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Irinotecan in Combined-Modality Therapy for Locally Advanced Non-Small-Cell Lung Cancer

Irinotecan in Combined-Modality Therapy for Locally Advanced Non-Small-Cell Lung Cancer

ABSTRACT: The management of non-small-cell lung cancer is undergoing rapid evolution. Although the advent of combined-modality therapy has led to improved survival, most patients eventually succumb to the disease. The arrival of a new generation of chemotherapeutic agents—including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar, CPT-11)—offers the hope of advances against this malignancy. Irinotecan, a camptothecin derivative, has shown impressive activity in a variety of solid tumors, including non-small-cell lung cancer. It is believed to act by stabilizing the topoisomerase-DNA complex formed during diverse cellular processes, including replication and transcription. A considerable body of evidence also demonstrates that camptothecin and its derivatives possess substantial radiosensitization properties. This article will review the in vitro and in vivo data on irinotecan’s ability to render tumors more susceptible to ionizing radiation. It will then focus on experience with irinotecan and thoracic radiation in the treatment of non-small-cell lung cancer, which has yielded acceptable toxicity results and response rates in excess of 60% in early trials. It is hoped that newer treatment strategies—such as the combination of radiation and irinotecan in lung cancer—will significantly impact cure rates in the future. [ONCOLOGY 15(Suppl 1):31-36, 2001]

Introduction

Lung cancer is the leading cause
of cancer-related morbidity and
mortality. The estimated incidences for the year 2000 are 164,100 new cases and
156,900 deaths in the United States alone.[1] Five-year survival figures for
lung cancer have remained in the 15% range from 1974 through 1995[1]; most of
these cures involve early cancers usually treated with surgery alone. However,
approximately 35% of patients present with locally advanced disease that is not
amenable to surgical therapy, but is nonetheless potentially curable.[2]
Tradition- al treatment with radiation alone in these patients has yielded low
cure rates. This has spurred investigations of new methods to improve outcome.

Peckham and Steele outlined several possible mechanisms of
interaction between radiation and chemotherapies: spatial cooperation,
enhancement of tumor response, radioprotection, and nonoverlapping toxicities
are all ways that chemotherapy and radiation may interact to improve therapeutic
ratio.[3] Spatial cooperation describes a situation where disease located in a
specific anatomic site is missed by one agent but treated by another.
Enhancement refers to the administration of an agent that increases the effect
of another agent, or when the effect of the combination is greater than would be
expected with either agent alone. Radioprotection refers to the administration
of a chemotherapeutic agent that would allow safe delivery of higher radiation
doses.

Finally, toxicity independence, or nonoverlapping toxicities,
describes when two partially effective agents can be used in combination without
having to substantially reduce dose levels to avoid unacceptable side effects.
Multiple phase III trials have shown benefits with the combined use of
chemotherapy and radiation in the treatment of non-small-cell lung cancer at
the expense of increased toxicity.[4-7] Overall, the meta-analysis from
Pritchard et al suggests that traditional chemotherapy added to radiotherapy
adds an average of 2 months to patient survival.[8]

Several new active agents that hold promise for improving
outcome in lung cancer patients are emerging. These include paclitaxel (Taxol),
docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), and
irinotecan (Camptosar, CPT-11), which have demonstrated response rates ranging
from 20% to 54% as single agents in metastatic disease.[2] Finding a cure for
this disease will require a better understanding of the mechanisms of action of
these agents and their interactions with ionizing radiation, and the proper
sequencing of these agents with other drugs and with radiation. This article
will review the literature on the use of irinotecan in combination with thoracic
irradition in the treatment of non-small-cell lung cancer.

Mechanism of Camptothecin Activity

Camptothecin and its derivatives target DNA topoisomerase I, the
DNA-relaxing enzyme.[9-12] This enzyme relaxes both positively and negatively
supercoiled DNA, which allows diverse essential cellular processes, including
DNA replication and transcription, to proceed. The key step for drug activity is
stabilization of the topoisomerase I-DNA intermediate that the enzyme forms
when cleaving DNA to allow for uncoiling to occur.[9-14] It is believed that
collision between the drug-trapped topoisomerase-DNA complex and the replication
material leads to G2-phase cell-cycle arrest and, ultimately, cell death.[15]

Camptothecin is the prototype drug that was initially studied in
the 1970s as a chemotherapeutic agent; however, its use was discontinued because
of excessive toxicity.[16] Ongoing research has begun to focus on camptothecin
derivatives that have antineoplastic activity with improved toxicity profiles.
This generation of drugs includes irinotecan. Irinotecan is a prodrug that is
metabolized intracellularly to its active metabolite, SN-38, by a
carboxylesterase- converting enzyme.[17] This metabolite is more than 1,000
times more potent than irinotecan as an inhibitor of topoisomerase I.[18] All of
the camptothecins have a terminal lactone ring that can be hydrolyzed to a less
active carboxylate species. Under acidic conditions, however, like that in the
tumor microenvironment, the active lactone species is favored.[17]

The plasma half-life of SN-38 after a short IV infusion is 10.2
hours (range: 5.9 to 13.8 hours), so that nanomolar concentrations of the drug
persist for more than 2 days.[17] This may affect its cytotoxicity. The major
method of elimination of SN-38 is hepatic glucuronidation; a decreased ability
to glucuronidate is thought possibly to correlate with increased
gastrointestinal side effects. Clinically, the dose-limiting toxicity of
irinotecan is delayed-onset diarrhea, which can be profuse and potentially life
threatening. The diarrhea is thought to be related to the 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
release of the drug in the intestinal lumen.[19] Other common toxicities include
neutropenia, nausea, and vomiting.

Interaction of Camptothecin and Radiation Therapy

In planning combined-modality chemoradiotherapy, it is important
to understand the mechanism of interaction between the two modalities. Several
investigators have reported that camptothecin enhances the cytotoxic effect of
radiation in vitro and in vivo.[20,21] Omura et al assessed the radiosensitizing
effects of SN-38 in HT-29 spheroids derived from a human colon cancer cell line.
Results showed significantly enhanced cell kill with combined radiation and
irinotecan; the largest gains in cytotoxicity occurred when irinotecan was
administered just before or just after the radiation. The data also suggest that
the mechanism of radiosensitization in the spheroids is through inhibition of
potentially lethal damage repair.[22]

Chen et al showed that camptothecin derivatives radiosensitized
log-phased human MCF-7 breast cancer cells in a schedule-dependent manner.
Essentially, cells exposed to 20(S)-10,11 methylenedioxycamptothecin before or
during radiation had sensitization ratios of 1.6, while those treated with the
drug after radiation had substantially less enhancement of radiation-induced DNA
damage.[23] The clinical implication of these results is that patients should be
treated with camptothecin derivative-based chemotherapy prior to or during
radiotherapy to receive the full benefits of combined-modality therapy. Emerging
data also show that other camptothecin derivatives—including 9-nitro-
20(S)-camptothecin,[24] 9-aminocamptothecin,[25] and topotecan (Hycamtin)[26]—can
potentiate the lethal effects of radiation.

There are several hypotheses, with varying amounts of supportive
evidence, regarding the mechanism of interaction between radiation and
irinotecan. The first hypothesis suggests that inhibition of topoisomerase I by
camptothecin or its derivatives leads to inhibition of repair of
radiation-induced DNA strand breaks. The second hypothesis suggests that
camptothecin or its analogs causes redistribution of cells into the more
radiosensitive G2 phase of the cell cycle. The third hypothesis is that
topoisomerase I-DNA adducts are trapped by irinotecan at the sites of
radiation-induced single-strand breaks, leading to their conversion into
double-strand breaks.[24] The primary mechanism involved with radiosensitization
may depend on which camptothecin derivative is being used; there is currently
insufficient evidence to identify the underlying mechanism with certainty.

Irinotecan in Combined-Modality Therapy

Combined-modality treatment relies on the ability of focused
radiation and concurrent radiosensitizing agents to treat locally, while leaving
the potential micrometastatic disease for chemotherapy to control. As such, it
is also important to maximize the cytotoxic effects of chemotherapy while
minimizing toxicities. This requires an understanding of the mechanisms of
interaction between different drugs. Basic principles used in selecting drugs
include nonoverlapping toxicities, differing mechanisms of action, and non-cross-
resistance.[27] Based on these criteria, both preclinical and clinical trials
have been undertaken to evaluate the cisplatin (Platinol)/irinotecan combination
in lung cancer.

In xenografts of the small-cell lung cancer tumor lines Mnsul
and LX1, Kudoh et al showed that irinotecan in combination with cisplatin led to
a larger reduction in tumor size than either agent alone.[20] However, in
xenografts of Mnqul, a cell line developed from human squamous cell lung
carcinoma, combination cisplatin/irinotecan treatment was more effective than
cisplatin alone but not more effective than irinotecan alone. According to the
authors, the data clearly suggest that the combination of radiation and
irinotecan should be effective in small-cell lung cancer; however, they
cautioned that more data are needed, using a different non-small-cell lung
cancer model, prior to concluding that the combination is better than irinotecan
alone.

In patients with advanced lung cancer, early studies using
irinotecan alone have yielded favorable response rates (> 30%).[28] The
combination of irinotecan and cisplatin has also been assessed in phase I and II
clinical trials; early data from phase II studies revealed a 48% response rate
in non-small-cell lung cancer[29] and 78% in small-cell lung cancer.[30] A
subsequent phase I trial looked at fractionation of both the cisplatin and
irinotecan doses, ie, 60 mg/m2 of cisplatin and escalating doses of irinotecan
were given on days 1 and 8. Cycles were repeated every 4 weeks. An impressive
78% response rate was seen in 18 patients with non-small-cell lung cancer.[31]
A North American phase II trial examined 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.[32] The irinotecan dose was ultimately modified to less than 40
mg/m2; the response rate was 28.8% in 52 patients.

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