Improved Survival with Bevacizumab in Advanced Cervical Cancer

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                                                         Improved Survival with Bevacizumab
                                                            in Advanced Cervical Cancer
                                                    Krishnansu S. Tewari, M.D., Michael W. Sill, Ph.D., Harry J. Long III, M.D.,
                                                    Richard T. Penson, M.D., Helen Huang, M.S., Lois M. Ramondetta, M.D.,
                                                        Lisa M. Landrum, M.D., Ana Oaknin, M.D., Thomas J. Reid, M.D.,
                                                    Mario M. Leitao, M.D., Helen E. Michael, M.D., and Bradley J. Monk, M.D.

                                                                                        A BS T R AC T

                                                 Background
From the University of California, Irvine,       Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of
Medical Center, Orange (K.S.T.); Roswell         disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF mono­
Park Cancer Institute, State University of
New York at Buffalo, Buffalo (M.W.S., H.H.);     clonal antibody, has single-agent activity in previously treated, recurrent disease.
Mayo Clinic, Rochester, MN (H.J.L.); Massa-      Most patients in whom recurrent cervical cancer develops have previously received
chusetts General Hospital, Boston (R.T.P.);      cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the
M.D. Anderson Cancer Center, Houston
(L.M.R.); University of Oklahoma, Oklaho-        time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum
ma City (L.M.L.); Vall d’Hebron University       combination chemotherapy in patients with recurrent, persistent, or metastatic cer-
Hospital, Barcelona (A.O.); University of        vical cancer.
Cincinnati College of Medicine–Women’s
Cancer Center at Kettering, Kettering, OH        Methods
(T.J.R.); Memorial Sloan-Kettering Can-
cer Center, New York (M.M.L.); Indiana
                                                 Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy
University School of Medicine, Indianapo-        with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemo-
lis (H.E.M.); and the University of Arizona      therapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area,
Cancer Center and Creighton University
at St. Joseph’s Hospital and Medical
                                                 plus paclitaxel at a dose of 135 or 175 mg per square meter or topote­can at a dose of
­Center, Phoenix (B.J.M.). Address reprint       0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square
 requests to Dr. Tewari at the Division          meter on day 1. Cycles were repeated every 21 days until disease progression, the de-
 of Gynecologic Oncology, University of
 California, Irvine, Medical Center, 101
                                                 velopment of unacceptable toxic effects, or a complete response was documented. The
 City Dr. S., Bldg. 56, Orange, CA 92868,        primary end point was overall survival; a reduction of 30% in the hazard ratio for death
 or at ktewari@uci.edu.                          was considered clinically important.
N Engl J Med 2014;370:734-43.
                                                 Results
DOI: 10.1056/NEJMoa1309748
Copyright © 2014 Massachusetts Medical Society   Groups were well balanced with respect to age, histologic findings, performance sta-
                                                 tus, 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%), thrombo­
                                                 embolic 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 recur-
                                                 rent, persistent, or metastatic cervical cancer was associated with an improvement
                                                 of 3.7 months in median overall survival. (Funded by the National Cancer Institute;
                                                 GOG 240 ClinicalTrials.gov number, NCT00803062.)

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Bevacizumab in Advanced Cervical Cancer

R
         ates of cervical cancer in devel-                they were candidates for curative therapy by means
         oped countries have decreased dramati-           of pelvic exenteration. All cancers were confirmed
         cally because of cytologic screening and         by a central pathology laboratory. A GOG perfor-
DNA testing for high-risk human papillomavirus            mance status score of 0 or 1 (on a scale of 0 to 4,
(HPV) types. Approximately 12,000 cases of cer-           with 0 indicating that the person is fully active
vical cancer are diagnosed in the United States           and 1 indicating that the person is restricted in
annually, and with continued increases in HPV             physically strenuous activities but ambulatory)
vaccination, numbers of cases are expected to de-         was required, and patients had to have adequate
crease further.1 However, for vulnerable popula-          renal, hepatic, and bone marrow function. All pa-
tions without access to health care in the United         tients were required to have measurable disease.
States and throughout the world, cervical cancer          Patients treated with chemotherapy for recurrence
remains a considerable problem, with 500,000 new          and those with nonhealing wounds, active bleeding
cases and 250,000 deaths annually.2 Although              conditions, or inadequately anticoagulated throm-
early-stage and locally advanced cancers may be           boembolism were ineligible. All patients provided
cured with radical surgery, chemoradiotherapy,            written informed consent before enrollment.
or both, patients with metastatic cancers and
those with persistent or recurrent disease after          Study Design and Treatment
platinum-based chemoradiotherapy have limited             Patients were randomly assigned to one of four
options.3-17 Nonplatinum combination chemo-               intravenous regimens that were repeated at 21-day
therapy has been proposed as a strategy to cir-           intervals. Control treatment consisted of cisplatin
cumvent platinum resistance, but new forms of             (at a dose of 50 mg per square meter of body-
therapy are needed.                                       surface area) plus paclitaxel (at a dose of 135 or
   Vascular endothelial growth factor (VEGF) is           175 mg per square meter on day 1). The non-
a key mediator of tumor angiogenesis, a process           platinum combination chemotherapy consisted
that correlates directly with the extent of disease       of topotecan (at a dose of 0.75 mg per square
and inversely with survival.18 Bevacizumab, a hu-         meter on days 1 to 3) plus paclitaxel (at a dose of
manized VEGF-neutralizing monoclonal antibody,            175 mg per square meter on day 1). Each of these
has single-agent activity in heavily pretreated,          regimens was studied with and without bevaciz­
recurrent cervical carcinoma.19,20 In GOG 240,            umab (at a dose of 15 mg per kilogram of body
a phase 3, randomized trial performed in the              weight on day 1). Treatment was discontinued at
United States and in Spain through the Gyneco-            the onset of d
                                                                       ­ isease progression or the develop-
logic Oncology Group (GOG) and the Spanish                ment of unacceptable toxic effects, or if the pa-
Research Group for Ovarian Cancer, we investi-            tient had a complete response.
gated the incorporation of bevacizumab and the
use of nonplatinum combination chemotherapy               Assessments
in the treatment of advanced cervical cancer.             Disease was assessed by means of physical ex-
                                                          amination and chest radiography, as well as by
                    Me thods                              means of computed tomography or magnetic
                                                          resonance imaging of the abdomen and pelvis
Study Oversight                                           within 28 days before the study treatment was
The study was sponsored by the National Cancer            initiated. In patients without disease progres-
Institute, which provided bevacizumab without             sion, imaging was repeated every other cycle.
charge. All the authors wrote the manuscript and          Tumor measurements according to the Response
take responsibility for the accuracy and com-             Evaluation Criteria in Solid Tumors (RECIST),
pleteness of the reported data and for the fidelity       version 1, were made within 1 week before the
of the study to the protocol, which is available          next planned cycle.21 After discontinuation of
with the full text of this article at NEJM.org.           treatment, disease was assessed every 3 months
                                                          for 2 years, followed by assessment every
Patients                                                  6 months for 3 years until disease progression
Patients with metastatic, persistent, or recurrent        was doc­umented.
cervical carcinoma were eligible for the study. Pa-          Three validated, sensitive instruments were used
tients with recurrent disease were excluded if            to measure health-related quality of life. The Trial

                                 n engl j med 370;8   nejm.org   february 20, 2014                                            735
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The   n e w e ng l a n d j o u r na l     of   m e dic i n e

              Outcome Index of the Functional Assessment of                tizing platinum, and disease status (recurrence
              Cancer Therapy (FACT)–Cervix (FACT-Cx-TOI) sur-              or persistence of disease vs. advanced primary
              vey was used to assess physical and functional               disease).
              well-being (on a scale from 0 to 4, with higher                 The primary end points were overall survival
              scores indicating worsening well-being). Pain was            and the frequency and severity of adverse events
              measured with the use of the Brief Pain Inven-               associated with each regimen. Progression-free
              tory (BPI) (on a scale from 0 to 10, with higher             survival and the response rate were secondary end
              scores indicating more severe pain). Neurotoxicity           points. Differences in overall survival and pro-
              was measured with the use of the neurotoxicity               gression-free survival according to intervention
              subscale short form (FACT/GOG-NTX) (on a scale               level were assessed primarily by means of the
              from 0 to 4, with higher scores indicating in-               log-rank test, stratified according to clinical
              creased neurotoxicity).22 Baseline assessments were          prognostic markers and the level of the other in-
              completed before randomization, before cycles 2              tervention.26 Hazard ratios were estimated with
              and 5, and 6 and 9 months after cycle 1.                     the use of a Cox proportional-hazards model.27
                  Safety, as assessed according to the National               We calculated that we would need to enroll
              Cancer Institute Common Terminology Criteria                 approximately 450 patients, with approximately
              for Adverse Events, was monitored during each                346 deaths expected, to provide the study with
              cycle.23,24 Myeloid growth factor was permitted              90% power to detect a reduction in the risk of
              only for hospitalized patients with grade 3 or               death of at least 30% with either experimental
              higher febrile neutropenia (absolute neutrophil              treatment, with the one-sided type I error rate
              count, 150 mm Hg             health-related quality of life were evaluated with
              or diastolic blood pressure >100 mm Hg), protein-            the use of a mixed model for analysis of re-
              uria (urine protein-to-creatinine ratio ≥3.5), arte-         peated measures.30
              rial thrombosis, venous thrombosis, coagulopathy,
              or intestinal obstruction or disruption.                                             R e sult s

              Statistical Analysis                                         Patients
              The statistical analysis plan is available with the          Between April 2009 and January 2012, a total of
              protocol at NEJM.org. Assuming an absence of                 452 women were enrolled from 164 institutions
              interaction between experimental agents, we used             in the United States and Spain. The data freezes
              a 2-by-2 factorial design to investigate the effect of       occurred on February 6, 2012, and December 12,
              anti-VEGF therapy (bevacizumab) and a regi-                  2012. Analyses provided in this article concerning
              men of nonplatinum combination chemotherapy                  the bevacizumab regimens are from the second
              (topotecan–paclitaxel).25 The study was based on             data freeze. Figure 1 shows randomization and
              the intention-to-treat principle. Patients were pro-         follow-up among patients assigned to chemother-
              spectively stratified according to GOG perfor-               apy with or without bevacizumab.
              mance status, prior use or nonuse of radiosensi-                Demographic characteristics and clinical and

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Bevacizumab in Advanced Cervical Cancer

pathological factors were evenly distributed be-                   30), and for those who received chemotherapy plus
tween the treatment groups (see Table S15 in                       bevacizumab, the median was 7 (range, 0 to 36).
the Supplementary Appendix). The majority of                       Ninety-seven percent of patients discontinued
patients (72%) had recurrent disease, and 11%                      the study treatment; the most common reason
of patients had persistent disease. More than                      was disease progression (in 51% of patients
70% of patients in each group had previously                       who received chemotherapy [either regimen]
received platinum-based chemoradiotherapy.                         alone and 38% of patients who received chemo-
   The median number of cycles for patients                        therapy [either regimen] plus bevacizumab).
treated with chemotherapy alone was 6 (range, 0 to                 Treatment was discontinued owing to adverse

                                                         425 Patients were enrolled and underwent
                                                                      randomization

    114 Were assigned to receive            111 Were assigned to receive              115 Were assigned to receive           112 Were assigned to receive
      cisplatin (50 mg/m2) plus           topotecan (0.75 mg/m2, days 1–3)          cisplatin (50 mg/m2) plus pacli-      topotecan (0.75 mg/m2, days 1–3)
    paclitaxel (135 or 175 mg/m2)            plus paclitaxel (175 mg/m2)             taxel (135 or 175 mg/m2) plus         plus paclitaxel (175 mg/m2) plus
                                                                                        bevacizumab (15 mg/kg)                 bevacizumab (15 mg/kg)

              225 Were assigned to chemotherapy alone                                            227 Were assigned to chemotherapy plus
                  with cycles repeated every 21 days                                                bevacizumab with cycles repeated
                                                                                                              every 21 days

                219 Were included in safety analysis                                              220 Were included in safety analysis
                  6 Did not have adverse-event data submitted                                       7 Did not have adverse-event data submitted

                225 Were included in efficacy analysis                                            227 Were included in efficacy analysis
                  184 Reached PFS end point                                                         183 Reached PFS end point
                  140 Died                                                                          131 Died

   225 Discontinued treatment           51 Crossed over to salvage therapy          227 Discontinued treatment            33 Crossed over to salvage
       6 Had complete response to         12 to bevacizumab                            15 Had complete response to             therapy
         assigned treatment               20 to cisplatin                                 assigned treatment                 7 to bevacizumab
     115 Had disease progression          16 to topotecan                              86 Had disease progression           12 to cisplatin
      36 Had toxic effects                 1 to both bevacizumab and                   57 Had toxic effects                 13 to topotecan
      35 Declined further treatment          topotecan                                 28 Declined further treatment         0 to both bevacizumab and
       5 Died                              2 to both bevacizumab                        6 Died                                 topotecan
       2 Had other disease                   and cisplatin                              4 Had other disease                  1 to both bevacizumab
      21 Had other reasons                                                             23 Had other reasons                    and cisplatin
       5 Had unspecified reason                                                         8 Had unspecified reason

 Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.
 All 452 patients (225 in the chemotherapy-alone group and 227 in the chemotherapy-plus-bevacizumab group) who underwent randomization
 were included in the efficacy analysis. Because data on adverse events were not included for 6 patients in the chemotherapy-alone group, the
 safety analysis in this group included 219 patients. Because data on adverse events were not included for 7 patients in the chemotherapy-plus-
 bevacizumab group, the safety analysis in this group included 220 patients. A total of 15 patients randomly assigned to chemotherapy alone
 crossed over to salvage bevacizumab at the time of disease progression. PFS denotes progression-free survival.

                                      n engl j med 370;8     nejm.org        february 20, 2014                                                           737
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The   n e w e ng l a n d j o u r na l     of   m e dic i n e

              events in a higher per­centage of patients in the           Treatment with cisplatin–paclitaxel–bevaciz­u­
              ­chemotherapy–beva­cizumab group than in the mab, as compared with cisplatin–paclitaxel alone,
               ­chemotherapy-alone group (25% vs. 16%).                was associated with a hazard ratio for death of
                                                                       0.68 (95% CI, 0.48 to 0.97) (Fig. 3C). The response
                Efficacy                                               rates were 50% (cisplatin–paclitaxel–bevacizumab)
                At the time of the interim analysis (the first data and 45% (cisplatin–paclitaxel) (P = 0.51, two-sided
                freeze), 62% of patients were alive, with a median test); 17 patients and 9 patients had a complete re-
                follow-up of 12.5 months. As compared with cis- sponse, respectively. Topotecan–paclitaxel–bevaciz­
                platin–paclitaxel (either with or without bevaciz­ umab, as compared with topotecan–paclitaxel
                umab) topotecan–paclitaxel was associated with a alone, was associated with a hazard ratio for
                significantly higher risk of progression (hazard death of 0.74 (95% CI, 0.53 to 1.05) (Fig. 3D). The
                ratio, 1.39; 95% confidence interval [CI], 1.09 to response rates were 47% (topotecan–paclitaxel–
                1.77) (Fig. 2A), but it did not significantly affect bevacizumab) and 27% (topotecan–paclitaxel)
                overall survival (hazard ratio for death, 1.20; 99% (P = 0.002, two-sided test); 11 patients and 5 pa-
                CI, 0.82 to 1.76) (Fig. 2B). There was also no sig- tients had a complete response, respectively.
                nificant difference in mortality between the che-         Figure 3E shows multiple prognostic factors.
                motherapy regimens in the subgroup of patients The treatment benefit with bevacizumab was also
                with previous exposure to platinum (hazard ratio, observed in subgroup analyses of age, perfor-
                1.18; 95% CI, 0.84 to 1.65) and in the subgroup mance status, race, squamous histologic type,
                with no previous exposure to platinum (hazard status with respect to prior platinum exposure,
                ratio, 1.35; 95% CI, 0.68 to 2.69) (Fig. S3 and S4 recurrent or persistent disease, and pelvic loca-
                in the Supplementary Appendix). Noting that tion of the target lesion.
                topotecan was not a superior (or an inferior) sub-
                stitute for cisplatin, the data and safety monitor- Quality of Life
                ing committee voted on March 12, 2012, for early The rate of compliance with health-related qual-
                release of data from this first data freeze to all ity of life surveys was 96%, 84%, 78%, 67%, and
                investigators and patients.                            63% among patients at cycles 1, 2, and 5, and at
                    At a median follow-up of 20.8 months, 6 months and 9 months of follow-up, respectively,
                271 deaths had been reported (60% of the to- and was balanced between treatment groups
                tal study population), and the results from the (P = 0.67). The mean FACT-Cx-TOI scores exceeded
                second data freeze were partially released after a 70 at each time point in each group. The fitted
                recommendation by the data and safety moni- mixed-model estimates for the FACT-Cx-TOI and
                toring committee. The interaction term was not BPI scores indicated that the addition of bevaciz­
                significant, indicating that there was no inter­action umab did not adversely affect health-related
                between the two treatment regimens under investi- quality of life; scores for patients who received
                gation. The incorporation of bevacizumab signif­ antiangiogenic therapy were 1.2 points lower, on
                icantly improved the median overall survival as average than scores for patients who did not re-
                compared with chemotherapy alone (17.0 months ceive such therapy, although the difference was
                vs. 13.3 months; hazard ratio for death, 0.71; not significant (99% CI, −4.1 to 1.7; P = 0.30). The
                98% CI, 0.54 to 0.95) (Fig. 3A). A sig­nificant im- fitted mixed-effects mixed-distribution model es-
                provement in progression-free survival was also timates for the FACT/GOG-NTX scores showed a
                seen (8.2 vs. 5.9 months; hazard ratio for disease nonsignificant trend for patients receiving beva­
                progression, 0.67; 95% CI, 0.54 to 0.82) (Fig. 3B). ciz­umab to report fewer neurotoxic symptoms
                The response rate was significantly higher among (overall odds ratio, 0.58; 99% CI, 0.29 to 1.17;
                patients who received bevaciz­u­mab than among P = 0.05), and the severity of neurotoxic symptoms
                those who did not receive bevaciz­u­mab (48% vs. reported was similar in the two groups (P = 0.70).
                36%) (relative probability of a response, 1.35;
                95% CI, 1.08 to 1.68; P = 0.008, two-sided test). Safety
                Among patients who received bevacizumab, 28 had Table 1 shows the frequency of adverse events
                a complete response, and among those who re- potentially associated with bevacizumab. Hyper-
                ceived chemotherapy alone, 14 had a complete tension of grade 2 or higher was significantly
                response (P = 0.03). Treatment was discontinued more common with bevacizumab-containing
                in 21 patients who had a complete response.            regimens than with regimens that did not con-

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Bevacizumab in Advanced Cervical Cancer

tain bevacizumab (25% vs. 2%, P
740
                                                                                                                                                 A                                                                               Median
                                                                                                                                                                                                                                                  B                                                                          Median                   C                                                                               Median
                                                                                                                                                                                                                    Events       Overall                                                                                 Progression-free                                                                                             Overall
                                                                                                                                                                                                                    no. (%)      Survival                                                                        Events      Survival                                                                                     Events      Survival
                                                                                                                                                                                                                                   mo                                                                            no. (%)       mo                                                                                         no. (%)       mo
                                                                                                                                                            Chemotherapy (N=225)                                    140 (62)          13.3                   Chemotherapy (N=225) 184 (82)                                          5.9                                                            CP (N=114)             69 (61)         14.3
                                                                                                                                                        Chemotherapy+Bev (N=227)                                    131 (58)          17.0               Chemotherapy+Bev (N=227) 183 (81)                                          8.2                                                        CP+Bev (N=115)             66 (58)         17.5
                                                                                                                                                                                                  Hazard ratio, 0.71 (98% CI, 0.54–0.95);                   Hazard ratio, 0.67 (95% CI, 0.54–0.82); two-sided P=0.002                                         Hazard ratio, 0.68 (95% CI, 0.48–0.97); one-sided P=0.04
                                                                                                                                                                                        1.0                 one-sided P=0.004                                        1.0                                                                                               1.0
                                                                                                                                                                                                       Median follow-up, 20.8 mo
                                                                                                                                                                                        0.8                                                                                              0.8                                                                                                  0.8

                                                                                                                                                                                        0.6                                                                                              0.6                                                                                                  0.6

                                                                                                                                                                                        0.4                                                                                              0.4                                                                                                  0.4

                                                                                                                                                                                                                                                                  Probability of
                                                                                                                                                                                        0.2                                                                                              0.2                                                                                                  0.2

                                                                                                                                                              Probability of Survival
                                                                                                                                                                                                                                                                                                                                                                   Probability of Survival

                                                                                                                                                                                                                                                             Progression-free Survival
                                                                                                                                                                                        0.0                                                                                              0.0                                                                                                  0.0
                                                                                                                                                                                              0        6     12     18    24     30          36                                                0    6      12     18     24        30      36                                                       0     6    12         18   24     30         36
                                                                                                                                                                                                     Months since Randomization                                                                    Months since Randomization                                                                            Months since Randomization
                                                                                                                                                                                                                                                                                                                                                                                                                                                       The

                                                                                                                                                     No. at Risk                                                                                      No. at Risk                                                                                         No. at Risk
                                                                                                                                                     Chemotherapy                         225        167     94     45    17      8                   Chemotherapy                         225     103     40     14      6        3                      CP                                       114   89    50         22   12     5
                                                                                                                                                     Chemotherapy                         227        184    121     69    30     10                   Chemotherapy                         227     132     70     22      6        3                      CP+bev                                   115   94    63         37   17     5
                                                                                                                                                       +bev                                                                                             +bev

                                                                                                                                                 D                                                                               Median
                                                                                                                                                                                                                                                  E
                                                                                                                                                                                                                                 Overall

                                                                                                                            n engl j med 370;8
                                                                                                                                                                                                                    Events       Survival             Subgroup                                                                          No. of Patients                                                  Hazard Ratio
                                                                                                                                                                                                                    no. (%)        mo
                                                                                                                                                                                                                                                      Age                                                ≤40 yr                                 112
                                                                                                                                                                                             TP (N=111)             71 (64)           12.7                                                               40 to ≤48 yr                           111
                                                                                                                                                                                         TP+Bev (N=112)             65 (58)           16.2                                                               48 to ≤56 yr                           108

                                                                                                                            nejm.org
                                                                                                                                                         Hazard ratio, 0.74 (95% CI, 0.53–1.05); one-sided P=0.09                                                                                        >56 yr                                 121
                                                                                                                                                                                                                                                      Performance status                                 0                                      263
                                                                                                                                                                                                                                                                                                                                                                                                                                                      n e w e ng l a n d j o u r na l

                                                                                                                                                                                        1.0                                                                                                              1                                      189

                                          The New England Journal of Medicine
                                                                                                                                                                                                                                                      Previous platinum                                  No
                                                                                                                                                                                                                                                                                                                                                                                                                                                       of

                                                                                                                                                                                                                                                                                                                                                115
                                                                                                                                                                                        0.8                                                             radiation therapy
                                                                                                                                                                                                                                                                                                         Yes                                    337
                                                                                                                                                                                        0.6                                                           Disease status                                     Advanced                                76
                                                                                                                                                                                                                                                                                                         Recurrent or persistent                376
                                                                                                                                                                                        0.4

                                                                                                                            february 20, 2014
                                                                                                                                                                                                                                                      Topotecan treatment                                No                                     229
                                                                                                                                                                                                                                                                                                         Yes                                    223

                            Copyright © 2014 Massachusetts Medical Society. All rights reserved.
                                                                                                                                                                                        0.2
                                                                                                                                                                                                                                                                                                                                                                                                                                                      m e dic i n e

                                                                                                                                                                                                                                                      Race                                               Not black                              392

                                                                                                                                                              Probability of Survival
                                                                                                                                                                                        0.0                                                                                                              Black                                   60
                                                                                                                                                                                              0        6     12     18    24     30          36       Histologic type                                    Adenocarcinoma                          86
                                                                                                                                                                                                                                                                                                         Adenosquamous                           44
                                                                                                                                                                                                     Months since Randomization                                                                          Other                                   12
                                                                                                                                                     No. at Risk                                                                                                                                         Squamous                               310
                                                                                                                                                     TP                                   111          78    44     23     5      3                   Pelvic disease                                     No                                     210
                                                                                                                                                     TP+bev                               115          90    58     32    13      5                                                                      Yes                                    242
                                                                                                                                                                                                                                                      Overall                                                                                   452
                                                                                                                                                                                                                                                                                                                                                            0.0                              0.5         1.0        1.5         2.0         2.5
                                                                                                                                                                                                                                                                                                                                                             Experimental Better                                     Control Better

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Bevacizumab in Advanced Cervical Cancer

                                                               maps to the C-terminal and correlates with
 Figure 3 (facing page). Effect of Incorporation
 of Bevacizumab on Survival.                                   displacement by E7 of the histone deacetylases
 Panel A shows overall survival and Panel B shows pro-         HDAC1, HDAC4, and HDAC7.37
 gression-free survival among patients who received ei-            Short-lived responses to chemotherapy in pa-
 ther chemotherapy regimen plus bevacizumab or either          tients with advanced cervical cancer indicate
 chemotherapy regimen alone. Panel C shows overall             that the disease is relatively chemorefractory. We
 survival among patients who received cisplatin–paclitaxel
                                                               selected overall survival as the primary end point
 with or without bevacizumab, and Panel D shows overall
 survival among those who received topotecan–paclitaxel        because, unlike patients with other cancers, pa-
 with or without bevacizumab. In Panel E, a forest plot        tients with advanced cervical cancer usually do
 shows the effect of chemotherapy with bevacizumab             not have a sustained response to chemotherapy
 (experimental), as compared with chemotherapy with-           and cannot receive multiple lines of chemother-
 out bevacizumab (control), on overall survival, stratified
                                                               apy because of unacceptable side effects. We
 according to multiple prognostic factors. A positive treat-
 ment benefit (orange) is indicated. The upper bound of        think that the 3.7-month improvement in me-
 the confidence interval for histologic type was truncated     dian overall survival attributed to the addition
 at 2.5. Its true upper bound, 7.07, resulted from a small     of bevacizumab to chemotherapy is clinically
 sample. An interaction test was performed, and nothing        meaningful. Antiangiogenic therapy and possi-
 was found to be significant. The factor with the smallest
                                                               bly other targeted agents may provide additional
 P value was histologic type (P = 0.07).
                                                               gains in survival time, allowing for multiple
                                                               lines of therapy with sustained health-related
                                                               quality of life. Given the well-recognized HPV
an aggressive course in cervical cancer. Vascular              epidemic, these data provide support for further
markings seen at colposcopy in women with ab-                  investigation of antivascular therapy in patients
normal Papanicolaou tests are hallmarks for in-                with other HPV-induced tumors, including vulvar,
vasive disease, and increased microvessel density              anal, penile, and oropharyngeal carcinomas.
and strong immunostaining for the endothelial-                     Two additional agents that may have activity in
cell marker, CD31, in cervical cancers suggest a               advanced cervical cancer are pazopanib, an intra-
poor prognosis.2 VEGF is involved in mitogenesis,              cellular small-molecule tyrosine kinase in­hib­
angiogenesis, endothelial-cell survival, and induc-            itor that targets VEGF receptor, and sorafenib,
tion of hematopoiesis.33 Patients with high-grade              a multikinase inhibitor.38 Data are lacking on
cervical dysplasia and invasive carcinoma have in-             drugs that inhibit angiogenesis through non–
creased expression of VEGF and hypoxia-inducible               VEGF-dependent pathways (e.g., the Tie2–angio-
factor 1α (HIF-1α).34 The invasive phenotype is                poietin-2 pathway), as well as vascular disrupting
present only with up-regulated VEGF. Overexpres-               agents (e.g., vadime­zan). Finally, drugs targeting
sion of oncogenic HPV subtypes enhances HIF-1α                 nonangiogenic signal-transduction pathways that
protein accumulation and VEGF expression.                      are integral to tumor progression may be con-
   The molecular mechanism through which                       sidered, including Wee1 checkpoint inhibitors
HPV mediates tumor angiogenesis has been elu-                  and Notch γ-secretase inhibitors, the latter be-
cidated. In the native form, HPV exists as circular            ing an evolutionarily conserved cell-fate deci-
double-stranded DNA episomes, and viral E2 ex-                 sion switch in cervical cancer.
pression prevents transcription of the viral onco-                 There has been a large unmet medical need
genes, E6 and E7. The E2 reading frame is dis-                 for active treatments for cervical cancer, which
rupted on viral integration into host DNA,                     is a leading cause of death from cancer in develop-
resulting in lack of repression of E6 and E7, which            ing countries. In the poorest regions, where rates
mediate neoplastic transformation through degra-               are highest (sub-Saharan Africa, Latin America,
dation or inactivation of cellular tumor-suppressor            and Southeast Asia, including India), many wom-
protein p53 and retinoblastoma protein, respec-                en are forced by socioeconomic and political cir-
tively.35 VEGF isoform expression can be con-                  cumstances to act as the sole provider for their
siderably reduced by silencing HPV E6 messen-                  young families. With their deaths, the effect on
ger RNA with specific small interfering RNAs                   families can be devastating. The improvement in
but not when p53 is silenced, suggesting that                  survival that is conferred by cisplatin–paclitaxel–
E6 induces VEGF through a p53-independent                      bevacizumab treatment warrants cost-effectiveness
mechanism.36 HIF-1α activity enhanced by E7                    studies because of the societal burden involved in

                                     n engl j med 370;8   nejm.org   february 20, 2014                                        741
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                              Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The   n e w e ng l a n d j o u r na l           of   m e dic i n e

               Table 1. Selected Adverse Events among the Study Patients, According to Treatment Group.*

                                                             Chemotherapy           Chemotherapy plus
                                                                Alone                 Bevacizumab                  Odds Ratio
               Event                                           (N = 219)                (N = 220)                   (95% CI)              P Value
                                                                           no. of patients (%)
               Gastrointestinal events, excluding                96 (44)                   114 (52)             1.38 (0.93–2.04)            0.10
                      fistulas (grade ≥2)
               Fistula (grade ≥3)
                   Gastrointestinal                                0                         7 (3)              NA (1.90–∞)                 0.02
                   Genitourinary                                   1 (
Bevacizumab in Advanced Cervical Cancer

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