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Irinotecan in Small-Cell Lung Cancer—Japanese Trials

Irinotecan in Small-Cell Lung Cancer—Japanese Trials

ABSTRACT: Irinotecan has appeared to have significant activity against previously treated and untreated small-cell lung cancer (SCLC). The major toxicities of irinotecan are neutropenia and diarrhea, although there is interpatient variability in the severity of symptoms. The combination of irinotecan and cisplatin is likewise significantly active against SCLC, with an acceptable toxicity profile. A phase III study comparing irinotecan and cisplatin with etoposide and cisplatin has been conducted in the treatment of previously untreated patients with extensive disease SCLC. The results of this study may define a new standard care for SCLC. Irinotecan and etoposide is also an active new combination in the treatment of both previously treated or untreated SCLC. Neutropenia was the most commonly observed toxicity in this combination; there were no severe gastrointestinal toxicities, including diarrhea. [ONCOLOGY 14(Suppl 5):57-62, 2000]

Introduction

Since 1998, lung cancer has been the leading cause of cancer death in
Japan. Small-cell lung cancer (SCLC) comprises approximately 20% of
all lung cancers. Characterized by early metastatic involvement,
recurrence at multiple distant sites, and frequent nodal spread, SCLC
is a systemic disorder that is highly sensitive to chemotherapy and,
in limited disease, to radiotherapy. Three decades of clinical
studies have shown that first-line combination chemotherapy with or
without radiotherapy improves survival in SCLC.[1] Nonetheless, most
patients relapse and die with drug-resistant tumors within 2 years of
initial treatment. New, more active agents are needed to increase
survival in SCLC. Irinotecan (Camptosar, CPT-11), a new semisynthetic
water-soluble analog of the plant alkaloid camptothecin, has
demonstrated significant activity against a variety of solid tumors,
including SCLC.[2,3] Irinotecan is transformed to an active
metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) by
carboxyl-esterase, an enzyme that is mainly found in the liver, bowel
mucosa, and tumor tissue.[4] SN-38 plays an essential role in the
cytocidal activity and toxicity of the parent compound.[5]
Camptothecin and its derivatives have a unique mechanism of action
that inhibits the nuclear enzyme topoisomerase-I, which relieves
torsional strain in DNA by inducing reversible single-strand
breaks.[6,7] The results of Japanese clinical studies of irinotecan
in the treatment of SCLC are described in this article.

The single-agent activity of irinotecan (camptosar, CPT-11) in
small-cell lung cancer (SCLC) has been evaluated in two phase II
studies in Japan.[8,9] One study was multi-institutional, involving
both previously treated and untreated patients.[8] The second was a
single-institution study conducted at Osaka Prefectural Habikino
Hospital in patients with refractory or relapsed SCLC.[9]

In both studies irinotecan was administered at a dose of 100
mg/m² by intravenous infusion over 90 minutes on a weekly
schedule. If a patient’s white blood cell (WBC) count was 2,000
to 2,999/µL on the day of administration, irinotecan was
omitted. Dosing of irinotecan was resumed only after recovery of the
WBC count. If the WBC count was 1,000 to 1,999/µL, irinotecan at
80 mg/m² was administered after recovery. If the WBC count was
< 1,000/µL, or a grade 3 or 4 nonhematologic toxicity was
observed, irinotecan was discontinued. Tumor responses and drug
toxicity were classified in accordance with the World Health
Organization (WHO) criteria. The duration of survival was calculated
from the start of irinotecan administration until death or last
follow-up. The characteristics of the patients in these phase II
studies are shown in Table 1,
and the results are shown in Table 2.

Forty-one patients (33 male; 8 female) were enrolled in the
multi-institutional study. The patients ranged in age from 40 to 74
years, with a median of 62 years. Based on criteria established by
the Eastern Cooperative Oncology Group (ECOG), 28 patients (68%) had
a performance status (PS) of 0 or 1, and 13 patients (32%) had a PS
of 2. Twelve patients had limited disease (LD) and 29 had extensive
disease (ED). Eight patients were previously untreated, and 33 were
treated.

Four of the eight previously untreated patients (50%) achieved a
partial response (PR). Twenty-seven of the 33 patients with
previously treated disease were evaluable for response. Two of them
achieved a complete response (CR) and seven achieved a PR, for an
overall response rate of 33%. The median survival time was 35 weeks
for all patients. The major toxicities of grade 3 or 4 were
leukopenia (31%) and diarrhea (15%); the diarrhea was persistent in
some patients. Marked interpatient variation in the severity of
diarrhea was observed during the trial.

Between May 1990 and May 1991, 16 patients with refractory or
relapsed SCLC were enrolled in a phase II study at Osaka Prefectural
Habikino Hospital, 15 of whom were evaluable for response and
toxicity. The median age of the 3 female and 12 male patients was 63
years. Six patients had an ECOG performance status of 0 or 1, and
nine patients had a performance status of 2. The most common
metastatic sites were the liver (four patients), adrenal gland (three
patients), extrathoracic lymph node (three patients), and brain
(three patients); other metastatic sites were observed in the lungs,
bones, and subcutaneous nodule. All 15 patients had been heavily
pretreated with cisplatin (Platinol)-based chemotherapy or concurrent
cisplatin and etoposide (VePesid, VP-16) plus thoracic radiotherapy.
Fourteen patients proved to be sensitive to chemotherapy, defined as
the recurrence of tumor with a chemotherapy-free interval of 90 days
or longer. A total of 102 cycles of weekly irinotecan were
administered (median, 7 per patient; range, 2 to 13).

Although there were no complete responses, seven patients achieved a
partial response (47%), with a median duration of 8 weeks (range, 4
to 22 weeks). Seven patients showed no change, and one patient
exhibited disease progression. The median survival time for all 15
eligible patients was 27 weeks. The most frequently observed adverse
event was myelosuppression, which primarily affected the leukocytes
(33% grade 3 or 4 leukopenia). Planned dosages remained unchanged in
seven patients and were withheld for more than 14 days in seven
patients. The dosage was reduced and delayed in only one patient due
to leukopenia and diarrhea. No patient experienced febrile
neutropenia. One patient had diarrhea of grade 3 or 4 (7%); the
diarrhea resolved 18 days following termination of treatment with
irinotecan. One patient (7%) experienced grade 4 paralytic ileus,
which was severe enough to stop administration of irinotecan after
four weekly doses. Grade 3 or 4 pulmonary toxicity occurred after the
administration of five and seven doses of irinotecan, respectively,
in two patients (13%). In one patient, pneumonitis responded well to
steroid therapy, but a second patient with pneumonitis did not
respond to the same treatment and subsequently died of progressive
respiratory insufficiency.

Irinotecan and Cisplatin in SCLC

Cisplatin is one of the most active and important drugs in the
treatment of SCLC. In addition, cisplatin has a different mechanism
of action from irinotecan and its principal toxicities do not overlap
with those of irinotecan. Cisplatin and irinotecan have shown a
synergistic effect against human SCLC cell lines and small-cell lung
tumor xenografts in nude mice.[10] Our phase I study of the
combination of irinotecan and cisplatin in the treatment of
non–small-cell lung cancer (NSCLC) and SCLC[11] showed promising
antitumor activity with acceptable toxicity, especially against SCLC.
Because a phase II study of this combination produced excellent
results in NSCLC,[12] we planned to conduct clinical trials of the
irinotecan and cisplatin combination in SCLC.

First-Line Phase II Study of Irinotecan and
Cisplatin in SCLC

The West Japan Thoracic Oncology Group (WJTOG) conducted a phase II
study of irinotecan and cisplatin in patients with previously
untreated SCLC.[13] The objectives of this study were to determine
the antitumor activity and toxicity of this combination.

Irinotecan was initially administered at a dose of 80 mg/m² to
10 patients by intravenous infusion on days l, 8, and 15. After 3 of
these 10 patients experienced severe hematologic toxicity, diarrhea,
and hepatic toxicity, and a fourth died of diarrhea and neutropenia,
the Monitoring Committee of the West Japan Lung Cancer Group reduced
the dose to 60 mg/m².

On completion of the 90-minute infusion of irinotecan on day 1,
cisplatin was administered intravenously at a dose of 60 mg/m²
over 60 minutes. Adequate hydration with diuretics and antiemetics
was provided before and after administration of cisplatin. This
treatment was repeated every 4 weeks. Patients with limited disease
received thoracic irradiation of 50 Gy after four cycles of this
combination; those with extensive disease received six cycles of
chemotherapy. Patients with disease progression after one cycle of
therapy or stable disease after two cycles were to receive salvage
therapy consisting of cyclophosphamide (Cytoxan), doxorubicin
(Adriamycin), and etoposide. Patients who achieved a CR were
scheduled to receive prophylactic cranial irradiation (PCI).

Irinotecan was not given on day 8 or 15 if the patient's WBC count
was less than 3,000/µL or if platelet counts were less than
75,000/µL. Irinotecan was also withheld if the patient
experienced diarrhea of grade 2 or greater, according to the ECOG
toxicity scale.

The next course of treatment could only be initiated if the WBC count
was 4,000/µL or greater, the platelet count was 100,000/µL
or greater, and diarrhea had resolved. However, if more than 6 weeks
passed from the time of the last treatment, the patient was removed
from the study. The dose of irinotecan in the next course was reduced
by 10 mg/m² if the WBC count was less than 2,000/µL, the
platelet count was less than 50,000/µL, or the severity of
diarrhea was grade 3 or greater.

Of the 75 patients enrolled in the study, 72 were evaluable for
efficacy; all were evaluable for toxicity. The characteristics of the
patient population are listed in Table
3
. Forty patients (53%) had limited disease and 35 (47%) had
extensive disease. The median age of the 17 women and 58 men was 64
years; 85% of the patients had a performance status of 0 or 1. Three
patients died before completing a full course of treatment: two
patients of treatment-related causes (on day 9 and day 16,
respectively) and the third following an exacerbation of underlying
interstitial pneumonia.

Of the patients with limited disease, 33 (83%) achieved an objective
response (OR) and 12 (30%) achieved a CR. Thirty (86%) of the
patients with extensive disease achieved an OR and 10 (29%) achieved
a CR (Table 4). The median
duration of response was 8.0 months for patients with limited disease
and 6.6 months for those with extensive disease. Median survival for
patients with limited disease and extensive disease was 14.3 months
and 13.0 months, respectively. The 2-year survival rate was 21.7% for
patients with limited disease and 17.5% for those with extensive
disease.

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