European Journal of Pharmacology 722 (2014) 197–202

Contents lists available at ScienceDirect

European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): Content and implementation in daily routine practice Karin Jordan a,n, Richard Gralla b, Franziska Jahn a, Alex Molassiotis c a

Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle/Wittenberg, Ernst-Grube-Straße 40, 06120 Halle/Saale, Germany Department of Medicine Director, Oncology Research for the North Bronx Healthcare Network Albert Einstein college of Medicine New York, NY c School of Nursing & WHO Collaborating Centre for Community Health Services, The Hong Kong Polytechnic University, Hong Kong, China b

art ic l e i nf o

a b s t r a c t

Article history: Accepted 30 September 2013 Available online 21 October 2013

Over the past decades major improvements in the management of chemotherapy induced nausea and vomiting (CINV) were obtained. With the correct use of antiemetic drugs, CINV can be prevented in almost 70%, and even up to, 80% of patients. Treatment guidelines enable physicians to integrate the latest clinical research into their daily practice. The large volume of rapidly evolving clinical data has been summarised and incorporated into treatment recommendations by well-known and reliable institutions. These organisations include the Multinational Association of Supportive Care in Cancer (MASCC), the European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN). However, despite the availability of these guidelines, there is an emerging evidence that adherence to, and implementation of, treatment recommendations is less than optimal. This review will especially focus on the content of the current antiemetic guidelines and will address the important question of how these guidelines are implemented in routine practice. & 2013 Elsevier B.V. All rights reserved.

Keywords: Antiemetic therapy ASCO antiemetic guidelines MASCC/ESMO antiemetic guidelines NCCN practice antiemesis guidelines 5-HT3 serotonin receptor antagonists Neurokinin1 receptor antagonist

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emetogenicity of chemotherapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient related risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. 5-HT3 serotonin receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Tachykinin NK1 receptor antagonist, aprepitant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Steroids, dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Dopamine receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Summary of antiemetic guideline based management of CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. High emetogenic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Moderate emetogenic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Low emetogenic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Minimal emetogenic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Management of breakthrough and refractory CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Implementation of CINV guidelines in daily routine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

n

Corresponding author. Tel.: þ 49 345 557 2924; fax: þ 49 345 557 2950. E-mail address: [email protected] (K. Jordan).

0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.09.073

198 198 198 198 198 199 199 199 200 200 200 200 200 200 200 200 200 201 201 201

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1. Introduction The goal of antiemetic therapy is to completely prevent nausea and vomiting. Twenty years ago, nausea and vomiting were common adverse side effects of distinct types of chemotherapy and forced up to 20% of patients to postpone or refuse potentially curative treatment (Herrstedt, 2002). Continuous research over the past 25 years has led to steady improvements in the control of chemotherapyinduced nausea and vomiting (CINV). The introduction of the 5-HT3 receptor antagonists in the early 90s has been one of the most significant advances in supportive care of cancer patients (Gralla, 1989). Thereafter, another group of antiemetics, the tachykinin neurokinin1 receptor antagonist (NK1-receptor antagonist) were developed. The first drug in this class, aprepitant, was introduced in 2003 and was incorporated in the antiemetic guidelines. In 1998 the first international MASCC antiemetic guidelines, based on the results of the Perugia consensus conference, were published followed by the ASCO guidelines in 1999 (Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC), 1998; Gralla et al., 1999). In the last years all of these guidelines were updated (Basch et al., 2011; Ettinger et al., 2013; Roila et al., 2010). 2. Classification of CINV CINV classification is widely agreed upon the antiemetic community. CINV is classified into three categories: acute onset (mostly serotonin related); occurring within 24 h of initial administration of chemotherapy; delayed onset (in part substance P related); occurring 24 h to several days after chemotherapy treatment; and anticipatory nausea and vomiting, observed in patients whose emetic episodes are triggered by taste, odour, sight, thoughts, or anxiety due to a history of poor response to antiemetic agents or by inadequate antiemetic prophylaxis in the previous cycle of chemotherapy (Aapro et al., 2005; Roila et al., 2002). 3. Emetogenicity of chemotherapeutic agents The emetogenic potential of the chemotherapeutic agents used is the main risk factor for the degree of CINV. The international guidelines classify chemotherapeutic agents into 4 risk groups: high (490%), moderate (30–90%), low (10–30%) and minimal (o10%) (the figures in parentheses represent the percentage of patients having emetic episode/s when no prophylactic antiemetic protection provided) (Roila et al., 2006). Therefore, the recommended antiemetic prophylaxis is based upon the emetogenic category (Tables 1 and 2) (Hesketh et al., 1997). Especially in the MASCC/ ESMO guidelines the emetogenic potential of oral chemotherapeutic agents is recognised separately (Table 2) (Grunberg et al., 2011). The ASCO guideline did not imply any of the oral chemotherapeutic agents in their classification system (Basch et al., 2011). 4. Patient related risk factors Patient risk factors including young age, female gender, a history of low alcohol intake, experience of emesis during pregnancy, impaired quality of life and previous experience of chemotherapy are known to increase the risk of nausea and vomiting after chemotherapy (Grunberg et al., 2005; Kris et al., 2006; National Comprehensive Cancer Network (NCCN), 2007; Roila et al., 2006, 1991). The recommended antiemetic prophylaxis is not based upon patient characteristics that have been found to alter the risk of emesis. Although integrating a patient risk factor profile into the

Table 1 Emetogenic risk of intravenous chemotherapeutic agents. Adapted from Basch et al. (2011), Ettinger et al. (2013), Roila et al. (2010). High (emesis risk 490% without antiemetics) Carmustine, BCNU Cisplatin Cyclophosphamide ( 41500 mg/m²) Dacarbazine, DTIC Dactinomycin, Actinomycin D

Lomustine Mechlorethamine Pentostatin Streptozotocin

Moderate (emesis risk 30–90% without antiemetics) Altretamine Ifosfamide Carboplatin Irinotecan Cyclophosphamide ( o 1500 mg/m²) Melphalan i.v. Cytarabine ( 41 g/m²) Mitoxantrone ( 412 mg/m²) Daunorubicin Oxaliplatin Doxorubicin Temozolomide Epirubicin Treosulfan Idarubicin Trabectedin Low (emesis risk 10–30% without antiemetics) Asparaginase Mitoxantron ( o 12 mg/m²) Bortezomib Paclitaxel Cetuximab Pegasparaginase Cytarabine ( o 1 g/m²) Pemetrexed Docetaxel Teniposide Etoposide i.v. Thiopeta 5-Fluorouracil Topotecan Gemcitabine Trastuzumab Methotrexat ( 4100 mg/m²) Minimal (emesis risk o 10% without antiemetics) Bleomycin α-, β-, γ-Interferone Bevacizumab Melphalan per os Busulfan Mercaptopurine Chlorambucil Methotrexat ( o 100 mg/m²) Cladribine Thioguanine Cytarabin ( o 100 mg/m²) Vinblastine Fludarabin Vincristine Hormone Vinorelbine Hydroxyurea

Table 2 Emetic risk of oral chemotherapeutic agents. Adapted from Roila et al. (2010). High (emesis risk 490% without antiemetics) Hexamethylmelamine

Procarbazine

Moderate (emesis risk 30–90% without antiemetics) Cyclophosphamide Etoposide Imatinib

Temozolomide Vinorelbine

Low (emesis risk 10–30% without antiemetics) Capecitabine

Fludarabine

Minimal (emesis risk o 10% without antiemetics) Chlorambucil Erlotinib Gefitinib Hydroxyurea L-Phenylalanine mustard

Melphalan Methotrexate Sorafenib Sunitinib 6-Thioguanine

guidelines may appear logical, further research would be necessary before implementation. It is uncertain how practical it would be to try to implement this into routine practice.

5. Antiemetics With modern antiemetics, vomiting can completely be prevented in up to 70%–80% of patients (Hesketh et al., 2003b; PoliBigelli et al., 2003). Combination antiemetic regimens as suggested

K. Jordan et al. / European Journal of Pharmacology 722 (2014) 197–202

by all antiemetic guidelines have become the standard of care for the control of chemotherapy induced nausea and vomiting.

199

 No schedule is better than a single dose daily (exception ondansetron) given before chemotherapy.

5.1. 5-HT3 serotonin receptor antagonists

5.2. Tachykinin NK1 receptor antagonist, aprepitant

The 5-HT3 receptor antagonists are without doubt the most effective antiemetics in the prophylaxis of acute CINV. The wide experience acquired with these drugs in daily clinical practice since the early 1990s has confirmed the remarkable safety profile (Hesketh, 2008). The 5-HT3 receptor antagonists form the cornerstone of therapy for the control of acute emesis with chemotherapy agents with moderate to high emetogenic potential. In addition, newer data suggest the value of these drugs specifically the 5-HT3 receptor antagonist palonosetron for the treatment of delayed emesis associated with chemotherapy as well (Saito et al., 2009). Six 5-HT3 receptor antagonists, dolasetron, granisetron, ondansetron, palonosetron, ramosetron and tropisetron are available. In a metaanalysis comparing the four 5-HT3 receptor antagonists, dolasetron granisetron, ondansetron, and tropisetron the 5-HT3 receptor antagonists were equally effective except for an inferior efficacy of tropisetron in comparison to granisetron (Jordan et al., 2007a). The guideline based dose recommendation is shown in Table 3. The newest 5-HT3 receptor antagonist Palonosetron differs from the other 5-HT3 receptor antagonists in having both a higher receptor binding affinity and much longer half-life and phase III trials in the setting of moderately emetogenic chemotherapy (MEC) have suggested possible superiority to older 5-HT3 receptor antagonists (Eisenberg et al., 2003; Gralla et al., 2003). In light of these results, the updated MASCC/ESMO and ASCO guidelines recommend palonosetron as the preferred agent in patients receiving MEC (Basch et al., 2011; Roila et al., 2010). When administering 5-HT3 receptor antagonists, several points should be taken into consideration (Ettinger et al., 2005; Gralla et al., 1999; Kris et al., 2005):

The first tachykinin NK1 receptor antagonist aprepitant was approved in 2003. They exert their antiemetic action through the inhibition of substance P in the emetic pathways in both the central (mainly) and peripheral nervous systems. Aprepitant and fosaprepitant as an iv formulation is currently the only agent available in this class. Other tachykinin NK1 receptor antagonists such as netupitant and rolapitant are also under investigation. For netupitant in a fixed combination with palonsetron promissing final results of the pivotal trials were presented at the ASCO annual meeting 2013. Aprepitant, the oral and fosaprepitant, the intravenous administration formulation should be administered as indicated in Table 3. Aprepitant-containing regimens have been shown to significantly reduce acute and delayed emesis in patients receiving HEC (Hesketh et al., 2003a; Poli-Bigelli et al., 2003; Schmoll et al., 2006) and MEC, compared with regimens containing a 5-HT3-RA plus dexamethasone only (Rapoport et al., 2009; Warr et al., 2005). Aprepitant is well tolerated. The most common low grade adverse effects reported during clinical trials include, headache, anorexia, fatigue, diarrhoea, hiccups and mild transaminase elevation (Hesketh et al., 2003a; Poli-Bigelli et al., 2003; Schmoll et al., 2006; Van Belle et al., 2002; Warr et al., 2005). Aprepitant is metabolised by cytochrome P450 (CYP) 3A4. It is a moderate inhibitor and an inducer of CYP3A4 (Shadle et al., 2004) and has been shown to cause a twofold increase in the area under the plasma concentration curve (AUC) of dexamethasone, which is a sensitive substrate of CYP3A4. Consequently, dexamethasone doses should be decreased by approximately 50% when used in combination with aprepitant (Dando and Perry, 2004; Massaro and Lenz, 2005; McCrea et al., 2003; Shadle et al., 2004). Potential interactions with cytotoxic drugs metabolised by CYP3A4 were intensively studied (Aapro and Walko, 2010). In a study by Nygren et al., aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients (Nygren et al., 2005), the metabolism of cyclophosphamide is not significantly reduced in the presence of aprepitant (de Jonge et al., 2005).

 The lowest fully effective dose for each agent should be used; 

higher doses do not enhance any aspect of activity because of the receptor saturation. Oral and intravenous route are equally effective.

Table 3 Dose of antiemetics. Adapted from Basch et al. (2011), Ettinger et al. (2013), Roila et al. (2010). 5-HT3 receptor antagonist

Route

Recommended dose (once daily)

Ondansetron

8 mg twice daily 8 mg (0.15 mg/kg) 2 mg 1 mg (0.01 mg/kg) 5 mg

Ramosetron

p.o. i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. i.v. i.v.

Steroids Dexamethasone

p.o.

12 mg (high emetogenic with aprepitant) 20 mg w/o aprepitant 8 mg (moderate emetogenic)

Granisetron Tropisetron Dolasetron Palonosetron

i.v. NK1 receptor antagonist Aprepitant

p.o.

Fosaprepitant

i.v.

100 mg oral only – 0.5 mg 0.25 mg 0.3 mg

125 mg day 1, 80 mg day 2þ3 150 mg day 1 only

5.3. Steroids, dexamethasone Although not approved as an antiemetic, dexamethasone plays a major role in the prevention of acute and delayed CINV and is an integral component of almost all antiemetic regimen (Gralla and Clark, 1993; Grunberg, 2007; Jordan et al., 2007b). Dexamethasone is the most frequently used corticosteroid, although no study has evaluated the superiority of one corticosteroid over another in terms of efficacy (Gralla et al., 1999). All guidelines recommend the use of dexamethasone for the acute prevention of highly, moderately and low emetogenic chemotherapy. For the prevention of delayed emesis dexamethasone is recommended in combination with aprepitant in highly emetogenic chemotherapy including anthracycline based regimens by the ASCO guidelines and in moderate emetogenic chemotherapy as dexamethasone monotherapy. When combined with aprepitant dose reduction of dexamethasone (dexamethasone is a sensitive substrate of CYP3A4) has to be undertaken. For the prevention of acute CINV, 20 mg (12 mg when coadministered with aprepitant) in high emetogenic chemotherapy and a single dose of 8 mg dexamethasone should be the dose of choice for moderate emetogenic chemotherapy (Table 3). These dose recommendations are largely driven by the studies from the Italian Group for Antiemetic Research (1998, 2004).

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Acute CINV: The guidelines suggested unanimously a combination of 5-HT3 receptor antagonists, dexamethasone and aprepitant/fosaprepitant within the first 24 h (Table 4). Delayed CINV: Trials have indicated that between 60% to nearly 90% of patients receiving cisplatin will experience delayed emesis if not given preventive antiemetics. Therefore an appropriate prophylaxis is indispensable. All guidelines suggested the combination of dexamethasone and aprepitant. If fosaprepitant was given on day 1, no further application of fosaprepitant is necessary.

5.4. Olanzapine Olanzapine, an atypical antipsychotic drug exhibits interesting antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting (Bymaster et al., 1996). In vitro and in vivo receptor binding studies showed that olanzapine exhibited a rich binding profile with high affinity for dopamine D1–D5, 5HT2A, 5HT2C, 5HT3, 5HT6, muscarinic, alpha1-adrenergic, and histamine H1 receptors (Bymaster et al., 1999; Zhang and Bymaster, 1999). Adverse effects reported are typical of those seen with other antipsychotics and include sleepiness, dizziness, weight gain and dry mouth (Lohr, 2008). By the ASCO guidelines olanzapine is recommended as an adjunctive drug and also for patients who experience nausea and vomiting despite optimal antiemetic prophylaxis (Basch et al., 2011). This recommendation is supported by the latest study by Navari where olanzapine showed superior efficacy in comparison to metoclopramide in the rescue setting (Navari et al., 2013).

6.2. Moderate emetogenic chemotherapy Acute CINV: Patients undergoing moderately emetogenic chemotherapy regimens should be given a combination of a 5-HT3 receptor antagonist, preferably palonosetron and the corticosteroid dexamethasone. In this setting, the key question is whether aprepitant should be part of the antiemetic prophylaxis. The ASCO guideline stated that the triple combination (5-HT3 receptor antagonist, dexamethasone and aprepitant) can be considered in selected patients, whereas the MASCC/ESMO guidelines only refers to the combination of palonosetron and dexamethasone in this setting. Delayed CINV: Dexamethasone is the preferred agent to use. Nonetheless, when aprepitant was used for the prevention of acute CINV than aprepitant should be used also for the prophylaxis of delayed CINV. 5-HT3 receptor antagonist can be used as an alternative. However, if palonosetron was the 5-HT3 receptor antagonists of choice a repeated application is not useful.

5.5. Dopamine receptor antagonists Prior to the introduction of 5-HT3 receptor antagonists, dopamine receptor antagonists formed the basis of antiemetic therapy (Feyer and Jordan, 2011; Gralla et al., 1981). These agents can be subdivided into phenothiazines, butyrophenones and substituted benzamides (Hesketh, 2008; Jordan et al., 2007b). One of the most frequently used benzamides is metoclopramide. Before establishing the 5-HT3 receptor antagonists in CINV prophylaxis, metoclopramide, usually at high doses and in combination with a corticosteroid, played a primary role in the management of acute CINV (Gralla et al., 1981). However, in patients receiving cisplatin-based chemotherapy, the effects of conventional doses of metoclopramide are not significantly different from placebo. Consequently, current guidelines do not recommend metoclopramide for prevention of acute CINV. The current ASCO guidelines recommend that metoclopramide be reserved for patients intolerant of or refractory to 5-HT3 receptor antagonists, dexamethasone and aprepitant (Basch et al., 2011).

6.3. Low emetogenic chemotherapy In patients receiving chemotherapy of low emetic risk, a single agent, such as a low dose of a corticosteroid, is effective. In principle 5-HT3 receptor antagonists are not constituents of the prophylactic armamentarium. In this area, over-treatment has been observed in clinical practice and should be avoided; for example, a patient who is treated with paclitaxel does not need a 5-HT3 receptor antagonist routinely.

5.6. Benzodiazepines 6.4. Minimal emetogenic chemotherapy They can be a useful addition to antiemetic regimens in certain circumstances such as anxiety and risk reduction of anticipatory CINV or in patients with refractory and breakthrough emesis as suggested by all antiemetic guidelines.

It is suggested by all guidelines that for patients treated with agents of low emetic risk, no antiemetic drug should be routinely administered before chemotherapy. 6.5. Management of breakthrough and refractory CINV

6. Summary of antiemetic guideline based management of CINV “Breakthrough CINV” is defined as an event that happens in spite of optimal preventative treatment. “Refractory CINV” recurs in subsequent cycles of therapy when all previous preventive and rescue treatments failed. If optimal treatment has been given as prophylaxis, repeated dosing of the same agents is unlikely to be successful; an addition of dopamine receptor antagonists

6.1. High emetogenic chemotherapy In contrast to the MASCC/ESMO guidelines combined anthracycline and cyclophosphamide regimens were reclassified by the ASCO guidelines as high emetogenic. Table 4 Antiemetic prevention based on the emesis risk category. Adapted from Basch et al. (2011), Ettinger et al. (2013), Roila et al. (2010) Emesis risk

Acute phase (day 1)

Followed by Delayed phase (day 2–5)

High (including AC based chemotherapy)

5-HT3 receptor antagonistþdexamethasone þaprepitant (or fosaprepitant only on day 1) 5-HT3 receptor antagonist, preferably palonosetron þdexamethasone Dexamethasone None

-

Dexamethasone for 3 days þaprepitant for 2 days

-

Dexamethasone or as an alternative 5-HT3 receptor antagonist (if palonosetron was not used on day 1) for three days None None

Moderate Low Minimal

-

K. Jordan et al. / European Journal of Pharmacology 722 (2014) 197–202

(metoclopramide) might be useful or adding other agents such as benzodiazepines or neuroleptics. Olanzapine, an atypical neuroleptic should be considered.

7. Implementation of CINV guidelines in daily routine The use of guidelines can contribute to improved clinical outcomes. In a European observational study (N ¼ 991) it was shown that complete response related to CINV was 59.9% in the group of patients which had received guideline-consistent antiemetics and 50.7% in the group not receiving guideline-consistent antiemetics (P ¼0.008) (Aapro et al., 2012). Similar data was shown in a single-centre UK observational study (N ¼102) (Molassiotis et al., 2008). However, both the above studies, among several others, clearly show that antiemetic guidelines are not used frequently; for example Aapro et al. showed that adherence to antiemetic guidelines in their sample was 55% for acute and 46% for delayed CINV, whereas for overall CINV this was 29% (Aapro et al., 2012). The reasons for this, generally low, use of guidelines is multifactorial and common across all fields of medicine, not just in relation to antiemetic guidelines. A key aspect for the use of guidelines is the behaviour of the clinician, and often changing that behaviour is difficult. Physician knowledge, clinician and institutional education, attitudes to guidelines, clinician agreement with them, awareness of their existence and familiarity with them, and expectations all place an important role (Grunberg, 2009; Kaiser, 2005). A small number of studies have tested different approaches to improve adherence with antiemetic guidelines, all hampered by methodological shortcomings. Nevertheless, some important messages derive from these studies. It is clear that passive dissemination of educational materials is an ineffective approach (Kaiser, 2005). Statistical process control (SPC) charts were created in a study to measure the effect of guideline development and distribution, a visiting lecturer acting as opinion leader, and ongoing feedback to clinicians regarding non-compliance (Mertens et al., 2003). The results were disappointing as the clinicians' antiemetic prescribing pattern did not improve with any of the previously outlined methods. The only notable exception is when clinicians received feedback about their patients CINV outcomes, when they accepted that there is a need to follow the guidelines and instituted nurse practitioner prescribing. This led to almost complete adherence with the antiemetic guidelines and a measurable reduction in day 3 nausea. Hence, sharing the patient CINV experience improved outcomes. In a similar fashion, a Canadian study (N¼ 195 patients) tested the effects of a pharmacist-driven multifaceted intervention programme over a period of 4 months, which included guideline dissemination, use of opinion leaders, interactive educational workshops, therapeutic reminders in the form of preprinted orders, clinical interventions by pharmacists for the event of inappropriate antiemetic orders, and physician audit and feedback(Dranitsaris et al., 2001). This six-step implementation programme produced improved clinical outcomes and may have saved unnecessary health care funds. In another study using a standardized chemotherapy order check box labelled “Antiemetics as per Guidelines” in the chemotherapy order sheet improved adherence to guidelines from 73% to 98% (Nolte et al., 1998). The authors postulated that antiemetic drug expenditures decreased from a projected US$ 2.8 million to 1.3 million annually. A study in Italian oncology centres evaluated the use of simple diffusion of guidelines (77 centres) or simple diffusion combined with an “audit and feedback” strategy (26 centres) and a triple strategy with the previous two plus an educational outreach visit (Roila, 2004). Some improvement was seen with the simple diffusion, but this was only for high-moderate emetogenic chemotherapy, but

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there were no significant differences with regards to cisplatin-based chemotherapy and the inappropriate use of antiemetics in the low emetogenic chemotherapy was common. Similar results were reported with the double strategy too. However, the triple strategy had a significant additional effect on cisplatin-based chemotherapy. Early studies from the wider field of medicine also support the idea of using financial incentives or penalties as a means of negative conditioning to improve adherence with and implementation of clinical guidelines. However, Kaiser (2005) questions “whether negative reinforcements to change [physician] behaviour is really an intelligent approach”. However, there is no research support for these approaches in relation to antiemetic guidelines. Beside the problem of implementation of guidelines there are still barriers to managing CINV for patients and care providers, as shown in a doctor and patient survey 2012. While patients tried to limit the number of their medications, many providers reported financial and patient-related factors to be the most common barriers (Salsman et al., 2012). Hence, multiple strategies need to be used concurrently in order to improve adherence and implementation of antiemetic guidelines, as single approaches seems to have little, if any, effect. The key approach seems to be patient feedback on outcomes. Patient-mediated approaches and computerised decision-support systems may be other promising approaches to be used in the future, probably alongside other strategies described earlier (Kaiser, 2005).

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