Download Successful Treatment with Nedaplatin in Patients with Ovarian

Jpn J Clin OncoI1998;28(5)343-346
Successful Treatment with Nedaplatin in Patients with Ovarian
Cancer that Recurred After Platinum-containing Chemotherapy:
Report of Two Cases
Kuniaki Itoh, Tomoyuki Yamashita, Hisashi Wakita, Yuko Watanabe, Keiji Kodama, Hirofumi Fujii,
Hironobu Minami, Tomoko Ohtsu, Tadahiko Igarashi and Yasutsuna Sasaki
Division of Oncology and Hematology, National CancerCenter Hospital East, Kashiwa, Chiba, Japan
We report thesuccessful treatment withnedaplatin oftwocases of ovarian cancer thatrecurred after
platinum-containing chemotherapy. A 52-year-old woman presented in June 1994 with massive
accumulation of ascitic fluid. Pathological diagnosis ofthespecimen obtained atsurgery in July 1994
was serous papillary adenocarcinoma of the ovary. In September 1995, approximately seven
months after the completion of six cycles of CAP chemotherapy (cyclophosphamide, adriamycin
and cisplatinum), she was referred to our hospital because of massive accumulation of ascitic fluid.
The carbohydrate antigen 125(CA-125) value was485 U/ml. Cytologic study of herascitic fluid was
positive for adenocarcinoma cells. She did not respond to intravenous irinotecan andtwo cycles of
intraperitoneal cisplatin. Nedaplatin 100 mg/m2 was administered. Complete response was
achieved in September 1996 and continued for four months with a total of seven cycles of
nedaplatin. The second case was a 60-year-old woman who was admitted to our hospital in
December 1994 because of ascitic fluid. Diagnosis of ovarian cancer was based on an elevated
level of CA-125 (1380 U/ml). Treatment with CAP and CC (cyclophosphamide and carboplatin)
maintained a partial response for seven months. In August 1996, herdisease progressed, although
she was receiving CC therapy. Nedaplatin 100 mg/m 2 was administered. Partial response was
achieved again in November 1996 and continued for four months, with a total of five cycles of
nedaplatin. Inthe lightof ourexperience, treatment withnedaplatin in a patient withrecurrent ovarian
cancer might be worthwhile as palliative chemotherapy.
Key words: ovary - palliative chemotherapy - cis-diammineglycolatoplatinum
INTRODUCTION
Advanced ovarian cancer is a chemosensitive tumor and most
patients initially respond to platinum-based combination chemotherapy with response rates of about 70%, including a high
proportion of complete responses (1). The majority of patients,
however, relapse after receiving first-line platinum-based chemotherapy. Although many patients will undergo second-line,
third-line and even further regimens of chemotherapy, salvage
chemotherapy in these patients results in a low response rate and
the duration of response is relatively short (2,3). Therefore, it is
Received December 17, 1997; accepted January 28,1998
For reprints and all correspondence: Kuniaki Itoh, Division of Oncology
and Hematology, National Cancer Center Hospital East, 5-1, Kashiwanoha
6-chome, Chiba 277-8577, Japan
Abbreviations: CAP, cyclophosphamide, adriamycin, cisplatinum; CC,
cyclophosphamide, carboplatin; CA-125, carbohydrate antigen 125; CEA,
carcinoembryonic antigen; aFP, alpha-fetoprotein; HCG, human chorionic
gonadotropin; CAI5-3, carbohydrate antigen 15-3; LDH, lactic
dehydrogenase; CT, computed tomography; CR, complete response; PR,
partial response .
important to search for various options of palliative chemotherapy in ovarian cancer.
Nedaplatin (cis-diammineglycolatoplatinum) is one of the new
platinum analogues, developed in Japan and marketed recently.
The drug was shown to be active against various solid tumors,
including lung cancer (4), esophageal cancer (5), head and neck
cancer (6) and testicular cancer (7), with a response rate of 37.7%
in patients with relapsed ovarian cancer (8). Its dose-limiting
toxicity is myelosuppression, particularly resulting in thrombocytopenia, but severe emetogenicity and nephrotoxicity occurred
less frequently. The recommended dose and schedule for clinical
practice were 100 mg/rn'' as a one-hour intravenous infusion
every four weeks (9). Because of little nephrotoxicity and
vomiting, outpatient administration of the drug without hydration
provides convenience in clinical practice.
We report here two cases of ovarian cancer that recurred after
platinum-containing chemotherapy who were successfully
treated with nedaplatin. The effect of most salvage treatments is
disappointing, and our cases might be of interest from the
viewpoint of palliative chemotherapy for ovarian cancer.
A
Figure 1. Time course of the CA-125 level in case I. CPT, i1inotecan.
B
CASE REPORTS
CASE
1
A 52-year-old woman presented in June 1994 because of a
massive accumulation of ascitic fluid. She was diagnosed as
having stage IIIC ovarian cancer and was operated on July 6,
1994. Pathological diagnosis was serous papillary adenocarcinoma of the ovary. Direct invasion was demonstrated to the
greater omentum, peritoneum, uterus and transverse colon.
Furthermore, there was invasion of cancer cells on the margin of
the resected specimen. A cycle of CAP (cyclophosphamide
750 mg/m 2 , adriamycin 55 mg/m-' and cisplatinum 75 mg/m-)
was administered every three weeks for a total of six cycles as
adjuvant therapy. The last CAP therapy was administered on
January 11,1995.
After a response of about seven months in duration, an elevated
carbohydrate antigen 125 (CA-125) value was detected in August
1995, and the patient was referred to our hospital in September
1995 because of a massive accumulation of ascitic fluid. Physical
examination revealed no remarkable findings except abdominal
distension. Laboratory findings were as follows: hemoglobin
11.0 g/dl, white blood cell count 3.7 x 109/1, platelets 233 x 109/1,
lactic dehydrogenase (LDH) 324 IU/1, total bilirubin 0.5 mg/dl
and creatinine 0.6 mg/dl. Tumor marker tests were within normal
limits, except that the CA-125 value was 485 Uzml. Computed
tomographic (CT) scan showed masses around the liver with a
massive accumulation of ascitic fluid. Cytology of the ascitic
fluid was positive for adenocarcinoma cells.
Three cycles of irinotecan 100 mg/rn-' were administered at
weekly intervals. Abdominal paracentesis was performed three
times, and a total 2800 ml of fluid were obtained. Unfortunately,
her disease did not respond to irinotecan infusion. Although the
CA-125 level decreased with paracentesis of a total of 20 I of
ascitic fluid over a period of two months, her disease did not .
respond to the two cycles of intraperitoneal administration of
cisplatin 75 mg/rri- which would be expected to produce a locally
high concentration of drug. After administration of nedaplatin
100 mg/m-' every four weeks beginning on January 16, 1996, the
Figure 2. Pretreatment CT scan of case 1 on January 12, 1996 (A) (the arrow
represents massive metastatic sites). CT scan at the partial response on April 25,
1996 (B) (the arrow represents the residual mass).
CA-125 level gradually decreased, as shown in Fig. 1. A CT scan
performed on February 15 showed a partial response (PR). The
dose of the second cycle of nedaplatin was decreased to 75 mg/m 2
because of grade 3 thrombocytopenia during four days (the nadir
platelet count of 26 x 109/1). The CA-125 level decreased to
normal range on June 12, 1996. CT scan also demonstrated
complete response (CR) on September 2, 1996 (Fig. 2). CR
continued for four months with a total of seven cycles of
nedaplatin. The progression-free interval from the start of the PR
by nedaplatin was 11 months. The patient could enjoy her daily
life during this period of response.
CASE
2
A 60-year-old woman was admitted to our hospital in December
1994 because of an accumulation of ascitic fluid. Results of a
cytologic study of her ascitic fluid at a local hospital had been
positive for malignant cells. Physical examination revealed
abdominal distention and a small mass on the right lower
Jpn J Clin OncoI1998;28(5)
abdominal wall. Laboratory fmdings were as follows: hemoglobin
12.4 g/dl, white blood cell count 4.9 x 109/l, platelets 255 x 109/l,
LDH 341 IU/l, total bililubin 0.8 mg/dl and creatinine0.6 mg/dl. The
tumor markers were CA-125 1380 U/ml, carcinoembryonicantigen
(CEA) 0.6 ng/ml, alpha-feto protein (a-FP) 2.0 ng/ml, human
chorionic gonadotropin (BCG) 1.2 mIU/ml and carbohydrate
antigen 15-3 (CA15-3) 35 U/ml. Chest X-ray films, CT scans of the
chest and abdomen, and endoscopic examinations of the stomach
and colon failed to fmd any primary lesion. Although there were no
abnormalities except ascitic fluid determined by CT scan and
magnetic resonance imaging, ovarian cancer was highly suspected
because of an elevated CA-125 level.
Abdominal paracentesis was performed twice, and a total of 2000
ml of fluid were obtained. The patient was treated with CAP
(cyclophosphamide 500 mg/m 2, adriamycin 50 mg/m2 and
cisplatinum 50 mg/m2) . After two cycles of CM her disease
showed PR in March 1995. Ten cycles of CAP were able to control
ascitic fluid for nine months. After her total dosage of adriamycin
reached 500 mg/nr', she received a total of eight cycles of CC
(cyclophosphamide 500 mg/m 2 and carboplatin 300 mg/m2) at
four-week intervals, and the PR was maintained until June 1996.
Although the patient was still receiving cyclophosphamide and
carboplatin on June 28, 1996, the tumor on her abdominal wall
progressed, accompanied by an elevation of CA-125. The ascitic
fluid increased again in August 1996 in spite of the use of
diuretics. Abdominal paracentesis was performed four times, and
a total of 7900 ml of fluid were obtained. Although this patient
was considered to be carboplatin resistant, nedaplatin 100 mg/m 2
was administered on August 28, 1996. The CA-125 level
gradually decreased as shown in Fig. 3. The second cycle of
nedaplatin was decreased to 75 mg/m- and then further decreased
to 66 mg/m 2 for the third cycle because of grade 4 thrombocytopenia. The duration of grade 4 thrombocytopenia was three
days in the first course and two days in the second course. The
nadir of platelet count was 5 x 109/l in the first course and 3 x 109/l
in the second course, respectively. After two cycles of nedaplatin,
she was determined to have PR in November 1996 through
evaluation of the tumor on her abdominal wall and by CT scan.
The PR continued for four months with a total of five cycles of
nedaplatin. The patient could enjoy her daily life with the
improvement of performance status.
After nedaplatin diminished in effectiveness in controlling her
disease, two cycles of irinotecan 100 mg/m 2 failed to control the
ascitic fluid.
DISCUSSION
Platinum-based combination chemotherapy can be expected to
yield relatively high response rates for advanced ovarian cancer
(1), and the combination of cisplatin and cyclophosphamide has
been standard chemotherapy for advanced ovarian cancer (10). A
recent randomized study demonstrated that the combination of
cisplatin and paclitaxel was more effective than the combination
of cisplatin and cyclophosphamide in response rate and survival
in untreated advanced ovarian cancer (11). Unfortunately, most
patients will relapse and require additional therapy. Salvage
345
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1- CA 125,
(U/ml)
It)
N
T""
«
o
1000
GAP
G'G
Nedaplatin
llllllllll~~~!~~~~ ~ ~~ ~~
Dec. '94
May '95
Oct. '95
Mar. '96
Aug. '96
Jan.'97
Figure 3. Time course of the CA-125 level in case 2. CAP, cyclophosphamide,
adriamycin, cisplatin: CC, cyclophosphamide, carboplatin.
chemotherapy in these patients, however, is disappointing and the
duration of response is relatively short (2,3). Therefore, it is
important to search for various salvage regimens against ovarian
cancer. Although paclitaxel, topotecan (12) and gemcitabine (13)
would be considered good candidates for salvage therapy, the
response rates of platinum-resistant ovarian cancer were <25% in
salvage therapy with various single agents (2,3). Moreover, there
are no prognostic factors that provide information which would
be helpful in the selection of appropriate salvage therapy. In
general, patients whose disease progressed during or shortly after
the completion of platinum-based treatment are unlikely to
respond again to additional therapy with a platinum-containing
regimen (2,14,15). If recurrence takes place less than six months
after cisplatin-based chemotherapy, the tumors are usually
considered cisplatin resistant (2). Case 1 might not be resistant to
cisplatin in a strict sense because she relapsed after a seven-month
therapy-free period. However, we believe that her disease was
chemotherapy resistant in a practical sense, considering that
irinotecan and intraperitoneal cisplatin were ineffective. In case
2, the disease had progressed during the treatment with carboplatin. Accordingly, case 2 was certainly resistant to carboplatin.
Concerning intraperitoneal cisplatin, a retrospective analysis
showed that the patients who previously responded to intravenous
cisplatin could have been predicted to respond to subsequent
intraperitoneal cisplatin (16). On the other hand, it was reported
that 34% of the 44 patients who had a tumor-free interval within
one year responded to intraperitoneal cisplatin (17). Moreover, in
a comparative study of stage III ovarian cancer, the median
survival was longer for patients receiving intraperitoneal cisplatin
than for those receiving intravenous administration. The toxic
effects of intraperitoneal cisplatin were less frequent than with
intravenous administration (18). Unfortunately, case 1 did not
respond to intraperitoneal cisplatin, probably because the tumors
had become cisplatin resistant and the sizes of the tumors were
several centimeters, through which intraperitoneal cisplatin
theoretically could not penetrate (19).
346
Nedaplatin in ovarian cancer
Irinotecan, a new promising topoisomerase I inhibitor, is active
against ovarian cancer and has entered routine clinical practice
recently in Japan (20). Both of our patients, however, did not
respond to irinotecan administration.
Cisplatin is the most active drug against ovarian cancer. In
response to the problems associated with the toxicity of cisplatin,
such as nephrotoxicity, emetogenicity and ototoxicity, research
has yielded less toxic analogues. Carboplatin is one such cisplatin
analogue. The drug is less nephrotoxic, but more myelosuppressive (1). Although cisplatin and carboplatin were reported to have
similar response rates and survival results in a randomized study,
the overall response for cross-over between cisplatin and
carboplatin was only 14.3% in 35 patients with progressive
disease or non-responding disease with the initial platinum
treatment (2 I). The other cisplatin analogue is nedaplatin, which
was developed in Japan. It was revealed that nedaplatin had a
wide spectrum of activity against solid tumor activity, similar to
that of cisplatin (4-8). Toxicity profiles of nedaplatin resembled
those of carboplatin. Alberts et al. (22) showed that the in vitro
cytotoxicity of nedaplatin was comparable to that of cisplatin and
carboplatin. Moreover, nedaplatin appeared relatively crossresistant with cisplatin in vitro; namely, only 28% of the ovarian
cancers resistant to cisplatin were sensitive to nedaplatin. In spite
of these findings in vitro, our patients showed remarkable
responses to nedaplatin.
The pharmacokinetic behavior of nedaplatin was similar to that
of carboplatin, and the protein-binding abilities of nedaplatin and
carboplatin were almost identical (23). A pharmacological study
showed that almost all nedaplatin exists as a free form in plasma,
as does carboplatin (23). However, Sasaki et al. (24) reported that
the anti-tumor activity index of nedaplatin-containing plasma
from patients through the colony-suppressive effect on human
lung cancer cell lines had a higher value than cisplatin or
carboplatin. The responses to nedaplatin observed in our patients
might be due to the existence of a major free form of nedaplatin.
Although it is unclear whether these patients were truly resistant
to cisplatin, Fukuda et al. (4) reported that three out of 16 patients
with non-small cell lung cancer who had received prior cisplatin
responded to nedaplatin. Similarly, it was shown that 33.3% of33
patients with ovarian cancer who had been previously treated
with cisplatin responded to nedaplatin (8). Clinical resistance
might be different from true platinum resistance.
In the light of our experience, a trial of nedaplatin in a patient
with recurrent ovarian cancer might be worthwhile. Further
studies are warranted to evaluate the palliative effect of nedaplatin as a second-line regimen for advanced ovarian cancer, and to
investigate cross-resistance between paclitaxel and nedaplatin,
and the combination chemotherapy of paclitaxel and nedaplatin
for untreated advanced ovarian cancer.
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