Chemotherapy-Related Nausea and Vomiting and Treatment-Related Nausea and Vomiting

Elizabeth Blanchard

The ability of chemotherapy to cause nausea and vomiting is legendary and remains a widespread fear among cancer patients. Indeed, nausea and vomiting related to chemotherapy significantly decreases patient quality of life (1). Over the past two decades, however, prevention of chemotherapy-induced nausea and vomiting (CINV) has improved dramatically. This is largely due to new classes of drugs used in prevention. This has meant improvements in quality of life for cancer patients and likely increased compliance in oncologic treatment. Radiation therapy also carries a risk of nausea and vomiting depending on the anatomic location of therapy, though there is less in the way of randomized data to guide therapy.

SYNDROMES OF CINV

CINV can be described as three distinct syndromes: acute, delayed, and anticipatory nausea and vomiting. Though in clinical practice these syndromes can overlap, the terms are helpful to define and categorize CINV. Acute CINV refers to nausea and vomiting that develops within the first 24 hours after chemotherapy administration, often within a couple of hours for most emetogenic chemotherapy agents. Delayed CINV refers to nausea and vomiting that develops more than 24 hours after chemotherapy and is generally considered to last 3 to 5 days following chemotherapy administration, but can vary, depending on many factors, including control of emesis during the acute period. Delayed emesis is considered not as severe as acute emesis (2), though less well understood and may be underappreciated and undertreated by clinicians. Cisplatin has been the most well studied in defining delayed emesis and is the archetype chemotherapy agent in the investigation of antiemetic agents. Without prophylaxis, more than 90% of patients will have some symptoms of nausea or vomiting in the delayed emesis period. Anticipatory CINV occurs when nausea or emesis is triggered by events or settings of prior chemotherapy such as the sights or smells of the infusion room, chemotherapy equipment, or care providers.

RISK OF CINV

The intrinsic emetogenicity of an individual chemotherapy agent appears to be the most important predictive factor for the development of CINV, though CINV is also influenced by patient characteristics. Such characteristics include gender, age, and history of alcohol consumption (3). In addition, experiencing nausea and vomiting with prior chemotherapy is also a risk factor. Consistently, women are more prone to both nausea and vomiting associated with chemotherapy. Older patients are less likely to experience nausea and vomiting compared with younger patients in some series (4). A history of alcohol consumption is protective against the risk of nausea and vomiting associated with chemotherapy. History of motion sickness and hyperemesis gravidarum are not wellestablished risk factors for CINV.

The emetogenicity of individual chemotherapy agents depends on the type of chemotherapy, dose and route, and rate of administration. Chemotherapeutic agents are classified by their risk of inducing CINV, and the most commonly used classification is modified from the Hesketh classification, originally described as five levels of emetic risk (5). It has now been modified to four levels: high, moderate, low, or minimal risk of inducing emesis (Table 12.1) (6).

RESEARCH IN PREVENTION OF CINV

The prevention of CINV is an area of very solid and consistent clinical research, which has resulted in the development of guidelines that are evidence based. In the research setting, it is useful to distinguish periods of acute and delayed emesis, as well as overall response. Vomiting is more frequently used as an endpoint, because it is a more consistent measure than nausea, which tends to be more subjective. Visual analogue scales do exist for nausea, which can help patients quantify their symptoms. Another endpoint used to judge the effectiveness of antiemetic therapy is the use of rescue medications as a measure of how well or poorly both nausea and emesis are controlled. Complete response or protection is often defined as no vomiting and no use of rescue medications. Episodes of vomiting and degree of nausea are often captured with the use of a diary or frequent telephone contact.

TABLE 12.1 Classification of emetic risk of intravenous antineoplastic agents

Emetic Risk (Estimated Incidence without Prophylaxis)	Antineoplastic Agents
High (>90%)	Cisplatin
	Mechlorethamine
	Streptozotocin
	Cyclophosphamide (≥1,500 mg/m²)
	Carmustine
	Dacarbazine
Moderate (30-90%)	Oxaliplatin
	Cytarabine (>1 g/m²)
	Carboplatin
	Ifosfamide
	Cyclophosphamide (<1,500 mg/m²)
	Doxorubicin
	Daunorubicin
	Epirubicin
	Idarubicin
	Irinotecan
	Azacitidine
	Bendamustine
	Clofarabine
	Alemtuzumab
Low (10-30%)	Paclitaxel
	Docetaxel
	Mitoxantrone
	Doxorubicin HCl liposome injection
	Ixabepilone
	Topotecan
	Etoposide
	Pemetrexed
	Methotrexate
	Mitomycin
	Gemcitabine
	Cytarabine (≤100 mg/m²)
	5-Fluorouracil
	Bortezomib
	Cetuximab
	Trastuzumab
	Panitumumab
	Catumaxomab
Minimal (<10%)	Bleomycin
	Busulfan
	2-Chlorodeoxyadenosine
	Fludarabine
	Vinblastine
	Vincristine
	Vinorelbine
	Bevacizumab
	Rituximab
Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21:v232-v243, by permission of Oxford University Press.

PATHOPHYSIOLOGY OF CINV

Nausea and vomiting resulting from chemotherapy involves a complicated and multifaceted physiology. Afferent stimulatory input likely comes from several sources, including vagal afferent nerves in the abdomen. These are known to have a number of receptors on their terminal ends, including 5-hydroxytryptamine-3 (5-HT₃), neurokinin (NK)-1, and cholecystokinin-1. Enteroendocrine cells located within the gastrointestinal tract release neurotransmitters in response to chemotherapy, including 5-HT, substance P, and cholecystokinin, which then bind to the vagal afferent nerves in the abdomen. The so-called chemotherapy trigger zone is also thought to provide afferent input in response to chemotherapy. Anatomically, this is the area postrema where the blood-brain barrier is less restrictive and thus may be an area exposed to chemotherapy or chemotherapy byproducts. Input then flows into the central nervous system proper to an area termed the “vomiting center,” though it is now more widely believed that this represents a number of separate brain stem areas that are connected to coordinate emesis, including the parvocellular reticular formation, the Botzinger complex, and the nucleus tractus solitarius (7).

Key to the process of emesis is the involvement of a number of neurotransmitters. In CINV, the most important neurotransmitters include dopamine, serotonin (5-HT₃), substance P, and the cannabinoids (8). Dopamine antagonists such as phenothiazines have been used for decades for prevention of CINV, exemplifying the importance of dopamine as an active neurotransmitter. More recently, the importance of 5-HT in CINV has been realized, with the type 3 receptor emerging as the most relevant. This is likely to be mainly at the level of the afferent signals in the gastrointestinal area, though 5-HT₃ receptors are found not only in the vagal afferent fibers but also in the area postrema and the nucleus tractus solitarius (8,9).

Substance P is a neuropeptide that also plays an important role in CINV. It belongs to a family of neurotransmitters called tachykinins, which bind to NK receptors. Substance P has an affinity for NK₁ receptors, which are located in the gastrointestinal tract, the area postrema, and the nucleus solitarius—all important areas active in the physiology of emesis (8). It was discovered in the initial animal studies that emesis was prevented by inhibitors of substance P, proving the principle of importance of this neurotransmitter. This occurred with both centrally acting and peripherally acting stimuli (10).

RADIATION THERAPY-INDUCED NAUSEA AND VOMITING

The risk of radiation therapy-induced nausea and vomiting (RINV) is primarily dependent on the area of the body being treated. Depending on the type of radiation, the risk of nausea and vomiting is divided into four categories: high, moderate, low, and minimal (11,12). High risk includes total body irradiation and total nodal irradiation. Moderate risk involves radiation sites in the upper abdomen, half-body irradiation, and upper body irradiation. Low risk includes cranial and craniospinal irradiation as well as head and neck, lower thorax, and pelvis. Minimal risk includes radiation to the extremities and breast.

Animal studies have demonstrated the importance of 5-HT₃ in the pathophysiology of RINV, with a better response to inhibition of 5-HT₃-mediated pathways than with dopamine pathways (13). It is speculated that the direct toxic effects on areas such as the gastrointestinal tract stimulate afferent fibers and transmit signals to the collective vomiting center. Additional potential stimuli include the tissue breakdown products that occur as a consequence of radiation treatment.

DRUGS USED IN THE PREVENTION OF TREATMENT-RELATED NAUSEA AND VOMITING

The three classes of drugs that have the most relevance in the prevention of treatment-related nausea and vomiting include the 5-HT₃ receptor antagonists, the NK₁ antagonists, and corticosteroids (Table 12.2). They may be given alone or in combination, depending on the clinical setting. These three classes are now in routine use in the place of dopamine antagonists, which are now mainly used as supplemental medications in cases where standard prophylaxis has not worked.

TABLE 12.2 Doses of commonly used antiemetic agents

			Prechemotherapy Dose
Drug			Acute Emesis Prophylaxis	Delayed Emesis Prophylaxis
Highest therapeutic index
	Aprepitant		125 mg orally	80 mg orally days 2 and 3
			110 mg IV
	Fosaprepitant		150 mg IV
	Dexamethasone
		With aprepitant	12 mg orally or IV	8 mg days 2-4^a
		Without aprepitant	20 mg orally or IV^a	8 mg bid days 2-4^a
			8 mg orally or IV^b	8 mg days 2 and 3^c
	Ondansetron		24 mg orally^a; 8 mg orally bid^b
			8 mg or 0.15 mg/kg IV
	Granisetron		2 mg orally
			1 mg or 0.01 mg/kg IV
	Tropisetron		5 mg orally or IV
	Dolasetron		100 mg orally
			100 mg or 1.8 mg/kg IV
	Palonosetron		0.25 mg IV
			0.5 mg orally
Lower therapeutic index
	Prochlorperazine		10 mg orally or IV	—
	Dronabinol		5 mg/m² orally	5 mg/m² orally q2-4h PRN
	Nabilone		1-2 mg orally	1-2 mg bid or tid PRN
	Olanzapine		5 mg orally daily for 2 d preceding chemotherapy; 10 mg on day 1	10 mg days 2-4
IV, intravenously; bid, twice daily; tid, thrice daily.
^aWhen used with highly emetic chemotherapy. ^bWhen used with moderately emetic chemotherapy. ^cWhen used with moderately emetic chemotherapy with potential for delayed emesis.

5-HT₃ Antagonists

This class of drugs includes the first-generation agents dolasetron, granisetron, ondansetron, tropisetron, and ramosetron and the second-generation agent palonosetron. They are given as oral, intravenous (IV), and transdermal preparations, with first-generation IV formulations considered equivalent to oral administration (14). Previously, all first-generation agents had been considered to be of equal efficacy and used interchangeably (15), though a meta-analysis (16) has suggested that while ondansetron and granisetron are equivalent, granisetron is more effective than tropisetron. Data for ramosetron and dolasetron
are more limited. Side effects of 5-HT₃ receptor antagonists include constipation, headache, and a transient rise in liver enzymes. The Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) guidelines laid out several principles in regard to 5-HT₃ receptor antagonists: the lowest therapeutic dose should be used; the adverse effects of this class are similar among agents; and the use of a single dose prior to chemotherapy remains the optimal integration of this class of medications.

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