Chemotherapy for recurrent and metastatic cervical cancer

Xia Tao
a,b
, Wei Hu
a
, Pedro T. Ramirez
a
, John J. Kavanagh
a,

a
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
b
Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
Received 18 April 2008
Available online 3 June 2008
Abstract
Objectives. Our purpose is to review the chemotherapy for recurrent and metastatic cervical cancer.
Methods. We reviewed the phase II and III clinical trials of chemotherapy regimens and recent advances of targeted therapy for treatment of
recurrent and metastatic cervical cancer. We also reviewed chemotherapy for rare histological subtypes of cervical cancer.
Results. Recent data has shown that the combination of cisplatinum and topotecan is the only regimen to demonstrate a progression-free
survival and overall survival advantage over single agent cisplatin in the setting of recurrent cervical cancer. Preliminary study results indicate that
targeted therapies may have an important role in the management of recurrent or metastatic cervical cancer.
Conclusion. There remains a need for novel agents and further research focusing on the management of recurrent and metastatic cervical
cancer. Future goals of therapy are to increase efficacy of treatment options while decreasing toxicity.
2008 Elsevier Inc. All rights reserved.
Keywords: Chemotherapy; Cervical cancer; Recurrent and metastatic
Introduction
According to the American Cancer Society's Global Cancer
Facts and Figures 2007, an estimated 555,094 new cases of
cervical cancer occurred worldwide in 2007, and 309,808
people died of the disease. More than 85% of the new
cases and deaths (an estimated 473,430 and 272,238 cases,
respectively) occurred in developing countries [1]. In the
United States, an estimated 11,150 new cases of invasive
cervical cancer were diagnosed in 2007, and 3,670 people died
of the disease [2].
Two inspiring landmarks have occurred in the fight against
cervical cancer. First, the development of the Papanicolaou
smear in 1943 made possible the screening and early detection
of the disease. Second, a study by Koutsky and colleagues
established the efficacy of the human papillomavirus (HPV)
vaccine in preventing cervical dysplasia [3], and the HPV
vaccine was approved by the U.S. Food and Drug Administra-
tion in 2006 [4]. Despite these innovations, one third of patients
with invasive cervical cancer die from recurrent or metastatic
disease and the lack of an optimal treatment option.
Systematic chemotherapy remains the major treatment modal-
ity for recurrent or metastatic cervical cancer. The intent of che-
motherapy is sufficient palliation because of the aggressive nature
of the disease and the toxicity of the drugs. Thus, effective pal-
liation and social support should be the considerations when
making treatment decisions.
Fifty-eight cytotoxic agents have been tested in recurrent or
advanced cervical cancer, 21 of themhad activity with a response
rate of 15%or greater [5]. The most active single agents have been
cisplatin, paclitaxel, topotecan, vinorelbine, and ifosfamide [6].
We reviewed the findings of randomized, controlled phase II and
phase III trials, especially GOG studies, which have reported
active single-agent and combined-agent chemotherapy regimens
and of targeted therapies for recurrent cervical cancer. We also
reviewed the chemotherapy for rare histological subtypes of
Available online at www.sciencedirect.com
Gynecologic Oncology 110 (2008) S67S71
www.elsevier.com/locate/ygyno

Corresponding author. Department of Gynecologic Oncology, The Uni-

versity of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Unit 1362,
Houston, TX, USA. Fax: +1 713 745 0695.
E-mail address: jkavanag@mdanderson.org (J.J. Kavanagh).
0090-8258/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2008.04.024
cervical cancer, such as small cell carcinoma, rhabdomyosarcoma
(RMS), and glassy-cell carcinoma (GCC).
Single-agent chemotherapy regimens for SCC
Cisplatin therapies
In 1981, Thigpen and colleagues first reported the use of
cisplatin alone in the treatment of advanced or recurrent cervical
cancer at an intravenous (IV) dose of 50 mg/m
2
every 3 weeks
(Q3w), whichachieveda response rate of 38%[7]. In1985, Bonomi
and colleagues conducted the GOG 43 phase III trial comparing
three IVdoses of 100 mg/m
2
for one day, 50 mg/m
2
for one day and
20 mg/m
2
per day for 5 days Q3w. There was no significant
difference in progression-free survival (PFS) or overall survival
(OS) with the 100 mg/m
2
dose compared with the 50 mg/m
2
dose,
and the 100 mg/m
2
dose produced greater myelosuppression and
nephrotoxicity [8]. In 1986, IV cisplatin 50 mg/m
2
Q3w was
adopted by the oncology community as the standard regimen for
recurrent cervical cancer. In subsequent trials, single-agent cisplatin
used as the control armshowedresponse rate (RR) of 13%to19%, a
PFS of 2.8 to 3.2 months, and an OS of 6.5 to 8.8 months [911].
Table 1
Single, nonplatinum agents for recurrent and metastatic cervical cancer
Agent Dose and
administration
No. of
patients
RR % PFS
month
OS month Toxicity %
grade 34
(N10%) Study type Author Ref.
Topotecan 1.5 mg/m
2
IV 41 12.5 2.1 6.6 Neutropenia
a
68 GOG 127-F Bookman, 2000 [15]
D1 to D5 Thrombocytopenia
a
39 Phase II
Q3w Anemia 24
1.5 mg/m
2
IV 43 18.6 2.4 6.4 Neutropenia 18 68 GOG 76-U Muderspach, [16]
D1 to D5 Thrombocytopenia 18 Phase II 2001
Q4w Anemia 13.6
Death
b
(1 case) 2.3
Paclitaxel 170 mg/m
2
IV, 52 17 3.4 Leukopenia 46 Phase II McGuire, [17]
Q3w 50
c
Neutropenia 40 1996
250 mg/m
2
/3 hs IV 32 25 7.3 Phase II Kudelka, [18]
Q3w 1997
Ifosfamide 1.2 g/m
2
, Q4w 27 11.1 Leukopenia 33 Phase II Sutton, 1989 [19]
(Mesna) D1D5 Anemia 26
Q4w Neurotoxicity 11
1.5 g/m
2
IV, 51
d
15.7 Granulocytopenia 13.5 Phase II Sutton, 1993 [20]
D1D5, Q4w 52
c
Neurotoxicity 11.5
Vinorelbine 30 mg/m
2
weekly 33
d
18 5.2 11 Leukopenia 57 Phase II Morris, [21]
35
c
Granulocytopenia 54 1998
30 mg/m
2
weekly 41 17 2.6 Leukopenia 44 EORTC Lhomme [22]
Granulocytopenia 47 Phase II 2000
Anemia 23
Gemcitabine 800 mg/m
2
weekly 25 8 1.9 4.9 b10 Phase II Schilder [23]
3 ws on 1 w off 2000
Doxil 40 mg/m
2
/1 h 26
d
11.1 3.2 8.9 Lymphocytopenia
e
18.5 Phase II Rose, [24]
Q4w 27
c
No grade 4 toxicity 2006
a
Grade 4 toxicity.
b
One death from septic complications was considered potentially due to treatment.
c
Numbers of patients evaluable for toxicity.
d
Numbers of patients evaluable for response.
e
Grade 3 toxicity.
Table 2
Combined chemotherapeutic agents in recurrent and metastatic cervical cancer
Agent Dose and administration No. of patients RR % PFS month OS month Toxicity % grade 3-4 N10% Study type Author Ref.
Cisplatin 50 mg/m
2
151(response) 31.1 4.6 8.3 Granulocytopenia 38 GOG 110 Omura, [11]
Ifosfamide 5 g/m
2
/24 h, 146 (toxicity) Thrombocytopenia 19 RCT 1997
Mesna Q3w Nauseavomiting 12
Cisplatin 50 mg/m
2
130 36 4.8 9.7 Leukopenia 53 GOG Moore, [10]
Paclitaxel 135 mg/m
2
/24 h Neutropenia 10 67 Phase II 2004
Q3w Anemia 28
Nauseavomiting 10
Cisplatin 50 mg/m
2
D1 147 27 4.6 9.4 Leukopenia 63 GOG 179 Long, [9]
Topotecan 0.75 mg/m
2
D1D3 Granulocytopenia 70 Phase III 2005
Thrombocytopenia 31
Q3w Anemia 38
S68 X. Tao et al. / Gynecologic Oncology 110 (2008) S67S71
Other platinum analogues
In 1990, Weiss and associates reported the results of a phase
II trial, in this study the authors found carboplatin administered at
400 mg/m
2
IVQ4wto have a RRof 15%[12]. In 1991, Lira-Puerto
and colleagues conducted a phase II trial of carboplatin at same
dose and found the regimen to be associated with a RRof 26%and
a median OS duration of 7.5 months [13]. The authors suggested
that carboplatin had a future as an anticancer agent because of its
low toxicity profile. In this same trial, iproplatin 270 mg/m
2
compared with carboplatin 400 mg/m
2
IV Q4w was associated
with a RR of 30% and a medial OS duration of 7.6 months [13].
Iproplatin is not available in the United States. Oxaliplatin 130 mg/
m
2
IVover 2-hour Q3w has been reported to have a RR of 8.3%
and showed limited activity in a phase II trial [14].
Nonplatinum therapies
The use of the following nonplatinum-based regimen has been
investigated in studies of recurrent and metastatic cervical cancer:
topotecan [15,16], paclitaxel [17,18], ifosfamide[1920], and
vinorelbine [21,22]. These agents produced RRs of 12.5% to
25%, PFS durations of 2.1 to 5.2 months, and OS durations of 6.4
to 11 months. Gemcitabine [23] and liposomal doxorubicin
(Doxil) [24] have also been studied because of their potential use
in combination. Table 1 lists the results of clinical trials of these
agents.
Doublet (double-agent) chemotherapy regimens for SCC
(listed in Table 2)
Cisplatin-based doublet therapies
The agents that have been used in combination with cisplatin
are ifosfamide, paclitaxel and topotecan. These modalities pro-
duced RR of 27% to 36%, PFS durations of 4.6 to 4.8 months,
and OS durations of 8.3 to 9.7 months. These outcomes were
higher than those demonstrated with most single agents. Lower
response rates were found in the subgroup of patients who had
received prior chemotherapy (Table 2).
Nonplatinum-based doublet therapies
Carboplatin, paclitaxel, topotecan, doxil, irinotecan, and
mitomycin-C (MMC) have been used in various combinations
and have produced RR of 25% to 54%, PFS durations of 3.8 to
5.7 months, and OS durations of 8.6 to 12.3 months. Carbo-
platin plus doxil showed the longest survival duration.
In 2006, topotecan plus cisplatin was approved as first-line
treatment of advanced, recurrent, and metastatic cervical cancer;
following the indication for recurrent ovarian cancer; and as the
second-line treatment of small cell lung cancer. In order to
identify combinations of chemotherapeutic agents that were
more active than topotecan plus cisplatin, the GOG 204 study
was performed. This study is evaluating the effects of several
doublets, including cisplatin plus paclitaxel, cisplatin plus
vinorelbine, and cisplatin plus gemcitabine.
Triplet (triple-agent) chemotherapy regimens for SCC
Some triple-agent combinations have been evaluated, such as
bleomycin plus cisplatin and ifosfamide, bleomycin plus car-
boplatin and ifosfamide, cisplatin plus fluorouracil and ifosfa-
mide, showed response rate to be more than 50% and OS of 9 to
12 months in phase II trials. But no triplets have been proven
superior to single-agent cisplatin or cisplatin-based doublets in
randomized phase III trials [6].
Quartlet (four-agent) chemotherapy regimens for SCC
In a randomized phase III trial, bleomycin, vindesine,
MMC, and cisplatin (BEMP) produced better response but
was more toxic than cisplatin alone. In an arm of the GOG
179 study, the combination of methotrexate, vinblastine,
doxorubicin, and cisplatin (MVAC) was evaluated; however,
this arm was closed by the Data Safety Monitoring Board
after 4 treatment-related deaths occurred among 63 patients
[9].
Treatments for non-SCC subtypes of cervical cancer
Non-SCC histological subtypes of cervical cancer are of
interest because of their increasing incidence [25,26]. Approxi-
mately 10% to 20% of all advanced or recurrent cases of cer-
vical cancer are of non-SCC histology for the recent 2 decades.
There are limited phase II and III trials of non-SCC cervical
cancer. Both single- and combination modalities have been
used in the treatment of non-SCC recurrent and metastatic
cervical cancer.
In a GOG trial, paclitaxel at 170 mg/m
2
IVover 24-hour Q3w
resulted in a RR of 31% and a median response duration of 4.8
month. These results were higher than those of other single-
agent regimens used in the treatment of non-SCC of the cervix
[27]. A phase II GOG trial of ifosfamide at 1.5 g/m
2
IV per day
for 5 days Q3w plus mesna produced a RR of 15.0% and a
median duration of response of 4.2 months [28]. In 2005,
Schilder and associates reported that single-agent gemcitabine at
a dose of 800 mg/m
2
IVover 30 min weekly, 3 weeks on/1 week
off, produced a RR of 4.5%, a PFS duration of 2.1 months, and
an OS duration of 6.5 months. These results confirmed that
gemcitabine as a single agent has minimal activity in previously
treated patients with non-SCC [29].
Treatments for small cell neuroendocrine carcinoma
Small-cell neuroendocrine carcinoma (SCNEC) accounts
for less than 2% of all gynecologic malignancies, which occur
most frequently in the cervix [30]. In 2004, Viswanathan
and associates reported a retrospective study of 21 patients
who received radical hysterectomy or radiation therapy
for SCNEC at M. D. Anderson Cancer Center. Prior to or
concurrent with local therapy, cisplatin plus etoposide with
or without doxorubicin was given to 12 patients (57%) and
cisplatin plus 5-FU was given to 1 patient (5%). The 5-year
overall survival rate was 29% [31].
S69 X. Tao et al. / Gynecologic Oncology 110 (2008) S67S71
Treatments for rhabdomyosarcoma
RMS is generated from myogenic progenitor cells and is the
most common soft-tissue tumor in children. Ferguson and asso-
ciates, reporting on a retrospective study of 8 cases of RMS, found
that the vincristine in combination with cyclophosphamide, dac-
tinomycin, or doxorubicin trended toward favorable PFS [32,33].
Treatments for glassy-cell carcinoma
GCC accounts for less than 5% of cervical cancers and often
occurs in young woman. Compared with their effect against
SCC, surgery with or without radiation therapy has had limited
effects against GCC of cervical cancer. Paclitaxel and carbo-
platin combination were reported to produce a response rate of
50% or more in 2 cases of GCC [34].
Targeted therapy
Gefitinib
In 2008, Goncalves and colleagues reported a multicenter,
open-label, noncomparative phase II trial (study 1839IL/0075)
showing that gefitinib (an HER1/EGFRtyrosine kinase inhibitor)
at 500 mg/day had minimal monotherapeutic activity against
cervical cancer; however, 20% of patients treated with gefitinib
had stable disease [35].
Cetuximab
In 2007, Bellone and associates evaluated the overexpression
of EGFR1 in metastatic and recurrent cervical cancer cell lines
and suggested that cetuximab (an anti-EGFR1 monoclonal
antibody) might have a therapeutic role in this disease [36]. The
GOG 0076DD phase II trial is an ongoing study of cetuximab in
combination with cisplatin in the treatment of advanced,
persistent, or recurrent cervical cancer. GOG0227E is an ongoing
phase II trial of cetuximab in the treatment of persistent or
recurrent squamous cervical carcinoma and non-SCC, data are not
available at present.
Erlotinib
Erlotinib (a HER1/EGFRinhibitor) combined with rapamycin
has been investigated preclinically. The results support further
clinical research of rapamycin and EGFR inhibitor combinations
in anticancer therapy [37].
Trastuzumab
Trastuzumab is a humanized monoclonal antibody against the
HER2 receptor. In 2004, Chavez-Blanco and co-workers ana-
lyzed HER-2 expression in cervical cancer cell lines as well as in
primary tumors and found a low frequency of HER-2 expression
in primary tumors, suggesting that trastuzumab could have
limited value in the primary management of cervical cancer.
However, the finding of HER-2 overexpression in the recurrent
tumors indicates the need to further evaluate its expression in a
larger number of recurrent cervical cancer patients [38].
Targeting angiogenesis
Bevacizumab
Bevacizumab is a VEGF monoclonal antibody (Mab). In
2006, Wright and colleagues conducted a retrospective study of
patients with recurrent cervical cancer who were treated with
bevacizumab combined of 5-FU or capecitabine. The RR was
34%, and median time to progression which is clinical benefit was
4.3 months, suggesting this combination might have potential
anti-tumor activity in pretreated recurrent cervical cancer [39].
Sunitinib
Sunitinib inhibits VEGF 1, 2, and 3 and PDGFR-A and -B. A
phase II clinical trial of sunitinib has been initiated in patients
with locally advanced or metastatic cervical cancer. If it is
shown to have activity in this application, future studies will
include investigations of sunitinib-based combinations [40].
TNP-470
TNP-470 is one of the first anti-angiogenic compounds to
enter clinical trial. A phase I trial of this angiogenesis inhibitor
in cervical cancer was reported by Kudelka and associates in
1997. The dose of TNP-470 recommended for further studies
was 60 mg/m
2
/h IV every other day for 4 weeks followed by
2 weeks rest [41].
Conclusions
Chemotherapy is the primary treatment for patients with this
disease, and cisplatin remains the standard single-agent therapy.
Topotecan combined with cisplatin was approved by the Food and
Drug Administration in 2006 as the first-line treatment of recur-
rent cervical cancer which showed prolonged survival time and
less toxicity. There is a definite need for new agents and further
research focusing on the ideal treatment for recurrent and metas-
tatic cervical cancer with high specificity and less toxicities.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgment
We thank Regina G. Richard and Vickie J. Williams for
editorial support.
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