Download Oral Etoposide, Ifosfamide and Cisplatin in the Treatment of

Cancer Research and Treatment 2002;34(6):421-425
Oral Etoposide, Ifosfam ide and Cisplatin in the Treatm ent of
Extensive Disease Sm all Cell Lung Cancer
Seok Jin Kim, M.D.1, Hwa Jung Sung, M.D.1, Kyong Hwa Park, M.D.1, So Young Yoon, M.D.1, Sang Cheul
Oh, M.D.1, Jae Hong Seo, M.D.1, Chul W on Choi, M.D.1, Byung Soo Kim , M.D.1, Sang W on Shin, M.D.1,
Yeul Hong Kim , M.D.1, Kwang Taek Kim , M.D.2, Young Ho Choi, M.D.2 and Jun Suk Kim , M.D.1
Departments of 1Internal Medicine and 2Chest Surgery, College of Medicine, Korea University, Seoul, Korea
Purpose: The com bination of cisplatin and etoposide
has been a com m on first line regim en for the treatm ent
of sm all cell lung cancer (SCLC). The schedule depen dence, and equal efficacy, of the oral and intravenous
dosing of etoposide has led to prolonged adm inistration
of oral etoposide, which is known to produce an
encouraging response in SCLC. To im prove the efficacy
of the cisplatin/etoposide com bination, we adm inistered
oral etoposide, with added ifosfam ide, which had sig nificant single agent activity against SCLC. We conducted
this study to evaluate the efficacy and toxicity of the
cisplatin, ifosfamide and oral etoposide (PIE) combination
in patients with extensive sm all cell lung cancer.
M aterials and Methods: Twenty-five patients with
histologically confirm ed extensive sm all cell lung cancer
were enrolled into this study between January 2000 and
M ay 2002. They were treated with, cisplatin at 20 m g/
m 2 /day, ifosfam ide 1.5 g/m 2 /day, with m esna (all given
2
intravenously on Days 1∼3), and oral etoposide 50 mg/m
on days 4∼17. This cycle was repeated every 4 weeks
for up to 6 cycles. W e evaluated the corresponding
disease responses and toxicities.
Results: The patients' characteristics were as follows:
m edian age 65 years (32∼75), 19 m ales and 6 fem ales.
The perform ance stati were ECOG 0 in 3 patients, ECOG
1 in 12 and ECOG 2 in 10. Sixteen patients had a partial
response, 2 had a stable disease and 4 had a progressive
disease. Thus, the overall objective response rate was
72.7% (95% CI: 49.6∼88.4% ), with a m edian response
duration of 7 m onths (95% CI: 3.5∼10.5 m onths). Myelosuppression was the major observed toxicity. Grades III
and IV neutropenia were observed in 42 (46.1%) of the 91
cycles. Significant non-hem atological toxicities (≥Grade
III) were uncom m on, with the exception of nausea and
vom iting.
Conclusion: The response rate to the com bination of
cisplatin, ifosfamide and oral etoposide was similar to that
of other com bination chem otherapy studies in patients
with extensive disease small cell lung cancer. The toxicity
of the regim en was considered acceptable. (Cancer
Research and Treatm ent 2002;34:421-425)
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Key W ords: Sm all cell lung cancer, Ifosfamide, Cisplatin,
Oral etoposide
are modest, and long-term survival and cure are rarely achieved.
Etoposide and cisplatin are highly synergistic, and are commonly
used as a first-line regimen in patients with SCLC (2).
The response to etoposide has proven to be dependent on the
administration schedule, which has led to changes in its
administration. Thus, the continuous administration of intravenous etoposide improved both the response rate and duration
in patients with SCLC compared to a larger single dose (3).
The oral administration of etoposide has equal efficacy and
toxicity as intravenous dosing in patients with SCLC (4);
moreover, high plasma concentrations of etoposide are associated with the development of severe myelotoxicity (5). It is
suggested that chronic exposure to relatively low levels of
etoposide might potentiate the anticancer effect of etoposide.
Thus, the prolonged administration of low dosages of
etoposide could help improve its efficacy, and decrease its
toxicity. The prolonged oral administration of etoposide was
reported to produce an 85% response rate in previously
untreated patients with SCLC (6).
In order to improve the efficacy of combined cisplatin and
INTRODUCTION
Small cell lung cancer (SCLC) accounts for approximately
15 to 20% of all lung cancers. Because the malignant cells are
characterized by rapid tumor growth and early metastatic
dissemination, 65 to 70% of SCLC patients present with an
extensive disease (ED). Thus, systemic chemotherapy is the
most important treatment modality for this disease (1).
Although multiple chemotherapeutic trials have demonstrated
response rates of 60 to 80% in ED SCLC, the survival benefits
Correspondence: Sang Won Shin, Department of Internal Medicine
College of Medicine, Korea University, 126-1, Anamdong 1-ga,
Sungbuk-gu, Seoul 136-705, Korea. (Tel) 02-920-5350, 5114,
(Fax) 02-922-5974, (E-mail) [email protected]
Received August 17, 2002, Accepted November 28, 2002
The abstract of this article was presented at the 28th annual meeting
of Korea Cancer Association.
421
422
Cancer Research and Treatment 2002;34(6)
etoposide (EP), many other drugs have been additionally used
with this standard regimen. Ifosfamide has a significant single
agent activity in previously untreated patients with SCLC. The
ECOG demonstrated a response rate of 45% in 44 chemotherapy nave patients with the use of ED SCLC (7). Ifosfamide
is known to be less myelotoxic than cisplatin and etoposide,
and its main dose-limiting toxicity, hemorrhagic cystitis, can be
prevented by the administration of mesna. Thus, ifosfamide
could be administrated safely with cisplatin and etoposide.
Although the combination of etoposide, ifosfamide and cisplatin
(VIP) was originally developed as a salvage regimen for
relapsed SCLC patients, the Hoosier Oncology Group (HOG)
compared the results of a phase III trial of this regimen to those
of EP in patients with previously untreated ED SCLC. This
study showed a modest survival advantage favoring the VIP
based regimen (8).
It was reported that ifosfamide, in combination with cisplatin
and oral etoposide administration, showed the significant
response rate of 93% in patients with ED SCLC (9). In the
phase II study, the authors added ifosfamide to the cisplatin and
etoposide combination, with the etoposide was administered
orally, and found a modest survival benefit, and acceptable
toxicity, for this regimen in ED SCLC. However, the chosen
patient population had good prognostic features, including good
performance stati and a median age of 59 years, which was
relatively younger than that of previous studies.
Therefore, based on the above results, we conducted a
prospective study using the same regimen used in the previous
study, and evaluate the efficacy and toxicity of cisplatin,
ifosfamide and prolonged oral etoposide in patients with ED
SCLC, and included relatively older patients with poorer performance stati.
history taking, a physical examination, complete blood cell
counts (CBCs) with differential blood counts, routine biochemical profile testing, an electrocardiogram, chest X-rays,
computed tomographic (CT) scan of the chest and brain, and
an isotope bone scan. Bone marrow aspiration and a biopsy
were performed when bone marrow involvement was suspected.
During the study, physical examinations, including a neurologic examination, were performed before each treatment cycle.
CBCs, with differential blood counts, were performed every
two weeks, and immediately before the next treatment cycle.
In the case of grade IV neutropenia, or febrile neutropenia,
CBCs were performed every 2 days until the ANC was more
than 1.0×109/l and all symptoms of infection had subsided.
To assess responses, all measurable lesions were re-evaluated
by a chest X-ray at every cycle. A chest CT scan was repeated
after every other cycle. The toxicity was evaluated after every
cycle, according to the NCI criteria.
3) Treatment schedule
The treatment protocol is described in Table 1, and each
treatment cycle was repeated every 4 weeks. The dosage of
ifosfamide was reduced by 25% when patients experienced
9
either grade IV neutropenia (ANC＜0.5×10 /l) for more than
7 days, or neutropenic fever lasting more than 3 days, or
9
thrombocytopenia (platelet counts＜25×10 /l) or any nonhematologic grade III or IV toxicity. Etoposide was discontinued,
9
if the granulocyte or platelet counts were below 1.0×10 /l or
9
50×10 /l, respectively. Because etoposide was available as
25mg capsules, the dose was calculated for a three or four day
period. A total of 6 cycles was planned, but patients had their
therapy stopped when the toxicity became non-manageable, or
when there was evidence of a progressive disease.
4) Definition of response and statistics
MATERIALS AND METHODS
1) Patient selection
Patients with histologically confirmed ED SCLC, were
enrolled onto the study. ED was defined as a disease beyond
the hemithorax of the origin and regional lymph nodes. Each
patient was required to meet the following criteria: ECOG
performance status 2; adequate bone marrow function (absolute
neutrophil count (ANC) 2.0×109/l, platelet count 100×109/l);
normal hepatic function (serum total bilirubin 1.5 mg/dl and
serum AST and ALT less than 3.0 the upper normal limit
(UNL)); normal renal function (serum creatinine 1.5 mg/dl).
Patients having previously received systemic chemotherapy
for SCLC were excluded. Pregnant, or lactating, patients or
those with a history of prior malignancies, other than previously
excised or curatively irradiated basal cell skin cancer or in situ
cervical cancer, were excluded. Patients with brain metastasis,
and in need of imminent brain radiotherapy at the time of
diagnosis, were excluded. Patients with severe heart disease,
active infection, a past history of significant neurologic or psychiatric disorder, a history of hypersensitivity or uncontrolled
medical illness were excluded.
2) Patient evaluation
Pretreatment evaluations consisted of complete medical
The WHO response criteria were used to define the tumor
response. The occurrence of pleural effusion was also considered as a sign of a progressive disease if this was substantiated by positive cytology. Patients were assessed for their
response after having received a minimum of 2 cycles of
treatment, and at least one follow-up tumor assessment.
The duration of a partial response was taken from the date
the partial response was documented to the first confirmed date
of disease progression, and the duration of a complete response
was taken from the moment the complete response was
documented. The survival duration was determined by measuring the time between the initial treatment and death; the
median survival was calculated using the Kaplan-Meier method.
Table 1. Treatment protocol
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Drug administration
Dosage
Day
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Cisplatin IV for 4 hours
20 mg/m/day
D1-3
Ifosfamide continuous IV
1.5 g/m/day
D1-3
Mix with Mesna
900 mg/m/day
D1-3
Etoposide PO
50 mg/m/day
D4-17
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
*Repeated every 4 weeks
Seok Jin Kim, et al：Oral Etoposide, Ifosfamide and Cisplatin in ED SCLC 423
RESULTS
1) Patient characteristics
Twenty-five patients were enrolled in this study between
January 2000 and May 2002; the patients' characteristics are
listed Table 2. The median patient age was 65 years; there were
19 male and 6 female patients. Fifteen patients (60%) had an
ECOG performance status of 0-1, and 8 had more than two
sites of metastasis. Three patients were not assessable for
response. After the first cycle, 2 of these 3 patients dropped
out due to the development of pneumonia. The remaining
patient withdrew from the study after the second cycle, due to
the patient opting for an alternative medication. Therefore, 22
patients were assessable for response, but all 25 were evaluated
for toxicity.
2) Response and survival
Twenty-two patients were assessable, and no complete
responses were observed. Sixteen patients achieved a partial
response, with an overall response rate of 72.7% (95% confidence interval: 49.6∼88.4%). Two patients had a stable
disease and 4 had a progressive disease (Table 3). Of the 4
patients with progressive disease, 1 patient, who had multiple
metastases, which included the liver and bone marrow, died due
to neutropenic fever after the first cycle. Of the 3 remaining
Table 2. Patient characteristics
ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ
No.
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No. enrolled
25
No. assessable
22
Age(years)
Median
65
Range
32∼75
Gender
Male
19
Female
6
ECOG performance status
0
3
1
12
2
10
Site of metastasis
Liver
13
Brain
7
Bone
6
Pleura
5
Pancreas
2
Adrenal gland
1
Lung
1
Bone marrow
1
No. of metastatic sites
1
17
2
5
3
3
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patients with a progressive disease, 1 had pleural and pericardial effusion, another had liver metastasis, and the third had
a brain lesion. These patients were all ECOG performance
status 2. The median response duration of all responders was
7 months (95% confidence interval: 3.5∼10.5 months). Of the
2 patients with a stable disease, the disease progression was
observed at 4 and 2 months following the diagnosis of a stable
disease. The median overall survival of all the patients was 10
months (95% confidence interval: 5.3∼14.7 months).
Of the 7 patients with brain metastasis, 5 had a partial
response, 1 a stable disease and the other developed a
progressive disease. Of the 5 responders, 1 was referred for
brain radiotherapy after completing six cycles of chemotherapy.
Two of the 5 who showed a progressing brain lesion were
removed from the study after the third cycle. The remaining
2 patients were withdrawn from the study because they refused
further treatment after the fourth cycle.
3) Toxicity and dose-intensity
The toxicity was evaluated in all the 25 patients during all
the 91 cycles. The hematologic and non-hematologic toxicities
encountered are listed in Table 4. The major hematologic
toxicities were: leukopenia, 19 cycles showing grade III and 25
cycles grade IV, and neutropenia, 15 cycles showing grade III
and 27 cycles grade IV. Grade III thrombocytopenia occurred
Table 3. Response rate
ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ
Assessable patients
Response
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No. of patients
%
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Complete response (CR)
0
0
Partial response (PR)
16
72.7
Stable disease (SD)
2
9.1
Progressive disease (PD)
4
18.2
All
22
100
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Table 4. Hematological and non-hematological toxicity
ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ
Number of cycles (total No.=91 cycles)
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Grade
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Toxicity
I
II
III
IV
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Leukopenia
10
18
19
25
Neutropenia
6
12
15
27
Thrombocytopenia
2
8
5
3
Anemia
7
8
3
1
Nausea/Vomiting
27
25
12
2
Diarrhea
5
4
2
0
Mucositis
4
3
2
0
Neuropathy
3
0
0
0
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
424
Cancer Research and Treatment 2002;34(6)
in 5 cycles and grade IV in 3. Six patients experienced febrile
neutropenia. Two cases of pneumonia were reported after the
first cycle, and these patients were withdrawn from the study.
Death related to drug-induced neutropenia occurred in 1 patient
after completing the first cycle.
The non-hematologic toxicities did not seem to be significant
during the treatment courses. Nausea and vomiting were the
most common toxicity related events. Fourteen cycles showed
grade III and IV nausea and vomiting, although the grade IV
occurred in only 2 cycles. Other toxicities included diarrhea,
mucositis and neuropathy. No hematuria, a known toxicity of
ifosfamide, was observed. The actually delivered doses were
13.4 mg/m2/wk of cisplatin, 139.7 mg/m2/wk of etoposide and
2
0.95 g/m /wk of ifosfamide. The dose-intensity (the actual dose
delivered as a proportion of the planned dose) was 89% for
cisplatin, 80% for etoposide and 84% for ifosfamide.
DISCUSSION
Systemic combination chemotherapy has been the mainstay
for the treatment of extensive disease small cell lung cancer.
The combination of cyclophosphamide, doxorubicin and vincristine (CAV) was common in the 1970s (10). In the 80s, the
etoposide and cisplatin (EP) regimen was reported as the first
effective second-line therapy, because of the synergy of
etoposide and cisplatin (11). Two phase III trials compared the
CAV and EP regimens, and by alternating the CAV and EP
regimens, in patients with an extensive disease. No differences
were observed in the response or survival, but the toxicity of
the CAV regimen was greater (12,13). Thus, EP was adapted
as the first line treatment, and this remains the case for ED
SCLC.
However, little improvement has been made over the last two
decades in improving the median survivals, of 8 to 10 months,
in patients with ED SCLC, despite improved the response rates.
Strategies to improve the efficacy of standard chemotherapy
include; dose intensification, the use of higher doses, with
cytokine support (14), maintenance treatment with other drugs
(15,16) and the addition of new drugs in multi-agent combinations.
Because SCLC relapses, largely as a result of drug resistance,
overcoming drug resistance may be the best way of preventing
a relapse and prolonging survival, and therefore, adding a new
effective agent to a commonly used regimen may be a strategy
for the improvement of the therapeutic efficacy, and to
overcome drug resistance development. Although the available
data remain unconvincing, three-drug regimens may confer a
meaningful benefit over two-drug regimens in SCLC. Ifosfamide has been shown to be synergistic with platinum compounds, by reversing the intracellular mechanisms of resistance,
and decreasing DNA repair and the detoxification of reactive
cisplatin and glutathione intermediates (17). It has been reported that adding ifosfamide to etoposide and cisplatin
improved the median survival from 7.3 to 9.0 months, and
resulted in a higher 2-year survival rate of 13% against 5% (7).
ECOG, incorporating ifosfamide and carboplatin in combination with prolonged oral etoposide (ICE), was reported to
have an overall response rate and 2-year survival rate of 83%
and 14%, respectively (18).
The previous phase II study on the combination of cisplatin,
ifosfamide and prolonged oral administration of etoposide used
the same protocol as ours. They reported a 93% overall response rate and a 54 week median survival (9). In our study,
the overall response rate was 72.7% and the median survival
duration was 10 months. This difference may be due to several
reasons. First, there were more patients with an ECOG
performance status of 2 in our population, and they were 6
years older than the population of the previous study. Second,
the total number of assessable patients in our study was
relatively small.
Despite the high incidence of grade IV neutropenia (27
cycles per total of 91 cycles), its duration was rarely prolonged.
However, there was a death related to drug induced neutropenia
occurred, and 2 cases of pneumonia developed after the first
treatment cycle, which was thought to be associated with orally
administered etoposide-induced myelosuppression. It was reported that the delayed development of myelosuppression on
days 16 through to 20 was observed in a study of advanced
non-small cell lung cancer with the same regimen as used in
this study. They suggested that myelosuppression development
could be related with etoposide administration and individual
differences in the etoposide absorption rate (19). Thus, careful
attention should be paid to monitor the development of
etoposide-induced myelosuppression, including CBC follow-up,
especially during the first treatment cycle.
Several cases of myelosuppression were observed on the
days the etoposide was orally administration, causing us to
reduce the dosage, or skip etoposide administration altogether.
However, the overall drug compliance for the oral etoposide
was satisfactory, with a dose intensity of 80%. Nausea and
vomiting were the most frequent non-hematological toxicity,
and grade IV toxicity was rare. Hemorrhagic cystitis, which is
known as the main ifosfamide-induced toxicity, was not observed, due to its effective prevention with mesna. Other
toxicities did not seem to be significant in the present study,
and the dose-intensity for each drug was over 80%. However,
unlike previous reports using the same regimen, our results
failed to demonstrate a significant improvement in the response
rate and median survival duration, even though the patient
population studied had poorer prognostic features.
CONCLUSIONS
The cisplatin, ifosfamide and oral etoposide combination
regimen was tolerated, but its response rate and median survival
were similar to other previously documented combination regimens in patients with ED SCLC. Therefore, new combination
chemotherapy regimens are needed for the treatment of ED
SCLC.
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