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Prevention of nausea and vomiting in adult cancer patients receiving tumour-directed therapy
Irrespective of the timing of their onset – acute, delayed or anticipatory – and of the underlying causative mechanisms, cancer treatment-induced nausea and vomiting represent an important burden on the quality of life for cancer patients. Prevention of these sequelae is therefore an essential component of supportive care in cancer, helping patients to better accept and tolerate their anti-neoplastic treatment and related emetic side effects.
Prevention of nausea and vomiting in adult cancer patients receiving tumour-directed therapyis the first edition in a series of booklets focusing on the quality of life of cancer patients and provides essential guidance in treatment decisions for healthcare professionals. This first booklet addresses chemotherapy- and radiotherapy-induced nausea and vomiting (CINV and RINV) in adult cancer patients. It includes, next to brief chapters on the pathophysiology of CINV and RINV, an overview of general risk factors and the emetogenicity of individual cancer therapies, and the currently available anti-emetic drugs and anti-emesis treatment guidelines, including the latest recommendations. The booklet, written by a team of independent experts in oncology and supportive care in cancer, is published with the generous help of Helsinn Healthcare SA in Lugano, Switzerland and reflects Helsinn's commitment to quality of life in the context of oncology. The present edition, as well as future issues in this series, will also feature as e-books in the Quality of Life in Oncology Resource Centre (www.qualityoflifeinoncology.org).
We hope that this booklet will help you in your daily practice, and that it can be of guidance in assessing the risk profile of your individual patients and in selecting the best anti-emetic treatment, thereby reducing the burden of these much feared side effects of anti-cancer treatment.
Dr Matti Aapro received his medical degree from the Faculty of Medicine, University of Geneva, Switzerland. He was subsequently a fellow at the Arizona Cancer Center in Tucson, USA, and later the founding chair of the Medical and Radiation Therapy Department at the European Institute of Oncology in Milan, Italy.
He is presently Dean of the Multidisciplinary Oncology Institute, Genolier, Switzerland. Dr Aapro serves as Executive Board member of the International Society for Geriatric Oncology (SIOG) and as director of the Sharing Progress in Cancer Care programme of the European School of Oncology (ESO). Dr Aapro is a board member and past-President of the Multinational Association for Supportive Care in Cancer (MASCC). He was a member of the Board of the European Organization for Research and Treatment of Cancer (EORTC) and of the European Society for Medical Oncology (ESMO).
Dr Aapro is Editor-in-Chief ofCritical Reviews in Oncology/Hematology, as well as Associate Editor for the geriatric section of theOncologist, and Editor-in-Chief ofwww.qualityoflifeinoncology.org. He is also founding editor of theJournal of Geriatric Oncology. He is past Associate Editor forAnnals of Oncologyand a member of several editorial boards. He has authored more than 300 publications and his major interests are new drug development, breast cancer, cancer in the elderly, and supportive care.
Dr Aapro is Doctor Honoris Causa of the University of Tampere (2013) and has received the 2010 Acta Oncologica Award and the 2012 ASCO B.J. Kennedy prize.
Dr Karin Jordan graduated from Martin Luther University of Halle-Wittenberg, Germany, after internships in the bone-marrow transplantation program at the University of California, San Diego, USA and surgery at the University of Newcastle, UK. Following a number of posts at the University Hospital, Halle, and Bernward Hospital, Hildesheim, she was appointed as a specialist in internal medicine and haematology/oncology. Since 2010 she has been Associate Professor of Medical Oncology and Supportive Care in the Department of Haematology/Oncology at the University Hospital, Halle. She has been the vice executive director of the ethics committee at the University of Halle since 2009. Dr Jordan has served as a board member of MASCC/ESMO Antiemetic Guideline Consensus Panel 2009 in Perugia, Italy, and the German Cancer Society Consensus Panel on paravasation induced by cytotoxic agents. She holds the co-chair of Supportive Care study group within the German Society of Medical Oncology (AIO) and is the associate chair of the German Association of Supportive Care in Oncology, Rehabilitation and Social Medicine (ASORS). Dr Jordan is also a member of the ESMO Young Oncologist Committee. She became the coordinator of the S3 Guidelines on Supportive Care within the Oncology Guideline Program of the German Cancer Society in 2013 and associate editor ofAnnals of Oncologyin 2014.
She has authored and co-authored more than 100 publications and her major area of interest is supportive care with a special focus on anti-emetic treatment of chemotherapy-induced nausea and vomiting, and side effects of new drugs.
Dr Petra Feyer studied medicine at the Universities of Sofia, Bulgaria and Leipzig, Germany. At the University of Leipzig she undertook a residency in the Department of Radiology before becoming consultant and then senior consultant in the Department of Radio-oncology. As well as undertaking fellowships at the Royal Marsden Hospital in London and Surrey and at the Western Infirmary, Glasgow, UK, she trained at the German Cancer Research Institute, Heidelberg. In 1994 she became Assistant Professor at the Charité University Hospital, Berlin. She moved in 1999 to the University of Cologne where she became Professor of Radiation Oncology. Since 2000 she has also been Director of the Clinic of Radiotherapy, Radio-oncology and Nuclear Medicine at the Vivantes Clinics, Neukölln, Berlin and Professor of Radiation Oncology at the Charité University Medicine Berlin.
Dr Feyer has served as a board member of the MASCC and was its secretary from 2006 to 2008. She is a faculty member of the ESMO, President of the German Association of Supportive Care in Oncology, Rehabilitation and Social Medicine (ASORS), Vice President of the Cancer Society of Berlin, and is a member of a number of national and international radio-oncology and haemato-oncology societies.
Dr Feyer has authored and co-authored more than 250 articles in national and international journals and books. Her principal areas of clinical interest are quality of life and supportive care in cancer patients, especially minimising side effects of radio- and chemotherapy, optimising multimodal treatment strategies in oncology and palliative radio-oncological treatment modalities.
ANS: autonomic nervous system
ANV: anticipatory nausea and vomiting
AP: area postrema
AVP: plasma arginine vasopressin
ASCO: American Society of Clinical Oncology
b.i.d.: twice daily
CINV: chemotherapy-induced nausea and vomiting
CNS: central nervous system
CR: complete response
CTZ: chemoreceptor trigger zone
DMV: dorsal motor nucleus of the vagus
DNV: delayed nausea and vomiting
EC: enterochromaffin cells
ESMO: European Society of Medical Oncology
FDA: Food and Drug Administration
HB[I]: half body [irradiation]
HEC: highly emetogenic chemotherapy
MASCC: Multinational Association of Supportive Cancer Care
MEC: moderately emetic chemotherapy
NCCN: National Comprehensive Cancer Network
NK-1 RA: neurokinin-1 receptor antagonist
NTS: nucleus tractus solitarius
RA: receptor antagonist
RINV: radiotherapy-induced nausea and vomiting
SP: substance P
TB[I]: total body [irradiation]
UB[I]: upper body [irradiation]
VRG: ventral respiratory group
Chapter I. Background
Section 1. Introduction
Despite advances over recent decades in the treatment of chemotherapy-induced nausea and vomiting (CINV), their control is still a problem ( Janelsins et al., 2013 ). While improvements have led to the relief of vomiting in some 70–80% of cases, nausea alone ( Russo et al., 2014 ; Andrews and Sanger, 2014 ), and anticipatory and delayed nausea and vomiting ( Hickok et al., 2005 ; Aapro, 2007 ; Roila et al., 2010 ; Kamen et al., 2014 ) remain often intractable and distressing symptoms for patients, and are thus a considerable area of study ( Hesketh, 2008 ; Flaherty, 2013 ; Caracuel et al., 2014 ; Feyer et al., 2014 ). With the acceptance that anti-emetics generally have greater efficacy against vomiting than against nausea has come the recognition of nausea as a separate clinical challenge and focal point for research ( Andrews and Sanger, 2014 ). Thus the quest for the perfect anti-emetic continues.
For patients undergoing radiotherapy, treatment-induced nausea and vomiting are generally less debilitating than CINV but are still clinically important and distressing side effects ( Feyer et al., 2014 ). CINV and radiotherapy-induced nausea and vomiting (RINV) can have a major effect on patients' quality of life and thus adherence to treatment ( Jordan et al., 2014 ; Feyer et al., 2014 ). They may also lead to significant clinical conditions that can be life threatening, such as dehydration and metabolic imbalance ( Feyer et al., 2014 ; NCCN, 2013 ).
Section 2. The development of anti-emetic treatment
The first chemotherapy agent, nitrogen mustard, and other early anti-neoplastic drugs caused varying degrees of nausea and vomiting. However, the clinical significance of the problem was not then fully appreciated ( Gralla, 1993 ). It was only in the late 1970s, with the introduction of cisplatin, a highly emetic therapy, that research into anti-emetics really began ( Alderden et al., 2006 ; Wong and Giandomenico, 1999 ). Since then, greater understanding of the pathophysiology and psychology of the emetic reflex has led to many therapeutic advances ( Sanger and Andrews, 2006 ). Agents used for CINV also form the basis of treatment for RINV. As the number and complexities of anti-neoplastic therapies increased, so did those for CINV; as a result the first MASCC guidelines for CINV were instituted in 1997 at the 1st Perugia Consensus Conference on anti-emetic therapy and the first ASCO guidelines in 1999; guidelines are also produced by the NCCN. These consensus guidelines are published and regularly updated. See Table 1 for an historical perspective of anti-neoplastic and anti-emetic therapies.
|1902||First use of radium to treat cancer||Grubbe, 1902|
|1939||Use of hormones for prostate cancer||Huggins and Hodges, 1941|
|1946||Mustine officially used to treat lymphomas (high emetic potential)||Goodman et al., 1946|
|1953||Chlorpromazine recognised as anti-emetic; leads to development of phenothiazine group of drugs. Wang and Borison identified the emesis chemoreceptor trigger zone in the area postrema||Courvoisier et al., 1953 ;
Brand et al., 1954 ;
Wang and Borison, 1950
|1958||Vinca alkaloids identified as anti-neoplastic; (low emetic potential)||Noble et al., 1958|
|1960||Phenothiazines introduced as anti-emetics||Black, 1960|
|1964||Metoclopramide found to have anti-emetic efficacy but not against CINV||Justin-Besançon and Laville, 1964|
|1969||Platinum compounds recognized as anti-tumour agents||Rosenberg et al., 1969|
|1970s||Cisplatin widely used; (high emetic potential with no effective anti-emesis treatment)||Alderden et al., 2006|
|Cannabinoids used as anti-emetics||Vincent et al., 1983|
|1980s||High-dose metoclopramide used with cisplatin||Gralla, 1983|
|Steroids introduced as anti-emetics||Aapro and Alberts, 1981|
|Anti-emetic action of 5-HT3 receptor antagonists (RA) discovered||Miner and Sanger, 1986|
|1990s||5-HT3 receptor antagonists widely used||Aapro, 1993|
|1997||1st Perugia Consensus Conference on anti-emetic therapy (MASCC)||Roila, 1998|
|1999||Anti-emetics: first ASCO Clinical Practice Guidelines||Gralla et al., 1999|
|2003||Palonosetron: a second generation 5-HT3 RA||Gralla et al., 2003|
|Aprepitant: first NK-1 RA approved||Hesketh et al., 2003a|
|Olanzapine: phase I trial with granisetron and dexamethasone||Pasik et al., 2004|
|2004||2nd Perugia Consensus Conference on anti-emetic therapy (MASCC/ESMO)||Roila et al., 2006|
|Olanzapine: phase II trial||Navari et al., 2005|
|2006||Anti-emetics: ASCO Clinical Practice Guidelines Update||Kris et al., 2006|
|2009||3rd Perugia Consensus Conference on anti-emetic therapy||Roila et al., 2010|
|2011||Anti-emetics: ASCO Clinical Practice Guidelines Update||Basch et al., 2011|
|2012||NK-1 RA rolapitant in development in a ferret emesis model||Duffy et al., 2012|
|2013||MASCC/ESMO Antiemetic Guideline 2013||MASCC, 2013|
|2014||Olanzapine's use supported in combination regimens, and as a single agent in breakthrough CINV||Hocking and Kichenadasse, 2014|
|A new class of broad-spectrum anti-emetic is explored in the shrew||Darmani et al., 2014|
|L-type calcium channel antagonists, e.g., nifedipine, amlodipine||Zhong et al., 2014|
|NEPA, fixed-dose anti-emesis combination netupitant and palonosetron: phase III||Aapro et al., 2014|
|Rolapitant phase III||Rapoport et al., 2014|
Section 3. Anti-emetic agents
Table 2 presents an overview of the main groups of anti-emetic agents.
|Drug type||First used||Comments|
|5-HT3 receptor antagonists, e.g., ondansetron||Ondansetron, approved by FDA 1991||One of the most significant advances in the treatment of CINV and RINV ( Aapro, 1993 )|
|Corticosteroids, e.g., dexamethasone||In use from the 1980s||Particularly useful in acute and delayed emesis, and in combination with other anti-emetic agents ( Aapro and Alberts, 1981 )|
|NK-1 receptor antagonists, e.g., aprepitant||Aprepitant, approved 2003||Particularly useful in combination with standard anti-emetics and especially in patients receiving cisplatin ( Hesketh et al., 2003a )|
|Dopamine antagonists, e.g., metoclopramide||In use from the 1980s||Most efficacious of dopamine antagonists for CINV ( Johnston et al., 2014 )|
Chapter II. Chemotherapy-induced nausea and vomiting: pathophysiology, psychological aspects, and classification
Identifying the physiological and psychological factors that make individuals susceptible to nausea and vomiting, and better understanding of the mechanisms leading to therapy-induced nausea, and anticipatory and delayed symptoms are key to improving treatment.
Section 1. Pathophysiology of nausea and vomiting
The central nervous system (CNS) plays a key role in the physiology of nausea and vomiting, receiving and processing a variety of emetic stimuli and generating signals, which at their target organs and tissues eventually lead to the spectrum that includes nausea, retching and vomiting. The existence of a vomiting centre was first suggested in 1950 ( Wang and Borison, 1950 ), but the simple concept of one discrete emetic centre that could be manipulated pharmacologically or surgically has been challenged ( Andrews and Horn, 2006 ), and although progress has been made in describing the physiological and neurophysiological pathways that are involved in emesis ( Figure 1 ), the precise circuitry is yet to be identified ( Babic and Browning, 2014 ).
Nausea, vomiting and retching are three separate phenomena, which may, but do not always, occur together ( Rhodes and McDaniel, 2001 ). They are part of a complex reflex ( Figure 2 ) with multiple contributory pathways ( Hesketh, 2008 ), which are still not fully understood, and when considering treatment they need to be evaluated independently ( Andrews and Sanger, 2014 ).
Section 2. Emetic pathways resulting from cytotoxic chemotherapy
Chemotherapy-induced nausea and vomiting involves the CNS and peripheral centres, neurotransmitters and receptors ( Figure 3 ).
Section 3. Neurotransmitters and their receptors
Serotonin(5-hydroxytryptamine, 5-HT) was first isolated in crystalline form and named in 1948 by Rapport et al. (1948) . It is a monoamine neurotransmitter found primarily in the GI tract, platelets and CNS. It plays a pivotal role in gastrointestinal regulation ( Beattie and Smith, 2008 ). Approximately 90% of the body's serotonin is located in the enterochromaffin cells (EC) of the gut, where it regulates intestinal movement in response to food in the lumen, and is believed to play an important role in acute CINV. After exposure to chemotherapy or radiotherapy, excess 5-HT is released from the EC and binds with the 5-HT3 receptors on the terminal vagal afferents ( Blackshaw et al., 2007 ).
The5-HT3 receptor is one of many 5-HT receptors and appears to be the most important in acute CINV. It is also thought to play a more minor role in delayed nausea and vomiting (DNV). Binding to the 5-HT3 receptors at the vagal afferents transmits information to the area postrema in the brain, initiating acute CINV.
The 5-HT3 receptor is the only monoamine neurotransmitter receptor that functions as a ligand-operated ion channel ( Figure 4 ). It has been identified only in neurons in the central and peripheral autonomic, sensory and enteric systems, with the highest brain densities located in the AP, NTS and the dorsal vagal motor nucleus. The receptors mediate a rapid depolarising response associated with an increase in membrane conductance following the opening of cation-selective channels; the influx of sodium and calcium contributing importantly to the response. This is usually described as a cooperative effect in which the occupation of one receptor subunit enhances the binding of other agonist molecules. The 5-HT3 receptor has probably evolved to mediate rapid synaptic events.
The hypothesis that 5-HT3 receptor antagonists (RAs) might be anti-emetic was confirmed in a number of studies including those showing that high-dose metoclopramide is effective against cisplatin-induced emesis ( Gralla, 1983 ). Usually, metoclopramide prevents nausea and vomiting via its D2 receptor antagonist activity, but at higher doses its 5-HT3 receptor antagonism may also contribute to an anti-emetic effect. The results of studies led to the development and clinical study of the first 5-HT3 RA for CINV ( Leibundgut and Lancranjan, 1987 ). DNV and prolonged nausea and vomiting may be the result of substance P (SP) being released in the gut ( Kris et al., 1997 ).
Substance P(SP) was first discovered in 1931 ( von Euler and Gaddum, 1931 ) but was not synthesised until the early 1970s ( Chang et al., 1971 ), and it was much later that its role as a neurotransmitter was first suggested ( Nicoll, 1980 ; Hökfelt et al., 2001 ); it preferentially binds to theneurokinin-1 receptor. SP is a neuropeptide that acts as a neurotransmitter or modulator in the peripheral and central nervous system by preferentially binding to the NK-1 receptor, and has been shown to be involved in the transmission of stimuli such as pain, mood, anxiety, stress, nausea and vomiting. Early studies showed that it induced vomiting in dogs ( Carpenter et al., 1983 ). Its role as a neurotransmitter in CINV was suggested by studies throughout the 1990s ( Kris et al., 1997 ).
Dopaminebinds with the dopamine1 (D1) and D2 receptors both found in the CNS, the latter being located in the CTZ. However, dopamine's role in CINV, though it may be involved in triggering nausea and vomiting and may play a part in acute and delayed CINV ( Darmani et al., 2011 ), is still unclear. However, dopamine receptor antagonists are suggested to have effects against dyspepsia ( Hesketh, 2008 ), and dopamine receptor antagonists such as metoclopramide are effective in treating CINV ( Rudd and Andrews, 2005 ).
Section 4. Psychological aspects of nausea and vomiting
Psychological factors are increasingly thought to affect the frequency and severity of treatment-related nausea and vomiting and are thought to play an important part in anticipatory nausea and vomiting (ANV). Historically up to 20% of patients experience anticipatory nausea before any cycle of treatment and up to 30% report it by the fourth cycle of chemotherapy ( Morrow and Roscoe, 1997 ), with the risk increasing with further cycles of treatment ( Stockhorst et al., 2007 ).
In cancer patients, high levels of anxiety are associated with treatment ( Roscoe et al., 2011 ) and with ANV ( Roscoe et al., 2004 ), probably due to both the emetogenic effect of anxiety itself and the increased sensitivity to somatic cues experienced by highly anxious individuals. Indeed, Cella et al. report 63% of Hodgkin's disease survivors who continued to experience ANV – 80% who experienced anxiety and 5% vomiting – from 6 to 140 months after completion of treatment ( Cella et al., 1986 ). A computational prediction of patients susceptible to CINV has been developed and reported ( Yap et al., 2012 ). Principal component analysis was used to analyse clinical endpoints of complete response (no vomiting and no rescue anti-emetics), complete protection (no vomiting, no significant nausea, and no rescue anti-emetics), and complete control (no vomiting, no nausea, and no rescue anti-emetics) in 710 patients with certain anxiety characteristics. Patients were undergoing anti-neoplastic therapy for breast, head and neck, and gastrointestinal cancers. CINV and anti-emetic use were recorded in a standardised diary. Patients suffered delayed CINV: 58% of patients achieving complete response, 42% complete protection, and 27% of patients achieving complete control. Patient-recorded anxiety symptoms – fear of dying, fear of the worst, unable to relax, hot/cold sweats, nervousness, faintness, and numbness – were identified as CINV predictors. Most patients reported delayed nausea with increasing symptoms as anti-neoplastic treatment progressed. The study shows the usefulness of identifying patients with specific anxiety characteristics, which might enable physicians to tailor anti-emetic treatment for highly anxious patients ( Yap et al., 2012 ).
Three main factors are related to and will increase the occurrence of acute and delayed CINV and ANV: classic conditioning (see Figure 5 ), which is particularly linked to ANV; demographic and treatment-related factors, from which ANV may be predicted; and negative experiences and anxiety, which can lead to or increase sensitivity to emetic stimulus. Anticipatory nausea has been reported by 30% of patients who have had previous treatment and anticipatory vomiting by 20% of patients ( Aapro et al., 2005 ).
The mechanism of classic conditioning essentially describes the process by which a conditioned stimulus, such as a nurse, treatment room, or a particular odour, is paired with an unconditioned stimulus, such as chemotherapy, which produces an unconditioned response of nausea and vomiting. When the conditioned stimulus and unconditioned stimulus are paired over time, the conditioned stimulus will eventually, of itself, elicit a conditioned, or learned, response of nausea, vomiting or both ( Matteson et al., 2002 ). Thus contact with nursing staff, the sight of the treatment room, or the smell associated with the treatment will produce ANV ( Figure 5 ).
Certain situational, demographic and treatment-related factors are correlated with ANV though no risk factors have been identified as definitely causative (see Table 3 ).
|<50 years of age|
|Susceptibility to motion sickness|
|Greater reactivity of the autonomic nervous system and slower reaction time|
|Morning sickness during pregnancy|
|Nausea and vomiting after last chemotherapy session|
|Feeling warm or hot all over after previous chemotherapy session|
|Sweating after previous chemotherapy session|
|Generalised weakness after previous chemotherapy session|
|Percentage of infusions of chemotherapy followed by nausea|
|Longer latency of onset of post-treatment nausea and vomiting|
|Emetogenic potential of chemotherapeutic agent used|
However, though age, gender, susceptibility to motion sickness and other factors are recognised as being associated with susceptibility to therapy-induced nausea and vomiting, it is not generally possible pre-anti-neoplastic therapy to identify specific patients for whom treatment must therefore change. As adherence to international anti-emetic guidelines is not the case in many patients' management, it is difficult to confidently identify other potential causes for therapy-related nausea and vomiting. Guideline adherence is therefore largely recommended with modification for subsequent cycles if anti-emetic treatment is unsatisfactory ( Warr, 2014 ).
Section 5. Types of nausea and vomiting experienced with anti-neoplastic therapy
Table 4 classifies the different types of nausea and vomiting experienced with anti-neoplastic therapy.
|Acute||Within 24 hours of treatment (CINV/RINV)||Mainly by 5-HT release from EC cells in the gut (CINV only)|||
|Delayed||Beyond 24 hours and up to 5–7 days (CINV/RINV)||Mainly SP mediated; disruption of GI motility (CINV only)||[1–3]|
|Anticipatory||Prior to either therapy||Possible after one cycle of treatment; involves classic conditioning (CINV and RINV)||[3–6]|
CINV: chemotherapy-induced nausea and vomiting; RINV: radiotherapy-induced nausea and vomiting; EC: enterochromaffin cells; SP: substance P; GI: gastrointestinal.
Chapter III. Chemotherapy: emetic potential and individual risk factors
The frequency and degree of nausea and/or vomiting in patients receiving anti-neoplastic therapy will depend on a number of factors, including the agents used (a prominent risk factor), their dosage and route of administration, and patient characteristics ( Roila et al., 2006 ).
Section 1. Emetogenicity of chemotherapy
Chemotherapies are divided into four emetogenic risk groups: high, moderate, low, minimal ( Grunberg et al., 2005 ; Hesketh et al., 1997 ; Kris et al., 2006 ; Grunberg et al., 2011a ). The emetic potential of the specific treatment, the dosage, the frequency, and the method of administration all affect the occurrence of CINV. Without an anti-emetic prophylaxis, cisplatin will cause severe vomiting in almost 99% of patients, whilst vincristine, for example, will cause minimal vomiting.
Prior to the 2004 Perugia Antiemetic Consensus Conference, there were five levels of emetogenic classification for agents: <10%, 10–30%, 30–60%, 60–90%, and >90%, with the 30–60% range considered moderately emetogenic ( Hesketh et al., 1997 ). These levels were designed by consensus after the introduction of the 5-HT3 anti-emetics, to provide a practical and easy route for assessing the emetogenic potential of individual and combination chemotherapeutic agents in the first 24 hours after administration; they also provided the framework for anti-emetic guidelines, thus ensuring optimal use of the new 5-HT3 RAs.
After the 2004 Perugia conference, this classification was changed to four levels by combining the earlier 3 and 4 levels (30–60% and 60–90%, respectively) to a single group of 30–90%. The change was made because clinical differentiation between the groups had become difficult with the introduction of new anti-emetic agents ( Grunberg et al., 2005 ). However, this broad range of emetogenic risk (30–90%) makes it difficult to give one recommendation for anti-emetic treatment for these agents. Therefore, it may be necessary in the future to ‘reclassify’ some agents, such as carboplatin, which were originally in Level 4 (60–90% emetogenicity), as ‘moderate–high’ agents in order to provide adequate guidance on relevant anti-emetics ( Jordan et al., 2014 ).
Different intensities of CINV will result from bolus injections, for instance, compared with continuous infusion because the peak drug levels will be lower over time with the latter. Table 5 shows the emetic potential of available intravenous and oral chemotherapies.
|Intravenous agents a||Oral agents b|
|High: emesis risk >90% without anti-emetics|
|Actinomycin D, Carmustine (‘BCNU’), Cisplatin, Cyclophosphamide (>1500 mg/m2), Dacarbazine (‘DTIC’), Dactinomycin, Lomustine, Mechlorethamine, Pentostatin, Streptozotocin||Hexamethylmelamine, Procarbazine|
|Moderate: emesis risk 30–90% without anti-emetics|
|Alemtuzumab, Altretamine, Azacitidine, Bendamustine, Clofarabine, Carboplatin, Cyclophosphamide (<1500 mg/m2), Cytarabine (>1 g/m2), Daunorubicin c , Doxorubicin c , Epirubicin c , Idarubicin c , Ifosfamide, Irinotecan, Melphalan, Mitoxantrone (>12 mg/m2), Oxaliplatin, Treosulphan, Trabectedin||Cyclophosphamide, Imatinib, Temozolomide, Vinorelbine|
|Low: emesis risk 10–30% without anti-emetics|
|Asparaginase, Bortezomib, Catumazomab, Cetuximab, Cytarabine (>100 mg/m2 – <1 g/m2), Docetaxel, Doxorubicin liposomal, Etoposide, 5-Fluorouracil, Gemcitabine, Ixabepilone, Methotrexate (>100 mg/m2), Mitoxantrone (<12 mg/m2), Paclitaxel, Panitumumab, Pegasparaginase, Pemetrexed, Teniposide, Thiotepa, Topotecan, Trastuzumab||Capecitabine, Etoposide, Everolimus, Fludarabine, Lapatinib, Lenalidomide, Sunitinib, Thalidomide|
|Minimal: emesis risk <10% without anti-emetics|
|Bleomycin, Bevacizumab, Busulphan, Chlorambucil, Cladribine, Cytarabine (<100 mg/m2), Fludarabine, α-, β-, γ-Interferon, Mercaptopurine, Methotrexate (<100 mg/m2), Thioguanine, Vinblastine, Vincristine, Vinorelbine||Chlorambucil, Erlotinib, Gefitinib, Hydroxyurea, Hormones, Melphalan, Methotrexate, Sorafenib, 6-Thioguanine|
Section 2. Anthracycline–cyclophosphamide
Although the classification into four emetogenic risk groups is generally accurate, specific circumstances may lead to alterations in policy; one of these concerns the combination of anthracycline and cyclophosphamide. This chemotherapeutic regimen has in the past been considered to be moderately emetogenic according to evidence-based emetogenicity classifications ( Roila et al., 2010 ). However, patients receiving this chemotherapy frequently have additional risk factors, for instance, they are young and/or female, which puts them at greater risk of CINV and so this combination in these circumstances should be classified as highly emetogenic ( Aapro et al., 2014 ). The recently updated ASCO guidelines have indeed reclassified the anthracycline–cyclophosphamide (AC) combination as highly emetogenic ( Basch et al., 2011 ). There may also be other instances when patients are at higher risk of CINV during treatment with MEC because of such intrinsic patient characteristics, for example, with ifosamide for testicular, cervical or ovarian cancer and methotrexate for breast cancer.
Section 3. Patient risk factors
Apart from the emetogenicity of the anti-neoplastic therapy, there are a number of patient characteristics which, alone or in combination, can influence the degree to which patients suffer from CINV ( Table 6 ).
|Risk factor a||Risk d|
|Patients with poorly controlled emesisin previous treatments are more likely to develop these side effects in further treatment cycles b||↑|
|Anticipatory nausea and vomitingare more likely to lead to symptoms during treatment||↑|
|Female genderis one of the most important individual prognostic factors for CINV||↑|
|<50 years of ageis predictive of greater post-treatment CINV||↑|
|Chemotherapy as an inpatient||↓|
|Chemotherapy as an outpatient||↑|
|History of high alcohol consumption, >100 g/day, linked with better CINV control c||↓|
|History of low alcohol consumptionis associated with worse control of CINV c||↑|
|Impaired quality of life||↑|
|A history of motion sicknessis a contributory factor with susceptible patients reporting greater CINV after therapy and greater severity and longer duration of each post-treatment episode of emesis||↑|
|Nausea and vomiting in pregnancy||↑|
d Risk raised (↑) or lowered (↓).
Chapter IV. Radiotherapy: emetic potential
The incidence of nausea and vomiting after radiotherapy is often underestimated by physicians, though some 50–80% of patients will experience these symptoms ( Feyer et al., 2011 ). The occurrence of radiotherapy-induced nausea and vomiting (RINV) will depend on radiotherapy-related factors, such as the site of irradiation, whether the dose is single or double, fractionation, irradiated volume and radiotherapy techniques. Fractionated radiotherapy, for instance, with as many as 40 fractions over a 2-month period may lead to ongoing, debilitating nausea and vomiting. As a result, patients may delay or refuse, and therefore compromise, their anti-neoplastic treatment. However, studies show that patients with RINV are nevertheless not optimally treated for their nausea and vomiting ( Enblom et al., 2009 ; Maranzano et al., 2010 ).
Section 1. Emetogenicity of radiotherapy
A major difficulty in ensuring effective anti-emetic treatment has been the lack of agreement on the emetic potential of different radiotherapy techniques and doses. The extent of irradiation is one of the determinants of risk for RINV. MASCC and ESMO guidelines for 2009, plus updates for 2013, and the ASCO guidelines from 2011 divide the RINV risk into four categories based upon the radiation field ( Roila et al., 2010 ; Basch et al., 2011 ; Feyer et al., 2014 ) (see Table 7 ).
|Emetic potential||Emesis risk level||Irradiation risk factors|
|High||>90%||Total body (TB), total nodes|
|Moderate||60–90%||Upper abdomen, half-body (HB), and upper body (UB)|
|Low||30–60%||Cranium and craniospinal, head and neck, lower thorax, pelvis|
|Minimal||<30%||Other sites, including breast and extremities|
Intensity-modulated radiation therapy (IMRT), which is becoming the treatment of choice for many head and neck cancers, such as oropharyngeal cancer, and abdominal cancers, reduces toxicity by reducing radiation doses to uninvolved normal tissue in the vicinity of tumour targets. However, previously unaffected tissues, such as the brainstem, may receive clinically significant doses that lead to side effects such as nausea and vomiting ( Ciura et al., 2011 ).
Individual patient characteristics also affect the potential for RINV. Apart from those seen in Table 8 , general health, concurrent or recent chemotherapy, psychological status, tumour stage, field size, dose per fraction, and overall length of treatment time will all increase or decrease the chance of nausea and vomiting.
|Patient characteristic/risk factor||Risk score|
|History of high alcohol consumption|
|Yes (>100 g/day)||0|
|Previous therapy-induced nausea and vomiting|
|Patient risk profile||≤4 = normal risk
5–6 = high risk
The pathophysiology of RINV is not well understood, but thought to be similar to that of CINV. The treatment of CINV has therefore guided that for RINV. However, estimation of risk and adherence to guidelines is variable across countries ( Dennis et al., 2012 ) and greater effort needs to be made to disseminate good practice internationally. Patients' risk factors, the incidence of delayed nausea and vomiting, and duration of treatment need to be investigated further ( Feyer et al., 2014 ).
Chapter V. Anti-emetic drugs
Anti-emetic drugs enable vomiting to be completely prevented in 70–80% of patients ( Hesketh et al., 2003a ; Jordan et al., 2007b ; Poli-Bigelli et al., 2003 ), and combination regimens have become standard therapy ( Hesketh, 2008 ). Anti-emetic drugs are classified according to their primary mode of action and have different efficacy in the acute and delayed phase of emesis, as well as in nausea ( Table 9 ). There has been recognition more recently of nausea as a specific clinical problem that is not always sufficiently well treated by anti-emetics. The development of an optimal anti-nausea treatment will require greater knowledge of the pathways that link the brainstem and cortex and their transmitters and of the mechanism by which cues for nausea are decoded by the brain ( Andrews and Sanger, 2014 ).
|Class/Drug||Site of action||Route||Examples|
|5-HT3 receptor antagonists||5-HT3 -receptor||p.o. only
p.o. & i.v.
|Steroids||Multiple||p.o. & i.v.||Dexamethasone
|NK-1 receptor antagonist||NK-1 receptor||p.o. only
|Substituted benzamides||Dopamine-D2 receptor||Alizapride
|Benzodiazepines||GABA-chloride channel receptor complex||Diazepam
|Antihistamines||Muscarinic cholinergic receptor||Dimenhydrinate|
|Herbs and spices||Inhibits activation of 5-HT3 RAs
Acts as an internal calcium channel-blocking agent
a Dolasetron i.v. has been withdrawn following a warning from the FDA; the FDA recommends caution with the oral form in susceptible patients (see p. 24 for further details).
b Ondansetron 32 mg i.v. has been withdrawn following a warning of the FDA (see p. 25 for further details).
p.o.: orally; i.v.: intravenously.
Section 1. 5-HT3 receptor antagonists
These are the most effective anti-emetics currently used to treat CINV and RINV. Past experience acquired with these drugs, which have been in widespread use since the 1990s, has confirmed their safety profile ( Hesketh, 2008 ). During this time they have provided the basis of therapy for the control of acute emesis in the context of chemotherapy agents with a moderate to high emetogenic profile. Particular 5-HT3 RAs are also valuable in the treatment of delayed vomiting after chemotherapy.
Available 5-HT3 RAs include three older agents: granisetron, ondansetron and tropisetron, which are deemed equally efficacious, though granisetron when compared directly with tropisetron shows greater efficacy ( Jordan et al., 2005 , 2007a , 2007c ). Dolasetron is still available as an oral anti-emetic, but is no longer available as intravenous therapy in the USA due to its cardiac effects ( FDA Drug Safety Communications, 2010 ) and is not recommended intravenously elsewhere (see further comment on p. 24). The second-generation 5-HT3 RA palonosetron has a higher receptor binding affinity, longer half-life and different mechanism of action to the other 5-HT3 RAs. Recent findings have also suggested that palonosetron inhibits cross-talk between the 5-HT3 and NK-1 receptor pathways in a dose and time dependent way ( Rojas et al., 2010 ).
Receptor cross-talk is defined as the activation of one receptor by its ligand affecting cellular responses to another receptor system(s). The precise mechanism is not yet understood, but reports show that there is cross-talk between NK-1 and 5-HT3 receptor signalling pathways; for example, the modulation of 5-HT3 receptors can directly affect NK-1 receptor signalling. Conversely, modulation of NK-1 receptors can influence 5-HT3 receptor-mediated activity (see Figure 6 ). It is thought that this pharmacology, distinct from older 5-HT3 RAs, may account for palonosetron's better efficacy in delayed CINV ( Ruhlmann and Herrstedt, 2010 ; Rojas et al., 2010 ; Popovic et al., 2014 ).
It has been shown and generally agreed that there are no major differences in efficacy between the first generation 5-HT3 RAs ( Jordan et al., 2005 , 2007a , 2007c , Roila et al., 2010 ). Due to positive result from several phase III trials ( Gralla et al., 2003 ; Eisenberg et al., 2003 ; Aapro et al., 2006 ), the MASCC 2009 and ASCO 2011 guidelines recommend palonosetron as the preferred agent in patients receiving moderately emetogenic chemotherapy, as well as in those receiving AC therapy if a NK-1-receptor antagonist is unavailable ( Roila et al., 2010 ).
The efficacy of a 0.75 mg dose of palonosetron (approved dose in Japan) plus i.v. dexamethasone (16 mg) compared with 40 µg/kg granisetron plus i.v. dexamethasone (16 mg) was reported in a phase III study of patients receiving cisplatin or AC-based regimens ( Saito et al., 2009 ). Doses were administered 30 minutes before chemotherapy on Day 1 in both cases, followed by additional doses on Days 2 and 3: dexamethasone 8 mg i.v. for patients receiving cisplatin or 4 mg i.v. for those receiving an AC combination. Primary endpoints were complete response (CR), defined as no emetic episodes and no rescue medication from 0 to 24 hours of chemotherapy (acute phase) or CR during the delayed phase (24–120 hours from chemotherapy). Primary efficacy endpoints showing that palonosetron was non-inferior when compared with granisetron in the acute phase and superior when compared with granisetron in the delayed phase were met.
Results were 75.3% and 56.8% for palonosetron/dexamethasone and 73.3% and 44.5% for the granisetron/dexamethasone regimen for acute and delayed emesis, respectively (delayed phase: p < 0.0001) ( Saito et al., 2009 ). Safety profiles were comparable.
Dose recommendations for 5-HT3 RAs take the following into consideration:
- The lowest dose should be used because receptors become saturated and therefore higher doses do not enhance efficacy.
- Oral and intravenous routes are equally effective.
- A single dose before treatment is the best schedule (for all recommended doses see Table 10 ).
|Class/Drug||Route||Daily recommended dose a|
|Dolasetron b||p.o.||100 mg|
|Granisetron||p.o. / i.v.||2 mg / 1 mg (0.01 mg/kg); transdermal via a patch over multiple days|
|Ondansetron c||p.o. / i.v.||24 mg (high)*, 16 mg (8 mg b.i.d. is recommended) (moderate)*
8 mg (0.15 mg/kg)
|Tropisetron||p.o. / i.v.||5 mg / 5 mg|
|Palonosetron||p.o. / i.v.||0.50 mg / 0.25 mg (0.75 mg in Japan)|
|Dexamethasone||p.o. / i.v.||12 mg (high with aprepitant)*; 20 mg without aprepitant: acute emesis
8 mg b.i.d. (high)*, 8 mg (moderate)*: delayed emesis
|Aprepitant||p.o.||125 mg on Day 1; 80 mg on each of Days 2 and 3|
|Fosaprepitant||i.v.||150 mg only on Day 1 (i.v.)|
a ()* reflects emetogenicity of therapy for a particular dose.
b Dolasetron i.v. has been withdrawn following a warning from the FDA; the FDA recommends caution with the oral form in susceptible patients (see p. 24 for further details).
c Ondansetron 32 mg i.v. has been withdrawn following a warning of the FDA (see p. 25 for further details).
Side effectswith 5-HT3 RAs are mild, with headache, constipation, diarrhoea and asthenia generally described ( Goodin and Cunningham, 2002 ). Small, transient, reversible changes in ECG parameters have been noted with the 5-HT3 RA ondansetron, but this is not a problem seen with palonosetron. Prescribing Information/Summary of Product Characteristics for each product should be consulted, particularly for patients with a risk of QTc prolongation.
With regard to cardiac side effects, in 2010 in the USA, the FDA informed patients and healthcare professionals that intravenous dolasetron should no longer be used for the treatment of CINV and RINV because in the doses used to treat these conditions i.v. dolasetron may cause dose-dependent prolongation in cardiac QT, PR, and QRS intervals, particularly in those patients with underlying heart conditions, and increase the risk of developing an abnormal and potentially fatal heart rhythm known as Torsades de Pointes ( FDA Drug Safety Communications, 2010 ). Its oral use remains in ASCO guidelines, but FDA guidelines ( FDA Drug Safety Communications, 2010 ) advise caution and close monitoring in patients with heart failure, a slow heart rate, underlying cardiac disease, the elderly, and in patients with renal impairment; its use should also be avoided in patients with congenital long-QT syndrome and in conjunction with drugs known to prolong the PR (e.g., verapamil) or QRS interval. Outside the USA, it appears that dolasetron guidance and availability vary: in Canada both intravenous and oral dolasetron have been withdrawn from the market; in Germany it is not available anymore in either form; but it remains in MASCC/ESMO guidelines with oral dosing recommended rather than intravenous treatment because of potential QT interval prolongation ( MASCC, 2013 ).
Additionally, in 2012 the FDA issued a warning regarding the 32 mg i.v. dose of ondansetron because of QT interval prolongation, which could also pre-dispose patients to develop Torsades de Pointes. This dose was therefore removed from usage ( FDA Drug Safety Communications, 2012 ) accompanied by the recommendation of a 0.15 mg/kg dose every 4 hours for three doses, but with no single i.v. dose being over 16 mg (MASCC/ESMO recommends 8 mg doses). However, it should be noted that ondansetron is the most widely used 5-HT3 RA with over 25 years of safe usage. Guideline revisions have not changed for recommended oral doses.
Section 2. Steroids
Although they are not approved as anti-emetics, steroids are an integral part of anti-emetic therapy for acute and delayed nausea and vomiting ( Grunberg, 2007 ). In combination with other anti-emetics, they have a booster effect thereby raising the emetic threshold. Dexamethasone is the most commonly used agent from this class though there are no studies to show it has superior efficacy to other steroids ( Gralla et al., 1999 ). Alongside NK-1 RAs, dexamethasone is one of the most important drugs in preventing delayed emesis ( Aapro and Walko, 2010 ). For recommended doses see Table 10 .
There are a number of comments to be made onsteroid dosage and side effects. Steroids are generally considered to be safe anti-emetics with the side effects dependent on dose and duration of therapy. However, in a study by Vardy et al. patients being treated for delayed CINV ( Vardy et al., 2006 ) reported problems with insomnia (45%), epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%). In a more recent study of a combined regimen of palonosetron and dexamethasone, 8.7% of patients receiving dexamethasone for 3 days had insomnia compared with only 2.6% of patients receiving dexamethasone for 1 day ( Aapro et al., 2010 ). Concerns that steroids may interfere with the efficacy of the chemotherapy have not been confirmed ( Herr et al., 2003 ).
Section 3. Neurokinin-1 receptor antagonists
Aprepitant was the first drug in this class of anti-emetics ( Hesketh et al., 2003a ). It blocks the NK-1 receptors in the brainstem and the GI tract ( Hesketh et al., 2003b ). Regimens of aprepitant plus a 5-HT3 RA plus a steroid have been shown to significantly reduce acute and delayed emesis in patients receiving highly emetic ( Hesketh et al., 2003a ; Poli-Bigelli et al., 2003 ; Schmoll et al., 2006 ) or moderately emetic therapy, including AC-based chemotherapy ( Rapoport et al., 2010 ; Warr et al., 2005 ), compared with those receiving a 5-HT3 RA plus dexamethasone only.
Aprepitant is also available as a water-soluble formulation, fosaprepitant. A single dose of fosaprepitant (150 mg i.v.) has been shown to be as effective as a 3-day oral aprepitant regimen and provides a more convenient mode of administration ( Grunberg et al., 2011b ).
Theside effects and adverse eventsseen with aprepitant plus a 5-HT3 RA and dexamethasone are similar to those reported with a 5-HT3 RA and dexamethasone alone: headache, anorexia, weakness/fatigue, diarrhoea; hiccups are seen with aprepitant ( Depré et al., 2005 ).
Interactions:Aprepitant is metabolised by cytochrome P450 CYP3A4 and is a moderate inhibitor and inducer of CYP3A4 ( Shadle et al., 2004 ). It has been shown to cause a 2-fold increase in the area under the plasma concentration curve (AUC) of dexamethasone, a substrate for CYP3A4. Dexamethasone doses should therefore be decreased by approximately 50% when used 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 have been studied: aprepitant has no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients ( Nygren et al., 2005 ), and the metabolism of cyclophosphamide is not significantly reduced in the presence of aprepitant ( Bubalo et al., 2012 ). A review has confirmed that there is no proven, clinically significant interaction with intravenous cytotoxic agents but caution is recommended with oral agents ( Aapro and Walko, 2010 ). Egerer et al. also reported that anti-emetic regimens, including aprepitant, have no clinically relevant effect on the pharmacokinetics of melphalan when administered one hour before melphalan infusion ( Egerer et al., 2010 ).
Section 4. NEPA
A new, highly selective NK-1 RA, netupitant, in combination with palonosetron, a 5-HT3 RA (NEPA) is currently in phase III development, and deemed through phase II and phase III studies to be a potential advance in efficacy and simplicity of dosing as well as maintenance of efficacy over multiple cycles of chemotherapy ( Andrews, 2014 ). A phase II, randomised, double-blind, parallel-group study in 694 chemotherapy-naïve patients undergoing highly emetogenic cisplatin-based chemotherapy reported that all doses of NEPA provided superior prevention of CINV in the acute and delayed phases compared with palonosetron alone ( Hesketh et al., 2014 ).
A multinational, randomised, double-blind, parallel group phase III study in 1455 chemotherapy-naïve patients undergoing moderately emetogenic chemotherapy showed that netupitant 300 mg + palonosetron 0.50 mg (NEPA) provided superior prevention of CINV compared with palonosetron alone ( Aapro et al., 2014 ).
A phase III study evaluating safety and efficacy of NEPA for nausea and vomiting over repeated cycles of chemotherapy showed that this single oral dose anti-emetic was safe, well tolerated and highly effective over multiple cycles of highly emetic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) ( Gralla et al., 2014 ).
Section 5. Dopamine receptor antagonists
These drugs can be divided into phenothiazines, butyrophenes and substituted benzamides ( Jordan et al., 2007a ; Lohr, 2008 ). Before the introduction of 5-HT3 RAs, these agents formed the basis of anti-emetic therapy ( Jordan et al., 2007a ). One of the most frequently used of the class is metoclopramide. Prior to 5-HT3 RAs, metoclopramide was used at high doses and in combination with a corticosteroid particularly in the treatment of acute CINV. However, metoclopramide has no better effect than placebo on nausea and vomiting in patients receiving highly emetogenic therapy. Current guidelines therefore do not recommend it for prevention of acute CINV.
Metoclopramide has in the past been considered effective in delayed emesis in combination with corticosteroids ( Kris et al., 1989 ; Moreno et al., 1992 ), but it has now been overtaken by more effective agents. In recent MASCC and ASCO guidelines it is no longer recommended for use in delayed emesis, but is reserved as a rescue medication for patients who are intolerant or refractory to 5-HT3 RAs, dexamethasone and aprepitant ( Roila et al., 2010 ; Kris et al., 2006 ). In 2013, the EMA recommended that metoclopramide should only be prescribed for short-term use (up to 5 days) because of side effects on the nervous system. In addition, the maximum recommended dose in adults has been restricted to 30 mg per day ( EMA, 2013 ).
Section 6. Olanzapine
Olanzapine is an atypical antipsychotic drug of the thiobenzodiazepine class. It blocks numerous neurotransmitter receptors, including a number thought to be involved in the emetic process ( Bymaster et al., 1996 , 2001 ). This has prompted its use in anti-emesis particularly in cases refractory to standard agents ( Vig et al., 2014 ). In a recent meta-analysis ( Hocking and Kichenadasse, 2014 ), the daily dose of olanzapine across all trials was equivalent at 10 mg daily for a duration of 3–5 days. Studies have revealed it to be efficacious in the treatment of chronic nausea, CINV and breakthrough nausea and vomiting ( Navari, 2014 ). Guidelines published by the National Comprehensive Cancer Network (NCCN) also include an olanzapine–palonosetron–dexamethasone regimen as an alternative prophylactic for HEC and MEC, which is in contrast to the MASCC/ESMO and ASCO guidelines.
Phase II and phase III clinical trials have shown that there is a significant improvement in nausea when olanzapine is added to 5-HT3 RAs and NK-1 RAs for patients receiving MEC or HEC. Side effects include substantial weight gain as well as diabetes mellitus with long-term treatment, but these are not seen with short-term usage of up to one week ( Navari, 2014 ).
Section 7. Nifedipine
Nifedipine is an L-type calcium channel antagonist currently in the early preclinical stages of investigation as a broad-spectrum anti-emetic, as well as an additive to the 5-HT3 RA palonosetron. Studies are being carried out in the least shrew (Cryptotis parva) ( Darmani et al., 2014 ).
Section 8. Cannabinoids
Cannabis has long been recognized as limiting or preventing nausea and vomiting, and its weak anti-emetic efficacy and some beneficial side effects, such as euphoria and sedation, have made cannabinoids a useful adjunct to anti-emetic therapies. However, other, less pleasant side effects, such as dizziness and dysphoria, have limited their general use ( Jordan et al., 2007a ; Roila et al., 2010 ) and cannabinoids are only advised in patients intolerant of 5-HT3 RAs, steroids, or aprepitant ( Roila et al., 2010 ; Basch et al., 2011 ).
Cannabinoid receptors are recognized as being distributed throughout the central and peripheral nervous system ( Howlett, 2002 ; Pertwee et al., 2010 ) and more recent studies have revealed two endogenous cannabinoid receptor ligands ( Di Marzo and De Petrocellis, 2012 ), which are found in the brain and in the GI tract. This continues to be a focus of research to identify the wider potential of cannabinoids and the endocannabinoid system in the prevention of nausea and vomiting ( Sharkey et al., 2014 ).
At a clinical level research also continues to explore the potential benefits of cannabis. A phase II randomised, double-blind, parallel, placebo-controlled trial on the preliminary efficacy and safety of an oromucosal standardized cannabis extract was carried out in 7 patients compared with 9 on placebo ( Duran et al., 2010 ). Patients all had CINV of over 24 hours despite standard anti-emetic treatment, which included steroids, as well as 5-HT3 RAs or metoclopramide. The study drug was added to standard treatment. The cannabis extract provided better protection against delayed CINV compared with placebo, 71.4% versus 22.2%, respectively; one patient discontinued treatment because of anxiety, hallucinations and confusion. This was the first controlled study to assess the tolerability of an acute dose titration of a synthetic cannabinoid.
Section 9. Benzodiazepines
These drugs can be useful additions to anti-emetic regimens. They are often used to treat anxiety and to reduce the risk of ANV, and can be used in patients with refractory and breakthrough emesis ( Jordan et al., 2007a ; Lohr, 2008 ). Lorazepam is well tolerated, reduces anxiety and the risk of anticipatory nausea, and can be a useful addition to anti-emetic regimens ( Aapro et al., 2005 ; Morrow and Roscoe, 1997 ). Midazolam, a short-acting benzodiazepine, has been shown to reduce nausea and vomiting, when added to granisetron and dexamethasone, in patients with refractory acute CINV in previous cycles of HEC ( Mandala et al., 2005 ).
Section 11. Herbs and spices
Herbs and spices are used medicinally by more than 80% of the world's population, and two agents can be mentioned here that show potential benefit in nausea and vomiting.
Gingerhas been used in GI-related conditions for centuries ( Baliga et al., 2011 ). Studies have shown ginger's effectiveness against nausea in motion sickness, pregnancy and surgery ( Arfeen et al., 1995 ; Bone et al., 1990 ; Grontved et al., 1988 ; Mowrey and Clayson, 1982 ; Visalyaputra et al., 1998 ). Previous studies have suggested that ginger may have efficacy against CINV, but poorly designed trials and small numbers have rendered the results controversial ( Dupuis and Nathann, 2003 ; Manusirivithaya et al., 2004 ). However, a randomised, double-blind, placebo-controlled dose-finding clinical trial carried out by Ryan et al. showed that ginger supplementation at daily doses of 0.5, 1.0, or 1.5 g compared with placebo significantly reduced the severity of acute chemotherapy-induced nausea in adult patients, with 0.5 g and 1.0 g showing the largest reductions (p = 0.017 and p = 0.036, respectively) ( Ryan et al., 2012 ). A recent study has shown for the first time that ginger extracts and arylalkane constituents concentration-dependently inhibit 5-HT3 receptor activation ( Walstab et al., 2013 ).
Peppermintacts as an internal calcium-blocking channel producing intestinal smooth muscle relaxation. Previously there has been evidence for its use in dyspepsia and irritable bowel syndrome. More recently a randomised, double-blind clinical trial was conducted in patients who were chemotherapy naïve and to receive varied chemotherapy regimens. During treatment patients received the normal anti-emetic treatment – granisetron, dexamethasone or metoclopramide – plus a spearmint or peppermint capsule every 4 hours. The study reported that the intensity and number of emetic events was significantly reduced in the first 24 hours in both treatment groups (p < 0.05) ( Tayarani-Najaran et al., 2013 ).
Chapter VI. Chemotherapy-induced nausea and vomiting: anti-emetic prophylaxis
It is crucial to clearly define the optimal prophylactic anti-emetic therapy for CINV before chemotherapy begins and to implement it from the start. Therapy instituted later in relation to symptoms is ineffective in most cases. This is especially important in delayed emesis.
The emetic potential of the chemotherapy must be established and the agent with the highest potential used to determine the emetogenicity of the entire chemotherapy. The patient risk factors, such as age and gender, must also be considered when identifying the emetic risk of the therapy. For outpatients it is important to establish a written plan for the treatment of delayed emesis; the lowest fully effective once-daily dose for each anti-emetic agent should be used. At equivalent doses and bioavailabilities, oral and intravenous routes have similar efficacy and safety ( Roila et al., 2010 ; Basch et al., 2011 ; NCCN, 2013 ).
Section 1. Prevention of acutenausea and vomiting: within the first 24 hours of chemotherapy
Section 1.1. Highly emetogenic chemotherapy (HEC)
Patients should be treated with a triple combination of a 5-HT3 RA, a NK-1 RA (aprepitant/fosaprepitant) and a corticosteroid.
Section 1.2. Moderately emetogenic chemotherapy (MEC)
Section 1.2.1. AC-based chemotherapy
Based on the emetogenic potential of anthracycline and cyclophosphamide, this regimen should be considered MEC. However, due to patient-related risk factors, this combination is considered differently in different guidelines.
Patients receiving an anthracycline–cyclophosphamide-based chemotherapy should be given the triple combination described for highly emetogenic therapy on Day 1 of therapy (MASCC/ESMO and NCCN guidelines). If aprepitant is not available, palonosetron is the preferred 5-HT3 RA ( Roila et al., 2010 ).
The updated ASCO guidelines have recategorised the anthracycline–cyclophosphamide-based chemotherapy to the ‘highly emetogenic’ level ( Basch et al., 2011 ), whilst MASCC/ESMO and NCCN guidelines still have the AC combination in the moderately emetogenic category, but at the same time recognising that it requires a specific anti-emetic regimen (see Table 11 ).
|Acute phase: up to 24 hours
after chemotherapy (Day 1)
|Delayed phase: 24–120 hours after chemotherapy (Days 2–5)|
|Highly emetogenic chemotherapy (HEC; >90%)|
Aprepitant 125 mg p.o.;
Fosaprepitant 150 mg i.v.
+ 5-HT3 RA
Dolasetron 100 mg p.o. a ;
Granisetron 2 mg p.o. or 1 mg / 0.01 mg/kg i.v.;
Palonosetron 0.50 mg p.o. or 0.25 mg i.v.;
Ondansetron 24 mg p.o. or 8 mg / 0.15 mg/kg i.v. b ;
Tropisetron 5 mg p.o. / i.v. c
Dexamethasone 12 mg p.o. / i.v.
Aprepitant 80 mg p.o. Days 2–3
(but not if 150 mg fosaprepitant i.v. on Day 1)
Dexamethasone 8 mg p.o. / i.v.
Days 2–3 or 2–4
|Moderately emetogenic chemotherapy (MEC; 30–90%)|
|1. AC chemotherapy
Aprepitant 125 mg p.o.;
Fosaprepitant 150 mg i.v.
Dolasetron 100 mg p.o. a ;
Granisetron 2 mg p.o. or 1 mg / 0.01 mg/kg i.v.;
Palonosetron 0.50 mg p.o. or 0.25 mg i.v.;
Ondansetron 16 mg p.o. (8 mg b.i.d.) or
8 mg / 0.15 mg/kg i.v. b ;
Tropisetron 5 mg p.o. / i.v. c
Dexamethasone 8 mg p.o. / i.v. e
|1. AC chemotherapy
Aprepitant 80 mg p.o. Days 2–3 (but not if 150 mg fosaprepitant i.v. on Day 1)
Patients with breast cancer receiving palonosetron for acute CINV: multiday dexamethasone p.o. may also be given
|2. Non-AC MEC
Palonosetron 0.50 mg p.o. or 0.25 mg i.v.
Dexamethasone 8 mg p.o. / i.v.
|2. Non-AC MEC
Dexamethasone 8 mg or 4 mg b.i.d. p.o., Days 2–3
|Low emetogenic chemotherapy (10–30%)|
|Dexamethasone or a 5-HT3 RA (see above) or a dopamine receptor antagonist||No routine prophylaxis|
|Minimally emetogenic chemotherapy (<10%)|
|No routine prophylaxis||No routine prophylaxis|
a Dolasetron i.v. has been withdrawn following a warning from the FDA; the FDA recommends caution with the oral form in susceptible patients (see p. 24 for further details).
b Ondansetron 32 mg i.v. has been withdrawn following a warning of the FDA (see p. 25 for further details); NCCN guidelines recommend 16–24 mg p.o. or 8–16 mg i.v.
c Not in NCCN guidelines.
d ASCO guidelines have updated AC chemotherapy to the highly emetogenic level.
e NCCN guidelines recommend 12 mg p.o. or i.v.
MASCC/ESMO Antiemetic Guideline 2013 ( MASCC, 2013 ).
Section 1.2.2. Non-AC MEC
Patients receiving moderately emetogenic non-AC chemotherapies should be treated with a combination of a 5-HT3 RA, preferably palonosetron, plus dexamethasone.
Section 1.3. Low emetogenic chemotherapy
A single agent should be used, such as a low-dose corticosteroid. Overtreatment should be avoided.
Section 1.4. Minimally emetogenic chemotherapy
No routine anti-emetic should be given to patients treated with minimal emetic risk agents.
Section 2. Prevention of delayednausea and vomiting: Days 2–5 after chemotherapy
Cisplatin, doxorubicin and cyclophosphamide, in particular, cause long-lasting nausea and vomiting. The likelihood of delayed emesis is often underestimated with the result that no adequate precautions are taken.
Section 2.2. Moderately emetogenic chemotherapy (MEC)
Section 2.2.1. AC-based chemotherapy
Patients receiving an AC chemotherapy combination should receive aprepitant to prevent delayed CINV. In patients with breast cancer, dexamethasone may also be given on Days 2 and 3 as suggested in the ASCO guidelines.
Section 2.2.2. Non-AC MEC
All patients receiving a moderately emetogenic non-AC chemotherapy should receive multiday oral dexamethasone for the delayed CINV.
Section 2.3. Low and minimally emetogenic chemotherapy
There is no routine prophylactic anti-emetic treatment recommended for the delayed phase of CINV.
Section 3. Prevention of anticipatorynausea and vomiting
The best approach to anticipatory nausea and vomiting (ANV) is to avoid it in the first place by using optimal anti-emetic prophylaxis for the first cycle of treatment. Benzodiazepines and conventional anti-emetics have shown some efficacy if given before chemotherapy, but ANV is a conditioned reflex (see Chapter II ) and drug therapy generally has little efficacy, though two studies show some success. Razavi used a benzodiazepine alongside a psychological support program in a double-blind, placebo-controlled study with some success ( Razavi et al., 1993 ). Fifty-seven women undergoing adjuvant chemotherapy for stage II primary breast cancer were given low-dose alprazolam (0.5 mg to 2 mg per day) plus a psychological support program including progressive relaxation training. A number of anxiety rating scales, as well as the Morrow Assessment of Nausea and Emesis (MANE), were used to compare the alprazolam and placebo arms of the study. The placebo arm showed a higher rate of anticipatory nausea compared with the alprazolam arm (18% versus 0%, respectively). However, further studies are needed to improve the efficacy reported in this study. Malik evaluated lorazepam added to a regimen of metoclopramide, dexamethasone and clemastine ( Malik et al., 1995 ) in patients receiving cisplatin (100 mg/m2 as a 24-hour continuous infusion), and the incidence of ANV was significantly reduced (p < 0.05), as well as acute emesis (p = 0.05). Other agents that may be of interest are cannabinoids ( Slatkin, 2007 ; Parker et al., 2006 , 2011 ).
In a recent review of ANV due to chemotherapy, Kamen et al. (2014) recognize that optimal use of anti-emetics to stop AVN before it begins is best, but acknowledge the need for better understanding of the basic biological and genetic predictors of a patient's susceptibility. They present the case for non-pharmaceutical treatments such as systematic desensitization, hypnosis, biofeedback, imagery, and relaxation, as well as complementary and alternative medicines, such as acupuncture and herbal supplements.
In an interesting conclusion to their review, Kamen et al. cite the case for optimism as expounded by Scheier and Carver (1987) , who suggest that patient optimism has a significantly positive effect on health and wellbeing and therefore better health outcomes; it is associated with increased motivation and persistence, and in patients undergoing treatment for cancer, amongst other examples, has led to less emotional distress during and after radiation therapy. By contrast, pessimism is associated with depression and lowered disease resistance, and poor health in middle and late adulthood. Kamen et al. suggest that treatment approaches that could use the ‘optimism construct’ might prove efficacious, and that further research is needed to identify the therapeutic possibilities in alternative medicine ( Kamen et al., 2014 ).
Section 4. Therapy in cases of insufficient anti-emetic efficacy
If emesis results despite preventative measures, it is necessary to check that the patient received treatment according to guidelines. If anti-emetic guidelines were adhered to, but the patient still suffers from CINV, the addition of anti-emetics belonging to the same class of anti-emetic will generally not help, but palonosetron because of its different mechanism of action may be useful ( Einhorn et al., 2011 ). A NK-1 RA (aprepitant) should be given to patients who receive a combination of a 5-HT3 RA with a steroid. With lasting emesis, metoclopramide, benzodiazepines, and olanzapine may be effective. In 2013, the EMA recommended that metoclopramide should only be prescribed for short-term use (up to 5 days) because of side effects on the nervous system. In addition, the maximum recommended dose in adults has been restricted to 30 mg per day ( EMA, 2013 ). Table 12 summarizes the options.
|Metoclopramide||10 mg or 20–30 mg a||i.v. or p.o.||Every 4–6 hours|
|Olanzapine||5–10 mg||p.o.||Once a day|
|Alprazolam||0.25–1.0 mg||p.o.||Once a day|
|Domperidone||10–20 mg||p.o.||3–4 times per day. Maximum dose/day 80 mg|
|Haloperidol||0.5–2 mg or 1–2 mg||p.o. or i.v.||Every 8–12 hours or short i.v. infusion|
|Promethazine||25–50 mg||p.o.||3–4 times per day|
|Dronabinol||5–10 mg||p.o.||Every 3–6 hours. Maximum dose/day 50 mg|
a Maximum dose/day 30 mg due to side effects on the nervous system, and for short-term use only; maximum 5 days ( EMA, 2013 ).
Drugs and dosages to be used with caution in frequently sedated patients. Other potential aetiological factors, such as brain metastases and gastrointestinal obstructions, should be evaluated.
Section 5. Multiple-day chemotherapy
- For multiple-day cisplatin therapy, the use of a 5-HT3 RA and a corticosteroid plus a NK-1 RA on the days when cisplatin is administered was seen in a recent study by Albany et al. in patients receiving a 5-day cisplatin regimen for testicular cancer ( Albany et al., 2012 ) and is recommended by recent guidelines ( Basch et al., 2011 ).
- ASCO guidelines recommend clinicians first determine the emetic risk of the agent(s) included in the regimen. Patients should then receive the agent of the highest therapeutic index daily during chemotherapy and for two days thereafter. Patients can also be offered the granisetron transdermal patch (Sancuso®) that delivers therapy over multiple days rather than taking a 5-HT3 RA daily ( Basch et al., 2011 ).
- Additionally, for delayed CINV, 2–3 days after chemotherapy, a corticosteroid alone should be given orally or intravenously.
- Aprepitant/fosaprepitant may be used where chemotherapy is highly emetogenic; it can be used in combination with a 5-HT3 RA and a corticosteroid.
- Fosaprepitant 150 mg intravenously with dexamethasone can also be given on Day 1 with no further need for oral aprepitant on Days 2 and 3.
- MASCC/ESMO guidelines recommend a single intravenous dose of 0.25 mg palonosetron prior to the start of a 3-day chemotherapy regimen, rather than multiple daily doses of another oral or intravenous 5-HT3 RA. Repeat dosing of 0.25 mg palonosetron i.v. once daily, on Days 1, 3 and 5, 30 minutes before chemotherapy, along with a regimen of dexamethasone was safe, well tolerated and effective in patients undergoing 5-day cisplatin-based therapy for testicular cancer ( Einhorn et al., 2007 ).
Section 6. High-dose chemotherapy
- Studies in this area of anti-emesis therapy have been lacking, but a body of evidence is slowly accumulating. In a randomised, placebo-controlled, double-blind, phase IIIb trial, the combination of aprepitant (Days 1–4), granisetron (Days 1–4), and dexamethasone (Days 1–3) was investigated in patients treated with high-dose melphalan for conditioning in autologous transplantation. This combination therapy resulted in significantly less CINV compared with the matching placebo/granisetron/dexamethasone combination ( Schmitt et al., 2014 ).
- In a prospective, randomised study of aprepitant in combination with ondansetron and dexamethasone during and for 3 days after high-dose preparative regimens for autologous and allogeneic haematopoietic stem cell transplant (n = 179), complete response rates were 81.9% for the aprepitant arm compared with 65.8% for the placebo non-aprepitant arm (p < 0.001). This combination significantly reduced emesis and nausea ( Stiff et al., 2013 ).
- On high-dose days, the use of a 5-HT3 RA plus a corticosteroid is recommended before therapy is begun.
- On Days 2 and 3 a corticosteroid can be given to prevent delayed CINV.
- Though not specifically recommended yet by guidelines, the addition of a NK-1 RA or the use of palonosetron as the 5-HT3 RA can be considered.
Section 7. The role of the nurse
Nurses play a substantial role in the care of patients undergoing anti-neoplastic therapy and thus in the prevention and management of CINV. Apart from the close relationship nurses inevitably have with patients in the care setting, which may help to alleviate symptoms of anxiety, they are also potentially available to answer questions at a physically and psychologically difficult time for the patient. They are able, as well, to educate patients in the course of their therapy and provide support with post-therapy symptoms. Unfortunately, there are still gaps in the knowledge base of nurses. For example, research undertaken in nine community hospitals in the Netherlands, which examined chemotherapy-induced nausea and vomiting in daily clinical practice, revealed that both physicians and nurses underestimated the incidence of delayed nausea and vomiting ( Hilarius and Kloeg, 2012 ).
Interestingly, a study measuring the effects of guideline development and distribution and using feedback to clinicians regarding non-compliance did not see any improvement in prescribing patterns. However, feedback on the clinical outcomes of patients with CINV led to acceptance of the need to follow guidelines and the institution of nurse practitioner prescribing, with the result of better adherence to guidelines and measurable improvements in the patients' CINV ( Mertens et al., 2003 ).
Findings from both these studies were echoed in one undertaken in 12 countries outside Europe (Australia, China, Hong Kong and nine in Latin America), which, through an international survey of attitudes, beliefs, skills and practices, explored nurses' roles in the prevention and management of CINV, and sought to identify skills gaps. Of the participating group (n = 458), 54% reported formal training in oncology and 53% had completed formal chemotherapy training. Data were collected through a self-reported survey. Participating nursing staff recognized that their knowledge of CINV care and management was insufficient ( Krishnasamy et al., 2014 ).
In another study, undertaken by an Expert Group of specialist cancer nurses working in a variety of settings in the UK (6), France (1), Spain (2) and Eire (1), the main aim was to share current experience of CINV management and to reach consensus on the development of a Patient Charter designed to help patients understand CINV management ( Young et al., 2013 ). They concluded that within healthcare systems effective guideline-based management of CINV is not offered to all eligible patients (as has been noted in other parts of this booklet); the reasons are multifactorial, and include insufficient education of all healthcare personnel on the needs of patients during chemotherapy; the lack of patient education of the importance of adherence to prescribed medications; the lack of empowerment of patients and absence of opportunity to ask (the right) questions; and the inadequacy of effective monitoring, particularly of patients at home. They noted particularly that nausea is often more distressing and debilitating for patients, but is less well managed by current anti-emetic regimens. Additionally, although all international guidelines are useful, they noted a lack of consideration for complementary and psychological strategies ( Young et al., 2013 ).
In conclusion, these studies indicated the areas where nurses (and patients) need support, training and ongoing education, as well as areas where nursing skills could be used more effectively:
- The introduction of standardised clinic and home-based symptom monitoring could provide healthcare workers with real-time information that would increase the quality of symptom management ( Hilarius and Kloeg, 2012 );
- The employment of nurses for monitoring CINV and RINV and prescribing guideline-adherent anti-emetics ( Mertens et al., 2003 );
- International guidelines should be made readily available to nurses in clinically relevant and accessible formats, and a CINV risk tool should be developed for use by nurses to enable identification and intervention for patients at high risk of CINV ( Krishnasamy et al., 2014 );
- The Patient Charter, designed to educate and inform chemotherapy recipients about CINV, to help them understand its management that often takes place at home, and to set out key questions that they may want to ask their healthcare professionals, should be widely disseminated. Its development led to the following conclusions:
- – Patients need to understand that prophylactic medication must be taken regardless of how they feel;
- – Open discussion between patients and their chemotherapy team about complementary remedies should be encouraged and normal practice;
- – Real-time monitoring, using diaries or follow-up phone calls, is essential to obtain accurate records of patients' symptoms between clinic visits;
- – Patients need clear contact information for seeking help when symptoms arise;
- – The Patient Charter on CINV management will help to educate patients and empower them to ask questions about their care ( Young et al., 2013 ).
Section 8. The role of the pharmacist
The position of the pharmacist in this setting of patient care for the management of side effects of cancer treatment would seem limited and not so obvious. However, as the uptake of guidelines is increasingly perceived as suboptimal ( Aapro et al., 2010 ), pharmacists may come to play a larger role in this area within the overall healthcare team. Two studies show that clinical intervention by pharmacists can be useful when inappropriate anti-emetic therapy is prescribed, both from an optimal patient experience and a cost consideration. The first study, by Dranitsaris (2001), examined the difference between results obtained in randomised trials and their implementation in clinical practice with a focus on high-cost 5-HT3 RA anti-emetics. The study employed six intervention methods to change physicians' 5-HT3 RA prescribing patterns to comply with evidence-based anti-emetic guidelines. Its main conclusion was that pharmacist-driven, multifaceted intervention programmes can ensure that guidelines are followed, that 5-HT3 RA anti-emetics are used appropriately, and that unnecessary drug costs are saved without compromising patient care ( Dranitsaris et al., 2001 ).
A second study, by Barbour (2008) , looked at the role of the pharmacist in the care of treatment-experienced breast cancer patients, specifically in managing side effects of chemotherapy. Because of the rise in the number of oral medications used in cancer therapy, patient adherence has become increasingly important. The research concluded that pharmacists have an important role to play in helping patients achieve the best possible results from their treatment and in management of side effects through education, in participating in the development of institutional guidelines for the monitoring and management of adverse effects and drug–drug interactions ( Aapro and Walko, 2010 ), in reconciliation of medications for hospitalized patients, and in helping to improve treatment adherence for patients taking oral therapies ( Barbour, 2008 ).
Section 9. The importance of evidence-based guidelines and their use in daily care
Evidence-based guidelines for the optimal use of anti-emetics and prevention of CINV and improved clinical outcomes are available and updated frequently – MASCC, ASCO and NCCN – but the uptake of these remains low; 55% for acute, 46% for delayed, and 29% overall for CINV are results from a recent multi-centre study ( Aapro et al., 2012 ). This research compared guideline-consistent, chemotherapy-naïve patients with guideline-inconsistent cohorts over a period of 120 hours after their first cycle of chemotherapy; the endpoint was complete response. The study results confirmed a significant benefit of guideline-consistent anti-emetic therapy (59.9%) versus guideline-inconsistent therapy (50.7%). Another study, in 1295 outpatients receiving HEC or MEC in 4 US community oncology practices, reported similar findings with a significantly higher lack of CINV in guideline-consistent patients, 53.4% versus 43.8% (p < 0.001) in non-guideline-consistent patients, and concluded that increased adherence to anti-emetic guidelines could significantly reduce incidence of HEC and MEC ( Gilmore et al., 2014 ). In contrast, a one-centre study in 299 patients ( Burmeister et al., 2012 ), though it showed that adherence to ESMO/MASCC recommendations for CINV prophylaxis was not optimal, reported overuse of serotonin antagonists for acute CINV in patients with low emetogenic chemotherapy and overuse of serotonin antagonists for delayed CINV in patients with highly and moderately emetogenic chemotherapy. Implementation of software-based prophylaxis, which automatically added appropriate anti-emetics to prescribed chemotherapy, was instituted to reduce overuse. These and similar studies ( Molassiotis et al., 2008 ) highlight the need to improve the use of anti-emetic therapy in clinical practice, and underline the need to examine the barriers to guideline usage and to test the effectiveness of different strategies to increase usage ( Aapro et al., 2012 ).
Studies examining the non-use of guidelines are small in number, but a review by Cabana et al. underlined some potential reasons for non-adherence to guidelines: lack of awareness or familiarity with guidelines, disagreement with guidelines, and physicians' lack of belief in the effectiveness of guideline-adherent management, lack of confidence in their ability to implement them, and general inertia ( Cabana et al., 1999 ). But nevertheless some other studies provide important pointers to which areas might be tackled to improve adherence to guidelines: The sharing of CINV patients' experiences to increase physicians' awareness and the use of nurses to prescribe anti-emetics ( Mertens et al., 2003 ); pharmacist-driven clinical intervention programmes to encourage use of guidelines and discourage inappropriate use of anti-emetics ( Dranitsaris et al., 2001 ); chemotherapy prescribing running alongside ‘Anti-emetics as per Guidelines’ to improve guideline usage ( Nolte et al., 1998 ); a triple approach of dissemination of guidelines, plus audit and feedback, plus educational outreach ( Roila, 2004 ). Further research to clarify and support these proposals towards better anti-emetic guideline use and thus improved patient care are needed ( Jordan et al., 2014 ).
In the meantime, there are a number of areas in which the drive to optimal anti-emesis treatment might be tackled and achieved, and these need to be used concurrently. Primarily, they include patient-mediated feedback on treatment outcomes and computerised prescribing-support systems, as well as educational means, and more imaginative use of healthcare workers such as nurses and pharmacists ( Kaiser, 2005 ; Jordan et al., 2014 ).
Guidelines for anti-emetic treatment are developed from the consensus of international experts based on the most recent clinical evidence and are updated frequently. It is important that the results of these data are optimally used for the benefit of the patient. A practical drive to better implementation of the guidelines is therefore crucially needed to improve anti-emetic care and ultimately clinical outcomes ( Jordan et al., 2014 ).
Chapter VII. Radiotherapy-induced nausea and vomiting: anti-emetic prophylaxis
RINV is often less severe than CINV, but can still be a debilitating and distressing side effect, which is often underestimated by clinicians. As many as 50–80% of patients undergoing radiotherapy will experience nausea and vomiting depending on the site of irradiation. The pathophysiology of RINV is not completely understood, but progress in understanding the pathophysiology and treatment of CINV has greatly informed that of RINV.
Uncontrolled nausea and vomiting can lead to patients delaying or refusing further radiotherapy thereby compromising their treatment plan. The factors relating to the incidence and severity of RINV have been discussed in Chapter IV (see p. 19).
Section 1. Anti-emetics and their efficacy for RINV
There have been only a few randomised clinical trials evaluating the efficacy of anti-emetic drugs for treating RINV. Generally, it is patients receiving TBI (total body irradiation), HBI (half body irradiation) or upper-abdominal irradiation who participate in these trials because these types of treatment lead to a higher risk of developing nausea and or vomiting. Evidence shows that prevention of these symptoms is better than intervention on an as-needed basis.
Section 1.1. 5-HT3 receptor antagonists
The 5-HT3 RA class of anti-emetics has been used more extensively in clinical practice to treat RINV over the last two decades.Table 13 and Table 14show randomised trials with 5-HT3 RAs and/or corticosteroids in patients treated with single or fractionated regimens of radiotherapy. Different compounds and a wide range of doses and schedules were used. Trials in Table 13 reported that in patients receiving upper abdominal irradiation, 5-HT3 RAs provided significantly greater protection against RINV than metoclopramide, phenothiazines or placebo.
|Study a||n||Radiotherapy regimens||Anti-emetic treatment||CR (% of patients)||Result|
|||154||≥5 fractions to minimum total dose of 20 Gy||DEX 2 mg ×3/day p.o. for 5–7 days
|DEX better than placebo|
|82||8–10 Gy single fraction||OND 8 mg ×3/day p.o. for 5 days
PCP 10 mg ×3/day p.o. for 5 days
|OND better than placebo|
|||135||1.8 Gy/day for at least 5 fractions||OND 8 mg ×3/day p.o. for 5 days
MCP 10 mg ×3/day p.o.
|OND better than MCP (for vomiting)|
|||111||≥1.7 Gy/day for ≥10 fractions||OND 8 mg ×2/day p.o.
|OND better than placebo|
| b||50||≥6 Gy single fraction||DOL 0.3 mg/kg i.v.
DOL 0.6 mg/kg i.v.
DOL 1.2 mg/kg i.v.
|DOL better than placebo|
|||23||2 Gy/day to 30 Gy in 15 fractions||TRO 5 mg/day p.o.
MCP 10 mg ×3/day p.o.
|TRO better than MCP|
|GRAN 2 mg/day
|GRAN better than placebo|
|||211||≥15 fractions to the upper abdomen to a dose of 20 or more Gy||OND 8 mg b.i.d. for 5 days +
Placebo for 5 days
OND 8 mg b.i.d. +
DEX 4 mg for 5 days
|OND + DEX better than OND alone|
|||288||Fractionated radiotherapy of moderate or high emetogenic potential||TRO 5 mg/day starting 1 day before RT until 7 days after RT
TRO 5 mg on an as-needed basis (rescue)
|Incidence of vomiting was 2.19 times higher in TRO rescue arm (p = 0.001)||Prophylactic TRO better than rescue TRO|
|||48||5 fractions/wk, 1.8–2.0 Gy per fraction Days 0–4 + cisplatin 40 mg/m2 on Day 1||PAL 0.25 mg + PRED 100 mg o.d. on Day 1, plus PRED 50 mg on Day 2 and PRED 25 mg on Days 3 and 4.||Cycle 1: 42% nausea free, after 5 cycles only 23% nausea free||PAL & PRED insufficient for this treatment regimen|
a References:  Priestman et al., 1990 ;  Priestman et al., 1993 ;  Franzen et al., 1996 ;  Bey et al., 1996 ;  Aass et al., 1997 ;  Lanciano et al., 2001 ;  Wong et al., 2006 ;  Mystakidou et al., 2006 ;  Ruhlmann et al., 2013 .
c CR: Complete plus major response.
d Primary endpoint: CR days 1–5.
e Secondary endpoint: CR days 1–15.
Adapted from Feyer et al., 2011 .
p.o.: orally; i.v.: intravenously; b.i.d.: twice daily; wk: week; DEX: dexamethasone; DOL: dolasetron; GRAN: granisetron; MCP: metoclopramide; PAL: palonosetron; PRED: prednisolone; OND: ondansetron; PCP: prochlorperazine; TRO: tropisetron.
|Study||n||Radiotherapy regimen||Anti-emetic treatment||CR (% of patients)||Result|
|Prentice et al., 1995||30||7.5 Gy TBI single fraction||GRAN 3 mg i.v. vs
MCP 20 mg i.v. + DEX 6 mg/m2 i.v. + LOR 2 mg i.v.
|GRAN better than MCP + DEX + LOR|
|Tiley et al., 1992||20||10.5 Gy TBI single fraction||OND 8 mg i.v.
|OND better than placebo|
|Spitzer et al., 1994||20||1.2 Gy ×3/day
TBI 11 fractions to a total dose of 13.2 Gy
|OND 8 mg ×3/day p.o.
|OND better than placebo|
|Sykes et al., 1997||66||8–12.5 Gy
HBI single fraction
|OND 8 mg ×2 p.o. vs
CLP 25 mg ×3 p.o. +DEX 6 mg ×3 p.o.
||OND better than CLP + DEX|
|Huang et al., 1995||116||7–7.7 Gy||OND 8 mg i.v. + DEX 10 mg vs
MCP 10 mg + DEX 10 mg
|OND + DEX better than MCP + DEX|
|Spitzer et al., 2000||34||1.2 Gy ×3/day
TBI 11 fractions to a total dose of 13.2 Gy
|OND 8 mg ×3/day p.o vs
GRAN 2 mg ×1/day p.o.
a All patients received i.v. dexamethasone (8 mg) and phenobarbitone (60 mg/m2).
Adapted from Feyer et al., 2011 .
CLP: chlorpromazine; CR: complete response; DEX: dexamethasone; GRAN: granisetron; HBI: half-body irradiation; LOR: lorazepam; MCP: metoclopramide; OND: ondansetron; TBI: total-body irradiation; p.o.: orally; i.v.: intravenously.
In patients treated with TBI or HBI, 5-HT3 RAs provided significantly greater protection against RINV than conventional anti-emetics or placebo ( Table 14 ).
Side effects were evaluated by Goodin and Cunningham (2002) . The side effects of 5-HT3 RAs are usually reported as mild, with headache, constipation, diarrhoea and weakness ( Jordan et al., 2007a ; Prentice et al., 1995 ; Priestman et al., 1993 ; Spitzer et al., 2000 ). Rather than causing constipation, 5-HT3 RAs sometimes reduce the frequency of diarrhoea, a debilitating side effect of acute enteric radiation toxicity ( Feyer et al., 1998 ; Franzen et al., 1996 ).
The 5-HT3 RA palonosetron and the transdermal granisetron patch (Sancuso®) might be a useful option for patients receiving radiotherapy, although to date only a few studies have been undertaken on their use ( Belli et al., 2008 ; Dimitrijevic and Medic-Milijic, 2009 ; Feyer et al., 2011 ). Looking at further options, a recent study by Ruhlmann et al. concluded that investigation of the addition of a NK-1 RA to anti-emetic treatment under some circumstances would be valuable ( Ruhlmann et al., 2013 ). This study evaluated anti-emetic therapy for 48 gynaecological patients receiving fractionated radiotherapy and concomitant weekly cisplatin (40 mg/m2). Anti-emetic treatment was palonosetron and prednisolone. Results showed that the probability of completing 5 cycles without emesis was 57%. During cycle 1, 42% of patients were nausea free, but by the fifth cycle only 23% of patients were continuously nausea free. Half the patients used rescue remedy at least once during the 5 cycles. The study concluded that palonosetron and prednisolone alone were insufficient anti-emetic treatment in these patients.
Section 1.2. Corticosteroids
These are interesting anti-emetic agents because of their widespread availability, low cost and reported benefits. One trial has recorded dexamethasone use as a single agent for the prophylaxis of RINV. This double-blind study ( Kirkbride et al., 2000 ) reported patients who underwent fractionated radiotherapy to the upper abdomen and received either oral dexamethasone (2 mg ×3/day) or placebo during the first week only of a six-week course of radiotherapy. A trial by Wong et al. (2006) ( Table 13 ) showed a non-significant trend towards improved complete control of nausea (50% versus 38% with placebo) and vomiting (78% versus 71%) (i.e., primary endpoint not reached). However, the effects of dexamethasone extended beyond the initial period: complete control of emesis was achieved by significantly more patients over the entire course of radiotherapy (23% versus 12% with placebo) (i.e., secondary endpoint was reached). Although the study did not show a statistically significant benefit for the primary endpoint, the results for the secondary endpoints and quality of life data strongly suggest that the addition of dexamethasone does provide benefits.
As the majority of episodes of nausea and vomiting occur early in the course of radiotherapy, it could be suggested that anti-emetics may only be necessary for the first week of treatment ( Feyer et al., 2005 ; Kirkbride et al., 2000 ; Kris et al., 2006 ).
Section 1.3. Neurokinin-1 (NK-1) receptor antagonists
The role of NK-1 RAs in the management of CINV is well established, however, aprepitant has not been studied in patients with RINV. A useful option in high-risk patients might be the combination of a 5-HT3 RA and a NK-1 RA. A trial is ongoing which is looking at this combination in radiochemotherapy patients with cervical cancer ( ClinicalTrials, 2014 ).
Section 1.4. Other agents
Less specific anti-emetic drugs, such as prochlorperazine, metoclopramide and cannabinoids, have been shown to have limited efficacy in the prevention and treatment of RINV, and this generally in patients with milder symptoms. The use of THC was slightly more beneficial than the use of prochlorperazine ( Ungerleider et al., 1984 ), but generally showed an inferior safety profile, including sedation and euphoria/dysphoria.
Section 1.5. Duration of prophylaxis
The decision on whether to continue treatment with 5-HT3 RAs beyond the first week of treatment for patients receiving fractionated radiotherapy is not clear. Although randomised trials have used 5-HT3 RAs for extended periods ( Franzen et al., 1996 ; Priestman et al., 1990 ; Wong et al., 2006 ) or just for the first five treatments, there have been no randomised trials to compare the two approaches.
Section 1.6. Rescue therapy
The benefits of 5-HT3 RAs as a rescue treatment have been suggested in all conducted trials ( Le Bourgeois et al., 1999 ; Maranzano et al., 2005 ; Mystakidou et al., 2006 ). Their role should be explored further for patients of low and minimal risk of RINV.
A web-based survey in which 1022 radiation oncologists from 12 countries participated investigated international patterns of practice in the management of RINV. The participants responded to 6 clinical case vignettes (one minimal-risk case, two low- and two moderate-risk cases, and one high-risk case) that described radiation therapy-only treatments of varying emetogenic potential. The outcome of the survey (908 evaluable respondents) was that risk estimates and management decisions for minimal- and high-risk patients did not vary very much and generally adhered to guidelines. However, the management of patients at low or moderate risk was very varied. Common management strategies initially were: rescue therapy for the minimal-risk case (opted by 63% of respondents), for the two low-risk cases (56% and 80%) and for one moderate-risk case (66%); and prophylactic therapy for the second moderate-risk case (75%) and the high-risk case (95% of respondents). 5-HT3 RAs were the most commonly used anti-emetic agents. Multivariate analysis showed that factors which predicted decisions to use prophylactic or rescue therapy were risk estimates of nausea and vomiting, awareness of the American Society of Clinical Oncology anti-emetic guideline, and European Society for Therapeutic Radiology and Oncology membership. The study concluded that radiotherapy-induced nausea and vomiting are understudied aspects of patients' treatment and that observational and translational studies are urgently needed to optimise patient management ( Dennis et al., 2012 ).
Section 2. MASCC/ESMO and ASCO guidelines
The development of new drugs to treat CINV and clinical trials in patients with RINV have led to improvements in the treatment of patients with RINV, with 5-HT3 RAs and corticosteroids being the most extensively evaluated drugs in these patients. Advances have been incorporated into the latest guidelines for anti-emetic prophylaxis and treatment (Table 15 and Table 16) ( Roila et al., 2010 ; Feyer et al., 2011 ; Basch et al., 2011 ). The tables show prophylaxis and treatment divided into the four guideline risk levels for RINV according to the area to be irradiated: high, moderate, low and minimal ( Feyer et al., 2011 ).
|Risk level||Anti-emetic guidelines||MASCC level of scientific confidence/consensus||ESMO level of evidence/grade of recommendation|
|High||5-HT3 RA + DEX||High/high;
Moderate/high for addition of DEX
(III/C for the addition of DEX)
|Moderate||5-HT3 RA + optional DEX||High/high;
Moderate/high for addition of DEX
(II/B for the addition of DEX)
|Low||Prophylaxis or rescue with 5-HT3 RAs||Moderate/high;
Low/high for rescue
|III/B for rescue|
|Minimal||Rescue with dopamine RAs or 5-HT3 RAs||Low/high||IV/D|
DEX: dexamethasone; RA: receptor antagonist.
In concomitant radio/chemotherapy, the anti-emetic prophylaxis corresponds with the chemotherapy-related anti-emetic guidelines for the same risk category, unless the radiotherapy risk category is higher.
100 mg p.o. only
2 mg p.o. / 1 mg or 0.01 mg/kg i.v.
8 mg p.o. b.i.d. or 8 mg or 0.15 mg/kg i.v.
0.50 mg p.o. or 0.25 mg i.v.
5 mg p.o. or i.v.
|5-HT3 RAs before each fraction throughout radiation therapy. Continue for at least 24 hours following completion of treatment.|
|Dexamethasone||4 mg p.o. or i.v.||During fractions 1–5.|
|5-HT3 RAs||Any of the above listed agents are acceptable; note preferred options c||5-HT3 RAs before each fraction throughout radiation therapy.|
|Dexamethasone||4 mg p.o. or i.v.
||During fractions 1–5.|
|5-HT3 RAs||Any of the above listed agents are acceptable; note preferred options||5-HT3 RAs either as rescue or prophylaxis. If rescue is used then prophylactic therapy should be given until the end of radiation therapy.|
|Any of the above listed agents are acceptable; note preferred options
20 mg p.o.
10 mg p.o./i.v.
|Patients should be offered either class or rescue therapy. If rescue is used, then prophylactic therapy should be given until the end of radiation therapy.|
a ASCO guidelines ( Basch et al., 2011 ).
c Preferred agents.
d No data are currently available on the appropriate dosing frequency with palonosetron in this setting. The Update Committee suggests dosing every second or third day may be appropriate for this agent.
RA: receptor antagonist. p.o.: orally; i.v.: intravenously; b.i.d.: twice daily.
Chapter VIII. Summary of approach to treatment
We conclude with a short summary to help plan anti-emetic prophylaxis in daily practice.
- Establish the emetogenic potential of the chemotherapy (see Table 5 , p. 16) and/or radiotherapy (see Table 7 , page 19):
- – The chemotherapeutic agent with the highest emetogenic potential determines the emetogenic potential of the whole therapy (see Table 11 , page 33); (exception: AC-based chemotherapy).
- – The radiotherapeutic risk level determines the emetogenic potential of the anti-emetic prophylactic treatment (seeTable 15 and Table 16, pages 50 and 51) unless concomitant chemotherapy is planned. Then the emetic prophylaxis is determined according to the guidelines for CINV, and with the emetogenic risk category of the chemotherapeutic regimen that is used.
- – There is no cumulative effect in the combination of therapies (with the exception of AC-based chemotherapy).
- Prophylactic anti-emetic treatment is crucial. It is important to note that the occurrence of delayed nausea and vomiting is greatly underestimated and prophylaxis for Days 2–5 of treatment must be planned in advance and instituted from the beginning. This is particularly important for patients at home.
- Rescue therapy.
- For persistent nausea and vomiting, it is necessary to consider a differential diagnosis such as brain metastases.
Chapter IX. Conclusions and future research
Considerable progress has transformed the field of CINV and RINV in the past 30 years with the introduction of new anti-neoplastic treatments on the one hand and new anti-emetic agents on the other. With the latter, chemotherapy-induced vomiting has become a more rare event, and the same is true for radiotherapy-induced vomiting. However, some 20–30% of patients still suffer from these side effects; of these, some are refractory (i.e., the recommended anti-emetic prophylaxis does not lead to resolution of the side effects), but others are incorrectly managed; this non-adherence to guidelines would be unacceptable in the context of anti-cancer treatment and should be just as unacceptable in the context of anti-emesis treatment.
There are many areas that need further exploration. Patients continue to suffer from nausea. Nausea may mean different unpleasant experiences for each patient, but there can be little doubt that its effect on the quality of life for patients with cancer can be enormous and adds further difficulties to an already stressful situation. Further research is needed in this area in order to understand nausea better and apply adequate prevention or treatment.
CINV studies have centred on single-day chemotherapy, but proper studies for multiple-day chemotherapy are needed, too. It is also necessary to address the nausea and vomiting related to daily oral treatments and the care and education of patients who are being treated at home outside the hospital situation. Understanding the reasons for failure to control acute or delayed nausea and vomiting will not be easy, as thanks to intervention these are now less frequent events. However, studies to determine the best interventions in such settings and to further reduce the burden of cancer and its related treatments and their side effects should continue to be a priority.
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a Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier, Vaud, Switzerland
b Clinic for Internal Medicine, Department of Haematology/Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany
c Department of Radio-oncology and Nuclear Medicine, Vivantes Clinics, Berlin-Neukölln, Berlin, Germany
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