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Gastrointestinal Toxicity of Irinotecan

Gastrointestinal Toxicity of Irinotecan

ABSTRACT: Irinotecan (CPT-11 [Camptosar]) is an important new chemotherapeutic drug that demonstrates activity against a broad spectrum of malignancies, including carcinomas of the colon, stomach, and lung. Unfortunately, frequent and often severe gastrointestinal toxicities, particularly diarrhea, have limited its more widespread use. A cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity by irinotecan is frequently seen within the first 24 hours after irinotecan administration but is easily controlled with atropine. Late diarrhea occurs in the majority of patients, however, and is National Cancer Institute (NCI) grade 3 or 4 in up to 40%. The late syndrome appears to be related to the effects on the bowel of SN-38, the active metabolite of irinotecan, which undergoes biliary excretion and inactivation. Early recognition and treatment of late diarrhea with high-dose loperamide have reduced, although not entirely eliminated, patient morbidity. Further study is needed to identify the mechanism of irinotecan-induced late diarrhea and to evaluate potential new therapies. [ONCOLOGY 12(Suppl 6):73-78, 1998]

Introduction

Irinotecan (CPT-11 [Camptosar]) is an important new drug in the
chemotherapeutic armamentarium. Irinotecan is active against a broad
spectrum of malignancies, including carcinomas of the colon, stomach,
and lung. Unfortunately, frequent and often severe gastrointestinal
toxicities, particularly diarrhea, have limited its more widespread use.

Clinical observations, preclinical models, and pharmacokinetic
studies have yielded some critical insights into the pathophysiology
of these side effects. Early recognition and treatment of these
toxicities have resulted in a reduction in patient morbidity. Despite
these new pathophysiologic insights and advances in treatment,
gastrointestinal toxicities remain a major problem with the clinical
use of irinotecan. The gastrointestinal side effects of irinotecan
administration can be divided into two distinct syndromes: early and late.

Early Diarrhea/Cholinergic Syndrome

Early toxicity occurs within the first 24 hours of irinotecan
administration and is characterized by diarrhea, emesis, diaphoresis,
abdominal cramping, and, less commonly, hyperlacrimation and
rhinorrhea.[1] Various components of the syndrome have been reported
in up to 80% of patients receiving the drug.[2,3]

The spectrum of symptoms appears to be dose-related. Patients who
receive lower doses experience abdominal cramping, diarrhea, and
diaphoresis, while those given over 300 mg/m2 also
complain of salivation, hyperlacrimation, and visual changes.[4] In a
study of patients treated with 250 mg/m2 of irinotecan
every 2 weeks, Petit et al found that most symptoms occurred within
the first 2 hours, and median duration was approximately 30 minutes.[5]

The constellation of early symptoms is consistent with cholinergic
hyperstimulation. Irinotecan has been shown to mimic the effects of
acetylcholine in various in vitro preparations.[6] This action is
mediated by inhibition of acetylcholinesterase and, perhaps less
importantly, by direct binding to and stimulation of muscarinic
receptors (Figure 1).[7]

In both animal models and humans, symptoms are inhibited by
administration of the anticholinergic drug atropine.[8] Atropine as
needed is now routinely used in patients treated with irinotecan, and
the incidence of cholinergic symptoms severe enough to interfere with
treatment is quite low. In the series of Petit et al, the use of
atropine was required in 34% of patients, and only one case of grade
3 early diarrhea occurred despite the use of a relatively high dose
of irinotecan.[5]

Late Diarrhea

In contrast to early diarrhea, late diarrhea, defined as that
occurring more than 24 hours after irinotecan administration, is a
common and often serious and dose-limiting side effect. Although
usually controllable with nonspecific and supportive measures, late
diarrhea can be particularly dangerous in elderly or debilitated
patients who experience other toxicities, such as neutropenia.[1]

Incidence

The overall incidence of late diarrhea in most US and European phase
I and II trials of irinotecan ranges from 60% to 87% and appears to
be dose-dependent.[1,9-11] The incidence of severe (National Cancer
Institute [NCI] grade 3 or 4) diarrhea in these studies varies from
20% to 40%.[1,9-12] The incidence in Japanese studies is somewhat
lower; however, most of these studies used less intensive dosing regimens.[13]

Timing

The onset and duration of late diarrhea may vary with the dosing
schedule. In European studies in which patients received 350 mg/m2
every 3 weeks, the median time to onset was 5 days and the median
duration was 5 days.[11] In the pivotal American trials, in which
patients received 125 mg/m2/wk for 4 out of 6 weeks, the
median time to onset was 11 days, and the median duration was 2 days (Figure
2
).[14]

Predisposing Factors

Identification of patient characteristics that predispose to diarrhea
may allow for the identification of patients who require close
monitoring and early treatment. Unfortunately, this approach has not
proven to be clinically useful.

In European studies, age older than 65 years, prior pelvic
irradiation, and low performance status were significantly associated
with an increased incidence of severe diarrhea.[1,3,11] In American
studies, however, the results are conflicting. Von Hoff reported that ³
65 years was a risk factor for grade 3/4 diarrhea,[14] whereas Pazdur
found no significant increase in these patients.[12] Schaaf et al
uncovered no differences in irinotecan pharmacokinetics between
patients older and younger than 65 years of age.[15]

Etiology

In normal states, intestinal fluids remain in homeostasis,
maintaining a finely regulated balance between fluid secretion and
absorption. The intestines receive 8 to 9 L of ingested and secreted
fluids each day and absorb all but 100 to 200 mL.[16] Alteration of
this balance by increased secretion or reduced absorption may result
in the clinical symptom of diarrhea.

One potential mechanism by which drugs may induce diarrhea is direct
damage to the intestinal epithelium. The resulting denuded mucosa is
leaky and unable to absorb fluid. This is the probable mechanism of
fluorouracil-induced diarrhea, which results from diffuse mucosal
injury.[17,18] Alternatively, compounds may increase secretion or
decrease absorption of fluid by intestinal epithelial cells.[16]

Irinotecan Pharmacology and Metabolism--Clues to the etiology
of irinotecan-induced late diarrhea may be found in the complex
pharmacology and metabolism of the drug (Figure
3
). Irinotecan is a prodrug that is converted to an active form, SN-38,
by carboxyl-esterases, which in humans are found predominantly in
the liver.[19-21] The SN-38 metabolite is 250 to 1,000 times as
potent an inhibitor of topoisomerase I as irinotecan.[22]

Inhibition of topoisomerase I, which correlates with antitumor
activity, results in the formation of cleavable complexes in DNA,
which induce strand breaks.[23] This DNA damage is thought to lead to
cell death by apoptosis,[24] which may be mediated through the
interleukin-1 beta-converting enzyme (ICE) pathway.[25] Both
irinotecan and SN-38 require an intact lactone ring for topoisomerase
I inhibition. They are inactivated by pH-dependent hydrolysis of the
ring to the hydroxy acid.[22,26]

SN-38 is further metabolized by glucuronidation to SN-38 glucuronide
(SN-38G), which is inactive.[27,28]. Glucuronidation is specifically
performed by the UGT*1.1 isoform of hepatic uridine diphosphate
glucuronosyltransferase,[29] which also glucur- onidates bilirubin
and is deficient in Gilbert’s syndrome.[30] The SN-38G
metabolite can also be deconjugated back to SN-38 in the gut by
bacterial glucuronidases, which may result in increased exposure of
the intestinal epithelium to toxic products. Takasuna et al found a
correlation between intestinal bacterial beta-glucuronidase activity
and the site of epithelial damage in rats exposed to irinotecan.[31]

Biliary excretion is an important mechanism in the elimination of
irinotecan and its metabolites, with 25%, 2%, and 1% of a dose
excreted in the bile as irinotecan, SN-38G, and SN-38,
respectively.[32] Levels of irinotecan and SN-38 in the bile are up
to 113- and 40-fold higher than levels in plasma.[33] Normal
excretion of these compounds into the bile is via the canalicular
multispecific organic anion transporter (cMOAT), as well as other
less-well characterized transporters.[34,35] Treatment with
cyclosporine (Neoral, Sandimmune), which decreases biliary flow and
inhibits MOAT, increases the areas under the curve (AUCs) of
irinotecan, SN-38, and SN-38G severalfold.[36]

The relationship between the pharmacokinetics of irinotecan and its
metabolites and diarrhea is also quite complex. Both the parent
compound and metabolites undergo enterohepatic circulation, and the
concentration of SN-38 has been correlated with diarrhea in mice[37]
and in humans.[10,38,39] Ratain’s group found that a calculated
biliary index [AUCCPT-11 × (AUCSN-38/AUCSN-38G)]
was predictive of diarrhea.[40,41] However, Conti et al did not find
the biliary index or other pharmacokinetic parameters to correlate
with diarrhea in patients dosed with irinotecan weekly.[10] The
clinical usefulness of any of these measures is limited by the large
overlap between putative high- and low-risk groups. Wasserman et al
reported severe irinotecan toxicity in two patients with
Gilbert’s syndrome, in which glucuronida- tion is deficient.[42]
This finding indicates the importance of glucuronidation in the
detoxification of irinotecan and its metabolites. Patients with
Gilbert’s syndrome, which may be found in up to 6% of the
general population,[43-45] may constitute a group at high risk for
late diarrhea.

In rats, treatment with valproic acid, which competes for
glucuronidation with SN-38, reduced SN-38G by 99% and increased the
AUC of SN-38 by 270%.[46] Phenobarbital, an inducer of
glucuronidation, increased the AUC of SN-38G while decreasing the
AUCs of irinotecan and SN-38.[46]

Unresolved Questions--Several questions remain, however: Why
is the gastrointestinal tract preferentially affected by irinotecan
or its metabolites, and by what mechanism do they induce diarrhea?
The excretion of biliary irinotecan and SN-38 may expose the
intestinal mucosa to high levels of the compound responsible for late diarrhea.

Further investigation of late diarrhea has been hampered by the lack
of a pathologic correlation with symptoms. There have been several
animal studies revealing bowel injury,[31,47] but no comparable human
reports, though human studies are under way. Ikuno et al reported
that mice treated with irinotecan exhibited intestinal wall thinning
with epithelial vacuolation, vascular dilatation, and an inflammatory
cell infiltrate. There was evidence of apoptosis in the ileum, as
well as epithelial cell hyperplasia with goblet cell metaplasia in
the cecum.[47]

Interspecies variation may exist with respect to susceptibility to
irinotecan toxicity. Guffroy and Hodge observed villous atrophy in
the small intestine but not cecal lesions in their mouse studies.[48]
Takasuna et al found characteristic intestinal changes that appeared
in a time-dependent fashion in rats treated with irinotecan. Gross
thinning of both the intestines and cecum was seen. Histologically,
there was cell death and apoptosis with crypt dropout, followed by
the development of severe submucosal edema and an inflammatory infiltrate.[31]

These results indicate that, at least in these models, diarrhea may
result from a direct toxic action of irinotecan on the intestinal
mucosa. One small human study of irinotecan-induced late diarrhea,
reported in abstract form only, found normal d-xylose absorption,
indicating a relatively intact intestinal mucosa[49] but increased
clearance of alpha-1-antitrypsin, which is associated with
protein-losing enteropathy.[50]

Other Effects of Irinotecan and Its Metabolites on the Intestinal Mucosa--Irinotecan
and its metabolites may have additional effects on the intestinal
mucosa that may induce diarrhea. In the normal intestine, secretion
of fluid is driven by active secretion of chloride.[51] Chloride is
actively transported into the cell across the basolateral membrane by
the Na+:K+:2Cl- cotransporter and then exits
the cell via chloride channels along an electrochemical gradient.

In the rat, Sakai et al demonstrated that colonic chloride secretion,
as measured with Ussing chambers as a short-circuit current, is
stimulated by irinotecan.[52] This stimulation is mimicked by stable
analogs of the unstable thromboxane A2 and is blocked by
inhibitors of cyclooxygenase, thromboxane synthase, and thromboxane A2
receptors.[53] Our unpublished data show that SN-38 stimulates the
short-circuit current in human colonic mucosa, indicating that a
metabolite of irinotecan can induce chloride secretion. This effect
is abrogated by cyclooxygenase inhibition.

Irinotecan may induce inflammation and intestinal secretion by
paracrine mechanisms as well. Exposure of both mouse and human
mononuclear cells to irinotecan induces secretion of tumor necrosis
factor (TNF).[54] Expression of TNF is associated with AIDS-related
diarrhea and induces chloride secretion in colonocytes.[55] Tumor
necrosis factor also induces inflammation and may be important in the
pathogenesis of inflammatory conditions, such as Crohn’s disease.[56]

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