The document discusses the adverse gastrointestinal effects of chemotherapy, particularly focusing on diarrhea caused by agents like fluoropyrimidines and irinotecan. It outlines the mechanisms of toxicity, risk factors associated with increased severity, and treatment options for patients experiencing chemotherapy-induced diarrhea (CID). Additionally, it covers strategies to manage chemotherapy-induced nausea and vomiting (CINV), including the use of 5-HT3 receptor antagonists and NK1 receptor antagonists, highlighting the importance of tailored treatment approaches based on individual patient risk factors.

1. Chemotherapy adverse effect
By : Somayyeh Nasiripour,Pharm.D
Baord of clinical pharmacy

2. Enterotoxicity of
chemotherapeutic agents

3. GI) toxicity due to chemotherapeutic drugs is a
common problem in cancer patien
include diarrhea, constipation, colitis
(neutropenic, C. difficile-induced, and immune-
mediated), and intestinal perforation

4. DIARRHEA

5. most commonly described with fluoropyrimidines
(particularly 5-fluorouracil [5-FU] and capecitabine )
and irinotecan
dose-limiting and major toxicity of regimens
containing a fluoropyrimidine with or without
irinotecan.
Both 5-FU and irinotecan cause acute damage to the
intestinal mucosa, leading to loss of epithelium

6. With irinotecan , early onset diarrhea occurs during or within several hours of drug infusion in
45 to 50 percent of patients and is cholinergically mediated
This effect is thought to be due to structural similarity of the drug with acetylcholine
In contrast, late irinotecan-associated diarrhea is not cholinergically mediated. The
pathophysiology of late diarrhea appears to be multifactorial with contributions from
dysmotility and secretory factors as well as a direct toxic effect on the intestinal mucosa
These changes appear related to the accumulation of the active metabolite of irinotecan, SN-
38, in the intestinal mucosa
SN-38 is glucuronidated in the liver and is then excreted in the bile
A direct correlation has been noted between mucosal damage and either low glucuronidation
rates or increased intestinal beta-glucuronidase activity
Severe toxicity has been described with irinotecan in patients with Gilbert's syndrome who
have defective hepatic glucuronidation
experimental studies have shown that inhibition of intestinal beta-glucuronidase activity with
antibiotics protects against mucosal injury and ameliorates the diarrhea

7. Clinical manifestations
can be debilitating and in some cases, life-threatening.
Findings in such patients include volume depletion, renal insufficiency, and
electrolyte disorders such as hypokalemia, metabolic acidosis, and
depending upon water intake, hyponatremia (increased water intake that
cannot be excreted because of the hypovolemic stimulus to the release of
antidiuretic hormone) or hypernatremia (insufficient water intake to
replace losses).
CID can also lead to treatment delays, increased cost of care, reduced
quality of life, and diminished compliance with treatment regimens.

8. 5-Fluorouracil
5-FU (and its oral derivatives capecitabine , cause diarrhea
Both the therapeutic efficacy and frequency of diarrhea associated with 5-FU
are increased when given with leucovorin (LV).
The highest frequency of diarrhea occurs with bolus rather than continuous
24-hour infusion of 5-FU/LV for up to five days, particularly with weekly
administration,
but it occurs with all schedules
In multiple reports of weekly 5-FU/LV, diarrhea has been seen in up to 50
percent of patients, one-half of whom required hospitalization for
intravenous fluids
treatment is routinely withheld for > grade 2 diarrhea, an approach that has
led to a significant reduction in severe enterotoxicity with these regimens

9. risk factor
the presence of an unresected primary tumor,
shortened bowel resulting from pervious surgery,
previous episodes of CID
, treatment during the summer season
bolus 5-FU and LV are combined with oxaliplatin
Women

10. Predictive markers
• Because early detection of patients who are at risk of developing life-
threatening toxicity to 5-FU might allow dose reduction or selection of an
alternative treatment regimen, various genotypic and phenotypic
approaches have been undertaken to predict toxicity.
• None has proven to be sufficiently reliable to be adopted in routine
clinical care.
• Dihydropyrimidine dehydrogenase (DPD), the first of three enzymes in the
fluoropyrimidine metabolic pathway, is the rate limiting enzyme in 5-FU
catabolism
• Patients who are partially or totally deficient in DPD activity cannot
adequately degrade fluoropyrimidines, leading to an increased risk of
severe, sometimes fatal toxicity.
• In patients with even partial DPD deficiency, administration of a
fluoropyrimidine can lead to life-threatening complications, including
severe diarrhea, mucositis, and pancytopenia

11. Capecitabine
oral fluoropyrimidine that is converted to 5-FU in three sequential enzymatic
reactions.
The dose-limiting toxicities are diarrhea, palmar-plantar erythrodysesthesia, and
neutropenia.
Like 5-FU, capecitabine is contraindicated in patients with known DPD deficiency.
The initially approved dose for treatment of metastatic breast and colorectal cancer
was 2500 mg/m 2 per day for 14 of every 21 days, but later studies suggest that this
dose is too high, particularly in American patients.
Lower doses (beginning at 2000 mg/m 2 per day for 14 of every 21 days) may
improve the therapeutic index without compromising efficacy.

12. Irinotecan
•often accompanied by other symptoms of cholinergic excess,
including abdominal cramping, rhinitis, lacrimation, and salivation.
•The mean duration of symptoms is 30 minutes;
• it is usually well controlled by subcutaneous or IV atropine
Early-
onset
• unpredictable, noncumulative, and occurs at all dose leve
•late diarrhea and neutropenia were the main dose-limiting toxicities
Late
diarrhea
Diarrhea of any grade was seen in 50 to 88 percent of patients and it
was severe in 9 to 31 percent.
Diarrhea has been less common in later studies because of the stricter
adherence to management guidelines (including routine early
institution of high-dose loperamide

13. • The median time to onset is about six days
with the 350 mg/m 2 every three weeks
schedule
• 11 days with the weekly schedule (125 mg/m
2 )
• Late diarrhea is less common with the every
three week schedul

14. Treatment

15. • nonpharmacologic and pharmacologic interventions
• Initial nonpharmacologic measures include avoidance of
foods that would aggravate the diarrhea and aggressive
oral rehydration with fluids that contain water, salt, and
sugar (since glucose promotes intestinal sodium
absorption)
• The mainstay of the drug therapy of CID is the opiates.
Loperamide (Imodium) and diphenoxylate (Lomotil) are the
most commonly used, and both are FDA-approved for this
indication.
• Both give a rapid onset of action.
• Loperamide appears to be more effective and has been
recommended in treatment guidelines

17. • The standard dose of loperamide is an initial 4
mg dose followed by 2 mg every four hours or
after every loose stool. This regimen is only
moderately effective in CID
• more aggressive regimen (4 mg initially, then 2
mg every two hours or 4 mg every four hours
until diarrhea-free for 12 hours) is often
required, particularly for irinotecan -induced
diarrhea

19. Octreotide: a synthetic long-acting somatostatin
analog, acts via several mechanisms
decreased secretion of a number of hormones,
such as vasoactive intestinal peptide (VIP);
prolongation of intestinal transit time’
reduced secretion
increased absorption of fluid and electrolytes
It is approved by the Food and Drug
Administration for the treatment of diarrhea
related to VIP-secreting tumors and symptoms
due to carcinoid syndrome.

20. Octreotide is also beneficial in patients with CID from fluoropyrimidines, irinotecan , and 5-FU-based
chemoradiotherapy
although the optimal dose has not been determined
Although one randomized trial in 41 5-FU-treated patients showed that octreotide was more effective than
standard-dose loperamide (90 versus 15 percent resolution of diarrhea by day 3)
octreotide is generally reserved as a second-line therapy for patients who do not respond to high dose
loperamide because of its high cost and the general effectiveness of loperamide,
The recommended starting dose of octreotide is 100 to 150 microg subcutaneously, three times a day
However, several reports suggest that higher doses (500 microg) may be more effective
The available data support upward titration of the dose (up to 2500 microg three times daily) in
nonresponders
The side effects of octreotide are generally mild, including bloating, cramping, flatulence and fat
malabsorption. Hypersensitivity-like reactions and hypoglycemia can occur at higher doses.

21. Other antidiarrheal agents
Anticholinergic drugs are not
commonly used because of side
effects. However, they can be
helpful when diarrhea is associated
with significant cramping.
Absorbents (eg, pectin, aluminum
hydroxide ) and adsorbents (eg,
kaolin, charcoal) bind osmotically
active substances and can be
effective adjunctive therapy in
patients with mild diarrhea.

22. Prevention and treatment of
chemotherapy-induced nausea and
vomiting

23. Three distinct types of CINV have been
defined
Acute emesis, which most commonly begins
within one to two hours of chemotherapy and
usually peaks in the first four to six hours
Delayed emesis, occurring more than 24 hours
after chemotherapy
Anticipatory emesis, occurring prior to
treatment as a conditioned response in patients
who have developed significant nausea and
vomiting during previous cycles of chemotherapy

24. CHEMOTHERAPY DRUG
EMETOGENICITY
Highly emetic — >90 percent risk of emesis
Moderately emetic — >30 to 90 percent risk of emesis
Low emetogenicity— 10 to 30 percent risk of emesis
Minimally emetic — <10 percent risk of emesis
For combination regimens, the emetic level is determined by identifying the most emetic
agent in the combination and then assessing the relative contribution of the other
agents. As an example, cyclophosphamide and doxorubicin are both moderately
emetogenic agents, but when given together, the regimen is highly emetic

27. 5-HT3 receptor antagonists
A key advance in the prevention of CINV was the development of selective
type three 5-hydroxytryptamine (5-HT3) receptor antagonists, a drug class
that has a high therapeutic index for prevention of CINV
single-agent 5-HT3 receptor antagonists are more effective than less specific
agents such as high-dose metoclopramide
and as effective as the combination of high-dose metoclopramide and
dexamethasone .
When 5-HT3 antagonists are used in combination with dexamethasone, they
are more effective than high-dose metoclopramide plus dexamethasone
In addition to increased efficacy, these agents are easier to administer and
are associated with significantly fewer serious side effects than the less
specific serotonin inhibitor metoclopramide

28. • dolasetron , granisetron ,
ondansetron , and tropisetron
first-
generation
• palonosetronsecond-
generation

29. First generation agents
The first-generation 5-HT3 receptor antagonists all appear equally effective at
preventing CINV at the recommended doses.
At least two meta-analyses have shown no clear advantage for either
ondansetron or granisetron in the prophylaxis of acute or delayed emesis
There is a plateau in therapeutic efficacy at a definable dose level for each drug,
and further dose escalation does not improve outcome [ 14 ].
A single dose of a 5-HT3 receptor antagonist prior to chemotherapy is
therapeutically equivalent to a multiple dose schedule [ 15-19 ].
The efficacy of 5-HT3 receptor antagonists is significantly improved when they
are combined with glucocorticoids.
Oral formulations of these agents are as effective as intravenous formulations

30. EKG interval changes and cardiac
arrhythmias
EKG interval changes are a class effect of the first-generation 5-HT3
antagonists, including ondansetron , granisetron and dolasetron ,
although they have not been reported with transdermal granisetron
EKG interval changes appear to be most prominent one to two hours after a
dose of these agents, are mostly small and clinically insignificant, and return
to baseline within 24 hours
However, potentially fatal cardiac arrhythmias, including torsade to pointes,
have been reported in association with QTc prolongation [ 23,25-27 ]. The
following sections describe the warnings/precautions regarding
cardiotoxicity of these agents from the US FDA.

31. Ondansetron
FDA has issued a warning about QTc prolongation and potentially fatal
cardiac arrhythmias
QT prolongation occurs in a dose-dependent manner and specifically at a
single IV dose of 32 mg.
Revised labeling includes a recommendation to limit single IV doses to no
more than 16 mg,
avoid use of ondansetron in patients with congenital long-QT syndrome,
and to use ECG monitoring in certain patients, including those with
hypokalemia or hypomagnesemia, heart failure, bradyarrhythmias, and
in patients taking other medications that increase the risk of QTc
prolongation

32. Neurokinin-1 receptor antagonists
The introduction of the NK1 receptor (NK1R) antagonists aprepitant and fosaprepitant (a
parenteral water-soluble prodrug of aprepitant that is effective as a one-day treatmen
have significantly improved the ability to prevent both acute and delayed CINV in patients
receiving highly and moderately emetic chemotherapy
he benefit of combining an NK1R antagonist ( aprepitant , fosaprepitant , or casopitant)
with an 5-HT3 receptor antagonist plus a glucocorticoid for the prevention of acute CINV
was addressed in a meta-analysis of 17 trials, totaling 8740 patients who were receiving
highly or moderately emetogenic chemotherapy

33. Need for a 5-HT3 agent
Aprepitant and fosaprepitant improve control of CINV
when combined with a 5-HT3 receptor antagonist and
dexamethasone .
Aprepitant plus dexamethasone alone is not as effective
as the three-drug combination regimen.
A 5-HT3 receptor antagonist remains necessary, at least
in patients receiving cisplatin -based chemotherapy.

34. One versus three-day administration
In the United States, both aprepitant and
fosaprepitant are approved for use in three-
day schedules.

35. Issues related to inhibition of CYP3A4
NK1 receptor antagonists such as aprepitant and fosaprepitant are
moderate inhibitors of the cytochrome P450 enzyme CYP3A4, which
is particularly important in drug metabolism
CYP3A4 is responsible for the metabolism of glucocorticoids, and
thus the dose of dexamethasone was reduced in clinical trials from
20 mg to 12 mg on day 1 and from 8 mg twice daily to 8 mg daily on
days 2 and 3 when given concurrently with aprepitant
This dose reduction applies only when glucocorticoids are used as
antiemetics in conjunction with NK1 receptor antagonists, not when
given as an antitumor component of a chemotherapy regimen

36. Glucocorticoids
Short courses of glucocorticoids are widely used both
as single agents for regimens with low risk of causing
CINV
and in combination with 5-HT3 receptor inhibitors
and/or NK1 receptor antagonists for more emetic
chemotherapy regimens.
. Although the various glucocorticoids are probably
equally effective when used at an appropriate dose,
dexamethasone has been the most extensively
evaluated and is the most widely used.

37. Combination with a 5-HT3 antagonist
• Glucocorticoids alone represent insufficient
first-line therapy for patients receiving either
moderate or highly emetic chemotherapy
agents. However, the antiemetic efficacy of
the 5-HT3 receptor antagonists is significantly
enhanced by the addition of a glucocorticoid

38. Dose
The optimal dose of dexamethasone for highly to moderately emetic
chemotherapy not containing cisplatin was evaluated by the Italian
Group for Antiemetic Research [ 52 ]. In this trial, all patients received IV
ondansetron and were randomized to one of three schedules of
dexamethasone following chemotherapy (either 8 or 24 mg IV prior to
chemotherapy, or 8 mg IV before treatment followed by 4 mg every six
hours). Rates of complete protection from acute or delayed emesis were
similar among the groups, and the authors concluded that a
single 8 mg IV dose prior to chemotherapy represented
the appropriate dexamethasone regimen.
the dose of dexamethasone is reduced when it is in combination with an NK1
receptor antagonist

39. Alopecia
• Is usually temporary, and the degree of hair loss varies widely.
• Loss of hair is not limited to the scalp; any area of the body
may be affected.
• Patients receiving a Taxane as part of their chemotherapy
regimen are especially prone to total body alopecia.
• Hair loss usually begins 1 to 2 weeks after chemotherapy, and
regrowth may begin before the chemotherapy courses are
completed

40. Single Agents Associated With Alopecia
Frequent Occasional
Cyclophosphamide Mechlorethamine
Ifosfamide Thiotepa
Fluorouracil Methotrexate
Dactinomycin Vinblastine
Daunorubicin Vincristine
Doxorubicin Etoposide
Bleomycin Carmustine
Vindesine Hydroxyurea
Paclitaxel Cytarabine
Irinotecan Topotecan
Epirubicin Gemcitabine
Docetaxel Erlotinib
Etoposide Sorafenib
Mitoxantrone

41. Nail Changes
• A reduction or a cessation of mitotic activity in the nail matrix
causes a horizontal depression of the nail plate.
• Within weeks, these pale horizontal lines (“Beau's lines”)
begin to appear in the nail beds.
• They are most commonly seen in patients receiving
chemotherapy for >6 months.

42. Nail changes
• Nail changes including Hemorrhagic onycholysis,
Discoloration, and Acute exudative paronychia are seen in
~40% of patients receiving Paclitaxel and Docetaxel
• Brown or blue lines deposit as horizontal or vertical bands in
the nails.
• These lines are seen more commonly in dark-skinned
patients.
• As with Beau's lines, these pigmentation lines generally grow
out with the nail

43. Beau's lines

44. Acral Erythema
Hand-foot Syndrome
 Mechanism:
 Direct toxic effect, accumulating in acral sites
• Clinical:
• Prodrome of dysesthesia
• 2-4 days later: pain, edema, well-demarcated erythema
beginning on lateral borders
• Significant desquamation
• Hands > feet
• Bullous variant (cytarabine, methotrexate)

45. Acral Erythema
• Agents reported to cause this reaction
include:
• Cytarabine, Fluorouracil, Doxorubicin,
Lipsomal Doxorubicin, Methotrexate,
Capecitabine, And Hydroxyurea

46. Acral Erythema