REVIEW ARTICLE

Chemotherapy-Induced Diarrhea: Options for

Treatment and Prevention
Elizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

Background: Chemotherapy-induced diarrhea (CID) is a predictable yet undertreated side

effect of several frequently used chemotherapy agents and can lead to delays in treatment
and poor quality of life. Although the exact cause of CID is not completely understood, various
theories point to a multifactorial process resulting in an imbalance between the absorption
and the secretion of fluid in the gastrointestinal tract. Medications such as loperamide and
diphenoxylate plus atropine are frequently used along with nonpharmacologic measures to
treat mild CID.
Objectives: To discuss the currently recommended treatment for CID, as well as other
potential medications for the treatment and the prevention of CID. With the emergence of new
therapeutic alternatives for severe CID, an update of the current treatment options is warranted.
Discussion: Although guidelines exist for the treatment of CID, patient needs often exceed
these recommendations. Through different mechanisms of action, medications such as corti-
J Hematol Oncol Pharm. costeroids, antibiotics, glutamine, palifermin, and activated charcoal have been studied for the
2012;2(4):143-151. prevention of CID. For patients with treatment-resistant CID, small clinical trials suggest that
www.JHOPonline.com probiotics or octreotide long-acting release may be an effective alternative.
Disclosures are at end of text Conclusion: Further investigations should be conducted with promising therapies for validation
before being recommended for guideline inclusion for the treatment of CID.

D
iarrhea is a well-recognized side effect that is apy, leading to potentially worsened clinical outcomes.2
associated with various phases of a patient with A study by Arbuckle and colleagues demonstrated that
cancer’s treatment cycle. Radiotherapy, chemo- grades 1 and 2 diarrhea may lead to an alteration in che-
therapy, infection, and graft-versus-host disease can all motherapy for 11% of patients, whereas approximately
potentially augment this dose-limiting toxicity. Some 45% of patients experiencing any-grade CID required
regimens, especially those targeting colorectal cancer dose reduction in chemotherapy.3,4 Although it is well
(CRC) and other malignancies of the gastrointestinal known that CID can result in significant morbidity and
(GI) tract, are associated with an increased incidence mortality, no comprehensive treatment guidelines exist
of severe or refractory chemotherapy-induced diarrhea for historically used and newly evaluated medications for
(CID). In some studies, CID has been reported as a side the treatment of CID.
effect in up to 82% of patients with cancer, with up to
33% experiencing grades 3 and 4 diarrhea.1 GI toxicity Mechanism of Chemotherapy-Induced Diarrhea
has also been linked to many cases of death and is often The exact mechanism of CID is not completely
an underrecognized and undertreated complication of understood; however, various theories point to a multi-
chemotherapy.2 factorial process resulting in an imbalance between the
Severe diarrhea resulting in dehydration, neutro­ absorption and the secretion of fluid in the GI tract.5
penia, fever, malnutrition, renal insufficiency, infectious Other contributing factors, such as diet, concomitant
complications, or severe electrolyte imbalances can lead medications, and infectious complications, can en-
to hospitalization.2 The presence of CID can influence hance diarrhea in patients with cancer.4 The frequency
providers to change chemotherapy agents, reduce treat- of CID varies based on the chemotherapy regimen and
ment doses, delay therapy, or even to discontinue ther- on the administration schedule.

Dr Koselke is Hematology/Oncology Pharmacy Resident, and Mechanism of Fluorouracil-Induced Diarrhea

Dr Kraft is Hematology/Oncology Clinical Pharmacist and Up to 50% of patients treated with weekly 5-fluoro-
Clinical Assistant Professor, University of Michigan Hospitals uracil in combination with leucovorin experience CID.6
and Health Centers, Pharmacy Services, Ann Arbor, MI. Fluorouracil therapy results in mitotic arrest and apop-
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 REVIEW ARTICLE

Table 1 Common Terminology Criteria for Adverse Events for Diarrhea

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Increase of <4 stools Increase of 4-6 stools Increase of ≥7 stools Life-threatening Death
per day over baseline; per day over baseline; per day over baseline; consequences;
mild increase in moderate increase in incontinence; hospi- urgent intervention
ostomy output ostomy output com- talization indicated; indicated
compared with pared with baseline severe increase in
baseline ostomy output com-
pared with baseline;
limiting self-care
activities of daily life
Source: Reference 11.

tosis of the crypt cells in the GI tract.5 Necrosis of this Therapy with ipilimumab, a human monoclonal anti–
tissue enhances the imbalance of the ratio of immature cytotoxic T-lymphocyte antigen (CTLA)-4 antibody
secretory crypt cells to mature villus enterocytes.7 It also used for the treatment of metastatic melanoma, often
causes bowel wall inflammation, thereby stimulating results in GI and skin toxicities.9 Weber and colleagues
additional secretion of fluid and electrolytes into the estimated the incidence of grade 2 or greater diarrhea
intestinal lumen5 and significantly altering the osmotic between 32% and 35%.10 Blockade of CTLA-4 in the GI
gradient in the GI tract, which contributes to the in- tract causes dysregulation of the mucosal immune sys-
creased secretion of fluid into the stool.8 tem, resulting in colitis and diarrhea.9 This mechanism
of diarrhea is significantly different from fluorouracil or
Mechanism of Irinotecan-Induced Diarrhea irinotecan and is often not adequately treated with con-
Irinotecan, a cornerstone in the management of CRC, ventional therapies.
with a 2-pronged effect, can induce acute (within 24
hours) and delayed (2-14 days postadministration) diar- Assessment of Chemotherapy-Induced Diarrhea
rhea.6 Irinotecan is a prodrug converted into its active Currently, there is a lack of comprehensive standard-
form, SN-38, both of which are released into the feces by ized assessment methods for CID.5 The most frequently
hepatobiliary and intestinal secretions.4 SN-38 is inacti- used criteria for categorizing CID is the Common
vated in the liver to SN-38G. As it eventually reaches Terminology Criteria for Adverse Events, which assesses
the intestinal lumen, SN-38G is transformed back into patient symptoms on a scale of 1 to 5 (Table 1).8,11 CID
its active form by beta-glucuronidase, an enzyme secret- is classified into 2 categories, complicated and uncom-
ed by intestinal microflora, causing direct mucosal dam- plicated. Uncomplicated diarrhea is defined as patients
age and toxicity.4 Irinotecan also induces the production with grade 1 or 2 diarrhea and no additional signs or
of prostaglandin E2 and thromboxane A2, inflammatory symptoms. Complicated CID is classified by patients
cytokines, and tumor necrosis factor alpha, all causing with grade 3 or 4 diarrhea or patients with grade 1 or 2
additional mucosal damage.4 diarrhea and 1 additional risk factor, such as moderate-
to-severe cramping, grade 2 or greater nausea and vom-
Additional Drugs Causing Chemotherapy- iting, decreased performance status, fever, sepsis, neutro-
Induced Diarrhea penia, frank bleeding, or dehydration.
Other chemotherapeutic regimens have been associ-
ated with diarrhea, although at a considerably lower rate Guideline-Recommended Therapy for Uncomplicated
than either fluorouracil or irinotecan. Epidermal growth Chemotherapy-Induced Diarrhea
factor receptor (EGFR)-targeted therapies result in grade The last consensus conference for the management
3 or greater diarrhea in <10% of cases.6 Patients treated of CID was published in 1998,7 and the resulting guide-
with EGFR tyrosine kinase inhibitors (eg, erlotinib, gefi- lines were last updated in 2004.2 Loperamide, tincture of
tinib, or lapatinib) experience diarrhea in up to 60% of opium, and octreotide remain the only agents currently
cases, with grades 3 and 4 diarrhea occurring much less recommended by treatment guidelines, because of the
often.6 Unlike irinotecan- and fluorouracil-based regi- lack of data supporting other therapies for CID (Figure).2
mens, EGFR therapies rarely need to be dose-reduced as These guidelines recommend dietary modification,
a result of severe diarrhea.6 The mechanism of CID for along with loperamide (4 mg initially, followed by 2
these therapies has not been adequately investigated.6 mg every 4 hours or after every unformed stool), as the
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144 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2012 l Vol 2, No 4

 Chemotherapy-Induced Diarrhea

standard first-line therapy for the treatment of uncom-

Figure Proposed Algorithm: Primary Treatment
plicated CID (Table 2).2,4,12-21 Patients can discontinue
Options for Uncomplicated
loperamide therapy when they have been free of diar- Chemotherapy-Induced Diarrhea
rhea for at least 12 hours.2
If diarrhea persists for more than 24 hours, high-dose
loperamide (2 mg every 2 hours) is recognized as an appro- Uncomplicated CIDa
priate therapeutic option in addition to initiating oral an-
tibiotics for the prevention of infectious complications.2 Yes
If diarrhea persists for more than 48 hours with high- Patient received irinotecan? Atropine
dose loperamide therapy, loperamide should be stopped No
and a second-line treatment should be considered when
the patient is evaluated by a physician; options include Standard-dose loperamide
subcutaneous (SC) octreotide, tincture of opium, or oral
budesonide.2
Reassess 12-24 hours later;
CID unresolved (grades 1-2)
Loperamide
Loperamide, a synthetic opiate derivative, is the ini- Yes
tial drug of choice for CID; it has reduced the incidence Ipilimumab-induced CID? Consider steroids;
CID unresolved
of irinotecan-induced diarrhea from 80% to 9% in sev-
No
eral studies.5,8 Loperamide acts as an antidiarrheal agent
by exerting agonistic effects on opioid receptors in the High-dose loperamide
GI tract, resulting in decreased peristalsis and increased and/or
diphenoxylate/atropine combination
fluid reabsorption.5 Loperamide is minimally absorbed
and produces a limited side-effect profile.6 Although
rare, loperamide can cause a paralytic ileus, and patients Reassess 12-24 hours later;
should be routinely monitored while using high-dose CID unresolved (grades 1-2)
loperamide.5 Other side effects include abdominal pain,
dry mouth, drowsiness, and dizziness.4 Although loper­
amide has been proved to be extremely effective in Change to or add on:
diphenoxylate/atropine (if not done
uncomplicated diarrhea, its utility as monotherapy for before, or tincture of opium)
severe diarrhea is limited.8,22

Tincture of Opium Reassess 12-24 hours later;

Tincture of opium, like loperamide, works by slowing CID unresolved (grades 1-2)
GI peristalsis and increasing intestinal transit time.4 No
studies have specifically evaluated tincture of opium in
Consider changing to, or adding,
the treatment of CID; however, it is frequently used as an nonguideline-based therapies
antidiarrheal agent and can safely be used as a second-line
therapy for refractory diarrhea.4 Common side effects are
usually mild and include nausea and vomiting.4 a
For grade 3 or 4 (complicated CID), or for grades
1 and 2 CID with additional symptoms, the patient
Atropine should be medically evaluated.
In the treatment of irinotecan-induced, acute-onset CID indicates chemotherapy-induced diarrhea.
Note: This proposed algorithm is based, in part, on
diarrhea, atropine monotherapy works as a competitive Reference 2.
antagonist at anticholinergic receptors, typically dosed
as 0.25 to 1 mg intravenous (IV) or SC.4 Grades 1 to 4
and grades 3 to 4 acute-onset diarrhea are typically seen Diphenoxylate plus Atropine
in 51% and 8% of patients receiving irinotecan infu- There are little efficacy data supporting the use of
sions, respectively.12 In a study by Yumuk and colleagues, diphenoxylate plus atropine compared with loperamide
66 patients with metastatic CRC who received irinotec- for the treatment of CID8; however, one double-blind
an were premedicated with 0.5 mg of SC atropine before study comparing these agents suggests that loperamide is
their infusion. In a total of 444 infusions, acute-onset the more effective agent.7 In one study of 614 patients
diarrhea was not seen in any of these patients.12 who experienced acute diarrhea, the efficacy of lopera-
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 REVIEW ARTICLE

Table 2 Dosing Guidelines for Selected Medications

Medication Suggested dosing guidelines
Loperamide 4 mg orally initially, then 2 mg every 4 hrs or after every unformed
stool; can increase to 2 mg every 2 hrs if needed2
Deodorized tincture of opium (10 mg/mL) 10-15 drops in water orally every 3-4 hrs3
Atropine 0.25-1 mg IV or SC3
Diphenoxylate/atropine 1-2 tablets by mouth every 6-8 hrs3
Octreotide 100-150 mcg SC 3 times daily, or 25-50 mcg/hr by continuous
infusion4
Budesonide 9 mg by mouth daily, or 3 mg by mouth 3 times daily13,14
Glutamine 0.3 mg/kg IV daily, or 20 g by mouth daily15,16
Celecoxib 400 mg by mouth twice daily12
Octreotide LAR 30-40 mg SC every 28 days17
Probiotics (Lactobacillus rhamnosus GG) 1-2 × 1010 by mouth twice daily18
Activated charcoal 250 mg by mouth every 8 hrs19
Kampo medicine 7.5 mg by mouth 3 times daily20
Palifermin 40 mcg/kg IV daily21
IV indicates intravenous; LAR, Long-acting release; SC, subcutaneous.
Sources: References 2-4, 12-21.

mide was compared with diphenoxylate plus atropine.23 acetate (100-150 mcg 3 times daily).2 The octreotide
Patients were initially treated with loperamide 2 mg dose can be titrated until the symptoms of diarrhea are
or with diphenoxylate 2.5 mg plus atropine 0.025 mg under control.2 In addition, patients should receive flu-
and were instructed to take an additional tablet after ids and antibiotic therapy according to the guidelines.2
each unformed stool. Of patients in the loperamide Hospitalization is often required for patients who are
group, 42% required 2 to 3 tablets to control diarrhea, unable to be adequately rehydrated orally or those who
whereas 2 to 3 tablets of diphenoxylate plus atropine have other complicating symptoms.1 Antidiarrheal treat-
controlled diarrhea in only 23% of patients. Diarrhea ment should be continued until the patient is symptom
was controlled within 24 hours in 47% of patients in the free for at least 24 hours.2 Patients experiencing grade
loperamide group compared with 37% of patients in the 2 or greater diarrhea before a scheduled chemotherapy
diphenoxylate plus atropine group. In addition, within session should have treatment suspended until complete
the 72-hour study period, fewer tablets of loperamide symptom resolution for at least 24 hours.4
were required versus in the diphenoxylate plus atropine
group (4.37 vs 5.75 tablets; P = .01).23 Octreotide
Diphenoxylate plus atropine can be used in combina- Octreotide is a synthetic somatostatin analogue that
tion with loperamide for the treatment of grade 1 or 2 regulates intestinal fluid and electrolyte transport.24
diarrhea at a dosage of 1 to 2 tablets every 6 to 8 hours.4 Octreotide inhibits the secretion of hormones in the
Side effects include dry mouth, blurred vision, insomnia, gut, including serotonin, gastrin, insulin, and secretin.24
and dyspepsia.4 Through these mechanisms, octreotide increases GI tran­
sit time and reduces intestinal secretions.8 Numerous
Guideline-Recommended Therapy for Aggressive studies have displayed the effectiveness of short-acting
Chemotherapy-Induced Diarrhea SC octreotide for the treatment of CID.25 In a study by
Standard- or high-dose loperamide therapy is often Gebbia and colleagues, patients were treated with 500
unsuccessful in the treatment of aggressive (complicat- mcg of SC octreotide 3 times daily compared with oral
ed) CID in 9% to 30% of cases.7,22 Patients experiencing loperamide 4 mg 3 times daily in patients with grade 3 or
refractory grade 1 or 2 CID, as well as grade 3 or 4 CID 4 diarrhea.26 Complete resolution of diarrhea was seen in
can be treated more aggressively with SC octreotide 80% of patients receiving octreotide compared with only
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146 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2012 l Vol 2, No 4

 Chemotherapy-Induced Diarrhea

30% of patients treated with loperamide (P <.001).26 mg, given once daily for 3 to 5 days, starting the day of
A dosage of SC octreotide 100 to 150 mcg 3 times chemotherapy. Most patients saw a reduction in diarrhea
daily has been shown in clinical trials to reduce grades 3 within 24 to 48 hours.13 A second study evaluated the
and 4 CID by 60% to 95%.1 As of the last revision (in effects of budesonide (3 mg 3 times daily) in patients with
2004), the guidelines recommend a dose of 100 to 150 advanced CRC.14 Patients in the budesonide arm expe-
mcg of SC octreotide 3 times daily or 25 to 50 mcg hour- rienced a shorter duration (1.8 vs 4.2 days, respectively)
ly by continuous infusion.2 This dose can be increased up and fewer episodes (0.7 vs 2.2, respectively) of diarrhea
to 0.5 mg 3 times daily until diarrhea is under control.2 than patients receiving placebo. Patients treated with
A study by Goumas and colleagues evaluated 100 mcg budesonide also required fewer doses of loperamide (24.9
versus 500 mcg of SC octreotide in patients with grades vs 36.2 capsules, respectively). Although findings were
3 or 4 diarrhea after loperamide failure.27 Patients treated not statistically significant, a trend toward clinical im-
with 500 mcg had significantly more symptom control provement with budesonide therapy was demonstrated.14
than those treated with the 100-mcg dose (approxi- Budesonide prophylaxis has been studied in the pre-
mately 90% vs 61%, respectively; P <.05), with a similar vention of severe colitis, a common adverse effect of
side-effect profile.2 Drawbacks for the use of octreotide therapy with ipilimumab. However, Weber and col-
include the administration of SC injection and a high leagues found no difference between the treatment
cost profile.8 Side effects of SC octreotide include GI arms of ipilimumab plus budesonide or ipilimumab plus
symptoms and, rarely, injection-site reactions.4 placebo in patients with grade 2 or higher diarrhea (33%
vs 35%, respectively).10 Likewise, Berman and colleagues
Antibiotics demonstrated that prophylactic oral budesonide did not
Widespread inflammation and necrosis in the bowel prevent GI toxicity in patients undergoing treatment
predisposes patients to infections from opportunistic with ipilimumab.9 The authors theorized that the lack of
pathogens, especially if they are immunocompromised effect was a result of insufficient amounts of budesonide
or neutropenic.5 Increased epithelial permeability, as reaching the distal colon.9
well as a reduced immune system, enable microflora to
translocate out of the GI tract, predisposing patients to Corticosteroids in Ipilimumab-Induced Colitis
potential life-threatening gram-negative sepsis.4 The Although ipilimumab-associated colitis did not show
guidelines suggest the initiation of antibiotics for pa- response to prophylaxis with oral budesonide, response
tients who are experiencing diarrhea for more than 24 has been demonstrated with drug withdrawal and with
hours for the prevention of septic complications.2 An systemic steroid administration.9,28 In 676 patients who
oral fluoroquinolone, such as ciprofloxacin, for 7 days, were treated with ipilimumab for metastatic melanoma,
has been recommended by the Independent Panel for the most common immune-related adverse event was
Management of Chemotherapy-Induced Diarrhea.2,4 diarrhea, with up to 32% of patients experiencing any
grade of CID.29,30 Thirty-four patients experienced grade
Nonguideline-Based Therapies 3 to 5 enterocolitis.30 Of these patients, 29 (85%) were
Budesonide treated with high-dose corticosteroids (≥40-mg predni-
Budesonide, an oral, topically active synthetic gluco- sone equivalent daily), with a median dose of 80 mg daily
corticoid, provides anti-inflammatory activity within the of prednisone or an equivalent.29,30 Complete resolution
intestines.4,13 Historically, budesonide has been used as was seen in 74% of patients treated with steroids, 3%
an anti-inflammatory agent in the treatment of inflam- of patients improved to grade 2 severity, and 24% did
matory bowel disease (IBD). Of note, when patients with not improve their Common Toxicity Criteria (CTC)
irinotecan-induced diarrhea underwent colonoscopy, score.30 Ipilimumab’s package insert recommends the dis-
findings were similar to those seen in patients with IBD.13 continuation of therapy in patients experiencing severe
Budesonide decreases inflammation through the inhi- enterocolitis and the initiation of systemic corticosteroids
bition of mucosal prostaglandins within the intestines, at a dose of 1 to 2 mg/kg daily of prednisone or an equiv-
restoring mucosal function and leading to intestinal fluid alent.30 When CID improves to grade 1 or less, steroids
absorption.4 With a 90% first-pass effect in the liver, can be tapered over a duration of at least 1 month. Trials
budesonide presents an improved safety profile compared have shown that rapid steroid tapering can result in the
with traditional oral glucocorticoids.14 recurrence or the worsening of CID in some patients.30
In a study of 21 patients with loperamide-refractory
diarrhea, budesonide decreased the severity of grade 3-4 Glutamine
diarrhea by at least 2 grades in 86% of patients treated Glutamine, the most abundant amino acid in the
with irinotecan.13 The dosage studied in this trial was 9 body, serves as oxidative fuel for enterocytes.22 It is es-
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 REVIEW ARTICLE

sential for normal intestinal structure, and it enhances FOLFIRI or FOLFIRI plus celecoxib.33 Celecoxib was
nutrient transport in the GI tract.4 Over time, marked given continuously as a 400-mg twice-daily dose starting
glutamine depletion develops in patients with cancer, on the first day of chemotherapy.33 No significant toxicity
enhancing the incidence and the severity of diarrhea. It differences were seen between groups. Although preclini-
has been proposed that glutamine supplementation may cal trials suggest that celecoxib may be beneficial in alle-
aid in protecting the gut mucosa from toxic chemother- viating CID, human studies have yet to show significant
apeutic agents. benefit of adding celecoxib to traditional chemotherapy.
In a randomized, double-blind, crossover study, Li and
colleagues evaluated the prophylactic effect of glutamine Long-Acting Octreotide
in 54 patients with GI cancer.31 Patients were admin- In the GI tract, octreotide suppresses gastric emptying
istered 20 g of IV alanyl-glutamine dipeptide (0.3 g/kg and inhibits active chloride secretion in the small intes-
daily) on day 1 of chemotherapy and continued therapy tine, allowing for water and electrolyte reabsorption.25
for 5 days. Nausea and vomiting, as well as diarrhea, Octreotide long-acting release (LAR) is the intramus-
decreased significantly in patients treated with gluta- cular form of octreotide, which is slowly released over a
mine (P <.05). A 2001 study by Daniele and colleagues period of 4 to 6 weeks.25 A case series by Rosenoff and
demonstrated that 18 g of oral glutamine daily increased colleagues evaluated 3 patients with severe refractory
intestinal absorption (P = .02) and decreased intestinal diarrhea who were treated with 30 mg of octreotide
permeability (P = .04) to a greater extent than placebo LAR every 28 days.34 All 3 patients experienced prompt
in patients with CRC.16 Although the exact mechanism resolution of diarrhea, improved quality of life, and com-
and extent with regard to decreasing CID remain uncer- pletion of full-dose chemotherapy.34
tain, these studies have shown promise for patients with In regard to the dosing of octreotide LAR, data sup-
CID who are undergoing treatment for GI cancer.16,31 porting the use of 30-mg versus 40-mg dosing every 28
days has not been convincing.17 In the STOP trial, an
open-label, randomized multicenter study by Rosenoff
Octreotide is generally reserved as a and colleagues, 147 patients with active or previous CID
second-line treatment of CID after were randomized to receive 30 mg or 40 mg of octreotide
patients fail treatment with loperamide, LAR every 28 days.17 The primary end point was the pro-
portion of patients with grade 3 or 4 diarrhea during the
based on the increased drug cost of study period; secondary end points included the number
octreotide. Octreotide LAR could be of patients requiring IV fluids or changes in chemother-
apy dosage, as well as a quality-of-life survey.17 Although
considered for patients with refractory fewer patients in the 40-mg treatment group experienced
CID as a part of their CID management CID (48.4% vs 61.7% in the 30-mg group), differences
did not reach significance (P = .14); however, with both
when other alternatives fail. dosages, the amount of CID was reduced significantly,
because all patients experienced CID with previous
COX-2 Inhibitors cycles. The authors concluded that although octreotide
Clinical trials suggest that diarrhea may be induced LAR can be used safely and effectively for CID, no spe-
by the overproduction of thromboxane A and prosta- cific prophylactic dosing recommendations (30 mg vs 40
glandins in the GI tract.32 The body uses cyclooxygenase mg) can be made at this time.17 Octreotide is generally
(COX), an enzyme found in normal tissue, to convert reserved as a second-line treatment of CID after patients
arachidonic acid into prostaglandins.32 The prostaglan- fail treatment with loperamide, based on the increased
din PGE2 stimulates mucous and chloride secretion from drug cost of octreotide.6 Octreotide LAR could be con-
the epithelial cells in the colon, leading to significant sidered for patients with refractory CID as a part of their
diarrhea.22 In preclinical data, both COX-2 and PGE2 CID management when other alternatives fail.17
levels increased in a direct relationship to diarrhea inci-
dence in rats given irinotecan.22 In this trial, celecoxib, Probiotics
a COX-2 selective inhibitor, at doses of ≥10 mg/kg daily Probiotics, nonpathogenic microorganisms such as
was shown to reduce PGE2 levels, ameliorate diarrhea, Lactobacillus rhamnosus, Lactobacillus acidophilus, and
and reduce weight loss while enhancing the anticancer bifidobacterium, have been extensively studied in the pre-
effect of irinotecan.22 vention of diarrhea associated with irritable bowel syn-
However, in a study by Maiello and colleagues, 81 drome and Crohn’s disease.4,6 The possible mechanisms
patients with advanced CRC were randomized to receive of action include providing a protective physical barrier
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148 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2012 l Vol 2, No 4

 Chemotherapy-Induced Diarrhea

from infectious bacteria, degrading carcinogens, and pro- 1 and 2, respectively. The patients received 98% of their
ducing anti-inflammatory effects on the bowel mucosa.35 planned chemotherapy in the first cycle as opposed to
One clinical trial assessed the efficacy of Lactobacillus only 70% in the second cycle. Again, activated charcoal
rhamnosus GG in reducing fluorouracil-induced CID in was well tolerated and had excellent patient compliance.37
patients with CRC.18 L rhamnosus GG was administered In these 2 trials, prophylactic use of activated charcoal has
orally twice daily at a dosage of 1 to 2 × 1010 daily for shown decreased grades 3 and 4 diarrhea and loperamide
24 weeks. A significant reduction in grade 3 to 4 diar- use, while optimizing the amount of irinotecan that could
rhea (22% vs 37% in the control group, respectively; be administered.19,37 A phase 3, randomized controlled
P = .027) was seen with probiotic therapy.18 In addition, trial should be considered to validate these results.
decreased abdominal discomfort and fewer dosage reduc-
tions in chemotherapy were seen with the use of probi- Neomycin
otics.18 Immunocompromised patients should, however, Irinotecan-induced diarrhea is enhanced by the in-
be cautious of severe infections, such as sepsis, resulting testinal bacterial production of beta-glucuronidases,
from the use of probiotics.4 In that trial, no blood cul- causing the transformation of SN38-G into its active
tures from any of the patients grew Lactobacillus during form, SN-38.38 Several trials have evaluated the use of
the study period18; however, case reports have identified neomycin, a poorly absorbed aminoglycoside antibiot-
probiotics as a source of clinical bloodstream infections, ic, in its effect in treating CID through the reduction
especially in immunocompromised patients.36 of intestinal microflora.39 In patients with CRC who
are experiencing delayed-type diarrhea after their first
Activated Charcoal irinotecan cycle, 1000-mg neomycin 3 times daily was
Activated charcoal, an adsorbent, has been used in administered for 2 days before and for 5 days after their
the acute treatment of drug overdoses and poisonings.4 second cycle.39 Of the 7 patients in the trial, 5 expe-
Its use as a prophylactic CID agent presents mechanistic rienced no diarrhea after the second treatment course
potential, because it decreases enterohepatic cycling with neomycin (P = .03).39 Fecal cultures did not reveal
and increases SN-38 (irinotecan’s toxic form) clearance any neomycin-resistant or pathogenic microorganisms.
from the gut.6 A 2008 study by Sergio and colleagues In addition, neomycin did not alter the plasma kinetics
evaluated the use of activated charcoal prophylaxis in of SN-38 or irinotecan, and thus did not alter the effica-
children who were receiving a chemotherapy regimen cy of chemotherapy.39
of irinotecan plus either cisplatin plus doxorubicin (N Another study evaluated the combination of neomy-
= 20) or carboplatin (N = 2).19 Activated charcoal was cin 25,000 IU plus bacitracin 2500 IU dosed 1000 mg
given as a 250-mg capsule starting the evening before 3 times daily for days 2 to 5 and days 16 to 19 of each
chemotherapy and every 8 hours thereafter until the cycle.40 All 15 patients with diarrhea in the first cycle
end of the cycle.19 Loperamide was given at the onset of had complete resolution of diarrhea for cycles 2 to 4.40
diarrhea (2 mg every 2 hours). Twenty-eight events of Neomycin was also studied as a prophylactic regimen at
diarrhea were recorded, with a frequency of 28.88% in a dose of 660 mg 3 times daily for 3 days, starting 2 days
the activated charcoal group and 71.42% in the control before receiving irinotecan (350 mg/m2 once every 3
group (P = .002).19 Grade 3 diarrhea was significantly weeks).41 The overall incidence, severity, and duration
more frequent in the control group (42.85% vs 2.22%, of diarrhea were not statistically significant between
respectively). Children in the activated charcoal group the neomycin arm and placebo (P = .33); however,
completed their chemotherapy cycles more often, and neomycin did show a 45% lower incidence of grade 3
compliance was nearly doubled. No significant adverse delayed-onset diarrhea and a reduced duration of di-
events to activated charcoal were reported in this trial.19 arrhea by 0.9 days.41 The variation seen among trials
Michael and colleagues completed a similar study of could result from a difference in the treatment dose and
activated charcoal in adults.37 Patients received 5 mL of duration of neomycin.
aqueous Charcodote (1000 mg activated charcoal) plus
25 mL of water the evening before and subsequently every Cefpodoxime
8 hours for 48 hours postirinotecan chemotherapy during Despite the potential risk for antibiotic-induced di-
their first cycle.37 The patients then served as their own arrhea, a number of antibiotics have shown promise in
control, and they received no activated charcoal during decreasing the incidence and the severity of CID.4 The
their second cycle. Grade 3 to 4 diarrhea was present in third-generation cephalosporin, cefpodoxime, possess-
7.1% versus 25% of patients in cycles 1 and 2, respec- es the benefit of eliminating Escherichia coli, a known
tively. The use of loperamide increased to more than 10 beta-glucuronidase producer, while not eradicating the
tablets in 25% of patients and in 54% of patients in cycles anaerobes that are important for intestinal coloniza-
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Vol 2, No 4 l December 2012 www.JHOPonline.com l Journal of Hematology Oncology Pharmacy 149

 REVIEW ARTICLE

tion. A phase 1, prospective, pediatric study performed trial by Mori and colleagues was conducted to investigate
by McGregor and colleagues investigated if this oral if the administration of TJ-14 would prevent and control
cephalosporin would allow for the dose escalation of CID.20 The trial included 41 patients with advanced
irinotecan.42 In this study, 17 patients were treated with non–small-cell lung cancer who were treated with irino-
escalating levels of irinotecan starting at 20 mg/m2 per tecan and cisplatin.20 The patients in the treatment arm
dose, the previously established maximum tolerated were given TJ-14 at a dose of 7.5 g 3 times daily begin-
dose, for days 1 to 5 and days 8 to 12 of a 21-day course. ning more than 3 days before chemotherapy.20 Treatment
Cefpodoxime (10 mg/kg daily, divided twice daily) was with TJ-14 continued for a minimum of 21 days after
given to patients starting 2 days before chemotherapy the start of treatment with irinotecan plus cisplatin.20
and was continued as long as the patient was participat- Loperamide was administered to patients with severe di-
ing in the study.42 arrhea (grade ≥2). All but 2 patients (95%) in the TJ-14
This study demonstrated that with the addition of group experienced some grade of diarrhea; however, the
cefpodoxime, the maximum tolerated dose of irinote­ treatment arm did show an improved overall grade of
can could be increased to 30 mg/m2 per dose; however, diarrhea (P = .044) and a significantly lower incidence
diarrhea and diarrhea-associated dehydration remained of grades 3 and 4 diarrhea (P = .018).20 The frequency
the major dose-limiting toxicities when doses exceeded and duration of diarrhea between the groups showed no
30 mg/m2. Although prolonged administration of antibi- difference. The major side effect of TJ-14, constipation,
otics may have the ability to increase the incidence of occurred in 11% of patients.20
infections, none were demonstrated in this trial.42 Based
on these results, further trials with cefpodoxime in chil- Palifermin
dren and adults are warranted and are under way. Palifermin, a recombinant form of human keratino-
cyte growth factor (KGF), has been approved to reduce
Levofloxacin plus Cholestyramine the incidence and the duration of severe oral mucositis
Flieger and colleagues hypothesized that the combina- in patients with hematologic malignancies who are
tion of cholestyramine, a bile acid chelator that reduces receiving myelotoxic therapy that requires hemato-
enterohepatic recirculation, plus levofloxacin to inhibit poietic stem-cell support.46 The binding of KGF to its
beta-glucuronidase production would be beneficial in receptor results in the proliferation and differentiation
patients with CID.43 Of patients with colorectal adeno- of epithelial cells in multiple tissues, including the buc-
carcinoma, 51 were treated with levofloxacin 500 mg cal mucosa, esophagus, stomach, and small intestine.46
daily and cholestyramine 4 g 3 times daily beginning Gibson and colleagues tested the efficacy of palifermin
the day before irinotecan administration and continu- as an antidiarrheal agent in rats that were treated with
ing for 3 days thereafter. The treatment of acute-onset irinotecan chemotherapy.47 One large dose (10 mg/kg)
diarrhea and delayed-onset diarrhea with standard doses of palifermin was compared with multiple small doses (3
of atropine and loperamide, respectively, was offered if mg/kg daily for 3 days) or with placebo before adminis-
necessary. Of the total patients in this trial, 78% report- tration of chemotherapy. The animals receiving palifer-
ed no diarrhea. Only 22% of patients developed grade min prophylaxis had less severe diarrhea (single dose,
1 to 2 diarrhea, 2% developed grade 3 diarrhea, and no 5%; multiple dose, 11%; and placebo, 28%; P <.05) in
patients developed grade 4 diarrhea.43 This prospective addition to maintaining their body weight.47
study illustrated that intestinal microflora suppression in In a study by Rosen and colleagues, 64 patients with
combination with the reduction of enterohepatic recir- metastatic CRC being treated with fluorouracil plus
culation of active chemotherapy provides suppression of leucovorin were receiving palifermin (40 mcg/kg) for
diarrhea to well below the normal incidence of 40%.43 3 consecutive days before 2 chemotherapy cycles.21
In addition, the short duration of antibiotic therapy Although the incidence of severe mucositis in patients
supports a prompt recovery time of intestinal microflora, treated with palifermin was half that of the placebo
thereby decreasing potential adverse effects. control group (P = .016) and reduced the need for che-
motherapy dose reductions, the incidence of diarrhea
Kampo Medicine (Hangeshashin-To) did not differ between the groups.21 Grade 2 or higher
Hangeshashin-to (TJ-14) is a Chinese herbal product CTC was observed in 20% of patients receiving placebo
that is used in the treatment of acute gastroenteritis and and in 18% of patients receiving palifermin during cycle
that contains baicalin, a beta-glucuronidase inhibitor.44,45 1.21 The most common adverse reactions to palifermin
Based on same mechanistic theory proposed for the use of include skin toxicities (ie, rash, erythema) and oral
oral antibiotics, TJ-14 may reduce active SN-38 concen- toxicities (ie, reversible tongue thickening and tongue
trations in the intestine.44 A randomized, single-center discoloration and alteration in taste).46
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150 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2012 l Vol 2, No 4

 Chemotherapy-Induced Diarrhea

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20. Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of kampo medicine
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Dr Koselke and Dr Kraft reported no conflicts of interest. patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
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