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Irinotecan in Advanced Lung Cancer: Focus on North American Trials

Irinotecan in Advanced Lung Cancer: Focus on North American Trials

ABSTRACT: New agents with improved systemic activity are needed for the treatment of lung cancer. Irinotecan (Camptosar) is a promising agent in advanced non–small-cell (NSCLC) and small-cell lung cancer (SCLC). In a Japanese phase III trial of advanced NSCLC, irinotecan or irinotecan/cisplatin demonstrated a significant survival advantage compared to the standard of vindesine/cisplatin. Similar North American phase III trials focusing on irinotecan’s role in NSCLC are under way. Ongoing trials have also been launched to corroborate the significant survival advantage reported by a Japanese phase III trial for irinotecan/ cisplatin vs standard etoposide/cisplatin in extensive SCLC. Current and planned trials in NSCLC with irinotecan in combination with gemcitabine (Gemzar), the taxanes, and other new agents, and thoracic radiotherapy should also provide useful clinical data. Moreover, trials in SCLC are investigating the rationale of combining irinotecan with a platinum agent as a component of chemoradiotherapy regimens. Promising data from these and other studies will further elucidate a role for irinotecan in the management of lung cancer.

Lung cancer is diagnosed in more
than 170,000 Americans yearly.
Although the mortality rate
is starting to plateau in North American
males, it continues to rise in American
women and in both genders
outside the United States, particularly
in Europe and the Orient. The 5-year
survival rate in the United States is
14%, compared with 8% in the United
Kingdom.[1,2] The majority of
patients manifest with disseminated
disease at diagnosis or develop distant
metastases shortly after initial local
regional therapy. Hence, new
agents with improved systemic activity
are desperately needed.

This paper will detail ongoing, randomized
phase III trials in North
America in extensive disease smallcell
lung cancer (ED SCLC), which
will serve to either confirm or refute
the role of irinotecan (Camptosar) established
by a critical Japanese effort.
It will also address the role of irinotecan
in combination with platinum up
front in treatment-naive non-
small-cell lung cancer (NSCLC) patients
and with nonplatinum agents in
both the first-line and second-line setting
in advanced NSCLC. We will
discuss these trials in the context of
current state-of-the art therapy in both
settings.

Non-Small-Cell Lung CancerSingle-Agent Therapy
Multiple phase II studies, particularly
in Japan, have established the
utility of irinotecan in the treatment
of advanced NSCLC (Table 1). Response
rates have ranged as high as
30% to 35%, using conventional
schedules of irinotecan at doses of
100 to 125 mg/m2 weekly 3 or 4,[3-
5] or doses of 300 to 350 mg/m2 every
3 weeks, with or without hematopoietic
growth factor support.[6] Toxicities
have been manageable and have
generally included myelosuppression
and diarrhea. In the sole US trial evaluating
single-agent irinotecan, Baker
and colleagues noted a 15% response
rate in 41 patients receiving a dose of
100 mg/m2 weekly 4 every 6 weeks;
79% had stage IV disease.[7]

Kamuyama et al (Hokkaido Institute
of Public Health, Sapporo, Japan)
examined the activation/
detoxification of irinotecan by human
lung cancer cell lines and determined
the expression of the putative
enzyme(s) that convert irinotecan to
the active moiety, SN-38.[8] Of 25
squamous cell carcinoma cell lines,
15 were strongly positive for carbox
ylesterase;
of 25 adenocarcinomas, 20
were positive, including 4 that expressed
strong positivity.

Cisplatin/Irinotecan Combinations
Cisplatin remains the cornerstone
of combination therapy in advanced
NSCLC. In preclinical models, cisplatin
in combination with irinotecan,
has yielded synergistic cytotoxicity.
With the exception of myelosuppression,
irinotecan and cisplatin have
nonoverlapping toxicities. Consequently,
investigators have sought to
assess the clinical activity of irinotecan
in combination with cisplatin. The
earliest efforts emanated from Japan.
Masuda and colleagues evaluated cisplatin
at 80 mg/m2 on day 1 every 4
weeks in combination with irinotecan
at 60 mg/m2 on days 1, 8, and 15.[9]
The overall response rate was 52%;
time to progression was 4.4 months,
median survival was 10.2 months, and
the 1-year survival rate was 33%.

Ueoka et al assessed the irinotecan
and cisplatin combination at doses of
50 and 60 mg/m2, respectively, on
days 1 and 8 every 4 weeks.[10] The
overall response rate was slightly lower
at 41%. Median survival was 13
months; the 1-year survival rate
proved promising at 58%. Mori et al
conducted a phase II study of irinotecan
at 160 mg/m2 bolus on day 1 in
combination with cisplatin at
20 mg/m2 daily 4 by continuous
infusion with granulocyte colonystimulating
factor (G-CSF) support.[
11] Twenty-four treatment-naive
advanced NSCLC patients were evaluated.
The overall response was
58.5%, with a median survival time of
44.8 weeks and 1-year survival rate of
44%. Major adverse events included
grade 3/4 diarrhea (23% of patients),
granulocytopenia (20%), thrombocytopenia
(15%), and anemia (15%), without
any treatment-related deaths.

In Europe, Cardenal and colleagues
mounted a multi-institutional phase II
trial combining infusional irinotecan
at 200 mg/m2 over 1 hour in combination
with cisplatin at 80 mg/m2 every
21 days.[12] Over an 8-month period,
48 patients were recruited; 43 were
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 32 evaluable
patients, 12 (37.5%) achieved a
partial response.

Phase III Randomized Trials
Two separate prospective, randomized
phase III trials evaluated the role
of irinotecan in advanced NSCLC.
Negoro et al compared irinotecan either
alone or in combination with cis-
platin to a vindesine/cisplatin combination.[
13] Eligibility stipulated
chemonaive stage IIIB or IV measurable
NSCLC, Eastern Cooperative
Oncology Group (ECOG) performance
status 0 to 2, and adequate
marrow, hepatic, renal, and pulmonary
functions. Patients older than 75
years were excluded; 241 patients
were enrolled. Demographics with respect
to age, performance status, prior
weight loss, albumin, and lactate
dehydrogenase were well matched for
each arm.

Patients received one of three
regimens (results are delineated in
Table 2):

  • Arm A:Irinotecan at 60 mg/m2
    days 1, 8, and 15 and cisplatin at 80
    mg/m2 on day 1 every 4 weeks (based
    on Masuda et al[9] and Negoro et
    al[13]).
  • Arm B: Vindesine at 3 mg/m2 on
    days 1, 8, and 15 and cisplatin at 80
    mg/m2 on day 1 every 4 weeks (the
    standard).
  • Arm C: Irinotecan at 100 mg/m2
    on days 1, 8, and 15 every 4 weeks.

Leukopenia was much more pronounced
in the vindesine/cisplatin
combination, while thrombocytopenia
was more common in the irinotecan
and cisplatin combination. Both
irinotecan arms resulted in substantially
more grade 3 and 4 diarrhea.
The cisplatin arms yielded considerably
more nausea and vomiting. The
incidence of anemia was driven by
cisplatin: 39% grade ≤ 3 for irinotecan
and cisplatin compared with 23%
for vindesine and cisplatin, and 6%
for irinotecan alone. Survival among
stage IV patients was significantly
better for those receiving irinotecan
(arm A or C) compared to those
receiving vindesine and cisplatin
(Figure 1).

In contrast, a second phase III trial
reported by Niho et al[14] and Kunitoh
and colleagues[15] comparing the
two platinum combinations alone did
not reveal a significant advantage or
disadvantage for irinotecan. Baseline
demographics were well matched in
the 199 randomized patients. Grade ≥3 neutropenia was more common for
the vindesine and cisplatin arm (83%)
compared with the irinotecan and cisplatin
arm (64%). Grade ≥ 3 anemia
was more common for the irinotecan
combination (24%) compared with the
vindesine and cisplatin arm (17%).
Likewise, grade ≥ 3 nausea/vomiting
and diarrhea were more common at
19% and 15%, respectively, for irinotecan
and cisplatin, compared with
12% and 2%, respectively, for the vindesine
and cisplatin combination.

Median survival for patients enrolled
in the irinotecan and cisplatin
arm was 10.6 months, with 1- and 2-
year survival rates of 36.4% and 8.7%,
respectively, in stage IV patients.
Median survival for vindesine and
cisplatin was 11.5 months, with 1-
and 2-year survival rates of 41.4%
and 10.3%, respectively (P = .668).
Significant negative prognostic factors
included male gender (P = .0028)
and performance status of 2 (vs 0/1)
(P = .0003).

It is unclear why one trial showed
an apparent survival advantage for the
irinotecan and cisplatin combination
in stage IV patients, while the other
did not. Nevertheless, irinotecan joins
the pantheon of other modern agents
(vinorelbine, gemcitabine, the taxanes)
which, in combination with a
platinum, have demonstrated comparable
if not superior activity to older
second-generation agents.

North American Trials
The initial combination effort in
North America reported by DeVore
and colleagues[16] recapitulated the
Japanese study of Negoro and colleagues.[
13] Cisplatin was dosed at
80 mg/m2 on day 1, and irinotecan
at 60 mg/m2 weekly 3 every 4
weeks.[16] A total of 52 patients were
enrolled. Overall response rate was
29%, with a median time to progression
of 5.1 months, a median survival
of 9.9 months; and a 1-year survival
of 37%.

Grade ≥ 3 neutropenia occurred in
46% of patients, with an overall 11.5%
incidence of febrile neutropenia. Nausea
and vomiting and asthenia were
driven by cisplatin. The relative grade
≥ 3 incidences were 32.7% and 23.1%,
respectively. Grade 3 or 4 diarrhea
occurred in 17.3% of patients. The
relative dose intensity of irinotecan
was 75.5%. Dose reductions of irinotecan
were required by 73% of patients.
Most patients ultimately had
their irinotecan dose reduced to ≤40
mg/m2 weekly. This trial has been
criticized for overly stringent dose modification
criteria.

Consequently, a follow-up study
mounted through Vanderbilt Cancer
Network (VCCAN) and Fox Chase
Cancer Center (FCCC) combined
weekly irinotecan with weekly cisplatin.[
17] There were three justifications
for this move: (1) same-day
administration could better exploit the
putative in vitro synergy of these two
agents; (2) improved sequencing of
irinotecan and cisplatin might potentially
improve efficacy; and (3) decreasing
the cisplatin dose per
administration could potentially diminish
toxicity. The regimen was
modeled after phase I data of Saltz
and colleagues.[18] Eligible patients
received irinotecan at 65 mg/m2 weekly
4 in combination with cisplatin at
30 mg/m2 weekly 4. Treatment was
repeated at 6-week intervals. A total
of 50 patients were enrolled.

Overall response rate was 36%;
median time to progression was 6.9
months, median survival was 11.6
months, and 1-year survival was 46%.
These results were the best ever observed
in advanced NSCLC in the
history of the VCCAN, and proved
comparable to previous results seen
with combination paclitaxel and carboplatin
(Paraplatin) at FCCC and its
affiliated network. The overall incidence
of grade ≥ 3 neutropenia was
25.5%; febrile neutropenia occurred
in 6% of patients. Grade ≥ 3 thrombocytopenia
occurred in 12% and grade
≥ 3 nausea and vomiting in 26% 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 the two North
American irinotecan and cisplatin regimens
is depicted in Table 3. Data to
date favor using weekly as opposed
to monthly cisplatin. Nausea and vomiting
were less pronounced. In addition,
serious neutropenia was less
common. Finally, the response rate
and survival appeared comparable to,
if not superior to, the standard established
approach using monthly cisplatin
and weekly irinotecan. Because
of cumulative asthenia, several investigators
have proposed a 2-weeks-on/
1-week-off schedule, although this
approach has never been formally
studied. Interest also exists in comparing
this schedule to other established
cytotoxic regimens, though
planned trials have not yet evolved.

Compared to cisplatin, carboplatin
yields considerably less nonhematologic
toxicity, in particular nausea and
vomiting. Fledgling phase I Japanese
efforts have integrated carboplatin and
irinotecan. In one effort, 17 patients,
71% of whom had stage IV NSCLC,
received carboplatin at area under the
concentration-time curve (AUC) of 5
every 4 weeks and irinotecan weekly
on days 1, 8, and 15 every 4 weeks.
The maximum tolerated dose of irinotecan
was 60 mg/m2 and the recommended
phase II dose was 50 mg/m2.
Dose-limiting toxicity included neutropenia
and thrombocytopenia. Median
survival was 10.5 months; 1-year
survival was 35%.[19]

Mukohara and colleagues evaluated
a similar regimen.[20] The incidence
of grade ≥ 3 neutropenia,
anemia, thrombocytopenia, and diarrhea
was 76%, 26%, 47%, and 6%,
respectively. Only 43% of the intended
day 15 irinotecan dose was administered.
Overall response rate was
25%. Median survival was 10.8
months and 1-year survival was
39%.[20]

Sunpaweravong et al[21] at the
University of Colorado evaluated this
combination further. A total of 14 patients
were enrolled onto this phase I/
II effort, including 10 with NSCLC
and 2 with SCLC. The initial dose of
carboplatin at AUC 6 and irinotecan
at 60 mg/m2 days 1 and 8 every 3
weeks proved too toxic. DLT included
neutropenia, thrombocytopenia,
diarrhea, and fatigue; hence the recommended
dose was AUC 5 for carboplatin
and 50 mg/m2 days 1 and 8
for irinotecan. Partial responses were
observed in one patient each with
NSCLC and SCLC, and stable disease
occurred in two patients
(NSCLC). A phase II trial by Kelly
and colleagues at this institution in
untreated extensive-stage SCLC is
under way.

Taxane and Irinotecan
Combinations

There are a number of reasons to
consider irinotecan and taxanes in
combination. Each is individually active
in both NSCLC and SCLC. Both
agents have nonoverlapping toxicities,
malleable schedules, and relative non-
cross resistance. Finally, preclinical
data suggest an additive, if not synergistic,
effect. Murren and colleagues
mounted a phase I trial of irinotecan
and paclitaxel, both agents administered
weekly 4 every 6 weeks.[22]
Twenty-one patients were enrolled in
this phase I study. A total of 53 cycles
were administered. The maximum tolerated
dose for irinotecan in this
schedule was 50 mg/m2 and paclitaxel
75 mg/m2 weekly. Pharmacokinetics
revealed no drug-drug interaction
based on levels of irinotecan and its
active metabolite SN-38. However,
chemotherapy on weeks 3 and 4 was
often dose-modified or omitted. Only
26% of cycles were administered as
planned.

An ongoing phase II trial by these
investigators enrolling advanced
NSCLC patients (performance status
0 to 2) was an abbreviated schedule:
irinotecan at 50 mg/m2 weekly 2
every 3 weeks in combination with
paclitaxel at 75 mg/m2 weekly 2
every 3 weeks. To date, 10 patients,
ages 47 to 68, have been accrued.
There has been no grade 4 neutropenia.
The relative dose intensity is 97%.
Two of six evaluable patients have
sustained partial response (18+
weeks), three have had stable disease,
and one only progressive disease.

Rosen et al combined irinotecan
with paclitaxel, both agents given once
every 3 weeks.[23] The maximum
tolerated doses were 225 and
100 mg/m2, respectively. Grade ≥3
diarrhea was observed in only one of
nine treatment courses at maximum
tolerated dose, whereas at higher doses,
grade ≥ 3 diarrhea occurred in five
of seven patients. Objective responses
were seen in NSCLC and in occult
primary squamous malignancy. As in
the Murren trial, paclitaxel coadministration
did not alter irinotecan pharmacokinetics
(irinotecan and SN-38
levels).

Socinski and colleagues have
mounted phase I and phase II studies
of irinotecan in combination with standard
paclitaxel and carboplatin.[24]
Thirty-three NSCLC patients were
enrolled in the initial phase I effort.
The maximum tolerated doses for
these three agents using an every-3-
week schedule were paclitaxel at 175
mg/m2 on day 1, irinotecan at 100
mg/m2 on day 1, and carboplatin at
AUC 5 on day 1. Myelosuppression
precluded more frequent weekly dosing
of irinotecan.

The overall response rate was 39%
(10% complete response). Median
time to progression was 6.8 months;
median survival was 11 months, and
1-year survival was 46%. Forty patients
were ultimately enrolled in the
subsequent phase II effort using the
maximum tolerated doses established
in the phase I trial. The response rate
of 32% proved comparable to the
phase I effort. Time to progression at
5.6 months was similar; median survival
exceeded 1 year.[25] The incidence
of neutropenic fever, significant
fatigue, and late diarrhea was 20%
each.

Based on these promising results,
a randomized phase II study in fit
stage IIIB/IV NSCLC patients assessing
the triple-agent regimen and its
constituent double-agent regimens
(irinotecan and carboplatin and paclitaxel
and irinotecan) using a 1:1:1
assignment was initiated. Unfortunately,
because of sluggish accrual, this
trial was shelved.

Phase I trials have also assessed
irinotecan in combination with docetaxel
(Taxotere).[26] Thirty-two treatment-
naive advanced NSCLC patients
(22 stage IV) received docetaxel on
day 2 and irinotecan on days 1, 8, and
15. Eligibility stipulated ECOG performance
status 0 to 2, ≤ 75 years of
age, and adequate marrow, hepatic,
and renal function. Median age was
55 years (range: 46 to 71 years); 17
were male. Doses were escalated
across sequential cohorts. The maximum
tolerated dose for each agent
was 50 mg/m2. Higher doses led to
dose-limiting toxicity, primarily neutropenia.
The overall response rate was
37%, median survival was 48 weeks,
and 1-year survival was 45%. There
was no effect of irinotecan on docetaxel
pharmacokinetics.

Murren and colleagues evaluated
weekly therapy using both agents.[27]
Cohort A received weekly therapy
4 every 6 weeks; cohort B received
weekly therapy 2 every 3 weeks. A
total of 44 patients were accrued; 26
were previously treated with chemotherapy;
20 were diagnosed with
NSCLC, 12 with pancreatic and biliary
primaries, and 14 with other diagnoses.
Seventy-five percent were
male. All but seven were performance
status 0 or 1. The maximum tolerated
doses for irinotecan and docetaxel
using the weekly 4 regimen were
50 and 35 mg/m2, respectively. The
maximum tolerated doses for the
weekly 2 regimen were 60 and 35
mg/m2, respectively.[25] From the
standpoint of cumulative toxicity and
dose intensity, the latter schedule was
considered preferable.

Adjei and colleagues[28] adopted
an opposite tactic, dosing each agent
at 3-week intervals. Irinotecan was
escalated from 160 to 200 mg/m2, and
docetaxel from 50 to 75 mg/m2 Eighteen
patients were accrued, and 85
courses were administered. Dose-limiting
toxicity proved to be myelosuppression;
neutropenic fever occurred
in three individuals. Diarrhea was
dose-dependent, but severe only in
those who neglected to take appropriate
antidiarrheals. Nonhematologic
toxicity was mild to moderate with
grade 3 anorexia and nausea observed
in one patient each. Five of 16 patients
responded, including three with
NSCLC and one each with soft tissue
sarcoma and cholangiocarcinoma.
The maximum tolerated doses and recommended
phase II doses for irinotecan
and docetaxel were 160 and
65 mg/m2, respectively.[28]

In a critical randomized phase II
study conducted in Japan, this combination
of docetaxel and irinotecan appeared
equivalent to docetaxel and
cisplatin[29] in the therapy of advanced
NSCLC (Table 4). Treatment
was cycled at 3-week intervals; patients
received a fixed dose of docetaxel
60 mg/m2 and were randomized to
either cisplatin at 80 mg/m2 or to irinotecan at 60 mg/m2 on days 1 and 8.

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