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Managing Gastrointestinal Side
Effects of Targeted Therapies
Amy Goodrich, MSN, NP-AC
The Johns Hopkins Kimmel Cancer
Center, Baltimore, MD
General Concepts of GI Toxicity in
Cancer Patients
• Chronic GI side effects commonly cause
significant morbidity and reduced quality of
life in cancer patients
• GI side effects commonly overlooked due to
focus on disease status
• GI symptoms can often be alleviated or
eliminated
GI Toxicity in Targeted Therapies
• Spectrum of GI toxicity and causes often
poorly defined
• Normal cells of the GI system, including liver,
may express molecular targets
• Hepatic or GI adverse events may be alternate
markers of treatment efficacy of some
targeted agents
• Extensive Drug-Drug interactions
• GI toxicity and management varies from single
agent to combination therapy
Diarrhea Grading
Grade
Description
1
Increase of > 4 stools per day over baseline; slight increase in ostomy
output over baseline
2
Increase of 4-6 stools per day over baseline; moderate increase in
ostomy output over baseline
3
Increase of > 7 stools per day over baseline
Incontinence
Requires hospitalization
Severe increase in ostomy output over baseline
Limiting self care/ADLs
4
Life-threatening; urgent intervention required
5
Death
Diarrhea
• Major cause of treatment discontinuation
• Common DLT
Agent
Prevalence
Sunitinib/Sorafenib
66%
Gefitinib/Erlotinib
54%
Bortezomib
51%
Bevacizumab
34%
Imatinib
Temsirolimus
33-49%
27%
Diarrhea
• EGFR overexpressed in normal GI mucosapossibly due to increased chloride secretion
leading to secretory diarrhea
• Imatinib- dose related
• Bortezomib- watery diarrhea with abdominal
pain and cramps
• Temsiroloimus- Immunosupressive or
antimicrobial effect could alter normal bowel
flora leading to mucoid feces and colitis
• Gefitinib- Inflammatory mediators in response to
cell immunity activation
Diarrhea Management
•
•
•
•
•
•
•
•
Hydration
Electrolyte management
BRAT diet
Culture
Loperamide
Octreotide
Antibiotics if prolonged or w/neutropenia
Low dose aspirin with gefitinib
Nausea and Vomiting Grading
Grade
Nausea Description
1
Loss of appetite without changed in eating habits
2
Decreased oral intake without weight loss, dehydration or
malnutrition
3
Inadequate caloric or fluid intake; requires tube feeding, TPN
or hospitalization
Grade
Vomiting Description
1
1-2 episodes at least 5 minutes apart in 24 hours
2
3-5 episodes at least 5 minutes apart in 24 hours
3
> 6 episodes at least 5 minutes apart in 24 hours
Tube feeding or TPN required
Hospitalization
4
Life threatening; urgent intervention required
5
Death
Nausea and Vomiting
Agent
Nausea Prevalence Vomiting Prevalence NCCN Emetogenic
potential
Bortezomib
64%
36%
Minimal
Sunitinib/Sorafenib
58%
39%
Minimal to Low
Not reported
52%
Minimal
47-68%
21-49%
Temsirolimus
37%
19%
Not reported
Gefitinib/Erlotinib
33%
23%
Minimal to Low
Bevacizumab
Imatinib
Minimal to Low
Nausea and Vomiting
• Cited as the most concerning symptom of
antineoplastic therapy
• Significantly impacts quality of life
• Affected by: specific agent, dose, schedule and
route, patient-related variables
• Multifactorial
• Most Targeted Therapies have low to minimal
emetogenic potential
• Is it time for a revised CTCAE to reflect long
term therapy vs. traditional chemo cycles?
Management of Nausea and Vomiting
• Follow guidelines for prevention and
treatment
• Hydration
• Dietary changes- small frequent meals, bland
foods, full liquids, room temperature foods
• Nonpharmacologic- acupuncture, guided
imagery, music therapy, progressive muscle
relaxation, many others
Recommended Antiemesis Prophylaxis
IV agents
Oral agents
• Low- Dexamethasone pre OR
Metaclopramide pre and prn OR
Prochlopreazine pre and prn
+/- lorazepam pre and prn
+/- H2 blocker or PPI
• PRN antiemetics recommended
• Minimal – No prophylaxis
Oral Mucositis Grading
Grade
Description
1
No symptoms or mild symptoms; no intervention
2
Moderate pain; no change in oral intake; modified diet
3
Severe pain; interfering with oral intake
4
Life threatening; urgent intervention required
5
Death
Stomatitis/Mucocitis
Agent
Prevalence
Sunitinib/Sorafenib
53%
Temsirolimus
41%
Bevacizumab
32%
Gefitinib/Erlotinib
17%
Oral Mucositis Management
•
•
•
•
•
Oral care- Saline rinses, soft tooth brushes
Hydration
Dietary modifications- Soft diet, bland foods
Analgesics- topical and systemic
Consider anti-infectives
Dyspepsia Grading
Grade
Description
1
Mild symptoms; no intervention
2
Moderate symptoms; medical intervention required
3
Severe symptoms; surgical intervention required
Dyspepsia
Agent
Prevalence
Sunitinib/Sorafenib
46%
Bevacizumab
24%
Bortezomib
13%
Imatinib
9-19%
Dyspepsia Management
• Pharmacologic treatment, watch for drug-drug
interactions
• Dietary changes- avoid spicy or fatty foods, no
eating within 2 hours of bedtime
Liver Function Abnormality Grading
Grade
ALT/AST Description
Grade
Alk Phos Description
1
Up to 3.0 x ULN
1
Up to 2.5 x ULN
2
>3.0-5 x ULN
2
>2.5-5 x ULN
3
>5-20 x ULN
3
>5-20 x ULN
4
>20 x ULN
4
>20 x ULN
Grade
Bilirubin Description
1
Up to 1.5 x ULN
2
>1.5-3 x ULN
3
>3-10 x ULN
4
>10 x ULN
Liver Function Abnormalities
Agent
Prevalence
Dose Reductions
Sunitinib/
Sorafenib
SGOT 72%
SGPT 61%
Bilirubin 37%
Sunitinib- Hold for Gr 3 or 4 hepatotoxicity;
discontinue if no resolution (Black Box Warning)
Sorafenib- Discontinue for drug induced
hepatitis
Gefitinib/
Erlotinib
2-4%
Gefitinib- Discontinue for drug induced
hepatitis
Erlotinib- Dose interruption and/or reduction,
may require discontinuation
Imatinib
Transaminases 1.1-3%
Bilirubin 0.4-3.5%
Dose interruption and reduction
GI Emergencies
Agent
Prevalence
Bevacizumab
GI Hemorrhage 24% (Black Box Warning)
Colitis 6%
GI perforation/Fistula 0.9-2.4% (Black Box
Warning)
Bortezomib
Paralytic ileus 21%
Imatinib
GI Hemorrhage 0.2-5%
GI perforation rare
Gefitinib/Erlotinib
GI perforation rare
Conclusions
• Targeted therapies carry high incidence of GI
toxicity
• Usually mild
• Patient distress easily overlooked by providers
• Chronic dosing of targeted therapies makes
side effect control critical