European Journal of Cancer (2013) 49, 1254 1263

Available at www.sciencedirect.com

journal homepage: www.ejcancer.info

Long-term results of weekly paclitaxel carboplatin

induction therapy: An eective and well-tolerated treatment
in patients with platinum-resistant ovarian cancer
M.E.L. van der Burg a, I. Vergote b, W. Onstenk a, I.A. Boere a,, K. Leunen b,
C.A.G.M. van Montfort c, H.C. van Doorn d
a

Department of Medical Oncology, Erasmus MC Rotterdam, Rotterdam, The Netherlands

Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium
c
Department of Statistics, Erasmus MC Rotterdam, Rotterdam, The Netherlands
d
Department of Gynecological Oncology, Erasmus MC Rotterdam, Rotterdam, The Netherlands
b

Available online 29 December 2012

KEYWORDS
Dose-dense therapy
Ovarian cancer
Paclitaxel/carboplatin
Platinum-resistant
Platinum-sensitive
Recurrent ovarian cancer
Weekly-regimen

Abstract Background: Weekly paclitaxel/cisplatin is effective in platinum-resistant epithelial

ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin.
Patients and methods: Patients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m2 and carboplatin area under
the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. Endpoints were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity.
Results: Median progression free interval after last platinum was 9 (081) months in 108
patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin
<6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was
low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 121) and
13 (146) months, median OS 15 (169) and 26 (493) months, respectively. The 13 platinumresistant patients with a platinum-therapy free interval <6 months had a signicant shorter
PFS (4 versus 10 months, p = 0.035) and OS (9 versus 15 months, p = 0.002).
Conclusion: Six cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.
2012 Elsevier Ltd. All rights reserved.

Corresponding author: Address: Department of Medical Oncology, Room He-122, Erasmus University Medical Center Rotterdam, P.O.
Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 703 48 97; fax: +31 10 703 46 27.
E-mail address: i.boere@erasmusmc.nl (I.A. Boere).

0959-8049/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejca.2012.11.027

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

1. Introduction
Platinum combination therapy is the most eective
treatment in both primary and recurrent epithelial ovarian cancer (EOC).14 In relapsing patients the benet of
chemotherapy relates to platinum progression free interval (platinum-PFI). In platinum-sensitive (platinum-PFI
>6 months) patients, platinum combination chemotherapy yields response rates (RR) of 4765% with a median
progression free survival (PFS) of 813 months and median overall survival (OS) of 1829 months.24 In platinum-resistant disease (platinum-PFI 66 months) the
RR to single-agent platinum is only 10%,5 to non-platinum therapy 735% with a median PFS of 24 and OS
of 612 months, respectively.610 Dose-dense regimens
with weekly cisplatin in combination with etoposide,
topotecan or paclitaxel showed RR of 4663%, PFS of
58 months and OS of 1011 months.1113 Since recurrent disease is rarely curable, symptom control, maintaining quality of life, reducing adverse events (AE) and
prolonging PFS and OS are of paramount importance.
When rst-line treatment 3-weekly paclitaxel/carboplatin
was shown to be equally eective, but less toxic than 3weekly paclitaxel/cisplatin,14 we performed a phase I
study that showed that weekly paclitaxel 90 mg/m2 could
safely be combined with carboplatin area under the curve
(AUC) 4.15 In the current study, we explored the activity
and toxicity of six cycles weekly paclitaxel/carboplatin
induction therapy followed by six cycles 3-weekly paclitaxel/carboplatin in recurrent EOC.

1255

one-hour infusion on days 1, 8, 15, 29, 36, and 43.

Patients with clinical benet (stable disease (SD), partial
response (PR) and complete response (CR)) continued
treatment with six 3-weekly maintenance cycles paclitaxel 175 mg/m2 in 3-hour infusion, and carboplatin
AUC 6 in 1-hour infusion. Standard premedication
was given according to local protocol (supplement 1).
2.3. Dose modications
If on days 8, 15, 36, and 43 WBC were <1.0  109/L
and/or platelets <50  109/L and if day 29 of the weekly
or day 1 of the 3-weekly cycles WBC were <3.0  109/L
and/or platelets <100  109/L treatment was delayed by
one week until recovery. In case of febrile neutropenia
or grade 4 neutropenia on 2 successive weekly counts
paclitaxel/carboplatin was reduced by 20%, in case of
thrombocytopenia grade 4 carboplatin was reduced by
10%. Red blood cell transfusion was administered at
symptomatic anaemia and/or erythropoietin was started
if haemoglobin was <6.2 mmol/L. In case of a hypersensitivity reaction, paclitaxel or carboplatin infusion was
interrupted immediately and 2 mg clemastine was
administered intravenously. After recovery, infusion
was restarted with a prolonged infusion rate; starting
with an infusion rate of 15 ml/h during 15 min, followed
by 84 ml/h during 15 min. If no reaction occurred, infusion was continued at the normal infusion rate. The
same schedule was used for all subsequent cycles,
together with extra dexamethasone premedication.

2. Patients and methods

2.4. Treatment monitoring and toxicity scoring

2.1. Patient selection

Pre- and on-treatment monitoring consisted of medical history, physical and gynaecological examination,
CT-scan of thorax, abdomen and pelvis, TVU and
CA125 measurement. Before each cycle, and during follow-up, AE were scored according to the Common Toxicity Criteria of the National Cancer Institute (CTC
version 2.0).16 Routine blood tests included CA125, haematology, electrolytes, kidney and liver function tests.
Response was evaluated according to the response evaluation criteria in solid tumours (RECIST)17 after six
weekly, and three and six 3-weekly cycles of paclitaxel/
carboplatin. During follow-up patients were checked
bimonthly the rst, three-monthly the second, fourmonthly the third and fourth, six-monthly the fth year
and thereafter once a year. This included physical and
gynaecological examination TVU, and blood tests
including CA125. A CT-scan was only performed in
case of clinical signs or symptoms of progression.

Patients with progressive EOC and prior treatment

with paclitaxel and carboplatin were treated according
to the standardised treatment protocol for weekly paclitaxel/carboplatin, regardless the number of prior therapies. Progressive disease (PD) was conrmed by spiral
computed tomography (CT-scan), trans-vaginal ultrasound (TVU), and/or gynaecological and physical
examination. Eligibility criteria were WHO performance
status 62, at least one measurable lesion, creatinine
clearance calculated by Cockcroft-Gault P50 ml/min,
bilirubin <20 lmol/L, serum transaminases <60 U/L,
white blood cell count (WBC) P3.0  109/L and platelets P100  109/L. All patients gave informed consent.
This study was conducted in agreement with the Helsinki declaration of 1996.
2.2. Treatment regimen

2.5. Statistical methods

Treatment according to standardised treatment protocol consisted of six weekly induction cycles paclitaxel
90 mg/m2 and carboplatin AUC 4, both administered by

Analyses were conducted according to the intentionto-treat-principle. Platinum-PFI was dened as the

1256

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

Table 1
Patient characteristics, PC = paclitaxel/carboplatin, PFI = progression free interval, TFI = therapy free interval.

Entered
Age in years, median (range)
WHO performance status, median (range)
FIGO stage at primary diagnosis:
I
II
III
IV
Histology:
Serous
Adenocarcinoma undened
Endometrioid
Mucinous
Clear cell
Tumour grade:
1
2
3
Unspecied
Tumour size prior to weekly PC > 5 cm
No. of prior therapy lines:
1
2
37
Prior treatment with weekly cisplatin therapy
Last treatment non-platinum therapy
Treatment interval, median (range in months):
Interval last platinum progression (platinum-PFI)
Interval last platinum start weekly
PC (platinum-TFI)

Platinum-resistant
(66 m PFI)

Intermediate platinum-sensitive
(612 m PFI)

Platinum-sensitive
(>12 m PFI)

Total

43 (40%)
60 (3979)
1 (02)

27 (25%)
64 (3280)
0 (03)

38 (35%)
61 (3785)
1 (02)

108 (100%)
61 (3285)
1 (03)

4 (9%)
3 (7%)
17 (40%)
19 (44%)

1 (4%)
1 (4%)
20 (74%)
5 (18%)

4 (11%)
1 (3%)
26 (68%)
7 (18%)

9 (8%)
5 (5%)
63 (58%)
31 (29%)

30 (70%)
6 (14%)
2 (5%)
2 (5%)
3 (7%)

23 (85%)
1 (4%)
1 (4%)
0
2 (4%)

29 (76%)
4 (11%)
3 (8%)
1 (3%)
1 (3%)

82 (76%)
11 (10%)
6 (6%)
3 (3%)
6 (6%)

3 (7%)
7 (16%)
28 (65%)
5 (12%)
12 (28%)

3 (11%)
4 (15%)
19 (70%)
1 (4%)
12 (46%)

4 (11%)
11 (29%)
15 (39%)
8 (21%)
12 (32%)

10
22
62
14
36

(9%)
(20%)
(58%)
(13%)
(34%)

18
12
13
11
12

(42%)
(28%)
(30%)
(25%)
(28%)

11 (41%)
7 (26%)
9 (33%)
10 (37%)
6 (22%)

20 (52%)
9 (24%)
9 (24%)
12 (32%)
7 (18%)

49
28
31
33
25

(45%)
(26%)
(29%)
(31%)
(23%)

4 (06)
8 (1108)

9 (712)
12 (823)

19 (1381)
21 (1382)

9 (081)
14 (1108)

interval between the last platinum-chemotherapy and

PD. Therapy free interval (TFI) was dened as the interval between the last chemotherapy, platinum and nonplatinum and the start of weekly paclitaxel/carboplatin.
Platinum-resistance was dened as platinum-PFI
66 months, intermediate platinum-sensitivity as platinum-PFI between 6 and 12 months, platinum-sensitivity
as platinum-PFI >12 months. Dose-intensity (mg/m2/
week or AUC/week) was measured as the total dose of
paclitaxel (mg/m2) and carboplatin (AUC) divided by
the interval between the rst weekly and the rst 3-weekly
paclitaxel/carboplatin, or between the rst 3-weekly paclitaxel/carboplatin and day 22 of the last cycle. Endpoints were PFS, OS, RR and AE. Survival curves were
visualised using KaplanMeier plots and compared using
log-rank tests (SPSS 17, IL, United States of America).

3.2. Treatment
A total of 633 cycles weekly paclitaxel/carboplatin,
median six (range 28), and 448 cycles 3-weekly paclitaxel/carboplatin, median 6 (range 16), were administered (Fig. 1). Six of the 108 patients discontinued
treatment early. Ninety-six patients (89%) received at
least six weekly cycles, duration of the weekly induction
therapy was median 7 weeks (range 214). Ninety
patients (83%) continued treatment with 3-weekly paclitaxel/carboplatin, 60 (67%) completed all six 3-weekly
cycles. Main reasons to stop treatment were PD
(N = 13) and haematological toxicity (N = 7). Median
dose-intensities for the weekly and 3-weekly regimen
are presented in Table 2.
3.3. Toxicity

3. Results
3.1. Patients
From September 2001 to April 2006, 108 patients
were treated. Patient and disease characteristics are
summarised in Table 1. All but one patient had prior
therapy with platinum and paclitaxel. Median number
of prior therapies was 2 (range 17).

Both the weekly and the 3-weekly cycles were well

tolerated. Haematological grade 3/4 toxicity was
comparable (Table 3a). Treatment delay of median
7 days (range 735) was necessary in 16% of the
weekly cycles, mainly after the third or the fourth
cycle, and in 29% of the 3-weekly cycles. Dose reduction was needed in 2% (in 6 patients) and in 15% (in
22 patients) of the cycles, respectively. Six patients in

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

1257

Fig. 1. Flow-chart for all 108 enrolled patients during the weekly paclitaxel/carboplatin induction therapy and 3-weekly paclitaxel/carboplatin
maintenance therapy.

Table 2
Planned and achieved dose-intensity of paclitaxel and carboplatin for the weekly paclitaxel/carboplatin induction therapy and 3-weekly paclitaxel/
carboplatin maintenance therapy. AUC = area under the curve.
Agent

Paclitaxel
Carboplatin

Dose-intensity weekly regimen

Dose-intensity 3-weekly regimen

Planned dose-intensity

Achieved dose-intensity median

(range)

Planned dose-intensity

Achieved dose-intensity median

(range)

60 mg/m2/week
2.7 AUC/week

54 (2762) mg/m2/week
2.4 (1.22.8) AUC/week

58 mg/m2/week
2.0 AUC/week

58 (2265) mg/m2/week
2.0 (0.92.3) AUC/week

the weekly and 7 in the 3-weekly regimen stopped

treatment due to haematologic toxicity. Five of the
6 patients in the weekly regimen continued treatment
with the 3-weekly cycles; 3 of the 7 patients in the 3weekly regimen continued o-protocol with weekly
cycles. Febrile neutropenia occurred thrice during
the weekly regimen. Non-haematological toxicity
was mild (Table 3b). Alopecia occurred mainly during
the 3-weekly cycles. No grade 3 neurotoxicity was
observed nor was treatment stopped because of
neurotoxicity. At baseline 37% (30% grade 1, 7%
grade 2) of the patients had sensory-neurotoxicity
due to prior treatment. During the weekly and 3weekly cycles sensory-neurotoxicity grade 1/2 was
reported in 27% (13% grade 1, 14% grade 2) and

34% (16% grade 1, 18% grade 2), respectively. Only

1% and 8% of the patients with neurotoxicity grades
1 and 2, respectively, had at baseline grade 0. Before
treatment 14% of the patients had already experienced an allergic reaction to paclitaxel and 3% to carboplatin. During the weekly cycles, 10% of the
patients had a hypersensitivity reaction to paclitaxel
and 13% to carboplatin, during the 3-weekly cycles
this was 0% and 8%, respectively. All patients except
one continued treatment successfully with the antiallergy infusion scheme.
One patient treated with three dierent chemotherapy regimens and two radiotherapy series died of
myelodysplastic syndrome 4 years after weekly paclitaxel/carboplatin and 17 years after primary diagnosis.

1258

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

Table 3a
Haematologic toxicity according to CTC 2.0. PC = paclitaxel/carboplatin.
Toxicity

Weekly PC induction therapy

3-Weekly PC maintenance

N = 633 cycles

N = 108 patients

N = 448 cycles

N = 90 patients

Nadir median Grade 2 Grade 3 Grade 4 At least once grade Nadir median Grade 2 Grade 3 Grade 4 At least once grade
(range)
cycles
cycles
cycles
3/4 per patient
(range)
cycles
cycles
cycles
3/4 per patient
Haemoglobin
(lmol/L)
Platelets (109/)
WBC (109/L)
Granulocytes
(109/L)
Febrile
neutropenia

6.6 (2.89.8)

29%

5%

1%

20%

6.6 (2.09.2)

180 (2593)
7%
3.1 (0.118.5) 28%
1.47 (0.115.7) 19%

5%
17%
19%

3%
2%
11%

29%
51%
79%

0.5%

2%

26%

4%

0.5%

13%

105 (13699) 18%

2.7 (0710.4) 35%
0.81 (0.045.5) 18%

8%
21%
30%

1%
1%
24%

29%
47%
83%

Table 3b
Non-haematologic toxicity according to CTC 2.0.
Toxicity

Weekly PC induction therapy (633 Cycles/N = 108

patients)
Grade 2

Nausea/vomiting
Diarrhoea
Fatigue
Myalgia
Hypomagnesaemia
Nephrotoxicity
Ototoxicity
Neuropathy-sensorya
Hypersensitivity:
Paclitaxel
Carboplatin

Grade 3

3-Weekly PC maintenance (448 Cycles/N = 90

patients)
Grade 2

Grade 3

Cycles

Patients

Cycles

Patients

Cycles

Patients

Cycles

Patients

3.0%
0.3%
2.6%
1.3%
1.2%
0.5%
1.5%

12%
2%
11%
6%
4%
3%
3%
14%

0%
0.2%
0.3%
0.3%
0%
0%
0%

0%
1%
2%
2%
0%
0%
0%
0%

1.2%
0.2%
4.2%
6.2%
1.6%
0.2%
2%

5%
1%
13%
15%
5%
1%
4%
18%

0.2%
0%
0%
1%
0%
0%
0%

1%
0%
0%
4%
0%
0%
0%
0%

0%
0%

0%
0%

2.5%
3.3%

10%
13%

0%
0%

0%
0%

0%
2.6%

0%
8%

At baseline 30% of the patients had already grade 1 and 7% grade 2 sensory-neuropathy due to prior treatment. And only 1% of the patients
with grade 1 and 8% with grade 2 sensory-neurotoxicity had grade 0 at base-line.

3.4. Response
Responses already occurred within nine weeks of
treatment (Table 4). After the weekly paclitaxel/carboplatin induction cycles, 51% of the 43 platinum-resistant
patients had a response, 16% had PD. During the following 3-weekly paclitaxel/carboplatin maintenance
cycles the RR increased to 58% (16% CR), and 77% of
the platinum-resistant patients had clinical benet at
the end of treatment. For the platinum-sensitive and
intermediate platinum-sensitive patients the overall RR
was 76% (26% CR) and 67% (30% CR) respectively,
and 94% and 97% respectively, had clinical benet.
Although 33 patients had received prior weekly cisplatin
combination therapy, this and the number of prior therapies did not aect the chance of response.
3.5. Survival
In the platinum-resistant patients, PFS was 8 months
(95% condence interval (CI) 6.79.9) compared to

11 months (95%CI 8.812.4, p = 0.233) in the intermediate platinum-sensitive patients, and 13 months (95%CI
10.315.1, p < 0.001) in the platinum-sensitive patients
(Table 5a and Fig. 2a). The median OS for platinumresistant patients was 15 months (95%CI 11.717.5)
compared to 28 months (95%CI 15.640.1, p = 0.004)
for intermediate platinum-sensitive and 26 months
(95%CI 16.136.1, p < 0.001) for platinum-sensitive
patients. Only 13 of the 43 platinum-resistant patients
started the weekly paclitaxel/carboplatin within
6 months, median 4 months (range 16), after the last
platinum administration (platinum-TFI 66 months).
The RR in these patients was 31% (CR 8%), and the
clinical benet 62%. The median PFS was 4 months
(95%CI 1.67.0) and OS 9 months (95%CI 4.212.8);
25% of these patients were still alive after 14 months
(Table 5bc and Fig. 2cd). The other 30 platinumresistant patients started weekly paclitaxel/carboplatin
>6 months after the last platinum administration,
median 9 months (range 7108); 10 had been treated
in-between with non-platinum therapy and 2 with

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

1259

Table 4
Response after weekly paclitaxel/carboplatin induction therapy and overall response rate (RR) at end of treatment.
Response

Evaluable patients
Complete response
Partial response
Stable disease
Progressive disease
ED, EP, NEa
RR
a

Response after induction therapy weekly paclitaxel/carboplatin

Best response at the end of treatment

Platinumresistant
(66 m)

Platinum- Intermediate
Platinum- Total
resistant
platinum sensitive sensitive
(6 6 m)
(612 m)
(> 12 m)

Intermediate
platinum- sensitive
(612 m)

Platinumsensitive
(> 12 m)

Total

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

43
1 (2%)
21 (49%)
11 (26%)
7 (16%)
3 (7%)
22 (51%)

27
1 (4%)
15 (56%)
10 (37%)
1 (4%)
0
16 (60%)

38
4 (11%)
19 (50%)
13 (34%)
2 (5%)
0
23 (61%)

108
6 (6%)
55 (51%)
34 (31%)
10 (9%)
3 (3%)
61 (56%)

43
7 (16%)
18 (42%)
8 (19%)
7 (16%)
3 (7%)
25 (58%)

27
8 (30%)
10 (37%)
8 (30%)
1 (4%)
0
18 (67%)

38
10 (26%)
19 (50%)
7 (18%)
2 (5%)
0
29 (76%)

108
25 (23%)
47 (44%)
23 (21%)
10 (9%)
3 (3%)
72 (67%)

ED = early death, EP = early progression, NE = not evaluable.

Table 5
Progression Free Survival (PFS) and Overall Survival (OS) according to (a) platinum-sensitivity (b) platinum-therapy free interval (TFI) and
platinum-sensitivity, (c) and platinum-TFI.
Platinum-PFI

Platinum-resistant (66 months)

Intermediate platinum-sensitive (612 months)

Platinum-sensitive (>12 months)

(a) Progression free interval after last platinum administration (platinum-PFI) (95% condence interval), log-rank (MantelCox) p value
Number (%)
43 (40%)
27 (25%)
38 (35%)
Response (CR)
58% (16%)
67% (30%)
76% (26%)
PFS (median, months)
8 (6.79.9)
11 (8.812.4) p = 0.233
13 (10.315.1) p < 0.001
OS (median, months)
15 (11.717.5)
28 (15.640.1) p = 0.004
26 (16.136.1) p < 0.001
Platinum-resistant

Platinum-sensitive

(b) Platinum-therapy free interval (Platinum-TFI) and platinum-sensitivity (95% condence interval), log-rank (MantelCox) p value
Platinum-TFI
66 months
>6 months
612 months
>12 months
Number (%)
13 (12%)
30 (28%)
17 (16%)
48 (44%)
Response rate (CR)
31% (8%)
70% (20%)
71% (29%)
73% (27%)
PFS (median, months)
4 (1.67.0)
10 (6.413.5) p = 0.035
12 (10.913.6) p = 0.016
12 (9.913.6) p < 0.001
OS (median, months)
9 (4.212.8)
15 (13.117.5) p = 0.002
24 (14.634.2) p = <0.001
27 (16.138.2) p < 0.001
Platinum-TFI

66 months

612 months

(c) Platinum TFI (95% condence interval), log-rank (MantelCox) p value

Number (%)
13 (12%)
37 (34%)
Response rate (CR)
31% (8%)
73% (27%)
PFS (median, months)
4 (67.0)
11 (9.112.5) p = 0.028
OS (median, months)
9 (4.212.9)
20 (16.523.8) p < 0.001

surgery and radiotherapy for a local recurrence, in 18

patients treatment was delayed until the development
of symptoms or rapid clinical progression. The RR in
these patients was 73% (27% CR) and 87% had clinical
benet. The median PFS was 10 months (95%CI 6.4
13.5) and median OS 15 months (95%CI 13.117.5),
which was signicantly better than in the group that
started the weekly paclitaxel/carboplatin within
6 months (p = 0.035 and 0.002, respectively) and comparable to the median PFS (12 months, p = 0.292) and OS
(24 months, p = 0.148) of the intermediate platinumsensitive patients (Table 5bc and Fig. 2cf). The same
ndings were obtained for OS after primary diagnosis
(Fig. 2f). PFS and OS according to PFI and TFI after
last treatment (platinum and non-platinum) showed no
better results (Table S1bc and Fig. S1cf).

> 12 months
58 (54%)
71% (24%)
12 (9.513.5) p < 0.001
26 (20.830.4) p < 0.001

4. Discussion
Weekly paclitaxel/carboplatin followed by 3-weekly
cycles is highly active in platinum-resistant EOC. After
6 weekly cycles, 51% of the platinum-resistant patients
had a response, and 77% had clinical benet with relief
of symptoms. The majority of the patients continued to
respond to the additional 3-weekly paclitaxel/carboplatin; the overall RR was 58% (16% CR), median
PFS 8 months, and OS 15 months (Table 5a and
Fig. 2ab). These results are similar to data found in
previous studies with weekly cisplatin/etoposide (RR
46%, PFS 5 months, OS 10 months) and cisplatin/
paclitaxel (RR 50%, PFS 8, OS 14 months), but weekly
paclitaxel/carboplatin seemed better tolerated.1113,18 In
particular the non-haematological toxicity (CTC-grade

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M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

Fig. 2. (a and b) PFS and OS according to platinum-PFI and platinum-sensitivity, (c and d) PFS and OS according to platinum-TFI, (e and f) PFS
and OS according to platinum-TFI and (g) OS from diagnosis according to platinum-TFI and platinum-sensitivity of 106 patients (2 patients date
of primary diagnosis unknown).

P2) nausea and vomiting (3% versus 49%), fatigue (3%

versus 25%) and hypomagnesaemia (1.2% versus 32%)
were less frequent in weekly paclitaxel/carboplatin.11

Although 92% of the patients treated with the weekly

and 42% with 3-weekly paclitaxel/carboplatin at
least once encountered a grade 3/4 neutropenia or

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

1261

Table 6
Seven studies (full paper or abstract) using dose-dense paclitaxel and/or carboplatin in patients with platinum-resistant ovarian cancer. If available,
number of platinum-resistant and platinum-sensitive patients is specied. Abbreviations: T = paclitaxel, C = carboplatin, AUC = area under the
curve, w = week, q = cycle length, m = months, PD = progressive disease, CR = complete response.
Study

Regimen

Platinum
sensitivity

N
RR CR PFS OS Toxicity grade 3/4% of patients
(evaluable) (%) (%) (m) (m) Anaemia Neutropenia Thrombocytopenia Neurotoxicity Hypersensitivity
(%)
(%)
(%)
(%)
(%)

45 (33)
Katsumata T 80 mgm2/ All
w
et al.
(2001)33 C AUC 2/w <6 months 11
18 weeks
>6 months 16
29
Havrilesky T 80 mgm2/ All
w
et al.
(2003)26 C AUC 2/w < 6 months 8
days 1, 8, 15 > 6 months 21
q4w until
PD/CR
Cadron
T90 mgm2/w
et al.
C AUC 4/w
(2007)27 Days 1, 8,
q3w
6 courses

All
<6 months
6
12 months
>12 months

Sharma
T 70 mgm2/ All
et al.
w
(2009)28 C AUC 3/w Refractory
Days 1, 8, 15 <6 months
q4w
>6 months

67

39

15

55
73

21

(gr 23)

83

55

11.5 NR 11

38
10

13
71

3.2 11.4
13.7

33 (29)
8
11

66
38
73

21
13
18

9
18 24
6.8 8
10.5 NR

10

80

30

12.8 NR

21

60

7.9

13.3 5

5
7

25
25

8.9
5.5

6.8

50

7.8

10.0

Hoekstra T 80 mgm2 All

20
et al.
days 1, 8, 15
(2009)32 C AUC 5
<6 months 5
day 1
q4w
6
5
12 months
>12 months 10

61

85

75

60

40

32

14

21

94

25

30

14

14

NR 0

35

25

93

87

Lotholary T 80 mgm2 <6 months 51

et al.
days 1, 8, 15
(2012)21 C AUC 5
day 1a

37

4.8

15.2 19

54

20

16

Present
study

67

23

10.6 20.2 20

79

29

22

<6 months 43
6
27
12 months

58
67

16
30

8.3 11.7
10.6 24.5

>12 months 38

71

26

12.7 26.1

T 90 mgm2/
w
C AUC 4/w
days 1, 8, 15,
29, 35, 42
then
6 courses
q3w

All

108

Only treatment group that received the combination paclitaxel/carboplatin.

thrombocytopenia, only 16% of the weekly and 29% of

the 3-weekly cycles were delayed by median 1 week,
dose-reductions were required in 2% and 15% respectively, and only 0.2% and 6% of the cycles were skipped
due to haematologic toxicity, respectively.
The RR to weekly paclitaxel/carboplatin in platinumresistant patients is higher compared to published series
on non-platinum monotherapy with paclitaxel (RR
20%), pegylated liposomal doxorubicin (PLD) (RR
16%), topotecan (RR 13%) or 3-weekly platinum
(RR 10%) with a median PFS varying from 2 to

4 months.59 Although a higher RR of 2156% was

found for weekly paclitaxel monotherapy, the median
PFS was usually only 3.65 months.1921 Non-platinum
combination therapy of weekly paclitaxel combined
with 4-weekly gemcitabine or PLD in combination with
gemcitabine, topotecan or trabectedin, showed RR of
1340% with a median PFS of 47.5 months, in some
studies at the cost of severe bone marrow toxicity.2225
Lortholary et al. compared weekly paclitaxel 80 mg/
m2/week day 1, 8, 15 q 28 days, with weekly paclitaxel
80 mg/m2/week in combination with carboplatin AUC

1262

M.E.L. van der Burg et al. / European Journal of Cancer 49 (2013) 12541263

5 every 4 weeks, or with topotecan 3 mg/m2/week. RR

were 35%, 37% and 39%, and median PFS were 4, 5
and 5 months (p = 0.45), respectively.21
Only three studies with weekly paclitaxel/carboplatin
included platinum-resistant patients (Table 7). In these
studies, the weekly paclitaxel/carboplatin was continued
during the total treatment, a RR of 2538%, PFS of 3
9 months and OS of 811 months were found in platinum-resistant patients.2628 Because of the low number
of patients and the dierences in dose-intensities for
both paclitaxel and carboplatin in these studies, and
the lack of direct comparison, it is hard to draw rm
conclusions. However, continuation of the weekly paclitaxel/carboplatin during the whole treatment period
did not show better RR or PFS, compared to our study
with 6 weekly paclitaxel/carboplatin followed by 3weekly cycles, which suggests that the rst six weekly
paclitaxel/carboplatin administrations are the most
important. Increasing the platinum-TFI interval by the
use of non-platinum agents is thought to increase the
RR and PFS in platinum-resistant patients.29,30 In our
study 12 of the 43 platinum-resistant patients received
non-platinum therapy before the start of weekly paclitaxel/carboplatin, and in 18 patients treatment was
delayed until symptoms or rapid progression, leading
to increased platinum-TFI of >6 months in 30 platinum-resistant patients. The 13 patients with a platinum-TFI 66 months had the worst prognosis
(Table 5cd and Fig. 2cd). Median PFS and OS for
these patients were 4 and 9 months, respectively compared to 10 (p = 0.035) and 15 months (p = 0.002) for
the platinum-resistant patients with a longer platinumTFI. The platinum-TFI seemed to be a better criterion
to select poor-risk platinum-resistant patients
(Table 5b and Fig. 2cf). The same survival trend is
shown in OS after primary diagnosis (Fig. 2f). Increasing the platinum-TFI either by non-platinum therapy
or just by delaying treatment increased the PFS and
OS. This corresponds well with the results found in
the MRC/EORTC CA125 study, which showed that
after rst-line therapy, second-line treatment can safely
be delayed until clinical signs or symptoms of a recurrence, without impairment of survival or quality of
life.31
Dose-dense weekly paclitaxel/carboplatin is also
highly eective in platinum-intermediate (RR 67%, PFS
11 months, OS 28 months) and platinum-sensitive
patients (RR 76%, PFS 13 months, OS 26 months).
Comparable results have been found in other studies
using continuous weekly paclitaxel/carboplatin and
continuous weekly paclitaxel with 4-weekly carboplatin
despite dierences in regimen, number of prior therapies,
PFI and prior treatment with paclitaxel.21,3238 Although
weekly paclitaxel/carboplatin is not directly compared
with 3-weekly paclitaxel/carboplatin (RR 66%,
PFS 13, OS 29 months)2 or 4-weekly PLD/carboplatin

(RR 63%, PFS 11, OS 31 months)3 the weekly regimen

does not seem to be more eective than these 3-weekly
or 4-weekly regimens in platinum-sensitive patients.
In conclusion, dose-dense weekly paclitaxel/carboplatin induction therapy is well-tolerated and highly
active in platinum-resistant and platinum-sensitive
patients. Platinum-resistant patients with a platinumTFI <6 months however, had a signicantly shorter
PFS and OS, compared to patients with a longer platinum-TFI. The platinum-TFI seemed to be a good
criterion to select poor-risk platinum-resistant patients.
Conict of interest statement
None declared.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at http://dx.doi.org/
10.1016/j.ejca.2012.11.027.
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