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The Emerging World Role of Irinotecan in Lung Cancer

The Emerging World Role of Irinotecan in Lung Cancer

ABSTRACT: Irinotecan (CPT-11, Camptosar), either alone or in combination with cisplatin (Platinol), has demonstrated activity in advanced non-small-cell lung cancer (NSCLC). In single-agent studies, response rates as high as 35% have been observed; in combination with cisplatin, response rates have ranged as high as 50%, with 1-year survival rates of 33% to 58%. A critical phase III randomized trial comparing irinotecan, either alone or in combination with cisplatin, to vindesine/cisplatin, demonstrated superior survival for stage IV patients receiving irinotecan. The first North American effort to replicate the schedule used in the phase III trial (cisplatin 80 mg/m2 and irinotecan 60 mg/m2 on days 1, 8, and 15 every month) yielded a response rate of 29%, median survival time of nearly 10 months, and 1-year survival rate of 37%. A subsequent multi-institutional trial conducted through Vanderbilt Cancer Center Affiliate Network and Fox Chase Cancer Center combined both agents on a weekly schedule in an attempt to exploit their putative synergy and to potentially decrease toxicity. This schedule, which employed irinotecan 65 mg/m2 and cisplatin 30 mg/m2 both weekly × 4, was better tolerated than the monthly cisplatin combination with a higher response rate (36%), median survival (11.6 months), and 1-year survival rate (46%). Multiple phase I and phase II studies have combined irinotecan with taxanes, either alone or in concert with carboplatin (Paraplatin), yielding similar response and survival rates. Finally, a critical phase III trial from Japan has demonstrated superior outcome for irinotecan and cisplatin vs standard etoposide/cisplatin in the treatment of extensive small-cell carcinoma of the lung. At least one North American trial will determine if these results are reproducible. [ONCOLOGY 15(Suppl 8):15-21, 2001]

Introduction

Lung cancer, with more than 1
million cases diagnosed worldwide annually, has become the most common malignancy in terms of incidence.
Although the incidence is starting to plateau in North American men, it
continues to rise in North American women and in both genders outside of the
United States, particularly in Europe and the Orient. The 5-year survival rate
in the United States is 14%, compared with 8% in Europe.[1] Generally, the
disease is either systemic at diagnosis, or manifests distant spread after
locoregional therapy. Hence, new agents with improved systemic activity are
desperately needed.

This article will review the activity of irinotecan (CPT-11,
Camptosar), either alone or in combination with cisplatin (Platinol) and other
agents, and will address its emerging role as a component of radiosensitizing
therapy in locally advanced non-small-cell lung cancer. Planned and ongoing
phase III trials to establish the utility of irinotecan in non-small-cell lung
cancer and small-cell lung cancer will also be discussed.

Irinotecan Alone and in Combination Therapy

Single-Agent Therapy

Multiple phase II studies, particularly in Japan, have
established the utility of irinotecan in the treatment of advanced non-small-cell
lung cancer. Response rates have ranged as high as 30% to 35%, using
conventional schedules of 100 to 125 mg/m2 × 4 every 6 weeks,[2-4] or doses of
300 to 350 mg/m2 every 3 weeks with or without hematopoietic growth factor
support.[5] Toxicities have generally included myelosuppression and diarrhea.
Work by Kameyama and colleagues on the activation and detoxification of
irinotecan by human lung cancer cell lines has revealed expression of the
enzyme(s) that convert(s) irinotecan to the active moiety, SN-38
(7-ethyl-10-hydroxycamptothecin).[6] Of 25 squamous cell carcinoma cell lines,
15 (60%) were strongly positive for carboxylesterase, the putative enzyme; of 25
adenocarcinomas, 20 (80%) proved positive, including 4 that were strongly
positive.

Irinotecan/Cisplatin Combinations

Cisplatin remains the cornerstone of combination therapy in
advanced non-small-cell lung cancer. Consequently, investigators have sought
to assess the activity of irinotecan in combination with cisplatin. The earliest
efforts in this regard were in Japan. Masuda and colleagues evaluated cisplatin
at 80 mg/m2/d on day 1 every 4 weeks in combination with irinotecan at 60
mg/m2/d on days 1, 8, and 15.[7] Overall response rate was 52%, time to disease
progression was 4.4 months, median survival time was 10.2 months, and the 1-year
survival rate was 33%.
Ueoka assessed irinotecan and cisplatin in combination at doses of 50 and
60 mg/m2, respectively, days 1 and 8 every 4 weeks.[8] Overall response rate was
slightly lower at 41%, but median survival time was 13 months, and the 1-year
survival rate was 58%.

Mori and colleagues conducted a phase II study of bolus
irinotecan at 160 mg/m2 day 1 in combination with cisplatin 20 mg/m2/d × 4 by
continuous infusion with granulocyte colony-stimulating factor (G-CSF
[Neupogen]) support.[9] Twenty-four treatment-naive non-small-cell lung cancer
patients with advanced disease were evaluated. Overall response rate was 58.5%,
median survival time was 44.8 weeks, and the 1-year survival rate was 44%. Major
toxic effects included grade 3/4 diarrhea in 23%, granulocytopenia in 20%,
thrombocytopenia in 15%, and anemia in 15% of patients. There were no
treatment-related deaths.

In Europe, Cardenal conducted a multi-institutional phase II
trial combining irinotecan at 200 mg/m2 as a
1-hour infusion in combination with cisplatin at 80 mg/m2 every 21 days.[10]
Over an 8-month period, 48 patients were recruited with 43 evaluable for
toxicity. Grade 4 neutropenia occurred in 11.6%, grade 4 diarrhea in 9.3%, and
grade 3 nausea and vomiting in 16.2% of patients. Of 32 evaluable patients, 12
(37.5%) achieved a partial response.

Phase III Randomized Trials

In a phase III trial, Masuda et al assessed irinotecan as a
single agent or in combination with cisplatin vs vindesine/cisplatin.[11]
Eligible patients had untreated stage IIIB or IV measurable non-small-cell
lung cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 2, and adequate marrow, hepatic, renal, and pulmonary function. Patients over
75 years old were excluded. A total of 398 patients were enrolled, of whom 246
had stage IV disease. Demographics—with respect to age, performance status,
previous weight loss, and levels of albumin and lactate dehydrogenase—were
well matched for each arm. Patients received one of three regimens: (1)
irinotecan 100 mg/m2/d on days 1, 8, and 15 every 4 weeks; (2) irinotecan 60
mg/m2/d on days 1, 8, and 15, and cisplatin 80 mg/m2/d on day 1 every
4 weeks; or (3) vindesine 3 mg/m2/d
on days 1, 8, and 15, and cisplatin
80 mg/m2/d on day 1 every 4 weeks.

Trial results are shown in Table
1
. Leukopenia was more
pronounced with the vindesine/cisplatin combination, while thrombocytopenia was
more common in the irinotecan/cisplatin arm. Patients in both irinotecan arms
had substantially more grade 3/4 diarrhea compared with those receiving
vindesine/cisplatin. The cisplatin arms yielded considerably more nausea and
vomiting. The incidence of anemia was driven by cisplatin: 39% grade ³ 3 for
irinotecan/cisplatin compared with 23% for vindesine/cisplatin and 6% for
irinotecan alone. Among stage IV patients, survival was significantly better in
those receiving irinotecan than in those receiving vindesine/cisplatin (Figure
1
).

In contrast, results from another phase III trial comparing the
two platinum combinations alone did not reveal a significant advantage or
disadvantage for irinotecan.[12,13] Again, baseline demographics were well
matched for the 117 randomized patients with stage IV disease. Grade ³ 3
neutropenia was more common in the vindesine/cisplatin arm (83%) than in the
irinotecan/cisplatin arm (64%). Grade ³ 3 anemia was slightly more common with
the irinotecan combination: 24% vs 17%. Likewise, grade ³ 3 nausea/vomiting and
diarrhea were more common at 19% and 15%, respectively, for irinotecan/cisplatin
vs 12% and 2% for vindesine/cisplatin. Median survival for patients receiving
irinotecan/cisplatin was 44.7 weeks, and 1- and 2-year survival rates were 36.4%
and 8.7%, respectively, in stage IV patients. Median survival time for
vindesine/cisplatin patients was 45.3 weeks, with 1- and 2-year survival rates
of 41.4% and 10.3%, respectively (P = .668) (Figure
2
). Significant negative
prognostic factors included male gender (P = .0028) and performance status of 2
(vs 0/1) (P = .0003).

North American Trials

The initial effort in North America to assess irinotecan
combinations, reported by DeVore and colleagues, was similar to the Japanese
study of Masuda and colleagues: cisplatin at
80 mg/m2/d on day 1 plus irinotecan at 60 mg/m2/wk × 3 every 4 weeks.[14]
Fifty-two patients were enrolled. Overall response rate was 29%, with a median
time to progression of 5.1 months, median survival time of 9.9 months, and a
1-year survival rate of 37%. Grade ³ 3 neutropenia occurred in 46% of patients,
with an 11.5% overall incidence of febrile neutropenia. Nausea, vomiting and
asthenia were driven by cisplatin: grade ³ 3 incidences were 32.7%, 13.5%, and
23.1%, respectively. Grade 3/4 diarrhea occurred in 17.3% of patients. The
relative dose intensity of irinotecan was 75.5%. Dose reductions of irinotecan
were required in 73% of patients; most patients ultimately had the irinotecan
dose reduced to ≤ 40 mg/m2.

A subsequent follow-up study assessed weekly irinotecan combined
with weekly cisplatin.[15] The rationale for this study included the following:
(1) the putative synergy of these two agents seen in vitro could be better
exploited by same-day administration; (2) improved sequencing of irinotecan and
cisplatin might potentially improve efficacy; (3) potentially diminished
toxicity could result from decreased cisplatin dose per administration. The
regimen was modeled after phase I
data of Saltz and colleagues.[16] Eligible patients received irinotecan at
65 mg/m2/wk × 4, in combination with cisplatin at 30 mg/m2/wk × 4. Treatment
was repeated at 6-week intervals. Fifty patients were enrolled.

Overall response rate (36%) was slightly higher than that in the
previous study, median time to progression was 6.9 months, median survival time
was 11.6 months, and the 1-year survival rate was 46%. These were the best
results observed to date in the Vanderbilt Cancer Center Affiliate Network
(VCCAN) trials. Overall incidence of grade ³ 3 neutropenia was 26%; febrile
neutropenia occurred in 6% of patients. Grade ³ 3 thrombocytopenia occurred in
14% and grade ³ 3 vomiting in 12% of patients. The relative dose intensity of
irinotecan in this combination was 89%, and the dose intensity was fairly well
maintained for both agents. Comparison of these two regimens is shown in Table
2
. Data to date thus favor using weekly rather than monthly cisplatin.

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