Improved survival with bevacizumab in advanced cervical cancer

Krishnansu S. Tewari, Michael W. Sill, Harry J. Long, Richard T. Penson, Helen Huang, Lois M. Ramondetta, Lisa M. Landrum, Ana Oaknin, Thomas J. Reid, Mario M. Leitao, Helen Michael, Bradley J. Monk

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.

Original languageEnglish
Pages (from-to)734-743
Number of pages10
JournalNew England Journal of Medicine
Volume370
Issue number8
DOIs
StatePublished - 2014

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Uterine Cervical Neoplasms
Survival
Drug Therapy
Paclitaxel
Cisplatin
Topotecan
Combination Drug Therapy
Vascular Endothelial Growth Factor A
Disease Progression
Radiation-Sensitizing Agents
Poisons
Body Surface Area
Platinum
Fistula
Bevacizumab
Radiotherapy
Monoclonal Antibodies
Body Weight
Confidence Intervals
Hypertension

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Tewari, K. S., Sill, M. W., Long, H. J., Penson, R. T., Huang, H., Ramondetta, L. M., ... Monk, B. J. (2014). Improved survival with bevacizumab in advanced cervical cancer. New England Journal of Medicine, 370(8), 734-743. https://doi.org/10.1056/NEJMoa1309748

Improved survival with bevacizumab in advanced cervical cancer. / Tewari, Krishnansu S.; Sill, Michael W.; Long, Harry J.; Penson, Richard T.; Huang, Helen; Ramondetta, Lois M.; Landrum, Lisa M.; Oaknin, Ana; Reid, Thomas J.; Leitao, Mario M.; Michael, Helen; Monk, Bradley J.

In: New England Journal of Medicine, Vol. 370, No. 8, 2014, p. 734-743.

Research output: Contribution to journalArticle

Tewari, KS, Sill, MW, Long, HJ, Penson, RT, Huang, H, Ramondetta, LM, Landrum, LM, Oaknin, A, Reid, TJ, Leitao, MM, Michael, H & Monk, BJ 2014, 'Improved survival with bevacizumab in advanced cervical cancer', New England Journal of Medicine, vol. 370, no. 8, pp. 734-743. https://doi.org/10.1056/NEJMoa1309748
Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM et al. Improved survival with bevacizumab in advanced cervical cancer. New England Journal of Medicine. 2014;370(8):734-743. https://doi.org/10.1056/NEJMoa1309748
Tewari, Krishnansu S. ; Sill, Michael W. ; Long, Harry J. ; Penson, Richard T. ; Huang, Helen ; Ramondetta, Lois M. ; Landrum, Lisa M. ; Oaknin, Ana ; Reid, Thomas J. ; Leitao, Mario M. ; Michael, Helen ; Monk, Bradley J. / Improved survival with bevacizumab in advanced cervical cancer. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 8. pp. 734-743.
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AU - Tewari, Krishnansu S.

AU - Sill, Michael W.

AU - Long, Harry J.

AU - Penson, Richard T.

AU - Huang, Helen

AU - Ramondetta, Lois M.

AU - Landrum, Lisa M.

AU - Oaknin, Ana

AU - Reid, Thomas J.

AU - Leitao, Mario M.

AU - Michael, Helen

AU - Monk, Bradley J.

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N2 - BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.

AB - BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.

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