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Topoisomerase I Inhibitors in the Combined-Modality Therapy of Lung Cancer

Topoisomerase I Inhibitors in the Combined-Modality Therapy of Lung Cancer

ABSTRACT: Locally advanced non–small-cell lung cancer represents 30% to 40% of all pulmonary malignancies. Most patients will die of the disease after aggressive contemporary treatments. Therefore, significant improvement in therapeutic methods must be implemented to improve overall survival rates. The arrival of a new generation of chemotherapeutic agents—including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar) and topotecan (Hycamtin)—offers the hope of significant advances in the treatment of lung cancer. Irinotecan and topotecan are camptothecin derivatives that inhibit topoisomerase I enzyme. It is believed that topoisomerase I inhibitors stabilize a DNA/topoisomerase I complex and interact with replication machinery to cause cell death. A significant amount of data demonstrates that these topoisomerase I inhibitors also act as radiosensitizers. With the increasing data that support concurrent chemoradiation treatment for malignancies, including lung cancer and head and neck cancers, there is an impetus to pursue the additional drugs that may potentially improve local control and survival. Irinotecan is undergoing early clinical trials in the combined-modality setting in several different disease sites. This paper will review the data on the role of camptothecin derivatives as a radiosensitizer and as a component of combined-modality therapy for lung cancer. It is hoped that newer treatment strategies, like the combination of radiation and topoisomerase I inhibitors, will have a significant impact on cure rates in the future.

In 2004, it is estimated that in the
United States there will be 68,510
deaths among women and 91,930
deaths among men due to lung cancer,
which is the leading cause of cancer
deaths in the United States. Lung
cancer accounts for 14% of new cancer
cases and 28% of cancer deaths
per year in the United States.[1] The
5-year survival rate for lung cancers
has been around 15% from 1974
through 1995.[2] Most of these cures
are related to surgical treatment of
patients presenting with stage I and II
cancers. However, about 35% of patients
present with locally advanced
disease that is not amenable to surgical
therapy but may be potentially
curable.[3] Traditional radiation treatment
alone in this group of patients
has yielded dismal cure rates at 5
years. Therefore, a combined-modality
therapy has been sought to improve
the poor outcome with single
modality alone.

Patients with clinical stage IIIA
have an overall 5-year survival rate of
10% to 15%. However, this figure
drops to 2% to 5% when there is grossly
visible disease in the mediastinum
on a chest x-ray.[4] The principal
forms of treatment for patients with
stage III non-small-cell lung cancer
(NSCLC) are radiation therapy, chemotherapy,
surgery, and combinations
of these modalities.

Several potential benefits are derived
from interactions of radiothera
py
and chemotherapy to improve therapeutic
outcome. Combined radiotherapy
and chemotherapy may increase
tumor response, protect normal tissues,
and exhibit nonoverlapping toxicities.[
5] There is potential synergistic
increase in enhancement of tumori-
cidal effect in specific anatomic sites
where single-modality therapy may
have limited efficacy. Chemotherapeutic
agents may reduce the radiotherapy-
induced normal tissue toxicity
to an acceptable level for patients.
Finally, two partially effective therapeutic
modalities may be combined
without having to significantly reduce
their dose levels to avoid treatmentrelated
toxicities.

Multiple phase III trials have confirmed
therapeutic benefits of combining
chemotherapy and radiotherapy
in locally advanced NSCLC, but with
increased treatment-related toxici-
y.[
6-9] A large meta-analysis of 22
trials (3,033 patients and 2,814 deaths)
comparing radiotherapy administered
alone or with chemotherapy demonstrated
a 10% reduction in the relative
risk of death with chemoradiotherapy
vs radiotherapy as a sole modality
(P = .006), with an absolute reduction
in deaths of 3% at 2 years and 2% at 5
years.[10] Another meta-analysis from
Pritchard et al suggested that traditional
chemotherapy added to radiotherapy
adds an average of 2 months
to patient survival.[11] Recent trials
have shown that concurrent chemoradiotherapy
results in a better overall
survival compared with sequential
chemoradiotherapy in NSCLC.[12,13]

Combined chemotherapy and radiotherapy
currently remains the standard
treatment for locally advanced
NSCLC. However, local failure rates
can be around 80%.[6,9] Therefore,
ongoing trials seek to improve the
outcome for treatment of lung cancer.
Multiple agents including paclitaxel,
docetaxel (Taxotere), vinorelbine,
gemcitabine (Gemzar), and irinotecan
(Camptosar) show a 20% to 54% response
rate for single-agent treatment
in metastatic NSCLC.[3] This review
will focus on the data surrounding the
use of topoisomerase I inhibitors in
combination with thoracic radiotherapy
in the treatment of locally advanced
NSCLC.

Camptothecin

Camptothecin is an alkaloid originally
found in the Chinese tree Camptotheca
acuminata.
The US National
Cancer Institute first discovered camptothecin
with antitumor activity in the
1960s.[14] In preclinical studies, the
antitumor activity was seen against
colon and gastric cancers and leukemia.
However, unpredictable toxicities,
including myelosuppression and
hemorrhagic cystitis, were seen in patients
treated with camptothecin.
Greater understanding of the mechanisms
of action of camptothecin and
development of water-soluble compounds
generated greater interest in
camptothecin as a potential chemotherapeutic
agent.

Camptothecin and its derivatives
target topoisomerase I, the DNArelaxing
enzyme.[15-18] Although
topoisomerase I was discovered in the
1970s, its mechanism of action in
DNA replication was not clearly understood
until the 1980s. Topoisomerase
I was shown to be the target
of camptothecin in 1985 by Hsiang et
al.[19] This enzyme serves to relax
both positively and negatively supercoiled
double-helix DNA to allow replication
and transcription. It causes
reversible single-strand breaks, which
allow rotation of the broken DNA
strand around the intact strand. The
critical step for drug interaction is stabilization
of the topoisomerase I/DNA
complex that the enzyme forms when
cleaving DNA to allow for uncoiling
to occur.[15-20] In the presence of
camptothecin, a camptothecin/topoisomerase
I/DNA complex becomes
stabilized because the 5'-phosphoryl
terminus of the enzyme-catalyzed
DNA single-strand break is bound
covalently to a tyrosine residue of topoisomerase
I. These complexes are
nonlethal and reversible.

However, the single-strand breaks
become irreversible double-strand
breaks when the DNA replication fork
collides with reversible complex during
S phase or during unscheduled
DNA replication. The resulting cell
death can be recognized by the p53
damage-sensing pathway and may result
in acceleration of apoptosis.[21-
24] Thus, the cytotoxic effect of the
camptothecin requires active DNA
replication. In vitro studies have
shown that cells in S phase may be
100 to 1,000 times more sensitive to
camptothecin than cells in the G1 or
G2 phase of the cell cycle.[25]

Irinotecan

In the 1970s, camptothecin proved
to be too toxic as a chemotherapeutic
agent. However, one of the water soluble
derivatives, irinotecan (7-ethyl-
10-[4-(1-piperidino)-1-piperidino]
carbonyloxycamptothecin) or CPT-11
(Figure 1) displayed antineoplastic
activity with improved toxicity profile.[
26] Irinotecan was first commercially
available in Japan in 1994 for
treatment of lung, cervical, and ovarian
cancers. Irinotecan is a prodrug
that is metabolized intracellullarly to
its active metabolite, SN-38, by a carboxyesterase
converting enzyme. This
metabolite is over 1,000 times more
potent as an inhibitor of topoisomerase
I than irinotecan.[27,28] All of the
camptothecins have a terminal lactone
ring, which can be hydrolyzed to
a less active form. However, under
acidic conditions such as in the microenvironment
of a tumor, the active
lactone species is favored.[27] The
plasma half-life of SN-38 after a short
intravenous infusion is approximately
11.5 hours. Thus, a low concentration
of the metabolite may remain after
2 days and have cytotoxic effect.[29]

The major excretory pathway of
SN-38 is via hepatic glucuronidation
and a decreased ability to glucuronidate
may possibly correlate with
increased gastrointestinal side effects.
One of the dose-limiting toxicities of
irinotecan is delayed onset diarrhea
that can be potentially life threatening.
The diarrhea is felt to be related
to the relatively high S-phase fraction
of the intestinal mucosa, as well as to
the action of intestinal flora glucuronidase
in cleaving the camptothecin
glucuronidase conjugate leading
to the release of the drug in the intestinal
lumen.[30] Other commonly observed
toxicities include neutropenia,
nausea, and vomiting.

Interaction of Camptothecin
Derivatives and Radiation

Several investigators have reported
that irinotecan enhances the cytotoxic
effect of radiation in vitro and in
vivo.[31,32] Omura et al[33] found
that the cell kill was significantly enhanced
when radiation was combined
with the irinotecan derivative SN-38.
The largest enhancement in cytotoxicity
was seen when irinotecan was
given just before or just after radiation
therapy. Their data suggested that
radiosensitization occurs by inhibition
of potentially lethal damage repair.[
33] Chen et al[34] showed that
human MCF-7 breast cancer cells that
were exposed to 20(S)-10,11 methylenedioxycamptothecin
before or during
radiation showed radiosensitization
ratios of 1.6, while those treated
with the drug after radiation showed
substantially less enhancement of radiation-
induced DNA damage.

Kim et al also found greater radiosensitization
when topotecan (Hycamtin)
was administered 2 to 4 hours
before radiation therapy compared to
2 hours after radiotherapy in the treatment
of murine fibrosarcomas.[35]
The radiobiology data imply that patients
should be treated with a camptothecin
derivative-based chemotherapy
prior to or during their radiotherapy
in order to derive full benefits
of combined-modality therapy. Data
also suggest that camptothecin derivatives
including 9-nitro-20 (S)-camptothecin,[
36] 9-aminocamptothecin,[
37] and topotecan[38] are able
to potentiate the tumoricidal effects
of radiation.

There are several hypotheses about
mechanism of interaction between radiation
and irinotecan. The first hypothesis
suggests that the inhibition
of topoisomerase I by camptothecin
or its derivatives leads to the inhibition
of repair of radiation-induced
DNA strand breaks. The second hypothesis
suggests that irinotecan or its
analogs cause redistribution of cells
into the more radiosensitive G2 phase
of the cell cycle. The third hypothesis
suggests topoisomerase I/DNA adducts
are trapped by irinotecan at the
sites of radiation-induced singlestrand
breaks leading to their conversion
into double-strand breaks.[36]
However, there is not sufficient evidence
to identify the underlying mechanism
with certainty. The predominance
of the particular mechanism
that is involved with radiosensitization
may depend on which derivative
of camptothecin is being used in combined-
modality therapy.

Irinotecan in Combination
for NSCLC

Basic principles used in the selection
of chemotherapy drugs include
nonoverlapping toxicities, differing
mechanisms of action, and non-cross
resistance.[39] Based on the above
criteria, both preclinical and human
data address the combination of cisplatin
and irinotecan in lung cancer.
Kudoh et al showed that in xenografts
of the small-cell lung cancer (SCLC)
tumor lines MNSUL and LX1, use of
irinotecan in combination with cisplatin
leads to a larger reduction in tumor
size than either agent alone.[31]

Early clinical studies in patients
with advanced NSCLC have yielded
favorable response rates in excess of
30%.[40] The combination of irinotecan
and cisplatin has also been used
in phase I and II clinical trials; early
data from phase II studies revealed a
48% response rate in NSCLC[41] and
78% for SCLC.[42] Ueoka et al[43]
reported a phase I trial with fractionation
of both the cisplatin and irinote-
can. Cisplatin (60 mg/m2) was given
on days 1 and 8 and escalating doses
of irinotecan were given on the same
days. Each cycle was repeated every
4 weeks. An impressive 78% response
rate was seen in 18 patients with
NSCLC.[43]

A Vanderbilt-Ingram Cancer Center
phase II trial looking at the combination
of cisplatin at 80 mg/m2 on day
1 and irinotecan at 60 mg/m2 on days
1, 8, and 15 in 4-week courses with
the possibility of escalating the irinotecan
dose according to side effects
was also undertaken.[44] The final
irinotecan doses were modified to less
than 40 mg/m2 with a response rate of
29% in 52 patients. The median time
to progression was 4.4 months, with a
1-year survival rate of 33%.

Negoro et al[45] reported a randomized
phase III trial in which the
combination of irinotecan and cisplatin
was compared to irinotecan alone
or a cisplatin/vindesine combination.
For stage IV patients, the irinotecan/
cisplatin combination was superior to
cisplatin/vindesine with respect to survival.
Median survival times were 50.0
and 36.4 weeks, respectively. No significant
difference in survival time
was seen between irinotecan/cisplatin
and irinotecan alone. In addition, no
significant difference in survival was
seen in stage IIIB disease. However,
the authors noted that no particular
restriction was placed on chest irradiation
in stage IIIB disease, which
might have produced a heterogeneous
group of IIIB patients.

Masuda et al[46] reported a phase
I study of docetaxel and irinotecan
for stage IIIB and IV patients. Thirtytwo
patients in the study were given
escalating doses of docetaxel and
irinotecan starting with 30/40 mg/m2
given at 4-week intervals in 10-mg/
m2 increments until the maximum tolerated
dose was reached. The maximum
tolerated dose of docetaxel and
irinotecan was 50/60 mg/m2 or 60/50
mg/m2. Neutropenia and diarrhea were
the dose-limiting toxicities. There was
a partial response of 37% with a median
survival time of 48 weeks. The
authors recommended 50 mg/m2 of
irinotecan on days 1, 8, and 15 and 50
mg/m2 of docetaxel on day 2 given
every 4 weeks for phase II trials.

Irinotecan and Radiotherapy
for NSCLC

Combined-modality treatment relies
on the ability of radiation and
chemotherapy to simultaneously address
both local and micrometastatic
disease. An enhancement of local control
is due to the radiosensitization
effects of concurrent chemotherapy.
In addition, concurrent chemotherapy
addresses potential micrometastatic
disease that local therapy, such as radiotherapy,
cannot address adequately.
Understanding the basic mechanisms
of interaction of different drugs
is also important to maximize the tumoricidal
effects of chemotherapy
while minimizing treatment-related
toxicities.

The optimal integration of irinotecan
and cisplatin or other irinotecanbased
chemotherapy integrated with
thoracic radiotherapy is unclear. Evidence
from previously completed trials
addresses sequencing of chemotherapy
and radiotherapy in combined
modality for lung cancer. In the
Cancer and Leukemia Group B
(CALGB) 9130 trial, all patients received
neoadjuvant platinum-based
chemotherapy followed by radiotherapy
with randomization to concurrent
carboplatin (Paraplatin) with no
improvement in survival, but there
was a decreased local relapse rate.[47]

The West Japan Lung Cancer
Group has also compared concurrent
and sequential combined-modality
treatment in 314 patients with unresectable
stage III NSCLC using a combination
of mitomycin (Mutamycin),
vindesine, and cisplatin chemotherapy.
Their results show a doubling of
5-year survival rates (P = .03998) with
concurrent treatment.[48] Curran et
al reported results of the Radiation
Therapy Oncology Group's RTOG
9410, which was a phase III, threearm
trial comparing standard sequential
chemoradiotherapy to two
different concurrent arms.[13] The
sequential arm used cisplatin at 100
mg/m2 on days 1 and 29 with vinblastine
at 5 mg/m2 weekly * 5 with 60
Gy of thoracic radiotherapy following
the chemotherapy. The second arm
used the same chemotherapy with 60
Gy of thoracic radiotherapy starting
on day 1. The third arm used cisplatin
at 50 mg/m2 on days 1, 8, 29, and 36,
with oral etoposide at 50 mg/m2 bid
for 10 doses on weeks 1, 2, 5, and 6,
with thoracic radiotherapy of 69.6 Gy
at 1.2 Gy bid starting on day 1.

Acute toxicity was higher with the
concurrent treatment regimen, although
late toxicities were not different
between the arms. With median
follow-up of 6 years, the arm with
chemotherapy given concurrently with
daily radiotherapy showed a median
survival of 17 months (P = .046). The
above trials support concurrent chemotherapy
and radiotherapy for locally
advanced NSCLC.

Several phase I and II trials have
administered irinotecan concomitantly
with thoracic radiotherapy in stage
III NSCLC (Table 1). Some trials added
other chemotherapeutic agents to
irinotecan. The response rates in these
trials are in excess of 60%. These
combinations appear to have reasonable
acute toxicities; however, it is
too early to assess the late complication
rates.

Takeda and colleagues examined
the combination of escalating doses
of weekly irinotecan with concurrent
thoracic radiotherapy (60 Gy in 30
fractions over 6 weeks) in a phase I/II
trial for locally advanced NSCLC.[49]
They enrolled patients with stage III
NSCLC who had an Eastern Cooperative
Oncology Group (ECOG) performance
status of 0 to 2 and started
irinotecan at 30 mg/m2 intravenous
weekly for 6 weeks. The maximum
tolerated dose was 60 mg/m2. At this
dose level, five patients had grade 3/4
toxicity, two had grade 3/4 esophagitis,
and three had grade 3/4 pneumonitis.
The irinotecan dose for the
phase II portion of the trial was 45
mg/m2. A further 10 patients were
treated at this dose level (17 total,
including seven patients from phase I
trial). One of the 10 patients in the
phase II portion developed pneumonitis
and died, while another patient developed
grade 3 diarrhea. The overall
response rate was 76.9%. After 22
months of follow-up, 1-year survival
was 61.5%.

Saka and colleagues performed a
phase II trial in which 24 patients
with locally advanced NSCLC were
enrolled and received irinotecan at 60
mg/m2 intravenous weekly * 6 with
concurrent 60 Gy of thoracic radiation
in 2-Gy/d fractions.[50] A total
of 71% of patients received the
planned chemotherapy, and 88% completed
the planned radiotherapy with
a partial response rate of 79%. Toxicities
included three (12.5%) cases of
grade 3 pneumonitis, two (8.3%) cases
of grade 3 esophagitis, two (8.3%)
cases of grade 3 neutropenia, and one
(4.2%) case of a grade 3 fever. There
were no grade 4 toxicities.

Choy et al reported results of a
phase I trial of weekly irinotecan 30
to 50 mg/m2 and concurrent radiotherapy
for unresectable stage III
NSCLC.[51] The response rate was
58% among 13 treated patients. Nau
sea, vomiting, and esophagitis were
the major toxicities. The maximum
tolerated dose of concurrent chest radiation
therapy and irinotecan was
40 mg/m2 weekly for 6 weeks.

Kodoh and colleagues also performed
a phase I/II trial of irinotecan
and concurrent thoracic radiotherapy
in locally advanced NSCLC.[52]
The maximum tolerated dose was
60 mg/m2 with dose-limiting toxicities
of esophagitis, pneumonitis, and
diarrhea.

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