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Irinotecan and Radiation in Combined-Modality Therapy for Solid Tumors

Irinotecan and Radiation in Combined-Modality Therapy for Solid Tumors

ABSTRACT: Irinotecan (CPT-11, Camptosar) is a camptothecin derivative that is thought to exert its cytotoxic effects by targeting topoisomerase I. It is believed that irinotecan stabilizes a DNA-topoisomerase I cleavable complex, and that interactions between this complex and the replication machinery may lead to cell death. There is a significant volume of in vitro and in vivo data demonstrating that irinotecan acts as a radiosensitizer. The exact mechanism of this radiosensitization is currently unknown. The increasing amount of data demonstrating improved outcomes with concurrent chemoradiation treatment of malignancies like lung cancer and head and neck cancer provide impetus for pursuing the addition of other drugs as radiosensitizers to improve local control further. Irinotecan is undergoing early clinical trials in the combined-modality setting in several disease sites. This article will provide an overview of the current status of irinotecan used concurrently with radiotherapy in the treatment of a variety of solid tumors. [ONCOLOGY 15(Suppl 8):22-28, 2001]

Introduction

Solid tumors account for the majority of all malignancies and are
responsible for a large proportion of deaths in the industrialized world. In the
United States in the year 2001, 1,268,000 new cases of invasive cancer will be
diagnosed and 553,400 Americans are expected to die from their cancers.[1] While
currently about half of all patients are cured, the other 50% will die of their
disease.[1] Current treatments are based on one of three modalities: surgery,
radiation, or chemotherapy. Surgical treatments often fail because either the
tumor recurs in the tumor bed, since an insufficient margin of normal tissue was
removed in order to preserve function and cosmesis, or distant metastases
develop. Radiation treatments fail because distant metastatic disease develops
or the dose required to sterilize the tumor is limited by the surrounding normal
tissues, and the tumor recurs locally. Chemotherapy tends to have less of a
curative effect on gross disease but may be able to decrease the risk of distant
relapse when administered in an adjuvant setting.

More traditional treatments like cisplatin (Platinol) and
doxorubicin are now being joined by a new generation of drugs active against a
broad range of solid tumors. These new agents—including paclitaxel (Taxol),
docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), irinotecan
(CPT-11, Camptosar), and others—are associated with promising response rates
of 20% to 50% in the setting of metastatic disease.[2] It is hoped that these
agents may improve outcomes
in patients with earlier-stage disease
as well.

Multiple Treatment Modalities

Modern clinical trials are focusing more on integrating multiple
treatment modalities to maximize outcomes. Steele and Peckham outlined several
mechanisms for the possible interaction of radiation and chemotherapies: spatial
cooperation, enhancement of tumor response, radioprotection, and nonoverlapping
toxicities (or toxicity independence).[3] Spatial cooperation describes a
situation in which disease located in a specific anatomic site is missed by one
agent but treated by another. Enhancement occurs when the administration of one
agent 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 administration of a chemotherapeutic agent that allows
for safe delivery of increased radiation.

Ample literature exists on the ability of different drugs to
enhance radiation effect when the two modalities are delivered concurrently.
This article will provide an overview of concurrent administration of irinotecan
and radiation to patients with solid tumors, with a focus on irinotecan’s
mechanism of action, its radiosensitizing effects, and current clinical trials
evaluating concurrent irinotecan and radiation.

Camptothecins

Background and Mechanism of Activity

Irinotecan is a member of a relatively new group of anticancer
agents, the camptothecins, whose activity is believed to be achieved by
targeting DNA topoisomerase I.[4-7] The human DNA topoisomerase I is a monomeric
100-kDa protein that relaxes supercoiled DNA by introducing a single-strand
break in DNA, followed by the passing of the intact strand through the break
prior to re-ligation.[4-9] This activity is key in many aspects of DNA
metabolism, including transcription, replication, and regulation of DNA
supercoiling, which is important in maintaining genomic stability. It is
believed that the camptothecins function by stabilizing a topoisomerase I-DNA
intermediate, called the cleavable complex, such that the 5¢
phosphoryl end of
the DNA single-strand break is bound covalently to a topoisomerase I tyrosine
residue.[10] It is believed that collision of this drug-trapped complex with the
DNA replication machinery will lead to G2 phase cell-cycle arrest and cell
death.[10]

Camptothecin, the parent compound, was initially isolated from
the tree Camptotheca acuminata and found to have a broad spectrum of activity in
a variety of solid tumors.[11] However, early clinical trials with the ring-open
form of the drug showed excessive toxicity and the trials were terminated.[12]
More recently, interest has been rekindled in these drugs with the advent of
derivatives that have significant antitumor activity and much less toxicity.
Irinotecan, one of these derivatives, is actually a prodrug that is metabolized
intracellularly into
SN-38.[13] SN-38 is approximately 1,000 times more potent than irinotecan in
inhibiting topoisomerase I.[14] All of the camptothecins have a terminal lactone
ring that can be hydrolyzed to a less active carboxylate species. Under acidic
conditions, however, like those expected in the tumor microenvironment, the
active lactone species is favored.[13]

The plasma half-life of SN-38 by intravenous infusion is 5.9 to
13.8 hours,[13] and this may have implications in terms of both direct
cytotoxicity and radiosensitization. SN-38 is eliminated primarily through hepatic
glucuronidation and it is thought that a decreased ability to glucuronidate the
drug correlates with increased gastrointestinal side effects.[13] One of the
major side effects of irinotecan is late-onset diarrhea, which is possibly
related to the high S-phase fraction of the intestinal mucosa as well as action
of intestinal flora glucuronidase in cleaving the camptothecin-glucuronidase
conjugate, leading to the drug’s release into the intestinal lumen.[15] Other
common toxicities include neutropenia, nausea, vomiting, anorexia, fatigue,
asthenia, and elevation of hepatic transaminase levels.[13]

Several other camptothecin derivatives have been shown to have
significant cytotoxic effects and are at varying stages of development. These
include topotecan (Hycamtin),[16,17] 9-aminocamptothecin (9 A-C),[18] and
9-nitrocamptothecin (RFS-2000).[19] Of these, topotecan has undergone the most
extensive clinical testing; it is indicated for treatment of patients with
platinum-resistant ovarian cancer and small-cell lung cancer after failure of
first-line therapy.[16]

Irinotecan Activity

Response rates with irinotecan have ranged from 18% to 32% in
metastatic colorectal cancer,[20,21] 15% to 32% in non-small-cell lung
cancer,[22,23] and 10% to 47% in small-cell lung cancer.[24,25] It is also
active in other malignancies, including cervical, gastric, ovarian, and central
nervous system tumors.[13] While its activity in advanced disease is promising,
convincing evidence now indicates that the camptothecins—including irinotecan—have
significant radiosensitizing properties.[10,17] This discovery may potentially
lead to improved local control of solid tumors when irinotecan is used
concurrently with radiation. In the setting of localized and potentially curable
disease, it is hoped that this enhanced activity will translate into improved
survival.

Several hypotheses exist regarding the mechanism of interaction
between radiation and irinotecan, each with varying amounts of supportive
evidence. One hypothesis suggests that inhibition of topoisomerase I by
camptothecin or its derivatives leads to inhibition of repair of
radiation-induced DNA strand breaks.[18,26,27] A second hypothesis suggests that
camptothecin or its analogs causes redistribution of cells into the more radiosensitive G2 phase of the cell cycle.[28]

Another 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.[29-31] In essence, the
drug-stabilized cleavable complex, with a concealed single-strand DNA break, may
potentially act as a point of sublethal DNA damage. Interaction with cellular
processes like transcription and DNA repair may act to turn this
"potentially sublethal damage" into "sublethal damage." It
is possible that the addition of radiation may in turn change this
"sublethal damage" into "lethal damage."[10] It is also
suggested that high levels of topoisomerase I are associated with high levels of
cleavable complex formation.[32] These high enzyme levels have been documented
in several tumor specimens,[33] suggesting that irinotecan use may be beneficial
in improving the therapeutic ratio vis-à-vis normal tissue effects.

Johnson and McNerney initially reported in 1985 that
topoisomerase I activity increased by about 300-fold after irradiation of human
peripheral blood lymphocytes or cultured lymphoblastoid cells.[34] Other
investigators have not found any increase in activity.[34] This variance could
be related to the cell population or to the genomic location of the
topoisomerase pool under examination. The predominance of the particular
mechanism involved in radiosensitization may depend on which camptothecin
derivative is used; now, there is insufficient evidence to identify the
underlying mechanism with certainty.

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