3 months vs. 15.6months), which corresponds to a hazard ratio for death of 0.66(P<0.001) (Table 3 and Figure 1), or a reduction of 34 percentin the risk of death in the bevacizumab group. The one-yearsurvival rate was 74.3 percent in the group given IFL plus bevacizumaband 63.4 percent in the group given IFL plus placebo (P<0.001).In the subgroup of patients who received second-line treatmentwith oxaliplatin, the median duration of overall survival was25.1 months in the group given IFL plus bevacizumab and 22.2months in the group given IFL plus placebo.
The median duration of survival (indicated by the dotted lines) was 20.3 months in the group given irinotecan, fluorouracil, and leucovorin (IFL) plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001).
The addition of bevacizumab to IFL was associated with increasesin the median duration of progression-free survival (10.6 monthsvs. 6.2 months; hazard ratio for progression, 0.54, for thecomparison with the group given IFL plus placebo; P<0.001);response rate (44.8 percent vs. 34.8 percent; P=0.004); andthe median duration of response (10.4 months vs. 7.1 months;hazard ratio for progression, 0.62; P=0.001) (Table 3). Figure 2shows the Kaplan–Meier estimates of progression-freesurvival. Treatment effects were consistent across prespecifiedsubgroups, including those defined according to age, sex, race,ECOG performance status, location of the primary tumor, presenceor absence of prior adjuvant therapy, duration of metastaticdisease, number of metastatic sites, years since the diagnosisof colorectal cancer, presence or absence of prior radiotherapy,baseline tumor burden, and serum concentrations of albumin,alkaline phosphatase, and lactate dehydrogenase (data not shown).
Figure 2. Kaplan–Meier Estimates of Progression-free Survival.
The median duration of progression-free survival (indicated by the dotted lines) was 10.6 months in the group given irinotecan, fluorouracil, and leucovorin (IFL) plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo, corresponding to a hazard ratio for progression of 0.54 (P<0.001).
Safety
Table 4 presents the incidence of selected grade 3 or 4 adverseevents during the assigned treatment, without adjustment forthe median duration of therapy (27.6 weeks in the group givenIFL plus placebo and 40.4 weeks in the group given IFL plusbevacizumab). The incidence of any grade 3 or 4 adverse eventswas approximately 10 percentage points higher among patientsreceiving IFL plus bevacizumab than among patients receivingIFL plus placebo, largely because of an increase in the incidenceof grade 3 hypertension (requiring treatment) and small increasesin the incidence of grade 4 diarrhea and leukopenia. However,there was no significant difference in the incidence of adverseevents leading to hospitalization or to the discontinuationof study treatment or in the 60-day rate of death from any cause.
Phase 1 and 2 trials had identified hemorrhage, thromboembolism,proteinuria, and hypertension as possible bevacizumab-associatedadverse effects. However, in our study, only the incidence ofhypertension was clearly increased in the group given IFL plusbevacizumab, as compared with the group given IFL plus placebo.All episodes of hypertension were manageable with standard oralantihypertensive agents (e.g., calcium-channel blockers, angiotensin-converting–enzymeinhibitors, and diuretics). There were no discontinuations ofbevacizumab therapy, hypertensive crises, or deaths relatedto hypertension in the bevacizumab group.
Rates of grade 2 or 3 proteinuria (there were no episodes ofgrade 4 proteinuria or nephrotic syndrome) and grade 3 or 4bleeding from any cause were similar in the two groups, althoughall three cases of grade 4 bleeding were in the group givenIFL plus bevacizumab. The incidence of all venous and arterialthrombotic events was 19.4 percent in the group given IFL plusbevacizumab and 16.2 percent in the group given IFL plus placebo(P=0.26).
Gastrointestinal perforation occurred in six patients (1.5 percent)receiving IFL plus bevacizumab. One patient died as a directresult of this event, whereas the other five recovered (threeof them were able to restart treatment without subsequent complications).Of the six patients with a perforation, three had a confirmedcomplete or partial response to IFL plus bevacizumab. Factorsother than the study treatment that may have been associatedwith gastrointestinal perforation were colon surgery withinthe previous two months in two patients and peptic-ulcer diseasein one patient.
Discussion
The results of this phase 3 study provide support for the useof antiangiogenic agents in the treatment of cancer. When thistrial was designed and initiated, the addition of irinotecanto fluorouracil and leucovorin had just been shown to prolongsurvival in patients with metastatic colorectal cancer and wasconsidered the new standard first-line therapy for this disease.Our randomized trial was designed to compare the relative safetyand efficacy of two regimens for metastatic colorectal cancer:IFL alone and with bevacizumab, a humanized monoclonal antibodyagainst VEGF.
We found that the addition of bevacizumab to IFL improved overallsurvival. Furthermore, the increase of 4.7 months in the medianduration of survival attributable to bevacizumab is as largeas or larger than that observed in any other phase 3 trial forthe treatment of colorectal cancer.11 The median survival of20.3 months in the bevacizumab-treated population occurred inspite of the limited availability of oxaliplatin for second-linetherapy during this trial.
As compared with IFL alone, the regimen of IFL plus bevacizumabincreased progression-free survival from a median of 6.2 monthsto 10.6 months, the overall response rate from 34.8 percentto 44.8 percent, and the median duration of response from 7.1months to 10.4 months. These improvements are clinically meaningful.We would not have predicted that the absolute improvement inthe response rate of 10 percent with IFL plus bevacizumab wouldhave been associated with an increase in survival of this magnitude.This observation suggests that the primary mechanism of bevacizumabis the inhibition of tumor growth, rather than cytoreduction.
This clinical benefit was accompanied by a relatively modestincrease in side effects of treatment, which were easily managed.There was an absolute increase of approximately 10 percent inthe overall incidence of grade 3 and 4 adverse effects, attributablelargely to hypertension requiring treatment, diarrhea, and leukopenia.The 60-day rates of death from any cause, hospitalization, anddiscontinuation of treatment were not significantly increasedby the addition of bevacizumab to IFL.
Previous phase 1 and 2 clinical trials suggested that treatmentwith bevacizumab alone or with chemotherapy resulted in an increasedincidence of thrombosis, bleeding, proteinuria, and hypertension.6,12With the exception of hypertension, we did not find an excessof these side effects as compared with their incidence in thegroup given IFL plus placebo — thus highlighting the importanceof randomized, placebo-controlled studies for the evaluationof safety as well as efficacy. One new potential adverse effectthat we did find was gastrointestinal perforation. This complicationwas uncommon and had variable clinical presentations. Severebowel complications, particularly in patients with neutropenia,have been reported with IFL and other chemotherapy regimensfor colorectal cancer,7,13 and in one series, fistulas werereported in over 2 percent of patients treated with fluorouracil-basedregimens.14 No such events occurred in the group given IFL plusplacebo, whereas six cases were observed in the group givenIFL plus bevacizumab (1.5 percent), sometimes in the settingof overall tumor responses. Although three of these six patientswere able to restart treatment without subsequent complications,one patient died and two discontinued therapy permanently asa result of this complication. VEGF is associated with woundhealing,15,16 and VEGF inhibitors can inhibit dermal-wound angiogenesisin patients with cancer. Although infrequent and associatedwith colorectal cancer and its complications, the risk of thisadverse event may be increased by bevacizumab therapy.
Recently, oxaliplatin has been approved in the United Statesfor both second-line and first-line treatment of colorectalcancer.17 Although there are not yet sufficient long-term dataon the efficacy of bevacizumab in combination with oxaliplatin-basedregimens, studies addressing the role of these combinationsare ongoing.18 The improvement in the clinical outcome affordedby the addition of bevacizumab to IFL or to fluorouracil alone6,19suggests that blocking VEGF may be a broadly applicable approachto the treatment of colorectal cancer.
In summary, the addition of bevacizumab to bolus IFL conferreda clinically meaningful and statistically significant improvementin overall survival, progression-free survival, and responserate. These results suggest that bevacizumab plus fluorouracil-basedchemotherapy should be considered a new option for the treatmentof metastatic colorectal cancer.
Funded by Genentech. Dr. Hurwitz was supported in part by aCareer Development Grant (K23 CA085582–04).
Dr. Hurwitz reports having received consulting fees from Genentech,Pfizer, and Imclone; lecture fees from Genentech and Pfizer;and research support from AstraZeneca, Cephalon, Bristol-MyersSquibb, Genentech, GlaxoSmithKline, and Sanofi-Synthelabo; Dr.Cartwright consulting fees from Genentech; Dr. Hainsworth lecturefees from Genentech and research support from Genentech, Sanofi-Synthelabo,and Novartis; Dr. Heim consulting fees from Genentech and havingequity in Genentech; Dr. Berlin consulting fees from Genentechand Pfizer and lecture fees from Sanofi-Synthelabo; and Dr.Kabbinavar lecture fees from Genentech. Ms. Griffing and Ms.Rogers and Drs. Ferrara, Novotny, Holmgren, and Fyfe are employeesof Genentech and report having equity in Genentech. Dr. Rosswas an employee of Genentech during the trial.
We are indebted to the patients who participated in this study,their families, and their support teams; to the health careteams at each center; to the members of the Data and SafetyMonitoring Board — Richard Schilsky (chair), Robert Mayer,Alan Venook, and Lee-Jen Wei — and to the members of theData Coordinating Center (Statistics Collaborative) for theirinvaluable assistance in the conduct of this study.
Source Information
From Duke University, Durham, N.C. (H.H.); Kaiser Permanente, Vallejo, Calif. (L.F.); Genentech, South San Francisco, Calif. (W.N., S.G., E.H., N.F., G.F., B.R., R.R.); Ocala Oncology, Ocala, Fla. (T.C.); Sarah Cannon Cancer Center, Nashville (J.H.); Hematology and Oncology Associates of Northeastern Pennsylvania, Scranton, Pa. (W.H.); Vanderbilt University, Nashville (J.B.); California Pacific Medical Center, San Francisco (A.B.); and the University of California at Los Angeles, Los Angeles (F.K.).
Address reprint requests to Dr. Hurwitz at the Department of Medical Oncology and Transplantation, Rm. 3802 Red Zone, Duke South Clinics, Box 3052, Duke University Medical Center, Durham, NC 27710, or at hurwi004{at}mc.duke.edu.
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Bevacizumab in Colorectal Cancer
Sonpavde G., Sharieff W., Hurwitz H. I., Novotny W., Kabbinavar F., the Bevacizumab Study Team
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351:1690-1691, Oct 14, 2004.
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(2008). Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer. JCO
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Van Buren, G. II, Yang, A. D., Dallas, N. A., Gray, M. J., Lim, S. J., Xia, L., Fan, F., Somcio, R., Wu, Y., Hicklin, D. J., Ellis, L. M.
(2008). Effect of Molecular Therapeutics on Liver Regeneration in a Murine Model. JCO
26: 1836-1842
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Laurie, S. A., Gauthier, I., Arnold, A., Shepherd, F. A., Ellis, P. M., Chen, E., Goss, G., Powers, J., Walsh, W., Tu, D., Robertson, J., Puchalski, T. A., Seymour, L.
(2008). Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non-Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group. JCO
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Adam, R., Wicherts, D. A., de Haas, R. J., Aloia, T., Levi, F., Paule, B., Guettier, C., Kunstlinger, F., Delvart, V., Azoulay, D., Castaing, D.
(2008). Complete Pathologic Response After Preoperative Chemotherapy for Colorectal Liver Metastases: Myth or Reality?. JCO
26: 1635-1641
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Seiwert, T. Y., Haraf, D. J., Cohen, E. E.W., Stenson, K., Witt, M. E., Dekker, A., Kocherginsky, M., Weichselbaum, R. R., Chen, H. X., Vokes, E. E.
(2008). Phase I Study of Bevacizumab Added to Fluorouracil- and Hydroxyurea-Based Concomitant Chemoradiotherapy for Poor-Prognosis Head and Neck Cancer. JCO
26: 1732-1741
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Kobayashi, H., Sugihara, K., Uetake, H., Higuchi, T., Yasuno, M., Enomoto, M., Kuramochi, H., Lenz, H.-J., Danenberg, K. D., Danenberg, P. V.
(2008). Messenger RNA Expression of Vascular Endothelial Growth Factor and Its Receptors in Primary Colorectal Cancer and Corresponding Liver Metastasis. Ann. Surg. Oncol.
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Hsu, A. R., Chen, X.
(2008). Advances in Anatomic, Functional, and Molecular Imaging of Angiogenesis. JNM
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Jaissle, G. B., Ulmer, A., Henke-Fahle, S., Fierlbeck, G., Bartz-Schmidt, K. U., Szurman, P.
(2008). Suppression of Melanoma-Associated Neoangiogenesis by Bevacizumab. Arch Dermatol
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Bianciotto, C., Shields, C. L., Kang, B., Shields, J. A.
(2008). Treatment of Iris Melanoma and Secondary Neovascular Glaucoma Using Bevacizumab and Plaque Radiotherapy. Arch Ophthalmol
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Italiano, A., Massard, C., Bahleda, R., Vataire, A.-L., Deutsch, E., Magne, N., Pignon, J.-P., Vassal, G., Armand, J.-P., Soria, J.-C.
(2008). Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy. Ann Oncol
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Benesch, M., Windelberg, M., Sauseng, W., Witt, V., Fleischhack, G., Lackner, H., Gadner, H., Bode, U., Urban, C.
(2008). Compassionate use of bevacizumab (Avastin(R)) in children and young adults with refractory or recurrent solid tumors. Ann Oncol
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Tol, J., Koopman, M., Rodenburg, C. J., Cats, A., Creemers, G. J., Schrama, J. G., Erdkamp, F. L. G., Vos, A. H., Mol, L., Antonini, N. F., Punt, C. J. A.
(2008). A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol
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Picchio, M., Beck, R., Haubner, R., Seidl, S., Machulla, H.-J., Johnson, T. D., Wester, H.-J., Reischl, G., Schwaiger, M., Piert, M.
(2008). Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography. JNM
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Brostjan, C., Gebhardt, K., Gruenberger, B., Steinrueck, V., Zommer, H., Freudenthaler, H., Roka, S., Gruenberger, T.
(2008). Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels. Clin. Cancer Res.
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Meyer-Losic, F., Nicolazzi, C., Quinonero, J., Ribes, F., Michel, M., Dubois, V., de Coupade, C., Boukaissi, M., Chene, A.-S., Tranchant, I., Arranz, V., Zoubaa, I., Fruchart, J.-S., Ravel, D., Kearsey, J.
(2008). DTS-108, A Novel Peptidic Prodrug of SN38: In vivo Efficacy and Toxicokinetic Studies. Clin. Cancer Res.
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Folprecht, G., Seymour, M. T., Saltz, L., Douillard, J.-Y., Hecker, H., Stephens, R. J., Maughan, T. S., Van Cutsem, E., Rougier, P., Mitry, E., Schubert, U., Kohne, C.-H.
(2008). Irinotecan/Fluorouracil Combination in First-Line Therapy of Older and Younger Patients With Metastatic Colorectal Cancer: Combined Analysis of 2,691 Patients in Randomized Controlled Trials. JCO
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Borner, M., Koeberle, D., Von Moos, R., Saletti, P., Rauch, D., Hess, V., Trojan, A., Helbling, D., Pestalozzi, B., Caspar, C., Ruhstaller, T., Roth, A., Kappeler, A., Dietrich, D., Lanz, D., Mingrone, W., for the Swiss Group for Clinical Cancer Research (,
(2008). Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Ann Oncol
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Dang, D. T., Chun, S. Y., Burkitt, K., Abe, M., Chen, S., Havre, P., Mabjeesh, N. J., Heath, E. I., Vogelzang, N. J., Cruz-Correa, M., Blayney, D. W., Ensminger, W. D., Croix, B. St., Dang, N. H., Dang, L. H.
(2008). Hypoxia-Inducible Factor-1 Target Genes as Indicators of Tumor Vessel Response to Vascular Endothelial Growth Factor Inhibition. Cancer Res.
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Norden, A. D., Young, G. S., Setayesh, K., Muzikansky, A., Klufas, R., Ross, G. L., Ciampa, A. S., Ebbeling, L. G., Levy, B., Drappatz, J., Kesari, S., Wen, P. Y.
(2008). Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence. Neurology
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(2008). VEGF Expression Predicts Survival in Patients with Peritoneal Surface Metastases from Mucinous Adenocarcinoma of the Appendix and Colon. Ann. Surg. Oncol.
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Sini, P., Samarzija, I., Baffert, F., Littlewood-Evans, A., Schnell, C., Theuer, A., Christian, S., Boos, A., Hess-Stumpp, H., Foekens, J. A., Setyono-Han, B., Wood, J., Hynes, N. E.
(2008). Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics. Cancer Res.
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Alferez, D., Wilkinson, R. W., Watkins, J., Poulsom, R., Mandir, N., Wedge, S. R., Pyrah, I. T., Smith, N. R., Jackson, L., Ryan, A. J., Goodlad, R. A.
(2008). Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in ApcMin/+ mice. Molecular Cancer Therapeutics
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Levchenko, T., Veitonmaki, N., Lundkvist, A., Gerhardt, H., Ming, Y., Berggren, K., Kvanta, A., Carlsson, R., Holmgren, L.
(2008). Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo. FASEB J.
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(2008). Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann Oncol
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(2008). Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients. Ann Oncol
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Maharaj, A. S.R., Walshe, T. E., Saint-Geniez, M., Venkatesha, S., Maldonado, A. E., Himes, N. C., Matharu, K. S., Karumanchi, S. A., D'Amore, P. A.
(2008). VEGF and TGF-{beta} are required for the maintenance of the choroid plexus and ependyma. J. Exp. Med.
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(2008). Update on Targeted Therapy--Focus on Monoclonal Antibodies. Journal of Pharmacy Practice
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(2008). What's new in oncology: targeted therapy. Contin Educ Anaesth Crit Care Pain
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Van Cutsem, E., Verslype, C., Beale, P., Clarke, S., Bugat, R., Rakhit, A., Fettner, S. H., Brennscheidt, U., Feyereislova, A., Delord, J.-P
(2008). A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients. Ann Oncol
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Beaudry, P., Nilsson, M., Rioth, M., Prox, D., Poon, D., Xu, L., Zweidler-Mckay, P., Ryan, A., Folkman, J., Ryeom, S., Heymach, J.
(2008). Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. Molecular Cancer Therapeutics
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Zhu, A. X., Holalkere, N. S., Muzikansky, A., Horgan, K., Sahani, D. V.
(2008). Early Antiangiogenic Activity of Bevacizumab Evaluated by Computed Tomography Perfusion Scan in Patients with Advanced Hepatocellular Carcinoma. The Oncologist
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Bender, J. L. G., Adamson, P. C., Reid, J. M., Xu, L., Baruchel, S., Shaked, Y., Kerbel, R. S., Cooney-Qualter, E. M., Stempak, D., Chen, H. X., Nelson, M. D., Krailo, M. D., Ingle, A. M., Blaney, S. M., Kandel, J. J., Yamashiro, D. J.
(2008). Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study. JCO
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(2008). Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107. JCO
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Garcia, A. A., Hirte, H., Fleming, G., Yang, D., Tsao-Wei, D. D., Roman, L., Groshen, S., Swenson, S., Markland, F., Gandara, D., Scudder, S., Morgan, R., Chen, H., Lenz, H.-J., Oza, A. M.
(2008). Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia. JCO
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Posner, M. C., Niedzwiecki, D., Venook, A. P., Hollis, D. R., Kindler, H. L., Martin, E. W., Schilsky, R. L., Goldberg, R. M., for the Cancer and Leukemia Group B,
(2008). A Phase II Prospective Multi-institutional Trial of Adjuvant Active Specific Immunotherapy Following Curative Resection of Colorectal Cancer Hepatic Metastases: Cancer and Leukemia Group B Study 89903. Ann. Surg. Oncol.
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(2008). Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Molecular Cancer Therapeutics
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Van Cutsem, E., Siena, S., Humblet, Y., Canon, J.-L., Maurel, J., Bajetta, E., Neyns, B., Kotasek, D., Santoro, A., Scheithauer, W., Spadafora, S., Amado, R. G., Hogan, N., Peeters, M.
(2008). An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol
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Li, X., Liu, Y.-H., Lee, S.-J., Gardner, T. A., Jeng, M.-H., Kao, C.
(2008). Prostate-Restricted Replicative Adenovirus Expressing Human Endostatin-Angiostatin Fusion Gene Exhibiting Dramatic Antitumor Efficacy. Clin. Cancer Res.
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Claes, A., Wesseling, P., Jeuken, J., Maass, C., Heerschap, A., Leenders, W. P.J.
(2008). Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Molecular Cancer Therapeutics
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Pawlik, T. M., Schulick, R. D., Choti, M. A.
(2008). Expanding Criteria for Resectability of Colorectal Liver Metastases. The Oncologist
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Miller, K., Wang, M., Gralow, J., Dickler, M., Cobleigh, M., Perez, E. A., Shenkier, T., Cella, D., Davidson, N. E.
(2007). Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. NEJM
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Kamat, A. A., Merritt, W. M., Coffey, D., Lin, Y. G., Patel, P. R., Broaddus, R., Nugent, E., Han, L. Y., Landen, C. N. Jr., Spannuth, W. A., Lu, C., Coleman, R. L., Gershenson, D. M., Sood, A. K.
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Little, R. F., Aleman, K., Kumar, P., Wyvill, K. M., Pluda, J. M., Read-Connole, E., Wang, V., Pittaluga, S., Catanzaro, A. T., Steinberg, S. M., Yarchoan, R.
(2007). Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood
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Korita, P. V., Wakai, T., Shirai, Y., Sakata, J., Takizawa, K., Cruz, P. V., Ajioka, Y., Hatakeyama, K.
(2007). Intrahepatic Lymphatic Invasion Independently Predicts Poor Survival and Recurrences after Hepatectomy in Patients with Colorectal Carcinoma Liver Metastases. Ann. Surg. Oncol.
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Lyman, G. H., Khorana, A. A., Falanga, A., Clarke-Pearson, D., Flowers, C., Jahanzeb, M., Kakkar, A., Kuderer, N. M., Levine, M. N., Liebman, H., Mendelson, D., Raskob, G., Somerfield, M. R., Thodiyil, P., Trent, D., Francis, C. W.
(2007). American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer. JCO
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(2007). Systemic chemotherapy does not increase the risk of gastrointestinal perforation. Ann Oncol
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(2007). Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis. Ann Oncol
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Ton, N.C., Parker, G.J.M., Jackson, A., Mullamitha, S., Buonaccorsi, G.A., Roberts, C., Watson, Y., Davies, K., Cheung, S., Hope, L., Power, F., Lawrance, J., Valle, J., Saunders, M., Felix, R., Soranson, J.A., Rolfe, L., Zinkewich-Peotti, K., Jayson, G.C.
(2007). Phase I Evaluation of CDP791, a PEGylated Di-Fab' Conjugate that Binds Vascular Endothelial Growth Factor Receptor 2. Clin. Cancer Res.
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Kaye, S. B.
(2007). Bevacizumab for the Treatment of Epithelial Ovarian Cancer: Will This Be Its Finest Hour?. JCO
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Burger, R. A., Sill, M. W., Monk, B. J., Greer, B. E., Sorosky, J. I.
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Cannistra, S. A., Matulonis, U. A., Penson, R. T., Hambleton, J., Dupont, J., Mackey, H., Douglas, J., Burger, R. A., Armstrong, D., Wenham, R., McGuire, W.
(2007). Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer. JCO
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Buyse, M., Burzykowski, T., Carroll, K., Michiels, S., Sargent, D. J., Miller, L. L., Elfring, G. L., Pignon, J.-P., Piedbois, P.
(2007). Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer. JCO
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Rudge, J. S., Holash, J., Hylton, D., Russell, M., Jiang, S., Leidich, R., Papadopoulos, N., Pyles, E. A., Torri, A., Wiegand, S. J., Thurston, G., Stahl, N., Yancopoulos, G. D.
(2007). Inaugural Article: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc. Natl. Acad. Sci. USA
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Jonker, D. J., O'Callaghan, C. J., Karapetis, C. S., Zalcberg, J. R., Tu, D., Au, H.-J., Berry, S. R., Krahn, M., Price, T., Simes, R. J., Tebbutt, N. C., van Hazel, G., Wierzbicki, R., Langer, C., Moore, M. J.
(2007). Cetuximab for the Treatment of Colorectal Cancer. NEJM
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Beer, A. J., Grosu, A.-L., Carlsen, J., Kolk, A., Sarbia, M., Stangier, I., Watzlowik, P., Wester, H.-J., Haubner, R., Schwaiger, M.
(2007). [18F]Galacto-RGD Positron Emission Tomography for Imaging of {alpha}v{beta}3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck. Clin. Cancer Res.
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McAuliffe, J. C., Lazar, A. J.F., Yang, D., Steinert, D. M., Qiao, W., Thall, P. F., Raymond, A. K., Benjamin, R. S., Trent, J. C.
(2007). Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate. Clin. Cancer Res.
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(2007). Biological Therapy and Other Novel Therapies in Early-Stage Disease: Are They Appropriate?. Clin. Cancer Res.
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(2007). New Approaches to Assessing and Treating Early-Stage Colon and Rectal Cancers: Cooperative Group Strategies for Assessing Optimal Approaches in Early-Stage Disease. Clin. Cancer Res.
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Lambert, L. A., Mansfield, P. F.
(2007). Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Colorectal Carcinomatosis: If at First You Don't Succeed.... Ann. Surg. Oncol.
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(2007). Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study. JCO
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