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ORIGINAL ARTICLE
Gemcitabine and Vinorelbine Combination
in Platinum-Sensitive Recurrent Ovarian Cancer
Annamaria Ferrero, MD, PhD, Vilma Logrippo, MD, Pier Giorgio Spanu, MD, Luca Fuso, MD,
Stefania Perotto, MD, Alberto Daniele, MD, and Paolo Zola, MD
Objectives: Most patients with ovarian cancer are candidates for second-line or salvage
treatments often for prolonged periods. Patients with platinum-sensitive disease can benefit
from a platinum retreatment with a likelihood of response dependents on the treatmentfree interval. Alternative agents and combination chemotherapy are potential therapeutic
approaches. At our institution, we carried out a phase II trial to evaluate feasibility, efficacy,
and toxicity of gemcitabine and vinorelbine combination in recurrent ovarian carcinoma.
The aim of the present study was to evaluate the role of this combination in patients with
platinum-sensitive disease.
Patients and Methods: Patients with platinum-sensitive disease recurring after 1 or more
lines of platinum-based chemotherapy were included. Vinorelbine at 25 mg/m2 followed by
gemcitabine at 1000 mg/m2 was administered intravenously on days 1 and 8 every 3 weeks.
Response Evaluation Criteria in Solid Tumors and cancer antigen 125 test (CA-125
Kinetics [Rustin criteria]) were adopted to classify responses. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria.
Results: Thirty-nine patients were eligible. Platinum-free interval (PFI) was 6 to 12 months
in 13 patients (33.3%; PFI 6Y12) and more than 12 months in 26 patients (66.7%; PFI 9 12).
The overall response rate was 48.7%, with 6 complete responses. Median response
duration was 38 weeks. The response rate was 23% in PFI 6Y12 and 62% in PFI >12. The
most frequently observed toxicity was hematological, with 23% of the patients having
grade 3 or 4 neutropenia.
Conclusions: Gemcitabine and vinorelbine combination is effective and well tolerated in
recurrent platinum-sensitive ovarian cancer. It may represent an option in the management
of these patients because the chronic nature of the disease.
Key Words: Ovarian cancer, Recurrent disease, Platinum sensitivity, Gemcitabine,
Vinorelbine
(Int J Gynecol Cancer 2009;19: 1529Y1534)
E
pithelial ovarian cancer is the most common cause of death
among gynecological malignancies in the Western world. Approximately 75% of patients with ovarian cancer show an advanced
disease at diagnosis, with a 5-year survival rate of 25% to 30%.
Although multimodality treatment regimens have resulted in a
greater number of responses and have prolonged both progression-
Academic Division of Gynecological Oncology, Institute for Cancer
Research and Treatment (IRCC) of Candiolo and AO Ordine Mauriziano,
Turin, Italy.
Address correspondence and reprint requests to Annamaria Ferrero, MD,
PhD, Via Carducci, 20-10044 Pianezza, Turin, Italy. E-mail: a.ferrero@
katamail.com.
Copyright * 2009 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1111/IGC.0b013e3181a8407e
International Journal of Gynecological Cancer
free and overall survival rates, the overall cure rate of the disease
has not changed dramatically. More than 75% of patients respond to
first-line chemotherapy, but approximately 75% of them eventually
develop disease recurrence and die of their disease.1
The treatment of recurrent ovarian cancer, also defined as
second-line or salvage treatment, has long been recognized as an
important element in the overall management of patients with this
disease. The life expectancy after first relapse is now longer than in
the past, and ovarian cancer could be considered a chronic disease.
Most patients are candidates for second-line or salvage therapy and
may also be on therapy for prolonged periods.2,3
According to current dogma in ovarian cancer treatment, the
potential for platinum sensitivity is the most important factor in
planning second-line treatment.4 Patients with ovarian cancer who
experience a durable response to platinum induction chemotherapy
(96 months) have a high probability of responding to platinum
& Volume 19, Number 9, December 2009
Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
1529
Ferrero et al
International Journal of Gynecological Cancer
retreatment again and the likelihood of response dependents on the
treatment-free interval (TFI).5 Carboplatin-paclitaxel combination
is, by now, the standard treatment of recurrent platinum-sensitive
ovarian cancer.6 Nevertheless, also these patients experience repeated disease recurrences, and further chemotherapy alternatives
are needed. Furthermore, patients relapsing between 6 and 12 months
after treatment with a platinum compound are now considered
partially platinum sensitive.
In the last decade, a large amount of drugs with significant
activity in recurrent ovarian cancer have been identified. Even the
most promising new second-line drugs have demonstrated response
rates ranging only from 10% to 30% with short response duration.7Y10 To maximize the benefits of second-line or salvage treatment, alternative novel agents and combination chemotherapy are
increasingly being recognized as potential therapeutic approaches.
In the last few years at our institution, we carried out a phase II
trial to evaluate feasibility, efficacy, and toxicity of gemcitabine and
vinorelbine combination in recurrent ovarian carcinoma.
Gemcitabine (2¶,2¶-difluorodeoxycytidine [dFdC]) is a nucleoside analogue of deoxycytidine. After sequential phosphorylation
by deoxycytidine kinase to the triphosphate dFdCTP, gemcitabine
is incorporated into DNA, causing masked chain termination.11 The
diphosphate dFdCDP also functions as an inhibitor of ribonucleotide
reductase.12 In ovarian cancer, the efficacy of gemcitabine as singleagent or combination therapy has been evaluated in several clinical
trials and tumor remission has been observed in patients with sensitivity and resistance to both platinum and paclitaxel.9,13Y15 The most
frequently occurring dose-limiting toxicities are hematological.
Vinorelbine is a semisynthetic vinca alkaloid. It exerts its
biologic effect like other vinca alkaloids by inhibiting the microtubule assembly, resulting in mitotic spindle dissolution and metaphase arrest in dividing cells.16 Compared with vincristine and
vinblastine, vinorelbine is equally active on mitotic microtubules
and less active on axonal microtubules, suggesting a better efficacytoxicity ratio.17 The activity of vinorelbine in the treatment of
ovarian cancer has already been demonstrated by some phase II
studies using vinorelbine as single agent in recurrent disease.10,18Y20
Both phases I and II studies have been conducted to assess the
feasibility and efficacy of vinorelbine combined with other cytotoxic
agents in recurrent ovarian cancer.21Y23
Gemcitabine and vinorelbine combination has been widely
used in advanced nonYsmall cell lung cancer (NSCLC) and in
advanced or metastatic breast cancer and less frequently in other
malignancies.24 Pharmacokinetic studies in head and neck cancer
have shown that the association does not alter the pharmacokinetic
profile of either drug.25
The rationale of our phase II study was based on the antitumoral activity of the 2 drugs in ovarian cancer, the different mechanisms of action and especially the nonoverlapping toxicity pattern.
We adopted the schedule consisting in vinorelbine at 25 mg/m2 followed by gemcitabine at 1000 mg/m2, 1:8:21 in accordance with the
experience of medical oncologists on NSCLC and breast cancer.26,27
The aim of the present study was to evaluate the role
of gemcitabine and vinorelbine combination in the treatment of
platinum-sensitive recurrent ovarian cancer.
PATIENTS AND METHODS
& Volume 19, Number 9, December 2009
normal) on 2 baseline determinations. Lesions as ascites and small
peritoneal implants were considered radiographically assessable but
not measurable.
Patients with platinum-sensitive disease recurring after 1 or
more lines of platinum-based chemotherapy were included. The
length of platinum-free interval (PFI) was evaluated and classified
as between 6 and 12 months or more than 12 months.
Further inclusion criteria were a life expectancy of more
than 12 weeks; an Eastern Cooperative Oncology Group (ECOG)
performance status of 2 or less; and adequate hematological,
renal, and hepatic functions at baseline (absolute neutrophil count
Q 1.500/KL, serum creatinine level e 1.5 mg/dL, total bilirubin
level e 1.5 mg/dL, and aspartate and alanine aminotransferases
e 2 times the upper limit of normal level or e 5 times the upper
limit of normal in case of metastatic liver disease).
Patients were excluded from the protocol if they had received previous treatment with gemcitabine and vinorelbine, showed
evidence of a concomitant second malignancy, or contraindication
to chemotherapy treatment.
The study was conducted in accordance with the Declaration
of Helsinki and Good Clinical Practice Guidelines and was approved
by the local ethics committee. Written informed consent was required from each patient before study entry.
Treatment Plan
The chemotherapy schedule consisted of intravenous (iv)
infusion of vinorelbine at 25 mg/m2 followed by gemcitabine at
1000 mg/m2 on days 1 and 8 every 3 weeks. Vinorelbine was administered by 10-minute iv infusion and gemcitabine by 30-minute iv
infusion.
Dexamethasone at 8 mg and tropisetron at 5 mg were
administered iv in 30 minutes before study drugs.
The treatment duration was at the discretion of the investigator, although it was recommended that responding patients
should receive at least 6 courses of chemotherapy. The treatment was
discontinued in case of progressive disease or unacceptable toxicity.
Response and Toxicity Assessment
Before study entry, baseline standard assessments were performed including a complete history, physical examination, laboratory assessments of hematological, renal, and hepatic functions,
ECOG performance status evaluation, instrumental evaluation with
CT scan at the pelvis and abdomen, and 2-view chest x-ray. Serum
chemistries and liver function tests were monitored on days 1 and
8 of every cycle. A physical examination and CA-125 evaluation
were performed every cycle, whereas a CT scan was done after the
third and sixth cycles of chemotherapy.
At study entry, patients were evaluated to detect measurable
and nonmeasurable lesions. Measurability of tumor lesions at
baseline was assessed according to the Response Evaluation Criteria
in Solid Tumors (RECIST).
The RECIST and the CA-125 criteria were adopted to classify
responses and to determine the best overall response.28,29 A minimum of 3 cycles were required to assess the response.
Responses according to PFI were assessed.
Toxicity was graded according to the National Cancer Institute Common Toxicity (NCI-CT) criteria.30
Patients
Statistical Methods
Eligibility criteria required that patients had a histologically
proven diagnosis of epithelial ovarian carcinoma with a recurrent disease either bidimensionally measurable on computed tomographic (CT) scan (Q2 cm) or assessable on CT scan with elevated
cancer antigen 125 test (CA-125) levels (Qtwice the upper limit of
The study was designed as a single-institution phase II study.
The primary end point of the study was response to treatment. Toxicity, time to progression, and survival were secondary end points.
Progression-free survival for all patients was recorded from
the date of protocol entry until disease progression, death from
1530
* 2009 IGCS and ESGO
Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 19, Number 9, December 2009
any cause, or date of last follow-up. Overall survival was calculated
from the date of study entry until death from any cause or date of
last follow-up. Progression-free survival and survival times were
calculated with the Kaplan-Meier product-limit method.
Analyses were performed using the SPSS software (version
12, SPSS Inc, Chicago, Ill).
RESULTS
PFI was between 6 and 12 months in 13 patients (33.3%) and
more than 12 months in 26 patients (66.7%). Most of the patients
(71.8%) had received 2 or more previous lines of platinum-based
chemotherapy.
Altogether, 34 patients (87.2%) had measurable disease
and 5 (12.8%) nonmeasurable but assessable disease. Thirty-seven
(94.9%) had a peritoneal relapse, and 2 (5.1%) of them had hepatic
metastasis.
Treatment and Dosing
Patient Characteristics
Thirty-nine patients were eligible for the study. They were
enrolled from 1998 to 2003.
Patient characteristics are summarized in Table 1. Median
age was 59 years, and the most common tumor histologic diagnosis
was papillary serous adenocarcinoma (84.5%). At first diagnosis,
87.2% of patients were at International Federation of Gynecology
and Obstetrics (FIGO) stage IIIC. All patients underwent prior upfront or interval debulking surgery and first-line platinum-based
chemotherapy.
TABLE 1. Patients characteristics
n
Registered patients
Age, yr
Median
Range
Histological type
Papillary serous
Mucinous
Clear cell
Undifferentiated
Endometrioid
FIGO stage
I
II
III
IV
PFI, mo
912
6Y12
No. previous chemotherapy regimens
1
2
3
Measurability of disease
Measurable disease
Nonmeasurable disease
Site of disease
Peritoneum
Visceral (liver)
ECOG performance status
0
1
Gemcitabine and Vinorelbine Combination
%
39
59
41Y80
33
1
1
3
1
84.5
2.6
2.6
7.7
2.6
2
1
34
2
5.1
2.6
87.2
5.1
26
13
66.7
33.3
11
19
9
28.2
48.7
23.1
34
5
87.2
12.8
37
2
94.9
5.1
36
3
92.3
7.7
A total of 238 triweekly cycles were administered. All the
patients received 3 or more courses of chemotherapy. The median
number of courses administered per patient was 6 (range, 3Y9).
Three patients (7.7%) required 1-week treatment delay because of toxicity. Four cycles were delayed because of inadequate
hematological recovery (granulocytes G 1.5 109/L and thrombocytes G 100 109/L). One cycle was delayed at patient’s request. In
5 patients (12.8%), day 8 was not administered owing to inadequate
hematological recovery. Only 1 patient (1.8%) required dose reduction because of hematological toxicity.
Planned dose intensity was maintained in 98% of patients.
Total mean dose per cycle was 1859 mg/m2 for gemcitabine and
46 mg/m2 for vinorelbine.
Toxicity
All 39 patients enrolled in our study were evaluated for
toxicity.
Toxicity is reported in Table 2 as the worst grade per patient
according to the NCI-CT criteria.
Neutropenia was the most frequently encountered toxicity,
with grade 3 or 4 observed in 9 patients (23%). The mean neutrophil nadir was 0.9 109/L. No sepsis or fever related to neutropenia was observed. No hospitalization was required. No blood or
platelet transfusion was needed. No hematological growth factor
was administered.
TABLE 2. Incidence of toxicity according to NCI-CT criteria
FIGO, International Federation of Gynecology and Obstetrics.
Grade, n (%)
Toxicity
Neutropenia
Thrombocytopenia
Anemia
Fatigue
Arthralgia/myalgia
Neuropathy-sensory
Nausea/vomiting
Patients with diarrhea
without colostomy
Stomatitis/pharyngitis
Gastritis
Abdominal pain or cramping
Constipation
GGT
AST-ALT
Creatinine
1
9
3
2
1
1
1
2
1
(23.1)
(7.7)
(5.1)
(2.6)
(2.6)
(2.6)
(5.1)
(2.6)
2 (5.1)
0
2 (5.1)
1 (2.6)
0
1 (2.6)
1 (2.6)
2
3
4
12 (30.8) 7 (17.9) 2 (5.1)
2 (5.1)
0
0
6 (15.4)
0
0
1 (2.6)
0
0
1 (2.6)
0
0
0
0
0
1 (2.6)
0
0
0
0
0
0
1 (2.6)
2 (5.1)
0
1 (2.6)
2 (5.1)
0
0
0
0
0
1 (2.6)
1 (2.6)
0
0
0
0
0
0
0
0
GGT, gamma-glutamiltranspeptidases; AST-ALT, aspartate and alanine
aminotransferases.
* 2009 IGCS and ESGO
Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
1531
International Journal of Gynecological Cancer
Ferrero et al
TABLE 3. Response to treatment according to PFI
PFI
Response
No. patients
CR
PR
SD
PD
RR
6Y12 months,
n (%)
1
2
9
1
3
13
(7.7)
(15.4)
(69.2)
(7.7)
(23.1)
91 year,
n (%)
Total,
n (%)
Total,
95% CI
26
5 (19.2)
11 (42.3)
10 (38.5)
0
16 (61.5)
39
6 (15.4)
13 (33.3)
19 (48.7)
1 (2.6)
19 (48.7)
4.0Y26.6
13.1Y50.0
32.0Y65.4
1.5Y3.5
24.2Y73.2
CR, complete response; PR, partial response; SD, stable disease; PD,
progressive disease; RR, response rate.
Non-hematological toxicity was mild and manageable. Gastrointestinal disturbance was the predominant non-hematological
toxicity with abdominal pain, constipation, and diarrhea. The
only grade 3 non-hematological toxicity was hepatic toxicity in
2 patients (5.1%).
Response and Survival
Of the 39 patients enrolled into the study, 19 patients obtained
an objective response to treatment (48.7%; 95% confidence interval
[CI], 24.2%Y73.2%). Six patients (15.4%; 95% CI, 4%Y26.6%) had
a complete response, with disappearance of any measurable or
evaluable disease and with normalization of CA-125 serum level.
Thirteen partial responses (33.3%%; 95% CI, 13.1%Y50%) were
registered. Nineteen patients (48.7%; 95% CI, 32.0%Y65.4%)
showed a stable disease, and 1 (2.6%, 95% CI, 1.5%Y3.5%) had a
progression.
Responses according to PFI are summarized in Table 3.
For all responders, the median time to response was 12 weeks
(range, 5.1Y18.6 weeks) and the median duration of response was
38 weeks (range, 8.2Y67.6 weeks).
The median progression-free survival was 32.7 weeks (95%
CI, 21.6Y43.8), and the median overall survival from on-study was
78.1 weeks (95% CI, 37.1Y119.1).
DISCUSSION
A number of questions related to treatment approaches have
emerged as a consequence of the chronic nature of ovarian cancer.4
One important question is whether combination chemotherapy
could produce better results than single-agent therapy in patients
with recurrent ovarian cancer. Historically, sequential single-agent
therapies have been administered, and the selection of which individual agent to use has primarily been based on toxicity considerations.3 Although the use of combinations has been usually
discouraged in the recurrent setting, it is conceivable that the
rationalized choice of drugs with different mechanisms of action
and toxicity patterns might increase the chance of response and
favorably effect the clinical outcome.31 The results of 2 parallel
randomized trials (International Collaborative Ovarian Neoplasm 4,
ICON 4, and Arbeitsgemeinschaft Gynaekologische Onkologie,
AGO) suggest that paclitaxel plus platinum chemotherapy improves
survival and progression-free survival in patients with platinumsensitive relapsed ovarian cancer compared with conventional
platinum-based chemotherapy.32 In another randomized trial,
comparing the combination of carboplatin and gemcitabine versus
single-agent carboplatin, the combination regimen produced a
1532
& Volume 19, Number 9, December 2009
significantly longer progression-free survival than the control
arm.33 In patients who are not candidate to a platinum rechallenge,
combination chemotherapy has been evaluated in the last few years.
Preclinical studies have shown that gemcitabine-based combinations increase cytotoxicity and can potentially overcome drug
resistance. These characteristics make gemcitabine an attractive
partner for combination with other cytostatic agents.14 Our study
showed that gemcitabine and vinorelbine combination is feasible.
To our knowledge, this is the first study evaluating this combination
in ovarian cancer. We did not perform a phase I study but adopted
the schedule consisting in vinorelbine at 25 mg/m2 followed by
gemcitabine at 1000 mg/m2, 1:8:21 in accordance with the experience of medical oncologists on NSCLC and breast cancer.
In NSCLC, several phase I dose-finding studies have been performed, and the proposed dose for expansion and future studies
was 25 mg/m2 vinorelbine and 1000 mg/m2 gemcitabine on days
1 and 8 every 21 days.26 The same schedule has been used in breast
cancer with promising results.27 As in ovarian cancer, treatment options in patients with NSCLC remain limited after platinum-based
chemotherapy. The combination of gemcitabine plus vinorelbine
is also active and well tolerated in patients with NSCLC recurring
after taxane-platinum therapy34 and seems to be appropriate for
patients unsuitable for cisplatin-based chemotherapy because of
physical or clinical contraindications.
In our study, the response rate was 48.7%, with a median
response duration of 38 weeks and a survival of 78 weeks. This
result is better than those obtained with gemcitabine or vinorelbine
single agents. In phases I and II studies with gemcitabine as single
agent, the overall response rates varied from 14% to 22%, with a
median survival of 6 to 9 months.9,13 Response rates of 15% to
30% have been obtained in clinical trials on administration of
vinorelbine to patients with recurrent ovarian cancer.10,18Y20 Furthermore, our results are better than those obtained with other
combinations including gemcitabine or vinorelbine.
Pegylated liposomal doxorubicin (PLD) is a promising drug
in recurrent ovarian cancer.8 In a phase II study to evaluate the
activity of gemcitabine and PLD combination, the response rate was
34.3%, with a median response duration of 22 weeks.35 In a multicenter phase II study, evaluating the combination of vinorelbine
and PLD in pretreated patients, we obtained a 37% overall response
with a progression-free survival and a overall survival of 5.5 and
9 months, respectively.23 Our population was surely more favorable
compared with these single-agent or combination studies, including
both patients with platinum-sensitive and platinum-resistant diseases. Nevertheless, our results are encouraging also if they are
compared with the recently published studies on platinum containing regimens in patients with platinum-sensitive disease.
In the ICON4-AGO trial comparing paclitaxel plus carboplatin versus conventional platinum-based chemotherapy, overall
and progression-free survivals of 29 and 13 months, respectively,
were reported in the paclitaxel plus platinum arm.32 In the trial
comparing the combination of carboplatin and gemcitabine versus
single-agent carboplatin, the combination regimen produced a
47.2% response rate with a progression-free survival of 8.6 months
and an overall survival of 18 months.33 PLD and carboplatin
combination was highly active in patients in late relapse after a
first- or second-line with platinum-taxaneYbased regimens: a 63%
response rate with a progression-free survival of 9.4 months and
an overall survival of 32 months were reported in a phase II trial.36
PLD and carboplatin combination has been compared with the
standard arm carboplatin plus paclitaxel in a recently closed intergroup trial. The higher number of previous lines and the absence of a
platinum compound in our combination make our results more
attractive. Furthermore, in a phase II study of gemcitabine and
oxaliplatin in patients with recurrent ovarian cancer, an overall best
* 2009 IGCS and ESGO
Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 19, Number 9, December 2009
response rate of 20% was reported (9.5% in patients with platinumresistant disease and 24.1% in patients with platinum-sensitive
disease).37 The author concluded that the combination is active, but
the regimen is unsatisfactory for further study owing to the modest
response and the relatively high toxicity. Despite oxaliplatin being
a platinum compound, our combination had a better response rate.
Several factors have been shown to affect response to secondline therapy, including duration of response to platinum induction
chemotherapy, TFI, and PFI.3,5 These factors are interrelated, and
PFI and TFI are often the same.38 Tumor response rates are directly
related to the PFI among all the agents currently used in secondline therapy.4,5 In addition, in our study, patients with a PFI of more
than 12 months had a better response than patients with a PFI of
6 to 12 months. Ovarian cancers that relapse 6 to 12 months after
treatment with a platinum compound are considered partially
platinum-sensitive. Phase III studies of combination regimens
versus platinum monotherapy and comparing various non-platinum
agents administered as monotherapy generally do not analyze
separately patients with platinum-sensitive or partially platinumsensitive disease. A platinum-taxane combination or single-agent
PLD is recommended by the United Kingdom National Institute for
Health and Clinical Excellence in this subset of patients.38
Gemcitabine and vinorelbine combination could be an alternative
treatment.
The high response rate (61.5%) in patients with a PFI of
more than 1 year makes our combination competitive with all the
experimented platinum combination.32,33,36 Patients who developed
hypersensitivity reactions to carboplatin or in which platinum is contraindicated are possible candidates to gemcitabine plus vinorelbine
administration.
Platinum-free interval is the most critical predictor of sensitivity to platinum rechallenge. It has been proposed that extending
the PFI with intervening non-platinum therapy increases the efficacy
of a later retreatment with platinum in platinum-sensitive recurrent
ovarian cancer. This hypothesis is based on data from small series,
and although it has not been validated prospectively, this strategy
has entered general practice. This strategy provides an alternate
sequence plan with greater recognition of the chronic nature of
relapsed ovarian cancer.4 The hypothesis has been questioned by
the Study of an Ovarian Cancer Cohort Recurred after First-Line
Treatment: a Retrospective Survey (SOCRATES), which retrospectively assessed the pattern of care of a cohort of patients with
recurrent platinum-sensitive ovarian cancer observed in the years
2000 to 2002 in 37 Italian centers.39 For the retrospective nature of
the SOCRATES study, further data are required. In the meantime,
gemcitabine and vinorelbine combination could have a place in
prolonging the PFI.
Nineteen patients (48.7%) showed a stable disease during the
treatment with our combination. In view of the chronic nature of
recurrent ovarian cancer, the achievement of stable disease with
maintenance of good performance status is considered an acceptable
goal for many patients.2
As therapy is palliative in relapsed disease, quality of life and
other factors must be considered in addition to response rates and
survival times. The aim of management in this setting was to provide
maximum time without symptoms of disease or treatment related
toxicity.3 In our study, a quality-of-life evaluation was not formerly
performed, but the toxicity was lower than in other second-line
schedules. The absence of alopecia and the very low incidence of
fatigue (1 case, grade 1 and 1 case, grade 2) are indirect signs of a
good quality of life associated with our proposed treatment. Toxicity
was mainly hematological, principally neutropenia, which was
manageable and non-cumulative. No hospitalization was required,
and no blood or platelet transfusion and no hematological growth
factors were needed. Considering the potentially high costs of
Gemcitabine and Vinorelbine Combination
toxicity management, this aspect should not be forgotten in this kind
of patients.
The most frequently reported dose-limiting toxicities of
gemcitabine are hematological, with neutropenia occurring more
often than thrombocytopenia. Nonhematological toxicities include
transient increase of liver enzymes, myalgia, fatigue, and gastrointestinal disorders. In our series, the only grades 3 and 4 toxicities
were grade 3 neutropenia (17.9%), grade 4 neutropenia (5.1%), and
grade 3 hepatic toxicity (5.1%). Despite the combination with
vinorelbine, the observed toxicity was less forced than described by
Mutch et al40 and Ferrandina et al41 for gemcitabine as single agent
in 2 recently published phase III trials on recurrent disease. On
the other hand, Villella et al42 reported lower grades of toxicity than
ours with platinum and gemcitabine combination. Nevertheless, our
toxicities were quite similar to those described when gemcitabine is
combined with carboplatin.33,43
The issue of how many treatment regimens to use in patients
with ovarian cancer has been an area of controversy. Patients
frequently have to make a decision about either continuing to be
treated with chemotherapy or receiving supportive care only.3 In a
study of treatment preferences in recurrent ovarian cancer, most
women indicated a desire for continuing aggressive treatment despite understanding that it was associated with poor outcomes.44 In
our study, 71.8% of the patients were treated after 2 previous lines of
chemotherapy. Nevertheless, the response rate was quite high and
the toxicity low.
In conclusion, gemcitabine and vinorelbine combination is
effective and well tolerated in recurrent platinum-sensitive ovarian
cancer. It may represent an option in the management of these
patients because of the chronic nature of the disease. At first recurrence, gemcitabine and vinorelbine combination could be administered to patients who experienced previous allergic reactions to
carboplatin or in which platinum is contraindicated. At further
recurrences, patients treated with previous lines of platinum-based
chemotherapy could benefit from gemcitabine and vinorelbine
administration. Furthermore, the combination could be proposed to
prolong the PFI or to treat patients with partially platinum-sensitive
disease.
REFERENCES
1. Poveda A. Ovarian cancer: is the news good enough? Int J Gynecol
Cancer. 2005;15:298Y306.
2. Markman M, Bookman MA. Second-line treatment of ovarian cancer.
Oncologist. 2000;5:26Y35.
3. Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer.
2005;15:3Y11.
4. Armstrong D. Relapsed ovarian cancer: challenges and management
strategies for a chronic disease. Oncologist. 2002;7:20Y28.
5. Markman M, Rothman R, Reichman B, et al. Second-line platinum
therapy in patients with ovarian cancer previously treated with cisplatin.
J Clin Oncol. 1991;9:389Y393.
6. Colombo N, Van Gorp T, Parma G, et al. Ovarian Cancer. Crit Rev Oncol
Hematol. 2006;60:159Y179.
7. Ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus
paclitaxel for the treatment of recurrent epithelial ovarian cancer.
J Clin Oncol. 1997;15:2183Y2193.
8. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian
carcinoma: a randomized phase III study of pegylated liposomal
doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312Y3322.
9. Fruscella E, Gallo D, Ferrandina G, et al. Gemcitabine current role and
future options in the treatment of ovarian cancer. Crit Rev Oncol
Hematol. 2003;48:81Y88.
10. Sorensen P, Hoyer M, Jakobsen A, et al. Phase II Study of vinorelbine in
the treatment of platinum-resistant ovarian carcinoma. Gynecol Oncol.
2001;81:58Y62.
* 2009 IGCS and ESGO
Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
1533
Ferrero et al
International Journal of Gynecological Cancer
11. Gucheral HJ, Richel DJ, Van Knapen A. Clinical, toxicological and
pharmacological aspects of gemcitabine. Cancer Treat Rev. 1996;
222:15Y31.
12. Huang P, Chubb S, Hertel L. Action of 2¶2¶difluorodeoxycytidine on
DNA synthesis. Cancer Res. 1991;51:6110Y6117.
13. Bookman MA. Gemcitabine monotherapy in recurrent ovarian cancer:
from the bench to the clinic. Int J Gynecol Cancer. 2005;15:12Y17.
14. Sehouli J. Review of gemcitabine-based combinations for
platinum-resistant ovarian cancer. Int J Gynecol Cancer. 2005;15:23Y30.
15. D’Agostino G, Amant F, Berteloot P, et al. Phase II study of gemcitabine
in recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol
Oncol. 2003;88:266Y269.
16. Cros S, Wright M, Morimoto M, et al. Experimental antitumor
activity of Navelbine. Semin Oncol. 1989;16:15Y20.
17. Rahmani R, Martin M, Barbet J, et al. Radioimmunoassay and
preliminary pharmacokinetic studies in rats of 5-noranhydrovinblatine
(Navelbine). Cancer Res. 1984;44:5609Y5613.
18. George MJ, Heron JF, Kerbrat P, et al. Navelbine in advanced epithelial
ovarian cancer: a study of the French oncology centers. Semin Oncol.
1989;16:30Y32.
19. Bajetta E, Di Leo A, Biganzoli L, et al. Phase II study of vinorelbine
in patients with pretreated advanced ovarian cancer: activity in
platinum-resistant disease. J Clin Oncol. 1996;14:2546Y2551.
20. Burger RA, DiSaia PJ, Roberts JA, et al. Phase II trial of vinorelbine in
recurrent and progressive epithelial ovarian cancer. Gynecol Oncol.
1999;72:148Y153.
21. Gonzales-Martin A, Crespo C, Garcia-Lopez JL, et al. Ifosfamide and
vinorelbine in advanced platinum-resistant ovarian cancer: excessive
toxicity with a potentially active regimen. Gynecol Oncol. 2002;84:
368Y373.
22. Aravantinos G, Bafaloukos D, Fountzilas G, et al. Phase II study of
docetaxel-vinorelbine in platinum-resistant, paclitaxel-pretreated
ovarian cancer. Ann Oncol. 2003;14:1094Y1099.
23. Katsaros D, Oletti MV, Rigault de la Longrais IA, et al. Clinical and
pharmacokinetic phase II study of pegylated liposomal doxorubicin and
vinorelbine in heavily pretreated recurrent ovarian cancer. Ann Oncol.
2005;16:300Y306.
24. Delord JP, Raymond E, Chaouche M, et al. A dose-finding stud of
gemcitabine and vinorelbine in advanced previously treated
malignancies. Ann Oncol. 2000;11:73Y79.
25. Airoldi M, Cattel L, Cortesina G, et al. Gemcitabine and vinorelbine in
recurrent head and neck cancer: pharmacokinetic and clinical results.
Anticancer Res. 2003;23:2845Y2852.
26. Herbst RS, Lynch C, Vasconcelles M, et al. Gemcitabine and vinorelbine
in patients with advanced lung cancer: preclinical studies and report
of a phase I trial. Cancer Chemother Pharmacol. 2001;48:151Y159.
27. Donadio M, Ardine M, Berruti A, et al. Gemcitabine and vinorelbine as
second line treatment in patients with metastatic breast cancer:
a phase II study. Cancer Chemother Pharmacol. 2003;52:147Y152.
28. Therasse P, Arbuck SG, Eisenhauer EA, 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.
2000;92:205Y216.
1534
& Volume 19, Number 9, December 2009
29. Rustin GJS. Use of Ca-125 to assess response to new agents in ovarian
cancer trials. J. Clin Oncol. 2003;21:187Y193.
30. Common Toxicity Criteria. National Cancer Institute Website.
Available at: http://ctep.cancer.gov/reporting/ctc.html. Accessed
October 16, 2009.
31. Colombo N, Parma G, Bocciolone L, et al. Role of chemotherapy in
relapsed ovarian cancer. Crit Rev Oncol Hematol. 1999;32:221Y228.
32. Parmar MK, Ledermann JA, Colombo N, et alICON and AGO
Collaborators. Paclitaxel plus platinum-based chemotherapy versus
conventional platinum-based chemotherapy in women with relapsed
ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:
2099Y2106.
33. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin
compared whit Carboplatin in patients with platinum-sensitive recurrent
ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CYG,
and EORTC GCG. J Clin Oncol. 2006;24:4699Y4707.
34. Kosmas C, Tsavaris N, Panopoulos C, et al. Gemcitabine and
vinorelbine as second-line therapy in non-small-cell lung cancer after
prior treatment with taxane + platinum based regimens. Eur J Cancer.
2001;37:972Y978.
35. D’Agostino G, Ferrandina G, Ludovisi M, et al. Phase II study of
liposomal doxorubicin and gemcitabine in the salvage treatment of
ovarian cancer. Br J Cancer. 2003;89:1180Y1184.
36. Ferrero JM, Weber B, Geay JF, et al. Second-line chemotherapy with
pegylated liposomal doxorubicin and carboplatin is highly effective in
patients with advanced ovarian cancer in late relapse: a GINECO phase
II trial. Ann Oncol. 2007;18:205Y214.
37. Harnet P, Buck M, Beale P, et al. Phase II study of gemcitabine and
oxaliplatin in patients with recurrent ovarian cancer: an Australian and
New Zealand Gynaecological Oncology Group study. Int J Gynecol
Cancer. 2007;17:359Y366.
38. Colombo N, Gore M. Treatment of recurrent ovarian cancer relapsing
6Y12 months post platinum-based chemotherapy. Crit Rev Oncol
Hematol. 2007;64:129Y138.
39. Pignata S, Ferrandina G, Scarfone G, et al. Extending the platinum-free
interval with a non-platinum therapy in platinum-sensitive recurrent
ovarian cancer. Results from the SOCRATES Retrospective Study.
Oncology. 2006;71:320Y326.
40. Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of
gemcitabine compared with pegylated liposomal doxorubicin in patients
with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25:
2811Y2818.
41. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of
gemcitabine compared with pegylated liposomal doxorubicin in
progressive or recurrent ovarian cancer. J Clin Oncol. 2008;26:
890Y896.
42. Villella J, Marchetti D, Odunsi K, et al. Response of combination
platinum and gemcitabine chemotherapy for recurrent epithelial ovarian
carcinoma. Gynecol Oncol. 2004;95:539Y545.
43. Kose MF, Sufliarsky J, Beslija S, et al. A phase II study of gemcitabine
plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma.
Gynecol Oncol. 2005;96:374Y380.
44. Donovan KA, Greene PG, Shuster JL, et al. Treatment preferences in
recurrent ovarian cancer. Gynecol Oncol. 2002;86:200Y211.
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