Gynecologic Oncology 128 (2013) 3437

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

The Leuven paclitaxel/carboplatin weekly regimen in patients with recurrent

ovarian cancer, a retrospective study
Isabelle Cadron , Leyla Abdulkadir, Evelyn Despierre, Patrick Berteloot, Patrick Neven, Karin Leunen,
Frdric Amant, Ignace Vergote
Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium
Division of Gynecological Oncology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium

H I G H L I G H T S
Weekly TC regimen was given in recurrent ovarian cancer patients.
RR were 37% and 40% in platinum resistant and sensitive patients.
Toxicity was tolerable and neutropenia was the most frequent side effect.

a r t i c l e

i n f o

Article history:
Received 1 February 2012
Accepted 4 October 2012
Available online 9 October 2012
Keywords:
Epithelial ovarian cancer
Weekly administration
Paclitaxel
Carboplatin
Dose dense
Chemotherapy

a b s t r a c t
Objective. To evaluate the Leuven weekly paclitaxel/carboplatinum (TC) regimen in recurrent ovarian
cancer in a retrospective study.
Methods. Eighteen courses of paclitaxel (60 mg/m2) and carboplatinum (AUC 2.7) were administered
weekly. Platinum-resistance was dened as progression during or within 6 months after platinum-based
chemotherapy.
Results. Sixty-three patients were included with a median number of prior treatment regimens of 4
(range 010). Forty-three patients were platinum resistant and 20 were platinum sensitive (14 intermediate
sensitive and 5 sensitive). One patient in the platinum resistant group and 2 patients in the platinum sensitive group achieved complete remission, 15 patients in the platinum resistant and 5 patients in the platinum
sensitive group achieved partial remission according to RECIST. In the entire patient population evaluable for
response (n = 62), the median progression free survival (PFS) was 6.7 months; the median overall survival
(OS) was 9.7 months. Median PFS was 6 months for the platinum resistant and 8 months for the platinum
sensitive group. The median OS was 9 months in the platinum resistant and 11 months in the platinum sensitive group.
Toxicity was mostly bone marrow related with neutropenia grade 3/4 in 67% and neutropenic fever in 6%
of patients. Dose reduction was necessary in 24% of patients. Nausea, vomiting and fatigue were the most
frequent non-hematological side effects.
Conclusion. Weekly paclitaxel and carboplatin is an effective regimen for patients with recurrence of ovarian
cancer with a response rate of 37% in platinum resistant disease and a manageable toxicity prole.
2012 Elsevier Inc. All rights reserved.

Introduction
Epithelial ovarian cancer (EOC) has a bad prognosis and in Europe
it was estimated that 66,700 women will be diagnosed and 41,900
women will die of cancer of the ovary in 2008 [1]. Despite multimodal
primary therapy a substantial number of patients will progress during
or relapse after primary therapy [2]. Treatment of recurrent ovarian
Corresponding author at: University Hospitals Leuven and Leuven Cancer Institute,
Division of Gynecologic Oncology, Herestraat 49, B-3000 Leuven, Belgium. Fax: +32 16
34 46 29.
E-mail address: Isabelle.Cadron@uz.kuleuven.ac.be (I. Cadron).
0090-8258/$ see front matter 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ygyno.2012.10.004

cancer will depend on the platinum free interval (PFI). Patients with a
PFI>6 months will preferably be treated with a platinum containing
regimen. The ICON 4 study showed that for platinum sensitive patients
(PFI> 6 months), there was a 7% improvement in survival at 2 years for
those who received the combination of paclitaxel and platinum vs.
monotherapy with a platinum compound. Median survival increased
by 5 months with the addition of paclitaxel to carboplatinum [3].
The CALYPSO trial showed that for platinum sensitive patients,
PFI > 6 months, carboplatinum with liposomal doxorubicin has a
more favorable risk benet prole then carboplatinum associated
with paclitaxel and should therefore be considered as second line
chemotherapy [4].

I. Cadron et al. / Gynecologic Oncology 128 (2013) 3437

In a previous study from our center, using a dose dense scheme of

paclitaxel (T)/carboplatinum (C) (T 90 mg/m 2C AUC 4) we were
able to achieve response rates (RR) of 66% (38% in the platinum resistant group) with a good tolerability in heavily pre-treated ovarian
cancer patients. Median PFS was 7 months for the platinum resistant
and 10 months for the platinum sensitive group. The median overall
survival (OS) was 9 months in the platinum resistant and 26.5 in
the platinum sensitive group [5]. Another way to increase efcacy of
a chemotherapeutic regimen is shortening the treatment interval
[6]. We therefore decided to implement a weekly regimen and compare this with our dose dense regimen.
The purpose of this retrospective study is to evaluate the response
and toxicity of weekly paclitaxelcarboplatinum in patients with
recurrent EOC, fallopian tube or primary peritoneal carcinoma.
Materials and methods
Eligibility
Consecutive patients with recurrent or advanced invasive EOC,
fallopian tube cancer or primary peritoneal carcinoma were enrolled.
Recurrence was proven by clinical examination, imaging and, if the
tumor secreted CA125, a raise in tumor marker. Inclusion was independent on the number of prior therapy lines. Other eligibility criteria
were: performance status (WHO) 3, adequate renal and liver function and an appropriate bone marrow function to start chemotherapy
dened as a neutrophil count of >1000 10**9/L and a platelet count
of > 100.000 10**9/L.
Pre-treatment evaluation consisted of a pelvic examination, chest
X-ray, abdominal and pelvic computerized tomography (CT) scan and
a blood sample (full blood count, liver function tests, urinary function
tests, electrolytes and CA 125). Clinical examination and blood tests
were repeated before every treatment course.

35

and i.v. iron therapy were started when the hemoglobin dropped below
10 g/dl.
Assessment of response, progression-free and overall survival
Response evaluation was performed on imaging (RECIST criteria)
[7] and CA 125 responses (GCIG criteria) [8]. Response to therapy
was evaluated after the ninth and eighteenth cycle with clinical
examination, CT abdomenpelvis (and if applicable CT thorax) and
serum CA 125. Patients with progressive disease were withdrawn
from the protocol.
The median PFS was dened as the median period of time between
the start of the treatment and disease progression, and the median OS
was dened as the median period of time between the start of the treatment and death. Both were calculated using KaplanMeier curves and
patients were censored if they were disease-free or still alive at the
1st of December 2011. PFI was dened as the time period between
the last platinum therapy and recurrence of disease.
Assessment of toxicity
Toxicity was evaluated according to the National Cancer Institute
(NCI) Common Toxicity criteria version 2.0. (http://ctep.cancer.gov/
forms/CTCv20_4-30-992.pdf).
Results
Sixty three patients were enrolled between January 2007 and June
2010 of which 62 patients were eligible for evaluation of response
and all patients were evaluable for toxicity prole. One patient
received four cycles of weekly paclitaxel/carboplatin after which the
therapy changed to a three weekly interval due to practical arrangements of transport; she was excluded for response evaluation. Patient
characteristics are presented in Table 1.

Chemotherapy regimen
Assessment of response, progression-free and overall survival
Pre-medication with oral antihistamines (cetirizine hydrochloride
10 mg) and oral steroids (10 mg dexamethasone) was given 12 h
and 3 h before start of the treatment. Hydratation was given with
1 l intravenous (i.v.) glucose 5%, and NaCl 0.9% was given when the
patient was glucose intolerant. Aprepitant 125 mg p.o., ondansetron
8 mg i.v. and ranitidine 50 mg i.v. were administered as anti-emetic.
This was followed by the i.v. infusion of paclitaxel 60 mg/m2 (in 250 ml
NaCl 0.9%) over 60 min, followed by 10 min of post-hydratation with
glucose 5% or NaCl 0.9%. Subsequently, the carboplatinum infusion,
2.7 area under the plasma concentrationtime curve (AUC) was
given. This was dissolved in 500 cc glucose 5% (adjusted to NaCl 0.9%
when needed) over 60 min. Aprepitant 80 mg on day 1 and 2 and
oral alizapride 50 mg if needed was prescribed for the following days.
If allergies occurred, an allergic scheme was given. In this scheme, the
premedication starts 3 days before the chemotherapy, infusion rate of
carboplatin is prolonged (4 h instead of 1 h) and methylprednisolone
125 mg i.v. is given in a bolus injection just before the start of the
chemotherapy.
This regimen was administered weekly with a maximum of 18
courses.
Dose adjustments were based on bone marrow toxicity. Treatment
was delayed for 1 week if on day 1 neutrophils was 500 10**9/L and
platelet count was 50.000 10**9/L. If the nadir of the platelets of the
previous course was lower than 25.000 10**9/L, carboplatinum was
reduced to 75%. If the nadir of the neutrophils was below 500 10**9/L
during 7 days or below 500 10**9/L with fever, then granulocyte
colony-stimulating factor (G-CSF) was preventively administered in
the following courses. If, with the use of G-CSF the nadir of the neutrophils still was below 500 10**9/L during 7 days or below 500 10**9/L
with fever, patients were withdrawn from the protocol. Erythropoietin

A total of 828 cycles of weekly paclitaxel/carboplatin were given

with a median of 17 cycles per patient (range 218). The regimen
was used in 14%, 25%, 24% and 32% as second, third, fourth, and fth
line or higher respectively. The overall response rate (RR) was 37%
of which 3 and 20 patients achieved a complete and partial remission
respectively. Seven patients achieved a stable disease and 30 patients
were progressive during or at the end of therapy. With regard to the
PFI, the platinum resistant patients (PFI b 6 months) responded in
37%, the intermediate sensitive patients (PFI 612 months) in 36%
and the platinum sensitive patients (PFI > 12 months) in 40% (Table 2).
The median OS was 9 and 7 months and according to PFI this was
9, 10 and 14 months for the platinum resistant, intermediate sensitive and sensitive group (Fig. 1). The median PFS was 6 and 7 months
and related to PFI 6, 6 and 11 months respectively (Fig. 2).
Sixty patients had an elevated CA125 at recurrence and in 12
patients (19%) a normalization of CA125 (value b 35 U/ml) was
observed.
Assessment of toxicity (Table 3)
In 15 patients (24%) a dose reduction was necessary due to hematological toxicity. In 39 patients (62%) or in 64 cycles (8%) a delay was
seen (in 41 cycles there was a delay of 1 week, in 17 cycles a delay of
2 weeks, in 2 cycles a delay of 2 weeks and in 4 cycles a delay of
4 weeks).
The most frequent grade 34 hematological side effect was neutropenia in 67% of patients. Of these only 4 patients (6%) developed
a neutropenic fever needing hospital admission. They were all treated
with i.v. antibiotics and G-CSF with an uneventful evolution. They

36

I. Cadron et al. / Gynecologic Oncology 128 (2013) 3437

100

Table 1
Patient characteristics according to PFI.
Platinum partial
sensitive
(612 mths)

Platinum
sensitive
(>12 mths)

Entered
Median age in years
(range)
FIGO at primary
diagnosis
Ia
Ib
Ic
IIb
IIc
III NOS
IIIa
IIIb
IIIc
IV
Histology
Serous
Clear cell
Mucinous
Endometrioid
Not known
n of prior therapy
lines
0
1
2
3
4
5

63
61
(3881)

43
61
(3880)

14
61
(4381)

6
57
(4570)

1
2
3
1
1
4
1
4
41 (65)
5

0
1
1
0
1
2
0
3
31 (72)
4

0
0
1
1
0
1
0
1
9 (64)
1

1
1
1
0
0
1
1
0
1
0

52 (83)
2
2
1
6

37 (86)
1
1
0
4

12 (86)
0
0
1
1

3 (50)
1
1
0
1

1
2 (3)
9 (14)
16 (25)
15 (24)
20 (32)

0
1
6
9
11
16

0
0
3
5
3
3

1
1
0
2
1
1

Platinum sensitive (6-12 m)

80

Platinum sensitive (> 12 m)

OS (%)

Platinum
resistant
(b6 mths)

Total

Platinum resistant

60

40

20

0
0

20

40

60

80

Months
Fig. 1. Overall survival of the TC weekly regimen according to platinum free interval.

PFI: platinum free interval, n: number, mths: months.

were reduced in subsequent cycles and received prophylactic G-CSF.

Fourteen patients (22%) received prophylactic G-CSF after an episode
of persistent neutropenia according to the protocol. Anemia grade
34 was present in 40% of patients. Erythropoietin, in combination
with i.v. iron therapy, was given in 36 patients (57%). Blood transfusions were given when patients were symptomatic, 1 to 2 units
of packed cells were given in 26 patients (41%). We experienced
22 patients who developed thrombocytopenia grade 34 of which
8 patients received a platelet transfusion when they were symptomatic
or had a platelet count of 10.000 10**9/L. No adverse effects on renal
function were seen and there was no grade 3/4 alopecia.
Despite premedication, 8 patients had an allergic reaction on
carboplatin of which 7 developed rash and 1 patient developed rash
with bronchospasm in her last cycle. They were treated with methylprednisolone and cetirizine hydrochloride with a quick resolution of
the symptoms. One patient reacted on the paclitaxel infusion with
rash and was treated equally. All 7 patients were continued on the
treatment with an allergic scheme without any problems.

Discussion
Treatment choice in recurrent ovarian cancer usually depends on
the PFI. If patients are platinum sensitive (PFI > 12 months) then a
re-challenge with a platinum based regimen is preferred. For platinum
resistant disease (PFIb 6 months) many products in monotherapy
have been used with RR ranging from 10 to 30%. In intermediate platin
sensitive patients retreatment with platin-based chemotherapy or therapy with pegylated liposomal doxorubicin with or without trabectedine
has been proposed [911].
Increasing the efcacy of a chemotherapy regimen can be done in
two ways, either by increasing the dose of the chemotherapy agents
or by shortening the treatment interval. We therefore evaluated in a
weekly paclitaxelcarboplatinum regimen.
Some studies with weekly regimens in recurrent ovarian cancer
patients were already published. Wu et al. [12] compared a weekly
regimen (T 60 mg/m 2 and C AUC 2) in 14 patients with a monthly
regimen in 15 patients and concluded that bone marrow suppression
was less in the weekly regimen with comparable non hematological
side effects and RR. Havrilesky [13] used a regimen of T 80 mg/m 2
and C AUC 2 on d1, 8, and 15 of a 28 day cycle and had RR of 82.8%
with RR of 37.5% for platinum resistant patients. Watanabe [14]
used a regimen of T 60 mg/m 2 and C AUC 2 on d1, 8 and 15 of a
28 day cycle, in platinum sensitive ovarian cancer patients and had
RR of 88%. Sharma [15] also used a four weekly regimen with T
70 mg/m 2 and C AUC 3 on day 1, 8 and 15 in platinum resistant
patients and reported RR of 60%. Neutropenia and anemia were the
most frequent bone marrow related side effects and fatigue and nausea the non hematological side effects.

Platinum resistant

100

Platinum sensitive (6-12 m)

Table 2
Response rates according to PFI, n = 62 (%).

CR
PR
RR
SD
PD

Platinum resistant
(b6 mths)
n = 43

Platinum partial
sensitive (612 mths)
n=14

Platinum sensitive
(>12 mths)
n=5

After
9 cycles

After
18 cycles

After
9 cycles

After
18 cycles

After
9 cycles

After
18 cycles

0
15 (35)
15(35)
12
16

1
15
16 (37)
5
22

0
7
7(50)
3
4

1
4
5(36)
2
6

0
3
3(60)
2
0

1
1
2(40)
0
2

PFI: platinum free interval, CR: complete remission, PR: partial remission, RR: response
rate, SD: stable disease, PD: progressive disease, n = number, mths: months.

PFS (%)

80

Platinum sensitive (> 12 m)

60

40

20

0
0

10

20

30

Months
Fig. 2. Progression free survival of the TC weekly regimen according to platinum free
interval.

I. Cadron et al. / Gynecologic Oncology 128 (2013) 3437

Table 3
Efcacy and toxicity of TC weekly in recurrent EOC.
TC weekly
Regimen

T (60 mg/m2) C(AUC 2.7)

n of patients

62

PFI

b6 mths
N = 43

612 mths
n = 14

>12 mths
n=5

1
15
16 (37)
6
9
63

1
4
5 (36)
6
10

1
1
2 (40)
11
14

Efcacy
CR
PR
RR (%)
Median PFS (mths)
Median OS (mths)
n of patients

37

pretreated then in the TC dose dense study. Seventy ve percent

(15/20) of the platinum sensitive patients in the weekly regimen vs.
42% (10/24) in the dose dense regimen received 3 previously chemotherapy regimens. This also translates in an increase in non hematological side effects in the weekly regimen such as fatigue and
nausea/vomiting. Hematological side effects varied; there was more
grade 34 anemia with more transfusion need and more trombopenia
with more need of platelet transfusions in the weekly regimen. The
advantage of the weekly scheme was though less neutropenia then
with the dose dense regimen and consequently less neutropenic fever.
In conclusion, weekly paclitaxelcarboplatinum in a heavily
pretreated group of ovarian cancer patients is effective, especially in
platin-resistant recurrent ovarian cancer.
Conict of interest statement

Toxicity
Hematological
Anemia grade 3/4
Neutropenia grade 3/4
Neutropenic fever
Trombopenia grade 3/4
Platelet transfusion
Non hematological
Muscle pain Grade 2
Hypersensitivity TC
Nausea/vomiting
Grade 2
Grade 3
Fatigue
Grade 2
Grade 3
Grade 4
Neuropathy
Grade 2
Grade 3

The authors declare that there are no conicts of interest.

25 (40)
42 (67)
4 (6)
22 (35)
8(13)
2 (3)
9 (14)
21 (33)
5 (8)
30 (48)
6 (9)
2 (3)
2 (3)
0

n: number, CR: complete remission, PR: partial remission, RR: response rate, PFS: progression free survival, OS: overall survival, TC: paclitaxelcarboplatinum.

In 2007 we published a series of patients with recurrent ovarian

cancer which were treated with paclitaxel and carboplatin in a dose
dense regimen (T 90 mg/m 2C AUC 4). RR for the platinum resistant
group was 38% (1 complete remission and 2 partial responses); this
correlates with the 37% for the current study with 1 complete remission and 15 partial responses. For the platinum sensitive group, RR
were 73% and 80% for the intermediate and sensitive group respectively. In the current study these results are lower with responses of
36% and 40% for the both groups respectively. The median PFS in
the platinum resistant group was 5 vs. 6 months for the dose dense
and the weekly regimen respectively, and the OS was 9 months in
both studies. For the platinum sensitive groups, median PFS was 9
and 13 months for the intermediate and sensitive group in the dose
dense regimen vs. 6 and 11 months for the same groups in the weekly
regimen. The median OS was 22 and 28 months compared with 10
and 14 months respectively.
Both regimens (dose dense and weekly) were already evaluated in
endometrial cancer as primary treatment or therapy for recurrent disease. Although the study groups were small and non randomized, in
the chemo naive patients RR, survival and toxicity were in favor of
the dose dense regimen though for the group who previously had
chemotherapy, the weekly regimen showed an improvement in RR
(39% vs. 21%). Recurrence, survival and hematological toxicity were
comparable [16,17].
Our results in the platinum resistant patients, resulting in a RR of
37%, are comparable with data from the literature. For platinum sensitive disease the results in literature are equal to our results in the TC
dose dense study. In the weekly regimen we have lower responses for
the platinum sensitive disease though these patients were more

Financial disclosures
The authors declare that there are no nancial disclosures.
References
[1] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765-81.
[2] The International Collaborative Ovarian Neoplasm (ICON) Group. Paclitaxel plus
carboplatin versus standard chemotherapy with either single-agent carboplatin
or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer:
the ICON3 randomised trial. Lancet 2002;360(9332):505-15.
[3] Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, et al.
Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based
chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR2.2
trial. Lancet 2003;361(9375):2099-106.
[4] Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey
PA, et al. Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late
relapse. J Clin Oncol Jul. 10 2010;28(20):3323-9.
[5] Cadron I, Leunen K, Amant F, Van Gorp T, Neven P, Vergote I. The Leuven
dose-dense paclitaxel/carboplatin regimen in patients with recurrent ovarian
cancer. Gynecol Oncol Aug. 2007;106(2):354-61.
[6] van der Burg ME, van der Gaast A, Vergote I, Burger CW, van Doorn HC, de Wit R,
et al. What is the role of dose-dense therapy? Int J Gynecol Cancer Nov.-Dec.
2005(15 Suppl. 3):233-40.
[7] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al.
New guidelines to evaluate the response to treatment in solid tumors. European
Organization for Research and Treatment of Cancer, National Cancer Institute of
the United States, National Cancer Institute of Canada. J Natl Cancer Inst Feb. 2
2000;92(3):205-16.
[8] Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials.
J Clin Oncol May 15 2003;21(10 Suppl.):187-93.
[9] Gladieff L, Ferrero A, De Rauglaudre G, Brown C, Vasey P, Reinthaller A, et al.
Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset
analysis of the CALYPSO phase III trial. Ann Oncol May 2012;23(5):1185-9.
[10] Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al.
Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer.
J Clin Oncol Jul. 1 2010;28(19):3107-14.
[11] Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, et al. Trabectedin plus
pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 612 months) subpopulation of
OVA-301 phase III randomized trial. Ann Oncol Jan. 2011;22(1):39-48.
[12] Wu CH, Yang CH, Lee JN, Hsu SC, Tsai EM. Weekly and monthly regimens of
paclitaxel and carboplatin in the management of advanced ovarian cancer. A preliminary report on side effects. Int J Gynecol Cancer 2001;11(4):295-9.
[13] Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, et al.
Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian
and peritoneal cancer. Gynecol Oncol Jan. 2003;88(1):51-7.
[14] Watanabe Y, Nakai H, Ueda H, Hoshiai H. Evaluation of weekly low-dose paclitaxel
and carboplatin treatment for patients with platinum-sensitive relapsed ovarian
cancer. Gynecol Oncol 2005;96(2):323-9.
[15] Sharma R, Graham J, Mitchell H, Brooks A, Blagden S, Gabra H. Extended weekly
dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated
platinum-resistant recurrent ovarian cancer. Br J Cancer Mar. 10 2009;100(5):707-12.
[16] Vandenput I, Vergote I, Leunen K, Berteloot P, Neven P, Amant F. Leuven dose-dense
paclitaxel/carboplatin regimen in patients with primary advanced or recurrent endometrial carcinoma. Int J Gynecol Cancer Aug. 2009;19(6):1147-51.
[17] Vandenput I. Clinicopathologic Study in Uterine Cancer. Doctoral Thesis in Biomedical Sciences. 2011.