Download Combination Chemotherapy in Patients With Malignant Pleural

Combination Chemotherapy in Patients
With Malignant Pleural Effusions From
Non-small Cell Lung Cancer*
Cisplatin, Ifosfamide, and Irinotecan With
Recombinant Human Granulocyte ColonyStimulating Factor Support
Akihisa Fujita, MD; Hirotsugu Takabatake, MD; Shigeru Tagaki, MD;
Kyuhichiro Sekine, MD
Objectives: Malignant pleural effusions develop frequently in patients with non-small cell lung
cancer (NSCLC), and the prognosis for these patients is very poor. We evaluated the role of
systemic chemotherapy for patients with malignant pleural effusions from NSCLC.
Methods: We analyzed 34 patients who were found to have malignant pleural effusions in the
course of diagnosis of 118 patients enrolled in three consecutive clinical trials on advanced
NSCLC assessing combination chemotherapy of cisplatin, ifosfamide, and irinotecan with
recombinant human granulocyte colony-stimulating factor support. The objective response in the
malignant pleural effusion was evaluated by CT scans every course with the response criteria of
the Japan Lung Cancer Society.
Results: All patients had adenocarcinoma. The pleural effusion showed a complete response in 13
patients, a partial response in 7 patients, and no response in 14 patients. In the assessment of the
efficacy of the treatment for the measurable primary or metastatic lesions, there was a partial
response in 25 patients, no change in 8 patients, and progressive disease in 1 patient. The
response rate in pleural effusions was 58.8%, and overall response in mensurable lesions was
73.5%. The median time to response and duration of response for pleural effusions were 54 days
and 151 days, respectively. The median survival time and 1-year survival rates were 362 days and
48.5%, respectively.
Conclusions: Both the response rate and survival data in this retrospective study suggest a high
degree of activity of this combination chemotherapy in patients with malignant pleural effusions
from NSCLC.
(CHEST 2001; 119:340 –343)
Key words: irinotecan; malignant pleural effusion; non-small cell lung cancer
Abbreviations: NSCLC ⫽ non-small cell lung cancer; rhG-CSF ⫽ recombinant human granulocyte colony-stimulating
factor
pleural effusions develop frequently in
M alignant
patients with non-small cell lung cancer
(NSCLC). When profuse, pleural effusion causes
respiratory insufficiency and affects the quality of
life. Treatment for patients with symptomatic pleural
effusions is urgent. In general, the treatment consists
of thoracentesis, chest tube drainage, and intrapleural administration of sclerosing agents or anticancer
*From the Division of Respiratory Disease, Minami-ichijo Hospital, Sapporo, Japan.
Manuscript received April 20, 2000; revision accepted September
8, 2000.
Correspondence to: Akihisa Fujita, MD, Division of Respiratory
Disease, Minami-ichijo Hospital, South-1 West-13, Chuo-ku,
Sapporo 060-0061, Japan; e-mail: [email protected]
agents.1 The major goal of therapy for pleural effusions is effective symptomatic palliation. Local control of malignant pleural effusion does not necessarily prolong survival, and most patients die of systemic
dissemination of the underlying disease. Pleural effusions associated with malignant lymphoma, small
cell lung cancer,2 and breast cancer3 are effectively
treated with systemic chemotherapy, but the value of
systemic chemotherapy for patients with NSCLC is
often poor. Patients with large amounts of pleural
effusion are not usually included in clinical trials of
chemotherapy due to their poor prognosis and serious respiratory symptoms. We conducted three consecutive clinical trials on NSCLC patients treated
with a combined chemotherapy of cisplatin, ifosf-
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Clinical Investigations
amide, and irinotecan with recombinant human
granulocyte colony-stimulating factor (rhG-CSF)
support. Patients with pleural effusions were not
excluded from these clinical trials if they met all of
the eligibility criteria and did not meet any of the
exclusion criteria. Patients who experienced serious
respiratory symptoms received thoracentesis prior to
chemotherapy.
We describe our experience with 34 patients with
malignant pleural effusions enrolled in three clinical
trials. The aim of this retrospective study was to
evaluate the role of systemic chemotherapy.
Materials and Methods
We analyzed 34 patients discovered to have histologically
and/or cytologically proven malignant pleural effusion in the
course of diagnosis of 118 patients entered in three consecutive
clinical trials on advanced NSCLC. The protocols of the three
trials are described below. The first study, between May 1994 and
June 1995, was a phase I study to determine the maximum
tolerated dose of irinotecan combined with a fixed schedule of
cisplatin and ifosfamide with rhG-CSF support.4 Cisplatin, 20
mg/m2, and ifosfamide, 1.5 g/m2, were administered at fixed
doses on days 1 to 4; irinotecan was given on days 1, 8, and 15,
starting at 40 mg/m2 and increased in 10-mg/m2 increments. The
next study, between June 1995 and June 1998, was a phase I/II
study to determine the maximum tolerated dose of cisplatin
combined with a fixed schedule of ifosfamide and irinotecan with
rhG-CSF support, as well as to the overall response rate and
median survival of the patients entered in this study.5 Ifosfamide,
1.5 g/m2, and irinotecan, 60 mg/m2, were administered at fixed
doses on days 1 to 4 and on days 1, 8, and 15, respectively.
Cisplatin was given on day 1 at 60 mg/m2 and increased in
10-mg/m2 increments. The third study, from June 1998, was a
phase II study to determine the overall response rate and median
survival of patients with stage IIIB or stage IV NSCLC treated
with a combined chemotherapy of cisplatin, ifosfamide, and
irinotecan with rhG-CSF support. Cisplatin, 20 mg/m2, and
ifosfamide, 1.5 g/m2, were administered at fixed doses on days 1
to 4; irinotecan, 60 mg/m2, was given on days 1, 8, and 15. In all
three trials, rhG-CSF was administered subcutaneously on days 5
to 18, excluding the days of irinotecan treatment, and the
regimens were repeated every 4 weeks. Informed consent for
participation was obtained from every patient enrolled. Patients
with serious respiratory symptoms at their initial medical visits
were treated with thoracentesis prior to chemotherapy.
Tumor responses were evaluated after every course by repeating appropriate radiographic studies on measurable lesions determined before registration. World Health Organization evaluation criteria were used for analysis of efficacy for all except the
malignant pleural effusion.6 The objective response in the malignant pleural effusion was evaluated by CT scans every course
using the response criteria of the Japan Lung Cancer Society.7
Complete response was defined as the complete disappearance of
pleural fluid and negative cytologic findings for ⬎4 weeks. Partial
response was defined as a distinguishable decrease or no increase
of pleural fluid and negative cytologic findings for ⬎4 weeks. No
response was defined as failure to meet the above criteria.
Toxicities were graded according to the common toxicity criteria.8
The survival was calculated from the start of chemotherapy.
Table 1—Patient Characteristics*
Characteristics
Patients, No.
Total
Sex
Male
Female
Age, yr
Median
Range
Performance status (ECOG)
1
2
Histology
Adenocarcinoma
Stage
IIIB
IV
Site of metastasis†
Lung
Brain
Bone
Adrenal glands
Skin
34
18
16
57.0
43–72
33
1
34
11
22
11
7
6
1
1
*ECOG ⫽ Eastern Cooperative Oncology Group.
†Eleven patients had no metastases.
Results
Patient characteristics are listed in Table 1. There
were 18 men and 16 women, with a median age of 57
years (range, 43 to 72 years). All patients had
adenocarcinoma. Twenty-two patients had stage IV
disease, and 12 patients had stage IIIB disease. The
most common sites for metastasis were the lung (11
patients), brain (7 patients), and bone (6 patients).
Five patients were asymptomatic at the time of
diagnosis. Fifteen patients presented with chest or
back pain, 8 patients with dyspnea, and 6 patients
with increasing cough. The size and biochemical
characteristics of the pleural effusion are repre-
Table 2—Size and Biochemical Characteristics of the
Pleural Effusion*
Size†
Data
Small
Moderate
Large
Massive
Biochemical characteristics
Glucose, mg/dL
Lactate dehydrogenase, IU/L
15
10
4
5
104 ⫾ 10
524 ⫾ 301
*Data are presented as No. of patients or mean ⫾ SE.
†Massive amount of effusion ⫽ volume of effusion more than three
fourths of hemithorax; large amount ⫽ between one half and three
fourths of hemithorax; moderate amount ⫽ between one fourth and
one half of hemithorax; small amount ⫽ less than one fourth of
hemithorax.
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341
Table 3—Response
Overall Response*
Response in the Pleural
Effusions (No. of Patients)
Partial
Response
No
Change
Progressive
Disease
Complete response (n ⫽ 13)
Partial response (n ⫽ 7)
No response (n ⫽ 14)
Total (n ⫽ 34)
13
6
6
25
0
0
8
8
0
1
0
1
*Overall response rate ⫽ 73.5% (95% confidence interval, 58.7–
88.3); response rate in the pleural effusion ⫽ 58.8% (95% confidence interval, 42.3–75.3).
sented in Table 2. Twelve of the 34 patients were
entered in the phase I study, 11 in the phase I/II
study, and 11 in the phase II study. All patients could
be assessed for toxicity and the responses of measurable lesions and pleural effusions. The mean number
of chemotherapy courses was 4.8. All patients were
assessed for survival.
In the pleural effusion, 13 patients achieved a
complete response, 7 patients achieved a partial
response, and there was no response in 14 patients.
In the assessment of the efficacy for the measurable
primary or metastatic lesions, 25 patients achieved a
partial response, 8 patients showed no change, and 1
patient showed progressive disease (Table 3). The
response rate in the pleural effusion was 58.8%, and
overall response to measurable lesions was 73.5%. Of
the 25 patients who achieved a partial response for
the measurable primary or metastatic lesions, 13 had
a complete response, 6 had a partial response, and 6
had no response in the pleural effusion. The six
patients who attained no response showed no increase of pleural effusion compared to the original
volume but had positive cytologic findings. The
median time to response and duration of response
for pleural effusion were 54 days and 151 days,
respectively. After reaccumulation of pleural effusions, seven patients were treated with intrapleural
administration of cisplatin for the palliation of symptoms. The median survival time and 1-year survival
rates were 362 days and 48.5%, respectively (Fig 1).
Median survival times according to stage were 414
days in stage IIIB and 317 days in stage IV.
Major toxicity was hematologic. Grade 3 and grade
4 neutropenia were observed in 3 patients and 16
patients, respectively. Five patients and 7 patients
experienced grade 3 and grade 4 thrombocytopenia,
respectively. The incidence and degree of hematologic toxicity were similar in patients with and without pleural effusions in these clinical trials. One
patient experienced grade 4 diarrhea. In the phase I
study on these three drugs, dose-limiting toxicity was
thrombocytopenia. In the phase I/II study, doselimiting toxicity was leukopenia. There were no treatment-related deaths.
Discussion
Malignant pleural effusions are a common presentation of NSCLC and can reduce the quality of life.
Most asymptomatic patients develop increasing
pleural fluid that eventually evokes symptoms and
requires palliation. Therapeutic thoracentesis can
provide temporary relief of symptoms but is associated with recurrence in a majority of patients within
1 to 3 days.9 The most common therapy for malignant pleural effusions is a chest tube drainage followed by intrapleural instillation of a sclerosing
Figure 1. Survival curve of all patients.
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Clinical Investigations
agent. Various agents have been used for pleurodesis
with valuable success. Bleomycin, doxorubicin, and
mitomycin C have been shown to be effective as
sclerosing agents rather than anticancer drugs.10 –12
Cisplatin has proven to be an effective intraperitoneal agent in ovarian cancer, with an efficacy related
to cytotoxic effects rather than a sclerosing action.13
Tohda et al14 reported that intrapleural chemotherapy with cisplatin and etoposide was effective for
patients with malignant pleural effusions from
NSCLC. Perng et al15 reported that intrapleural
paclitaxel treatment probably had both an anticancer
effect and a sclerosing effect.15 However, the role of
intrapleural therapy in the management of malignant
pleural effusion has proven to be limited to symptomatic palliation. Unfortunately, many patients with
malignant pleural effusions have systemic dissemination that often kills them. Previously, systemic chemotherapy was disappointing for the control of
malignant pleural effusion. Recent investigations
suggest that combined chemotherapy with new
drugs exerts potent actions in patients with NSCLC.
We expected that systemic chemotherapy might
bring about resolution of the pleural effusion.
There are no standard criteria to evaluate the
response to treatment in patients with malignant
pleural effusions. Most investigations have attempted to evaluate patients by correlating the response to intrapleural therapy with traditional solid
tumor responses without looking at cytologic findings. However, according to the response criteria of
the Japan Lung Cancer Society, volume changes of
pleural fluid alone should not be used to assess
response since they do not truly reflect alterations in
tumor burden and since negative cytologic findings
are also important to define the response. Therefore,
it is difficult to compare our results with those of
other studies. The median survival time was 362 days
and the 1-year survival rate was 48.5%, which was
considered satisfactory.
Patients who have a multiloculated effusion,
trapped lung, or bronchial obstruction are unlikely to
benefit from intrapleural therapy but can be treated
with systemic chemotherapy successfully. Patients
with large amounts of pleural effusion did not meet
the eligibility criteria and were treated with therapeutic thoracentesis prior to chemotherapy. Patients
whose symptoms were promptly relieved fulfilled the
eligibility criteria. The incidence and degree of
hematologic toxicity were similar in patients with and
without pleural effusions in these clinical trials.
It seems clear that a combined chemotherapy of
cisplatin, ifosfamide, and irinotecan with rhG-CSF
support can produce high rates of improvement of
malignant pleural effusions as well as primary and
metastatic lesions. We believe that control of not
only malignant pleural effusions but also systemic
dissemination prolongs survival in patients with malignant pleural effusions from NSCLC. Intrapleural
therapy should be reserved for patients who are
refractory or meet the exclusion criteria for systemic
chemotherapy.
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