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Current Role of Irinotecan in the Treatment of Non-Small-Cell Lung Cancer

Current Role of Irinotecan in the Treatment of Non-Small-Cell Lung Cancer

ABSTRACT: Lung cancer remains the primary cause of cancer-related death in both men and women in the United States. Chemotherapy has been shown to provide a survival benefit in patients with advanced non-small-cell lung cancer (NSCLC), and current regimens have produced median survivals of approximately 8 months and 1-year survival rates of 30% to 35% in patients with stage IIIB and IV disease. Nevertheless, there remains room for improvement. Irinotecan (CPT-11, Camptosar) has demonstrated efficacy in the treatment of small-cell lung cancer (SCLC). It also appears to have promising activity in advanced NSCLC, producing overall response rates of up to 32%. Combinations of irinotecan and cisplatin or carboplatin (Paraplatin) have resulted in overall response rates of 25% to 56% in phase II and III studies in patients with advanced disease, with median survivals ranging from 9 to 13 months and 1-year survival rates of 33% to 58%. Current irinotecan-based doublet and triplet regimens appear to produce promising response rates with manageable toxicities. In addition, irinotecan has demonstrated potential as a radiosensitizing agent and is currently being evaluated in several trials of combined-modality therapy in patients with locally advanced NSCLC. Early trials of irinotecan in combination with cisplatin or carboplatin along with radiation therapy have reported overall response rates of 60% to 67%. The approach appears to have potential and warrants further study. [ONCOLOGY 16:1153-1168, 2002]

Lung cancer is the leading cause of cancer-related death in both men and
women in the United States. In 2002, an estimated 169,400 new cases of lung
cancer will be diagnosed, and the disease will cause 154,900 deaths.[1] Non-small-cell
histologies account for approximately 80% of new lung cancer cases, and the
majority of these patients initially present with advanced or metastatic
disease.[2] The long-term survival prognosis for patients with advanced non-small-cell
lung cancer (NSCLC) remains poor. In recent years, however, more effective
chemotherapy regimens have improved the survival outlook, and hopefully progress
will continue with the development of new agents.[3]

The benefit of platinum-based therapy in the treatment of patients with
advanced NSCLC was demonstrated in a meta-analysis of clinical trials that
compared chemotherapy to best supportive care.[4] With the use of cisplatin-based
regimens, median overall survival improved to 6 months compared to 4 months
with best supportive care, and the 1-year survival rate rose from 15% to 25%.
Based on these data, platinum-based regimens have been considered a standard of
care for advanced NSCLC.

New Platinum Combinations

In an effort to further improve survival, investigators have evaluated the
efficacy of combining platinum agents with several newer drugs that have
demonstrated promising single-agent activity in NSCLC, including paclitaxel,
docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), irinotecan
(CPT-11, Camptosar), and topotecan (Hycamtin).[3] In the United States, efforts
have focused on platinum agents combined with taxanes, gemcitabine, and
vinorelbine.

Major US Trials

The preliminary results of two US randomized phase III trials evaluating
platinum-based regimens in advanced NSCLC were recently reported. A four-arm
study conducted by the Eastern Cooperative Oncology Group (ECOG) compared
doublets of cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and
docetaxel, and carboplatin (Paraplatin) and paclitaxel[5]; a two-arm study
conducted by the Southwest Oncology Group (SWOG) compared the combination of
cisplatin and vinorelbine to carboplatin and paclitaxel.[6]

In each of these trials, no differences in median overall survival or 1-year
survival were reported between arms. However, some differences did emerge with
respect to specific toxicities. At present, platinum doublet combinations such
as those used in the ECOG and SWOG trials can be expected to produce a median
overall survival of approximately 8 months and 1-year survival rates ranging
from 30% to 35% in patients with advanced NSCLC. Although these results indicate
progress in terms of survival, room for improvement remains, and the evaluation
of newer agents and combinations is necessary.

Irinotecan in SCLC

Irinotecan, a camptothecin analog, has demonstrated meaningful clinical
activity in a number of solid tumors, including colorectal and other
gastrointestinal cancers and both small-cell lung cancer (SCLC) and NSCLC.[7] In
SCLC, single-agent irinotecan has produced response rates of 50% in previously
untreated patients and 16% to 33% in previously treated patients.[8-10] With the
combination of irinotecan and cisplatin as first-line therapy, overall response
rates of 83% and 86% were reported in patients with limited and extensive SCLC,
respectively.[11]

Based on this activity, the Japan Clinical Oncology Study Group conducted a
randomized phase III trial comparing the combination of irinotecan and cisplatin
to a standard regimen of etoposide and cisplatin in patients with extensive
SCLC.[12,13] The median overall survival of 13.5 months in the irinotecan/cisplatin
arm was significantly longer than the 9 months observed in the etoposide/cisplatin
arm (P = .0021). The combination of irinotecan and cisplatin has been adopted as
the standard of care in Japan for patients with extensive SCLC and is currently
being evaluated in phase III randomized trials in the United States.

Given its high degree of activity in SCLC, the potential of irinotecan in the
treatment of NSCLC was considered. Investigators in Japan have been the first to
systematically evaluate the role of irinotecan in NSCLC, and interest in the
agent has recently been increasing in both the United States and Europe.

Irinotecan in NSCLC

Single-Agent Irinotecan

In patients with previously untreated advanced NSCLC, phase II studies of
single-agent irinotecan have evaluated both weekly administration and
once-every-3-week dosing schedules (Table 1).[14-17] Fukuoka et al reported an
overall response rate of 32% in 72 evaluable patients, 40 of whom had stage IV
disease, and achieved a response rate of 32.5% with a weekly irinotecan dose of
100 mg/m2.[14] The median duration of response for all patients was
3.5 months, and median overall survival was 10 months. Leukopenia, nausea
and vomiting, and diarrhea were the most common toxicities, with grade 3/4
toxicity occurring in 20% to 25% of patients.

In a study reported by Baker et al, irinotecan, 100 mg/m² administered weekly
for 4 weeks of a 6-week cycle, produced an overall response rate of 15% in 41
evaluable patients, with a median response duration of 4.7 months and a
median overall survival of 6 months.[15] Grade 3 neutropenia was noted in 15% of
patients, and grade 3/4 diarrhea in 17%.

Two studies evaluated irinotecan administered on an every-3-week schedule.
Nakai et al reported an overall response rate of 20% in 35 evaluable patients
given 200 mg/m² of irinotecan every 3 weeks, while a study by Douillard et al
reported an overall response rate of 22% in 19 patients receiving a dose of
350 mg/m² every 3 weeks.[16,17] Major toxicities included leukopenia, diarrhea,
nausea, and vomiting.

Given the promising single-agent activity of irinotecan in advanced NSCLC,
current studies are investigating platinum-based and nonplatinum doublet and
triplet regimens with irinotecan (Table 2).

Irinotecan/Platinum Doublets

Irinotecan and Cisplatin 

Preclinical studies, lung cancer cell lines,
and tumor xenograft models have indicated a potential synergism between
irinotecan and cisplatin.[18,19] Given the established role of platinum agents
in the treatment of NSCLC, their subsequent combination with irinotecan was a
logical step. The combination of cisplatin and irinotecan has been studied most
frequently.

Numerous phase I studies evaluating various administration schedules of
irinotecan and cisplatin have been conducted in patients with previously
untreated NSCLC.[20-27] In a series of trials, Masuda et al evaluated
combinations of cisplatin at a fixed dose on day 1 with escalating doses of
irinotecan on days 1, 8, and 15 of a 28-day cycle in patients with advanced
NSCLC. Their initial study used a fixed cisplatin dose of 80 mg/m², and
dose-limiting toxicities (diarrhea and leukopenia) occurred at an irinotecan
dose of 70 mg/m².[20] Among 26 evaluable patients, 14 achieved partial
responses, for an overall response rate of 54%.

A second study decreased the cisplatin dose to 60 mg/m² on day 1, and
diarrhea was found to be dose-limiting at an irinotecan dose of
90 mg/m².[21] The overall response rate was 43% among the 14 evaluable
patients, with one complete and five partial responses.

In an effort to increase dose intensity, a third study used a fixed cisplatin
dose of 80 mg/m² with escalating doses of irinotecan, and granulocyte
colony-stimulating factor (G-CSF, Neupogen) added on days 4 to 21 except on the
days that irinotecan was administered. Dose-limiting diarrhea and leukopenia
developed at an irinotecan dose of 90 mg/m², and a partial response rate of 50%
was noted in 20 evaluable patients.[22]

Using fractionated doses of both cisplatin and irinotecan on days 1, 8, and
15, Kobayashi et al reported a maximum tolerated cisplatin dose of 33 mg/m² in
combination with a fixed irinotecan dose of 60 mg/m².[23] Leukopenia was
dose-limiting, and 7 of 13 patients (54%) achieved partial responses. Ueoka et
al administered a fixed dose of cisplatin (60 mg/m²) on days 1 and 8 with
escalating doses of irinotecan.[24] The maximum tolerated dose of irinotecan was
60 mg/m², with diarrhea being dose-limiting; partial responses were seen in
13 of 17 evaluable patients, for an objective response rate of 76%.

Mori et al evaluated escalating doses of irinotecan in combination with a
5-day infusion of cisplatin. Maximum tolerated doses were cisplatin at
20 mg/m²/d × 5 in combination with irinotecan at 80 mg/m² on day 1 without
G-CSF, and irinotecan at 160 mg/m²/d with G-CSF; overall response rates ranged
from 47% to 55%.[25,26]

Phase II Trials

With the promising overall response rates (43% to 76%)
reported in phase I trials for the combination of irinotecan and cisplatin,
several phase II trials evaluating various regimens were initiated (Table
3
).[28-36] Masuda et al administered irinotecan, 60 mg/m² on days 1, 8, and
15, in combination with cisplatin, 80 mg/m² on day 1.[28] Of the 64 patients
evaluable for response, 1 achieved a complete response and 32 had a partial
response for an overall response rate of 52%. The median overall survival of the
69 enrolled patients was 10 months, and the 1-year survival rate, 33%.
Predominant toxicities included leukopenia, neutropenia, and diarrhea, although
all were considered manageable.

In the United States, DeVore et al evaluated the combination of irinotecan at
60 mg/m² on days 1, 8, and 15 and cisplatin at 60 mg/m² on day 1.[29] Irinotecan
was preferentially dose-reduced for toxicity, and actual delivered dose
intensities were 75% for irinotecan and 100% for cisplatin. Among the 52
evaluable patients, 29% achieved an objective response, with a median survival
of 10 months and a 1-year survival rate of 37%. Grade 3/4 neutropenia, which
occurred in 46% of patients, was the most common serious toxicity.

As a follow-up to their phase I trial, Mori et al conducted a phase II trial
of irinotecan at 160 mg/m² on day 1 with cisplatin at 20 mg/m² on days 1 to 5,
with G-CSF support.[30] The overall response rate was 56% for the 41 evaluable
patients, the median survival was 10 months, and the 1-year survival rate was
44%. Grade 3/4 toxicities included diarrhea in 23%, granulocytopenia in 20%, and
thrombocytopenia and anemia in 15% of patients.

Coadministration of irinotecan and cisplatin on a weekly schedule,
facilitating potential synergism between these agents, has also been evaluated.
Based on previous clinical experience,[31] Jagasia et al administered irinotecan
at 65 mg/m² with cisplatin at 30 mg/m²/wk for 4 weeks of a 6-week cycle. Ueoka
et al administered irinotecan at 50 mg/m² with cisplatin at 60 mg/m² on days 1
and 8 of a 28-day cycle.[31,32] Overall response rates of 36% and 41%, median
survivals of 12 and 13 months, and 1-year survival rates of 46% and 58%,
respectively, were reported for the two studies. Both regimens were reasonably
well tolerated. Jagasia et al reported a 26% incidence of grade 3/4
neutropenia and diarrhea, while grade 3/4 toxicities reported by Ueoka et al
included leukopenia in 48%, thrombocytopenia in 43%, anemia in 42%, diarrhea in
27%, and nausea and vomiting in 26%.

Cardenal and associates opted to administer an intensive irinotecan dose of
200 mg/m² with cisplatin at 80 mg/m², both on day 1.[34] Grade 3/4
neutropenia occurred in 51% of patients, with an 11% rate of febrile neutropenia,
and grade 3/4 delayed diarrhea occurred in 31% of patients. Preliminary data
indicated an overall response rate of 41%.

Phase III Trials

Two multicenter randomized phase III trials evaluating
irinotecan and cisplatin have been completed by Japanese investigators (Table
3
).[28-36] The first was a three-arm trial comparing combination irinotecan/cisplatin
to vindesine/cisplatin or irinotecan alone.[35] The second trial compared
irinotecan/cisplatin to vindesine/cisplatin.[36] Updated response and survival
analyses for both studies have recently been presented.[33,37]

In the three-arm study,[35] the combination of irinotecan and cisplatin
produced an overall response rate of 43%, with a median survival of 12 months
and a 1-year survival rate of 49%. For the vindesine/cisplatin arm and the
single-agent irinotecan arm, overall response rates were 31% and 40%,
respectively, and 1-year survival rates were 21% and 44%, with a median overall
survival of 11 months in both arms. In the two-arm study,[36] irinotecan and
cisplatin produced an overall response rate of 29%, median survival of
10 months, and 1-year survival rate of 36%, compared to an overall response
rate of 22%, median survival of 10 months, and 1-year survival rate of 41%
for vindesine and cisplatin.

There was a trend toward improved survival in the irinotecan/cisplatin arm of
the three-arm study that was not apparent in the two-arm study. More recently, a
combined analysis of the two studies indicated that the combination of
irinotecan and cisplatin significantly improved survival over the vindesine/cisplatin
regimen in patients with metastatic disease.[37] Notably, the median survival in
the irinotecan/cisplatin arms was 10 months or longer.

Irinotecan and Carboplatin

The activity of carboplatin appears to be
similar to that of cisplatin in the treatment of lung cancer,[38] and given the
drug’s favorable toxicity profile and ease of administration, the use of
carboplatin may be preferable. Investigation of carboplatin-based regimens is
necessary, and several studies of the combination of irinotecan and carboplatin
have recently been reported (Table 4).[39-42]

Okamoto et al performed a phase I study of escalating doses of both
irinotecan and carboplatin with G-CSF support.[39] Diarrhea was dose-limiting at
an irinotecan dose of 70 mg/m² administered on days 1, 8, and 15 with
carboplatin at an area under the concentration-time curve (AUC) of 5. Of 20
evaluable patients, 7 (35%) achieved an objective response, and the median
overall survival was 8 months.

Fukuda et al conducted a phase I trial of irinotecan plus carboplatin without
G-CSF in untreated patients with advanced solid tumors, primarily lung cancer
patients.[40] Escalating doses of irinotecan were administered starting at 40
mg/m² on days 1, 8, and 15 with carboplatin at AUC 5 on day 1 of a 28-day cycle.
Dose-limiting toxicities, including neutropenia, thrombocytopenia, and diarrhea,
occurred at an irinotecan dose of 60 mg/m². Of the 11 evaluable patients, 4
(36%) with NSCLC achieved an objective response. On this schedule, irinotecan at
50 mg/m² with carboplatin at AUC 5 was recommended for future testing.

Two phase II studies using this regimen were conducted by Mukohara et al and
Kinoshita et al.[41,42] In the preliminary reports, overall response rates of
25% and 35%, median survivals of 11 and 9 months, and 1-year survival rates of
39% and 34%, respectively, were reported for the two studies. Mukohara et al
reported the following grade 3/4 toxicities: neutropenia (77%), thrombocytopenia
(47%), anemia (25%), and nausea or vomiting (36%).[41] Febrile neutropenia
developed in four patients. Investigators were concerned that less than 50% of
patients received the day 15 dose of irinotecan, possibly contributing to the
lower than expected response rate. Kinoshita et al observed grade 3/4
neutropenia, thrombocytopenia, and diarrhea in 55%, 22%, and 5% of patients,
respectively.[42]

At the University of Colorado Cancer Center, we are currently conducting a
phase I dose-escalation trial of irinotecan administered on days 1 and 8 with
carboplatin administered on day 1 every 21 days in previously treated patients
with solid tumors. The current dose level being explored is irinotecan, 50
mg/m², and carboplatin, AUC 5.

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