Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Patients

Malignant neoplasms remain a leading cause of death worldwide (Siegel et al., 2014). At the beginning of this century, comprehensive treatment for malignant neoplasm had progressed considerably with advances in molecular targeted therapy, immunotherapy and gene therapy. However, chemotherapy is still the primary treatment. Chemotherapy-induced nausea and vomiting (CINV) is the most common and intolerable adverse event, which impedes or even interrupts the scheduled therapeutic program and severely impairs the efficacy (Hassan and Yusoff, 2010; Janelsins et al., 2013; Keat et al., 2013; nccn, 2014). The goal of each antiemetic therapy is to prevent chemotherapy induced nausea and vomiting (CINV). Twenty years ago, these were inevitable adverse events of chemotherapy and forced up to 20% of patients to postpone or refuse potentially curative treatment (Jordan et al., 2007). Clinical and basic research over the past 25 years has led to steady improvements in the control of CINV. The chemotherapy available in the 1950s and 1960s varied greatly in its capacity to induce emesis. Agents such as vinca alkaloids and 5-fluoruracil were in common usage, and only infrequently caused emesis. In contrast, nitrogen mustrard were known for association with emesis. There was some awareness of the problem of CINV, but appreciation of its magnitude was not great (Gralla, 1993). Based on the current studies, it is generally believed


Introduction
Malignant neoplasms remain a leading cause of death worldwide (Siegel et al., 2014). At the beginning of this century, comprehensive treatment for malignant neoplasm had progressed considerably with advances in molecular targeted therapy, immunotherapy and gene therapy. However, chemotherapy is still the primary treatment. Chemotherapy-induced nausea and vomiting (CINV) is the most common and intolerable adverse event, which impedes or even interrupts the scheduled therapeutic program and severely impairs the efficacy (Hassan and Yusoff, 2010;Janelsins et al., 2013;Keat et al., 2013;nccn, 2014). The goal of each antiemetic therapy is to prevent chemotherapy -induced nausea and vomiting (CINV). Twenty years ago, these were inevitable adverse events of chemotherapy and forced up to 20% of patients to postpone or refuse potentially curative treatment (Jordan et al., 2007).
Clinical and basic research over the past 25 years has led to steady improvements in the control of CINV. The chemotherapy available in the 1950s and 1960s varied greatly in its capacity to induce emesis. Agents such as vinca alkaloids and 5-fluoruracil were in common usage, and only infrequently caused emesis. In contrast, nitrogen mustrard were known for association with emesis. There was some awareness of the problem of CINV, but appreciation of its magnitude was not great (Gralla, 1993).
Based on the current studies, it is generally believed

Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Patients
Abhishek Shankar¹*, Shubham Roy², Abhidha Malik¹, PK Julka¹, GK Rath¹ that 5-HT3 plays a dominant role in acute vomiting, while substance P seems to play a more important role in delayed vomiting (Bergstrom et al., 2011). In cisplatin-induced CINV, serum 5-HT3 levels peak at 6-8 h after the administration of cisplatin. At this time-point, the clinical symptoms are obvious and the efficacy of 5-HT3 antagonists is excellent. Neurokinin-1 (NK1) receptor antagonists are effective for both acute and delayed vomiting, especially the latter, on which the studies are also focused. The advent and application of Palonosetron, a second-generation 5-HT3 antagonist, furthers our understanding of the mechanisms of CINV. In contrast to the first-generation 5-HT3 antagonist, it is efficacious in both acute and delayed CINV. If this efficacy is based solely on enhanced binding to the receptors and lengthened half-life, then increased administration frequency or dosage of the first-generation drugs should ensure binding saturation of receptors; however, this is not the case.
More extensive studies have indicated that the 5-HT3 receptor that binds Palonosetron has allosteric sites, and that internalization occurs following binding, thus inhibiting receptor recycling for up to 2.5h (Rojas et al., 2010;Rojas et al., 2014). Additionally, Palonosetron treats both acute and delayed vomiting via the crosstalk that exists between the 5-HT3 and substance P receptor pathways (Rojas et al., 2014).
Corticosteroids show good antiemetic efficacy in the prevention of acute and delayed emesis, especially when combined with other antiemetic agents. However, their role is sometimes underestimated. Another group of antiemetic, the neurokinin-1 (NK-1) receptor antagonists, has been developed. The first drug in this class, Aprepitant, was approved in 2003(Hesketh et al, 2003.
Another drug Fosaprepitant in intravenous form was approved for prevention of chemotherapy induced acute and delayed emesis.
Studies have shown that the patients benefit from the use of Aprepitant in combination with standard antiemetic therapy, both in the acute and delayed setting of highly and moderately emetogenic chemotherapy. However, although significant progress has been made with the development of a number of effective and well tolerated antiemetic treatments, CINV remains an important adverse effect of treatment.

History of development of chemotherapy and antiemetic therapy for CINV
1950-60 Nitrogen mustard and Actinomycin D induce severe emesis 1960 Introduction of phenothiazines -antiemetic effect via D2 blockage, Area postrema responsible for emesis by chemotherapy(Barison) 1970s Introduction of cisplatin, no effective antiemetic therapy available; Metaclopromide found to have antiemetic efficacy 1980s High dose metaclopromide improves antiemetic response rates; Introduction of steroids in prophylaxis; Studies with Ondansetron 1990s Introduction

Pathophysiology of CINV
The central nervous system plays a critical role in the physiology of nausea and vomiting, serving as the primary site that receives and processes a variety of emetic stimuli. The central nervous system also plays a primary role in generating efferent signals which are sent to a number of organs and tissues in a process that eventually results in vomiting. It was Wang and Borison who first proposed the idea of a vomiting centre (Wang and Borison, 1950).

Mechanism of CINV
Three key components involving area in the hindbrain and the abdominal vagal afferents have been identified. Now a day, it is thought that the existence of anatomically discrete vomiting centres is unlikely (Hesketh, 2008). The locations of neurons that coordinate the bodily functions associated with emesis are spread throughout the medulla, supporting the notion that a central pattern generator receives indirect input from both the area postrema (chemoreceptor trigger zone) and the abdominal vagus by means of the nucleus tractus solitaries.
Chemoreceptor Trigger Zone (CTZ): The Chemoreceptor Trigger Zone is located in the area postrema at the bottom end of the fourth ventricle. The area postrema has afferent and efferent connections with underlying structures, the subnucleus gelatinosus and nucleus tractus solitaries, receiving vagal afferent fibres from the gastrointestinal tract.
Abdominal vagal afferents: The abdominal vagal afferents appear to have the greatest relevance for CINV. A variety of receptors, including 5-HT, NK-1, and cholecystokinin-1, are located on the terminal ends of the vagus afferents. The receptors lie in close proximity to the enterochromaffin cells located in the gastrointestinal mucosa of the proximal small intestine, which contains a number of local mediators, such as 5-HT, substance P and cholecystokinin.
Neurotransmitters: Research over the past three decades have gradually elucidated the clinical significance of several neurotransmitters in the vomiting process. The neurotransmitters serotonin, substance P and dopamine all appear to play important roles in this process.

CINV can be classified into three categories
Acute Onset Nausea and Vomiting: Occurring within 24 hours of initial administration of chemotherapy. Mainly by serotonin (5-HT) release from the enterochromaffin cells Delayed Onset Nausea and Vomiting: After 24 hours to 5 days after chemotherapy. Various mechanism -Mainly substance P mediated, disruption of the blood-brain barrier, disruption of the gastrointestinal motility, adrenal hormones (Roila et al., 2002) Anticipatory Nausea and Vomiting: Occurrence is possible after 1 cycle of chemotherapy. Involves an element of classic conditioning. Triggered by taste, odour, sight, thoughts or anxiety secondary to a history of poor response to antiemetic agents (Roila et al., 2002;Aapro et al., 2005).

Emetogenic potential of chemotherapy
It is thought that chemotherapy is the most important risk factors for the occurrence of CINV. The emetogenic potential of chemotherapeutic agents is classified into four emetic risk groups: high, moderate, low and minimal (Hesketh et al., 1997;Grunberg et al., 2005;Kris et al., 2006). The emetogenic potential of an antineoplastic therapy varies with specific drug used ranging from cisplatin, which results in severe vomiting in almost all patients, to vinca alkaloids, with only minimal inducible emesis. The chemotherapeutic agents can cause different intention of emesis, depending on the way the drugs are administered.

Patient risk factors
Following is a breakdown of factors that increase susceptibility to nausea and vomiting Previous experience of poorly controlled emesis: If patients have previous experience of poorly controlled emesis they are more likely to develop post-chemotherapy nausea and vomiting in response to a new treatment. If emesis control was sufficient during previous chemotherapy, the percentage of patients who do not experience emesis in subsequent chemotherapy courses is larger than it is for patients who had insufficient previous  antiemetic treatment (Gralla et al., 1999). Dose intensity: The more frequently treatment is given, the more severe nausea might be. This dose-intensive therapy is better at curing cancer, but can also increase the severity of side effects.
Agents: Certain drugs tend to cause more nausea and vomiting than others. Among the worst culprits are Platinum (cisplatin) and Adriamycin (doxorubicin). Both are given intravenously-injected with a needle into a vein.
Target site: Treatment in the brain and gut causes more nausea and vomiting than in other areas of the body. The nerve impulses that trigger nausea and vomiting are in the brain.
Administration: Chemotherapy injected into a vein (intravenously) tends to cause more nausea than pills.
Gender: Women are more apt to experience nausea than men. "This might be due to women's hormonal changes and emotions".
Hyperemesis: Women who had significant nausea and vomiting during pregnancy are more likely to have these same side effects when undergoing cancer treatment.
Age: Patients younger than 30 years tend to experience more nausea than older folks. Older people have a higher tolerance because of previous exposure to various toxins over their lifetime.
Alcohol and drug use: People who don't drink alcohol or take prescription drugs might have more nausea because they are not used to chemical alterations occurring in their bodies. A few types of chemotherapies actually contain alcohol.
History: People who are prone to motion sickness may be more likely to have nausea and vomiting during treatment.

Antiemetic Prophylaxis Prevention of Acute Nausea and Vomiting
Before chemotherapy, it is crucial to clearly define the optimal prophylactic antiemetic therapy for acute and delayed nausea and vomiting and to implement it from the beginning, since symptom-oriented therapy at later stage is ineffective in most cases. This is important especially for the prophylaxis of delayed emesis. Emetogenic potential of the planned chemotherapy regimen needs to be established first. For patients who are taking chemotherapy on outpatients, it is important to decide treatment plan for the prophylaxis of delayed emesis.

Highly emetogenic chemotherapy
Patients should be treated with combination of 5-HT3-RA, a NK-1-RA (Aprepitant) and a corticosteroid.

Moderately emetogenic chemotherapy
Patients receiving AC chemotherapy for breast cancer should be treated with combination of 5-HT3-RA, a NK-1-RA (Aprepitant) and a corticosteroid. If Aprepitant is not available, women should receive a combination of Palanosetron plus dexamethasone (Roila et al., 2010) Patients undergoing other moderately emetogenic chemotherapy should be given combination of with combination of 5-HT3-RA palanosetron and a corticosteroid dexamethasone.

Low emetogenic chemotherapy
Patients receiving low emetogenic chemotherapy should be treated with single agent such as low dose of corticosteroid. Patients of this group should not be overtreated with 5-HT3-RA routinely.

Minimally emetogenic chemotherapy
No antiemetic drug should be routinely administered before chemotherapy.

Prevention of Delayed Nausea and Vomiting
The presence of delayed emesis is often underestimated, with the consequence that no adequate preventive measures are taken.

Highly emetogenic chemotherapy
Routinely, Patients are treated with combination of NK-1-RA (Aprepitant) and a corticosteroid. The addition of 5-HT3-RA is not necessary most of the time (Schmoll et al., 2006).

Moderately emetogenic chemotherapy
Aprepitant or Fosaprepitant should be used to prevent delayed nausea and vomiting. A patient who has received Palanosetron for acute emesis, dexamethasone treatment is the preferred treatment for prevention of delayed nausea and vomiting. Patients can also be considered for multiday oral dexamethasone treatment for prevention of delayed emesis.

Low and minimally emetogenic chemotherapy
No prophylactic antiemetic treatment is planned for delayed emesis.

Therapy against Anticipatory Nausea and Vomiting (ANV)
ANV is a learned conditional reflex and drug therapy has modest efficacy. It may be best managed by psychological techniques, although this may not represent an easy solution in our day to day practice. The best approach is to avoid this by using optimal antiemetic prophylaxis from the first cycle. Conventional antiemetic are mostly ineffective however treatment with benzodiazepines in addition to conventional therapy has shown some efficacy if given before chemotherapy. Muscle relaxation, systemic desensitisation, hypnosis and cognitive distraction are possible interventions but its usefulness is doubtful.

Therapy in Cases of Insufficient Antiemetic Efficacy
If patient presents with emesis despite of preventive measures, it should first be checked that patient received the antiemetic according to guidelines. In general, a DOI:http://dx.doi.org/10.7314/APJCP.2015.16.15.6207 Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Patients  Oral dose: 5 mg daily for 2 days preceding chemotherapy; 10 mg on day 1 Oral dose: 10 mg on days 2-4 **This dose is for use only in patients who cannot tolerate or do not have a response to 5-HT3-receptor antagonists, dexamethasone, and aprepitant, given the risk of adverse neurologic events with this higher dose of metoclopramide repetition of the previously given antiemetic agents usually does not produce the desired result. This is true particularly for first generation 5-HT3-RAs (Musso, 2009). It has been suggested that in view of different mechanism of action, addition of palanosetron will be a better rationale (Einhorn, 2010). For patients, who received a combination of a 5-HT3-RA with a corticosteroid, a NK-1-RA (Aprepitant/Fosaprepitant) should be added. With lasting emesis the addition of metaclopromide, benzodiazepines, and neuroleptic agents and in particular olanzapine may be effective (Hesketh, 2008 In addition, other conditions like emetogenic drug therapy, brain metastasis and gastrointestinal obstructions leading to continuous emesis should be ruled out.

Therapy in Multiple Day chemotherapy
For multiple day cisplatin therapy, the use of a 5-HT3-RA and a corticosteroid is recommended on the days when cisplatin is administered to the patients (Acute phase). In addition, for prophylaxis of delayed emesis, a corticosteroid alone should be administered. Aprepitant may be useful for multi-day chemotherapy regimens that are likely to be highly emetogenic. Use of 5-HT3-RA an day 1-5 or Palanosetron on days 1, 3, 5 is also recommended (Roila et al., 2010).

Therapy in High Dose Chemotherapy
On the day when high-dose chemotherapy is administered (acute phase), the use of a 5-HT3-RA and a corticosteroid is recommended before initiation of chemotherapy. On days 2-3 after high dose chemotherapy, a corticosteroid alone should be given for prevention of delayed nausea and vomiting. The addition of NK-1 RA or use of Palanosetron can be taken into consideration, although not recommended by recent guidelines.

Novel Therapy
Netupitant: Netupitant is a highly selective NK1 receptor antagonist, which is thought to work by blocking the action of substance P, an endogenous neurotransmitter contained in high concentrations in the vomiting center of the brainstem that can stimulate the vomiting reflex. Netupitant is currently under phase III trials.
Akynzeo: this is a fixed combination capsule of Netupitant and palanosetron, which is currently in Phase III trials helps in preventing CINV. The blockage of P/ NK1 receptors by Netupitant in the central nervous system inhibits the binding of endogenous tachykinin neuropeptide substance and this result in preventing the chemotherapy-induced nausea and vomiting. Moreover, Palonosetron helps in the blockage of serotonin at 5-hydroxytryptamine type 3 (5-HT3) receptors and it also helps in the chemotherapy-induced nausea and vomiting. USA FDA approved this drug on 10 th October, 2014 for treatment of CINV.