Int J Clin Oncol (2003) 8:343347

DOI 10.1007/s10147-003-350-8

The Japan Society of Clinical Oncology 2003

ORIGINAL ARTICLE
Yoshimitsu Niwa Toru Nakanishi Kazuo Kuzuya
Akihiro Nawa Shigehiko Mizutani

Salvage treatment with docetaxel for recurrent epithelial ovarian cancer

Received: November 21, 2002 / Accepted: July 17, 2003

Abstract
Background. We investigated the clinical usefulness and
toxicity of salvage treatment with docetaxel (70 mg/m2) infused at 3-week intervals in patients with recurrent ovarian
cancer.
Methods. Retrospectively, we reviewed the clinical records
of 24 patients diagnosed with recurrent ovarian cancer who
had received the salvage treatment.
Results. A total of 128 courses (median, 5.5 courses; range,
28 courses) were administered to the 24 patients. The
mean number of prior chemotherapy courses in the patients
was 16.4 (range, 435 courses); they had already been
treated heavily. The tumor response was evaluable at the
end of the treatment in 20 patients, with the overall response rate being 15.0%. Using the criterion of serum carbohydrate antigen (CA)125 level, the response rate was
13.0%. By the time of the final docetaxel treatment, all 24
patients had relapsed and 19 had died of the disease. The
median progression-free interval was 4.6 months (range,
1.37.8 months), and the median overall survival time was
13.7 months (range, 2.127.0 months). While hematological
toxicity was not severe, 20.8% of patients experienced
grade 3 asthenia/fatigue, and 5 patients refused further
treatments with docetaxel because of this toxicity.
Conclusion. Salvage treatment using docetaxel (70 mg/m2)
was somewhat effective for recurrent ovarian cancer, although severe asthenia/fatigue was frequently observed.
Docetaxel provides sufficient palliation of disease-related
symptoms and some improvement in the length of life in

Y. Niwa T. Nakanishi (*) K. Kuzuya A. Nawa

Department of Gynecology, Aichi Cancer Center Hospital,
1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Tel. 81-52-762-6111; Fax 81-52-763-5233
e-mail: trnakans@aichi-cc.jp
S. Mizutani
Department of Obstetrics and Gynecology, Nagoya University
Graduate School of Medicine, Nagoya, Japan

patients with recurrent ovarian cancer, when asthenia/

fatigue is mild.
Key words Docetaxel Ovarian cancer Salvage treatment

Introduction
Because the probability of a response to second-line chemotherapy following platinum-based treatments is mainly
related to the platinum-free interval, platinum agents
are important drugs in the treatment of recurrent ovarian
cancer, as well as in primary chemotherapy.14 For some
patients whose platinum-free interval is longer than 24
months, re-treatment with a platinum agent is the most
appropriate choice, and both a sufficient effect and an adequate disease-free survival period can be expected. However, many patients who suffer from tumor progression
or recurrence within 6 months after primary therapy are
considered to be resistant to platinum.36 Generally, these
patients would not be considered curable, and the main
option is salvage treatment, performed for the palliation of
disease-related symptoms and the improvement of quality
and length of life.5,6
Several treatments have been reported to be effective for recurrent ovarian cancer resistant to platinum
plus paclitaxel, such as weekly single-agent paclitaxel;7
docetaxel;811 oral etoposide;12 irinotecan;13 topotecan;14
gemcitabine;15 and liposomal doxorubicin.16 While the antitumor effects of these drugs would be much weaker than
those of the primary chemotherapy, the treatment would be
repeated until evidence of disease progression was confirmed, or severe adverse effects threatened the life of a
patient. Although the effects on the quality and length of
life of patients should be considered as the more important
effects of salvage treatment, it is the response rates of these
treatments that have been reported most frequently.
In the current study, we focused on the salvage effects of
treatment in which docetaxel was administered successively
at 3-week intervals in patients with recurrent ovarian

344

cancer. We hoped to determine whether the treatment

would be useful for the improvement of the quality and
length of life in these patients.

Patients and methods

The treatment records of patients with recurrent ovarian
cancer treated at our hospital from May 2000 to October
2001 were reviewed. Recurrent disease was diagnosed by
histological, radiological, or biochemical methods. The criterion of the carbohydrate antigen (CA)125 level was used
to define progression,17 and this level was used for the diagnosis of biochemical recurrence. All patients had normal
renal function (serum creatinine, 0.79 mg/dl); normal hepatic function (serum bilirubin, 1.0 mg/dl; serum glutamicoxaloacetic transaminase, alanine aminotransferase, and
alkaline phosphatase less than two times the upper limits
of institutional normal levels), adequate bone marrow
reserves (WBC 4000 cells/ml and platelets 100 000/ml),
performance status (Eastern Cooperative Oncology
Group) less than or equal to 2, a life expectancy enabling
completion of at least two courses of therapy, and no recent
(within at least 28 days) cytotoxic chemotherapy or widefield radiation therapy. We found 24 patients who met the
inclusion criteria, and they received docetaxel as a salvage
treatment. No exclusions were made based on the number
of previous regimens undergone by the patients. Measurable (indicator) lesions were assessed by clinical examination (nodes and subcutaneous nodules), and computed
tomography/magnetic resonance imaging scans (hepatic,
pelvic, or abdominal masses).
The starting dose of docetaxel in the 24 patients was
70 mg/m2. All patients were hospitalized for each treatment
course, which involved a 1-h intravenous infusion every 3
weeks. They were premedicated with 8 mg of dexamethasone, given orally every 12 h for 3 days, commencing before
the initiation of each infusion. The calculated dose of
docetaxel was delivered as a 1-h infusion diluted in 250 ml of
5% glucose in sterile water. Complete blood counts and
platelet counts were done at least weekly after discharge.
Repeat courses of docetaxel were administered every 21
days as long as there was no evidence of tumor progression
and blood counts had returned to pretreatment levels. The
treatment was repeated until patients suffered disease progression and/or a severe adverse effect.
Tumor evaluations were repeated at minimum intervals
of 6 weeks (after two courses). In the present study, the
response to evaluable disease was classified according to the
World Health Organization (WHO) criteria, by which a
more than 50% reduction in the product of the largest two
perpendicular tumor diameters is considered to be a partial
response, and total disappearance of the disease is regarded
as a complete response. Patients were also classified as assessable if they satisfied the criterion of CA125 definition of
progression.17 This marker of assessable disease was measured at least at 4-week intervals, and a response was defined as one showing a 50% decrease in the marker level,

while disease progression was defined according to the criterion of CA125 definition of progression.17 Toxic effects
were graded according to the WHO criteria.
The progression-free interval was calculated from the
first day of treatment until the day of documented disease
progression. Overall survival was calculated from the initiation of chemotherapy. The progression-free interval and
overall survival of patients were calculated by the method
of Kaplan and Meier, using SPSS (Chicago, IL, USA) software, version 11.5.

Results
The characteristics of the patients are summarized in
Table 1. The mean age at initiation of docetaxel treatment
was 59.0 years (range, 42.9 to 74.0 years), and the median
follow-up time of surviving patients was 21.7 months. Most
patients included in this study had already been treated
heavily; 19 (79.2%) of them had received more than ten
courses of chemotherapy before the docetaxel treatment.
All patients had received paclitaxel, 23 had been treated
with platinum drugs, and 21 had previously received chemotherapy with paclitaxel plus a platinum regimen at some
time in the course of their disease. In total, in the present
study, 128 courses (median, 5.5 courses; range, 28 courses)
were administered to the 24 patients. Although no dose
modification was performed, 5 patients refused further
treatment because of asthenia/fatigue. Treatments in the
other patients were interrupted by progression of disease.
The tumor response was evaluable in 20 patients. Three
(15.0%) achieved a partial response, while stable disease
was noted in 8 (40.0%), and progression in another 9
(45.0%) (Table 2). Although the other 4 patients did not
have evaluable disease, they did have carcinomatous peritonitis. Twenty-three patients were assessable using the serum
CA125 level. In the course of the docetaxel treatment, the

Table 1. Patient characteristics

Total no. of patients
Age (years)
WHO performance status
Histology
Number of prior regimens
Number of prior chemotherapy
courses
Treatment interval from the
last chemotherapy (months)
Site of lesion

24
Mean
Range
0
1
2
Serous
Endometrioid
Mucinous
1
2
3
Median
Range
Median
Range
Pelvic
Peritoneal
Lymph node
Marker

59.0
42.974.0
8
12
4
20
3
1
5
12
7
16
435
1.3
0.511.1
9
8
3
4

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CA125 of 9 (45.0%) patients showed a 50% decrease for a

time, although this marker in 6 of them increased after
additional treatments. Finally, only 3 (13.0%) patients
achieved a response at the end of the docetaxel treatment,
while 10 (43.5%) showed stable disease and another 10
(43.5%) satisfied the criterion of the CA125 definition of
progression17 at the end of the treatment (Table 2). This
marker level in the 1 remaining patient was within the normal range before treatment, although she had evaluable
disease. No significant difference was observed in analyses
of responses compared between patients whose treatment
interval from the last chemotherapy was less than 3 months
and those with an interval of more than 3 months.
By the time of the final docetaxel treatment, all 24 patients had relapsed disease, and 19 had died of the disease
despite the successive treatments. The median progression-free interval was 4.6 months (range, 1.37.8 months)
(Fig. 1). The estimated 3-month progression-free survival
rate was 79.2%, while at 6 months it was 19.1%. The median
overall survival time was 13.7 months (range, 2.127.0
months) (Fig. 1), and the 6-month estimated overall survival
rate was 74.6%, while for 12 months this rate was 60.8%,
and this rate was 33.8% for 18 months. No significant difference was observed in analyses of prognoses compared
between patients with a treatment interval from the last
chemotherapy of less than 3 months and those with a treatment interval of more than 3 months.

Table 2. Response to docetaxel and survival

Number of patients

24

Measurable disease
Complete response
Partial response
Stable disease
Disease progression
Response rate
Measurable marker
Response
Stable
Progression
Response rate

20
0
3
8
9
15.0%
23
3
10
10
13.0%

Fig. 1. Progression-free interval

and overall survival curve

Table 3 summarizes the toxicity data from this study.

Hematological toxicity was not severe, while febrile neutropenia was observed in 8 patients (33.3%). Although grade 4
neutropenia was observed in 18 (75.0%) patients, it lasted
no more than 3 days, and they recovered immediately
whether granulocyte-colony-stimulating factor (G-CSF)
was used or not. Severe thrombocytopenia or anemia was
not observed in any patient. Dose reductions were not prescribed for any patient. Although 5 patients did not experience any asthenia/fatigue, the other 19 (79.2%) complained
of this symptom throughout treatment, of whom 5 had
grade 3. The asthenia/fatigue in most patients worsened as
the infusions of docetaxel were repeated, and 5 patients
who experienced severe asthenia/fatigue refused further
docetaxel treatments. Nail change was observed in 18
(75.0%) patients, and in 2 of these patients this was accompanied by pain. There were rare episodes of severe nausea/
vomiting, diarrhea, stomatitis, fluid retention/peripheral
edema, myalgia/arthralgia, neuropathy, and hypersensitivity reaction, none of which were clinically significant.

Table 3. Adverse effects

WHO grade
Hematological
Anemia
Thrombocytopenia
Leucopenia
Neutropenia
Nonhematological
Asthenia/fatigue
Nausea/vomiting
Diarrhea
Fluid retention/edema
Alopecia
Myalgia/arthralgia
Neuropathy
Nail change
Hypersensitivity reaction
Mucositis
Hypesthesia of gustation
Febrile neutropenia

34 (%)

7
20
3
3

4
3
1
0

7
1
3
1

5
0
8
2

1
0
9
18

25.0
0.0
70.8
83.3

5
5
19
16
0
14
11
6
20
20
17
16

6
9
3
6
22
8
10
16
3
1
7

8
8
2
2
2
2
3
2
1
3
0

5
2
0
0
0
0
0

0
0
0
8

0
0
0
0
0
0
0

0
0
0
0

20.8
8.3
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
33.3

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Discussion
The prognosis of patients with recurrent ovarian cancer is
extremely poor.36 Although many antitumor agents have
been produced and examined for their efficacy, the survival
rates of patients with recurrent ovarian cancer have not
sufficiently improved.316 For these reasons, the important
aims of salvage treatments for recurrent ovarian cancer
should be the palliation of disease-related symptoms, extension of the platinum-free interval, and improvement of the
quality and longevity of life.36 Therefore, salvage treatment
must demonstrate more antitumor effects as well as fewer
adverse effects. Fortunately, several antitumor agents have
been reported as demonstrating sufficient beneficial effects
on recurrent ovarian cancer,316 and docetaxel has been
described as one of the best.811
In this study, the response rate of recurrent ovarian
cancer to docetaxel seemed to be extremely low compared
to previous studies.811 Because we examined the data retrospectively, the responses were evaluated at the end of the
treatments, which were repeated until either the disease
progressed or a severe adverse effect was confirmed. While
most patients in this study had previously been heavily
treated using platinum compounds and/or paclitaxel, treatments using 70 mg/m2 of docetaxel were repeated for a total
of 128 courses in 24 patients. In spite of these conditions, the
median progression-free interval in this study (4.6 months)
was no less than that in previous studies,811 and the median
overall survival time (13.7 months) was rather longer. These
results suggested that docetaxel is suitable for the salvage
treatment of recurrent ovarian cancer, and sufficient results
could be expected in terms of the palliation of symptoms
and longer life.
Hematological toxicities constituted the most frequent
adverse effect in the current study. Although most patients
were heavily treated, these toxicities were mostly transient
and tolerable. Although fluid retention and peripheral
edema have been reported to be common adverse effects of
docetaxel, mild peripheral edema was observed in only
eight patients, and no fluid retention was observed. Hypersensitivity reaction has also been reported frequently, but
no patient suffered from a reaction of more than grade 2
in this study. These results suggested that the severe fluid
retention, peripheral edema, and hypersensitivity reaction
to docetaxel could be prevented by using a recommended
premedication, such as the oral administration of 8 mg
dexamethasone every 12 h for 3 days.
Though other toxicities were generally mild and tolerable, asthenia/fatigue was the most severe and troublesome toxicity in this study. While only 20.8% of patients
suffered from grade 3 asthenia/fatigue, five patients refused
further treatment because of this toxicity. Of these patients,
two with evaluable disease achieved a partial response,
and the serum CA125 level of the other three patients
showed a 50% decrease at the time of their refusal. These
results suggested that asthenia/fatigue is the most important toxicity, and that the use of docetaxel treatment
could be ruled out because the toxicity would also threaten

the patients quality of life. In such cases, docetaxel

treatment should be discontinued in favor of treatment
alternatives.
While asthenia/fatigue has been reported to be caused
principally by the toxicity of docetaxel infused weekly,18,19 a
high level of toxicity has rarely been encountered in treatments with docetaxel infused every 3 weeks.811 Because the
docetaxel infusion in the present study was repeated until
either disease progression or a severe adverse effect was
confirmed, 70.8% (17/24) of the patients were thus treated
more than five times. Considering that the asthenia/fatigue
in most patients was exacerbated as the number of
docetaxel infusions increased, it follows that the toxicity
would also become more severe for the same reason. This
suggests that docetaxel would not be suitable for treatment
when administered repeatedly, and that further studies
should be performed to reduce the asthenia/fatigue in
docetaxel treatment.
In conclusion, the overall response rate to single-agent
docetaxel treatment for recurrent ovarian cancer was
15.0%, the median progression-free interval was 4.6 months,
and the median overall survival time was 13.7 months.
Though these results suggested that salvage treatment with
docetaxel for recurrent ovarian cancer patients would be
sufficiently effective, severe asthenia/fatigue was frequently
observed; 20.8% of patients experienced severe asthenia/
fatigue and five refused further treatment because of this
toxicity. Docetaxel, therefore, is one of the appropriate options for the relief of disease-related symptoms and for
improvement in the length of life in patients with recurrent
ovarian cancer whenever quality of life is not compromised
by severe asthenia/fatigue.

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