6/16/2015 DISCLOSURES ● Leah Edenfield declares no conflicts of interest, real or apparent, CHEMOTHERAPY TOXICITY AND and no financial interests in any company, product, or service SUPPORTIVE CARE: mentioned in this program, including grants, employment, gifts, MANAGEMENT OF stock holdings, and honoraria. GASTROINTESTINAL SYMPTOMS Leah Edenfield, PharmD, BCPS PGY2 Oncology Pharmacy Resident June 12, 2015 OBJECTIVES Identify gastrointestinal effects frequently associated with chemotherapy Design a strategy to prevent chemotherapy-induced nausea and vomiting and to manage breakthrough symptoms Recommend over-the-counter medications for diarrhea and NAUSEA AND VOMITING constipation as well as treatments for refractory symptoms Evaluate appetite stimulants for oncology patients Select appropriate therapy for management of mucositis PATHOPHYSIOLOGY CONTRIBUTING CAUSES Impulses to the vomiting center come from the chemoreceptor trigger zone, pharynx and GI tract, and cerebral cortex Bowel obstruction Impulses are then sent to the salivation center, abdominal muscles, Vestibular dysfunction respiratory center, and cranial nerves Hypercalcemia, hyperglycemia, or hyponatremia Uremia Opiates or other concomitant mediations Gastroparesis Anxiety Serotonin and dopamine receptors are involved in the emetic response and are activated by chemotherapy Other relevant receptors include acetylcholine, corticosteroid, histamine, cannabinoid, opiate, and neurokinin-1 receptors in the vomiting and vestibular centers Antiemesis. NCCN Guidelines. Version 1.2015. Antiemesis. NCCN Guidelines. Version 1.2015. Image available at www.aloxi.net 1 6/16/2015 EMETIC RISK OF CHEMOTHERAPY ASCO GUIDELINES: EMETIC RISK Emetic risk categories .High (>90%) .Moderate (30-90%) .Low (10-30%) .Minimal (<10%) *Anthracycline + cyclophosphamide = high risk American Society of Clinical Oncology 2011. www.asco.org/guidelines/antiemetics. American Society of Clinical Oncology 2011. www.asco.org/guidelines/antiemetics. ASCO GUIDELINES: MANAGEMENT ASCO GUIDELINES: MANAGEMENT High Risk Breakthrough nausea and vomiting despite appropriate •NK1 antagonist: fosaprepitant 150mg or aprepitant 125mg day 1 and 80mg prophylaxis days 2-3 •5-HT3 receptor antagonist day 1 . Add lorazepam or alprazolam •Dexamethasone 12mg day 1 and 8mg days 2-3 or 2-4 . Add olanzapine Moderate Risk . Substitute metoclopramide for 5-HT3 receptor antagonist •Palonosetron 0.25g IV or 0.5g PO day 1 (alternatively may use another 5-HT3 . Add dopamine antagonist receptor antagonist ) •Dexamethasone 8mg IV or PO days 1-3 Low Risk •Dexamethasone 8mg Minimal Risk •No routine antiemetic American Society of Clinical Oncology 2011. www.asco.org/guidelines/antiemetics. American Society of Clinical Oncology 2011. www.asco.org/guidelines/antiemetics. NCCN GUIDELINES: HIGH EMETIC RISK NCCN GUIDELINES: MODERATE RISK Aprepitant- Netupitant- Olanzapine- Aprepitant- Netupitant- Olanzapine- containing regimen containing regimen containing regimen containing regimen containing regimen containing regimen •Aprepitant 125mg PO •Netupitant 300mg/ •Olanzapine 10mg PO •5-HT3 antagonist AND • Netupitant 300mg/ • Olanzapine 10mg PO day 1 and 80mg PO day palonosetron 0.5mg PO days 1-4 dexamethasone day 1 palonosetron 0.5mg PO days 1-3 2-3 once •Palonosetron 0.25mg IV •5-HT3 antagonist OR once • Palonosetron 0.25mg IV OR Fosaprepitant • Dexamethasone 12mg once dexamethasone days 2-3 • Dexamethasone 12mg once PO/IV day 1 and 8mg 150mg IV once PO/IV day 1 and 8mg • Dexamethasone 20mg • With or without • Dexamethasone 20mg IV PO/IV days 2-4 aprepitant or PO/IV days 2-3 once •5-HT3 antagonist day 1 IV once fosaprepitant then • Dexamethasone days 1- dexamethasone days 2-3 4 Antiemesis. NCCN Guidelines. Version 1.2015. Antiemesis. NCCN Guidelines. Version 1.2015. 2 6/16/2015 EMETOGENIC POTENTIAL OF ORAL NCCN GUIDELINES: LOW RISK AGENTS: MODERATE TO HIGH Dexamethasone 12mg PO/IV daily OR Class Drug Metoclopramide 10-40mg PO/IV then every 4-6h prn OR Tyrosine kinase inhibitors Ceritinib Crizotinib Prochlorperazine 10mg PO/IV then every 6h prn OR Lenvatinib 5-HT3 antagonist Alkylating agents Busulfan (≥4mg/day) . Dolasetron 100mg PO daily Cyclophosphamide (≥100mg/m2/day) . Granisetron 1-2mg PO daily Estramustine . Ondansetron 8-16mg PO daily Temozolomide (>75mg/m2/day) Procarbazine Lomustine Altretamine Other Etoposide Mitotane Olaparib Panobinostat Antiemesis. NCCN Guidelines. Version 1.2015. Vismodegib Antiemesis. NCCN Guidelines. Version 1.2015. EMETOGENIC POTENTIAL OF ORAL NCCN GUIDELINES: ORAL AGENTS: MINIMAL TO LOW CHEMOTHERAPY EMESIS PREVENTION Class Drug Class Drug Class Drug High to moderate risk Tyrosine Afatinib Alkylating agents Melphalan Other Bexarotene kinase Axitinib Busulfan Everolimus . Start 5-HT3 antagonist before chemotherapy and continue inhibitors (<4mg/day) Bosutinib Hydroxyurea daily Chlorambucil Dasatinib Idelalisib Temozolomide Tretinoin Erlotinib (≤75mg/m2/day) Palbociclib Low to minimal risk Cabozantinib Cyclophosphamide Imatinib (<100mg/m2/day) Topotecan . PRN recommended Lapatinib Vorinostat Antimetabolites Mercaptopurine . Start antiemetic before chemotherapy and continue daily if Nilotinib Thioguanine nausea or vomiting occurs Ibrutinib Fludarabine Trametinib . Metoclopramide prn Capecitabine Vemurafenib Methotrexate . Prochlorperazine prn Pazopanib Immunomodulators Lenalidomide . Haloperidol prn Ponatinib Pomalidomide Regorafenib . 5-HT3 antagonist prn Thalidomide Ruxolitinib Sorafeib Antiemesis. NCCN Guidelines. Version 1.2015. Sunitinib Antiemesis. NCCN Guidelines. Version 1.2015. NCCN GUIDELINES: ANTICIPATORY NCCN GUIDELINES: BREAKTHROUGH NAUSEA/VOMITING Olanzapine 10mg PO daily for 3 days Behavioral therapy Lorazepam 0.5-2mg PO/SL/IV q6h Acupuncture/acupressure Dronabinol 5-10mg PO q3-6h Anxiolytic therapy Haloperidol 0.5-2mg PO/IV q4-6h . Alprazolam 0.5-1mg or lorazepam 0.5-2mg PO Scopolamine patch q72h . Night before treatment and repeated 1-2h before Prochlorperazine 25mg PR q12h or 10mg PO/IV q6h chemotherapy Promethazine 25mg PTR q6h or 12.5-25mg PO/IV every 4-6h Dexamethasone 12mg PO/IV daily Dolasetron 100mg PO daily Granisetron 1-2mg PO daily or 1mg PO bid or 0.01mg/kg IV daily Ondansetron 16mg PO/IV daily Antiemesis. NCCN Guidelines. Version 1.2015. Antiemesis. NCCN Guidelines. Version 1.2015. 3 6/16/2015 ETIOLOGY Causes of constipation in cancer patients . Diet . Inadequate fluid intake or fiber intake . Lack of exercise . The tumor itself . Drug therapy CONSTIPATION . Comorbidities such as organ failure, decreased mobility, and depression . Environmental factors National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all DRUGS AND CONSTIPATION CHEMOTHERAPY AND CONSTIPATION May be the result of autonomic neuropathy causing decreased Phenothiazines Antacids motility Inflammatory neuropathy has been demonstrated with Anticholinergics Diuretics ipilimumab Drugs associated with chemotherapy-induced constipation . Vinca alkaloids (vinblastine, vincristine, vinorelbine) . Taxanes (paclitaxel, docetaxel, cabazitaxel) Iron Opioids supplements . Thalidomide . Cisplatin Can be exacerbated by concomitant opioid use Chemotherapy Constipation Sedatives National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all Gibson RJ, Keefe DMK. Support Care Cancer 2006;14:890-900. Shailender B, Huber B, Upton MP et al. J Immunother. 2009;32:203-5. PashankarP, Season JH, McNamara J et al. J Pediatr Hematol Oncol 2011;33:e300-3. National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all NONPHARMACOLGIC MANAGEMENT DRUG THERAPY Increase dietary fiber Opioid-induced constipation . Fruit . Prevent with stimulant and stool softener (e.g., senna 8.6mg and . Green, leafy vegetables docusate 50mg two tablets daily) . Whole grains . If patient experiences constipation, increase dose and add agent Increase fluid intake . Miralax 17g . Milk of magnesia Exercise regularly Avoid rectal agents in cancer patients at risk for thrombocytopenia, neutropenia, or mucositis Lactulose has been successful in vincristine-induced constipation National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all Harriis AC, Jackson JM.. Med J Aust. 1977;2:573-4. 4 6/16/2015 Mechanism Onset Precautions Dose Bulk Hold water in GI 12-24h, up Hydrate, avoid in Methylcellulose 5-20ml tid producers tract, soften to 72h obstruction Psyllium 1 tbsp 1-3 times stool daily NCCN GUIDELINES: PREVENTION Saline High osmolarity 0.5-3h May alter fluid and Milk of magnesia 10-20ml laxatives pulls water into electrolyte balance conc or 15-30ml regular, intestines magnesium citrate 240ml Increase fluids and dietary fiber Stimulant Increase motor 6-10h May cause cramping, Senna 2 tablets, bisacodyl Exercise laxatives activity of dependency 10-15mg PO or 10mg PR bowels Prophylactic stimulant laxative +/- stool softener Lubricant Lubricate 6-8h Aspiration potential, Mineral oil 5-30ml at bedtime Titrate up with goal of 1 non-forced bowel movement laxatives intestinal prevents absorption of mucosa oil-soluble drugs every 1-2 days Stool Promote water 3 days Increases mineral oil Docusate sodium 50-240mg