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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