Gynecologic Oncology 103 (2006) 489 – 493
www.elsevier.com/locate/ygyno
Bevacizumab combination therapy in heavily pretreated,
recurrent cervical cancer
Jason D. Wright a,⁎, Dana Viviano a , Matthew A. Powell a , Randall K. Gibb a , David G. Mutch a ,
Perry W. Grigsby a,b , Janet S. Rader a
a
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine,
4911 Barnes Hospital Plaza, Box 8064, St. Louis, MO 63110, USA
b
Department of Radiation Oncology, Washington University School of Medicine, USA
Received 14 January 2006
Available online 2 May 2006
Abstract
Objective. To report the utility of the monoclonal, anti-vascular endothelial growth factor antibody bevacizumab in combination with cytotoxic
chemotherapy for women with recurrent cervical cancer.
Methods. A retrospective analysis of women with recurrent cervical cancer treated with bevacizumab combination therapy was performed.
Results. Six patients were identified. The patients had a median of 3 prior regimens. All of the patients had multisite, metastatic disease. The
combination regimen included IV 5-fluorouracil in 5 (83%) patients and capecitabine in one (17%) subject. Treatment was well tolerated. Grade 4
toxicity occurred in one patient who developed neutropenic sepsis. Clinical benefit (CR, PR, or SD) was noted in 67% of the subjects. This
included 1 (17%) complete response, 1 (17%) partial response and two (33%) patients with stable disease. The median time to progression for the
four women who demonstrated clinical benefit was 4.3 months.
Conclusions. Combination bevacizumab is well tolerated and displayed encouraging anti-tumor activity in heavily pretreated recurrent cervical
cancer.
© 2006 Elsevier Inc. All rights reserved.
Keywords: Bevacizumab; Cervical cancer; Angiogenesis; Biologic therapy
Introduction
Worldwide cervical cancer remains a major cause of morbidity and mortality in women [1]. Over the past decade, the
introduction of chemoradiation for advanced stage cervical
cancer had led to improvements in survival [2]. Despite these
advances, the prognosis for patients with recurrent, metastatic
cervical cancer remains poor. The failure rate for stage I–II
disease is approximately 15–30% and increases to 40–60% for
women with stage III neoplasms [3–6]. Only 10% of patients
with recurrent disease will be salvaged and alive at 5 years [3,7].
This highlights the need for more effective treatment strategies
for the management of recurrent cervical cancer.
⁎ Corresponding author. Fax: +1 314 362 2893.
E-mail address: wrightj@msnotes.wustl.edu (J.D. Wright).
0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2006.03.023
Angiogenesis appears to play a prominent role in cervical
cancer development and progression. A number of studies have
correlated increased tumor vascularization with impaired
survival [8–12]. In a series of 56 patients with early stage
cervical adenocarcinomas, increased tumor microvessel density
(MVD) was associated with worse progression-free (PFS) and
overall survival (OS). The 5-year OS was 85% for patients with
low MVD compared to 63% for women with high MVD [9].
Other authors have correlated increased cervical MVD with
tumor progression, recurrence, and nodal metastases [11,13]. It
appears that cervical neovascularization begins early in the
carcinogenic process. Comparisons of normal cervical tissue,
dysplastic epithelium, and invasive cervical cancer have shown
that MVD progressively increases with advancing disease
[10,12,14]. The observed vessel development begins with the
sprouting of new vessels along the cervical basement membrane
[12,15]. The newly formed vascular structures eventually spread
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J.D. Wright et al. / Gynecologic Oncology 103 (2006) 489–493
upward into the dysplastic epithelium [12]. The developing
vascular network provides support for growth and invasion of
the neoplasm.
Given the importance of angiogenesis in cervical carcinogenesis, therapeutic strategies incorporating the anti-vascular
endothelial growth factor (VEGF) antibody bevacizumab are
theoretically appealing. VEGF is a pro-angiogenic factor that
stimulates vascular growth and increases vascular permeability
[16]. A number of phase II and III trials have documented the
efficacy of bevacizumab for a variety of solid tumors [17,18].
We reviewed our experience with bevacizumab for patients with
recurrent, metastatic cervical cancer. To our knowledge, this is
the first series of patients with cervical cancer treated with
bevacizumab.
Case series
Patients
Six patients with recurrent cervical cancer who were treated
with bevacizumab and 5-fluoruracil-based combination therapy
were identified. Table 1 displays the demographic characteristics
of the study group. The median age of the cohort at diagnosis
was 43 years old (range, 31–57). The stage distribution at diagnosis was IB2 (2), IIB (2), and IIIB (2). Squamous cell carcinomas were found in 4 (67%) women, while one (17%) patient
had an adenocarcinoma, and one (17%) had a poorly differentiated carcinoma. Primary treatment consisted of cisplatinbased chemoradiation in five and radical hysterectomy in one
patient. The subject who underwent radical hysterectomy had
multiple positive lymph nodes and was treated with adjuvant
radiation and weekly cisplatin. The most common locations for
recurrence were the chest (67%) and retroperitoneal lymph
nodes (50%). The cohort was heavily pretreated. All of the patients had received prior platinum-based salvage therapy. Five
(83%) had received prior topotecan. The median number of prior
regimens, including cisplatin used as a radiosensitizer, was 3 and
ranged from 2 to 4. At the initiation of bevacizumab/5-FU
therapy, all patients had measurable disease.
Safety and tolerability
Table 1
Population demographics and baseline disease characteristics
Characteristic
Age
Median
Range
Race
White
Black
Stage
IB2
IIB
IIIB
Histology
Squamous
Adenocarcinoma
Poorly differentiated carcinoma
Primary Treatment
Radical hysterectomy/lymphadenectomy
Chemoradiation
Adjuvant Treatment
None
Chemoradiation
Recurrence location a
Lung
Retroperitoneal nodes
Intraabdominal
Liver
Brain
Prior regimens b
Median
Range
Prior chemotherapeutic agents c
Cisplatin
Carboplatin
Topotecan
Paclitaxel
Vinorelbine
5-Fluorouracil-based combination
5-Fluorouracil
Capecitabine
Bevacizumab doses
Median
Range
Bevacizumab administered (mg)
Median
Range
Patients, n = 6 (%)
43
31–57
3 (50)
3 (50)
3 (50)
2 (33)
1 (17)
4 (67)
1 (17)
1 (17)
1 (17)
5 (83)
5 (83)
1 (17)
4
3
1
2
1
(67)
(50)
(17)
(33)
(17)
3
2–4
6
5
5
5
1
(100)
(83)
(83)
(83)
(17)
5 (83)
1 (17)
3.5
2–15
1289
670–18,290
a
Several patients recurred in multiple locations.
Number of prior regimens included cisplatin used as a chemosensitizing
agent during radiation.
c
Number of patients who had received the listed chemotherapeutic agents.
b
Bevacizumab was most commonly administered with
intravenous 5-flurouracil in 5 (83%) women and with oral
capecitabine in 1 (17%) subject. 5-Fluorouracil was administered weekly to all patients. The starting dose ranged from 250 to
500 mg. Capecitabine was administered at a dose of 2000 mg
bid. Bevacizumab was given intravenously every other week to
5 of the 6 subjects. The starting dose was either 5 mg/kg or
10 mg/kg. The dose was escalated in one patient to 10 mg/kg
then 15 mg/kg. The sixth study subject was given bevacizumab
at a dose of 15 mg/kg every 3 weeks. A total of 30 doses of
bevacizumab were administered. The median number of bevacizumab doses received was 3.5 (range 2–15); the median
cumulative dose received was 1289 mg (range 670 mg–
18,290 mg). No patient underwent a reduction of his/her bevacizumab dose.
Toxicity was assessed according to the National Cancer
Institute's Common Toxicity Criteria version 3.0. Overall, the
regimen was well tolerated. The most common toxicity experienced was anemia. Grade 3 anemia was noted in 1 (17%), grade
2 anemia occurred in 2 (33%) patients, while grade 1 anemia was
found in 3 (50%). Table 2 displays the grade 2–4 toxicities of the
cohort. Grade 4 neutropenic sepsis was encountered in one
patient after 2 doses of bevacizumab. While none of the patients
developed hemorrhagic complications, progression of a lower
extremity thrombosis occurred in one subject. Mild hypertension
(grade 1) was seen in one patient, while one patient developed
J.D. Wright et al. / Gynecologic Oncology 103 (2006) 489–493
Table 2
Incidence of grade ≥2 toxicity
Patients, n (%)
Neutropenia
Anemia
Thrombocytopenia
Fatigue
Diarrhea
Nausea
Proteinuria
Renal obstruction
Vesicovaginal fistula
Bowel obstruction
Thrombotic
Grade 2
Grade 3
Grade 4
0
2 (33)
0
0
0
1 (17)
1 (17)
0
1 (17)
2 (33)
1 (17)
0
1
1
2
1
2
0
1
0
1
0
1 (17)
0
0
0
0
0
0
0
0
0
0
(17)
(17)
(33)
(17)
(33)
(17)
(17)
grade 2 proteinuria on treatment. Three bowel obstructions were
identified, but no gastrointestinal perforations were seen.
Efficacy
Patient assessment was performed using the Response
Criteria in Solid Tumors (RECIST) [19]. As patients were
treated outside of a clinical protocol, confirmatory examinations
were usually not available to document response. The overall
response rate was 33% (2 of 6 patients), including one complete
response and one partial response. The complete responder had
retroperitoneal and supraclavicular nodal disease previously
unresponsive to salvage therapy. The partial responder had multiple pulmonary metastases that decreased in size. In addition to
the 2 responders, there were two (33%) patients with disease
stabilization. One of the patients with disease stabilization had a
large tumor burden with multiple pulmonary and hepatic metastases. The remaining two patients had progressive disease. One
patient had widely metastatic disease and died 5 months after her
initial treatment (Table 3).
The median time to progression for the four women who
demonstrated clinical benefit (CR, PR, SD) was 4.3 months and
ranged from 2.5 to 5.9 months. While no patients had a progression-free interval (PFI) of >6 months, 2 women experienced a
PFI of >4 months. At last follow-up, 3 (50%) patients were alive
with disease, and 3 (50%) subjects had died from progressive
disease. The median overall survival (OS) for the cohort at the
time of reporting was 5.1 months (range, 1.5–7.3 months).
491
conducted a number of phase III trials of cisplatin-based
combination regimens. While regimens of cisplatin and ifosfamide and cisplatin and paclitaxel have yielded improved response rates and enhanced progression-free survival (PFS), these
more toxic regimens have not translated into improvements in
overall survival [21,22]. The GOG recently reported the results
of a phase III trial of cisplatin versus cisplatin and topotecan. The
combination regimen was associated with a 27% response rate
and a median PFS of 4.6 months. The OS for the multiagent arm
was 9.4 months compared to 6.5 months for single agent cisplatin. Notably, this was the first study that demonstrated a
survival advantage for combination chemotherapy over single
agent cisplatin [23].
VEGF inhibition appears to be a rationale therapeutic strategy
for cervical cancer. The importance of VEGF expression during
cervical carcinogenesis has been demonstrated in a number of
studies [14,24,25]. In an analysis of 117 women with stage Ib
cervical cancer, Lee and colleagues noted that high VEGF
expression was associated with deep tumor invasion, pelvic
node metastases, pelvic and distant failure as well as impaired
survival [25]. The increased production of VEGF within cervical
neoplasms is likely multifactorial. Cervical carcinomas are often
associated with significant tumor hypoxia, a strong stimulus for
expression of hypoxia inducible factor 1 (HIF-1) [26]. HIF-1 is a
powerful stimulus for VEGF secretion. Emerging data also
suggest the human papillomavirus, the major etiologic agent of
cervical cancer, may directly stimulate VEGF production
[27,28]. Upregulation of the E6 oncoprotein is associated with
VEGF production. E6 appears to promote VEGF in a p53independent manner [28]. Further, HPV 16 E6 and E7 have been
shown to downregulate the angiogenesis inhibitors thrombospondin-1 and maspin [27].
Our initial strategy for the use of bevacizumab therapy for
cervical cancer has focused on combining the agent with 5fluorouracil or the 5-FU prodrug capecitabine. The regimen was
based on the initial reports of bevacizumab activity in the
combination regimen of bevacizumab with irinotecan/5-fluorouracil/leucovorin (IFL) for patients with metastatic colorectal
cancer [17]. The reported response rates for 5-FU and capecitabine in the setting of recurrent cervical cancer have ranged
from 0 to 49% [29–32]. The GOG reported a response rate of 4%
for 5-FU combined with low-dose leucovorin [29]. The response
rate was improved to 9% when high-dose leucovorin was added
to 5-FU [30]. In a phase II study of combination 5-FU/cisplatin
Kaern et al. reported a 49% response [31]. In addition to activity
Discussion
Our findings reveal that combination bevacizumab/5-fluorouracil-based chemotherapy is well tolerated and associated with
significant activity in heavily pretreated patients with recurrent
cervical cancer. Treatment for metastatic cervical cancer has
traditionally relied upon cytotoxic chemotherapy. Cisplatin is
considered the most active single agent in the setting of recurrent
cervical cancer. In a study of 497 evaluable patients, the response
rates for three single agent cisplatin dosing schedules ranged
from 21 to 31%, while median survival times varied from 6.1 to
7.1 months [20]. The Gynecologic Oncology Group has since
Table 3
Response and outcome
Patients, n (%)
Response
Complete response
Partial response
Stable disease
Progression
Vital status
Alive with disease
Dead of disease
1
1
2
2
(17)
(17)
(33)
(33)
3 (50)
3 (50)
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J.D. Wright et al. / Gynecologic Oncology 103 (2006) 489–493
in the recurrent setting, 5-FU appears to act as a radiation
sensitizer in the setting of primary chemoradiation [33,34]. We
noted 2 (33%) responses, including a complete response, and
two (33%) patients with disease stabilization. Given that all of
the subjects in our cohort had received prior radiotherapy and
had received multiple salvage regimens, we believe that our
results compare favorably with the previously reported data for
5-FU.
Mounting evidence suggests that combining an anti-angiogenic agent with either cytotoxic chemotherapy or radiation
enhances anti-tumor activity. A number of mechanisms have
been proposed to account for this additive effect. Preclinical data
have shown that bevacizumab may normalize tumor vasculature,
thereby relieving tumor hypoxia and promoting drug delivery
[35]. Other investigators have proposed that low-dose chemotherapy, so-called metronomic therapy, selectively targets and
damages endothelial cells [36]. Combining bevacizumab with a
low-dose regimen may block vascular repair and survival,
thereby enhancing the anti-tumor effects of the cytotoxic agent
[36]. The GOG is currently enrolling patients in a phase II trial,
GOG 227C, of single agent bevacizumab for patients with
recurrent cervical cancer. Our encouraging preliminary data of
combination bevacizumab therapy support the development of
novel bevacizumab based combination regimens for recurrent
cervical cancer.
While the current study is a retrospective review with small
numbers, our cohort represents the first reported use of combination bevacizumab therapy for recurrent cervical cancer. Our
finding of clinical benefit in 67% of the cohort is encouraging,
particularly given the poor responsiveness to chemotherapy
typically displayed by this malignancy and the fact that all of
the subjects had received prior salvage therapy. Overall, the
regimen was well tolerated and associated with acceptable
toxicity. These encouraging findings warrant further evaluation
of combination bevacizumab and 5-fluorouracil in a prospective setting.
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