We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin.

No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST).

Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment.

Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Epithelial ovarian cancer (EOC) is expected to occur in 22,430 women and to cause 15,280 deaths in the United States in 2007.1 Because patients with early-stage disease are often asymptomatic, most will present with advanced (stage III or IV) disease that has already spread to the upper abdomen. Despite the sensitivity of EOC to several chemotherapeutic agents, particularly the taxanes and platinum compounds, only 10% to 30% of patients presenting with stage III or IV disease remain alive 5 years after diagnosis.2 For patients who become resistant to primary platinum-based chemotherapy (defined as persistent or progressive disease during, or recurrence within 6 months after completing, a platinum-based regimen), response to other cytotoxic chemotherapeutic regimens is low.3

Topotecan and liposomal doxorubicin are currently approved by the US Food and Drug Administration for treating relapsed or refractory EOC, with objective response rates (RRs) of approximately 10% to 15% in platinum-resistant patients.4 The median progression-free survival (PFS) is 9.1 weeks with liposomal doxorubicin and 13.6 weeks with topotecan in platinum-resistant disease (P = .733).4 The median overall survival (OS) in this population is 35.6 weeks with liposomal doxorubicin and 41.3 weeks with topotecan (P = .455).4 Given these low RRs and short survival times, new treatment options with improved therapeutic indices are needed in this patient population.

Angiogenesis appears to play a central role in the pathogenesis and clinical behavior of EOC. In this regard, vascular endothelial growth factor A (VEGF-A) is an important mediator of angiogenesis and is expressed in the majority of tumor specimens from patients with EOC, as assessed by either in situ hybridization or immunohistochemistry.5,6 In addition to stimulating angiogenesis, VEGF-A induces vascular permeability and is thought to be partly responsible for the development of ascites in both animal models and patients with EOC.7 Several studies have suggested that high levels of VEGF-A expression in either tumor or patient serum correlate with poor survival in this disease.8-12 Taken together, these observations suggest that VEGF-A may be an important therapeutic target in patients with EOC.

Bevacizumab, an immunoglobulin (Ig) G1 monoclonal antibody targeting VEGF-A,13 has demonstrated clinical activity in recurrent ovarian cancer. In a phase II, single-arm, single-agent trial in patients with relapsed EOC conducted by the Gynecologic Oncology Group (GOG), 62 assessable patients treated with bevacizumab 15 mg/kg every 3 weeks experienced an RR of 17.7% (90% CI, 10.3% to 27.7%), with two complete responses (CRs).14 Patients must have received no more than two prior treatment regimens to be eligible for this trial. The median response duration was 10.3 months, with 38.7% of patients remaining progression free at 6 months (90% CI, 28.3% to 49.9%). Furthermore, in another phase II, single-arm study, bevacizumab in combination with low-dose oral cyclophosphamide demonstrated an RR of 28% in patients with relapsed EOC, with 57% of patients remaining progression free at 6 months.15 Both studies enrolled a mixture of platinum-sensitive and -resistant patients.

In this report, we evaluated the efficacy of single-agent bevacizumab in women with platinum-resistant EOC or peritoneal serous cancer (PSC) who subsequently progressed during, or within 3 months of discontinuing, treatment with topotecan or liposomal doxorubicin therapy.

Patient Population

Patients with platinum-resistant EOC or PSC were enrolled. Platinum-resistant disease was defined as progression during or within 6 months after completing either first- or second-line platinum-based chemotherapy. Patients were also required to have subsequently progressed during, or within 3 months after discontinuing, treatment with topotecan or liposomal doxorubicin. Patients must have received no more than three prior treatment regimens, which could include chemotherapy, biologics, or other targeted therapies. They were also required to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST)16 and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients were excluded if they had brain metastases or a history of other malignancies within 5 years before study entry; uncontrolled blood pressure (> 150/100 mmHg); unstable angina; New York Heart Association grade 2 or greater congestive heart failure (CHF); prior liposomal doxorubicin therapy with an ejection fraction less than 50%; myocardial infarction, stroke, or transient ischemic attack within 6 months; clinically significant peripheral vascular disease; major surgical procedure within 28 days; history of abdominal fistula, GI perforation (GIP), or intra-abdominal abscess; or urine protein/creatinine ratio more than 1.0 at screening. Patients were not excluded from participation if they had signs or symptoms of intestinal obstruction or required parenteral hydration and/or nutrition. Eligibility criteria also included an absolute neutrophil count more than 1,500/μL; platelet count more than 75,000/μL; hemoglobin more than 8.5 g/dL; serum bilirubin less than 2.0× the upper limit of normal (ULN); alkaline phosphatase, AST, and ALT less than 2.5× ULN; serum creatinine less than 2.0 U/mL; international normalized ratio less than 1.5; and activated partial thromboplastin time less than 1.5× ULN (except for patients receiving anticoagulation therapy).

Study Design

This multicenter trial was to be conducted at 40 investigative sites in the United States and include approximately 120 patients. The trial was sponsored and monitored by Genentech Inc (South San Francisco, CA). A two-stage design was employed. If two or more of 35 enrolled patients achieved a confirmed CR or partial response (PR; stage 1), an additional 85 patients were to be enrolled (stage 2). Each patient provided written informed consent, and the trial was conducted in accordance with the Helsinki Declaration.

Bevacizumab 15 mg/kg was administered by intravenous infusion on the first day of each 3-week cycle until unacceptable toxicity or radiographic progression. The bevacizumab dosage was based on the patient's baseline weight at study entry and remained unchanged throughout the study. The initial dosage was administered over 90 ± 10 minutes; in subsequent cycles, infusions could be shortened to 60 minutes, and then to 30 minutes, as tolerated.

The primary objective was to evaluate the activity of bevacizumab in patients with platinum-resistant EOC or PSC, as measured by objective RR. Secondary objectives included estimating durations of PFS and OS, in addition to characterizing the safety of single-agent bevacizumab in this patient population.

Toxicity and Efficacy

At baseline, patients were evaluated by treatment history (including prior cancer and concomitant medications) and physical evaluation (vital signs, height, and weight), ECOG PS, CBC, chemistry panel, CA-125, serum pregnancy test, urine protein creatinine ratio (UPCR), and by computed tomography (CT) scan to define RECIST-measurable disease.16

Every 3 weeks and before each bevacizumab infusion, patients were reassessed for toxicity and evaluated by physical examination (including vital signs), CBC, and serum chemistry testing. Every 6 weeks, patients on study underwent UPCR evaluation, tumor assessment with CT scan (up to week 24), and CA-125 testing (until week 24). After week 24, patients were assessed by CT scan and CA-125 every 12 weeks until disease progression. Toxicity was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 3 (http://ctep.cancer.gov/forms/CTCAEv3.pdf).

Statistical Analysis

The primary and secondary efficacy end points were analyzed using the intent-to-treat (ITT) patient population, based on patients who received a subject identification number from the Interactive Voice Response System. The primary efficacy end point was the objective RR as determined by an independent review facility (IRF). A two-stage design was used to test Ho: RR = 0.05 versus Ha: RR more than 0.05 at the .05 significance level. The null hypothesis was rejected if 12 or more of 120 patients achieved an objective response by the IRF. The protocol was modified between stages 1 and 2 to allow 67 additional patients into stage 2. This rule is adjusted to control the type I error resulting from protocol modification occurring with knowledge of the stage 1 RR; 95% Blyth-Still-Casella exact CI for objective RR was to be calculated.


Between January 26 and August 30, 2005, 44 patients were enrolled at 14 centers. Patients received at least one infusion of bevacizumab. As of August 2005, there were two objective responses in stage 1, and enrollment continued into stage 2. The sponsor closed the study early, after enrollment of 44 patients, because of a higher than expected incidence of GIP (11.4%).

Demographic and baseline characteristics are presented in Table 1. Patients had a mean age of 59.5 years, more than half had a baseline ECOG PS of 0, and 81.8% had serous tumors. All patients had platinum-resistant disease, and close to half (47.7%) of the patients had received three prior chemotherapy regimens.

Patients received a median of five (range, two to 16) bevacizumab doses. Twenty-four patients had one dose omission; one patient had a dose interruption because of grade 1 oral hypoaesthesia, and one had an infusion prematurely discontinued because of grade 3 hypersensitivity and urticaria.


Seven patients (15.9%; 95% CI, 7.2% to 29.0%) experienced a confirmed PR based on RECIST (Table 2). Four of these patients had received two prior chemotherapy regimens, and three patients had received three prior chemotherapy regimens. All seven patients were platinum resistant on the basis of progressing within 6 months of receiving first-line platinum-based chemotherapy. No patient experienced a CR; 27 (61.4%) had stable disease as their best response, 11 (25.0%) had stable disease for at least 12 weeks, and five (11.4%) had progressive disease. For the seven patients with an objective response, the median response duration was 4.2 months (range, 1.7 to 9.2 months).

Thirty-six patients died or experienced disease progression during the 15-month study period. Eight patients were excluded for being removed from the study before radiographic progression or death on study: four for a clinical impression of disease progression (usually based on a rising CA-125 level), three for adverse events, and one for early study closure. The median PFS was 4.4 months (95% CI, 3.1 to 5.5 months), with 27.8% of patients remaining progression free at 6 months. Of interest, we obtained an equivalent median PFS of 4.4 months by assessing progression on the basis of previously published CA-125 criteria (doubling of the CA-125 nadir value; 95% CI, 3.2 to 5.6 months; data not shown).17 The median survival duration was 10.7 months, with the longest survival time excluded at study termination at 14.6 months (Fig 1). At data cutoff (May 26, 2006), 25 patients had died. The median follow-up duration was 10.2 months. Nineteen survival dates were excluded because of study termination.


The sponsor halted the study because of a higher than expected incidence of GIP after 44 patients had received at least one bevacizumab dose. The most common reason for discontinuation was disease progression in 25 patients (65.9%). Eight patients (18.2%) discontinued because of an adverse event. One patient discontinued because of the early closure of the trial and had an ongoing PR. Overall, 17 patients (38.6%) had a grade 3 event, five (11.4%) a grade 4 event, and three (6.8%) a grade 5 event (Table 3). Serious adverse events occurred in 18 of 44 patients (40.9%; Table 4). Perforation and obstruction of the GI tract and arterial thromboembolic events (ATEs) were the most commonly reported serious adverse events.

Twenty-five patients died during the study, including 21 (47.7%) because of disease progression. The remaining four (9.1%) were attributed to adverse events: one from bowel obstruction related to metastatic disease, one from cerebrovascular ischemia, one from intestinal perforation, and one from sepsis due to an abdominal fistula. Three of these deaths were suspected to be related to bevacizumab treatment: one patient died of myocardial infarction and cerebrovascular ischemia, one of intestinal perforation, and one of convulsion and hypertensive encephalopathy.

Five patients (11%) developed an event attributed to GIP, one of which was grade 5. Perforation occurred 51 to 178 days after starting bevacizumab. All five patients had radiographic evidence of bowel involvement at study entry, and all had received three prior chemotherapy regimens. Each of these five patients had stable disease at the time of perforation. To assess potential radiographic risk factors for GIP, an IRF radiologist, blinded to patients' tumor responses and adverse events (including GIP), reviewed baseline radiographs from all study patients (Table 5). Radiographic variables for assessment of GIP risk included tumor involvement of the stomach, small bowel, or colon. In cases where the anatomic site of bowel involvement could not be accurately identified, a separate category of GI tumor involvement was used. Other radiographic variables included the presence of bowel obstruction, distention, or wall thickening. None of these variables seemed related to GIP. However, a trend toward increased frequency of GIP was observed for bowel wall thickening and bowel wall obstruction (Table 5). These associations were not statistically significant after accounting for multiple possible risk factors.18 There appeared to be an association between GIP and increased number of prior chemotherapy regimens. Specifically, five (23.8%) of 21 patients who received three prior chemotherapy regimens developed GIP compared with 0 of 23 patients who had received two prior chemotherapy regimens (P < .01; Table 5).

Five patients (11.3%) experienced bowel obstruction, in each case associated with disease progression. Four patients underwent surgical correction of the obstruction; two developed postoperative wound complications (one developed a grade 3 incision site hematoma requiring evacuation, and one developed grade 3 wound dehiscence). One patient developed bowel obstruction after being withdrawn from study because of hypertensive encephalopathy, and she subsequently died. This death was attributed to disease progression and bowel obstruction, although a contribution of the hypertensive event could not be ruled out.

Four ATE events were reported in three patients (6.8%), all of whom were younger than 65 years and had not received aspirin before their ATE event. One patient experienced a grade 3 silent myocardial infarction and grade 2 CHF after surgical correction of a bowel obstruction. A second patient with a history of deep venous thrombosis had an indwelling inferior vena cava filter and migratory thrombophlebitis at study entry. During the study, this patient developed a grade 3 venous thromboembolism, grade 5 cerebral ischemia, and myocardial infarction. The third patient experienced a grade 4 myocardial ischemia event, which was attributed to bevacizumab and to her underlying hypertension.

Fourteen patients (31.8%) experienced hypertension of any grade, most of which were grade 1 to 2 events; 4 (9.1%) experienced grade 3 hypertension, all of which resolved; no patient developed grade 4 hypertension. One patient experienced grade 5 hypertensive encephalopathy that presented with seizure, somnolence, blood pressure of 203/105 mmHg, epileptiform activity on EEG in the right occipital/parietal region, and magnetic resonance imaging changes in the right occipital lobe, most likely representing an area associated with hypertensive encephalopathy. The patient's death was attributed to disease progression and bowel obstruction, although a contribution of hypertensive encephalopathy could not be excluded.

This trial demonstrates antitumor activity of single-agent bevacizumab in heavily pretreated, platinum-resistant patients with EOC or PSC. The observed RR of 15.9% compares with the 17.9% RR observed in another prospective study involving a mixture of platinum-sensitive and -resistant patients who were less heavily pretreated.14 It is noteworthy that single-agent bevacizumab is active in EOC as well as in renal cell cancer,19 whereas it appears to have relatively low activity when used by itself in other tumor types such as colorectal or breast cancers.20,21 The mechanism for this differential effect is unclear, although it may reflect a greater contribution of VEGF-dependent angiogenesis to the biology of relapsed EOC when compared with these other tumor types. Nonetheless, bevacizumab used in combination with chemotherapy has been shown to confer a survival advantage in patients with advanced colorectal, breast, and lung cancers, suggesting the potential for synergy when this drug is combined with standard cytotoxic agents in the appropriate clinical setting.22-24

Despite the activity of this agent in platinum-resistant patients, the incidence of GIP (11.4%) was higher than that reported in previously-conducted bevacizumab trials of other tumor types. The prescribing information for bevacizumab notes a GIP incidence of 0% to 3.7% across all studies.25 The higher GIP incidence in this study may be related to the advanced nature of this patient population. In this regard, exposure to three rather than two prior regimens of chemotherapy appeared most strongly associated with the development of GIP (Table 5). Five (23.8%) of 21 patients who had received three prior chemotherapy regimens experienced GIP compared with none of the 23 patients who had received two prior chemotherapy regimens. Compared with our findings, the incidence of GIP was lower in less heavily pretreated patients who received either single-agent bevacizumab (0%) or a combination of bevacizumab and oral cyclophosphamide (3%) in previous studies.14,15 Furthermore, a retrospective analysis of patients with platinum-refractory EOC treated with bevacizumab in combination with chemotherapy revealed a GIP incidence of 9% (two of 23).26 These studies suggest that GIP may be a greater concern with bevacizumab in heavily pretreated, platinum-resistant patients with EOC.

Tumor involvement of the GI tract was common in this study population (90.9%). However, radiographic findings such as stomach, small bowel, or large bowel tumor involvement did not appear to increase the risk of developing GIP. There was a trend toward higher risk of GIP in patients with radiographic evidence of bowel wall thickening or bowel obstruction, although this did not reach statistical significance. Because of the small patient numbers, conclusions regarding risk factors for GIP with bevacizumab therapy should be interpreted cautiously. An ongoing randomized, placebo-controlled phase II study of carboplatin and gemcitabine, with or without bevacizumab, in patients with platinum-sensitive relapse should better define the risk of GIP in this disease.

In addition to GIP, we noted that arterial thromboembolic events also occurred at a higher incidence (6.8%) than previously reported in bevacizumab trials.27 Bevacizumab-associated grade 3 or 4 hypertension, proteinuria, bleeding, venous thromboembolic events, wound healing complications and CHF occurred at expected incidences for this agent.

In conclusion, single-agent bevacizumab has activity in patients with recurrent, platinum-resistant EOC or PSC who have been previously treated with either liposomal doxorubicin or topotecan. However, the incidence of GIP appears to be higher in this heavily pretreated patient group, and risk factors that predispose to this complication require further investigation. It is unknown whether the risk of GIP will be lower when this agent is used in the first-line setting in patients with EOC, although prospective randomized trials addressing this question are ongoing.

Employment or Leadership Position: Julie Hambleton, Genentech (C); Jakob Dupont, Genentech (C); Howard Mackey, Genentech (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Stephen A. Cannistra, Genentech; Ursula A. Matulonis, Genentech; Richard T. Penson, Genentech; Jeffrey Douglas, Genentech; Robert A. Burger, Genentech; Deborah Armstrong, Genentech; Robert Wenham, Genentech; William McGuire, Genentech Expert Testimony: None Other Remuneration: None

Provision of study materials or patients: Stephen A. Cannistra, Ursula A. Matulonis, Richard T. Penson, Jeffrey Douglas, Robert A. Burger, Deborah Armstrong, Robert Wenham, William McGuire

Collection and assembly of data: Stephen A. Cannistra, Julie Hambleton, Jakob Dupont

Data analysis and interpretation: Stephen A. Cannistra, Julie Hambleton, Jakob Dupont, Howard Mackey

Manuscript writing: Stephen A. Cannistra, Jakob Dupont

Final approval of manuscript: Stephen A. Cannistra, Ursula A. Matulonis, Richard T. Penson, Julie Hambleton, Jakob Dupont, Howard Mackey, Jeffrey Douglas, Robert A. Burger, Deborah Armstrong, Robert Wenham, William McGuire


Table 1. Demographic and Baseline Patient Characteristics (n = 44)

Table 1. Demographic and Baseline Patient Characteristics (n = 44)

Age, years
Primary site
    Peritoneal serous cancer818.2
Histopathologic type
    Clear cell12.3
Duration of ovarian cancer, years
Prior surgery
Prior radiotherapy
Response to platinum (n = 43)
    Primary resistant3683.7
    Secondary resistant716.3
Prior therapy postplatinum
    Liposomal doxorubicin2659.1
    Topotecan and liposomal doxorubicin715.9
No. of prior chemotherapy regimens
Sum of longest diameters of target lesions, cm
CA-125, U/mL

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.


Table 2. Objective Response (n = 44)

Table 2. Objective Response (n = 44)

RECIST ResponseNo.%
Complete response00
Partial response715.9
Stable disease2761.4
Stable disease ≥ 12 weeks1125.0
Not assessable49.1
Progressive disease511.4

Abbreviation: RECIST, Response Evaluation Criteria in Solid Tumors.

*One patient died before first radiograph was obtained.


Table 3. Adverse Events Occurring in ≥ 10% of Patients

Table 3. Adverse Events Occurring in ≥ 10% of Patients

EventAny Grade
Grades 3-5
GI disorders
    Abdominal pain1329.524.5
    Abdominal digestion920.524.5
General disorders
Infections and infestations
    Urinary tract infection613.612.3
    Weight decreased511.40
Metabolism and nutrition disorders
Musculoskeletal/connective tissue
Nervous system disorders
Psychiatric disorders
Renal and urinary disorders
Respiratory, thoracic and mediastinal
Skin and subcutaneous tissue
Vascular disorders

NOTE. Adverse events that occurred in five or more patients are presented. The adverse events were attributable to all causes, including bevacizumab.


Table 4. SAEs (n = 44)

Table 4. SAEs (n = 44)

Patients with SAEs1840.9
Cardiac disorders
    Myocardial infarction12.3
    Myocardial ischemia12.3
    Silent myocardial infarction12.3
GI disorders
    Small intestinal obstruction49.1
    GI perforation511.4
General disorders
Hepatobiliary disorders
    Bile duct obstruction12.3
Infections and infestations
    Catheter site infection12.3
    Pelvic abscess12.3
    Urinary tract infection12.3
Procedural complications
    Incision site hematoma12.3
    Wound complication12.3
Metabolism and nutrition
Nervous system
    Cerebral ischemia12.3
    Hypertensive encephalopathy12.3
Respiratory, thoracic, and mediastinal
    Pulmonary hypertension12.3
Vascular disorders
    Deep vein thrombosis12.3

NOTE. Adverse events attributable to all causes including bevacizumab.

Abbreviation: SAE, serious adverse event.


Table 5. Possible Risk Factors for GI Perforation

Table 5. Possible Risk Factors for GI Perforation

Risk FactorGI Perforation
No. of Patients With (n = 5)No. of Patients Without (n = 39)% of Patients With
    GI tumor involvement
    Stomach involvement
    Small bowel involvement
    Colon involvement
    Bowel obstruction
    Bowel distention
    Bowel wall thickening
Prior treatment
    3 prior chemotherapy regimens51623.8
    2 prior chemotherapy regimens0

*P <.10. Exact two-sided P values under multinomial sampling, unadjusted for multiplicity.18

P <.01.

© 2007 by American Society of Clinical Oncology

Supported by Genentech Inc.

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

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DOI: 10.1200/JCO.2007.12.0782 Journal of Clinical Oncology 25, no. 33 (November 20, 2007) 5180-5186.

Published online September 21, 2016.

PMID: 18024865

ASCO Career Center