This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reidy, D. L. Articles by Saltz, L. B. Search for Related Content PubMed PubMed Citation Articles by Reidy, D. L. Articles by Saltz, L. B. Related Articles Related Editorial Social Bookmarking                            What's this?

Bevacizumab 5 mg/kg Can Be Infused Safely Over 10 Minutes

Diane L. Reidy, Ki Y. Chung, John P. Timoney, Vivian J. Park, Ellen Hollywood, Nancy T. Sklarin, Raymond J. Muller, Leonard B. Saltz

From the Divisions of Solid Tumor Oncology and Pharmacy Services, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Leonard B. Saltz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H-917, New York, NY 10021; e-mail: saltzl{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
Purpose Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor. As a result of concerns for potential infusion-related hypersensitivity reactions (HSRs), initial phase I trials used a 90-, 60-, 30-minute initial infusion sequence. We sought to determine if the initial prolonged infusion was still necessary and if an infusion time of fewer than 30 minutes could be safely used.

Methods We used computerized pharmacy records to identify all patients who received bevacizumab at our institution in the first 2 years of commercial availability (February 1, 2004, to June 30, 2006). Our institutional adverse drug reaction reporting program was used to identify any infusion reactions possibly related to bevacizumab, and patient medical records were reviewed for confirmation.

Results A total of 1,077 patients were treated with 10,606 doses of bevacizumab, and 765 of these patients received a 5-mg/kg dose (total of 8,494 doses). No HSRs occurred with the 90-, 60-, 30-minute infusion sequence in the first 202 patients. The standard infusion rate was then modified to 30 minutes for all bevacizumab doses. No HSRs were encountered. The infusion was again modified to a rate of 0.5 mg/kg/min. Of the 370 patients who received a total of 2,311 doses of bevacizumab at 5 mg/kg over 10 minutes, six (1.6%) experienced events of minor clinical consequence that were possibly consistent with nonserious HSRs.

Conclusion Ninety- and 60-minute initial infusion times are unnecessary. Use of a standard infusion rate of 0.5 mg/kg/min is safe, logical, and the current policy at our institution.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
Bevacizumab is a monoclonal antibody that targets and binds to vascular endothelial growth factor-A (VEGF-A), thereby preventing the activation of the VEGF receptor and the signaling cascade.^1,2

Randomized clinical trials have now demonstrated that the addition of bevacizumab to standard chemotherapy improves overall survival, progression-free survival, and response rate when compared with chemotherapy alone in metastatic colorectal cancer.^3-5 Additional trials have reported similar findings in non–small-cell lung cancer and in metastatic breast cancer.^6,7 As such, bevacizumab is now considered to be part of standard treatment for these common malignancies, and trials in other solid tumors are under way.^8-10 Therefore, administration of bevacizumab is now a widespread common practice, and efforts to streamline and facilitate this administration could lead to improved efficiency and convenience, as well as cost savings for patients and third-party payers.

Because bevacizumab is a monoclonal antibody—and humanized, but not fully human (it contains < 10% murine protein)—a potential concern at the outset of clinical development was that of infusion-related hypersensitivity reactions (HSRs). Five monoclonal antibodies that predated bevacizumab were available for clinical use (rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan), and with all of these, the potential adverse events included infusion-related reactions.^11-13 Because of this experience, and with extrapolation of this concern to the then-unknown risk of HSRs to bevacizumab, the initial bevacizumab infusion rate in first-in-man phase I studies was set at 90 minutes for the first dose. If the dose was tolerated without evidence of an HSR, the next dose was to be administered over 60 minutes. If that dose did not produce an HSR, then the following dose was to be administered over 30 minutes. If that was tolerated, then all subsequent doses were to be administered over 30 minutes thereafter.

This 90-, 60-, 30-minute infusion sequence has remained part of standard administration of bevacizumab throughout the development and registration of this drug. However, the continued need for this somewhat cumbersome practice, which was established when virtually no clinical experience with bevacizumab was available, has never before been readdressed. Despite the theoretical concern that existed at the start of development, no clinically significant infusion-related HSRs were reported in the pivotal phase III registration trial, which used the aforementioned administration schedule, or in any of the bevacizumab phase II or III trials reported to date (Table 1). Furthermore, we noted in our institution that all patients were moving to 30-minute infusions after the third dose as a matter of routine course. Therefore, we postulated that bevacizumab could be safely administered without the initial prolonged infusion times. We further questioned whether the duration of the 30-minute maintenance doses was longer than necessary and whether a briefer infusion time could be safely administered on the basis of available clinical experience.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

In May 2005, following positive reports for the use of bevacizumab in breast and non–small-cell lung cancer, doctors at our center began to use bevacizumab routinely for these diseases, at the recommended dose of 15 mg/kg every 3 weeks.^7,15 In addition, an ongoing National Cancer Institute (Bethesda, MD) -sponsored trial of bevacizumab in gastric cancer at our center also administered this 15-mg/kg dose. In October 2005, records of 89 consecutive patients who received one or more infusions over 30 minutes were available for review. None of these patients experienced infusion-related HSRs. The rate of infusion for these 15-mg/kg doses when administered over 30 minutes was 0.5 mg/kg/min.

Based on this information, on November 1, 2005, the Pharmacy and Therapeutics Committee of MSKCC adopted this 0.5 mg/kg/min as the institutional standard infusion rate for all nonresearch bevacizumab infusions. As a result, 15 mg/kg at 0.5 mg/kg/min is administered over 30 minutes, 10 mg/kg at 0.5 mg/kg/min is administered over 20 minutes, and 5 mg/kg at 0.5 mg/kg/min is administered over 10 minutes for all doses, including the initial dose. From November 1, 2005, through June 30, 2006, 370 patients received a total of 2,311 doses of bevacizumab at 5 mg/kg over 10 minutes. One hundred eighty-five of the 370 patients converted from ongoing 30-minute infusions to 10 minutes. No HSRs were reported among the 185 patients. The other 177 of the 370 patients began therapy with all doses, including the initial dose, administered over 10 minutes. Six patients did experience events, which were felt to be at least possibly consistent with nonserious HSRs. These events were considered to be of minor clinical consequence and are described in detail below.

Possible HSR No. 1.
A 71-year-old man with CRC received dose No. 1 of leucovorin, fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab (5 mg/kg over 10 minutes) without incident. During the second dose, the patient complained of abdominal pain and had a small-volume emesis 5 minutes into his bevacizumab infusion. He reportedly felt flushed and was noted to have a red face. Oxygen saturation was 95%. Due to the possibility that the event could be an HSR, the patient was given diphenhydramine at 50 mg intravenously (IV) and ranitidine at 50 mg IV. Symptoms resolved rapidly, and the patient completed the remainder of the bevacizumab infusion over 1 hour. He received two further doses of bevacizumab, with the treating physician electing to give diphenhydramine and ranitidine as premedications and then administered the bevacizumab over 90 minutes. These administrations proceeded without incident, and then the patient was changed to a different therapy due to progression of disease.

Possible HSR No. 2.
A 70-year-old man with metastatic CRC, obesity, and chronic obstructive pulmonary disease received his first dose of FOLFOX plus bevacizumab (5 mg/kg over 10 minutes) without incident. During the second dose, at completion of the bevacizumab 10-minute infusion, the patient reported feeling hot. Facial flushing was noted. Oxygen saturation was 97%. Diphenhydramine at 50 mg IV was administered, and the planned FOLFOX was then completed without incident. The patient remains on treatment with 25-mg diphenhydramine before bevacizumab, and he has received nine further doses of bevacizumab at 5 mg/kg over 10 minutes without incident. Treatment is ongoing at the time of this writing.

Possible HSR No. 3.
A 49-year-old man with metastatic CRC received three doses of FOLFOX plus bevacizumab (5 mg/kg over 10 minutes) without incident. During the fourth dose, at the completion of bevacizumab over 10 minutes the patient reported having an itchy throat. He denied shortness of breath, chest pain, or throat tightness. Oxygen saturation was 99%. Diphenhydramine at 50 mg IV was administered, and FOLFOX was completed. The patient remained on treatment, with diphenhydramine at 25 mg IV administered before each bevacizumab dose. He subsequently received 6 doses of bevacizumab at 5 mg/kg over 30 minutes, followed by four doses of bevacizumab 5 mg/kg over 10 minutes, all without incident. At the time of this writing, he has elected to take a break from treatment and his progress is being monitored.

Possible HSR No. 4.
A 33-year-old man with metastatic CRC received his first dose of FOLFOX plus bevacizumab (5 mg/kg over 10 minutes). At the completion of bevacizumab (10 minutes), he reported a single hive on his left forearm. Examination revealed one other hive on his right midback. Oxygen saturation was 99%. Diphenhydramine at 50 mg IV was administered, and FOLFOX was completed. The patient remains on treatment with diphenhydramine 25 mg administered before each bevacizumab dose. At the time of this writing, he has received seven further doses of bevacizumab at 5 mg/kg over 30 minutes without incident.

Possible HSR No. 5.
A 61-year-old man with metastatic CRC has been receiving cetuximab, bevacizumab (5 mg/kg over 10 minutes), and irinotecan. On his 19th dose of bevacizumab, after the completion of the infusion, the patient reported having a hot feeling in the face with no associated pruritus or shortness of breath. Oxygen saturation was 100%. The next bevacizumab dose was given with diphenhydramine 25 mg as premedication over 30 minutes. All subsequent bevacizumab doses have been given over 10 minutes with the same premedication without incident.

Possible HSR No. 6.
A 66-year-old woman with metastatic breast cancer and a history of an allergic reaction to carboplatin was receiving longstanding paclitaxel. Following presentation of data for efficacy of bevacizumab in breast cancer, bevacizumab at 15 mg/kg over 30 minutes was added to her paclitaxel. The first dose of bevacizumab, administered over 30 minutes (0.5 mg/kg/min) was tolerated without incident. Fifteen minutes into the second bevacizumab dose, the patient developed shaking chills. Oxygen saturation was 99%. She had no shortness of breath or erythema. Patient had received prior diphenhydramine, ranitidine, and dexamethasone for paclitaxel. She was given additional doses of ranitidine at 50 mg IV, diphenhydramine at 50 mg IV, and dexamethasone at 20 mg IV, after which she completed bevacizumab infusion without incident. She has continued on bevacizumab plus paclitaxel and remains on bevacizumab at a dose of 10 mg/kg over 20 minutes 6 months later without further incident.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
Doses of drugs are established in phase I studies, but the administration schedules (bolus versus infusion, length of infusions or frequency of administration) are usually determined empirically, before the phase I study is started, based on reasonable extrapolations from available laboratory data, plus practical logistical considerations, and any other available information. Sometimes, however, decisions of schedule and duration are made on a purely pragmatic basis, and then subsequent observations either reinforce or modify these decisions. Consider, for example, the practice of giving chemotherapy on a frequency of every 7, 14, or 21 days. Clearly, there is no scientific basis for dividing our treatment plans into these pharmacokinetically arbitrary 7-day units. We have a society that functions on a 7-day workweek, so for practical considerations, we adjust our treatment schedules accordingly.

Similar to the administration schedule, the appropriate duration of an infusion is difficult to establish in the early development of a new drug. The half-life of most monoclonal antibodies is such that the infusion duration could not realistically be expected to impact efficacy. Indeed, the half-life of bevacizumab is in excess of 20 days, and the clearance is 0.2 L/d.^18,19

Often the administration schedule is based on other considerations, such as safety or volume necessary for administration. Other monoclonal antibodies, particularly those with a larger amount of murine protein component, had previously demonstrated a concerning level of HSRs. For this reason, the schedule of a more prolonged initial infusion (arbitrarily and empirically set at 90 minutes) was selected, so that if hypersensitivity was detected, the infusion could be interrupted with a relatively small amount of drug having been administered. Greater antihypersensitivity precautions, such as steroids and/or antihistamines, could then be introduced and the patient could then be rechallenged with these protections, with the slower (90-minute) infusion rate maintained. However, if the first infusion was tolerated without evidence of a HSR, then the next infusion could be shortened to 60 minutes, again with monitoring for, and intervention in the case of a HSR. Again, if the infusion was tolerated at the 60-minute duration, then 30-minute infusions were to be attempted and maintained, unless HSRs were noted, which dictated continuation of the slower infusion.

What is noteworthy about reported bevacizumab trials is that virtually no ocurrence of an HSR, which required a longer infusion time or which prevented the ultimate adoption of the 30-minute infusion time, was reported. As there is no hypothesis that any sort of desensitization is accomplished with the initial decreasing infusion times, the only purpose of a prolonged initial treatment is to screen for patients who are hypersensitive. As virtually all patients progress through this screening, the likelihood that a meaningful safety margin is added by the use of these extending initial infusion times would appear to be vanishingly small.

Our data strongly support the reasoning outlined above. A review of patients treated with bevacizumab at MSKCC during the first 28 months of commercial availability confirms that the routine use of the initial 90- and 60-minute infusions of bevacizumab does not appear to provide any meaningful margin of safety and, therefore, is unnecessary. The arbitrary nature of the 90-, 60-, and 30-minute infusion sequence is further underscored by the observation that the same infusion times are used over all dose levels. This use of a fixed infusion time regardless of dose is inherently illogical; a patient being treated at 15 mg/kg would receive a 90-minute infusion at a rate of 0.166 mg/kg/min, and the 30-minute infusion would afford a rate of 0.5 mg/kg/min. However, a patient treated at 5 mg/kg/min would be receiving a 90-minute infusion at a rate of 0.055 mg/kg/min and a 30-minute infusion at a rate of 0.166 mg/kg/min, the same rate as the initial treatment at the 15 mg/kg dose. Surely, if 0.166 mg/kg/min is an acceptable standard starting infusion rate for the 15 mg/kg dose, it is an acceptable starting rate for the 5 mg/kg dose, thus further supporting the lack of need for an initial dose of longer than 30 minutes at the 5 mg/kg level.

Even the 30-minute initial infusion of bevacizumab would appear to be longer than necessary at the 5 mg/kg dose level. The 0.5 mg/kg/min infusion rate, which affords a 10-minute infusion time for the administration of 5 mg/kg, has been extensively studied in large-scale trials of the 15 mg/kg dose in patients with lung cancer and breast cancer and has not resulted in either HSRs or the need for a slower infusion. The use of this rate as a standard infusion for bevacizumab administration is both evidence-based and logical.

Ten-minute infusions were tolerated without incident and without any suggestion of possible HSRs by more than 98% of patients treated. The six possible HSRs encountered were clinically minor events, none of which were serious enough to require hospital admission, and none of which prevented further treatment with bevacizumab.

Several elements of our study lend weight to the veracity of the findings. All patients receiving bevacizumab were identified by use of computerized pharmacy records, thereby preventing any recall bias and ensuring a rigorous methodology. Patient medical records were checked for further confirmation if any grade of potential HSR was reported. The study included patients treated for different common solid tumor types (colorectal, breast, lung, and ovary) with a total of 10,606 doses administered, enabling our results to be reasonably generalized to all patients treated with bevacizumab regardless of cancer type.

In summary, our data strongly suggest that the current standard practice, as cited in the product package insert, of prolongation of the initial doses of bevacizumab to 90 and 60 minutes, is unnecessary. Furthermore, in contrast to the current labeling recommendations, our data support a standardization of the infusion rate of bevacizumab of 0.5 mg/kg/min. Widespread use of this standardized infusion rate, with the resultant decrease in bevacizumab infusion time and so decreased overall treatment time, would be expected to improve patient convenience and satisfaction, as well as to lower the associated costs of longer duration infusions, without evidence of compromise in patient safety or treatment efficacy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Leonard B. Saltz, Genentech, Roche, Pfizer, Sanofi-aventis, Access, YM Bioscience Stock: N/A Honoraria: Diane L. Reidy, Roche; Ki Y. Chung, Genentech Research Funds: Leonard B. Saltz, Genentech, Roche, Imclone, Bristol Myers Squibb, Bayer, Taiho, Pfizer Testimony: N/A Other: N/A

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
Conception and design: Diane L. Reidy, Ki Y. Chung, John P. Timoney, Vivian J. Park, Ellen Hollywood, Nancy T. Sklarin, Raymond J. Muller, Leonard B. Saltz

Administrative support: Diane L. Reidy, Ki Y. Chung, Ellen Hollywood, Nancy T. Sklarin, Leonard B. Saltz

Provision of study materials or patients: Diane L. Reidy, Ki Y. Chung, Leonard B. Saltz

Collection and assembly of data: Diane L. Reidy, Ki Y. Chung, John P. Timoney, Vivian J. Park, Raymond J. Muller, Leonard B. Saltz

Data analysis and interpretation: Diane L. Reidy, Ki Y. Chung, Leonard B. Saltz

Manuscript writing: Diane L. Reidy, Ki Y. Chung, Raymond J. Muller, Leonard B. Saltz

Final approval of manuscript: Diane L. Reidy, Ki Y. Chung, John P. Timoney, Vivian J. Park, Ellen Hollywood, Nancy T. Sklarin, Raymond J. Muller, Leonard B. Saltz

	NOTES

 
Supported by funds from the Memorial Sloan-Kettering Cancer Center.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions REFERENCES

 
1. Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841-844, 1993[CrossRef][Medline]

2. Prewett M, Huber J, Li Y, et al: Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 59:5209-5218, 1999[Abstract/Free Full Text]

3. Kabbinavar FF, Schulz J, McCleod M, et al: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697-3705, 2005[Abstract/Free Full Text]

4. Giantonio BJ, Catalano PF, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results From the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007

5. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

6. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004[Abstract/Free Full Text]

7. Miller KD, Wang M, Gralow J, et al: E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: A trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 94, 2005 (suppl 1; abstr 3)

8. Raefsky EL, Spigel DR, Greco FA, et al: Irinotecan (I), carboplatin (C), and radiotherapy (RT) followed by bevacizumab (B) in the treatment of limited-stage small cell lung cancer (SCLC): A phase II trial of the Minnie Pearl Cancer Res Network. J Clin Oncol 23:633S, 2005 (abstr 7050)

9. Vokes EE, Cohen EEW, Mauer AM, et al: A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC). J Clin Oncol 23:501s, 2005 (abstr 5504)

10. Burger RA, Sill M, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study. J Clin Oncol 23:457S, 2005 (abstr 5009)

11. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract]

12. Giles FJ, Cortes JE, Halliburton TA, et al: Intravenous corticosteroids to reduce gemtuzumab ozogamicin infusion reactions. Ann Pharmacother 37:1182-1185, 2003[Abstract/Free Full Text]

13. Dillman RO: Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev 18:465-471, 1999[CrossRef][Medline]

14. Timoney JP, Eagan MM, Sklarin NT: Establishing clinical guidelines for the management of acute hypersensitivity reactions secondary to the administration of chemotherapy/biologic therapy. J Nurs Care Qual 18:80-86, 2003[Medline]

15. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC# 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599. J Clin Oncol 23:2S, 2005 (abstr LBA4)

16. Lu J, Gaudreault J, Novotny W, et al: A population pharmacokinetic model for bevacizumab. Clin Pharmacol Ther 75:91, 2004 (abstr PII-149)

17. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001[Abstract/Free Full Text]

18. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003[Abstract/Free Full Text]

19. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005[Abstract/Free Full Text]

Submitted September 27, 2006; accepted January 22, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Shortening the Infusion Time of Anticancer Drugs: Who Will Benefit?
  Kim Margolin and Michael Gordon
  JCO 2007 25: 2642-2643 [Full Text]

This article has been cited by other articles:

				S. M Gressett and S. R Shah Intricacies of Bevacizumab-Induced Toxicities and Their Management Ann. Pharmacother., March 1, 2009; 43(3): 490 - 501. [Abstract] [Full Text] [PDF]

				M. B. Toma and P. J. Medina Update on Targeted Therapy--Focus on Monoclonal Antibodies Journal of Pharmacy Practice, February 1, 2008; 21(1): 4 - 16. [Abstract] [PDF]

				K. Margolin and M. Gordon Shortening the Infusion Time of Anticancer Drugs: Who Will Benefit? J. Clin. Oncol., July 1, 2007; 25(19): 2642 - 2643. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reidy, D. L. Articles by Saltz, L. B. Search for Related Content PubMed PubMed Citation Articles by Reidy, D. L. Articles by Saltz, L. B. Related Articles Related Editorial Social Bookmarking                            What's this?