original articles

Annals of Oncology

Annals of Oncology 25: 251257, 2014

doi:10.1093/annonc/mdt527

Quality-of-life outcomes from a randomized phase III

trial of dose-dense weekly paclitaxel and carboplatin
compared with conventional paclitaxel and carboplatin
as a first-line treatment for stage IIIV ovarian cancer:
Japanese Gynecologic Oncology Group Trial
(JGOG3016)
K. Harano1, F. Terauchi2, N. Katsumata1*, F. Takahashi3, M. Yasuda4, S. Takakura4, M. Takano5,
Y. Yamamoto6 & T. Sugiyama7
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital, Kawasaki; 2Department of Obstetrics and Gynecology, Tokyo Medical University,
Tokyo; 3Research Center for Clinical Pharmacology, Kitasato University, Tokyo; 4Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo;
5
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa; 6Department of Obstetrics and Gynecology, Toho University Ohashi Hospital,
Tokyo; 7Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

Received 24 June 2013; revised 30 September 2013; accepted 22 October 2013

Background: Dose-dense weekly paclitaxel (Taxol) and carboplatin (dd-TC) improved survival compared with conventional tri-weekly paclitaxel and carboplatin (c-TC) as a rst-line chemotherapy for newly diagnosed stage IIIV ovarian
cancer in the Japanese Gynecologic Oncology Group 3016 trial. We report the quality-of-life (QoL) results from this trial.
Patients and methods: A total of 637 patients were randomly assigned to receive c-TC or dd-TC (c-TC, n = 319;
dd-TC, n = 312) and were asked to complete a QoL assessment at baseline, just after the third and sixth chemotherapy
cycles, and at 12 months after randomization. QoL was assessed using Functional Assessment of Cancer Therapy
(FACT)-general (FACT-G), FACT-taxane subscale (FACT-T), and FACT-ovary subscale (FACT-Ov). The overall QoL and
that according to each subscale were analyzed using mixed-effects models adjusted for treatment and time.
Results: Baseline QoL assessment was completed by 204 out of 319 (63.9%) and 200 out of 312 (64.1%) patients in
the c-TC and dd-TC groups, respectively. In these groups, the compliance rates with regard to QoL assessment were
74.5% and 73.0%, respectively, after three chemotherapy cycles; 86.8% and 86.9%, respectively, after six chemotherapy
cycles; and 74.2% and 71.6%, respectively, at 12 months after randomization. The overall QoL did not differ signicantly
between the two treatment groups up to 12 months after randomization (P = 0.46). However, QoL according to the
FACT-T subscale was signicantly lower in the dd-TC group than in the c-TC group (P = 0.02).
Conclusion: dd-TC does not decrease overall QoL compared with c-TC.
Clinical trial information: NCT00226915.
Key words: carboplatin, neurotoxicity, ovarian cancer, paclitaxel, quality of life

introduction
Ovarian cancer is the sixth most common cause of cancer death
of women in developed countries, with an estimated 220 000
cases and 140 000 deaths occurring annually worldwide [1].
The standard treatment for advanced ovarian cancer has been
surgery and platinum-based combination chemotherapy.
*Correspondence to: Dr Noriyuki Katsumata, Department of Medical Oncology, Nippon
Medical School Musashikosugi Hospital, 1-396, Kosugi-cho, Nakahara-ku, Kawasaki
City, Kanagawa 211-0063, Japan. Tel: +81-44-733-5181; Fax: +81-44-711-8726;
E-mail: nkatsuma@nms.ac.jp

Paclitaxel and carboplatin administered every 3 weeks have

been used as the standard rst-line intervention. In spite of
attempts to improve this combination chemotherapy by adding
other drugs, the results of several randomized trials have not
shown any improvement in survival [2, 3]. The addition of
bevacizumab, a humanized vascular endothelial growth factorneutralizing monoclonal antibody, to standard combination
chemotherapy resulted in a signicant improvement in progression-free survival (PFS) compared with chemotherapy alone,
but only by modest improvement (24 months) [4, 5].
Moreover, further consideration needs to be given to the

The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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original articles

patients and methods

eligibility
This study was coordinated by the Japanese Gynecologic Oncology Group
(JGOG) and was designed as a randomized, multicenter, non-blinded phase
III trial (JGOG 3016) [7]. The details of the trial have been reported previously. Briey, the eligible patients had a histologically or cytologically
conrmed diagnosis of stage IIIV epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Other inclusion criteria were age of
20 years or more; an Eastern Cooperative Oncology Group performance
status of 03; and adequate bone marrow, renal, and hepatic function.
Patients were excluded if they had an ovarian tumor with a low malignant
potential or a synchronous or metachronous (within 5 years) malignancies
other than carcinoma in situ. All patients provided informed consent before
enrollment in this study. The study protocol was approved by the institutional review boards at all participating centers.

treatment plan
Patients were randomly assigned to receive paclitaxel (Taxol) and carboplatin as part of either a conventional regimen (conventional therapy group,
c-TC group) or a dose-dense regimen (dose-dense therapy group, dd-TC
group). Both groups received carboplatin at a dose calculated to produce an
area under the plasma concentrationtime curve of 6 mg/ml/min on day 1
of a 21-day cycle. Carboplatin was administered as intravenous infusion over
the course of 1 h. The c-TC group additionally received paclitaxel administered as intravenous infusion for 3 h at a dose of 180 mg/m2 on day 1. In the
dd-TC group, paclitaxel was administered as intravenous infusion over 1 h at
a dose of 80 mg/m2 on days 1, 8, and 15. The treatments were repeated every
3 weeks for six cycles. Patients with measurable lesions who had a partial
response or complete response received three additional cycles of
chemotherapy.

(FACT-Ov). FACT-G (Version 4) is a 27-item self-reporting QoL measure

developed and validated among cancer patients for use in clinical trials [9].
It contains four subscales measuring physical well-being, social well-being,
emotional well-being, and functional well-being. Each subscale contains
seven, seven, six, and seven items, respectively. The FACT-T subscale is a
16-item self-reporting questionnaire focusing on patient-reported neurotoxicity symptoms and concerns [10]. The FACT-Ov subscale is an 11-item
self-reporting questionnaire focusing on well-being related to ovarian
cancer [11].
The FACT questionnaires use a ve-point response scale: 0 referred to not
at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. The range
of possible scores was 0108 for FACT-G, 064 for FACT-T, and 044 for
FACT-Ov. In FACT-G, the range of possible scores for the physical, social,
emotional, and functional subscales were 028, 028, 024, and 028,
respectively.
Patients were asked to complete the QoL assessment at four time points:
baseline (before treatment), after the third and sixth chemotherapy cycles,
and at 12 months after randomization. At the third and sixth cycle, patients
were given questionnaires at day 1, which were completed at home and
mailed to the researchers within 3 weeks. The QoL assessment was not obligatory in the study, and we collected the data on patients who cooperated
in the QoL assessment. If treatment was delayed, the corresponding QoL
assessment was to be completed as near to the scheduled time point as
possible.

statistical analyses
To assess QoL, scores were computed if more than 80% of items were
answered in the overall FACT-G and more than 50% of items in the FACTT, FACT-Ov, and FACT-G subscales. The baseline completion rate was calculated for each treatment arm, and compliance rates at subsequent time
points were dened as the proportion of patients completing QoL assessment based on the number of patients who completed QoL assessment at
baseline. QoL assessments were collected irrespective of the patients disease
status. Differences in patient characteristics between treatment arms were
calculated using the 2 test. The mean scores and standard deviation at baseline and at each time point were calculated for the overall scale (the sum of
all subscales) as well as for the physical, social, emotional, functional, taxane,
and ovary subscales.
To examine whether the follow-up QoL scores were affected by the treatment, a linear mixed effects model was applied and adjusted for the effects of
time and treatment [12]. All QoL analyses were restricted to those patients
who completed baseline QoL assessment.

results
patient characteristics
Between April 2003 and December 2005, a total of 637 patients
were enrolled in the study. Of these, 319 patients were randomized to the c-TC group and 312 were randomized to the ddTC group. Two hundred and four (63.9%) patients in the c-TC
group and 200 (64.1%) patients in the dd-TC group completed
baseline QoL assessment. Baseline characteristics did not differ
signicantly between the two treatment groups (Table 1).

compliance with QoL assessment

QoL assessment
QoL was assessed using the following validated patient self-reported questionnaires: Functional Assessment of Cancer Therapy (FACT)-general
(FACT-G), FACT-Taxane subscale (FACT-T), and FACT-Ovary subscale

| Harano et al.

The compliance rates for QoL assessment in the c-TC and ddTC groups were 74.5% (152/204) and 73.0% (146/200), respectively, after three cycles of treatment; 86.8% (132/152) and 86.9%
(127/146), respectively, after six cycles of treatment; and 74.2%

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addition of bevacizumab because of its high cost and toxic

effects such as hypertension and bowel perforation [6].
In the Japanese Gynecologic Oncology Group trial (JGOG
3016 trial), dose-dense administration of paclitaxel combined
with carboplatin (dd-TC) improved PFS and overall survival
(OS) compared with conventional, tri-weekly paclitaxel and carboplatin (c-TC) in patients with newly diagnosed stage IIIV
ovarian cancer [7, 8]. The dd-TC group showed a signicantly
better median PFS than the c-TC group [28.1 versus 17.5
months, hazard ratio (HR) 0.75, 95% condence interval (CI),
0.620.91; P = 0.0037], and the 5-year OS rate was higher in the
dd-TC group than in the c-TC group (58.6% versus 51.0%, HR
0.79, 95% CI, 0.630.99; P = 0.0448) according to 6.4-year
follow-up data [8]. The frequency of grade 3 or 4 anemia was
higher in the dd-TC group than in the c-TC group, but the frequency of other toxic effects was similar between the two
groups.
These benets are likely to be reected in patients quality of
life (QoL), and the assessment of QoL is a critical end point if
the treatment shows improved survival but also has the potential
for increased toxicity. We aimed to compare the QoL of patients
receiving dd-TC and c-TC in the JGOG 3016 trial.

Annals of Oncology

original articles

Annals of Oncology

Table 1. Patient characteristics

Conventional triweekly paclitaxel
and carboplatin
(n = 204)
No. (%)

P
value

56
2582

0.651

181 (90.5)
17 (8.5)
2 (1)

0.411

43 (21.5)
3 (1.5)
14 (7)
106 (53)
34 (17)

0.85

Before treatment
After 3 cycles
After 6 cycles
12 months after
randomization

250

Conventional
tri-weekly
paclitaxel and
carboplatin
Valid/expected
(%)

Dose-dense
weekly paclitaxel
and carboplatin

204/319 (63.9)
152/204 (74.5)
132/152 (86.8)
98/132 (74.2)

200/312 (64.1)
146/200 (73)
127/146 (86.9)
91/127 (71.6)

Valid/expected
(%)

: Conventional tri-weekly paclitaxel and carboplatin

: Dose-dense weekly paclitaxel and carboplatin

200

168 (84)
9 (4.5)
23 (11.5)

150

100

50

160 (80)
40 (20)

0.188
0
Prior to
treatment

91 (45.5)
109 (54.5)

0.487

ECOG, Eastern clinical oncology group; PS, performance status;

FIGO, International Federation of Gynecology and Obstetrics.

(98/132) and 71.6% (91/127), respectively, at 12 months after

randomization (Table 2). These differences were not signicant
across time points.
There was no patient with disease progression at third and
sixth chemotherapy cycles, but there were 17 and 10 patients
with disease progression in the c-TC and dd-TC groups,
respectively, at 12 months after randomization.

QoL on treatment
The arms did not differ signicantly with respect to the overall
QoL score (Figure 1, Table 3) at any of the time points. QoL
according to the physical, social, emotional, functional, taxane,
and ovary subscales also did not differ signicantly between the
groups at any time point (Figure 2; Table 3).
Figure 1 shows the baseline and changes in the mean scores
for overall QoL scale of each group. The mixed linear model was
tted for the overall QoL scale. The reported scores did not
change over time in each group, and there was no statistical difference between two groups (P = 0.46). Both groups presented
nearly stable scores during the assessment period, and the interaction of time and treatment was not statistically signicant.

Volume 25 | No. 1 | January 2014

Assessment point

After
After 12 months after
3 cycles
6 cycles randomization
Assessment points

Figure 1. Box plot showing the baseline and changes in overall quality-oflife scores for each treatment group.

Figure 2 shows the baseline and changes in the mean scores

for physical subscale, social subscale, emotional subscale, functional subscale, taxane subscale, and ovary subscale. The mixed
linear model was tted for these subscales. Among subscales,
only the FACT-T subscale showed statistically signicant difference between treatment groups. The FACT-T subscale of the
dd-TC group showed signicantly lower QoL than that of the
c-TC group (P = 0.02). However, there was no statistical difference of QoL between two groups in physical subscale (P = 0.90),
social subscale (P = 0.24), emotional subscale (P = 0.23),
functional subscale (P = 0.14), and ovary subscale (P = 0.46).
We additionally analyzed QoL in patients without disease
progression. The FACT-T subscale of dd-TC showed lower QoL
than that of c-TC, although it was not statistically signicant
(P = 0.06). There was no statistical difference of QoL between
two groups in overall (P = 0.25), physical subscale (P = 0.97),
social subscale (P = 0.18), emotional subscale (P = 0.17),
functional subscale (P = 0.20), and ovary subscale (P = 0.11).

discussion
This trial showed that dd-TC signicantly improved PFS and
OS compared with c-TC in patients with newly diagnosed
advanced ovarian cancer. The toxicity of dd-TC was comparable
to that of c-TC, except for grade 3 or 4 anemia.

doi:10.1093/annonc/mdt527 |

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Age
Median
56
Range
2584
ECOG PS
01
181 (88.7)
2
17 (7.8)
3
7 (3.4)
FIGO stage
II
40 (19.6)
IIIa
6 (2.9)
IIIb
13 (6.4)
IIIc
116 (56.9)
IV
29 (14.2)
Primary disease
Ovarian
172 (84.3)
Fallopian tube
12 (5.9)
Primary
20 (9.8)
peritoneal
Histological type
Serous/others
174 (85.3)
Clear cell/
30 (14.7)
mucinous
Residual disease
1 cm
100 (49)
>1 cm
104 (51)

Dose-dense
weekly paclitaxel
and carboplatin
(n = 200)
No. (%)

Overall QOL score

Characteristic

Table 2. Compliance rate

original articles

Annals of Oncology

Table 3. Quality-of-life scores according to the overall questionnaire and the subscales in both treatment arms
Domain

Conventional tri-weekly
paclitaxel and carboplatin
Mean score
SD

Dose-dense weekly paclitaxel

and carboplatin
Mean score
SD

Before treatmenta

Overall
Physical
Social
Emotional
Functional
Taxane
Ovary
Overall
Physical
Social
Emotional
Functional
Taxane
Ovary
Overall
Physical
Social
Emotional
Functional
Taxane
Ovary
Overall
Physical
Social
Emotional
Functional
Taxane
Ovary

154.2
19.4
22.4
15.2
15.6
53.9
27.2
153.3
19.4
21.1
15.8
15.5
53.6
27.6
157.3
20.5
21.7
16.3
15.5
55.2
27.5
150.5
19.1
21.6
15.9
15.3
51.6
26.7

149.9
19.1
21
14.8
16.1
51.1
27.3
153.4
19.8
21.6
15.6
16.1
51.8
28.3
156.1
20.1
21.8
15.4
16.6
53
28.9
154.4
19.9
21.4
15.8
15.2
53.9
27.7

After 3 cyclesb

After 6 cyclesc

12 months after randomizationd

23.3
4.9
4.5
5.7
6.7
9.8
6.3
22.8
4.7
5.4
6.1
6.3
10.2
5.6
22.5
5
5.6
5.6
7.2
9.8
5.8
25.9
5.4
4.8
5.5
6
12.1
6

26.4
5.6
5.5
5.7
6.4
11.5
6
25.2
4.5
5.2
5.3
6.4
10.9
6
22.4
4.8
4.9
5.7
6.3
9.2
5.5
21.6
5.2
5.5
5.5
6.2
9.7
5.5

QoL, quality of life; SD, standard deviation.

Conventional tri-weekly paclitaxel and carboplatin, n = 204; dose-dense weekly paclitaxel and carboplatin, n = 200.
b
Conventional tri-weekly paclitaxel and carboplatin, n = 152; dose-dense weekly paclitaxel and carboplatin, n = 146.
c
Conventional tri-weekly paclitaxel and carboplatin, n = 132; dose-dense weekly paclitaxel and carboplatin, n = 127.
d
Conventional tri-weekly paclitaxel and carboplatin, n = 98; dose-dense weekly paclitaxel and carboplatin, n = 91.
a

Measurement of QoL was the secondary end point of the

JGOG 3016 study. The aim of this current study was to test the
hypothesis that dose-dense weekly administration of paclitaxel
has a signicant effect on the impact of QoL relative to the triweekly administration of paclitaxel. We found that there was no
signicant difference in the overall QoL between the two groups,
suggesting that the PFS and OS benet of dd-TC was not
achieved at the expense of QoL.
In this study, QoL only according to the taxane subscale was
worse for patients treated with dd-TC than for those treated
with c-TC (P = 0.02). The incidence of paclitaxel-induced peripheral neurotoxicity (PIPN) depends on several factors, including the cumulative dose delivered [13], the dose per
treatment cycle [14], the schedule of treatment administration
[15, 16], and dose intensity [15]. In the phase III Cancer and
Leukemia Group B (CALGB) 9840 trial for the treatment of
metastatic breast cancer comparing weekly administration of
paclitaxel (80 mg/m2) with the administration of paclitaxel

| Harano et al.

(175 mg/m2) every 3 weeks, grade 3 neuropathy occurred more

commonly with weekly dosing (24 versus 12%, P = 0.0003)
and the dose intensity was higher with the weekly regimen
[15]. In our original study, the mean delivered dose intensity
of paclitaxel was higher in the dd-TC group than in the c-TC
group [63.0 mg/m2 per week (SD 13.0) versus 51.7 mg/m2 per
week (SD 10.6)], suggesting that the dose-dense administration
of paclitaxel increased the severity of PIPN and impaired QoL
due to neurotoxicity. In our study, the frequency of grade 3 or
4 neurotoxicity was found to be similar in both groups (ddTC, 7% versus c-TC, 6%). The proportion of patients who
received six or more cycles of treatment was lower in the ddTC group (62%) than in the c-TC group (73%), which may
explain why the frequency of neurotoxicity was apparently
similar between the two groups. We additionally examined
QoL in patients without disease progression. The taxane subscale showed a similar trend, although it was not statistically
signicant (P = 0.06).

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Assessment time point

original articles

Annals of Oncology

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

B
30

25

25

20

20
Social

Physical

30

15

15

10

10

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

0
Prior to
treatment

After
3 cycles

After 12 months after

6 cycles randomization

Prior to
treatment

Assessment points
30

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

Assessment points

30
25

20

20
Functional

25

15

10

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

15

10

0
Prior to
treatment

After
3 cycles

After 12 months after

6 cycles randomization

Prior to
treatment

Assessment points

E 100

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

F 50
45

80

40

70

35

60

30

50
40

After 12 months after

6 cycles randomization

: Conventional paclitaxel/carboplatin
: Dose-dense paclitaxel/carboplatin

25
20

30

15

20

10

10

After
3 cycles

Assessment points

Ovary

Taxane

90

After 12 months after

6 cycles randomization

0
Prior to
treatment

After
3 cycles

After 12 months after

6 cycles randomization

Assessment points

Prior to
treatment

After
3 cycles

After 12 months after

6 cycles randomization

Assessment points

Figure 2. Box plot showing the baseline and changes in quality-of-life scores according to the Functional Assessment of Cancer Therapy-General (FACT-G)
subscales: (A) physical, (B) social, (C) emotional, (D) functional, (E) taxane (FACT-T), and (F) ovary (FACT-O) for each treatment group.

This study has a number of limitations. The completion rate

of the QoL questionnaires was not high at baseline, nor was the
compliance rate throughout the study. The reason for a missed
assessment was not documented in the trial. The extent of
missing data likely biases estimates of the mean improvement in

Volume 25 | No. 1 | January 2014

QoL with time because patients with deteriorating QoL scores

are less likely to ll out the questionnaires. This bias may result
in some spurious improvements in QoL sores with time in both
treatment groups. However, the completion rate of baseline QoL
assessment and the rates of compliance across time points were

doi:10.1093/annonc/mdt527 |

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Emotional

After
3 cycles

original articles
similar between the treatment groups (Table 2). This might
negate the potential for biases that could be caused by missing
data. Moreover, the QoL assessment tool used in this study
was sufciently reliable to detect clinically signicant differences
in QoL.
In conclusion, this study showed that the overall QoL did not
differ between the dose-dense administration of paclitaxel combined with carboplatin and conventional tri-weekly paclitaxel
combined with carboplatin in patients with newly diagnosed
advanced ovarian cancer. As it has also been shown that dd-TC
improves survival compared with c-TC, these results suggest
that dd-TC is the better treatment choice in this patient population. In this trial, QoL according to the taxane subscale was signicantly lower in the dd-TC group than in the c-TC group.
These ndings justify further investigation into the prevention
and treatment of neurotoxicity in order to improve QoL.

acknowledgements

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10.

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funding
This work was supported by the Japanese Gynecologic
Oncology Group (JGOG): a non-prot organization supported
by unrestricted donations from several pharmaceutical
companies [no grant number].

disclosure
NK received honoraria and research funding from Nippon
Kayaku Co., Ltd. The remaining authors have declared no
conicts of interest.

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| Harano et al.

appendix
The following institutions participated in this study: the Jikei
University Kashiwa Hospital, National Cancer Center Hospital,
Kitasato University Hospital, Keio University Hospital, Toho
University Ohashi Medical Center, Osaka City General
Hospital, Iwate Medical University Hospital, Niigata Cancer
Center Hospital, The Jikei University Third Hospital, The Jikei
University Aoto Hospital, Kure Medical Center, Shikoku
Cancer Center, Kinki University Hospital, National Defense
Medical College, The Jikei University Hospital, St. Marianna
Medical University School of Medicine, Kagoshima City
Hospital, Okayama University, Tohoku University, Nagoya City
University, Chiba University, Oita University, Kyoto Prefectural
University of Medicine, Kousei General Hospital, Hokkaido
Cancer Center, Kurume University, Kyoto Daini Red-cross
Hospital, Osaka Saiseikai Suita Hospital, Tsukuba University,
Asahikawa Medical University, Hirosaki University, Tokyo
Medical University, Shizuoka Cancer Center, Asahikawa Redcross Hospital, Hamamatsu Medical University, Shinshu
University, Yokohama City University, Niigata University
Medical and Dental Hospital, Dokkyo Medical University, Aichi
Cancer Center, Saga University, Hokkaido University, Nagoya
University, Kochi Medical Center, Showa University, Teikyo
University, Toho University Omori Medical Center, Hiroshima
University, Nikko Memorial Hospital, Shimane Prefectural
Central Hospital, Mazda Hospital, Saga Koseikan Hospital, Jichi
Medical University, Chiba Cancer Center, Saint Marianna
University Toyoko Hospital, Nagasaki City Hospital, Sapporo
Medical University, Tokai University, Yamanashi Prefectural
Central Hospital, Kobe Medical Center, Shiga University of
Medical Science, Saitama Social Insurance Hospital, Matsuzaka
Central Hospital, Hyogo Cancer Center, Toyohashi Municipal

Volume 25 | No. 1 | January 2014

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We thank all the women who participated in this trial, Masahiro

Takeuchi, PhD, and other staff members of the Japanese
Gynecologic Oncology Group data center for data management.

Annals of Oncology

original articles

Annals of Oncology

Hospital, Gifu University, Yamaguchi University, Kyoundo

Hospital, Niigata City General Hospital, Cancer Institute
Hospital, Takamatsu Red Cross Hospital, Gunma University,
Himeji Red Cross Hospital, Juntendo University Urayasu
Hospital, Toyama University, Hamamatsu Medical Center,

Kushiro Rosai Hospital, Kawasaki Medical School Hospital,

Asahikawa City Hospital, Kansai Medical University,
Yokohama Municipal Citizens Hospital, Osaka Medical College
Hospital, Okazaki City Hospital, Tottori Prefectural Central
Hospital, Saitama Medical Center Jichi Medical University.

Annals of Oncology 25: 257264, 2014

doi:10.1093/annonc/mdt409
Published online 19 November 2013

Physician-assessed and patient-reported outcome

measures in chemotherapy-induced sensory peripheral
neurotoxicity: two sides of the same coin

1
Department of Surgery and Translational Medicine; 2Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca,
Monza, Italy; 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA; 4Department of Neurology, Spaarne Hospital, Hoofddorp;
5
Department of Neurology, Maastricht University Medical Center, Maastricht; 6Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands;
7
Unit of Neuro-Oncology, Department of Neurology, University Hospital of Bellvitge-ICO Duran I Reynals, LHospitalet, Barcelona, Spain; 8Division of Clinical Oncology,
Department of Medicine, University Hospital of Patras, Patras, Greece; 9Service de Neurologie Mazarin, Hpital de la Piti-Salptrire, AP-HP, Paris; 10Service de
Neurologie, Hpital du Val-de-Grce, Service de Sant des Armes, Paris, France; 11Neurology Unit, National Cancer Institute Regina Elena, Rome,; 12Department of
Neurological, Psychiatric, Sensorial, Reconstructive and Rehabilitative Sciences, University of Padova, Padova, Italy; 13Division of Medical Oncology, Department of Internal
Medicine, GROW-School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht; 14Department of Neuro-Oncology, Netherlands
Cancer Institute, Amsterdam, The Netherlands; 15Department of Neurology and West German Cancer Center, University of Essen, Essen, Germany; 16Edinburgh Centre for
Neuro-Oncology and Edinburgh Cancer Research Center, Western General Hospital, Edinburgh, UK; 17Department of Neuroscience, Ophthalmology and Genetic, Center
of Excellence for Biomedical Research, University of Genova, Genova, Italy

Received 27 May 2013; revised 23 August 2013; accepted 26 August 2013

Background: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN)
between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conicting interpretation, especially regarding sensory impairment.
Patients and methods: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute
Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc), the modied
Inammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for
Research and Treatment of Cancer CIPN specic self-report questionnaire (EORTC QOL-CIPN20).
Results: Patients probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly
related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be
scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between
35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a signicant
trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores.

*Correspondence to: Prof. Guido Cavaletti, Department of Surgery and Translational

Medicine, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Milano-Bicocca,
Italy. Tel: +39-02-6448-8039; Fax: +39-02-6448-8250; E-mail: guido.cavaletti@unimib.it

Equally contributed to the paper.

See appendix for the complete list of participating centers and investigators.

The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.

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P. Alberti1, , E. Rossi2,, D. R. Cornblath3, I. S. J. Merkies4,5, T. J. Postma6, B. Frigeni1, J. Bruna7,

R. Velasco7, A. A. Argyriou8, H. P. Kalofonos8, D. Psimaras9, D. Ricard10, A. Pace11, E. Gali11,
C. Briani12, C. Dalla Torre12, C. G. Faber5, R. I. Lalisang13, W. Boogerd14, D. Brandsma14,
S. Koeppen15, J. Hense15, D. Storey16, S. Kerrigan16, A. Schenone17, S. Fabbri17, M. G. Valsecchi2
& G. Cavaletti1* the CI-PeriNomS Group