Gynecologic Oncology 80, 13–15 (2001)
doi:10.1006/gyno.2000.5995, available online at http://www.idealibrary.com on
Response and Toxicity to Topotecan in Sensitive Ovarian Cancer
Cases with Small Residual Disease after First-Line Treatment
with Carboplatinum and Paclitaxel
Giorgio Bolis,* ,† Giovanna Scarfone,* Saverio Tateo,‡ Giorgia Mangili,§ Antonella Villa,† and Fabio Parazzini* ,¶
*I a Clinica Ostetrico Ginecologica, Università di Milano, Milan; †Divisione di Oncologia Ginecologica, Istituto Nazionale Tumori, Milan;
‡Clinica Ostetrico Ginecologica, Università di Pavia, Pavia; §Clinica Ostetrico Ginecologica, Ospedale S. Raffaele, Milano;
and ¶Istituto di Ricerche Farmacologiche “Mario Negri,” 20157 Milan, Italy
Received February 4, 2000; published online December 4, 2000
Objective. The objective of this open uncontrolled study was to
evaluate the toxicity and efficacy of topotecan in ovarian cancer
cases with microscopic small residual disease to a first-line treat-
ment, given as sequential treatment, including carboplatinum and
paclitaxel.
Methods. Inclusion criteria were laparotomically or laparoscopi-
cally documented microscopic or macroscopic (<2 cm) residual
disease after first-line chemotherapy including carboplatinum plus
paclitaxel in patients with histologically documented epithelial
ovarian cancer FIGO stage III or IV at first diagnosis. All patients
had a response >50% after first-line treatment. Eligible patients
received 1.25 mg/m 2/day of topotecan intravenously as a 30-min
infusion for 5 consecutive days every 21 days for four cycles. A
total of 38 women entered the study. Surgical “third-look” lapa-
rotomy or laparoscopy was performed in patients without clinical/
instrumental evidence of progressive disease within 1 month from
the last topotecan administration.
Results. A complete response was observed in 10 cases (28.6%,
95% confidence interval, based on the Poisson’s approximation,
15.6 –59.5), a partial response in 1 (2.5%), progressive disease in 11
(31.4%) and no change/stable disease in 13. The median duration
of response was 8 months (range 5–20). The overall 1-year survival
after treatment was 82.8% (SE 6.4).
Conclusion. This study indicates that sequential therapy with
carboplatin plus paclitaxel followed by topotecan, all given at
standard doses, is feasible and provides favorable response
rates. © 2001 Academic Press
Common therapy of advanced ovarian carcinoma following
maximal surgical cytoreduction is carboplatinum or platinum
plus paclitaxel regimens. After this first-line chemotherapy a
small residual disease is observed in about 20 –30% of cases. In
these patients, further treatment may be useful in order to
obtain a complete response [1].
Phase II and III studies have shown that topotecan is effec-
tive therapy in ovarian cancer cases who failed prior therapy,
including platinum [2, 3]. In this study we will evaluate the
toxicity and efficacy of topotecan in ovarian cancer cases with
13
microscopic/small residual disease to a first-line treatment in-
cluding carboplatinum and paclitaxel. We gave topotecan as
sequential treatment after carboplatinum–paclitaxel, thus we
can evaluate the cumulative toxicity of the three drugs.
METHODS
The objective of this phase II study was to evaluate the
response rate and duration of response to topotecan in ad-
vanced epithelial ovarian carcinoma patients who had micro-
scopic or small residual (⬍2 cm) disease after a carboplati-
num–paclitaxel chemotherapeutic regimen. Further, this study
evaluated the toxicity of topotecan administered as sequential
therapy after standard carboplatinum plus paclitaxel regimens.
Inclusion criteria were laparotomically or laparoscopically
documented microscopic or macroscopic residual disease (⬍2
cm) after first-line chemotherapy including carboplatinum plus
paclitaxel in patients with histologically documented epithelial
ovarian cancer FIGO stage III or IV at first diagnosis. All
patients had partial responses to first-line treatment (i.e., all
patients had a response ⬎50% after first-line treatment). Mi-
croscopic disease was defined as positive random biopsies
and/or positive peritoneal washings. Macroscopic response
was defined as residual tumor ⬍2 cm with or without positive
peritoneal washings at second-look surgery. Patients debulked
during the second-look surgery at ⬍2 cm residual disease were
excluded. In our istitution most of the patients are enrolled in
clinical trials. Thus second-look surgery is generally performed
in all subjects without clinical/instrumental evidences after
first-line chemotherapy of progressive disease or marked (more
than fivefold) increase in CA125 values.
Other inclusion criteria were performance status ⱕ2 (WHO
scale), life expectancy ⱖ3 months, and age ⱖ18 –75 years.
At study entry, current laboratory values were hemoglobin
ⱖ9.0 g/dL, WBC ⱖ3.5 ⫻ 10 9/L, granulocytes ⬎1.5 ⫻ 10 9/L,
platelets ⱖ100 ⫻ 10 9/L, serum creatinine ⱖ15 ␮g/100 ml,
0090-8258/01 $35.00
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved.
14 BOLIS ET AL.

serum bilirubin ⱕ1.5 ␮g/100 ml, SGOT/AST, SGPT/ALT, and TABLE 1

alkaline phosphatase ⬍2 times the upper limit of normal. Characteristics of Study Subjects and Response to Topotecan
All eligible women were observed at Istituto Nazionale
No. %
Tumori, S. Raffaele Hospital of Milan, and the Obstetric and
Gynecologic Clinic University of Pavia between October 1996 Age (years, mean, SD, range) 52 (31–70)
and March 1999. Stage at diagnosis
Before entry the study, written informed consent was ob- III 35 (92.1)
tained. Investigators obtained approval of the protocol from the IV 3 (7.9)
Residual disease after surgery (cm)
internal review boards of their own institutions. ⱕ1 11 (28.9)
Eligible patients received 1.25 mg/m 2/day of topotecan in- ⬎1 20 (52.6)
travenously as a 30-min infusion for 5 consecutive days every Carcinosis 7 (18.4)
21 days for four cycles. The appropriate volume of the recon- Hystotype
stituted topotecan solution was diluited in 100 ml of 5% Serous 31 (81.6)
Other 7 (18.4)
dextrose water. The protocol allowed routine antiemetic ther- Grading
apy with 5-HT (serotonin) antagonists; no G(M)CSF support 2 10 (26.3)
was foreseen. 3 28 (73.7)
All patients were treated in a monitored outpatient unit. Response after first-line chemotherapy
The study parameters were assessed within 7 days of the first Microscopic disease 29 (76.3)
Macroscopic disease (⬍2 cm) 9 (23.7)
scheduled infusion for entry into the study; vitals signs and Response to topotecan
body surface were measured on day 1 of each treatment cycle; Complete response 10 (28.6)
WBC with differential count and platelets were measured Partial response 1 (2.9)
every week, while blood chemistry was checked only on days Progressive disease 11 (31.4)
1 and 15 of each treatment cycle. No change 13 (37.1)
Not available 3 —
Toxicity was recorded according to WHO guidelines [4].
Patients who reduced their drug dose continued with the re-
duced dose on all subsequent courses. The dose of topotecan
was cut to 1 mg/m 2/day if the platelets count was ⱕ50 ⫻ 10 9/L and no change/stable disease in 13 (37.1%, 95% CI 20.0 –
and or ANC ⱕ1.0 ⫻ 10 9/L for ⱖ7 days. If the platelets count 64.3). The median duration of response was 8 months (range
was ⱕ100 ⫻ 10 9/L and/or ANC ⱕ1.5 ⫻ 10 9/L on the recovery 5–20). In particular, the mean duration of complete response
day, the treatment was delayed for 1 week. was 20.9 months (range 7–33⫹). The median duration of
“Third-look” laparotomy or laparoscopy was performed in follow-up was 18 months. Of the 10 cases with complete
patients without clinical/instrumental evidence of progressive response, 5 relapsed. The overall 1-year survival after treat-
disease within 1 month from the last topotecan administration. ment was 82.8% (SE 6.4). We have also analysed response
CA125 was assayed in all patients and in each treatment according to the presence of microscopic or macroscopic dis-
course. A pathological complete response was defined as the ease at study entry. Considering the 29 patients with micro-
disappearance of disease at histological examination assessed scopic disease, the complete response rate was 27.6%. The
by at least 10 random biopsies, with negative peritoneal cytol- corresponding value of 9 patients with macroscopic disease
ogy. A partial response was defined as a reduction in tumor was 22.2%.
size of 50% or more in the macroscopic (⬍2 cm) response A total of 148 courses were assessable for toxicity (two
group of patients. patients stopped after 2 courses). Eleven courses of 148 (7.4%)
All patients were followed every 3 months for 3 years or till had a delay of 1 week.
death. The planned doses were given to 31 of the 38 patients.
G(M)CSF support was necessary in 2 patients.
RESULTS Neutropenia, thrombocytopenia, and anemia grade 3– 4 were
reported, respectively, in 52.6, 23.7, and 26.3% of cases.
A total of 38 women entered the study. Their characteristics
are shown in Table 1. Of the 38 women, 29 had microscopic DISCUSSION
and 9 macroscopic residual disease at study entry. Information
on response to treatment with topotecan was available for 35 Topotecan is, among more recent drugs, one of the most
women. Three women refused third-look laparotomy. active compounds in relapsed ovarian cancer [2, 3]. Thus its
A complete response was observed in 10 cases (28.6%, 95% introduction in first-line treatment of advanced ovarian cancers
confidence interval (CI), based on the Poisson’s approxima- may be useful to improve survival. However, concerns have
tion, 15.6 –59.5), partial response in 1 (2.9%, 95% CI 0.5– been raised regarding the potential cumulative toxicity of plat-
98.8), progressive disease in 11 (31.4%, 95% CI 6.1– 62.8), inum/carboplatinum, paclitaxel, and topotecan.
 SEQUENTIAL TOPOTECAN IN SENSITIVE OVARIAN CANCER
Our study suggests that sequential treatment with topotecan
after carboplatinum plus paclitaxel is well tolerated and there is
not marked increased toxicity. In this phase II study, in fact,
planned doses of topotecan were given to about 80% of pa-
tients.
The most frequent adverse events reported were neutropenia
and thrombocytopenia. However, G(M)CSF support was nec-
essary in only two cases. Neurotoxicity grade 2 was observed
in one woman.
These findings are generally consistent with those reported
by Chan et al. [5] in a study including 20 patients treated with
1.25 mg/m 2 of hycamtin following five cycles of paclitaxel
plus carboplatin.
The second objective of the study was to evaluate the effi-
cacy of topotecan given as consolidation treatment. The topic
of consolidation treatment has been the object of continuous
debate during the past years [6]. However, few data are avail-
able on the efficacy of treatment after partial response follow-
ing first-line therapy. In particular, few studies have conducted
a third-look laparotomy. The Memorial Sloan-Kettering Can-
cer Center Study conducted by Hakes et al. [7] evaluated the
efficacy of a further five cycles of cyclophosphamide, doxoru-
bicin, and cisplatinum (CAP) in patients with a partial response
after five cycles with the same schedule. Of 7 patients who
underwent a third-look laparotomy, 1 had a complete response.
In a study conducted by the Danish Ovarian Cancer Group with
a design very similar to that of the Memorial-Sloan-Kettering
study, 15 patients underwent third-look laparotomy. Of those,
1 had a complete pathological response with a further six
cycles of CAP after a partial response to second-look laparot-
omy [8].
Higher rates of complete response had been reported after
intraperitoneal treatments [9 –11].
In order to improve the response to sequential/consolidation
treatment, the use of no cross-resistant chemotherapy has been
advocated [12]. We used topotecan, given at standard doses.
Our complete response rate seems to be higher than that
previously reported with intravenous platinum-based sched-
ules, although it is not possible to make any statistical evalu-
ation of the differences.
However, our study included a small number of patients,
most of whom had microscopic disease at second-look. Fur-
ther, the impact of obtaining a complete response on survival in
this subset of patients is not documented.
In other terms, giving topotecan as sequential treatment
during front-line treatment seems to increase the frequency of
complete response; however, we do not know whether the
benefit is long lasting and whether the women who respond to
sequential treatment after first-line therapy are the same sub-
jects who respond to second-line treatment after progression.
In conclusion, this study indicates that sequential therapy
with carboplatin plus paclitaxel followed by topotecan, all
15
given at standard does, is feasible and well tolerated. Further,
it shows that, in patients with small residual disease after
chemotherapy with carboplatin plus paclitaxel, topotecan given
sequentially converted about 30% of these patients to complete
response. This finding, however, is based on only a few cases.
We have observed a favorable rate of complete response in
women with microscopic disease at second-look surgery. Since
the main goal is to obtain a complete response in order to cure
ovarian cancer, it is important to identify, using second-look
surgery, patients who may benefit from second-line treatment
(i.e., those with microscopic disease).
ACKNOWLEDGMENTS
The authors thank Raffaella Bertazzi and Ivana Garimoldi for their editorial
assistance.
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