- Email: [email protected]
Comparison of bevacizumab alone or with chemotherapy in recurrent ovarian cancer patients
Comparison of Bevacizumab Alone or with Chemotherapy in Recurrent Ovarian Cancer Patients Katherine C. Fuh, Angeles A. Secord, Kerri S. Bevis, Warner Huh, Adam ElNaggar, Kevin Blansit, Rebecca Previs, Todd Tillmanns, Daniel S. Kapp, John K. Chan PII: DOI: Reference:
S0090-8258(15)30062-7 doi: 10.1016/j.ygyno.2015.06.041 YGYNO 975975
To appear in:
Gynecologic Oncology
Received date: Revised date: Accepted date:
29 April 2015 27 June 2015 30 June 2015
Please cite this article as: Katherine C. Fuh, Angeles A. Secord, Kerri S. Bevis, Warner Huh, Adam ElNaggar, Kevin Blansit, Rebecca Previs, Todd Tillmanns, Daniel S. Kapp, John K. Chan, Comparison of Bevacizumab Alone or with Chemotherapy in Recurrent Ovarian Cancer Patients, Gynecologic Oncology (2015), doi: 10.1016/j.ygyno.2015.06.041
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ACCEPTED MANUSCRIPT Comparison of Bevacizumab Alone or with Chemotherapy in Recurrent Ovarian Cancer Patients
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Katherine C. Fuh, M.D.,Ph.D.1,6,8, Angeles A. Secord, M.D.2, Kerri S. Bevis, M.D.3, Warner Huh, M.D.3, Adam ElNaggar, M.D.4, Kevin Blansit1,5, Rebecca Previs, M.D.2, Todd Tillmanns, M.D.4, Daniel S. Kapp M.D., Ph.D.7, John K. Chan, M.D.1,5 1
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Division of Gynecologic Oncology Helen Diller Family Comprehensive Cancer Center University Of California, San Francisco 1600 Divisadero Street San Francisco, CA 94143-1702 2
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Division of Gynecologic Oncology Department Of Obstetrics and Gynecology Duke University, School Of Medicine DUMC 3079 Durham, NC 27710 3
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Division of Gynecologic Oncology Department of Obstetrics and Gynecology University of Alabama at Birmingham 1700 6th Ave South Birmingham, AL 35233
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The West Clinic . University of Tennessee 100 N. Humphreys Blvd, Memphis, TN 38120
Palo Alto Medical Foundation Research Institute 795 El Camino Real, Ames Building Palo Alto, CA 94301 6
Division of Gynecologic Oncology Department of Obstetrics and Gynecology Washington University, School of Medicine St. Louis, MO 63108 7
Department of Radiation Oncology Division of Gynecologic Oncology Department of Obstetrics and Gynecology Stanford University, School of Medicine 400 Pasteur Drive Stanford, CA 94305 8
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Number of Pages: 18 Number of Tables: 4 Number of Figures: 1 Disclosure Statement: The authors report no financial disclosures. Financial Support: The authors would like to acknowledge The Dr. John A Kerner Research Fund for support of this project.
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Please address correspondence to: Dr. John K. Chan Division of Gynecologic Oncology California Pacific & Palo Alto Medical Foundation / Research Institute Sutter Cancer Research Consortium 3838 California Street San Francisco, CA 94115 Office: (415) 751-1847 Fax: (415) 387-2613 Email: [email protected]
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Portions of this study were presented as a poster at the 43rd Annual Society of Gynecologic Oncology 2012 in Austin, TX.
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ACCEPTED MANUSCRIPT Abstract Background: To compare the efficacy of chemotherapy (C) combined with
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bevacizumab (Bev) versus Bev alone in recurrent, heavily pretreated epithelial ovarian
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cancer (EOC).
Methods: A multicenter analysis of patients treated from 2004 to 2011 was performed.
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Demographic, treatment, response, and adverse event information were obtained.
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Progression-free (PFS) and overall survival (OS) were analyzed. Results: Of 277 patients (median age: 58 years), the majority had Stage III and IV
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(86%) disease, and 72% had serous histology. 244 (88%) were treated with C+Bev and 33 (12%) with Bev. Corresponding median progression-free survival (PFS) was 8.7 and
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6.7 months, and median overall survival (OS) was 14.3 and 10.5 months, respectively. The chemotherapeutic agents combined with Bev and the median OS include:
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pegylated liposomal doxorubicin (n=19, OS of 20.4 months), taxanes (n=55, OS of 20.2 months), gemcitabine (n=106, OS of 14.1 months), topotecan (n=43, OS of 13 months), and cyclophosphamide (n=21, OS of 13 months). There was no significant difference in toxicities between the C+Bev vs. Bev alone group. Conclusion: This retrospective analysis supports that combination chemotherapy and bevacizumab prolongs PFS and OS compared with bevacizumab alone. Keywords: recurrent epithelial ovarian cancer; bevacizumab; chemotherapy; survival; platinum-resistant; liposomal doxorubicin, taxanes
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ACCEPTED MANUSCRIPT Background Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic
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malignancy[1]. In patients with recurrent, platinum-resistant, heavily pretreated disease,
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single agent chemotherapy has been generally recommended given the increased toxicity and lack of data showing additional benefit with combination chemotherapy [2-
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7].
(Bev) improved the
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In clinical trials, chemotherapy with bevacizumab
progression-free survival of those with primary and recurrent, platinum-sensitive and
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resistant disease compared to chemotherapy alone [8-14]. Preclinical studies have shown that Bev can potentially enhance the delivery of chemotherapeutic agents by
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normalizing blood vessels and reducing interstitial fluid pressure [15-17]. More recently,
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a randomized clinical trial compared the efficacy of physician-selected chemotherapy
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versus chemotherapy combined with bevacizumab in platinum-resistant ovarian cancer. These investigators found that the combination therapy including Bev improved the progression-free survival over chemotherapy alone (6.7 vs 3.4 months, p<0.001). However, there was no difference in overall survival between the treatment groups (16.6 vs 13.3 months, p<0.174) [18].
However there are no studies that have compared the efficacy of chemotherapy and Bev versus Bev alone. Bev has been shown to have significant activity as a single agent [19, 20]. It is possible that single agent biologic therapy may achieve similar results compared to chemotherapy and bevacizumab without the increased toxicity associated with combination therapy [19, 20]. In this current report, the objective was to evaluate the efficacy of chemotherapy with bevacizumab vs. bevacizumab alone in 4
ACCEPTED MANUSCRIPT patients with recurrent, heavily pretreated epithelial ovarian, peritoneal, or fallopian tube cancer and to determine whether either regimen would result in a survival difference.
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Methods
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A multi-institutional, retrospective analysis of efficacy for women with recurrent EOC treated with chemotherapy in combination with Bev or single-agent Bev was
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performed. Study approval was obtained from the Institutional Review Boards of the
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study sites: University of California San Francisco, Duke Cancer Institute, University of Alabama at Birmingham, University of Tennessee, and Stanford University. Women
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with recurrent, epithelial ovarian, peritoneal or fallopian tube cancer treated with chemotherapy combination with bevacizumab (C+Bev) or Bev alone between 2004 and
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2011 were included in the analysis. Patients who had progressed within 6 months of completing platinum-based therapy prior to beginning bevacizumab were identified and
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included in this analysis and defined as resistant to platinum therapy. Patients who were treated with bevacizumab as part of first-line therapy were excluded. None of the patients had secondary cytoreductive surgery. Patients had not previously received the chemotherapy that was combined with bevacizumab used in this analysis. Patients were followed for relapse with CA-125 levels, and imaging was obtained when a significant increase in CA-125 was seen and/or for symptoms. Treatment information including response to platinum, number of prior chemotherapy regimens, type of chemotherapy regimens, and duration of therapy was collected and analyzed. For those who received taxanes, the particular taxane administered was recorded. For those who received paclitaxel, the frequency of administration was not recorded for this study collection. Patients who received one or 5
ACCEPTED MANUSCRIPT more cycles of chemotherapy and Bev or Bev alone were assessed for antitumor activity and toxicity. Responses were determined through serial radiographic evaluation
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of measurable disease. An imaging study was obtained prior to initiation of
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chemotherapy with bevacizumab or bevacizumab alone and location of recurrence was recorded as local (pelvic disease) or distant (upper abdominal, lymph node metastases
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and pleural effusions). Imaging was repeated if the patient had worsening signs and/or
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symptoms, a doubling of CA-125 or at the end of the prescribed regimen generally after completing 4-6 cycles. Those with measurable disease were assessed by Response
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Criteria in Solid Tumors (RECIST) 1.1 [21, 22].
Complete response (CR) was defined as disappearance of all target lesions.
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Partial response (PR) was defined as at least 30% decrease of the target lesions, progressive disease (PD) was defined as at least 20% increase in the sum of the
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diameters of lesions, and stable disease (SD) was defined as small changes that did not meet the above criteria for PR or SD. The best response for each patient was documented. Progression-free survival was defined as the interval between the initiation of chemotherapy and Bev or single agent Bev and the first radiologically documented disease progression or death. Patients lost to follow-up were censored at the time of their last visit. Overall survival was defined as the interval between the initiation of C+Bev or Bev alone and date of death or date of last follow-up. Toxicity was determined through review of medical records and assessed according to the National Cancer Institute’s Common Toxicity Criteria version 4.0. T-test, ANOVA, and Chi-square were used for statistical analyses of clinico-demographics using R 3.0.2 (R Foundation for Statistical Computation; Vienna, Austria). Kaplan-Meier curves were developed to 6
ACCEPTED MANUSCRIPT examine stage-specific survival and compared using the log-rank test. Cox proportional hazards models were developed to examine both progression-free survival and overall
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survival.
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Results All Patients
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Of 277 recurrent, platinum-resistant EOC patients treated with either C+Bev or
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Bev alone, the median age of the cohort was 58 years (range: 19 to 85). The clinicopathologic factors of these patients are summarized in Table 1. The majority (64%)
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underwent initial optimal (<1 cm residual disease) surgical cytoreduction. Most (86%) patients had advanced (stage III-IV) disease, 72% had serous histology, and 73% had
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poorly-differentiated tumors. The median time to first relapse was 10 months. Most of these women had multiple relapses for which they were treated with various
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chemotherapy regimens for recurrent disease with a median number of three treatment regimens prior to receiving C+Bev or Bev alone. The length of treatment with either C+Bev or Bev alone was similar between both groups of four months. The various chemotherapy regimens used with Bev are shown in Table 1. Efficacy between C+Bev vs Bev alone 244 (88%) women were treated with C+Bev, and 33 (12%) were treated with Bev alone.
Based on RECIST criteria, the overall complete or partial response rate of
patients who underwent C+Bev vs. Bev alone was 37% vs. 21% (p=0.01) (Table 2). The 6-month PFS for patients treated with C+Bev was 63% compared to 50% in those treated with Bev alone with median PFS of 8.7 vs 6.7 months (p=0.01) (Figure 1A). C+Bev was associated with an improved overall survival of 14.3 months vs. 10.5 7
ACCEPTED MANUSCRIPT months with Bev alone (p<0.01) (Figure 1B). Efficacy of regimens between patients with radiographic recurrence only
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When excluding the 32 patients who had C+Bev therapy initiated based on
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chemical recurrence, median overall survival continued to be higher (13 vs. 10.5 months, p=0.022) for those treated with C+Bev vs. Bev only. The median PFS for
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C+Bev was also greater at 8.7 months vs. 6.7 months, p=0.033 for the Bev only group.
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Efficacy among the various chemotherapies with Bev
Of those treated with Bev and various chemotherapy regimens, there was no
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statistical difference in response rates based on the type of chemotherapy used with Bev (Table 2). However, there was a difference in PFS among the chemotherapy
was
94%,
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combinations with Bev: 6-month PFS of pegylated liposomal doxorubicin+Bev (n=19) taxanes+Bev
(n=55)
at
65%,
topotecan+Bev
(n=43)
at
64%,
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gemcitabine+Bev (n=106) at 59%, and cyclophosphamide+Bev (n=21) at 54% (p=0.02). The median PFS of those treated with bevacizumab and topotecan, taxanes, gemcitabine, cyclophosphamide, or Bev alone was 13.7, 10.7, 8.7, 6.7, and 6.7 months, respectively (median PFS was not yet reached for pegylated liposomal doxorubicin). Of those treated with Bev and various chemotherapy regimens, the 5-year and median OS of those treated with bevacizumab with taxanes and bevacizumab with pegylated liposomal doxorubicin was higher than the other C+Bev combinations (Table 3). However, there was no statistically significant difference in overall survival based on the chemotherapy regimen combined with bevacizumab (p=0.06). To evaluate whether any demographic or clinico-pathologic factors could have influenced OS or PFS, we compared C+Bev vs. Bev alone with respect to these factors. 8
ACCEPTED MANUSCRIPT There was no significant difference in age, race, cell type, tumor grade and extent of cytoreductive surgery, adjuvant treatment, and time to initial recurrence. More patients
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in the C+Bev group had a performance status of either 0 or 2 compared to the Bev
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group that had more patients with a performance status of 1 (p=0.048). However, those who received C+Bev had a longer treatment free interval (TFI) of 4 months vs. 2 months
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for those treated with Bev alone (p=0.02). Additionally, C+Bev were treated with fewer
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prior regimens (3 vs. 4, p<0.01) (Table 1). However, further analysis showed that performance status (p=0.36), TFI (p=0.32), and the number of prior regimens (p=0.55)
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was not prognostic for OS. On multivariate analysis, only treatment with C+Bev (HR=0.51, 95%CI: 0.32 to 0.83; p<0.01) and recurrence based on CA-125 values (HR=
4).
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Safety
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0.54, 95%CI: 0.3 to 1.01; p=0.05) were independent predictors for improved OS (Table
Those who had C+Bev had an overall 39% rate of toxicity compared to 55% in those with Bev alone (p=0.09). The rate of serious gastrointestinal complications was 3% vs. 6% for C+Bev versus Bev alone, respectively (p=0.33). The rate of overall cardiovascular events was not different between the treatment groups (36% vs. 48%; p=0.17), and most of these cardiovascular events were grade 2 or higher hypertension. Discussion In this retrospective cohort of heavily-pretreated, recurrent EOC patients, treatment with chemotherapy combined with Bev had improved efficacy based on response rates, progression-free and overall survival compared to Bev alone. This significant improvement in overall and progression-free survival was also seen when 9
ACCEPTED MANUSCRIPT patients with chemical recurrences were excluded and only those with radiographic recurrences were analyzed. Additionally, receiving chemotherapy with bevacizuamb
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was an independent predictor for overall survival after adjusting for significant factors.
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There has been four published randomized phase III trials of Bev in ovarian cancer demonstrating the activity of this novel biologic agent: two in the upfront setting
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and two in the relapsed setting [8, 18, 23, 24]. In the most recent Avastin Use in
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Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial, investigators compared chemotherapy combined with bevacizumab to chemotherapy alone in patients with
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platinum-resistant disease [18]. They found that the addition of Bev to chemotherapy improved PFS from 3.4 months to 6.7 months (p<0.001). However, the AURELIA study
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did not evaluate the benefit of Bev alone. We hypothesized that Bev as a single agent may have had similar activity compared to combination therapy [23, 24]. However, our
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data suggests that the combination of chemotherapy with bevacizumab versus Bev alone yielded improved clinical outcomes and was not associated with significantly increased toxicity. Both the AURELIA study and our data support an advantage of combination chemotherapy and bevacizumab compared to either agent alone. The biological advantage of combining chemotherapy with Bev may be explained by an enhanced delivery of chemotherapy agents with Bev. As cancer cells produce vascular endothelial growth factor (VEGF-A) and other pro-angiogenic cytokines, newly formed vessels are maintained in a constant angiogenic state [15-17]. Bev can reduce the interstitial fluid pressure and enhance the delivery of the chemotherapeutic agents into the tumors [15-17]. The potential synergism of Bev and chemotherapy is based on the action of chemotherapy on proliferating endothelial cells, while VEGF-targeted 10
ACCEPTED MANUSCRIPT therapy affects survival signaling pathways in endothelial cells; this combination leads to increased susceptibility of chemotherapy-induced apoptosis of cancer cells [25].
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Furthermore, Bev normalizes the blood vessels and redistributes blood flow while
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increasing the overall delivery of chemotherapy and oxygen, which may further explain the mechanism of how combination chemotherapy and Bev is more effective than Bev
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or chemotherapy alone [15-17]. The majority of patients in this study received Bev+C
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rather than Bev alone. This may have been due to the uncertainty of the activity of Bev alone during this time period.
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The combination of chemotherapy and bevacizumab may be of particular interest in platinum-resistant, heavily-pretreated patients. Previously these patients have been
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typically treated with single agent chemotherapy due to the excessive toxicity related to combination chemotherapies. Sehouli et al, demonstrated that combination therapy did
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not improve the overall survival but increased the toxicity of treatment [7]. In contrast, our data suggests that bevacizumab combined with single agent chemotherapy may improve the median survival with acceptable toxicity. Perhaps the combination of a biologic agent and chemotherapy provides a biologic advantage with respect to efficacy, but it also prevents the additive toxicity related to combination chemotherapies from the same class of drugs. In the AURELIA trial, the combination of chemotherapy and Bev did not improve the overall survival over chemotherapy alone. These authors suggested that the lack of OS benefit may be attributed to the fact that 40% of patients on the chemotherapy alone arm crossed over to Bev for their subsequent treatment. In our study, because both groups of patients received Bev, crossover is unlikely to be a confounding factor. Our findings in this retrospective study warrant further validation 11
ACCEPTED MANUSCRIPT from prospective randomized studies. Our study also provides information regarding the combination of various
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chemotherapy agents with bevacizumab. Of 244 patients who received Bev and various
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chemotherapeutic agents, we have a large group of patients treated with different chemotherapies to compare therapeutic efficacy combined with Bev. In this report, we
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showed that there was a trend of either pegylated liposomal doxorubicin or taxanes
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combined with bevacizumab as the most active treatment combinations. Dose-dense paclitaxel has been described to have anti-angiogenic properties, through reducing
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tumor secreted VEGF and interleukin-8, and may synergize with Bev. This finding has been supported in preclinical models of platinum-resistant ovarian cancer with an
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improvement in overall survival of those treated with bevacizumab and paclitaxel compared to either single agent bevacizumab or paclitaxel [26].
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Ongoing clinical trials from the Gynecologic Oncology Group (262) and ICON 8 are currently evaluating the benefit of using dose-dense paclitaxel with Bev to exploit the potential synergistic activity of chemotherapy and biologic treatment. Early results show that dose-dense paclitaxel may have a progression-free survival benefit in a subgroup of patients [27]. Our data regarding pegylated liposomal doxorubicin with bevacizumab revealed a 6-month PFS rate of 94%. These results are much higher than expected, and we acknowledge that this is a small group of patients comprising of only 19 patients. Recent results from the AURELIA trial did not publish a specific combination that resulted in an improved outcome among pegylated liposomal doxorubicin, topotecan, and weekly paclitaxel [18]. In addition, we noted that the synergistic effects of these compounds with respect 12
ACCEPTED MANUSCRIPT to its anti-vascular activity may also result in more toxicity. In this current analysis, we did not find a significant increase in cardiovascular toxicity in a subgroup analysis.
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Furthermore, there was no additive toxicity of pegylated liposomal doxorubicin and
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bevacizumab in relation to serious cardiovascular toxicity such as cardiomyopathy Further research with a larger number of patients is warranted to evaluate the
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combination and sequencing of these agents with bevacizumab to improve the
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response and quality of life in these patients. For example, recent studies by Gourley and colleagues have demonstrated that an immune molecular subgroup of high grade
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serous ovarian cancer have superior survival to other high grade serous ovarian cancer group, and the addition of Bev significantly reduces survival in this subgroup [28]. This
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suggests that evaluating tumor gene expression is important to determine the patient population that will best respond to bevacizumab treatment. Additionally, the cost
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effectiveness of using C+Bev may appear to be more than Bev alone given the increase in PFS and OS. Other groups have looked at cost-effectiveness of C+Bev in ovarian cancer and other gynecological cancers[29, 30]. The limitations of our study include its retrospective nature, lack of centralized pathology review, lack of randomization and standardization of imaging and treatment, imbalance of cohort groups, lack of inclusion of patients who received Bev after initial treatment with Bev, possible bias of patients with a better performance status and those with a recurrence in localized regions receiving Bev alone, the retrospective collection of safety and surgical data which may not accurately reflect every encountered toxicity as well as whether patients had optimal cytoreduction to no residual disease rather than to less than 1 cm, other prognostic factors that are challenging to document in a 13
ACCEPTED MANUSCRIPT retrospective study, and variation in chemotherapy regimens given with bevacizumab due to the multi-institutional aspect of this analysis. In addition, the outcome was based
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on progression-free and overall survival without information on quality of life and limited
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data on toxicity. Although there is a potential bias that the Bev alone group has a better performance status and a greater rate of recurrence in localized regions, this group also
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received a greater number of prior regimens, had a shorter time to initial recurrence,
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and a shorter treatment-free interval prior to treatment than those treated with C+Bev. Although the numbers in the bevacizumab alone group was small, the width and
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magnitude of the 95% confidence interval for overall survival was adequate. To our knowledge, this study is the largest series to date evaluating the efficacy
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and safety of bevacizumab combination compared to single-agent bevacizumab in recurrent ovarian cancers. All participating institutions are academic centers with
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gynecologic oncologists and expert gynecologic pathologists. The collected data is reflective of a diverse population of heavily pretreated, platinum-resistant ovarian cancer patients from five treatment centers throughout the United States. It is unlikely that a prospective randomized study would be implemented to study the various combinations of chemotherapy with bevacizumab. Thus, the results of this large, retrospective, multiinstitutional study from five academic centers may provide some guidance towards treatment of platinum-resistant ovarian cancer. Clearly, further molecular studies are warranted to identify relevant biomarkers to individualize treatment of selected patients with unique genomic profiles in the setting of relapsed ovarian cancer with attention to groups that may be harmed by bevacizumab and chemotherapy but not bevacizumab alone [31]. 14
ACCEPTED MANUSCRIPT Despite these limitations, our data suggest that combination chemotherapy and bevacizumab may result in improved response and survival outcomes with a tolerable
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general safety profile compared to bevacizumab alone. Further evaluation is warranted
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to confirm our findings. Conclusion
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In heavily pretreated, recurrent epithelial ovarian cancer patients, treatment with
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chemotherapy and bevacizumab may result in a higher response rate, better progression free and overall survival than treatment with bevacizumab alone.
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Conflict of Interest Statement:
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The authors declare that there are no conflicts of interest.
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Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 May 1;32(13):1302-8. PubMed PMID: 24637997. 19. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Nov 20;25(33):5165-71. PubMed PMID: 18024863. 20. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Nov 20;25(33):5180-6. PubMed PMID: 18024865. 21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009 Jan;45(2):228-47. PubMed PMID: 19097774. 22. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute. 2000 Feb 2;92(3):205-16. PubMed PMID: 10655437. 23. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The New England journal of medicine. 2011 Dec 29;365(26):2473-83. PubMed PMID: 22204724. 24. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. The New England journal of medicine. 2011 Dec 29;365(26):2484-96. PubMed PMID: 22204725. 25. Xiong YQ, Sun HC, Zhu XD, Zhang W, Zhuang PY, Zhang JB, et al. Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression. Journal of cancer research and clinical oncology. 2011 Mar;137(3):505-12. PubMed PMID: 20490863. 26. Rein DT, Volkmer AK, Volkmer J, Beyer IM, Janni W, Fleisch MC, et al. Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pretreated ovarian cancer. Oncology letters. 2012 Mar;3(3):530-4. PubMed PMID: 22740945. Pubmed Central PMCID: 3362354. 27. Chan JK. Every 3-week versus dose dense weekly paclitaxel combined with carboplatin +/- bevacizumab in advanced epithelial ovarian, peritoneal, or fallopian tube cancer (GOG 262). ESGO meeting. 2013. 28. Gourley C, McCavigan, A., Perren, T., Paul, J., Michie, C., Churchman, M., Williams, A., McCluggage, W., Parmar, M., Kaplan, R., Hill, L., Halfpenny, I., O'Brien, E., Raji, O., Deharo, S., Davison, T., Johnston, P., Keating, K., Harkin, D., Kenndy, R. . Molecular subgroup of highgrade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. JCO. 2014;32(5s):abstr 5502. 29. Cohn DE, Kim KH, Resnick KE, O'Malley DM, Straughn JM, Jr. At what cost does a 18
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potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011 Apr 1;29(10):1247-51. PubMed PMID: 21383297. 30. Minion LE, Bai J, Monk BJ, Robin Keller L, Ramez EN, Forde GK, et al. A Markov model to evaluate cost-effectiveness of antiangiogenesis therapy using bevacizumab in advanced cervical cancer. Gynecologic oncology. 2015 Jun;137(3):490-6. PubMed PMID: 25766118. 31. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 Aug 15;14(16):5198-208. PubMed PMID: 18698038.
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All (n=277)
Bev + Chemo (n=244)
58 (19 – 85)
59 (19 – 85)
227 (82%) 3 (1%)
Age*
p=0.35
197 (81%)
30 (91%)
p=0.37
3 (1%)
0 (0%)
38 (16%)
2 (6%)
Asian
4 (1%)
4 (2%)
0 (0%)
Other or Unknown
3 (1%)
2 (1%)
1 (3%)
37 (15%)
1 (3%)
161 (58%)
134 (55%)
27 (82%)
63 (23%)
58 (24%)
5 (15%)
4 (1%)
4 (2%)
0 (0%)
11 (4%)
11 (5%)
0 (0%)
I
11 (4%)
11 (5%)
0 (0%)
II
21 (8%)
19 (8%)
2 (6%)
III
192 (69%)
168 (69%)
24 (73%)
IV
46 (17%)
39 (16%)
7 (21%)
7 (3%)
7 (3%)
0 (0%)
GOG Performance Status*
1 2 3 Unknown Stage*
Unknown
38 (14%)
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0
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40 (14%)
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Black
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Hispanic
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Race White
p-value
56 (35 – 77)
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Median (Range)
Bev Only (n=33)
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Factor
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Table 1. Patient Characteristics
Grade*
21
p=0.05
p=0.56
ACCEPTED MANUSCRIPT 15 (5%)
15 (6%)
0 (0%)
2
47 (17%)
39 (16%)
8 (24%)
3
202 (73%)
178 (73%)
24 (73%)
13 (5%)
12 (5%)
199 (72%)
177 (73%)
Clear Cell
16 (6%)
15 (6%)
Endometrioid
23 (8%)
19 (8%)
Mucinous
6 (2%)
6 (2%)
0 (0%)
33 (12%)
27 (11%)
6 (18%)
Unknown
1 (3%)
Cytoreductive Surgery* Optimal (<1cm residual)
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Other or Unknown
22 (67%)
p=0.62
1 (3%) 4 (12%)
161 (66%)
17 (52%)
74 (30%)
12 (36%)
9 (4%)
4 (12%)
265 (96%)
234 (96%)
31 (94%)
11 (4%)
9 (4%)
2 (6%)
1 (0%)
1 (0%)
0 (0%)
10 (0 – 180)
11 (0 – 180)
9 (0 – 60)
p=0.08
Local
143 (52%)
118 (48%)
25 (76%)
p<0.01
Distant
100 (36%)
92 (38%)
8 (24%)
Chemical CA-125
32 (12%)
32 (13%)
0 (0%)
86 (31%)
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Suboptimal (>1cm residual)
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178 (64%)
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Histology* Serous
p=0.21
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1
13 (5%)
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Unknown
p=0.28
Carboplatin/Paclitaxel adjuvant chemotherapy Yes No Unknown
p=0.52
Time to Initial Recurrence (Months) Median (Range) Location of Recurrence
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2 (1%)
2 (1%)
3 (1 – 5)
3 (1 – 5)
0 (0%)
Mean (Range)
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Number of Prior Regimens 4 (1 – 5)
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106 (43%) Gemcitabine
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Chemotherapy combination with bevacizumab
p<0.01
55 (23%) Taxanes ^13
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- Nanoparticle albumin bound - Docetaxel # - Paclitaxel (wkly or q3wk) Topotecan
^25
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^17
43 (18%)
Cyclophosphamide
21 (9%)
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Liposomal doxorubicin
19 (8%)
Treatment-free Interval prior to treatment
Length of treatment
4 (0 – 71)
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Mean no of months (Range)
4 (0 – 71)
2 (0 – 10)
p=0.02
4 (1-27)
4 (1-23)
p=0.96
41.4 (2.8 – 248.1)
41.7 (11.1 – 146.7)
p=0.53
Median months (Range)
Follow up Time (from time of diagnosis) Mean no of months (Range)
41.4 (2.8 – 248.1)
Abbreviations: GOG = Gynecologic Oncology Group, Bev = bevacizumab, Chemo = chemotherapy *At time of initial diagnosis Percentages do not equal 100% due to rounding #
Number of patients receiving weekly vs q3weeks not recorded
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Table 2. Response to bevacizumab or chemotherapy + bevacizumab by radiographic response N
Complete or Partial Response
Bevacizumab Alone
33
7 (21%)
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Bevacizumab Combination Regimen
244
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Chemotherapy + Bevacizumab (p=0.2 among different regimens) Bevacizumab + Liposomal Doxorubicin
19
106
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Bevacizumab + Topotecan
Bevacizumab + Taxane Bevacizumab + Cyclophosphamide
43
55
21
24
24 (73%)
43 (18%)
111 (45%)
10 (53%)
6 (32%)
3 (16%)
39 (37%)
13 (12%)
54 (51%)
16 (37%)
9 (21%)
18 (42%)
20 (36%)
10 (18%)
25 (45%)
5 (24%)
5 (24%)
11 (52%)
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Bevacizumab + Gemcitabine
2 (6%)
Progression
90 (37%)
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(p=0.01 compared to C+Bev)
Stable Disease
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Table 3. Overall survival based on chemotherapy regimen N
5-year Survival
Bevacizumab Alone (p<0.01 compared to bevacizumab +chemotherapy) Bevacizumab + Chemotherapy (p=0.06) Bevacizumab + Taxane
33
3% (1-22%)
244 55
12% (7-21%) 25% (9-68%)
Bevacizumab + Liposomal Doxorubicin
19
23% (5-100%)
Bevacizumab + Topotecan
43
Bevacizumab + Gemcitabine
106
10% (5-21%)
21
13% (2-78%)
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21% (7-7%)
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Bevacizumab + Cyclophosphamide
Median Survival Months (range)
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Treatment Regimen
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10.5 (8.2-13.9)
14.2 (12-18.3) 20.2 (12-N/A) 20.4 (9.1-N/A) 13.0 (5.6-N/A) 14.1 (10.6-17.9) 13.0 (9-N/A)
ACCEPTED MANUSCRIPT Table 4. Cox proportional hazards model of progression-free and overall survival PFS
OS Referent 1.31 (0.88-1.96)
Referent 1.32 (0.9-1.41) 1.32 (0.38 -1.20) 1.17 (0.85-1.28)
Referent 1.32 (0.68-2.55) 1.32 (0.62-2.8) 1.22 (0.4-3.76)
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Referent 1.45 (0.57-3.7)
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Referent 1.27 (0.64-2.52)
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Referent 1.05 (0.68-1.61)
Referent 0.39 (0.09-1.62)
Referent 0.61 (0.32-1.2) Referent 0.56 (0.16-1.94) 0.59 (0.16-2.22)
Referent 1.12 (0.74-1.69)
Referent 1.21 (0.83-1.77)
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Referent 5.31 (2.05-13.74)** 4.53 (1.63-12.6)**
Referent 0.89 (0.57-1.41)
Referent 1.15 (0.72-1.83)
Referent 1.09 (0.69-1.71) 0.51 (0.23-1.10)
Referent 1.14 (0.72-1.79) 0.54 (0.31-1.01)*
Referent 0.73 (0.43-1.24)
Referent 0.51 (0.32-0.83)**
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Age (years) <58 >58 Histology Clear cell Endometrioid Serous Mucinous Grade Grade 2/3 Grade 1 Stage Stage III/IV Stage I/II GOG Performance Status 0 1 2 Treatment-free Interval <11 months >11 months Number of prior regimens <3 >3 Recurrence Local Distant Chemical Treatment regimen Bevacizumab alone Chemotherapy+bevacizumab *p=0.05, **p<0.01
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ACCEPTED MANUSCRIPT Highlights (for review)
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1. Chemotherapy and bevacizumab shows improved progression-free and overall survival benefit compared to bevacizumab alone in recurrent, heavily pretreated ovarian cancer.
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2. Pegylated liposomal doxorubicin and taxanes have a trend towards improved survival compared to other chemotherapy and bevacizumab regimens.
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3. Treatment with chemotherapy and bevacizumab is generally well-tolerated.
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S0090-8258(15)30062-7 doi: 10.1016/j.ygyno.2015.06.041 YGYNO 975975
To appear in:
Gynecologic Oncology
Received date: Revised date: Accepted date:
29 April 2015 27 June 2015 30 June 2015
Please cite this article as: Katherine C. Fuh, Angeles A. Secord, Kerri S. Bevis, Warner Huh, Adam ElNaggar, Kevin Blansit, Rebecca Previs, Todd Tillmanns, Daniel S. Kapp, John K. Chan, Comparison of Bevacizumab Alone or with Chemotherapy in Recurrent Ovarian Cancer Patients, Gynecologic Oncology (2015), doi: 10.1016/j.ygyno.2015.06.041
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Comparison of Bevacizumab Alone or with Chemotherapy in Recurrent Ovarian Cancer Patients
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Katherine C. Fuh, M.D.,Ph.D.1,6,8, Angeles A. Secord, M.D.2, Kerri S. Bevis, M.D.3, Warner Huh, M.D.3, Adam ElNaggar, M.D.4, Kevin Blansit1,5, Rebecca Previs, M.D.2, Todd Tillmanns, M.D.4, Daniel S. Kapp M.D., Ph.D.7, John K. Chan, M.D.1,5 1
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Division of Gynecologic Oncology Helen Diller Family Comprehensive Cancer Center University Of California, San Francisco 1600 Divisadero Street San Francisco, CA 94143-1702 2
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Division of Gynecologic Oncology Department Of Obstetrics and Gynecology Duke University, School Of Medicine DUMC 3079 Durham, NC 27710 3
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Division of Gynecologic Oncology Department of Obstetrics and Gynecology University of Alabama at Birmingham 1700 6th Ave South Birmingham, AL 35233
5
4
The West Clinic . University of Tennessee 100 N. Humphreys Blvd, Memphis, TN 38120
Palo Alto Medical Foundation Research Institute 795 El Camino Real, Ames Building Palo Alto, CA 94301 6
Division of Gynecologic Oncology Department of Obstetrics and Gynecology Washington University, School of Medicine St. Louis, MO 63108 7
Department of Radiation Oncology Division of Gynecologic Oncology Department of Obstetrics and Gynecology Stanford University, School of Medicine 400 Pasteur Drive Stanford, CA 94305 8
1
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Number of Pages: 18 Number of Tables: 4 Number of Figures: 1 Disclosure Statement: The authors report no financial disclosures. Financial Support: The authors would like to acknowledge The Dr. John A Kerner Research Fund for support of this project.
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Please address correspondence to: Dr. John K. Chan Division of Gynecologic Oncology California Pacific & Palo Alto Medical Foundation / Research Institute Sutter Cancer Research Consortium 3838 California Street San Francisco, CA 94115 Office: (415) 751-1847 Fax: (415) 387-2613 Email: [email protected]
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Portions of this study were presented as a poster at the 43rd Annual Society of Gynecologic Oncology 2012 in Austin, TX.
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ACCEPTED MANUSCRIPT Abstract Background: To compare the efficacy of chemotherapy (C) combined with
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bevacizumab (Bev) versus Bev alone in recurrent, heavily pretreated epithelial ovarian
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cancer (EOC).
Methods: A multicenter analysis of patients treated from 2004 to 2011 was performed.
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Demographic, treatment, response, and adverse event information were obtained.
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Progression-free (PFS) and overall survival (OS) were analyzed. Results: Of 277 patients (median age: 58 years), the majority had Stage III and IV
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(86%) disease, and 72% had serous histology. 244 (88%) were treated with C+Bev and 33 (12%) with Bev. Corresponding median progression-free survival (PFS) was 8.7 and
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6.7 months, and median overall survival (OS) was 14.3 and 10.5 months, respectively. The chemotherapeutic agents combined with Bev and the median OS include:
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pegylated liposomal doxorubicin (n=19, OS of 20.4 months), taxanes (n=55, OS of 20.2 months), gemcitabine (n=106, OS of 14.1 months), topotecan (n=43, OS of 13 months), and cyclophosphamide (n=21, OS of 13 months). There was no significant difference in toxicities between the C+Bev vs. Bev alone group. Conclusion: This retrospective analysis supports that combination chemotherapy and bevacizumab prolongs PFS and OS compared with bevacizumab alone. Keywords: recurrent epithelial ovarian cancer; bevacizumab; chemotherapy; survival; platinum-resistant; liposomal doxorubicin, taxanes
3
ACCEPTED MANUSCRIPT Background Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic
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malignancy[1]. In patients with recurrent, platinum-resistant, heavily pretreated disease,
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single agent chemotherapy has been generally recommended given the increased toxicity and lack of data showing additional benefit with combination chemotherapy [2-
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7].
(Bev) improved the
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In clinical trials, chemotherapy with bevacizumab
progression-free survival of those with primary and recurrent, platinum-sensitive and
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resistant disease compared to chemotherapy alone [8-14]. Preclinical studies have shown that Bev can potentially enhance the delivery of chemotherapeutic agents by
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normalizing blood vessels and reducing interstitial fluid pressure [15-17]. More recently,
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a randomized clinical trial compared the efficacy of physician-selected chemotherapy
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versus chemotherapy combined with bevacizumab in platinum-resistant ovarian cancer. These investigators found that the combination therapy including Bev improved the progression-free survival over chemotherapy alone (6.7 vs 3.4 months, p<0.001). However, there was no difference in overall survival between the treatment groups (16.6 vs 13.3 months, p<0.174) [18].
However there are no studies that have compared the efficacy of chemotherapy and Bev versus Bev alone. Bev has been shown to have significant activity as a single agent [19, 20]. It is possible that single agent biologic therapy may achieve similar results compared to chemotherapy and bevacizumab without the increased toxicity associated with combination therapy [19, 20]. In this current report, the objective was to evaluate the efficacy of chemotherapy with bevacizumab vs. bevacizumab alone in 4
ACCEPTED MANUSCRIPT patients with recurrent, heavily pretreated epithelial ovarian, peritoneal, or fallopian tube cancer and to determine whether either regimen would result in a survival difference.
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Methods
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A multi-institutional, retrospective analysis of efficacy for women with recurrent EOC treated with chemotherapy in combination with Bev or single-agent Bev was
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performed. Study approval was obtained from the Institutional Review Boards of the
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study sites: University of California San Francisco, Duke Cancer Institute, University of Alabama at Birmingham, University of Tennessee, and Stanford University. Women
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with recurrent, epithelial ovarian, peritoneal or fallopian tube cancer treated with chemotherapy combination with bevacizumab (C+Bev) or Bev alone between 2004 and
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2011 were included in the analysis. Patients who had progressed within 6 months of completing platinum-based therapy prior to beginning bevacizumab were identified and
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included in this analysis and defined as resistant to platinum therapy. Patients who were treated with bevacizumab as part of first-line therapy were excluded. None of the patients had secondary cytoreductive surgery. Patients had not previously received the chemotherapy that was combined with bevacizumab used in this analysis. Patients were followed for relapse with CA-125 levels, and imaging was obtained when a significant increase in CA-125 was seen and/or for symptoms. Treatment information including response to platinum, number of prior chemotherapy regimens, type of chemotherapy regimens, and duration of therapy was collected and analyzed. For those who received taxanes, the particular taxane administered was recorded. For those who received paclitaxel, the frequency of administration was not recorded for this study collection. Patients who received one or 5
ACCEPTED MANUSCRIPT more cycles of chemotherapy and Bev or Bev alone were assessed for antitumor activity and toxicity. Responses were determined through serial radiographic evaluation
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of measurable disease. An imaging study was obtained prior to initiation of
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chemotherapy with bevacizumab or bevacizumab alone and location of recurrence was recorded as local (pelvic disease) or distant (upper abdominal, lymph node metastases
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and pleural effusions). Imaging was repeated if the patient had worsening signs and/or
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symptoms, a doubling of CA-125 or at the end of the prescribed regimen generally after completing 4-6 cycles. Those with measurable disease were assessed by Response
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Criteria in Solid Tumors (RECIST) 1.1 [21, 22].
Complete response (CR) was defined as disappearance of all target lesions.
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Partial response (PR) was defined as at least 30% decrease of the target lesions, progressive disease (PD) was defined as at least 20% increase in the sum of the
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diameters of lesions, and stable disease (SD) was defined as small changes that did not meet the above criteria for PR or SD. The best response for each patient was documented. Progression-free survival was defined as the interval between the initiation of chemotherapy and Bev or single agent Bev and the first radiologically documented disease progression or death. Patients lost to follow-up were censored at the time of their last visit. Overall survival was defined as the interval between the initiation of C+Bev or Bev alone and date of death or date of last follow-up. Toxicity was determined through review of medical records and assessed according to the National Cancer Institute’s Common Toxicity Criteria version 4.0. T-test, ANOVA, and Chi-square were used for statistical analyses of clinico-demographics using R 3.0.2 (R Foundation for Statistical Computation; Vienna, Austria). Kaplan-Meier curves were developed to 6
ACCEPTED MANUSCRIPT examine stage-specific survival and compared using the log-rank test. Cox proportional hazards models were developed to examine both progression-free survival and overall
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survival.
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Results All Patients
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Of 277 recurrent, platinum-resistant EOC patients treated with either C+Bev or
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Bev alone, the median age of the cohort was 58 years (range: 19 to 85). The clinicopathologic factors of these patients are summarized in Table 1. The majority (64%)
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underwent initial optimal (<1 cm residual disease) surgical cytoreduction. Most (86%) patients had advanced (stage III-IV) disease, 72% had serous histology, and 73% had
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poorly-differentiated tumors. The median time to first relapse was 10 months. Most of these women had multiple relapses for which they were treated with various
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chemotherapy regimens for recurrent disease with a median number of three treatment regimens prior to receiving C+Bev or Bev alone. The length of treatment with either C+Bev or Bev alone was similar between both groups of four months. The various chemotherapy regimens used with Bev are shown in Table 1. Efficacy between C+Bev vs Bev alone 244 (88%) women were treated with C+Bev, and 33 (12%) were treated with Bev alone.
Based on RECIST criteria, the overall complete or partial response rate of
patients who underwent C+Bev vs. Bev alone was 37% vs. 21% (p=0.01) (Table 2). The 6-month PFS for patients treated with C+Bev was 63% compared to 50% in those treated with Bev alone with median PFS of 8.7 vs 6.7 months (p=0.01) (Figure 1A). C+Bev was associated with an improved overall survival of 14.3 months vs. 10.5 7
ACCEPTED MANUSCRIPT months with Bev alone (p<0.01) (Figure 1B). Efficacy of regimens between patients with radiographic recurrence only
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When excluding the 32 patients who had C+Bev therapy initiated based on
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chemical recurrence, median overall survival continued to be higher (13 vs. 10.5 months, p=0.022) for those treated with C+Bev vs. Bev only. The median PFS for
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C+Bev was also greater at 8.7 months vs. 6.7 months, p=0.033 for the Bev only group.
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Efficacy among the various chemotherapies with Bev
Of those treated with Bev and various chemotherapy regimens, there was no
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statistical difference in response rates based on the type of chemotherapy used with Bev (Table 2). However, there was a difference in PFS among the chemotherapy
was
94%,
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combinations with Bev: 6-month PFS of pegylated liposomal doxorubicin+Bev (n=19) taxanes+Bev
(n=55)
at
65%,
topotecan+Bev
(n=43)
at
64%,
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gemcitabine+Bev (n=106) at 59%, and cyclophosphamide+Bev (n=21) at 54% (p=0.02). The median PFS of those treated with bevacizumab and topotecan, taxanes, gemcitabine, cyclophosphamide, or Bev alone was 13.7, 10.7, 8.7, 6.7, and 6.7 months, respectively (median PFS was not yet reached for pegylated liposomal doxorubicin). Of those treated with Bev and various chemotherapy regimens, the 5-year and median OS of those treated with bevacizumab with taxanes and bevacizumab with pegylated liposomal doxorubicin was higher than the other C+Bev combinations (Table 3). However, there was no statistically significant difference in overall survival based on the chemotherapy regimen combined with bevacizumab (p=0.06). To evaluate whether any demographic or clinico-pathologic factors could have influenced OS or PFS, we compared C+Bev vs. Bev alone with respect to these factors. 8
ACCEPTED MANUSCRIPT There was no significant difference in age, race, cell type, tumor grade and extent of cytoreductive surgery, adjuvant treatment, and time to initial recurrence. More patients
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in the C+Bev group had a performance status of either 0 or 2 compared to the Bev
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group that had more patients with a performance status of 1 (p=0.048). However, those who received C+Bev had a longer treatment free interval (TFI) of 4 months vs. 2 months
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for those treated with Bev alone (p=0.02). Additionally, C+Bev were treated with fewer
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prior regimens (3 vs. 4, p<0.01) (Table 1). However, further analysis showed that performance status (p=0.36), TFI (p=0.32), and the number of prior regimens (p=0.55)
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was not prognostic for OS. On multivariate analysis, only treatment with C+Bev (HR=0.51, 95%CI: 0.32 to 0.83; p<0.01) and recurrence based on CA-125 values (HR=
4).
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Safety
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0.54, 95%CI: 0.3 to 1.01; p=0.05) were independent predictors for improved OS (Table
Those who had C+Bev had an overall 39% rate of toxicity compared to 55% in those with Bev alone (p=0.09). The rate of serious gastrointestinal complications was 3% vs. 6% for C+Bev versus Bev alone, respectively (p=0.33). The rate of overall cardiovascular events was not different between the treatment groups (36% vs. 48%; p=0.17), and most of these cardiovascular events were grade 2 or higher hypertension. Discussion In this retrospective cohort of heavily-pretreated, recurrent EOC patients, treatment with chemotherapy combined with Bev had improved efficacy based on response rates, progression-free and overall survival compared to Bev alone. This significant improvement in overall and progression-free survival was also seen when 9
ACCEPTED MANUSCRIPT patients with chemical recurrences were excluded and only those with radiographic recurrences were analyzed. Additionally, receiving chemotherapy with bevacizuamb
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was an independent predictor for overall survival after adjusting for significant factors.
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There has been four published randomized phase III trials of Bev in ovarian cancer demonstrating the activity of this novel biologic agent: two in the upfront setting
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and two in the relapsed setting [8, 18, 23, 24]. In the most recent Avastin Use in
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Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial, investigators compared chemotherapy combined with bevacizumab to chemotherapy alone in patients with
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platinum-resistant disease [18]. They found that the addition of Bev to chemotherapy improved PFS from 3.4 months to 6.7 months (p<0.001). However, the AURELIA study
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did not evaluate the benefit of Bev alone. We hypothesized that Bev as a single agent may have had similar activity compared to combination therapy [23, 24]. However, our
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data suggests that the combination of chemotherapy with bevacizumab versus Bev alone yielded improved clinical outcomes and was not associated with significantly increased toxicity. Both the AURELIA study and our data support an advantage of combination chemotherapy and bevacizumab compared to either agent alone. The biological advantage of combining chemotherapy with Bev may be explained by an enhanced delivery of chemotherapy agents with Bev. As cancer cells produce vascular endothelial growth factor (VEGF-A) and other pro-angiogenic cytokines, newly formed vessels are maintained in a constant angiogenic state [15-17]. Bev can reduce the interstitial fluid pressure and enhance the delivery of the chemotherapeutic agents into the tumors [15-17]. The potential synergism of Bev and chemotherapy is based on the action of chemotherapy on proliferating endothelial cells, while VEGF-targeted 10
ACCEPTED MANUSCRIPT therapy affects survival signaling pathways in endothelial cells; this combination leads to increased susceptibility of chemotherapy-induced apoptosis of cancer cells [25].
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Furthermore, Bev normalizes the blood vessels and redistributes blood flow while
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increasing the overall delivery of chemotherapy and oxygen, which may further explain the mechanism of how combination chemotherapy and Bev is more effective than Bev
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or chemotherapy alone [15-17]. The majority of patients in this study received Bev+C
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rather than Bev alone. This may have been due to the uncertainty of the activity of Bev alone during this time period.
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The combination of chemotherapy and bevacizumab may be of particular interest in platinum-resistant, heavily-pretreated patients. Previously these patients have been
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typically treated with single agent chemotherapy due to the excessive toxicity related to combination chemotherapies. Sehouli et al, demonstrated that combination therapy did
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not improve the overall survival but increased the toxicity of treatment [7]. In contrast, our data suggests that bevacizumab combined with single agent chemotherapy may improve the median survival with acceptable toxicity. Perhaps the combination of a biologic agent and chemotherapy provides a biologic advantage with respect to efficacy, but it also prevents the additive toxicity related to combination chemotherapies from the same class of drugs. In the AURELIA trial, the combination of chemotherapy and Bev did not improve the overall survival over chemotherapy alone. These authors suggested that the lack of OS benefit may be attributed to the fact that 40% of patients on the chemotherapy alone arm crossed over to Bev for their subsequent treatment. In our study, because both groups of patients received Bev, crossover is unlikely to be a confounding factor. Our findings in this retrospective study warrant further validation 11
ACCEPTED MANUSCRIPT from prospective randomized studies. Our study also provides information regarding the combination of various
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chemotherapy agents with bevacizumab. Of 244 patients who received Bev and various
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chemotherapeutic agents, we have a large group of patients treated with different chemotherapies to compare therapeutic efficacy combined with Bev. In this report, we
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showed that there was a trend of either pegylated liposomal doxorubicin or taxanes
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combined with bevacizumab as the most active treatment combinations. Dose-dense paclitaxel has been described to have anti-angiogenic properties, through reducing
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tumor secreted VEGF and interleukin-8, and may synergize with Bev. This finding has been supported in preclinical models of platinum-resistant ovarian cancer with an
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improvement in overall survival of those treated with bevacizumab and paclitaxel compared to either single agent bevacizumab or paclitaxel [26].
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Ongoing clinical trials from the Gynecologic Oncology Group (262) and ICON 8 are currently evaluating the benefit of using dose-dense paclitaxel with Bev to exploit the potential synergistic activity of chemotherapy and biologic treatment. Early results show that dose-dense paclitaxel may have a progression-free survival benefit in a subgroup of patients [27]. Our data regarding pegylated liposomal doxorubicin with bevacizumab revealed a 6-month PFS rate of 94%. These results are much higher than expected, and we acknowledge that this is a small group of patients comprising of only 19 patients. Recent results from the AURELIA trial did not publish a specific combination that resulted in an improved outcome among pegylated liposomal doxorubicin, topotecan, and weekly paclitaxel [18]. In addition, we noted that the synergistic effects of these compounds with respect 12
ACCEPTED MANUSCRIPT to its anti-vascular activity may also result in more toxicity. In this current analysis, we did not find a significant increase in cardiovascular toxicity in a subgroup analysis.
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Furthermore, there was no additive toxicity of pegylated liposomal doxorubicin and
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bevacizumab in relation to serious cardiovascular toxicity such as cardiomyopathy Further research with a larger number of patients is warranted to evaluate the
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combination and sequencing of these agents with bevacizumab to improve the
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response and quality of life in these patients. For example, recent studies by Gourley and colleagues have demonstrated that an immune molecular subgroup of high grade
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serous ovarian cancer have superior survival to other high grade serous ovarian cancer group, and the addition of Bev significantly reduces survival in this subgroup [28]. This
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suggests that evaluating tumor gene expression is important to determine the patient population that will best respond to bevacizumab treatment. Additionally, the cost
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effectiveness of using C+Bev may appear to be more than Bev alone given the increase in PFS and OS. Other groups have looked at cost-effectiveness of C+Bev in ovarian cancer and other gynecological cancers[29, 30]. The limitations of our study include its retrospective nature, lack of centralized pathology review, lack of randomization and standardization of imaging and treatment, imbalance of cohort groups, lack of inclusion of patients who received Bev after initial treatment with Bev, possible bias of patients with a better performance status and those with a recurrence in localized regions receiving Bev alone, the retrospective collection of safety and surgical data which may not accurately reflect every encountered toxicity as well as whether patients had optimal cytoreduction to no residual disease rather than to less than 1 cm, other prognostic factors that are challenging to document in a 13
ACCEPTED MANUSCRIPT retrospective study, and variation in chemotherapy regimens given with bevacizumab due to the multi-institutional aspect of this analysis. In addition, the outcome was based
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on progression-free and overall survival without information on quality of life and limited
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data on toxicity. Although there is a potential bias that the Bev alone group has a better performance status and a greater rate of recurrence in localized regions, this group also
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received a greater number of prior regimens, had a shorter time to initial recurrence,
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and a shorter treatment-free interval prior to treatment than those treated with C+Bev. Although the numbers in the bevacizumab alone group was small, the width and
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magnitude of the 95% confidence interval for overall survival was adequate. To our knowledge, this study is the largest series to date evaluating the efficacy
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and safety of bevacizumab combination compared to single-agent bevacizumab in recurrent ovarian cancers. All participating institutions are academic centers with
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gynecologic oncologists and expert gynecologic pathologists. The collected data is reflective of a diverse population of heavily pretreated, platinum-resistant ovarian cancer patients from five treatment centers throughout the United States. It is unlikely that a prospective randomized study would be implemented to study the various combinations of chemotherapy with bevacizumab. Thus, the results of this large, retrospective, multiinstitutional study from five academic centers may provide some guidance towards treatment of platinum-resistant ovarian cancer. Clearly, further molecular studies are warranted to identify relevant biomarkers to individualize treatment of selected patients with unique genomic profiles in the setting of relapsed ovarian cancer with attention to groups that may be harmed by bevacizumab and chemotherapy but not bevacizumab alone [31]. 14
ACCEPTED MANUSCRIPT Despite these limitations, our data suggest that combination chemotherapy and bevacizumab may result in improved response and survival outcomes with a tolerable
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general safety profile compared to bevacizumab alone. Further evaluation is warranted
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to confirm our findings. Conclusion
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In heavily pretreated, recurrent epithelial ovarian cancer patients, treatment with
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chemotherapy and bevacizumab may result in a higher response rate, better progression free and overall survival than treatment with bevacizumab alone.
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Conflict of Interest Statement:
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The authors declare that there are no conflicts of interest.
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References:
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8. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Jun 10;30(17):2039-45. PubMed PMID: 22529265. Pubmed Central PMCID: 3646321. 9. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Jan 1;26(1):76-82. PubMed PMID: 18165643. 10. Hagemann AR, Novetsky AP, Zighelboim I, Gao F, Massad LS, Thaker PH, et al. Phase II Study of Bevacizumab and Pemetrexed for Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer. Gynecologic oncology. 2013 Oct 3. PubMed PMID: 24096113. 11. Kudoh K, Takano M, Kouta H, Kikuchi R, Kita T, Miyamoto M, et al. Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers. Gynecologic oncology. 2011 Aug;122(2):233-7. PubMed PMID: 21601912. 12. McGonigle KF, Muntz HG, Vuky J, Paley PJ, Veljovich DS, Greer BE, et al. Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. Cancer. 2011 Aug 15;117(16):3731-40. PubMed PMID: 21815133. 13. Tillmanns TD, Lowe MP, Walker MS, Stepanski EJ, Schwartzberg LS. Phase II clinical trial of bevacizumab with albumin-bound paclitaxel in patients with recurrent, platinumresistant primary epithelial ovarian or primary peritoneal carcinoma. Gynecologic oncology. 2013 Feb;128(2):221-8. PubMed PMID: 22960352. 14. Verschraegen CF, Czok S, Muller CY, Boyd L, Lee SJ, Rutledge T, et al. Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxaneresistant ovarian cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012 Dec;23(12):3104-10. PubMed PMID: 22851407. 15. Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y, et al. Bevacizumab improves the delivery and efficacy of paclitaxel. Anti-cancer drugs. 2010 Aug;21(7):687-94. PubMed PMID: 20559127. 16. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, et al. Bevacizumabinduced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 Jul 1;13(13):3942-50. PubMed PMID: 17606728. 17. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. British journal of cancer. 2003 Jun 16;88(12):1979-86. PubMed PMID: 12799646. Pubmed Central PMCID: 2741115. 18. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. 17
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Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 May 1;32(13):1302-8. PubMed PMID: 24637997. 19. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Nov 20;25(33):5165-71. PubMed PMID: 18024863. 20. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Nov 20;25(33):5180-6. PubMed PMID: 18024865. 21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009 Jan;45(2):228-47. PubMed PMID: 19097774. 22. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute. 2000 Feb 2;92(3):205-16. PubMed PMID: 10655437. 23. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The New England journal of medicine. 2011 Dec 29;365(26):2473-83. PubMed PMID: 22204724. 24. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. The New England journal of medicine. 2011 Dec 29;365(26):2484-96. PubMed PMID: 22204725. 25. Xiong YQ, Sun HC, Zhu XD, Zhang W, Zhuang PY, Zhang JB, et al. Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression. Journal of cancer research and clinical oncology. 2011 Mar;137(3):505-12. PubMed PMID: 20490863. 26. Rein DT, Volkmer AK, Volkmer J, Beyer IM, Janni W, Fleisch MC, et al. Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pretreated ovarian cancer. Oncology letters. 2012 Mar;3(3):530-4. PubMed PMID: 22740945. Pubmed Central PMCID: 3362354. 27. Chan JK. Every 3-week versus dose dense weekly paclitaxel combined with carboplatin +/- bevacizumab in advanced epithelial ovarian, peritoneal, or fallopian tube cancer (GOG 262). ESGO meeting. 2013. 28. Gourley C, McCavigan, A., Perren, T., Paul, J., Michie, C., Churchman, M., Williams, A., McCluggage, W., Parmar, M., Kaplan, R., Hill, L., Halfpenny, I., O'Brien, E., Raji, O., Deharo, S., Davison, T., Johnston, P., Keating, K., Harkin, D., Kenndy, R. . Molecular subgroup of highgrade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. JCO. 2014;32(5s):abstr 5502. 29. Cohn DE, Kim KH, Resnick KE, O'Malley DM, Straughn JM, Jr. At what cost does a 18
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potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011 Apr 1;29(10):1247-51. PubMed PMID: 21383297. 30. Minion LE, Bai J, Monk BJ, Robin Keller L, Ramez EN, Forde GK, et al. A Markov model to evaluate cost-effectiveness of antiangiogenesis therapy using bevacizumab in advanced cervical cancer. Gynecologic oncology. 2015 Jun;137(3):490-6. PubMed PMID: 25766118. 31. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 Aug 15;14(16):5198-208. PubMed PMID: 18698038.
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All (n=277)
Bev + Chemo (n=244)
58 (19 – 85)
59 (19 – 85)
227 (82%) 3 (1%)
Age*
p=0.35
197 (81%)
30 (91%)
p=0.37
3 (1%)
0 (0%)
38 (16%)
2 (6%)
Asian
4 (1%)
4 (2%)
0 (0%)
Other or Unknown
3 (1%)
2 (1%)
1 (3%)
37 (15%)
1 (3%)
161 (58%)
134 (55%)
27 (82%)
63 (23%)
58 (24%)
5 (15%)
4 (1%)
4 (2%)
0 (0%)
11 (4%)
11 (5%)
0 (0%)
I
11 (4%)
11 (5%)
0 (0%)
II
21 (8%)
19 (8%)
2 (6%)
III
192 (69%)
168 (69%)
24 (73%)
IV
46 (17%)
39 (16%)
7 (21%)
7 (3%)
7 (3%)
0 (0%)
GOG Performance Status*
1 2 3 Unknown Stage*
Unknown
38 (14%)
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0
D
40 (14%)
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Black
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Hispanic
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Race White
p-value
56 (35 – 77)
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Median (Range)
Bev Only (n=33)
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Factor
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Table 1. Patient Characteristics
Grade*
21
p=0.05
p=0.56
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15 (6%)
0 (0%)
2
47 (17%)
39 (16%)
8 (24%)
3
202 (73%)
178 (73%)
24 (73%)
13 (5%)
12 (5%)
199 (72%)
177 (73%)
Clear Cell
16 (6%)
15 (6%)
Endometrioid
23 (8%)
19 (8%)
Mucinous
6 (2%)
6 (2%)
0 (0%)
33 (12%)
27 (11%)
6 (18%)
Unknown
1 (3%)
Cytoreductive Surgery* Optimal (<1cm residual)
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Other or Unknown
22 (67%)
p=0.62
1 (3%) 4 (12%)
161 (66%)
17 (52%)
74 (30%)
12 (36%)
9 (4%)
4 (12%)
265 (96%)
234 (96%)
31 (94%)
11 (4%)
9 (4%)
2 (6%)
1 (0%)
1 (0%)
0 (0%)
10 (0 – 180)
11 (0 – 180)
9 (0 – 60)
p=0.08
Local
143 (52%)
118 (48%)
25 (76%)
p<0.01
Distant
100 (36%)
92 (38%)
8 (24%)
Chemical CA-125
32 (12%)
32 (13%)
0 (0%)
86 (31%)
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Suboptimal (>1cm residual)
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178 (64%)
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Histology* Serous
p=0.21
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1
13 (5%)
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Unknown
p=0.28
Carboplatin/Paclitaxel adjuvant chemotherapy Yes No Unknown
p=0.52
Time to Initial Recurrence (Months) Median (Range) Location of Recurrence
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2 (1%)
2 (1%)
3 (1 – 5)
3 (1 – 5)
0 (0%)
Mean (Range)
PT
Number of Prior Regimens 4 (1 – 5)
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106 (43%) Gemcitabine
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Chemotherapy combination with bevacizumab
p<0.01
55 (23%) Taxanes ^13
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- Nanoparticle albumin bound - Docetaxel # - Paclitaxel (wkly or q3wk) Topotecan
^25
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^17
43 (18%)
Cyclophosphamide
21 (9%)
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Liposomal doxorubicin
19 (8%)
Treatment-free Interval prior to treatment
Length of treatment
4 (0 – 71)
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Mean no of months (Range)
4 (0 – 71)
2 (0 – 10)
p=0.02
4 (1-27)
4 (1-23)
p=0.96
41.4 (2.8 – 248.1)
41.7 (11.1 – 146.7)
p=0.53
Median months (Range)
Follow up Time (from time of diagnosis) Mean no of months (Range)
41.4 (2.8 – 248.1)
Abbreviations: GOG = Gynecologic Oncology Group, Bev = bevacizumab, Chemo = chemotherapy *At time of initial diagnosis Percentages do not equal 100% due to rounding #
Number of patients receiving weekly vs q3weeks not recorded
23
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Table 2. Response to bevacizumab or chemotherapy + bevacizumab by radiographic response N
Complete or Partial Response
Bevacizumab Alone
33
7 (21%)
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Bevacizumab Combination Regimen
244
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Chemotherapy + Bevacizumab (p=0.2 among different regimens) Bevacizumab + Liposomal Doxorubicin
19
106
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Bevacizumab + Topotecan
Bevacizumab + Taxane Bevacizumab + Cyclophosphamide
43
55
21
24
24 (73%)
43 (18%)
111 (45%)
10 (53%)
6 (32%)
3 (16%)
39 (37%)
13 (12%)
54 (51%)
16 (37%)
9 (21%)
18 (42%)
20 (36%)
10 (18%)
25 (45%)
5 (24%)
5 (24%)
11 (52%)
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Bevacizumab + Gemcitabine
2 (6%)
Progression
90 (37%)
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(p=0.01 compared to C+Bev)
Stable Disease
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Table 3. Overall survival based on chemotherapy regimen N
5-year Survival
Bevacizumab Alone (p<0.01 compared to bevacizumab +chemotherapy) Bevacizumab + Chemotherapy (p=0.06) Bevacizumab + Taxane
33
3% (1-22%)
244 55
12% (7-21%) 25% (9-68%)
Bevacizumab + Liposomal Doxorubicin
19
23% (5-100%)
Bevacizumab + Topotecan
43
Bevacizumab + Gemcitabine
106
10% (5-21%)
21
13% (2-78%)
RI
SC
NU
MA
21% (7-7%)
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Bevacizumab + Cyclophosphamide
Median Survival Months (range)
PT
Treatment Regimen
25
10.5 (8.2-13.9)
14.2 (12-18.3) 20.2 (12-N/A) 20.4 (9.1-N/A) 13.0 (5.6-N/A) 14.1 (10.6-17.9) 13.0 (9-N/A)
ACCEPTED MANUSCRIPT Table 4. Cox proportional hazards model of progression-free and overall survival PFS
OS Referent 1.31 (0.88-1.96)
Referent 1.32 (0.9-1.41) 1.32 (0.38 -1.20) 1.17 (0.85-1.28)
Referent 1.32 (0.68-2.55) 1.32 (0.62-2.8) 1.22 (0.4-3.76)
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Referent 1.45 (0.57-3.7)
SC
NU
Referent 1.27 (0.64-2.52)
PT
Referent 1.05 (0.68-1.61)
Referent 0.39 (0.09-1.62)
Referent 0.61 (0.32-1.2) Referent 0.56 (0.16-1.94) 0.59 (0.16-2.22)
Referent 1.12 (0.74-1.69)
Referent 1.21 (0.83-1.77)
D
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Referent 5.31 (2.05-13.74)** 4.53 (1.63-12.6)**
Referent 0.89 (0.57-1.41)
Referent 1.15 (0.72-1.83)
Referent 1.09 (0.69-1.71) 0.51 (0.23-1.10)
Referent 1.14 (0.72-1.79) 0.54 (0.31-1.01)*
Referent 0.73 (0.43-1.24)
Referent 0.51 (0.32-0.83)**
TE
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Age (years) <58 >58 Histology Clear cell Endometrioid Serous Mucinous Grade Grade 2/3 Grade 1 Stage Stage III/IV Stage I/II GOG Performance Status 0 1 2 Treatment-free Interval <11 months >11 months Number of prior regimens <3 >3 Recurrence Local Distant Chemical Treatment regimen Bevacizumab alone Chemotherapy+bevacizumab *p=0.05, **p<0.01
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ACCEPTED MANUSCRIPT Highlights (for review)
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1. Chemotherapy and bevacizumab shows improved progression-free and overall survival benefit compared to bevacizumab alone in recurrent, heavily pretreated ovarian cancer.
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2. Pegylated liposomal doxorubicin and taxanes have a trend towards improved survival compared to other chemotherapy and bevacizumab regimens.
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3. Treatment with chemotherapy and bevacizumab is generally well-tolerated.
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