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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Suzuki, H., Ohkuchi, A., Matsubara, S., Takei, Y., Murakami, M., Shibuya, M., Suzuki, M., Sato, Y.
(2009). Effect of Recombinant Placental Growth Factor 2 on Hypertension Induced by Full-Length Mouse Soluble fms-Like Tyrosine Kinase 1 Adenoviral Vector in Pregnant Mice. Hypertension
54: 1129-1135
[Abstract][Full Text]
Hendifar, A., Yang, D., Lenz, F., Lurje, G., Pohl, A., Lenz, C., Ning, Y., Zhang, W., Lenz, H.-J.
(2009). Gender Disparities in Metastatic Colorectal Cancer Survival. Clin. Cancer Res.
15: 6391-6397
[Abstract][Full Text]
Hedlund, E.-M., Hosaka, K., Zhong, Z., Cao, R., Cao, Y.
(2009). Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature. Proc. Natl. Acad. Sci. USA
106: 17505-17510
[Abstract][Full Text]
Zangari, M., Fink, L. M., Elice, F., Zhan, F., Adcock, D. M., Tricot, G. J.
(2009). Thrombotic Events in Patients With Cancer Receiving Antiangiogenesis Agents. JCO
27: 4865-4873
[Abstract][Full Text]
Friedman, H. S., Prados, M. D., Wen, P. Y., Mikkelsen, T., Schiff, D., Abrey, L. E., Yung, W.K. A., Paleologos, N., Nicholas, M. K., Jensen, R., Vredenburgh, J., Huang, J., Zheng, M., Cloughesy, T.
(2009). Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma. JCO
27: 4733-4740
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Grothey, A., Sargent, D. J.
(2009). Reply to F. Montagnani et al. JCO
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Nomoto, H., Shiraga, F., Kuno, N., Kimura, E., Fujii, S., Shinomiya, K., Nugent, A. K., Hirooka, K., Baba, T.
(2009). Pharmacokinetics of Bevacizumab after Topical, Subconjunctival, and Intravitreal Administration in Rabbits. IOVS
50: 4807-4813
[Abstract][Full Text]
Sakurai, K., Akiyama, H., Shimoda, Y., Yoshida, I., Kurabayashi, M., Kishi, S.
(2009). Effect of Intravitreal Injection of High-Dose Bevacizumab in Monkey Eyes. IOVS
50: 4905-4916
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Khorana, A. A.
(2009). Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol
20: 1619-1630
[Abstract][Full Text]
Maitland, M. L., Kasza, K. E., Karrison, T., Moshier, K., Sit, L., Black, H. R., Undevia, S. D., Stadler, W. M., Elliott, W. J., Ratain, M. J.
(2009). Ambulatory Monitoring Detects Sorafenib-Induced Blood Pressure Elevations on the First Day of Treatment. Clin. Cancer Res.
15: 6250-6257
[Abstract][Full Text]
Rini, B. I., Garcia, J. A., Cooney, M. M., Elson, P., Tyler, A., Beatty, K., Bokar, J., Mekhail, T., Bukowski, R.M., Budd, G. T., Triozzi, P., Borden, E., Ivy, P., Chen, H. X., Dowlati, A., Dreicer, R.
(2009). A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors. Clin. Cancer Res.
15: 6277-6283
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Luke, M, Januschowski, K, Luke, J, Peters, S, Wirtz, N, Yoruk, E, Luke, C, Bartz-Schmidt, K U, Grisanti, S, Szurman, P
(2009). The effects of ranibizumab (Lucentis) on retinal function in isolated perfused vertebrate retina. Br J Ophthalmol
93: 1396-1400
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Damjanov, N., Weiss, J., Haller, D. G.
(2009). Resection of the Primary Colorectal Cancer Is Not Necessary in Nonobstructed Patients with Metastatic Disease. The Oncologist
14: 963-969
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Goldberg, R. M., Sargent, D. J., Morton, R. F., Green, E., Sanoff, H. K., McLeod, H., Buckner, J.
(2009). NCCTG Study N9741: Leveraging Learning from an NCI Cooperative Group Phase III Trial. The Oncologist
14: 970-978
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Grothey, A.
(2009). Review: Medical treatment of advanced colorectal cancer in 2009. Therapeutic Advances in Medical Oncology
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[Abstract]
Okita, N. T., Yamada, Y., Takahari, D., Hirashima, Y., Matsubara, J., Kato, K., Hamaguchi, T., Shirao, K., Shimada, Y., Taniguchi, H., Shimoda, T.
(2009). Vascular Endothelial Growth Factor Receptor Expression as a Prognostic Marker for Survival in Colorectal Cancer. Jpn J Clin Oncol
39: 595-600
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Crane, C. H., Winter, K., Regine, W. F., Safran, H., Rich, T. A., Curran, W., Wolff, R. A., Willett, C. G.
(2009). Phase II Study of Bevacizumab With Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer: Radiation Therapy Oncology Group RTOG 0411. JCO
27: 4096-4102
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Eskens, F. A.L.M., Steeghs, N., Verweij, J., Bloem, J. L., Christensen, O., van Doorn, L., Ouwerkerk, J., de Jonge, M. J.A., Nortier, J. W.R., Kraetzschmar, J., Rajagopalan, P., Gelderblom, H.
(2009). Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor {beta}, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors. JCO
27: 4169-4176
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Morelli, M. P., Brown, A. M., Pitts, T. M., Tentler, J. J., Ciardiello, F., Ryan, A., Jurgensmeier, J. M., Eckhardt, S. G.
(2009). Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines. Molecular Cancer Therapeutics
8: 2546-2558
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Kozloff, M., Yood, M. U., Berlin, J., Flynn, P. J., Kabbinavar, F. F., Purdie, D. M., Ashby, M. A., Dong, W., Sugrue, M. M., Grothey, A., for the investigators of the BRiTE study,
(2009). Clinical Outcomes Associated with Bevacizumab-Containing Treatment of Metastatic Colorectal Cancer: The BRiTE Observational Cohort Study. The Oncologist
14: 862-870
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Schiller, J. H., Larson, T., Ou, S.-H. I., Limentani, S., Sandler, A., Vokes, E., Kim, S., Liau, K., Bycott, P., Olszanski, A. J., von Pawel, J.
(2009). Efficacy and Safety of Axitinib in Patients With Advanced Non-Small-Cell Lung Cancer: Results From a Phase II Study. JCO
27: 3836-3841
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Wei, G., Srinivasan, R., Cantemir-Stone, C. Z., Sharma, S. M., Santhanam, R., Weinstein, M., Muthusamy, N., Man, A. K., Oshima, R. G., Leone, G., Ostrowski, M. C.
(2009). Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood
114: 1123-1130
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Herbst, R. S., Hong, D., Chap, L., Kurzrock, R., Jackson, E., Silverman, J. M., Rasmussen, E., Sun, Y.-N., Zhong, D., Hwang, Y. C., Evelhoch, J. L., Oliner, J. D., Le, N., Rosen, L. S.
(2009). Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors. JCO
27: 3557-3565
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Lucio-Eterovic, A. K., Piao, Y., de Groot, J. F.
(2009). Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy. Clin. Cancer Res.
15: 4589-4599
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Allegra, C. J., Yothers, G., O'Connell, M. J., Sharif, S., Colangelo, L. H., Lopa, S. H., Petrelli, N. J., Goldberg, R. M., Atkins, J. N., Seay, T. E., Fehrenbacher, L., O'Reilly, S., Chu, L., Azar, C. A., Wolmark, N.
(2009). Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer. JCO
27: 3385-3390
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Poultsides, G. A., Servais, E. L., Saltz, L. B., Patil, S., Kemeny, N. E., Guillem, J. G., Weiser, M., Temple, L. K.F., Wong, W. D., Paty, P. B.
(2009). Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment. JCO
27: 3379-3384
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Lim, H. J., Gill, S., Speers, C., Melosky, B., Barnett, J., Fitzgerald, C., O'Reilly, S., Kennecke, H.
(2009). Impact of Irinotecan and Oxaliplatin on Overall Survival in Patients With Metastatic Colorectal Cancer: A Population-Based Study. J Oncol Pract
5: 153-158
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Larkin, J. M.G., Kipps, E. L.S., Powell, C. J., Swanton, C.
(2009). Review: Systemic therapy for advanced renal cell carcinoma. Therapeutic Advances in Medical Oncology
1: 15-27
[Abstract]
Memarzadeh, F., Varma, R., Lin, L.-T., Parikh, J. G., Dustin, L., Alcaraz, A., Eliott, D.
(2009). Postoperative Use of Bevacizumab as an Antifibrotic Agent in Glaucoma Filtration Surgery in the Rabbit. IOVS
50: 3233-3237
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Bhargava, P.
(2009). VEGF kinase inhibitors: how do they cause hypertension?. Am. J. Physiol. Regul. Integr. Comp. Physiol.
297: R1-R5
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Roland, C. L., Dineen, S. P., Lynn, K. D., Sullivan, L. A., Dellinger, M. T., Sadegh, L., Sullivan, J. P., Shames, D. S., Brekken, R. A.
(2009). Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Molecular Cancer Therapeutics
8: 1761-1771
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Rapisarda, A., Hollingshead, M., Uranchimeg, B., Bonomi, C. A., Borgel, S. D., Carter, J. P., Gehrs, B., Raffeld, M., Kinders, R. J., Parchment, R., Anver, M. R., Shoemaker, R. H., Melillo, G.
(2009). Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Molecular Cancer Therapeutics
8: 1867-1877
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Schmid-Kubista, K E, Krebs, I, Gruenberger, B, Zeiler, F, Schueller, J, Binder, S
(2009). Systemic bevacizumab (Avastin) therapy for exudative neovascular age-related macular degeneration. The BEAT-AMD-Study. Br J Ophthalmol
93: 914-919
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Banerjee, S., Gore, M.
(2009). The Future of Targeted Therapies in Ovarian Cancer. The Oncologist
14: 706-716
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Willett, C. G., Duda, D. G., di Tomaso, E., Boucher, Y., Ancukiewicz, M., Sahani, D. V., Lahdenranta, J., Chung, D. C., Fischman, A. J., Lauwers, G. Y., Shellito, P., Czito, B. G., Wong, T. Z., Paulson, E., Poleski, M., Vujaskovic, Z., Bentley, R., Chen, H. X., Clark, J. W., Jain, R. K.
(2009). Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study. JCO
27: 3020-3026
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Yeh, E. T.H., Bickford, C. L.
(2009). Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.. J Am Coll Cardiol
53: 2231-2247
[Abstract][Full Text]
Ichihara, E., Ohashi, K., Takigawa, N., Osawa, M., Ogino, A., Tanimoto, M., Kiura, K.
(2009). Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo. Cancer Res.
69: 5091-5098
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Hurwitz, H. I., Dowlati, A., Saini, S., Savage, S., Suttle, A. B., Gibson, D. M., Hodge, J. P., Merkle, E. M., Pandite, L.
(2009). Phase I Trial of Pazopanib in Patients with Advanced Cancer. Clin. Cancer Res.
15: 4220-4227
[Abstract][Full Text]
Kim, G. P., Sargent, D. J., Mahoney, M. R., Rowland, K. M. Jr, Philip, P. A., Mitchell, E., Mathews, A. P., Fitch, T. R., Goldberg, R. M., Alberts, S. R., Pitot, H. C.
(2009). Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841. JCO
27: 2848-2854
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Shord, S. S., Bressler, L. R., Tierney, L. A., Cuellar, S., George, A.
(2009). Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm
66: 999-1013
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Onaitis, M. W., Petersen, R. P., Haney, J. C., Saltz, L., Park, B., Flores, R., Rizk, N., Bains, M. S., Dycoco, J., D'Amico, T. A., Harpole, D. H., Kemeny, N., Rusch, V. W., Downey, R.
(2009). Prognostic Factors for Recurrence After Pulmonary Resection of Colorectal Cancer Metastases.. Ann. Thorac. Surg.
87: 1684-1688
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Park, C. M., Goo, J. M., Lee, H. J., Kim, M. A, Kim, H.-C., Kim, K. G., Lee, C. H., Im, J.-G.
(2009). FN13762 Murine Breast Cancer: Region-by-Region Correlation of First-Pass Perfusion CT Indexes with Histologic Vascular Parameters. Radiology
251: 721-730
[Abstract][Full Text]
Bidard, F.-C., Tournigand, C., Andre, T., Mabro, M., Figer, A., Cervantes, A., Lledo, G., Bengrine-Lefevre, L., Maindrault-Goebel, F., Louvet, C., de Gramont, A.
(2009). Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol
20: 1042-1047
[Abstract][Full Text]
Courtwright, A., Siamakpour-Reihani, S., Arbiser, J. L., Banet, N., Hilliard, E., Fried, L., Livasy, C., Ketelsen, D., Nepal, D. B., Perou, C. M., Patterson, C., Klauber-DeMore, N.
(2009). Secreted Frizzle-Related Protein 2 Stimulates Angiogenesis via a Calcineurin/NFAT Signaling Pathway. Cancer Res.
69: 4621-4628
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Loges, S., Schmidt, T., Carmeliet, P.
(2009). "Antimyeloangiogenic" Therapy for Cancer by Inhibiting PlGF. Clin. Cancer Res.
15: 3648-3653
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Chi, A. S., Sorensen, A. G., Jain, R. K., Batchelor, T. T.
(2009). Angiogenesis as a Therapeutic Target in Malignant Gliomas. The Oncologist
14: 621-636
[Abstract][Full Text]
Schicher, N., Paulitschke, V., Swoboda, A., Kunstfeld, R., Loewe, R., Pilarski, P., Pehamberger, H., Hoeller, C.
(2009). Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma. Clin. Cancer Res.
15: 3495-3502
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Hanrahan, E. O., Ryan, A. J., Mann, H., Kennedy, S. J., Langmuir, P., Natale, R. B., Herbst, R. S., Johnson, B. E., Heymach, J. V.
(2009). Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non-Small Cell Lung Cancer. Clin. Cancer Res.
15: 3600-3609
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Van Cutsem, E., Vervenne, W. L., Bennouna, J., Humblet, Y., Gill, S., Van Laethem, J.-L., Verslype, C., Scheithauer, W., Shang, A., Cosaert, J., Moore, M. J.
(2009). Phase III Trial of Bevacizumab in Combination With Gemcitabine and Erlotinib in Patients With Metastatic Pancreatic Cancer. JCO
27: 2231-2237
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Izzedine, H., Ederhy, S., Goldwasser, F., Soria, J. C., Milano, G., Cohen, A., Khayat, D., Spano, J. P.
(2009). Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol
20: 807-815
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McDermott, U., Ames, R. Y., Iafrate, A. J., Maheswaran, S., Stubbs, H., Greninger, P., McCutcheon, K., Milano, R., Tam, A., Lee, D. Y., Lucien, L., Brannigan, B. W., Ulkus, L. E., Ma, X.-J., Erlander, M. G., Haber, D. A., Sharma, S. V., Settleman, J.
(2009). Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-{alpha} Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors. Cancer Res.
69: 3937-3946
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Mir, O., Ropert, S., Alexandre, J., Goldwasser, F.
(2009). Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol
20: 967-970
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Muggia, F. M., Peters, G. J., Landolph, J. R. Jr.
(2009). XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on September 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center. Molecular Cancer Therapeutics
8: 992-999
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Power, D. G., Kemeny, N. E.
(2009). The role of floxuridine in metastatic liver disease. Molecular Cancer Therapeutics
8: 1015-1025
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Fakih, M. G., Pendyala, L., Fetterly, G., Toth, K., Zwiebel, J. A., Espinoza-Delgado, I., Litwin, A., Rustum, Y. M., Ross, M. E., Holleran, J. L., Egorin, M. J.
(2009). A Phase I, Pharmacokinetic and Pharmacodynamic Study on Vorinostat in Combination with 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Refractory Colorectal Cancer. Clin. Cancer Res.
15: 3189-3195
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Kohne, C.-H., Lenz, H.-J.
(2009). Chemotherapy with Targeted Agents for the Treatment of Metastatic Colorectal Cancer. The Oncologist
14: 478-488
[Abstract][Full Text]
Delmonte, A., Ghielmini, M., Sessa, C.
(2009). Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin's Lymphomas. The Oncologist
14: 511-525
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Van Cutsem, E., Oliveira, J., On behalf of the ESMO Guidelines Working Group,
(2009). Advanced colorectal cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol
20: iv61-iv63
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Mause, S. F., Weber, C.
(2009). Intrusion through the fragile back door immature plaque microvessels as entry portals for leukocytes and erythrocytes in atherosclerosis.. J Am Coll Cardiol
53: 1528-1531
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Sargent, D. J., Kohne, C. H., Sanoff, H. K., Bot, B. M., Seymour, M. T., de Gramont, A., Porschen, R., Saltz, L. B., Rougier, P., Tournigand, C., Douillard, J.-Y., Stephens, R. J., Grothey, A., Goldberg, R. M.
(2009). Pooled Safety and Efficacy Analysis Examining the Effect of Performance Status on Outcomes in Nine First-Line Treatment Trials Using Individual Data From Patients With Metastatic Colorectal Cancer. JCO
27: 1948-1955
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Au, H.-J., Karapetis, C. S., O'Callaghan, C. J., Tu, D., Moore, M. J., Zalcberg, J. R., Kennecke, H., Shapiro, J. D., Koski, S., Pavlakis, N., Charpentier, D., Wyld, D., Jefford, M., Knight, G. J., Magoski, N. M., Brundage, M. D., Jonker, D. J.
(2009). Health-Related Quality of Life in Patients With Advanced Colorectal Cancer Treated With Cetuximab: Overall and KRAS-Specific Results of the NCIC CTG and AGITG CO.17 Trial. JCO
27: 1822-1828
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Minor, D. R.
(2009). Risk of Venous Thromboembolism With Bevacizumab in Cancer Patients. JAMA
301: 1434-1434
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Van Cutsem, E., Kohne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pinter, T., Lim, R., Bodoky, G., Roh, J. K., Folprecht, G., Ruff, P., Stroh, C., Tejpar, S., Schlichting, M., Nippgen, J., Rougier, P.
(2009). Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer. NEJM
360: 1408-1417
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Chen, W.-L., Lin, C.-T., Lin, N.-T., Tu, I-H., Li, J.-W., Chow, L.-P., Liu, K.-R., Hu, F.-R.
(2009). Subconjunctival Injection of Bevacizumab (Avastin) on Corneal Neovascularization in Different Rabbit Models of Corneal Angiogenesis. IOVS
50: 1659-1665
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Barros Costa, R. L.
(2009). Review Article: Targeted Therapy: Comprehensive Review. AM J HOSP PALLIAT CARE
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[Abstract]
Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., Gorbounova, V., Hirsh, V., Leighl, N., Mezger, J., Archer, V., Moore, N., Manegold, C.
(2009). Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer: AVAiL. JCO
27: 1227-1234
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Kanate, A. S, Auber, M. L, Higa, G. M
(2009). Priorities and uncertainties of administering chemotherapy in a pregnant woman with newly diagnosed colorectal cancer. J Oncol Pharm Pract
15: 5-8
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Ma, W. W., Adjei, A. A.
(2009). Novel Agents on the Horizon for Cancer Therapy. CA Cancer J Clin
59: 111-137
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Ruan, J., Hajjar, K., Rafii, S., Leonard, J. P.
(2009). Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma. Ann Oncol
20: 413-424
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Dallas, N. A., Xia, L., Fan, F., Gray, M. J., Gaur, P., van Buren, G. II, Samuel, S., Kim, M. P., Lim, S. J., Ellis, L. M.
(2009). Chemoresistant Colorectal Cancer Cells, the Cancer Stem Cell Phenotype, and Increased Sensitivity to Insulin-like Growth Factor-I Receptor Inhibition. Cancer Res.
69: 1951-1957
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Gressett, S. M, Shah, S. R
(2009). Intricacies of Bevacizumab-Induced Toxicities and Their Management. The Annals of Pharmacotherapy
43: 490-501
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Sharma, A., Sharma, A. K., Madhunapantula, S. V., Desai, D., Huh, S. J., Mosca, P., Amin, S., Robertson, G. P.
(2009). Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates. Clin. Cancer Res.
15: 1674-1685
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Giusti, R. M., Cohen, M. H., Keegan, P., Pazdur, R.
(2009). FDA Review of a Panitumumab (VectibixTM) Clinical Trial for First-Line Treatment of Metastatic Colorectal Cancer. The Oncologist
14: 284-290
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Chen, H., Campbell, R. A., Chang, Y., Li, M., Wang, C. S., Li, J., Sanchez, E., Share, M., Steinberg, J., Berenson, A., Shalitin, D., Zeng, Z., Gui, D., Perez-Pinera, P., Berenson, R. J., Said, J., Bonavida, B., Deuel, T. F., Berenson, J. R.
(2009). Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis. Blood
113: 1992-2002
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Cao, Y.
(2009). Positive and Negative Modulation of Angiogenesis by VEGFR1 Ligands. Sci Signal
2: re1-re1
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Chen, E., Jonker, D., Gauthier, I., MacLean, M., Wells, J., Powers, J., Seymour, L.
(2009). Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer. Clin. Cancer Res.
15: 1481-1486
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Hecht, J. R., Mitchell, E., Chidiac, T., Scroggin, C., Hagenstad, C., Spigel, D., Marshall, J., Cohn, A., McCollum, D., Stella, P., Deeter, R., Shahin, S., Amado, R. G.
(2009). A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer. JCO
27: 672-680
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Blanke, C. D.
(2009). Dual-Antibody Therapy in Advanced Colorectal Cancer: Gather Ye Rosebuds While Ye May. JCO
27: 655-658
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Tol, J., Koopman, M., Cats, A., Rodenburg, C. J., Creemers, G. J.M., Schrama, J. G., Erdkamp, F. L.G., Vos, A. H., van Groeningen, C. J., Sinnige, H. A.M., Richel, D. J., Voest, E. E., Dijkstra, J. R., Vink-Borger, M. E., Antonini, N. F., Mol, L., van Krieken, J. H.J.M., Dalesio, O., Punt, C. J.A.
(2009). Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer. NEJM
360: 563-572
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Aranda, E., Valladares, M., Martinez-Villacampa, M., Benavides, M., Gomez, A., Massutti, B., Marcuello, E., Constenla, M., Camara, J. C., Carrato, A., Duenas, R., Reboredo, M., Navarro, M., Diaz-Rubio, E.
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