Managing Gastrointestinal Side Effects of Targeted Therapies

Amy Goodrich, MSN, NP-ACThe 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 GradingGrade 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 baselineIncontinenceRequires hospitalizationSevere increase in ostomy output over baselineLimiting 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 33-49%

Temsirolimus 27%

Diarrhea

• EGFR overexpressed in normal GI mucosa- possibly 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 GradingGrade 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 hoursTube feeding or TPN requiredHospitalization

4 Life threatening; urgent intervention required

5 Death

Nausea and VomitingAgent Nausea Prevalence Vomiting Prevalence NCCN Emetogenic

potentialBortezomib 64% 36% Minimal

Sunitinib/Sorafenib 58% 39% Minimal to Low

Bevacizumab Not reported 52% Minimal

Imatinib 47-68% 21-49% Minimal to Low

Temsirolimus 37% 19% Not reported

Gefitinib/Erlotinib 33% 23% 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 ProphylaxisIV agents Oral agents

• Low- Dexamethasone pre OR Metaclopramide pre and prn OR Prochlopreazine pre and prn+/- lorazepam pre and prn+/- H2 blocker or PPI

• Minimal – No prophylaxis

• PRN antiemetics recommended

Oral Mucositis GradingGrade 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/MucocitisAgent 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 GradingGrade Description

1 Mild symptoms; no intervention

2 Moderate symptoms; medical intervention required

3 Severe symptoms; surgical intervention required

DyspepsiaAgent 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 GradingGrade ALT/AST Description

1 Up to 3.0 x ULN

2 >3.0-5 x ULN

3 >5-20 x ULN

4 >20 x ULN

Grade Alk Phos Description1 Up to 2.5 x ULN2 >2.5-5 x ULN3 >5-20 x ULN4 >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 hepatitisErlotinib- Dose interruption and/or reduction, may require discontinuation

Imatinib Transaminases 1.1-3%Bilirubin 0.4-3.5%

Dose interruption and reduction

GI EmergenciesAgent 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