Accepted Manuscript

Title: Management of patients with recurrent/advanced

cervical cancer beyond first line platinum regimens: Where do
We Stand? A literature review

Author: Stergios Boussios Esmeralda Seraj George

Zarkavelis Dimitrios Petrakis Aristomenes Kollas Aikaterini
Kafantari Abraam Assis Konstantina Tatsi Nicholas Pavlidis
George Pentheroudakis

PII: S1040-8428(16)30321-3
DOI: http://dx.doi.org/doi:10.1016/j.critrevonc.2016.11.006
Reference: ONCH 2270

To appear in: Critical Reviews in Oncology/Hematology

Received date: 9-2-2016

Revised date: 10-10-2016
Accepted date: 14-11-2016

Please cite this article as: Boussios Stergios, Seraj Esmeralda, Zarkavelis George,
Petrakis Dimitrios, Kollas Aristomenes, Kafantari Aikaterini, Assis Abraam, Tatsi
Konstantina, Pavlidis Nicholas, Pentheroudakis George.Management of patients with
recurrent/advanced cervical cancer beyond first line platinum regimens: Where
do We Stand? A literature review.Critical Reviews in Oncology and Hematology
http://dx.doi.org/10.1016/j.critrevonc.2016.11.006

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 Management of patients with recurrent / advanced cervical
cancer beyond first line platinum regimens: Where do We
Stand? A literature review

Stergios Boussios1, Esmeralda Seraj1, George Zarkavelis1, Dimitrios Petrakis1,

Aristomenes Kollas1, Aikaterini Kafantari1, Abraam Assis1, Konstantina Tatsi2,
Nicholas Pavlidis1, George Pentheroudakis1

1
Department of Medical Oncology, Medical School, University of Ioannina, Stavros
Niarchos Avenue, 45500, Ioannina, Greece
2
Gynaecology Unit, General Hospital G. Hatzikosta,Makrigianni Avenue, 45001,
Ioannina, Greece

Correspondencing Author:

Dr Stergios Boussios MD, PhD candidate

Medical Oncologist
Clinical Research Fellow
Department of Medical Oncology, Medical School,
University of Ioannina, Greece
Tel: +30 26510 99394
E-mail: stergiosboussios@gmail.com

Abstract
Background: Cervical cancer is the fourth most common cancer affecting women
worldwide. Despite advances in screening and human papillomavirus (HPV)
vaccination, a significant number of women present with or develop advanced
disease. Palliative platinum-based chemotherapy (CT) is the standard first-line
treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and
effective second line options are urgently needed.

Methods: We searched the English-language medical literature as well as relevant

guideline databases, published from January 1981 to December 2015 and identified
publications related to cervical cancer and its therapies. Our effort was to highlight
the available treatment options in the setting of recurrent/metastatic disease.

Results: Although there have been important advances in the management of

women with cervical cancer, the optimal treatment for patients with locally recurrent
and metastatic disease after platinum failure is still problematic. Overall, there is a
trend in terms of longer overall survival (OS) and better quality of life for the
combination of cisplatin/paclitaxel (PC) as compared to the doublets of
cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC).
Currently available single agents beyond first-line platinum-based therapy
have limited efficacy in this setting and include topoisomerase inhibitors, vinca
alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies
have demonstrated activity in advanced cervical cancer. Bevacizumab has been
evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan
and has been approved in the first-line setting by the U. S. Food and Drug
Administration.
Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs)
may represent a novel therapeutic tool in this setting, but its use alone or in
combination with CT is still investigational. Early reports have implicated PI3KCA
somatic mutations suggesting that mTOR-targeted agents should be explored in this
disease. Development of the immune checkpoint programmed cell death 1 (PD-1)
and T-lymphocyteassociated molecule-4 (CTLA-4) inhibitors have been of
considerable interest, leading to ongoing phase II studies in patients with advanced
cervical cancer.

Conclusions: Progress in the management of recurrent and advanced cervical

cancer patients has been slow and restricted to palliative intent. These patients
should be considered for clinical trials of novel targeted agents and/or
immunotherapy.

Keywords: Cervix, chemotherapy, targeted agents, recurrence

1. Introduction
Data from GLOBOCAN 2012 have demonstrated that cervical cancer is the
fourth most common cancer in females worldwide with an estimated 528,000 cases
diagnosed annually and with 266,000 disease related deaths [1]. In countries with
established screening programmes, the incidence of invasive cervical cancer has
dramatically decreased in comparison with 40 years ago. However, a significant
number of women presenting with either advanced or locally advanced disease is still
present.
Although stage IV disease accounts for only 5% of new diagnoses of cervical
cancer 4, metastatic disease develops in 15-61% of women, usually within the first
two years of completing primary treatment [2]. Surgical resection or radiotherapy may
potentially be curative for selected women with locally recurrent or limited metastatic
disease, however in the majority of cases this will not be feasible. Women with
recurrent and metastatic cervical cancer have limited systemic treatment options and
the prognosis is dismal [2].
For women with recurrent or metastatic disease not amenable to therapy with
curative intent, the goal of treatment is palliation of symptoms and prolongation of
survival with systemic therapy. Among the standard of care regimens in the first-line
setting is combination chemotherapy (CT) with the addition of the anti-vascular
endothelial growth factor (VEGF) monoclonal antibody, bevacizumab [3]. The
landmark phase III GOG240 trial demonstrated an improvement in overall survival
from 13.3 months to 17 months with the addition of bevacizumab to first-line CT
[cisplatin/paclitaxel (PC) or topotecan-paclitaxel] (HR 0.71; 98% confidence interval
[CI], 0.54 - 0.95; p=0.004) [3]. Importantly, the addition of bevacizumab to CT did not
adversely affect health-related quality of life in these women [4]. This significant
improvement in overall survival (OS) with the addition of bevacizumab to first-line CT
is likely to result in a greater number of women needing effective second-line
treatment options.
Patients with metastatic and non-operable recurrent cervical cancer constitute
a high risk population and more research is needed to improve efficacy and reduce
the adverse effects associated with treatment in this setting. There is currently no
standard of care for second-line treatment, and as such, this represents a significant
unmet clinical need. Accruing enough patients to obtain sufficient power to test novel
strategies is a challenge.
The purpose of this study is to highlight advances in systemic treatment
choices, antiangiogenesis therapy and immunotherapy and evaluate the associated
outcome for patients with recurrent/metastatic cervical cancer following first line CT.

2. Literature Search Strategy

The literature in PubMed database and the Cochrane Database of Systematic

Reviews were searched for reports of new or ongoing trials. Relevant articles and
abstracts were selected and reviewed, and the reference lists in those sources and
recent review articles were also searched for additional trials. Publications between
January 1981 and December 2015 in English were eligible for inclusion.

3. Cervical cancer recurrences

Patients with cervical cancer may develop pelvic recurrence, distant
metastases, or a combination of both. The relapse rate of cervical cancer ranges
between 11 and 22% in International Federation of Gynecology and Obstetrics
(FIGO) stages IBIIA and between 28 and 64% in FIGO stages IIBIVA [5]. As the
bulk of a pelvic tumor increases, the proportion of patients with disease recurrent or

persistent in the pelvis as the only site of failure exceeds that of distant metastases.
Perez et al., reported a total pelvic failure rate of 10% in stage IB, 17% in stage IIA,
23% in stage IIB, 42% in stage III, and 74% in stage IVA after radiotherapy alone [6].
The most common extra-pelvic metastases involve para-aortic lymph nodes, lungs,
liver and bones predominantly involving the lumbar and thoracic spine [7, 8].
The management of recurrent cervical cancer depends mainly on previous
therapeutic approaches and on the site and extent of recurrence [5]. The vast
majority of patients receive pelvic radiotherapy at some point during their treatment,
and tumour failure in an irradiated pelvis is usually related to a dismal prognosis.
Cervical cancer recurrences may be central pelvic, lateral pelvic and extra-pelvic [9].
Central pelvic relapse can be located in the vaginal vault or usually involve the
bladder and/or rectum. Lateral pelvic recurrence includes parietal and visceral pelvic
side disease developed above and below the level of the obturator nerve,
respectively.

3.1. Central or lateral pelvic recurrence in patients not primarily received

adjuvant radiotherapy
Radiotherapy or concurrent platinum-based chemoradiation is the gold
standard treatment for patients with pelvic recurrence after radical hysterectomy
alone [10-14]. However, the safe delivery of high doses of radiotherapy in this clinical
setting is demanding as compared to the primary radiotherapy, taking into
consideration that post-surgical adhesions increases the radiation dose to the bowel
[15]. The 5-year survival rates mainly dependent on the site of relapse, ranging from
6 to 77% [16]. Vaginal vault relapses can be treated with external radiotherapy plus
brachytherapy as compared to the nodal disease in which external radiotherapy
alone is the only therapeutic option.

3.2. Central pelvic recurrence in patients previously underwent

radiotherapy
Pelvic exenteration usually represents the only curative treatment for patients
with central pelvic failure who have previously undergone radiotherapy. The 5-year
OS and operative mortality ranged from 21 to 73% and from 1 to 10%, respectively
[17-20]. Long disease-free interval [17], small tumour volume [21] and negative
surgical margins [17, 19, 20] or lymph nodes [20] are factors related with better
prognosis. In terms of pelvic reconstructive procedures performed after exenteration,
an ileocolonic segment is currently constructed for continent urinary diversion [22-
24]. Patients who undergo a supralevator pelvic exenteration are candidates for a low
colorectal anastomosis. However, this approach may be associated to an increased
risk of anastomotic breakdown or fistula in previously irradiated patients [19, 24].
Gastro-intestinal fistulas represent a postoperative event that could be avoided with
the proposed pelvic floor and vaginal reconstruction with myocutaneous flaps [18, 25,
26]. Intra-operative radiotherapy is an additional approach particularly in the
presence of microscopically positive margins on frozen-section evaluation [27].

3.3. Lateral pelvic recurrence in patients previously underwent radiotherapy

In case when recurrent disease involves the pelvic side wall and the primary
treatment included chemoradiation or surgery followed by adjuvant radiotherapy,
then palliative CT is a reasonable option due to limitations of exenteration in this
setting. Lopez-Graniel et al., [28] evaluated the use of neoadjuvant CT prior to
exenteration in this subset of patients, with the aim of shrinking the pelvic tumour and
allowing a subsequent pelvic exenteration. Nine out of 17 patients (53%) who
responded to platinum-based CT underwent pelvic exenteration and 4 of them

achieved a pathological complete response (CR), reflected in improved median

survival of 32 months. Further investigations and randomised controlled trials are
required to demonstrate the therapeutic potential of this approach.

3.4. Isolated para-aortic recurrence

The incidence of isolated para-aortic recurrence after definitive treatment of
cervical cancer ranges from 2 to 12% [29] and is associated with dismal prognosis
[30]. Nevertheless, concurrent chemoradiation may influence favourably the clinical
outcome especially in asymptomatic patients with an isolated para-aortic failure [29,
30].

4. CT for recurrent or advanced cervical cancer

For the vast majority of patients with recurrent or metastatic disease, palliative
CT represents the only treatment option [Tables 1, 2 and 4]. Historically, cisplatin has
been considered as the most active agent [31]. Although PC has shown no
significant OS advantage as compared to cisplatin alone, this combination has
resulted in a doubling of both response rate (RR) and median PFS with tolerable
toxicity [32, 33].

4.1. Platinum-based combination regimens

The GOG trial 204 compared the doublets of PC, cisplatin/vinorelbine (VC)
and cisplatin/gemcitabine (GC) with the combination of cisplatin/topotecan (TC) in
this clinical setting [33]. There was no significant difference in survival among the
different arms, with a trend in favour of PC doublet that was also associated with a
better quality of life. The median OS for the reference PC arm was 12.87 months as
compared to 9.99 for VC, 10.28 for GC, and 10.25 for TC respectively. The median
PFS was 5.82 months for the PC, 3.98 for the VC, 4.70 for the GC, and 4.57 for TC
respectively [Table 1]. Overall, VC, GC, and TC were not superior in terms of RR,
OS, and PFS as compared to PC. Analysis of prognostic factors revealed that age
was not a significant factor. Performance status appeared to be the strongest
prognostic factor detected for both OS and PFS.
The combination of TC as compared to single-agent cisplatin showed an
improvement in overall RR and PFS [34]. On the other hand, 78% of patients
required hospital admissions for supportive care and management of toxicities.
Kitagawa et al., [35] conducted a randomized phase III trial, and
demonstrated the inferiority of the combination of carboplatin and paclitaxel to PC in
terms of PFS and OS [Table 1]. Treatment benefit was more evident with PC in
patients not previously treated with platinum-based CT. On the other hand, the
combination of carboplatin and paclitaxel was the treatment of choice in the subgroup
of patients exposed to platinum compounds, underlining the possibility of non-cross-
resistance of cisplatin analogue with cisplatin.
Pemetrexed a third-generation antifolate combined with cisplatin has
demonstrated activity in the treatment of recurrent cervical carcinoma [36, 37]. In a
phase II GOG trial [GOG-0076GG], 54 patients with advanced, persistent, or
recurrent disease were treated with the doublet and assessed with regard to the
objective tumor response, including partial response (PR) and CR [38]. The regimen
was well tolerated with 26% of patients receiving more than nine cycles. One out of
54 patients achieved CR and 16 PR with the total ORR of 31%. The RR for non-
irradiated disease sites was 38% (95% CI, 23.8% to 53.5%; 17 of 45). The median
PFS and OS was 5.7 months and 12.3 months, respectively [Table 1].

 Cisplatin-based three- or four-drug regimens are not associated with better

clinical response as compared to cisplatin-containing doublets or single-agent
cisplatin in the setting of persistent or recurrent cervical cancer [39-43]. Nevertheless,
the combination of ifosfamide, paclitaxel and cisplatin (TIP regimen) obtained a
significantly higher pathological optimal RR compared to the doublet of ifosfamide
and cisplatin in patients with locally advanced squamous cell cervical cancer treated
in neoadjuvant setting [44]. Even so, three phase II trials demonstrated RR of 46
67% for TIP in patients with recurrent or persistent disease, which is in accordance
with those achieved with cisplatin-based doublets [39-41]. Patients with excellent
performance status, non squamous tumors and recurrent disease only outside the
previous radiotherapy field, exhibited the higher response which was not always
statistically significant. [Table 1].

4.2. Second line CT with single agents

Patients who have progressed after platinum-based therapy could be treated
with second-line regimens, included in clinical studies or receive best supportive care
measures. Phase II studies with single agents have demonstrated rather modest
efficacy [Table 2]. Overall, the responses are partial and have short duration, with a
median OS not exceeding 15.5 months. Higher RR have been reported for lesions in
previously unirradiated areas. Cisplatin is still an option as active monotherapy in
recurrent or metastatic cervical cancer with an ORR ranging between 13% and 23%
[34, 45]. Irinotecan is also a reasonable approach with ORR of 21-24% [46, 47].
The potential role of fluoropyrimidines has been validated. Several phase II
trials produced unclear results as regarding the efficacy of capecitabine in this setting
[48-50]. On the other hand, S-1 - an oral fluoropyrimidine - is associated with
remarkable activity [51]. The reported ORR for the patients who had previously
received platinum-based treatment including chemoradiotherapy was 31.8%; the
median PFS and OS were 5.2 and 15.4 months, respectively. Interestingly enough, a
randomized phase III study evaluating the efficacy and safety of the combination of
S-1 with cisplatin versus cisplatin monotherapy in patients with metastatic, or
relapsed cervical carcinoma is due to be completed [52].
Administration of topotecan, vinorelbine and pemetrexed as second line
treatment resulted in RR ranging between 10 and 18% [53-58], 7-14% [59, 60] and
14-15% [61, 62], respectively. Docetaxel and gemcitabine have minimal activity of
9% [63] and 4.5-8% [64, 65], respectively. The use of new chemotherapeutic agents,
should be further investigated in the salvage setting.

4.3. Vascular endothelial growth factor (VEGF)-dependent tumor

angiogenesis
Tumor neovascularization is related to the extent of cervical cancer and
affects inversely survival. Elevated microvessel density and strong
immunohistochemical expression of the endothelial cell marker, CD31, indicate a
poor outcome [66]. High-grade cervical dysplasia and invasive carcinomas are
associated with increased expression of VEGF and hypoxia-inducible factor 1 (HIF-
1) [67]. Under hypoxic conditions HPV oncoproteins form a complex with HIF-1
and enhance both hypoxia-induced HIF-1 as well as VEGF expression.
Bevacizumab as a single agent, has shown activity in heavily pretreated and
relapsed patients [68, 69].
GOG 240, phase III four-arm randomized trial, investigated the addition of
bevacizumab to either platinum-based or nonplatinum-based combination regimen
in patients with advanced or recurrent cervical cancer [3]. Patients were randomly

assigned to one of four treatment arms. Control treatment consisted of PC and non-
platinum combinations with topotecan and paclitaxel. Each of these regimens was
evaluated with or without bevacizumab. As compared with PC (either with or without
bevacizumab), the non-platinum doublet was associated with a significantly higher
risk of progression (hazard ratio [HR], 1.39), although this appears to have no
adverse impact on OS (HR for death, 1.20). Treatment with PC and bevacizumab, as
compared to PC alone, provided an estimated HR for death of 0.68. RR were 50%
and 45% for the combined arm and CT arm respectively (P = 0.51, two-sided test).
Topotecanpaclitaxelbevacizumab, as compared to topotecanpaclitaxel alone,
showed a HR for death of 0.74. The estimated RR were 47% and 27% for the
bevacizumab arm and CT arm respectively (P = 0.002, two-sided test).
In summary, the bevacizumab-containing regimens were associated with a
reduced hazard of disease progression and substantially prolonged OS, including
previously irradiated pelvic lesions. On August 14, 2014, the U. S. Food and Drug
Administration approved bevacizumab in combination with paclitaxel and either
cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical
cancer based on the results of this study.

4.4. Epidermal growth factor receptor (EGFR) inhibition in cervical cancer

Beyond antiangiogenesis compounds, monoclonal antibodies and TKIs
targeting the EGFR as well as human epidermal growth factor receptor 2
(HER2/neu), represent a challenging area of clinical practice in cervical cancer [70,
71]. Bellone et al., found that the obtained primary cervical cancer cell lines from
cervical biopsies and recurrent sites of disease expressed EGFR-1 [72]. Overall, the
expression of EGFR in cervical cancer, varies from 6% to 90% and together with the
overexpression of HER2/neu is related to dismal prognosis in this population [72-74].
HPV is the primary etiologic agent of cervical cancer. EGFR expression is associated
with HPV infection taking into consideration the prominent EGFR cytoplasmic
expression with high grade of intraepithelial neoplasia but seems not to be correlated
with the HPV subtype [75].
A randomized, open-label, phase II trial compared the concurrent
administration of pazopanib in metastatic or recurrent patients [76]. This study
illustrated the activity of pazopanib based on the prolonged PFS (HR 0.66; P =
0.013), OS (HR, 0.67; P = 0.045) and the acceptable toxicity. PFS was shorter in the
subgroup of patients treated with lapatinib as compared to those who received
pazopanib (17.1 and 18.1 weeks respectively). Median OS was improved by 11.6
weeks (50.7 versus 39.1) while RRs were 9% and 5%, respectively. The toxicity in
the combination arm resulted into the discontinuation of treatment. The lack of
efficacy with combination therapy may also be the consequence of the antagonistic
interaction between the agents.
Two other GOG studies investigating EGFR-based therapies had negative
results. Cetuximab, a chimeric human-murine monoclonal antibody targeting EGFR,
added to intravenous cisplatin in persistent or recurrent cervical cancer, was
associated with increased toxicity and an estimated RR of only 9% [77]. In another
phase II trial, treatment with doublet of cisplatin and topotecan combined with
cetuximab was withheld due to unacceptable toxicity although ORR reached 32%
[78]. Eventually, previous treatments and poor performance status are factors that
may contribute to the observed toxic effects. A randomized phase II trial evaluating
carboplatin and paclitaxel with or without cetuximab, in recurrent cervical cancer
(ClinicalTrials.gov identifier: NCT00997009), is still ongoing.
Erlotinib, an EGFR TKI, was also selected by the GOG for evaluation in
patients with recurrent cervical squamous cell cancer. No objective responses were

observed and only one patient (4%) achieved progression free interval longer than 6
months [79]. Studies evaluated gefitinib [80] and imatinib [81] in recurrent disease did
not obtain objective response. Gefitinib achieved stabilization in 20% of the evaluated
30 patients with disease resistant to standard treatment [80]. The rationale for
imatinib was based on the expression of the PDGFR [82]. These results are
expected taking into account the lack of mutations on exons 1821 [83, 84] and the
lack of c-kit on cervical cancer cells [85].

4.5. PI3K/Akt/mTOR pathway

Targeting the PI3K/AKT/mTOR pathway has emerged as a rational
therapeutic strategy in several cancers and its activation represents a common
feature of nearly all HPV-associated squamous cell carcinomas of the cervix.
Interestingly enough, inhibition of mTOR activity blocks cervical cancer cell growth
[86-88]. When phosphorylated by mTOR, the overexpressed downstream regulators
P70S6K [89] and 4EBP1 [90] may enhance translation of mRNAs encoding proteins
involved in cell cycle proliferation [90]. The rapalogs, a class of agents which include
temsirolimus, target the mTOR pathway by partially inhibiting MTORC1, part of the
MTOR complex, which is activated in most HPV-associated squamous cell
carcinomas, including cervical carcinomas. Temsirolimus can be used as a single
agent in a neoadjuvant setting. It may also reduce the dose of radiation/CT required
for local control, or delay tumor recurrence after conventional surgical excision with
or without chemoradiation either. The toxicity profile is favourable and includes
mucocutaneous toxicity such as mucositis, rash, and diarrhoea and fatigue, anorexia,
neutropenia, thrombocytopenia, hyperglycaemia, and hyperlipidaemia either.
A 2-stage phase II study evaluated the activity of the mTOR inhibitor
temsirolimus, in patients with metastatic or recurrent cervical carcinoma [91]. One out
of the 38 enrolled patients achieved PR (3.0%), and 19 patients experienced stable
disease (SD) (57.6%) with a median duration of 6.5 months (range 2.412.0). The
estimated 6-month PFS rate and median PFS was 28% (95% CI: 1443%) and 3.52
months [95% CI (1.814.70)] respectively. These data demonstrated that
temsirolimus had no activity in this population of patients.

4.6. Viral oncogenes E6 and E7 and therapeutic vaccines

Significant advances have been achieved in recent years regarding
immunotherapy in oncology. It has been suggested that HPV-negative cervical
cancers may represent a biologically distinct subgroup of tumours that negatively
affect patients outcome than HPV-positive types [92]. Nevertheless, the significance
of HPV-negativity in cervical cancers is rather unclear but more frequently found in
adenocarcinomas [93-96]. It has been detected that some subtypes of
adenocarcinomas are commonly HPV-negative, including minimal deviation
adenocarcinoma, gastric-type, clear-cell, serous, and mesonephric
adenocarcinomas. A recent study evaluating 760 cervical adenocarcinomas has
concluded that over 80% of these tumours are of the conventional or mucinous type,
whereas non-mucinous variants are rare. Indeed, 30% of the conventional mucinous
tumours were HPV-negative [97].
Two HPV16 proteins, E6 and E7, are consistently expressed in tumor cells,
and promote cell replication and immortalization. Most therapeutic vaccines target
one or both of these proteins. Due to safety and no human leukocyte antigen
restriction, protein vaccine is considered the most popular type of HPV therapeutic
vaccines.

 Identification of T cells that target cervical cancer HPV oncoproteins, following

by enrichment and ex vivo expansion, attempt toward attack of cervical tumors that
have not been immunologically targeted previously. A recent study assessed the
HPV-targeted tumor-infiltrating lymphocyte therapy in patients diagnosed with
metastatic cervical cancer who had previously received platinum-based CT or
chemoradiotherapy [98]. T cells collected from tumor tissue were cultured. The most
reactive for HPV viral protein E6 and E7 cultures were evaluated and expanded T
cells were infused into the patient. The HPV reactivity of T cells in the infusion
product correlated positively with clinical response. Similarly, the frequency of HPV-
reactive T cells in peripheral blood one month after treatment was positively
associated with clinical response. Three out of nine patients who received tumor-
infiltrating lymphocytes responded completely or partially (2 and 1 out of nine patients
respectively).
Another challenge of treating persistent or recurrent cervical cancer is live
attenuated Listeria monocytogenes-based immunotherapy (ADXs11-01), intended to
create a T helper type 1 immunologic response [99]. In a phase 2 study, patients who
underwent previously CT, radiotherapy, or both were randomized to either 3 or 4
dosages of ADXS11-001 combined with cisplatin [100]. The achieved 18- and 12-
month survival was 28% and 36%, respectively. ORR was 11%, with an average
duration of 10.5 months after 1 cycle of ADXS11-001. Prior therapy, baseline
performance status, and the combination with cisplatin had no impact on survival or
response. Current studies are required to determine the optimal dosage and, whether
the inclusion of multiple cycles of ADX11-001, combined or not with other agents,
could be implemented as an active agent against recurrent cervical cancer.

4.7. Emerging immunotherapies

Based on these data, other immunotherapies such as ipilimumab and
nivolumab are currently under evaluation in phase 2 clinical trials [101-104]. These
agents are monoclonal antibodies that target and block the CTLA-4 and, the PD-1
receptors respectively that are negative regulatory molecules [105], on the T-cell
activation. The CTLA-4 receptor outcompetes CD28 for binding to B7 on antigen-
presenting cells, and functions as an immune checkpoint molecule [105]. Similarly,
when PD-1 binds to its ligand PD-L1, the ability of the activated T cell to stimulate an
effective immune response is decreased [105]. The roles of CTLA-4 and PD-1 in
immune modulation are nonredundant and do not overlap [106]. Inhibition results in
compromised activation and suppressed effector functions such as proliferation,
cytokine secretion, and tumor cell lysis that block immune checkpoints. Overall,
breaking of immune tolerance may represent a robust strategy to overcome immune
suppression and improved outcome as compared to short-lived immune-activating
approaches could be achieved. Further studies are required.

5. Comparison of treatment outcomes between squamous cell carcinomas

and adenocarcinomas
Adenocarcinoma of the cervix accounts for approximately 2025% of all
cervical malignancies. In general, patients with this histologic subtype of cervical
cancer undergo the same first-line treatment as those with squamous cell
carcinoma, which is the most common histopathologic subtype. However, it is
uncertain whether the treatment strategies should be the same.

 The difference in survival outcomes of squamous cell carcinomas and

adenocarcinomas of the uterine cervix is still controversial. Lee et al., reported
that adenocarcinomas are associated with worse OS compared to squamous cell
carcinomas in the era of platinum-based chemoradiation [107]. In a study by Chen et
al, 56.8 % of patients received chemoradiation (60 % in adenocarcinomas and 56.2
% in squamous cell carcinomas), and the results showed that the treatment response
was significantly higher in squamous cell subtype as compared to adenocarcinomas
(87.1 vs. 71.4%, p = 0.018) [108]. It has not been elucidated whether patients with
cervical adenocarcinomas have a higher incidence of pelvic lymph node involvement
compared to those with squamous cell carcinomas. Probably, the worse outcome of
patients with adenocarcinomas is due to ineffective adjuvant treatment, rather than a
higher incidence of lymph node involvement as compared to squamous cell
carcinomas. Furthermore, in a multicenter retrospective study, the outcome of
patients with stage I disease did not differ between adenocarcinomas and squamous
cell carcinomas [109]; however, patients with cervical adenocarcinoma exhibited a
significantly worse outcome compared to those with squamous cell carcinoma in
stage II. Indeed, when adjuvant treatment was administered, patients with
adenocarcinomas had a significantly worse outcome as compared to those with
squamous cell carcinomas (73.7 vs. 83.1%, respectively; P=0.0368). Interestingly
enough, among patients not receiving adjuvant treatment, those with
adenocarcinomas exhibited a similar 5-year overall survival rate as compared to
those with squamous cell carcinomas (93.1 vs. 94.0%, respectively; P=0.9497).
Studies have suggested the potential mechanism of radioresistance in
cervical adenocarcinomas. Cyclooxygenase-2 (COX-2) was more frequently
expressed in adenocarcinomas than in squamous cell subtype and may be a
predictor of treatment response [110]. Complete response was found in all patients
with COX-2negative disease, and COX-2 expression was an independent
prognostic factor for patients received radiotherapy [110].
PD-L1 is more frequently expressed by squamous cell carcinoma than by
adenocarcinoma. Diffuse PD-L1 expression in squamous cell carcinoma patients is
correlated with poor disease-free survival and disease-specific survival compared
with marginal PD-L1 expression, which is associated with a remarkably favorable
prognosis. In adenocarcinoma, there is a survival benefit for patients with tumor
lacking PD-L1-positive tumor-associated macrophages. These findings point to a
difference in immunological microenvironments and tumor escape mechanisms
between cervical adenocarcinoma and squamous cell carcinoma.

6. Perspective on treatment of patients with recurrent / advanced cervical

cancer beyond first line platinum regimens
The international standard or care for locally advanced cervical cancer is
platinum-based chemoradiation [111]. The 5-year survival rates remain poor at 55%,
35% and 15% for FIGO stages II, III and IVA, respectively [112]. For
recurrent/metastatic disease, the treatment is usually systemic anti-cancer therapy
with palliative intent. The RR after previous cisplatin-based chemoradiation are worse
as compared to CT nave patients [113, 114]. Palliative platinum-based CT, with the
aim of prolonging survival and maintaining quality of life, is the first-line standard
treatment of choice for metastatic/recurrent cervical cancer and is associated with an
OS not exceeding 19 months. Some randomized trials for recurrent and advanced
cervical cancer reported a RR of 31% to 36% for a platinum-based combination
treatment [32-34, 39, 115] [Table 1]. Tewari and Monk reported the impact of prior
platinum exposure in this setting. The RR in platinum nave patients was 20% in
cisplatin monotherapy, 39% in TC, and 37% in PC combination CT. The respective

10

RR after previous cisplatin based exposure was estimated 5% to 8% in cisplatin

monotherapy, and 15% and 32% in the combination of cisplatin with topotecan and
paclitaxel respectively [116]. These results recommend that a history of platinum
exposure could be an indicator in predicting the response of second-line systemic
treatment, and that platinum combination CT is likely to be more effective as
compared to cisplatin monotherapy for patients initially treated with platinum. Results
from the phase III Gynecologic Oncology Group-0240 (GOG)-0240 trial demonstrate
that the addition of bevacizumab to first line combination CT in patients with
recurrent, persistent, or metastatic cervical cancer was associated with a 3.7 months
improvement in median OS [3].
First line platinum-based CT are frequently short-lived and effective second-
line options are urgently needed. Chemotherapeutic agents associated with response
include paclitaxel, docetaxel, irinotecan, topotecan, etoposide, vinorelbine,
ifosfamide, pegylated liposomal doxorubicin, gemcitabine, capecitabine, S-1 and
pemetrexed [Table 2]. However, the median progression-free survival (PFS) and OS
are approximately 2-5 and 5-16 months, respectively.
There is increasing interest in the role of immunotherapy in advanced cervical
cancer, particularly since the causative role of HPV is well established. A number of
immunotherapy trials have been undertaken evaluating vaccine-based therapies,
adoptive T-cell therapy and immune-modulating agents in patients with advanced
cervical cancer [117]. In particular, there has been a surge of interest in immune-
checkpoint inhibitor therapy, due to the recent success of these agents in advanced
melanoma, non-small cell lung cancer, and renal cancer [118-125]. This could
potentially lead to further advancements in the treatment of locally advanced,
recurrent, or metastatic cervical cancer.
The results from a recent study involving next-generation sequencing, in situ
hybridization, and immunohistochemistry of 592 cervical cancer specimens may help
guide therapy in clinical trials of novel agents for women who have progressed
following first-line therapy [126]. Next-generation sequencing of 224 tumour samples
identified mutational hotspots corresponding to PI3KCA (26%), BRCA2 (21%),
BRCA1 (10%), KRAS (10%), TP53 (10%), and FBXW7 (10%). Gene amplification of
EGFR (11%) and HER2 (8%) was also demonstrated. These results suggest that
poly ADP ribose polymerase (PARP) inhibition, PI3K/AKT/mTOR pathway inhibitors,
EGFR- and HER2-directed therapy, may be promising areas for future research in
advanced cervical cancer. In this regard, the participation in clinical trials could be the
key element for the development of new strategies in the treatment of locally
advanced, recurrent, or metastatic cervical cancer.

7. Conclusions
There is currently no consensus on the standard of care for second-line
systemic treatment of recurrent/metastatic cervical cancer and as such, this
represents a significant unmet clinical need. So far, there is no evidence that
treatment in the second-line setting improves OS compared to best supportive care.
However, women in this situation are often symptomatic and relatively young.
Treatment options that offer improvement in disease-related symptoms, quality of life
and prolongation of PFS are worthwhile. More clinical trials are needed in this area
and patients should be considered for early clinical studies whenever feasible,
including phase I/II trials of novel targeted agents and immunotherapy.

11

Conflict of interest
The authors declare no conflict of interest.

Acknowledgements
Dr. Boussios is clinical research fellow funded by the University of Ioannina
and the department of Medical Oncology.

12

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Table 1: Summary of reported platinum-based combination regimens for recurrent / advanced

cervical cancer
Year of ORR PFS OS
Author Agent N
publication (%) (months) (months)
Cisplatinpaclitaxel
229 38.9 7.6 15.0
bevacizumab
Cisplatintopotecan
223 28.7 5.7 12.5
Tewari KS [3] 2014 bevacizumab
Cisplatinpaclitaxel 114 21.4 NS 14.3
Cisplatinpaclitaxel +
115 43.4 NS 17.6
bevacizumab
Cisplatin 19 2.8 8.8
Moore DH [32] 2004 280
Cisplatin paclitaxel 36 4.8 9.7

Cisplatin paclitaxel 103 29.1 5.8 12.9

Cisplatin vinorelbine 108 25.9 4.0 10.0
Monk BJ [33] 2009
Cisplatin gemcitabine 112 22.3 4.7 10.3
Cisplatin - topotecan 111 23.4 4.6 10.3
Cisplatin 146 13 2.9 6.5
Long HJ [34] 2005
Cisplatin topotecan 147 27 4.6 9.4

Cisplatinpaclitaxel 121 6.9 18.3

Kitagawa R [35] 2012 NS
Carboplatin-paclitaxel 123 6.2 17.5
Miller DS [38] 2014 Cisplatinpemetrexed 54 31 5.7 12.3
Cisplatin ifosfamide 32 4.6 8.5
Bloss JD [39] 2002 Cisplatin ifosfamide 303
31 5.1 8.4
bleomycin
Zanetta G [40] 1999 TIP 45 67 NS 6-13
Dimopoulos MA
2002 TIP 60 46 8.3 18.6
[41]
Choi CH [42] 2006 TIP 53 46.7 8 19
van Luijk IF [43] 2007 BEMP 161 45 NS NS
Cisplatin 18 3.2 6.1
Omura GA [115] 1997 454
Cisplatin ifosfamide 31 4.6 7.1

Vermorken JB Cisplatin 144 25 4.5 9.3

2001
[127] BEMP 143 42 5.3 10.1
Cisplatin and
Mannel RS [128] 2000 44 9 NS 6
pentoxifylline
Vermorken JB
2000 VBMP 50 40 4,4 8,6
[129]
Wagenaar HC
2001 Cisplatin mitomycin-C 33 42 5 11.2
[130]

24

NS, indicates not stated; OS, overall survival; ORR, objective response rate; PFS, progression free survival;
TIP,paclitaxel, ifosfamide and cisplatin; BEMP, bleomycin, vindesine (Eldisine), mitomycin C and cisplatin;
VBMP, vincristine, bleomycin, mitomycin C and cisplatin

25

Table 2: Summary of reported second line single agents for recurrent / advanced cervical cancer
Year of ORR PFS OS
Author Agent N
publication (%) (months) (months)
Cisplatin 190 23 NS NS
Thigpen T [45] 2003
Ifosfamide 35 14-40 NS NS
Takeuchi S [46] 1991 Irinotecan 55 24 NS NS
Verschraegen CF [47] 1997 Irinotecan 42 21 NS NS
Garcia AA [48] 2007 Capecitabine 26 15.4 2.9 5.9
Look KY [49] 2008 Capecitabine 21 0 NS NS
Lorvidhaya V [50] 2010 Capecitabine 45 2 4.1 9.3
Katsumata N [51] 2011 S-1 36 31.8 5.2 15.4
Bookman MA [53] 2000 Topotecan 45 12.5 2.1 6.6
Noda K [54] 1996 Topotecan 22 18 NS NS
Abu-Rustum NR [55] 2000 Topotecan 12 17 NS NS
Nascimento de Oliveira [56] 2013 Topotecan 21 10 2.93 4.66
Coronel J [57] 2009 Topotecan 18 NS 3.5 7.0
Fiorica JV [58] 2009 Topotecan 25 NS 2.4 6.2
Muggia FM [59] 2004 Vinorelbine 44 13.7 NS NS
Muggia FM [60] 2005 Vinorelbine 28 7.1 NS NS
Miller DS [61] 2008 Pemetrexed 29 15 3.1 7.4
Lorusso D [62] 2010 Pemetrexed 43 13.9 2.5 8.8
Garcia AA [63] 2007 Docetaxel 27 8.7 3.8 7.0
2005 Gemcitabine 22 4.5 2.1 6.5
Schilder RJ [64, 65]
2000 Gemcitabine 24 8 1.9 4.9
Thigpen T [131] 1981 Cisplatin 12 17 NS NS
Pegylated
2006 liposomal 26 11 NS NS
doxorubicin
Rose PG [132-134]
1996 Altretamine 29 0 NS 4.6

1998 Etoposide 24 8 NS 3.7

Curtin JP [135] 2001 Paclitaxel 41 32 NS 7.3
1993 Ifosfamide 39 15 NS 4.2
Sutton GP [136, 137]
1989 Ifosfamide 27 11 NS NS
Vermorken JB [138] 1991 DAC 15 0 NS NS

26

 van der Burg ME [139] 1992 4'-epidoxorubicin 24 4.2 3.2 NS

NS, indicates not stated; OS, overall survival; ORR, objective response rate; PFS, progression free survival; DAC,
5-aza-2'-deoxycytidine

27

Table 3: Summary of reported second line novel agents for recurrent / advanced cervical
cancer
Year of ORR PFS OS
Author Agent N
publication (%) (months) (months)
Monk BJ [68] 2009 Bevacizumab 46 10.9 3.4 7.29
Lapatinib 78 5 4.3 9.8
Monk BJ [76] 2010
Pazopanib 74 9 4.5 12.6
Farley J [77] 2011 Cisplatin cetuximab 44 9 NS NS
Cisplatin topotecan
Kurtz JE [78] 2009 19 32 5.7 7.3
cetuximab
Schilder RJ [79] 2009 Erlotinib 28 0 1.87 4.96
Goncalves A [80] 2008 Gefitinib 28 0 1.23 3.56
Candelaria M [81] 2009 Imatinib 12 0 NS NS
Tinker AV [91] 2013 Temsirolimus 38 3 3.52 NS
Stevanovi S [98] 2015 HPV-TILs 9 33.3 NS NS
Basu P [100] 2014 Cisplatin ADXs11-01 110 11 NS NS
Mackay HJ [140] 2010 Sunitinib 19 0 3.5 NS
Santin AD [141] 2011 Cetuximab 38 0 1.97 6.7
Hertlein L [142] 2011 Cetuximab 5 0 NS 8.6
NS, indicates not stated; OS, overall survival; ORR, objective response rate; PFS, progression
free survival; TILs, tumor-infiltrating T cells

Table 4: Summary of reported non-platinum-based combination regimens for recurrent /

advanced cervical cancer
Year of ORR PFS OS
Author Agent N
publication (%) (months) (months)
Topotecan
111 24.3 NS 12.7
paclitaxel
Tewari KS [3] 2014 Topotecan
paclitaxel + 112 42 NS 16.2
bevacizumab
5-FU and
1996 45 9 NS NS
Leucovorin
Look KY [143, 144]
Isotretinoin and
1998 34 3 NS 3.9
interferon alfa
NS, indicates not stated; OS, overall survival; ORR, objective response rate; PFS, progression
free survival

28