NCCN Guidelines Insights: Antiemesis, Version 2.2017

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.

Abstract

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-17-007-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/81405; and 3) view/print certificate.

Release date: July 10, 2017; Expiration date: July 10, 2018

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Antiemesis

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Antiemesis

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Vomiting (emesis) and nausea induced by systemic or radiation therapy (RT) can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy or RT. Nausea and/or vomiting (N/V) can result in metabolic imbalances, degeneration of self-care and functional ability, nutrient depletion, anorexia, decline of performance status and mental status, wound dehiscence, esophageal tears, and withdrawal from potentially useful or curative anticancer treatment.14 Systemic therapy includes chemotherapy, targeted therapy, and immunotherapy, herein referred to as chemotherapy. Patients receiving whole-body RT, upper abdominal RT, or chemotherapy combined with RT can develop N/V,57 which is often referred to as chemotherapy-induced nausea and vomiting (CINV), and is commonly classified as acute, delayed, anticipatory, breakthrough, or refractory.8

The incidence and severity of N/V in patients receiving chemotherapy, RT, or chemoradiation

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

are affected by numerous factors, including: (1) the specific therapeutic agents used; (2) dosage of the agents; (3) schedule and route of administration of the agents; (4) target of the RT, such as whole body or upper abdomen; and (5) individual patient variability, such as age, sex, prior chemotherapy, and history of alcohol use.9,10 More than 90% of patients receiving highly emetogenic chemotherapy (HEC) will have episodes of vomiting. However, if patients receive prophylactic (preventive) antiemetic regimens before treatment with HEC, the incidence of vomiting decreases to approximately 30%.9,11,12 Although vomiting can often be prevented or substantially decreased by using prophylactic antiemetic regimens, nausea is much harder to control.1318

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis are intended to provide an overview of the treatment principles for preventing chemotherapy-induced (or RT-induced) N/V, and to provide recommendations for antiemetic prophylaxis according to the emetogenic potential of antitumor therapies. These NCCN Guidelines are updated at least once a year by a multidisciplinary panel of experts; the first guidelines were published in 1997.19 Major updates to the 2017 version, described in these NCCN Guidelines Insights, are as follows: (1) carboplatin is now categorized as HEC if administered at an area under the curve (AUC) of ≥4, and remains categorized as moderately emetogenic chemotherapy (MEC) if administered at an AUC of <4; (2) subcutaneous granisetron extended-release injection is a new formulation that is now recommended in antiemetic regimens for HEC and MEC; and (3) a new 4-drug antiemetic regimen containing olanzapine is now recommended (category 1) for HEC.

Emetogenicity of Chemotherapy

Frequency of chemotherapy-induced emesis depends on the emetogenic potential of the systemic agents used.8 The Grunberg classification is updated each

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

year by the NCCN Antiemesis Panel with recently introduced drugs.14,20 The NCCN Guidelines outline treatment using 4 categories of emetogenic potential for intravenous agents:
  • High emetic risk: >90% of patients experience acute emesis

  • Moderate emetic risk: >30% to 90% of patients experience acute emesis

  • Low emetic risk: 10% to 30% of patients experience acute emesis

  • Minimal emetic risk: <10% of patients experience acute emesis

The NCCN panel also categorized the emetogenic potential of oral antineoplastic agents as (1) high to moderate emetic risk (>30% frequency of emesis) or (2) low to minimal emetic risk (<30% frequency of emesis).14

For the 2017 update, the panel revised the emetogenic classification for carboplatin. When dosed at an AUC of ≥4, it is now categorized as HEC, whereas at an AUC of <4 it remains categorized as MEC (see AE-2; page 885). Data suggest that carboplatin, although less emetogenic than cisplatin, is perhaps on the higher end of emetogenic potential within the MEC classification.2124 Several trials and a subset analysis have shown benefit in terms of complete response (CR) in the overall and delayed phases with the addition of a neurokinin-1 (NK1) receptor antagonist (RA) to the 2-drug regimen of a 5-HT3 antagonist and dexamethasone for the prevention of CINV associated with carboplatin-based regimens, thereby affirming the higher emetogenic potential of carboplatin.2124 All of the commercially available NK1 RAs have an FDA-approved indication for MEC chemotherapy, but previous versions of the NCCN Guidelines have supported the addition of an NK1 RA only for select patients receiving MEC with additional CINV risk factors or in those for whom previous therapy with a steroid and 5-HT3 antagonist alone failed. The panel did not want a “carboplatin subset” within the MEC classification;

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

therefore, high-dose carboplatin (AUC ≥4) was escalated to the HEC classification, where 3- or 4-drug regimens are recommended (category 1) for all patients.

Prevention of Acute and Delayed Emesis

The NCCN Guidelines recommend several different antiemetic regimen options for patients receiving HEC. Recommended antiemetic regimens may include 5-HT3 antagonists, dexamethasone, NK1 RAs, and olanzapine (see AE-5 and AE-7; pages 886 and 888). Lorazepam and a histamine (H2) blocker or a proton pump inhibitor may also be added to all of these regimens to manage anxiety and dyspepsia/reflux-related symptoms, respectively.7,25,26 Regimens for day 1 of therapy (all are category 1) include those containing dexamethasone, a 5-HT3 antagonist option (ie, dolasetron, granisetron, ondansetron, palonosetron), and an NK1 RA option (ie, aprepitant, fosaprepitant, rolapitant). Other antiemetic regimens (category 1) for HEC on day 1 include (1) oral netupitant combined with oral palonosetron (NEPA) in a single capsule plus dexamethasone; (2) olanzapine, palonosetron, and dexamethasone; or (3) olanzapine, aprepitant or fosaprepitant, palonosetron, and dexamethasone; this 4-drug regimen was added for the 2017 update (see “Olanzapine,” page 891). Note that the regimens and doses are often modified on days 2 to 4 after chemotherapy.

The NCCN Guidelines recommend several antiemetic regimens for intravenous MEC, including (1) dexamethasone and one of the 5-HT3 antagonist options with or without one of the NK1 RA options; (2) NEPA in a single tablet plus dexamethasone; or (3) olanzapine, palonosetron, and dexamethasone. If needed, lorazepam and either an H2 blocker or a proton pump inhibitor may be added to these regimens to manage anxiety and dyspepsia/reflux-related symptoms, respectively.9 Adding an NK1 RA to a regimen with dexamethasone and one of the 5-HT3 antagonist options is recommended for select patients with

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

additional risk factors or failure of previous therapy with a 2-drug regimen of dexamethasone and a 5-HT3 antagonist. Any one of the 5-HT3 antagonists can be used in the first regimen for day 1; however, palonosetron and subcutaneous granisetron extended-release injection are preferred options when an NK1 RA is not included.27,28 The NCCN Guidelines recommend the use of 5-HT3 antagonists as one of several options to prevent delayed emesis for MEC.

Granisetron

All of the 5-HT3 antagonists (dolasetron, granisetron, ondansetron, palonosetron) have been shown to be effective in controlling acute N/V associated with cancer chemotherapy when used in multidrug antiemetic regimens.2945 For the 2017 update, the NCCN panel added recommendations for a new formulation of granisetron—subcutaneous granisetron extended-release injection—in antiemetic regimens for HEC and MEC based on published data and recent FDA approval (see AE-5, AE-6, AE-7, and AE-A 2; pages 886–888 and 890). It is important to note that subcutaneous granisetron extended-release injection is a unique formulation of granisetron using a polymer-based drug delivery system. This formulation is specifically intended for subcutaneous administration and is NOT interchangeable with the intravenous formulation (see AE-A 2; page 890). Subcutaneous granisetron has an extended half-life and should not be administered at <1-week intervals. To date, subcutaneous granisetron has only been studied with single-day chemotherapy regimens. Efficacy and safety with multiday chemotherapy regimens are currently unknown.

A phase III trial assessed subcutaneous granisetron extended-release injection versus intravenous palonosetron in a 2-drug regimen with dexamethasone for patients receiving HEC or MEC.28 A limitation of this study was that the emetogenicity of the chemotherapy regimens was reclassified after the study. For example, anthracycline

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NCCN Guidelines Insights: Antiemesis, Version 2.2017

Version 2.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 7; 10.6004/jnccn.2017.0117

plus cyclophosphamide is now classified as HEC by the NCCN panel, whereas it was classified as MEC for the study. Two doses of subcutaneous granisetron were assessed: 5 and 10 mg. Data showed that subcutaneous granisetron was not inferior to intravenous palonosetron for preventing acute and delayed CINV after either HEC or MEC. For patients receiving HEC, acute CRs (98% CI difference vs palonosetron) for the 5- and 10-mg dose of subcutaneous granisetron were 77.7% (−12.1, 6.1) and 81.3% (−8.2, 9.3), respectively, compared with 80.7% for those receiving palonosetron at 0.25 mg. For patients receiving MEC, acute CRs (98% CI difference) for 5 or 10 mg of subcutaneous granisetron were 74.8% (−9.8, 9.3) and 76.9% (−7.5, 11.4), respectively, compared with 75.0% for palonosetron. The FDA approved the use of a 10-mg dose of subcutaneous granisetron extended-release injection when used for the prevention of acute and delayed CINV associated with MEC. Based on this trial and FDA approval, the NCCN panel now recommends subcutaneous granisetron extended-release injection as a preferred 5-HT3 antagonist option for MEC when used with dexamethasone in antiemetic regimens that do not contain an NK1 RA (see AE-6 and AE-7; pages 887 and 888). The panel also recommends intravenous palonosetron as a preferred 5-HT3 antagonist option for MEC. Although 2-drug regimens can be used for MEC, the panel recommends 3- or 4-drug regimens for HEC (see AE-5 and AE-7; pages 886 and 888).

A phase III trial (MAGIC) assessed a single dose of subcutaneous granisetron extended-release injection compared with a single dose of intravenous ondansetron in a 3-drug regimen with dexamethasone and fosaprepitant for patients receiving cisplatin or anthracycline plus cyclophosphamide (both are classified as HEC by the NCCN panel).46 No 5-HT3 antagonists were administered on days 2 to 5. When administered subcutaneously, granisetron extended-release injection is effective for ≥5 days. The subcutaneous granisetron regimen improved the CR rate (no emesis or rescue medication) for delayed-phase CINV (24–120 hours) compared with the ondansetron regimen (P=.014). More patients receiving the subcutaneous granisetron regimen had delayed-phase CR (291/450; 64.7%) versus those receiving ondansetron (256/452; 56.6%); the absolute treatment difference was 8.0% (95% CI, 1.7–14.4; P=.014). Based on this trial, the FDA approved the use of a 10-mg dose of subcutaneous granisetron extended-release injection when used for the prevention of acute and delayed CINV associated with anthracycline plus cyclophosphamide chemotherapy (classified as HEC). The NCCN panel added a new recommendation in the 2017 update for a 10-mg dose of subcutaneous granisetron extended-release injection on day 1 only for patients receiving HEC when used in the antiemetic regimens recommended in the NCCN Guidelines based on the MAGIC trial and FDA approval (see AE-5, AE-6, AE-7, and AE-A; pages 886–888 and 890).28,46

Olanzapine

Olanzapine is an atypical antipsychotic agent that is also useful as an antiemetic agent; it is an antagonist of multiple receptors involved in CINV, including acetylcholine-muscarine, dopamine, histamine, and serotonin receptors.47 For the 2017 update, the NCCN panel added a new 4-drug regimen for HEC based on trial data: oral olanzapine (10 mg given once before HEC, then daily for 3 days), aprepitant or fosaprepitant, a 5-HT3 antagonist, and dexamethasone (see AE-5 and AE-7; pages 886 and 888). A phase III randomized trial assessed adding olanzapine or placebo to an antiemetic regimen of aprepitant or fosaprepitant, a 5-HT3 antagonist, and dexamethasone for patients receiving single-day HEC.48 Data showed that the 4-drug regimen with olanzapine increased the CR rate (no emesis, no rescue) compared with placebo during 3 time periods (<24 hours after chemotherapy, 25–120 hours, and overall 120-hour period): 86% versus 65% (P<.001), 67% versus 52% (P=.007), and 64% versus 41% (P<.001), respectively. More patients receiving the 4-drug regimen with olanzapine had no chemotherapy-induced nausea compared with placebo during the 3 time periods: 74% versus 45% (P=.002); 42% versus 25% (P=.002); and 37% versus 22% (P=.002), respectively. Based on results of this trial, the panel recommends (category 1) this 4-drug regimen with olanzapine as a first-line option. The panel also recommends that clinicians consider switching to the 4-drug regimen after the first cycle of HEC if patients have significant emesis using other antiemetic regimens such as (1) NK1 RA–containing regimens; or (2) the olanzapine, dexamethasone, and palonosetron regimen (see AE-10; page 889). For the 2017 update, the NCCN panel revised the recommendation for olanzapine for breakthrough emesis to category 1 (from category 2A) given the magnitude of superiority shown over another rescue agent in a double-blind, randomized, prospective trial.49

Common side effects with olanzapine included fatigue, drowsiness, and sleep disturbances. Olanzapine should be used with caution in elderly patients (see boxed warning/label indication regarding death in patients with dementia-related psychosis, and additional warnings and precautions [eg, type II diabetes and hyperglycemia]).50 A preliminary study suggests that a 5-mg dose of olanzapine may be considered in elderly or oversedated patients.51 To avoid excessive dopamine blockade, clinicians should be cautious when using olanzapine concurrently with metoclopramide, phenothiazines, or haloperidol. Other drug–drug interactions may be important when including olanzapine in the antiemetic regimen. Rarely olanzapine is associated with a serious skin reaction (drug reaction with eosinophilia and systemic symptoms [DRESS]) (see prescribing information), but other symptoms include a fever with a rash and swollen lymph glands, or swelling in the face; patients with these symptoms should seek medical care as soon as possible. Thoughtful patient selection is key in order to take all of these concerns into account when considering olanzapine. Note that olanzapine-containing regimens are not approved by the FDA for CINV.

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