Open Issues for CINV Do we reliably measure that? Do we control nausea optimally? Are guidelines useful for oral therapies related nausea and vomiting? Breakthrough and refractory nausea and vomiting: where we are? Are we missing something regarding anticipatory nausea and vomiting?
PERCEPTIONS AND REALITY Underestimation of Emesis with Chemotherapy Percent of Patients 100 80 60 40 20 0 34 MD/RN prediction Patient experience 35 Acute Nausea 17 13 Acute Vomiting 24 52 Delayed Nausea 15 28 Delayed Vomiting Physicians and nurses from 14 oncology practices in 6 countries Patients [N=298] 75% women; 78% Mod emetic chemo; 50% breast cancer; 18% lung cancer Grunberg S et al., Cancer 2004; 100: 2261-8
The ANCHOR Study: Prediction vs Observed HEC MEC MD/RD prediction (N=24) Patients perception (N=231) Grunberg S et al., Cancer 2004; 100: 2261-8
Perceptions and Reality Agreement between patient and physician reporting Subjective toxicities are at high risk of under- reorting by phisicians, even when prospectively collected within randomized trials. Di Maio M et al, JCO 2015
Perceptions and Reality Agreement between patient and physician reporting Di Maio M et al, JCO 2015
BUT WHAT IS NAUSEA? Nausea is subjective; vomiting is objective. Therefore the accurate measuremnet of nausea is more of an obstacle For patients nausea ( if they understand the word at all) often means << feeling bad>> 7 2016 V.1.2 Aapro M & Grunberg S, Educational ASCO 2012
NAUSEA AND APPETITE Several agents that have appetite stimuing properties also have anti- nausea properties: Corticosteroid Megestrol Olanzapine Dronabinol Nausea/anorexia may be a more valid construct then nausea/vomiting A low dose anti-nausea agent might complement anti-vomiting agents 8 2016 V.1.2 Modified by Grunberg S & Clark-Snow, Educational ASCO 2012
COMMITTEE II (5/5): ANTIEMETIC GUIDELINES: MASCC/ESMO The MASCC/ESMO Antiemetics Guidelines Committee has discussed the presently available published data about olanzapine, which suggest that it is an effective antiemetic agent. Olanzapine may be considered with a 5-HT 3 receptor antagonist plus dexamethasone, particularly when nausea is an issue. (NOTE: Patient sedation may be a concern for the 10 mg dose.) MASCC Level of Confidence : Low MASCC Level of Consensus: Low ESMO Level of Evidence: II ESMO Grade of Recommendation: B
Are guidelines useful for oral therapies related nausea and vomiting? 10 2016 V.1.2
Committee I (5/5): Emetic Risk Groups Adults Single Oral Agents 11 HIGH Hexamethylmelamine Procarbazine MODERATE Bosutinib Ceritinib Cyclophosphamide Imatinib Vinorelbine Crizotinib Temozolomide LOW Afatinib Axatinib Capecitabine Dabrafenib Dasatinib Everolimus Etoposide Fludarabine Ibrutinib Idelalisib Lapatinib Lenalidomide Olaparib Nilotinib Pazopanib Ponatinib Regorafenib Sunitinib Tegafur Uracil Thalidomide Vandetanib Vorinostat MINIMAL Chlorambucil Erlotinib Gefitinib Hydroxyurea Melphalan Methotrexate L-Phenylalanine mustard Pomalidomide Ruxolitinib Sorafenib 6-Thioguanine Vemurafenib Vismodegib
No recommendations for single oral agents-related nausea/vomiting Caveats: Drug-drug interactions Polipharmacotherapies Adherence Duration of antiemetic prophylaxis? Rescue with antiemetic therapies? Same guidelines of iv emetogenic therapies?
Breakthrough Nausea and Vomiting Breakthrough CINV is defined as nausea and/or vomiting attributable to antineoplastic chemotherapy that occurs during the acute or delayed phase despite CINV prophylaxis.
For example Initial Presentation Mary T. is a 56-year-old female had a mastectomy and auxiliary lymph node dissection. Diagnosis T3 (more than 5 cm) N0(0/6 lymph nodes) M0; poorly differentiated invasive ductal carcinoma of right breast, ER/PR positive and HER-2/neu negative.
Medical history. PAST MEDICAL HISTORY: Unremarkable. SOCIAL HISTORY: School teacher, married, mother of two grown children, non smoker, occasional drink on the weekends. MEDICATIONS: Ranitidine 150 mg b.i.d., Lorazepam 1 mg prn Allergies : NKA (drugs, food, environmental allergens)
First Cycle of Chemotherapy (FEC) The patient is prescribed FEC (Fluorouracil, Epirubicin, Cyclophosphamide) for 3 cycles followed by Taxotere for 3 cycles. She was given Ondansetron 8 mg and Dexamethasone 8 mg prior to her first cycle of chemotherapy. She was given a prescription for Ondansetron 8 mg and Dexamethasone 4 mg po b.i.d. x 2 days post chemotherapy as well as Metoclopramide 10 mg po q6hprn to be taken post chemotherapy.
Breakthrough nausea Nausea and Vomiting post Cycle 1 When she returned for cycle two she informed that she had vomited on day 2 and that she had experienced nausea for days 2-5 post chemotherapy. She rates this nausea as a 8/10 for days 2-4 and 6/10 for day 5, olanzapine 10 mg for three days was administered without results.
COMMITTEE V (3/3): ANTIEMETIC GUIDELINES: MASCC/ESMO 18 Guideline for Breakthrough Nausea and Vomiting The available evidence for breakthrough nausea and vomiting suggests the use of 10 mg oral olanzapine, daily for 3 days. (The mild to moderate sedation in this patient population, especially elderly patients, is a potential problem with olanzapine.) MASCC Level of Confidence: Moderate MASCC Level of Consensus: Moderate ESMO Level of Evidence: II ESMO Grade of Recommendation: B NOTE: No guideline was felt to be appropriate for refractory nausea and vomiting.
Olanzapine Breaktrough
Refractory Nausea and Vomiting Refrectory CINV is defined as nausea and/or vomiting attributable to antineoplastic chemotherapy which occurs during the acute or delayed phase despite CINV prophylaxis in patients who have experienced brekthrough CINV in a previous chemotherapy cycle
Second Cycle of Chemotherapy (FEC) She was given Ondansetron 12 mg and Dexamethasone 12 mg prior to her second cycle of chemotherapy. She was given a prescription for Ondansetron 8 mg po b.i.d. and Dexamethasone 4 mg po b.i.d. x 5 days post chemotherapy
Refractory nausea Nausea and Vomiting post Cycle 2 When she returned for cycle three she informed that she had vomited on day 3-5 and that she had experienced nausea for days 3-7 post chemotherapy. She rates this nausea as a 10/10 for days 3-4 and 6/10 for day 5-7
Practical Suggestions for refractory nausea and vomiting 1) For patients receiving minimally, low emetogenic chemotherapy, upgrade or escalate the acute CINV prophylaxis to that recommended for chemotherapy of the next higher level of emetogenic risk. 2) For patients receiving moderately or highly emetogenic chemotherapy, we suggest that the 5-HT3 antagonist given for CINV prophylaxis be changed from ondansetron or granisetron to palonosetron or pass to NK1 antagonist 3) Stimulation of Nei Gaun (P6) by means of acupressure or electroacupuncture.
MASCC/ESMO 2016 RECOMMENDATIONS Refractory emesis another 5-HT3 add benzodiazepines metopimazine NK1 antagonist
Anticipatory nausea and vomiting Anticipatory nausea and/or vomiting is the occurrence of nausea and/or vomiting before patients receive their chemotherapy treatment. Challenge - Anticipatory nausea and/or vomiting occurs in 18% to 57% of chemotherapy patients. Younger patients may be more susceptible as they generally receive more aggressive therapy and have poorer emesis control than older patients. Adapted from: 1. Roscoe JA, et al. J Pain Symptom Manage 2000;20:113. 2. Morrow GR, et al. Support Care Cancer 1998;6:244.
Risk Factors Kamen C et al, Eur J Pharmacol, 2014
991 patients; perspective observational european study AN reported in 8.3-13.8% of patients Increase frequency and intensity over each cycle Key predictors of AN: pre-chemotherapy anxiety; AN and CINV experience in previous cycle
COMMITTEE VI (1/2): ANTIEMETIC GUIDELINES: MASCC/ESMO 29 Prevention of Anticipatory Nausea and Vomiting The best approach for the prevention of anticipatory nausea and vomiting is the best possible control of acute and delayed nausea and vomiting. MASCC Level of Confidence: High MASCC Level of Consensus: High ESMO Level of Evidence: III ESMO Grade of Recommendation: A
COMMITTEE VI (2/2): ANTIEMETIC GUIDELINES: MASCC/ESMO 30 Prevention of Anticipatory Nausea and Vomiting Behavioral therapies (progressive muscle relaxation training, in particular), systematic desensitization, and hypnosis may be used to treat anticipatory nausea and vomiting. MASCC Level of Confidence: Moderate MASCC Level of Consensus: Moderate ESMO Level of Evidence: II ESMO Grade of Recommendation: B Benzodiazepines can reduce the occurrence of anticipatory nausea and vomiting. MASCC Level of Confidence: Moderate MASCC Level of Consensus: Moderate ESMO Level of Evidence: II ESMO Grade of Recommendation: A
.and what about ANTIEMETIC GUIDELINES: nausea MASCC/ESMO between 5 to 21 days after chemotherapy? 31 2016 V.1.2
Grazie per la Vostra Attenzione ANTIEMETIC GUIDELINES: MASCC/ESMO 32 2016 V.1.2