DOI: 10.1111/tog.
12270 2016;18:182–8
The Obstetrician & Gynaecologist
http://onlinetog.org
Update on chemotherapy in gynaecological cancers
Nicholas S Reed BM MRCP FRCR,* Azmat H Sadozye
Consultant Clinical Oncologist, Beatson Oncology Centre, Gartnavel General Hospital, Glasgow G12 0YN, Scotland, UK
*Correspondence: Nicholas S Reed. Email: nick.reed@ggc.scot.nhs.uk
Accepted on 9 October 2015
Key content
 Ovarian cancer requires multidisciplinary management, usually
with postoperative adjuvant chemotherapy. In some cases, however,
neo-adjuvant chemotherapy and delayed surgery may be offered.
 Recurrent ovarian cancer management is usually treated with
chemotherapy, with drug choice often influenced by the platinum-
free interval.
 The role of adjuvant chemotherapy for endometrial cancer remains
open to debate. Adjuvant chemotherapy is increasingly offered for
high-risk cases with lymphovascular space invasion. Carboplatin
and paclitaxel are the most effective drugs in adjuvant and
recurrent settings.
 Concomitant cisplatin with radiation therapy is the standard of
care for locally advanced cervical cancer; recent studies have shown
that the addition of bevacizumab to carboplatin and paclitaxel
leads to improved response rates in the recurrent,
metastatic setting.
 There are many rare gynaecological cancers that require
multidisciplinary management, and entry into clinical trials should
be strongly supported.
Please cite this paper as: Reed NS, Sadozye AH. Update on chemotherapy in gynaecological cancers. The Obstetrician & Gynaecologist 2016;18:182–8.
DOI: 10.1111/tog.12270
Introduction
This article reviews the use of chemotherapy in all
gynaecological cancers. The aim is to give the general
reader an overview of current therapeutic options.
Chemotherapy is part of the multidisciplinary approach
and all cases will be discussed at team meetings. Traditional
chemotherapy has reached a plateau in most cancers;
however, the identification of molecular pathways that lead
to aberrant cell signalling and tumourigenesis has the
potential to revolutionise care as we move towards
‘personalised medicine’. For cervical cancer, chemotherapy
is integrated with surgery and radiation, whereas in
endometrial cancers the use of chemotherapy is mainly as
an adjuvant for high-risk cases, especially when there is
lymphovascular space invasion.
This review focuses on what is new in chemotherapy for
gynaecological cancers but can really only touch the surface
(although some of the referenced articles give more detail).
182
Review
MBBS MRCP FRCR CCST
Learning objectives
 To understand the role and scheduling of chemotherapy in both
newly diagnosed and recurrent epithelial ovarian cancer.
 To understand when chemotherapy should be offered in cervical
and endometrial cancers.
 To be able to seek information sources for the management of rare
and uncommon gynaecological cancers.
Ethical issues
 The question of systemic lymphadenectomy remains controversial
and should be carefully discussed with the patient.
 Women should be encouraged to participate in clinical trials to
help address some of the controversies in endometrial
cancer management.
Keywords: carcinoma of the cervix / carcinoma of the
endometrium / carcinoma of the ovary / carcinoma of the vulva /
chemotherapy
Linked resource: Single best answer questions are available for this
article at https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
Most of the new developments relate to ovarian cancer.
However, cervical, endometrial, vulval and vaginal
carcinomas and gynaecological tract sarcomas are playing
catch-up, particularly with the belated development of new
molecular targeted agents. The recognition of molecular
pathways that cause abnormal cell signalling pathways has
given us a greater understanding and has led to identification
of new targets and drugs.1–3
Chemotherapy has moved on from single-agent therapy
with alkylating agents and antimetabolites in the 1950s and
1960s to the use of contemporary combination
chemotherapy regimens that include the taxanes,
platinums, anthracyclines and other miscellaneous drugs.
These newer approaches will be discussed later in the article.
Recent experience would suggest that developments with
conventional agents have reached a plateau. Indeed, the only
new agent to emerge in the past few years has been
trabectedin, the marine-derived compound. The greatest
developments have come through the molecular-targeted
ª 2016 Royal College of Obstetricians and Gynaecologists

agents, such as monoclonal antibodies, the tyrosine kinase
inhibitors (TKIs), and perhaps most excitingly, the poly-ADP
ribosome polymerase (PARP) inhibitors.
Ovarian cancer
There are currently five recognised subtypes of ovarian
cancer,1–3 which have different molecular pathways and
therefore behave and respond to treatment in different
clinical ways (Table 1). Although it is likely that there are
multiple pathways involved in tumorigenesis, Table 1 lists
the currently identified pathway disturbances. It is therefore
important to recognise these variants when dealing with
ovarian epithelial tumours.
Surgery remains at the forefront of treatment, either as the
initial therapy or as a delayed primary procedure.4 However,
the conventional agents that continue to be used most
frequently are carboplatin and paclitaxel. Following primary
surgery, the conventional approach has been to use six cycles
of standard carboplatin and paclitaxel at 3-weekly intervals,
although alternatives are emerging. Before discussing new
drugs and treatments, it is important to review the best time
to administer chemotherapy. Primary debulking surgery with
the aim of optimal cytoreduction (that is, no residual disease)
remains the standard of care.
Primary medical therapy, that is neo-adjuvant
chemotherapy (NACT), is now accepted as an alternative
standard of care for patients with bulky supracolic omental
disease and/or liver metastases that cannot be optimally
resected. Two important European trials, the European
Organisation for Research and Treatment of Cancer
(EORTC) 55971 study and the UK-led CHORUS study,
have shown that NACT followed by delayed primary surgery
is not inferior to initial surgery in women with bulky
supra-colic omental disease and/or extensive liver metastases
who are not suitable for optimal resection.5,6 Cases should
always be discussed for appropriate selection at the
multidisciplinary team meetings. Ultraradical debulking
surgery is still controversial and remains the subject of
further investigation.7
Table 1. Histological types and molecular targets
Histological type Mutations isolated
Serous: high grade TP53 and BRCAm
Serous: low grade BRAF, KRAS
Endometrioid pTEN, BRAF, KRAS, beta-catenin, PI 3-kinase
Clear cell ARID1a
Mucinous KRAS
Carcinosarcoma Non-specific but include TP53
ª 2016 Royal College of Obstetricians and Gynaecologists
Reed and Sadozye
Newer approaches
Newer approaches include changing the dose frequency and
dosage to give dose-dense and dose-intense schedules.
Alternatively, other traditional agents may be added, but
none of the studies performed so far have shown any real
benefit of additional agents; from adding a third drug or
using alternating doublets. Intraperitoneal (IP) chemotherapy
has been around for 20 years with variable levels of usage in
the UK. Finally, newer targeted agents that interfere with cell
signalling pathways have become established.
Firstly, in women who have had optimally resected disease,
extended follow-up in four randomised trials has shown that
IP chemotherapy with platinums and taxanes is highly
effective in reducing the risk of recurrence and prolonging
survival.8–12 The uptake of IP chemotherapy has been mixed
because of the perceived risk of toxicity and difficulties in
managing intraperitoneal catheters. Despite a general
reluctance to adopt IP chemotherapy in Europe, attitudes
are now beginning to change. The greatest impact of IP
chemotherapy has been seen in patients with minimal
residual disease after debulking surgery.
A second approach emerging from experience in Japan has
been to look at dose-dense schedules with weekly intravenous
carboplatin and paclitaxel. The Japanese data, now with
mature follow-up, show significant benefit to patients who
received dose-dense schedules.13 The downside of this
schedule is that patients need more frequent attendances
for treatment; however, the overall toxicity is lower. The
International Collaborative Ovarian Neoplasm (ICON)
8 studies in the UK are leading the way in efforts to
confirm whether the benefit of dose-dense schedules is
applicable to Western populations. Moreover, the ICON 8B
study will evaluate the addition of bevacizumab, as there are
conflicting data regarding combining dose-dense schedules
with bevacizumab.
Bevacizumab is a monoclonal antibody that targets the
vascular endothelial growth factor (VEGF) receptor. The use
of bevacizumab in front-line treatment was investigated by
the Gynaecological Oncology Group (GOG) 218 and the
ICON 7 studies,14–16 and showed a significant improvement
in progression-free survival. This improvement was seen to
be the most pronounced in women who had residual
macroscopic disease. However, some of the longer term
follow-up data are beginning to show that this benefit stops
when maintenance treatment is complete. Suggestions
regarding longer treatment schedules are being explored by
the AGO (Arbeitsgemeinschaft Gynaekologische Onkologie
Studiengruppe), in order to provide study continuation of
bevacizumab beyond 15 months to 29 months. Based on
recent studies, findings are starting to emerge that show that
certain molecular markers and subtypes may predict which
women are most likely to benefit from bevacizumab.17,18
183
 Update on chemotherapy in gynaecological cancers
Bevacizumab is very expensive and therefore the ability to
select patients most likely to benefit will clearly be useful in
improving cost-effectiveness. Studies investigating this are
still very preliminary but look very exciting. Other agents that
have been investigated in the adjuvant or maintenance setting
include TKIs, such as nintedanib and pazopanib in an
adjuvant setting, and cediranib in a relapsed setting; however,
these agents have not yet been licensed.19,20
Relapsed disease
In patients with relapsed disease, it is important to
distinguish between platinum-sensitive and platinum-
resistant disease. Table 2 shows the definitions of
platinum-free intervals. Platinum-resistant disease is
normally defined as patients who develop recurrent
disease within 6 months of completing their last dose of
platinum. Platinum refractory disease is usually reserved for
patients who develop resistance while receiving
chemotherapy. Therefore, platinum-sensitive disease refers
to patients who develop recurrence beyond six months after
completing their last dose of platinum. In a subgroup of
these patients, known as partially platinum-sensitive,
recurrence occurs between 6 and 12 months. The
importance of this is that for women with platinum-
resistant or refractory disease, retreatment with
conventional agents often has very disappointing results
and even nonplatinum agents such as pegylated liposomal
doxorubicin hydrochloride (PLDH) (CAELYXTM/Doxil -
Johnson & Johnson, New Brunswick, New Jersey, USA) will
have a response rate that is less than 20%. It is therefore an
important area for identifying investigational new drugs and
many clinical trials with new agents are performed in
this setting.
In the late 1980s, Blackledge et al.21 first showed the
importance of the treatment-free interval after platinum
chemotherapy predicting the response to second line
chemotherapy. More recently, however, Markman et al.22
and the French group GINECO23 have shown that beyond
12 months, the rate of response increases with rechallenge
with carboplatin and paclitaxel. Nevertheless, a number of
women have residual neuropathy and this may influence the
treatment options for recurrent disease. Carboplatin with
gemcitabine is an acceptable alternative and two randomised
Table 2. Platinum-free intervals and prognostic groups
Platinum-free interval
0–6 months Platinum-resistant
6–12 months Partially platinum-sensitive
>12 months Platinum-sensitive
184
controlled trials (CALYPSO and the Hellenic Cooperative
Oncology Group) have shown that carboplatin and PLDH
are not inferior to carboplatin and paclitaxel.23,24 In older
and less fit women, single agent carboplatin remains a useful
alternative with reasonable activity. The predicted response
rates are shown in Table 3.
More recent drug developments have included adding
TKIs and VEGF receptor antagonists for treating relapsed
disease, as in first line therapy. The OCEANS study
investigated the use of additional bevacizumab and found
that it appears to show a significant benefit in this setting.25
There is some debate as to whether it is better to use
bevacizumab up front or for relapse, and other debates have
focused on retreating with bevacizumab when there has been
prior exposure in first line. The ICON 6 study showed that
adding cediranib, an oral VEGF receptor antagonist, to
carboplatin and paclitaxel also improves progression-free
survival.26 Cediranib is not yet commercially licensed for
this indication.
Increasingly, patients are treated with multiple lines of
therapy and other agents that may be used include PLDH,
gemcitabine, topotecan and dose-dense platinum schedules
with taxanes or etoposide. Other new targeted agents remain
under development and include folate receptor antagonists,
antiangiogenesis agents and other emerging TKIs. To date,
none of these other agents have been licensed for
this indication.27
Platinum resistance
Since rechallenge with platinum-based regimens has low
response rates, many experts recognise this as an area for
exploring new investigational agents or combinations.
Weekly dose-dense paclitaxel has been accepted by many as
a standard of treatment for patients with platinum
resistance,28 and in the UK this has been used as the
control arm in a number of clinical trials. Again, use of
bevacizumab in these patients in the Aurelia trial shows that
improved progression-free survival can be achieved, and
some have argued that bevacizumab may offer better value in
this setting.29
For partially platinum-sensitive patients, that is those who
experience recurrence within 6–12 months, an international
study with CAELYXTM and trabectedin rather surprisingly
Table 3. Response rates with platinum free interval
Platinum-free interval Response rate
Platinum-sensitive >12 months 40–75%
Partially platinum-sensitive 6–12 months 25–30%
Platinum-resistant <6 months 10–20%
Platinum-refractory <10%
ª 2016 Royal College of Obstetricians and Gynaecologists
 Reed and Sadozye

However, an increased toxicity profile has been reported

Table 4. Response rates to chemotherapy in major trials
when PARP inhibitors are combined with other agents.
PFS OS Ironically, it has also been demonstrated that women with
Study Years Drugs RR % median Median BRCA mutations have a higher response rate to some of the
conventional drugs, in particular the platinums, alkylating
GOG 48 1970–80s A vs 22 3.2 6.7
ACy 30 3.9 7.3
agents and liposomal doxorubicin. This may help to explain
GOG 107 1989–91 A vs 25 3.8 9.2 why in the past there have been patients who have
AP 42 5.7 9.0 unexpectedly continued to show benefit from repeated
GOG 139 1993–96 AP vs AP 49 5.9 13.2 courses of treatment (that is, it could be speculated that
circadian 46 6.5 11.2
GOG 163 1996–99 AP vs 40 7.2 12.6 these patients probably had BRCA mutations).
AT/GCSF 43 6.0 13.6
GOG 177 1998–2000 AP vs 34 5.3 12.3
TAP/GCSF 57 8.3 15.3 Uterine cancer
GOG 209 2003–09 TC vs NA 14.0 32
TAP/GCSF NA 14.0 38 Traditionally, chemotherapy for uterine cancer was reserved
EORTC 1987–1993 A vs 17 7 7 for relapsed disease. Uterine tumours were viewed as
55872 AP 43 8 9 relatively insensitive to chemotherapy and hormonal
A = doxorubicin, Cy = cyclophosphamide: carboplatin, EORTC = therapies with progestogens were the principal treatments.
European Organisation for Research and Treatment of Cancer, More recently, it has been recognised that endometrioid
GOG = Gynaecological Oncology Group, OS = overall survival, P = endometrial cancer and high-grade serous cancers have
cisplatin, PFS = platinum-free survival, RR = response rate, T =
paclitaxel.
similar responsiveness to chemotherapy as their
counterparts in epithelial ovarian cancer. Over the past
30 years, the GOG and the EORTC have led the way with
studies that have demonstrated that adriamycin (A) with
showed that this was superior to CAELYXTM alone. This has platinum (C) was superior to adriamycin alone,33,34 and
led to an application for a licence for this combination in this subsequently, that the addition of paclitaxel (T) to
setting.30,31 Trabectedin, however, is a drug with moderate adriamycin and platinum (TAP) led to improved response
toxicity, which requires a central line and carries a high risk rates (although with additional toxicity) (Table 4).35
of neutropenia and sepsis. Most recently, the use of carboplatin with paclitaxel (TC),
particularly in the community, has become the standard of
BRCA mutation care, both for relapsed disease and in the adjuvant setting,
The ability to identify germline BRCA mutations in women and has the great advantage of substantially lower toxicity
has had a significant therapeutic impact in the past few than TAP.36 For recurrent disease after undergoing previous
years. Previously, while it was important to recognise TC, second line responses are very disappointing. A study
families with the BRCA mutation to facilitate family from the Memorial Sloan Kettering Cancer Center showed
screening, it was not recognised that this would have any zero response rates using doxorubicin.37 It is a clinical
significant bearing on treatment. However, the development scenario that desperately requires new drugs and new agents,
of the PARP inhibitors has led to substantial interest in and conventional agents have so far been disappointing.
investigating these agents, particularly in the maintenance It is recognised that numerous important molecular
setting. Lederman et al.32 showed that in relapsed disease, pathways are disrupted in endometrial cancer, in particular
patients who received a PARP inhibitor had a significantly the mechanistic target of rapamycin (mTOR), phosphatase
longer remission period compared with those who did not. and tensin homolog (pTEN) and the phosphoinositide 3-
Other studies on PARP inhibitors have now been carried kinase (PI 3-kinase).38,39 Therefore, it is not surprising that
out in both the first line and recurrent settings. Olaparib agents that appear to modify these pathways have been
(AstraZeneca, London, UK) was licensed in Europe in 2015 introduced with lower than predicted benefits, as the
and rucaparib (Clovis Oncology, Boulder, Colorado, USA) response rates do not necessarily correlate with
has been identified for fast track development in the USA. demonstrable molecular pathway abnormalities. There is
Rucaparib is most likely to be used as a maintenance continuing interest in using other agents, including target of
treatment in patients with BRCA mutations. It is still very rapamycin 2 (TORC2), dual TORC and PI 3-kinase pathway
early days with regard to the development of these agents inhibitors, and we will keenly follow the progress of these
and it is anticipated that their use will be far wider in efforts. Interestingly, metformin, the oral medication used for
different clinical settings over the next few years. There is diabetes, has also been shown to have significant effects on
emerging evidence that PARP inhibitors combined with these pathways, and further trials are ongoing on the use of
other new agents, such as cediranib, may be effective. metformin in endometrial cancer.40

ª 2016 Royal College of Obstetricians and Gynaecologists 185

 Update on chemotherapy in gynaecological cancers
Cervical cancer
Chemotherapy in cervical cancer has been used most
frequently concomitantly with radiation for primary
treatment. Following the National Cancer Institute
consensus statement in 2000, the use of weekly cisplatin in
combination with pelvic radiation was recommended, and it
has now become the gold standard of care.41 There is some
controversy as to whether the addition of paclitaxel increases
efficacy, but this combination may be more useful
in adenocarcinomas.
Neo-adjuvant chemotherapy for bulky disease has been
shown to be effective in a phase 2 study by McCormack
et al.,42 using a short dose-dense schedule, and we have used
a more conventional three-weekly schedule in women with
tumours greater than 5 cm (unpublished data). The
INTERLACE study is now open and recruiting and will
compare standard concomitant weekly chemotherapy with
cisplatin and pelvic radiation (CCRT) with 6 weeks of dose-
dense induction carboplatin and paclitaxel followed
by CCRT.
Other approaches have explored NACT with platinum and
paclitaxel or paclitaxel, ifosfamide and platinum (TIP)
followed by surgery.43,44 Advocates of this strategy report
good response rates, but one criticism has been that a high
proportion of patients required postoperative radiation,
which was accompanied by higher rates of late morbidity.
The EORTC 55994 study compared standard CCRT against
NACT and surgery. The results of this study are
eagerly awaited.
For relapsed disease, cisplatin was for many years the agent
of choice. Other drugs such as bleomycin, vinca alkaloids,
mitomycin-c and ifosfamide were added, often with very
little additional benefit although they increased toxicity. The
GOG has conducted a number of studies over the past
20 years, including GOG 169, 179, 204 and 240, which
have helped to crystallise optimal regimens for recurrent
disease.45–48 Moore et al.45 also reviewed the prognostic
factors in a meta-analysis of the early GOG experience. It was
shown that cisplatin with paclitaxel was superior to cisplatin
alone. Cisplatin and topotecan appeared to show a benefit
but when cisplatin and paclitaxel, cisplatin and topotecan,
and a nonplatinum schedule of topotecan with paclitaxel
were compared, no advantage over the newer regimens was
shown and cisplatin/paclitaxel has re-emerged as the
preferred standard treatment. Advanced cervical cancer is
thought to induce the release of VEGF and increase hypoxia,
resulting in chemo- and radioresistance. Thus, the GOG 240
study, in which bevacizumab was added to these agents, has
shown a significant improvement in both progression-free
and overall survival,49 leading to bevacizumab becoming
licensed and approved for the treatment of recurrent cervical
cancer. In a small study, cediranib showed a small benefit in
186
relapsed cervical cancer and was associated with a reduction
in VEGF levels in a subgroup of patients whose tumours had
higher levels of expression of VEGF.50 There remains an
outstanding need for new drugs to treat recurrent disease, as
traditional agents have probably reached a plateau. Indeed,
there is widespread interest in exploiting pathways that
influence the consequences of human papillomavirus (HPV)
infection. A recent study has reported a high response rate
with T cell immunotherapy but patient numbers were small
and corroborative data will be needed.51 Other pathways of
interest include the PI 3-kinase pathway and programmed
cell death PD1 (PLD-1).
Vaginal and vulval cancer
Similar to cervical cancer, many vulval and vaginal cancers are
squamous and often HPV-associated. Thus, drugs used in the
treatment of cervical cancer are also used for vulval and
vaginal cancers. For primary treatment, if radiation is used,
concomitant cisplatin will be given, assuming that the patient
is fit enough. For relapsed disease, cisplatin with 5-fluorouracil
(5-FU) have been used, but emerging alternatives are cisplatin
and capecitabine or carboplatin and paclitaxel. If a
nonplatinum schedule is indicated, mitomycin-C and 5-FU
or capecitabine are viable alternatives.
There are some limited reports on using NACT to reduce
tumour size prior to delayed surgery or radiation, although
some have argued that for these large tumours, concomitant
chemoradiation with cisplatin is effective.52,53 Conducting a
clinical trial to evaluate this would be near impossible
because of the relatively small number of cases and
uncertainty of obtaining universal agreement to mount
such a study.
Uterine sarcomas
The term uterine sarcomas includes carcinosarcomas, which
should be managed in exactly the same way as high-grade
uterine carcinomas.54 However, leiomyosarcomas (LMS) are
very different. Active drugs for LMS include doxorubicin,
either alone or combined with ifosfamide, and, more recently,
docetaxel and gemcitabine combinations have emerged.55,56
To date, no study has shown any proven benefit for adjuvant
chemotherapy. Nevertheless, an International Rare Cancer
Initiative (IRCI) study is investigating adjuvant docetaxel and
gemcitabine. High-grade uterine sarcomas are highly lethal
cancers and another IRCI study is investigating adjuvant
cabozantanib (another multitargeted TKI) after doxorubicin-
based schedules.57 Low-grade endometrial stromal sarcomas
are generally more indolent and respond to hormonal
manipulation,58 but may also respond to combinations of
carboplatin and paclitaxel or platinum, doxorubicin
and ifosfamide.
ª 2016 Royal College of Obstetricians and Gynaecologists

Rare tumours
Rare tumours include the nonepithelial ovarian cancers such
as teratomas, sex cord/stromal tumours and miscellaneous
sarcomas. These are generally infrequent and are best
managed in specialist units. In younger women,
consideration should always be given to fertility sparing
surgery. Many of these are included in recent Gynecological
Cancer InterGroup guidelines, published as a supplement by
the International Journal of Gynecological Cancer,59 and in a
textbook on rare gynaecological cancers.60 It is beyond the
scope of this article to cover these rare tumours in
more detail.
Conclusion
Gynaecological cancers require multidisciplinary
management. Chemotherapy may be used as an adjuvant
therapy or for management of locally advanced or recurrent
tumours. Traditional chemotherapy drugs have probably
reached a plateau for development and as in most other
cancers, the way forward is with personalised medicine.
Tumour tissue with identification of the molecular pathways
will be the way forward together with greater use of
recognising the importance of genetic differences as already
shown for ovarian cancer and BRCA mutations.
Contribution of authorship
The authors have prepared this manuscript jointly.
Disclosure of interests
The authors have no direct conflicts of interest and received
no funding for this manuscript. Nicholas Reed has received
travel bursaries and sat on Advisory Boards for Novartis,
Ipsen, Roche, Eisai and AstraZeneca.
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