Gynecologic Oncology 133 (2014) 117–123

Contents lists available at ScienceDirect

Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Review

A systematic review comparing cisplatin and carboplatin plus

paclitaxel-based chemotherapy for recurrent or metastatic
cervical cancer
Domenica Lorusso a, Fausto Petrelli b,⁎, Andrea Coinu b, Francesco Raspagliesi a, Sandro Barni b
a
Gynecologic Oncology Unit, Fodazione IRCCS National Cancer Institute, Via Venezian 1, 20133 Milan, Italy
b
Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio, BG, Italy

H I G H L I G H T S

• Platinum-taxane combinations are active agents in advanced cervical cancer.

• Which of cisplatin or carboplatin is the better platinum agent when combined with paclitaxel is a matter of debate.
• We report a review of cisplatin- vs carboplatin-taxane studies that confirms similar outcome for the two doublets.

a r t i c l e i n f o a b s t r a c t

Article history: Introduction. The prognosis of advanced/recurrent cervical cancer patients is generally poor with 1-year
Received 27 November 2013 survival ranging between 15 and 20%. Cisplatin (CDDP) based treatments are considered the most effective
Accepted 23 January 2014 regimens; unfortunately toxicity is an issue in a population in which the treatment remains palliative in the
Available online 31 January 2014 finality. Carboplatin (CBDCA), with its more favorable non toxicity profile and the convenience of outpatient
administration, may be a suitable alternative to CDDP in combination regimens.
Keywords:
Materials and methods. We performed a systematic review of the literature comparing CDDP and CBDCA
Advanced cervical cancer
Carboplatin
based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies
Cisplatin that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel
Paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the
Chemotherapy following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP),
overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled.
Results. 17 eligible studies comprehensive of 1181 patients were included in the final analysis. The objective
RR was 48.5% for CBDCA and 49.3% for CDDP-based chemotherapy. Median PFS for CDDP and CBDCA-based
treatments was 6.9 months and 5 months respectively (p = 0.03); the corresponding figures for median OS
were 12.87 and 10 months respectively (p = 0.17).
Discussion. Our study indicates that CBDCA may represent an attractive and valid alternative to the more toxic
and equally effective CDDP in the treatment of advanced or recurrent cervical cancer.
© 2014 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Literature search and study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Objective RR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Progression free survival or TTP and OS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

⁎ Corresponding author at: Piazzale Ospedale 1, 24047 Treviglio, (BG), Italy. Fax: +39 0363424380.
E-mail address: faupe@libero.it (F. Petrelli).

0090-8258/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ygyno.2014.01.042
118 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123

Subgroup analysis according to previous CDDP exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Comparison of CBDCA/paclitaxel with CDDP/paclitaxel combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Factors predictive of survival of platinum-paclitaxel combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Introduction Study selection

Cervical cancer is still a leading cause of cancer-related death in
women, accounting for 14% of all deaths due to gynecologic cancers
worldwide [1]. Although several advances in screening, diagnostic
and treatment modalities have been made, the overall prognosis of
cervical cancer has not changed dramatically, and the mortality
still approaches 50%. The treatment of choice of cervical cancer is
represented by radiotherapy or surgery for early stage disease and
concurrent chemoradiation for advanced stage patients. Chemo-
therapy remains an option for metastatic patients (FIGO stage IVB)
or persistent/recurrent disease after primary treatment not suitable
for curative surgery or radiotherapy. The prognosis of advanced/
recurrent patients generally remains poor with 1-year survival
ranging between 15 and 20% [2]. Single agent cisplatin (CDDP) is
considered the most active agent in the treatment of advanced/
recurrent disease [3], and the combination of CDDP-paclitaxel (P)
has been reported to be better to CDDP monotherapy in terms of
response rate (RR), progression free survival (PFS) but not overall
survival (OS) [4]. The recently closed GOG 204 moreover reported
CDDP-P as the most active combination in the treatment of ad-
vanced or recurrent cervical cancer [5] thus confirming the treat-
ment as the new standard of care in advanced cervical carcinoma.
Unfortunately, the toxicity of the treatment and the discomfort of
the schedule, with P given as 24-hour infusion in order to minimize
neurologic toxicity, make the combination hardly to propose in a
setting of disease where, despite the improved clinical outcomes,
all treatments remain palliative in the finality. In this context,
CBDCA, with its more favorable toxicity profile and the convenience
of the outpatient administration, may be a suitable substitute of
CDDP in combination regimens. In ovarian cancer, CBDCA has been
reported to be equally effective than CDDP but better tolerated
[6,7]. Recently a randomized JCOG phase III trial on stage IVB,
persistent or recurrent cervical cancer reported that CBDCA-P is
equally effective with respect to CDDP-P in terms of PFS and OS,
the latter being more efficacious in chemo naive patients [8]. We
performed a systematic review of the literature comparing CDDP
and CBDCA paclitaxel-based chemotherapy for recurrent or metastatic
cervical cancer in order to describe the activity and outcomes associated
with both doublets.
Methods
Literature search
PubMed, EMBASE, Web of Science and The Cochrane Library
were systematically searched in March 2013, to identify relevant
publications. Keywords included in the search were “uterine cer-
vical neoplasm [Mesh]”, “cisplatin or carboplatin”, “paclitaxel”
and “recurrent or relapsed or advanced or metastatic”. The litera-
ture search was limited to “human studies” in “English” language.
We also reviewed conference abstracts to identify unpublished
papers. All potentially relevant studies were retrieved, and their
references were checked to see if there were further eligible
studies.
To summarize the effectiveness of CDDP and CBDCA + paclitaxel-
based chemotherapy, only studies that met all of the following criteria
were considered eligible to be included in the present review: 1) patients
with advanced cervical cancer (recurrent, persistent or metastatic
disease); 2) treated with CDDP/paclitaxel or CBDCA/paclitaxel combina-
tions as first line chemotherapy for metastatic disease; 3) one or more of
the following information available: overall RR (the amount of complete
response and partial response), PFS or TTP (time to progression), OS;
4) single-arm retrospective or prospective study, which means that the
platinum/ paclitaxel arms of randomized controlled trials were also eligi-
ble, and 5) at least 20 patients enrolled. Studies were excluded if they in-
cluded less than 20 patients, if included patients treated after 1st line
chemotherapy, and if they did not report outcome data for platinum–
paclitaxel combinations.
For the comparison of CDDP/paclitaxel and CBDCA/paclitaxel, only
randomized controlled trials were included, with the above mentioned
criteria 1–3 remaining unchanged.
When the same population was studied in more than one publica-
tion, only one with the most relevant data was included in this review.
Two investigators (DL and FP) independently reviewed the “potentially
eligible” studies and then cross-checked their results. Disagreements
between them were resolved by consensus after discussion with a
third expert (SB) for final decision.
Data extraction
The following data were extracted independently by two investiga-
tors from included studies: first author's name, year of publication,
study design, number of patients treated by platinum/ paclitaxel combi-
nations, age (median) of patients, regimen type and dose, stage, rate
of previous chemo-radiation, rate of objective response, PFS or TTP, OS
and hazard ratio (HR) for the comparison of PFS/TTP and OS of CDDP/
paclitaxel-treated patients with that of patients receiving CBDCA/
paclitaxel. When available, data on the first line chemotherapy only
were abstracted, if more pretreated patients were included. We also
extracted RR and OS according to previous (or not) treatment with
CDDP with or without radiotherapy. The HRs of CBDCA/ paclitaxel
for PFS, TTP and OS in comparison with their counterparts treated
with CDDP/ paclitaxel, and the results about potential predictive factors
for CBDCA and CDDP-based treatment were summarized descriptively
due to insufficient data for a formal meta-analysis.
Statistical analysis
The objective RRs (for both CDDP and CBDCA combinations) were
meta-analyzed by using the Comprehensive Meta Analysis software
v.2.2.64 July 27th 2012 with the random or fixed-effects model [9].
The statistical heterogeneity among studies was assessed by the
Cochran's Q-test and the I2 statistic. A p value b0.10 for the Q-test or
an I2 N 50% was suggestive of substantial between study heterogeneity
and so a random effect model was chosen. The PFS/TTP and OS with
both CDDP/paclitaxel and CBDCA/paclitaxel combinations, the compar-
ison of them in randomized trials and the results for RR according to
 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123 119

exposure to CDDP during the primary treatment were summarized
descriptively due to the inappropriateness for meta-analysis. The
weighted median PFS and OS were calculated. The median PFS
and OS values of the two groups were compared through a T-test for
two samples [10]. Main grades (G) 3–4 toxicities were recorded and
compared between the 2 arms. Egger's funnel plots were initially
planned to be employed but eventually not used to assess the possibility
of publication bias, due to either the limited number of studies included
for meta-analysis or the significant heterogeneity among studies.
Results
Literature search and study characteristics
The flow of study selection is reported in Fig. 1. Initially, 860 refer-
ences were identified (PubMed: n = 138, Web of Science: n = 262,
Cochrane register of Controlled trials: n = 26, EMBASE: n = 434).
After careful selection, a total of 17 eligible studies comprehensive of
1181 patients were included in the final analysis (7 for CBDCA/paclitaxel
analysis, 9 for CDDP/paclitaxel analysis and 1 for both analyses)
[4,5,8,11–19,22–25,27].
Table 1 summarizes the key characteristics of the included studies.
Table 2 reported principal risk factors potentially impacting the
effectiveness of chemotherapy in the studied populations: the two
arms appear well balanced according to the analyzed factors.
For CBDCA/paclitaxel analysis (n = 473 patients) 2 studies were
single arm phase II CBDCA/paclitaxel trials and one was a phase III
trial comparing CBDCA/P with CDDP/P. In addition, there were five
retrospective patient series. The sample sizes of included studies ranged
from 21 to 154 patients. The median ages of patients in these studies
were similar and ranged from 45 to 54 years. In all except 1 trial [16]
where CBDCA-based triplet (CBDCA/P/Ifosfamide) constituted the
treatment arm, CBDCA-based doublets were the main treatments
(all containing CBDCA + P). CBDCA/P combinations were given as
first-line therapy to cervical cancer in all studies except in two [8,25]
where treatment after the second recurrence was permitted. Also in
the retrospective series of Torfs et al. the inclusion was independent
of prior therapy lines [18]. The average rate of patients exposed to
CDDP-based chemoradiation or chemotherapy for initial treatment
at presentation was 61%.
For CDDP/paclitaxel analysis (n = 711 patients) 4 studies were
the CDDP + P treatment arms of randomized trials (3 phase III and 1
phase II), 5 were single arm phase II trials and 1 was a prospective series.
The sample sizes of included studies ranged from 34 to 130. The median
ages of patients ranged from 47 to 56 years. In all except 5 trials, where
CDDP-based triplets (CDDP/P/Ifosfamide) represented the treatment
arms, CDDP + P doublets were the schedules adopted. In all trials
except the Kitagawa et al. phase III trial [8], CDDP/paclitaxel-based
treatment was the first line therapy for advanced or recurrent disease
after primary radiotherapy ± chemotherapy ± surgery. In these studies,
the mean proportion of patients exposed to CDDP-based chemoradiation
or chemotherapy for initial treatment at presentation was 31%.
Objective RR
Objective RRs were reported in all 18 studies, ranging from
33% to 67.9% for CBDCA/paclitaxel studies and from 29.1% to 67% for
CDDP/paclitaxel studies. The combined objective RR estimated by the
random-effects model was 48.5% (95% CI 37.9%–59.3%; P for heteroge-
neity = b 0.0001; I2 = 75%) for CBDCA and 49.3% (95% CI 41.1%–

PRISMA 2009 Flow Diagram

Records identified through Pubmed Additional records identified

Id
searching through other sources (EMBASE,
en
(n =138) Web of Science, The Cochrane
tifi Register of Controlledi Trials)
ca (n = 722)
tio
n

Records after duplicates removed

Sc (n = 578)
re
en
in
Records excluded
g Records screened (n = 320 were review, letters,
(n = 258) commentaries, metanalysis)

Eli Full-text articles excluded, with

gi Full-text/abstract articles reasons
bil assessed for eligibility (n = 240 were studies in patients
ity (n = 18) pretreated with more of 1 line,
studies with < 20 patiens or
(neo)adjuvant settting)

Studies included in
qualitative synthesis
(n = 18)
In
cl
ud
ed Studies included in
quantitative synthesis
(meta-analysis)
(n = 18)

Fig. 1. Selection of publications included in the pooled-analysis.

120 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123

survival; recurr = recurrent; persist = persistent; M + =metastatic; dd = dose dense; w = weekly; NR = not reported; ^ = CBDCA + P arm only; ° = first line only; # = CCDP + P arm; * = evaluable for response rate; °° = dose escalation to
N° = number; Pts = patients; CDDP = cisplatin; CBDCA = carboplatin; P = paclitaxel; AUC = area under the curve; Doc = docetaxel; IFO = ifosfamide; RR = response rate; TTP = time to progression; PFS = progression-free survival; OS = overall
57.5%; P for heterogeneity = b 0.0001; I2 = 77.7%) for CDDP-based

10/10 (dd/w)
chemotherapy (Figs. 2 and 3). After exclusion of studies that used
a triple combination the results were slightly better for CBDCA-

12.87

39**
16.5
18.3
17.5

18.6
114

NA
NA
8.4

9.7
9.6
combinations (50.3% vs 43%) but this is probably related to the greater
OS

10
10

21
11

9
number of patients exposed to chemotherapy in CBDCA-doublets
arms (median: 55% vs 24%).
5/NR (dd/w)

8.3 (TTP)
PFS/TTP

7 (TTP)

5 (TTP)
Progression free survival or TTP and OS
4.07

5.82

NA
8**
NA

5.4
4.8
6.2

2.9

6.9

7.9
5.3

5
7

Among CBDCA-based trials PFS was reported in 7 trials ranging

from 2.9 to 7 months; the median weighted PFS was 5 months. Overall
34.4°
RR %

35.1

46.3
62.6

67.9

58.8
29.1

46.7
survival was available in all except one trial ranging from 8.4 to

67
33

62

47
53

36
59

40

59

46
21 months; the median weighted OS was 10 months.
For CDDP-based trials PFS was reported in nine (TTP was the
CBDCA (AUC4 d1.8 q 21 or AUC 2.7 w) + P (90 d1.8 q 21 or 60 w)

outcome measure in 3 trials) trials and the medians ranged from 4.8
to 8.3 months; the median weighted PFS was 6.9 months. Overall
survival was available in all except one trial, with a range from 9 to
CDDP (50 q 21) + IFO (1500 d 1–3 q 21) + P (135 q 21)

CDDP (75 q 28) + IFO (1500 d 1–3 q 28) + P (175 q 28)

CDDP (70 q 21) + IFO (1500 d1–3 q 21) + P (175 q 21)
CDDP (40 d1,2 q 21) + IFO (2500 d1,2 q 21) + P (175)

39 months; the median weighted OS was 12.87 months.

CBDCA (AUC 5 q 28) + P (175 q 28) + IFO (2 g q 28)

CDDP (75 q 21) + IFO (5000 q 21) + P (175 q 21)

The difference between median PFS of CBDCA and CDDP-based
treatments was significant (p = 0.03); on the contrary median OS
differences were not significant according to T-test. These results are
CBDCA (AUC 5–6 q 28) + P (175 q 28) ^^

probably related to the inferior exposure to CDDP-based treatment

CBDCA (AUC 5 q 21) + P (175 q 21)
CBDCA (AUC 5 q 21) + P (175 q 21)

in CDDP arms (median chemotherapy exposure: 24 vs 56.5% in CDDP

CBDCA (AUC 5–6) + P (175–155)

CDDP (75 q 21) + P (135 q 21°°)

and CBDCA arms respectively).

CDDP (75 q 21) + P (175 q 21)
CDDP (50 q 21) + P (135 q 21)
CDDP (50 q 21) + P (135 q 21)
CDDP (50 q 21) + P (135 q 21)
Treatment schedule (mg/m2)

Subgroup analysis according to previous CDDP exposure

CBDCA (NA) + P (NA)

CBDCA (NA) + P (NA)

170 mg/m2 in 6 patients; ** = first line only; ^^ = 2 patients treated with a weekly regimen; d = day; hrs = hours; and NA = not available.

The RRs for patients previously treated with CDDP-based chemora-

diation were 42.3% and 43.9% in CBDCA (n = 5 trials with information
available) and CDDP arms respectively (n = 4 trials with information
available) (p = 0.54).
In the same way, the RRs for patients not previously treated with
CDDP-based therapy were 68.3% and 59.1% for CBDCA-based chemo-
therapy (n = 4 trials with data available) and CDDP-based chemother-
1st (48/41%)

apy (n = 4 trials with data available) respectively (p = 0.73).

1st (96,4%)
1st–2nd
1st–2nd

1st–2nd

A systematic survival analysis according to CDDP exposure was not

Line

possible because only 1 trial reported analysis of OS according to it.

1st
1st

1st
1st

1st
1st
1st
1st

1st
1st

1st
1st

1st

In the Moore trial [27], CBDCA/P seems to fare better if there was no pre-
vious CDDP exposure (OS: 19 vs 10 months, p = 0.007), but this analy-
IVB/persist./1st recurr. (86)
IVB/persist./1st recurr. (87)

sis included only 14 patients treated with CDDP/P among the overall
IVB/recurr./persist. (100)
Stage IVB/recurr. (100)
Stage IVB/recurr. (100)

population. In one retrospective study [24], TTP was better in patients

Recurr. (90); IVB (10)

Recurr./persist. (100)
Recurr./persist. (100)

Recurr./persist. (100)
Persist/recurr. (84,4)

Recurr./M + (100)
Recurr./M + (100)

Recurr./M + (100)
Recurr./M + (100)
Recurr./M + (100)

not previously treated with CDDP (5.9 vs 2.9 months, p not reported).
recurr./M + (100)

Recurr. (100)

recurr. (100)

Comparison of CBDCA/paclitaxel with CDDP/paclitaxel combinations

Stage (%)

Among the randomized controlled trials we identified, only

Kitagawa et al. [8] directly compared CBDCA/P and CDDP/P. The
objective RRs were similar (63% vs 60%, respectively) and no difference
N° pts

in OS (HR 0.99, 90% CI, 0.79–1.25) was observed. However, among

20/9°

127#
103#
126^
154

130
39*

21*

41*
25

60
28

42

34
53
76

45
48

women not previously treated with CDDP, CBDCA/P resulted in a

worse OS compared to CDDP/P (13 versus 23 months, HR 1.57; 95% CI
1.06–2.32). Among women previously treated with CDDP (n = 127),
Design of study

Retrospective
Retrospective

Retrospective

Retrospective
Retrospective

CBDCA/P resulted non inferior to CDDP-P in terms of OS (19 versus

Prospective

16 months, HR 0.69; 95% CI 0.47–1.02). The authors concluded that

Phase III

Phase III
Phase III

Phase III
Phase II
Phase II
Phase II
Phase II

Phase II

Phase II
Phase II

Phase II

the 2 treatments were equally effective and that CBDCA/P presented a

more favorable toxicity profile especially in terms of grade 4 neutropenia
(45% vs 75%), febrile neutropenia (7.1% vs 16%), grades 2–4 renal
Characteristics of included trials.

toxicity (4.8% vs 9.6%), and grades 2–4 nausea vomiting (23% vs 36.8%
Kitagawa/2012 (CBDCA arm)

Kitagawas/2012 (CDDP arm)

for CBDCA and CDDP-based treatments respectively).

Papadimitriou/1999

Toxicity
Dimopoulos/2002
Mountzios/2009
Kitagawa/2012

Mabuchi/2009

Kosmas/2009

Zanetta/1999
Downs/2011
Autore/anno

Garces/2012

Moore/2004
Moore/2007
Tinker/2005

Monk/2009

Main hematological and non hematological toxicities (G3–4 events)

Torfs/2012

Rose/1999
Choi/2006

analyzed were anemia, neutropenia, febrile neutropenia, thrombo-

Table 1

cytopenia, fatigue, vomiting, neurotoxicity, diarrhea and stomatitis.

For CDBCA + paclitaxel combinations average weighted rates were
 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123 121

Table 2
Risk factors influencing chemotherapy effectiveness according to treatment.

Autore/anno N° pts PS 0–1/median age (years) CDDP-based adjuvant CT only/CTRT (%) Prior RT (%) Site of relapse (in/outside field RT)

Carboplatin + paclitaxel studies

Torfs/2012 20/9° NR/47 34.8 (1 line)/70.5 53 NR
Kitagawa/2012 39* 95%/49–48 52 (CT or CTRT) 85 (CTRT or RT) 21/79%
Kitagawa/2012 (CBDCA arm) 126 97%/53 57 (previous CDDP)/NA NA 45/60%
Garces/2012 154 NR/NR NA NA NR
Downs/2011 21* NR/52 0/71 79 25/64%
Mabuchi/2009 28 NR/54 3.6/39.3 NA 25/46.4%
Moore/2007 48 NR/51.1 0/70,8 89.6 NR/NR
Tinker/2005 25 68%/45 0/56 92 (CTRT or RT) 16/16%

Cisplatin + paclitaxel studies

Kosmas/2009 42 93%/56 0/67 12 43/40%
Kitagawa/2012 (CDDP arm) 127 98%/53 48 (previous CDDP)/NA NA 36/64%
Monk/2009 103 100%/50 0/70 0 40%/NR
Mountzios/2009 76 93%/50 21/51 22 49/75%
Choi/2006 53 68.1%/48.6 39.6/43.4 18.9 54.7/45.3%
Moore/2004 130 87%/48.5 0/24 90 40/47%
Dimopoulos/2002 60 74%/52 NA/3 53 37/51%
Papadimitriou/1999 34 59%/51 NA/6 35 32/47%
Rose/1999 41* 90%/47 0/NA 90 57/43%
Zanetta/1999 45 100%/50 40 (CT or CT/RT) NA 42/44%

N° = number; Pts = patients; * = evaluable for response rate; CDDP = cisplatin; CBDCA = carboplatin; CT = chemotherapy; CTRT = concomitant chemoradiotherapy; RT = exclusive
radiotherapy; ° = first line only patients; NA = not available.

as follow: anemia 39.5%, febrile neutropenia 7.6%, thrombocytopenia
21.6%, neutropenia 51.1%, fatigue 7%, vomiting 2.8%, neurotoxicity
3.3%, diarrhorrea 1.5% and stomatitis 0% (but this was reported only in
2 trials). In CDDP + paclitaxel arms the weighted mean G3–4 toxicity
rates were: anemia 23.2%, febrile neutropenia 15.6%, thrombocytopenia
9.2%, neutropenia 60.6%, fatigue 7.5%, vomiting 17.9%, neurotoxicity
3.3%, diarrhea 1.9% and stomatitis 0.7% (but this was reported only
in 2 trials).
Factors predictive of survival of platinum-paclitaxel combinations
Some authors explored clinical variables independently associated
with better OS. Mabuchi et al. [17] reported that site of recurrence
(irradiated vs not irradiated field; p = 0.0098) and chemotherapy
regimen (CBDCA/P: p = 0.0214) were independent prognostic factors
for predicting response to chemotherapy.
Among the CDDP-paclitaxel trials Monk et al. [5] analyzed the
variables associated with better OS and reported that platinum free
interval N 24 months, PS 0, recurrence outside the irradiated field and
Hispanic origin were associated with better OS (HR 0.598 and 0.677).
Mountzious et al. [14] showed that PS (0 vs ≥ 1), age at diagnosis as
a continuous variable and treatment regimen (CDDP/P/Ifosfamide)
maintained predictive significance for PFS and OS.
Discussion
The experience with substituting CBDCA for CDDP is limited
in advanced or recurrent uterine cervical cancer, and our systematic
literature review seems to confirm that CDDP and CBDCA are equally
effective in the treatment of the disease. Traditionally CDDP, with RRs
ranging from 20 to 30% and OS of 7 months [20], has been considered
the most effective single agent for cervical cancer treatment. Even in
the absence of a direct comparison, other platinum analogs were con-
sidered less active than CDDP after the publication of a phase II GOG
trial reporting 15% RR for CBDCA and 11% for iproplatin [21]. The combi-
nation of CDDP-P became the preferred treatment for advanced cervical
cancer after the publication of 2 phase II trials reporting RRs in the range
of 45–50% [22,23] and following a phase III trial demonstrating in-
creased RR and PFS (but not OS) for the combination with respect to
CDDP single agent [4]. More recently [5] CDDP-P has emerged as the
winner arm of the GOG 204 trial comparing CDDP-P vs CDDP-based
doublets with Topotecan, Gemcitabine and Vinorelbine in the treatment
of advanced cervical cancer. Unfortunately, the toxicity of the combina-
tion is not scanty especially in terms of myelo- and neurotoxicity
(grades 3–4 neutropenia 78.2%; febrile neutropenia 12.9%; grades 3–4
neuropathy 3%, grades 3–4 vomiting 19.8%) and, given the palliative
intent of systemic chemotherapy in this setting, therapeutically equiva-
lent options, with more favorable toxicity profile are a challenge.
Carboplatin may represent an acceptable alternative to CDDP: it can
be delivered in an outpatient setting and, in a different way to CDDP,
the dose is calculated according to renal function, which may be
impaired in cervical cancer patients. Moreover, the reduced nephro
and neurotoxicity of CBDCA allow the administration of P in 3 h rather
than in 24 h without massive hydration, and also the platelet-sparing
activity of P can reduce the myelotoxicity of CBDCA, which is often
increased in this population due to prior pelvic irradiation on bone

Study name Statistics for each study Event rate and 95% CI
Event Lower Upper
rate limit limit Z-Value p-Value
Torfs 2012 0,344 0,196 0,530 -1,651 0,099
Kitagawa 2012 0,590 0,432 0,731 1,118 0,264
Kitagawa 2012 (JCOG 0505) 0,626 0,538 0,706 2,798 0,005
Garces 2012 0,351 0,280 0,430 -3,641 0,000
Downs 2011 0,330 0,166 0,550 -1,526 0,127
Mabuchi 2009 0,679 0,489 0,824 1,851 0,064
Moore 2007 0,530 0,390 0,665 0,415 0,678
Tinker 2005 0,400 0,230 0,597 -0,993 0,321
0,485 0,379 0,593 -0,268 0,789
-1,00 -0,50 0,00 0,50 1,00

Fig. 2. Pooled analysis of response rate carboplatin + paclitaxel studies.

122 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123
Study name Statistics for each study
Event Lower Upper
rate limit limit Z-Value p-Value
Kitagawa 2012 (JCOG 0505) 0,588 0,501
Kosmas 2009 0,620 0,467
Monk 2009 0,291 0,212
Mountzios 2009 0,590 0,477
Choi 2006 0,467 0,338
Moore 2004 0,360 0,282
Dimopoulos 2002 0,460 0,339
Papadimitriou 1999 0,470 0,311
Rose 1999 0,463 0,318
Zanetta 1999 0,670 0,522
0,493 0,411
Fig. 3. Pooled analysis of response rate cisplatin + paclitaxel studies.
marrow reserve. Several retrospective and prospective phase II trials
have addressed the effectiveness of CBDCA-P combination in advanced
cervical cancer [24–28] reporting RRs between 40 and 78%, median
PFS ranging between 3 and 6 months and median OS between 9.6 and
13 months. As far as toxicity the authors in general conclude that
CBDCA-P is a well tolerated outpatient regimen with hematological
toxicity (especially thrombocytopenia) being the most significant toxic-
ity of the combination. The only trial directly comparing CBDCA-P vs
CDDP-P in advanced and recurrent cervical cancer patients did not
reveal any difference in terms of RR, PFS and OS between treatments,
although CDDP seemed to be more active in patients not previously
treated with chemotherapy [8] and the authors concluded that the 2
treatments were equally effective with CBDCA/P presenting a more
favorable toxicity profile. Our analysis confirmed the equivalence of
treatments in terms of objective RRs and OS with a slight 2-month PFS
advantage for CDDP-P combination. We were unable to discover any
difference in terms of RRs between treatments in patients previously
treated or not with platinum; moreover a systematic survival analysis
according to previous CDDP exposure was not possible because only 1
trial reported analysis of OS according to it. Otherwise, our study con-
firms that previous platinum-exposure, in combination or not to radio-
therapy, significantly reduces responses to subsequent platinum based
chemotherapy, regardless of CDDP or CBDCA. Several explanations
have been suggested to clarify the differences in responses: previous ra-
diotherapy and/or chemotherapy may select radio and chemo-resistant
clones; the severe radio-induced blood vessel disruption may lead
to lower perfusion of the relapsed cancer and, therefore, reduced
concentration of cytotoxic agents within the tumor; hypoxia resulting
from poor blood supply may lower the proliferating fraction of
cancer and reduce the potential cytotoxic effects of chemotherapeutic
agents.
Pertinent limitations of our study include the retrospective and not
randomized nature of this pooled analysis, the absence of cost data, de-
tailed toxicity data, and quality of life data and the potential imbalances
in relevant clinical characteristics that may also affect clinical outcome
of cervical cancer patients such as different previous platinum exposure
and platinum-free interval. However, with a satisfactory number of tri-
als included in the analysis, this is the first systematic review to estab-
lish substantial similarity in the outcome and activity with CDDP and
CBDCA doublets as first line chemotherapy in advanced cervical cancer.
Keeping in mind the palliative aim of chemotherapy treatment in
recurrent cervical cancer, and considering the overall dismal prognosis
of the patients, an effective and low-toxic regimen is needed. The results
of our analysis seem to indicate that CBDCA may represent an attractive
and valid alternative to the more toxic and equally effective CDDP in the
treatment of advanced or recurrent cervical cancer.
Conflict of interest statement
The authors declare no conflict of interest.
Event rate and 95% CI
0,670 1,973 0,048
0,753 1,540 0,124
0,386 -4,105 0,000
0,694 1,561 0,119
0,600 -0,480 0,631
0,446 -3,149 0,002
0,586 -0,619 0,536
0,635 -0,350 0,727
0,614 -0,473 0,636
0,791 2,234 0,025
0,575 -0,168 0,867
-1,00 -0,50 0,00 0,50 1,00
References
[1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin
2007;57:43Y66.
[2] Cadron I, Van Gorp T, Amant F, et al. Chemotherapy for recurrent cervical cancer.
Gynecol Oncol 2007;107(1 Suppl. 1):S113Y118.
[3] Thigpen T, Shingelton H, Homesley H, LaGasse L, Blessing J. Cis-dichlorodiammineplatiunm
(II) in the treatment of gynecologic malignancies: phase II trials by the Gynecologic
Oncology Group. Cancer Treat Rep 1979;63:1549–55.
[4] Moore DH, Blessing JA, Mc Quellon RP, et al. Phase III study of cisplatin with or
without paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of
the cervix: a Gynecologic Oncology Group study. J Clin Oncol 2004;22(15):3113–9.
[5] Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing
doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma:
a Gynecologic Oncology Group study. J Clin Oncol 2009;27:4649.
[6] Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel
compared with cisplatin and paclitaxel in patients with optimally resected
stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol
2003;21(17):3194–200.
[7] du Bois A, Luck HJ, Meier W, et al. Carboplatin/paclitaxel versus cisplatin/paclitaxel
as first-line chemotherapy in advanced ovarian cancer: an interim analysis of a
randomized phase III trial of the Arbeitsgemeinschaft Gynakologische Onkologie
Ovarian Cancer Study Group. Semin Oncol 1997;24(5 Suppl. 15):S15–44.
[8] Kitagawa R, Katsumata N, Shibata T, et al. A randomized, phase III trial of paclitaxel
plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent
or recurrent cervical cancer: Japan Clinical Oncology Group study (JCOG0505).
J Clin Oncol 2012;30 [Abstr 5006].
[9] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
1986;7:177–88.
[10] Altman DG, Gore SM, Gardner MJ, Pocock SJ. Statistical guidelines for contributors
to medical journals. Br Med J (Clin Res Ed) May 7 1983;286(6376):1489–93.
[11] Choi CH, Kim TJ, Lee SJ, Lee JW, Kim BG, Lee JH, et al. Salvage chemotherapy with a
combination of paclitaxel, ifosfamide, and cisplatin for the patients with recurrent
carcinoma of the uterine cervix. Int J Gynecol Cancer May–Jun 2006;16(3):1157–64.
[12] Dimopoulos MA, Papadimitriou CA, Sarris K, Aravantinos G, Kalofonos C, Gika D,
et al. Combination of ifosfamide, paclitaxel, and cisplatin for the treatment of
metastatic and recurrent carcinoma of the uterine cervix: a phase II study of the
Hellenic Cooperative Oncology Group. Gynecol Oncol Jun 2002;85(3):476–82.
[13] Kosmas C, Mylonakis N, Tsakonas G, Vorgias G, Karvounis N, Tsavaris N, et al.
Evaluation of the paclitaxel–ifosfamide–cisplatin (TIP) combination in relapsed
and/or metastatic cervical cancer. Br J Cancer Oct 6 2009;101(7):1059–65.
[14] Mountzios G, Dimopoulos MA, Bamias A, Vourli G, Kalofonos H, Aravantinos G, et al.
Randomized multicenter phase II trial of cisplatin and ifosfamide with or without
paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic
Cooperative Oncology Group (HeCOG) study. Ann Oncol Aug 2009;20(8):1362–8.
[15] Zanetta G, Fei F, Parma G, et al. Paclitaxel, ifosfamide and cisplatin (TIP)
chemotherapy for recurrent or persistent squamous-cell cervical cancer. Ann
Oncol Oct 1999;10(10):1171–4.
[16] Downs Jr LS, Chura JC, Argenta PA, Judson PL, Ghebre R, Geller MA, et al. Ifosfamide,
paclitaxel, and carboplatin, a novel triplet regimen for advanced, recurrent,
or persistent carcinoma of the cervix: a phase II trial. Gynecol Oncol Feb
2011;120(2):265–9.
[17] Mabuchi S, Morishige K, Fujita M, Tsutsui T, Sakata M, Enomoto T, et al. The activity
of carboplatin and paclitaxel for recurrent cervical cancer after definitive radiotherapy.
Gynecol Oncol May 2009;113(2):200–4.
[18] Torfs S, Cadron I, Amant F, Leunen K, Berteloot P, Vergote I. Evaluation of paclitaxel/
carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or
primary metastatic cervical cancer. Eur J Cancer Jun 2012;48(9):1332–40.
[19] Garces AH, Mora PA, Alves FV, et al. First-line paclitaxel and carboplatin
in persistent/recurrent or advanced cervical cancer: a retrospective analysis
of patients treated at Brazilian National Cancer Institute. Int J Gynecol Cancer May
2013;23(4):743–8.
[20] Bonomi P, Blessing JA, Stehman FB, et al. Randomized trial of three cisplatin dose
schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology
Group study. J Clin Oncol 1985;3:1079Y1085.
 D. Lorusso et al. / Gynecologic Oncology 133 (2014) 117–123
[21] McGuire III WP, Arseneau J, Blessing JA, et al. A randomized comparative trial
of carboplatin and iproplatin in advanced squamous carcinoma of the uterine
cervix: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:1462Y1468.
[22] Papadimitriou CA, Sarris K, Moulopoulos LA, et al. Phase II trial of paclitaxel and
cisplatin in metastatic and recurrent carcinoma of the uterine cervix. J Clin Oncol
1999;17:761Y766.
[23] Rose PG, Blessing JA, Gershenson DM, et al. Paclitaxel and cisplatin as first-line
therapy in recurrent or advanced squamous cell carcinoma of the cervix: a Gynecologic
Oncology Group study. J Clin Oncol 1999;17:2676Y2680.
[24] Tinker AV, Bhagat K, Swenerton KD, et al. Carboplatin and paclitaxel for advanced
and recurrent cervical carcinoma: the British Columbia Cancer Agency experience.
Gynecol Oncol 2005;98:54Y58.
123
[25] Kitagawa R, Katsumata N, Yamanaka Y, Ando M, Fujiwara Y, Watanabe T,
et al. Phase II trial of paclitaxel and carboplatin in patients with
recurrent or metastatic cervical carcinoma. Proc Am Soc Clin Oncol
2004;23:5048.
[26] Sit AS, Kelley JL, Gallion HH, et al. Paclitaxel and carboplatin for recurrent or
persistent cancer of the cervix. Cancer Investig 2004;22(3):477–8.
[27] Moore KN, Herzog TJ, Lewin S, et al. A comparison of cisplatin/paclitaxel
and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer.
Gynecol Oncol 2007;105:299Y303.
[28] Pectasides D, Fountzilas G, Papaxoinis G, et al. Carboplatin and paclitaxel
in metastatic or recurrent cervical cancer. Int J Gynecol Cancer 2009;19(4):
777–81.