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Role of Topoisomerase I Inhibitors in Small-Cell Lung Cancer

Role of Topoisomerase I Inhibitors in Small-Cell Lung Cancer

ABSTRACT: Combination chemotherapy is the cornerstone of treatment that confers a meaningful survival benefit for patients with small-cell lung cancer. However, because there have been no major therapeutic advances for small-cell lung cancer during the last decade, more effective new treatments are necessary to improve the outcome of therapy. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, is one of the new active agents that provide hope for more effective therapies. In single-agent phase II studies, irinotecan yielded response rates between 16% and 47% in patients with previously treated small-cell lung cancer. A phase II study of irinotecan in combination with cisplatin (Platinol) resulted in a response rate of 86% and a median survival of 13.0 months in patients with extensive-disease small-cell lung cancer. A phase III trial that was conducted by the Japan Clinical Oncology Group (JCOG) clearly demonstrated a survival advantage for the combination of irinotecan and cisplatin vs the standard regimen of etoposide (VP-16, VePesid) and cisplatin. Based on these results, the irinotecan and cisplatin combination is a new standard regimen in the treatment of extensive-disease small-cell lung cancer. [ONCOLOGY 15(Suppl 8):9-14, 2001]

Introduction

Small-cell lung cancer accounts
for approximately one-fifth of
primary lung cancer cases. It possesses different biologic characteristics
compared with other types of lung cancers, including rapid tumor growth, early
metastases, and high level of sensitivity to chemotherapy and radiotherapy.
Since patients with small-cell lung cancer usually present with disseminated
disease, combination chemotherapy is the cornerstone of treatment for patients
in all disease stages, with major responses in 65% to 85% of cases, including
25% to 50% complete responses.

Most patients experience tumor relapse and die within 2 years,
however. With chemotherapy and thoracic radiotherapy, the median survival
duration is 10 to 15 months for limited-disease patients, and patients with
extensive disease show a median survival time of 7 to 11 months with
chemotherapy.[1]

Combination chemotherapy regimens include CAV (cyclophosphamide
[Cytoxan, Neosar], doxorubicin [Adriamycin], and vincristine [Oncovin]); CAE
(cyclophosphamide, doxorubicin, and etoposide [VP-16, VePesid]); CAVE
(cyclophosphamide, doxorubicin, vincristine, and etoposide; PE (cisplatin
(Platinol) and etoposide; and CE (carboplatin [Paraplatin] and etoposide). In
randomized trials, three regimens—CAV, PE, and CAV alternating with PE—yielded
similar survival rates, but PE resulted in less myelosuppression.[2,3]
Therefore, the most widely used regimen is the combination regimen PE.

There have been no major advances in the treatment of small-cell
lung cancer during the last decade. The recent advent of new active agents
including camptothecins, the taxanes, and gemcitabine (Gemzar) provides hope for
more effective therapies and, among these drugs, irinotecan (CPT-11, Camptosar)
is the most promising agent.

Irinotecan is a water-soluble derivative of camptothecin, and
exhibits strong antitumor activity in a broad spectrum of experimental
models.[4,5] Camptothecin and its derivatives possess a unique mechanism of
action that inhibits DNA topoisomerase I.[6] Irinotecan is transformed to an
active metabolite (SN-38) by carboxylesterase, an enzyme that is mainly found in
the liver, bowel mucosa, and tumor tissue. Clinical studies have now shown that
irinotecan possesses significant activity against a variety of malignant
diseases, including small-cell lung cancer.

Phase II Trials of Irinotecan Monotherapy

A Japanese phase I trial of irinotecan administered as a weekly
IV infusion demonstrated that its dose-limiting toxicities included leukopenia
and diarrhea, and the recommended dose for phase II studies was 100 mg/m2.[7]
Based on these results, irinotecan was administered at a dose of 100 mg/m2 IV
once weekly in two phase II studies.[8,9] The results from four phase II trials
of irinotecan monotherapy in small-cell lung cancer are enumerated in Table
1
.

In a multi-institutional phase II trial, Negoro and coworkers
enrolled 41 patients, 35 of whom were evaluable for response.[8] The overall
response rate was 37%, with a median response duration of 7 weeks. The response
rate was 33% in 27 previously treated patients and 50% in 8 previously untreated
patients. The median survival time was 35 weeks for all patients. The major
toxicities were grade 3 or higher leukopenia (31%) and diarrhea (15%).

A single-institution trial by Masuda and colleagues[9] delivered
the same dose and schedule of irinotecan to 16 patients with refractory or
relapsed small-cell lung cancer, of whom 15 were evaluable for response and
toxicity. (All 15 patients had been heavily pretreated with some form of
cisplatin-based regimens.) Only one patient was refractory to chemotherapy as
defined by tumor growth during chemotherapy. Although there were no complete
responses in the 15 patients, a partial response was obtained in 47% of
patients, with a median duration of response of 8 weeks (range, 4 to 22 weeks).
The median survival time from the onset of irinotecan therapy was 27 weeks.

The most frequent adverse event was myelosuppression: 34% and 0%
of patients had severe leukopenia and thrombocytopenia (WHO grade 3 or 4),
respectively. Greater than grade 2 nausea and vomiting occurred in 13% of
patients, and diarrhea was observed in 7%. One patient (7%) experienced grade 4
paralytic ileus. Grade 3 or 4 pulmonary adverse events occurred in two patients
(13%).

A French trial used a different approach with a dosage of 350
mg/m2 every 3 weeks that resulted in a lower overall response rate of 16% in 32
previously treated patients who had received etoposide-cisplatin-based
first-line chemotherapy.[10] The median duration of response was 131 days, and
median survival was 125 days. The major grade 3 or 4 toxicities were neutropenia
(58%), febrile neutropenia (22%), delayed diarrhea (37%), and nausea and
vomiting (22%).

Seventeen sensitive-relapse patients (those who initially
responded but progressed after a treatment-free interval of at least 90 days)
and 27 refractory patients (those who failed first-line treatment, or who
initially responded but progressed within 90 days of the end of therapy) were
enrolled in a US phase II study conducted by DeVore et al.[11] Patients received
irinotecan at an initial dosage of 125 mg/m2 weekly for 4 of 6 weeks. Response
rates were 35.3% in patients with sensitive disease and 3.7% in patients with
refractory disease, and median survivals were 5.9 and 2.8 months, respectively.
Overall survival was 4.8 months. Grade 3 or 4 late diarrhea was reported in
26.6% of patients, and grade 3 or 4 neutropenia in 26.7%.

Overall, single-agent irinotecan exhibited encouraging response
rates in pretreated small-cell lung cancer patients, although studies examining
irinotecan in first-line therapy were lacking.

Combination Regimens With Irinotecan

Irinotecan and Cisplatin

The preclinical synergism between irinotecan and cisplatin,[12]
irinotecan’s lack of cross-resistance,[9] and differing mechanisms of action
and toxicity profiles between the two drugs provided a rationale for examining
the use of these agents in the treatment of small-cell lung cancer. Masuda and
co-workers[13] conducted a phase I trial to determine the maximum tolerated dose
of irinotecan together with a fixed dose (60 mg/m2) of cisplatin in patients
with advanced lung cancer, and the dose-limiting toxicities of this combination.
The maximum tolerated dose of irinotecan was 90 mg/m2 on days 1, 8, and 15, plus
cisplatin 60 mg/m2 on day 1, every 4 weeks, with diarrhea being the
dose-limiting toxicitiy. In this phase I study, five (36%) partial responses and
one (7%) complete response were observed for an overall response rate of 43%.
The response rates for non-small-cell lung cancer and small-cell lung cancer
were 33% (4 out of 12 patients) and 100% (2 out of 2 patients), respectively.
The recommended dosages for phase II studies were irinotecan 80 mg/m2 on days 1,
8, and 15, plus cisplatin 60 mg/m2 on day 1, every 4 weeks.

The West Japan Thoracic Oncology Group (WJTOG) conducted a phase
II trial of this combination regimen in previously untreated small-cell lung
cancer patients.[14] Kudoh et al initially administered irinotecan at
80 mg/m2 to 10 patients on days 1, 8, and 15, in combination with cisplatin 60
mg/m2 on day 1. The irinotecan dose was reduced to 60 mg/m2 because 3 of the
initial 10 patients experienced severe toxicity, and 1 of them died of diarrhea
and neutropenia.

Among the 75 patients that were enrolled, 72 were evaluable for
response, and all were assessable for toxicity (Table
2
). Forty patients with
limited disease achieved an overall response rate of 83% and a complete response
rate of 30%; 35 patients with extensive disease achieved an overall response
rate of 86% and a complete response rate of 29%. The median response duration
was 8.0 months for limited-disease patients and 6.6 months for extensive-disease
patients. The median survival was 14.3 months for limited-disease patients and
13.0 months for extensive-disease patients. The 2-year survival rate was 21.7%
for limited-disease patients and 17.5% for extensive-disease patients. The major
grade 3 or 4 toxicities were neutropenia (77%), anemia (39%), and diarrhea
(19%).

In a similar study, patients with prior chemotherapy also
received irinotecan 60 mg/m2 on days 1, 8, and 15 with cisplatin 60
mg/m2 on day
1.[15] Sixteen patients were enrolled; the chemotherapy-free interval was more
than 90 days in nine patients, and less than 90 days in seven patients. The
overall response rate was 19%, and the median survival was 5.7 months. The
percentage of the projected dose of irinotecan administered was relative low
(57%), mainly due to leukopenia.

Other schedules have also been investigated. Both irinotecan (60
mg/m2) and cisplatin (30 mg/m2) were administered together on days 1, 8, and 15,
every 4 weeks.[16] Among the five patients with refractory small-cell lung
cancer, one achieved a partial response.

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