A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients

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Abstract

Olanzapine is an atypical antipsychotic agent that blocks multiple neuronal receptors involved in the nausea and vomiting pathways. It has therefore been studied for the prevention and treatment of chemotherapy-induced emesis and in patients in palliative care presenting nausea and vomiting refractory to standard antiemetics.

Some studies have shown that olanzapine was not inferior to aprepitant in the prophylaxis of highly and moderately emetogenic chemotherapy and that it increased the rate of complete response when added to a combination of a 5-HT3 antagonist, aprepitant and dexamethasone. These studies present so many shortcomings, however, that they do not permit us to draw any firm conclusions.

Oral olanzapine showed superior antiemetic efficacy to metoclopramide as rescue treatment to control breakthrough emesis induced by chemotherapy. However, an oral formulation is not appropriate because in patients with vomiting or severe nausea the mere ingestion of an oral drug could induce emesis.

Finally, in palliative care olanzapine could control or reduce the intensity of nausea and vomiting refractory to standard antiemetics.

Introduction

One of the most distressing problems in cancer patients is nausea and vomiting. These symptoms may lead to a significant deterioration in patient's quality of life and other severe consequences such as malnutrition, electrolyte imbalance, dehydration and weight loss.

In patients receiving chemotherapy, intense nausea and vomiting may require dose reduction, treatment delay or even permanent interruption. According to the period of its occurrence, chemotherapy-induced nausea and vomiting can be classified as acute (within 24 h from chemotherapy administration), delayed (24–120 h after chemotherapy) or anticipatory emesis (hours to days before chemotherapy). Anticipatory emesis occurs in patients with a previous experience of chemotherapy-induced acute and delayed emesis. In the past 20 years, important progress has been achieved in the prevention of acute and delayed emesis and consequently there has been an important reduction in anticipatory emesis. With the current recommended prophylaxis for acute/delayed cisplatin-induced emesis (aprepitant, a 5-HT3 antagonist and dexamethasone/aprepitant and dexamethasone) about 85–95%/70–90% of patients can achieve a complete response (no vomiting and no rescue treatment), respectively. The current recommended prophylaxis for acute/delayed emesis induced by anthracyclines and cyclophosphamide in women with breast cancer is a combination of aprepitant, a 5-HT3 antagonist and dexamethasone/aprepitant that yields about 75–85%/55–75% complete response, respectively, in acute/delayed emesis [1], [2].

In advanced cancer patients nausea and vomiting are common and often undertreated problems. There are several causes of nausea and vomiting, including central nervous system (metastases and primary tumors which increase intracranial pressure), metabolic (hypercalcemia), medications (chemotherapy, radiotherapy, opioids), psychiatric (anxiety and depression) and gastrointestinal (bowel obstruction, gastroparesis) etiologies. Any identifiable and reversible cause is treated first. In these patients a recent systematic review analyzed 93 articles [3]. Of these, 14 were randomized clinical trials, most of low quality due to lack of blinding, lack of description of the method of randomization, concealment and/or attrition. The results of the systematic review: showed that metoclopramide has modest evidence based on prospective cohort studies and a double-blind study carried out in 26 patients showing its superiority with respect to placebo [4]. Furthermore, octreotide, dexamethasone and hyoscine butylbromide are efficacious in reducing symptoms of bowel obstruction, based on prospective studies and/or one randomized clinical trial; there is no evidence that either multiple antiemetics or the antiemetic of choice based on the etiology of emesis were better than a single antiemetic. In conclusion, prospective randomized trials of single antiemetics are needed to appropriately establish evidence-based guidelines. In clinical practice, despite the modest evidence, metoclopramide is considered a first-line treatment [5]. Haloperidol is used particularly in bowel obstruction. Second-line agents are generally phenothiazines or butirophenones [5]. On July 26, 2013 the European Medicines Agency recommended changes to the use of metoclopramide to reduce the risk of neurological side effects such a short-term extrapyramidal disorders and tardive dyskinesia. Metoclopramide should be prescribed for short-term use (up to 5 days) and at a maximum dose of 30 mg a day [6]. Opioid-induced nausea and vomiting may be due to multiple opioid effects, including enhanced vestibular sensitivity (may include vertigo and worsening with motion), direct effects on the chemoreceptor trigger zone and delayed gastric emptying (early satiety, bloating and postprandial worsening). A dopamine receptor antagonist such as prochlorperazine, haloperidol or metoclopramide is generally used to treat opioid-induced nausea and vomiting [7]. In a randomized double-blind study ondansetron was compared to metoclopramide and placebo in 94 advanced cancer patients reporting nausea during opioid treatment. Ondansetron and metoclopramide were not more efficacious than placebo [8]. Therefore, the 5-HT3 receptor antagonists do not reduce emesis from opioids and could be used in patients with emesis unresponsive to dopamine receptor antagonists even if evidence regarding their efficacy is lacking.

Recently, the antiemetic activity/efficacy of olanzapine, an atypical antipsychotic agent approved by the FDA for the treatment of the manifestation of psychotic disorders, has been suggested in some studies [6], [9]. The aim of this review is to critically analyze the available data on olanzapine for the prophylaxis and treatment of chemotherapy-induced emesis and emesis in terminal cancer patients.

Section snippets

Olanzapine

Olanzapine antagonizes multiple neurotrasmitter receptors including dopaminergic at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, cathecolamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors [9]. The drug has five times the affinity for 5-HT2 receptors as D2 receptors [10]. The mechanism by which olanzapine reduces chemotherapy-induced emesis is still unclear even if the antiemetic effects of

Phase I–II studies

After a case report in a patient with leukemia who reported a significant improvement in chronic nausea with the use of olanzapine [14] and a retrospective chart review of 28 patients who received olanzapine on an as-needed basis following moderately to highly emetogenic chemotherapy and who suggested that olanzapine was well tolerated and may decrease delayed emesis [15] a phase I study of olanzapine was published [16].

In this trial patients receiving their first dose of highly or moderately

Olanzapine for breakthrough chemotherapy-induced emesis

Breakthrough chemotherapy-induced nausea and vomiting is the nausea and vomiting occurring after administration of chemotherapy despite an adequate antiemetic prophylaxis. Antiemetic recommendations suggest that for this condition there are no known effective therapies and that in clinical practice the prophylactic regimen in subsequent chemotherapy cycles should be changed by switching to a different 5-HT3 receptor antagonist, adding benzodiazepines or antidopaminergic agents [1], [2].

Olanzapine for refractory emesis in terminal cancer patients

A series of case reports described the possible efficacy of olanzapine for the treatment of nausea or vomiting due to different pathophysiologic mechanisms mediated by multiple neurotrasmitters. In 6 patients receiving palliative care olanzapine was found to be effective for intractable nausea due to opioids, neoplasm and/or medications [30]. In other two patients with advanced cancer olanzapine relieved nausea failing to respond to the usual antiemetics [31]. In another case report olanzapine

Olanzapine toxicity

Except in a study in which 73% of patients receiving olanzapine reported sleepiness during chemotherapy [19], in the other phase III trials no differences in toxicity, in particular no difference in drowsiness or fatigue, were observed among patients receiving a short-course of olanzapine to prevent chemotherapy-induced emesis [20], [23], [24]. Also in patients receiving olanzapine as a rescue treatment there were no significant differences with respect to metoclopramide in fatigue and

Discussion

In this review of the literature we analyzed all published studies of olanzapine on the prevention and treatment of nausea and vomiting induced by chemotherapy and in patients in palliative care.

Unfortunately, the phase III studies on the prevention of chemotherapy-induced emesis in patients submitted to highly or moderately emetogenic chemotherapy present so many shortcomings that we cannot draw firm conclusions on its role with respect to aprepitant, whether combined with a 5-HT3 receptor

Conflict of interest

None declared.

Role of the funding source

No funding for this study.

Authors’ contribution

Authors contributed equally to the article.

Reviewers

Bernardo Leon Rapoport, The Medical Oncology Centre of Rosebank, 129 Oxford Road, Saxonwold, Johannesburg, Gauteng 2196, South Africa.

Karin Jordan, Consultant, University of Halle, Hematolgy/Oncology, Ernst-Grube-Str. 40, Halle, SA 06120, Germany.

Carla Fonte earned her medical degree in 2007 at University of Perugia and she received her diploma in medical oncology in 2014 at University of Florence. At present she is a medical oncologist at “S. Maria” Hospital, Terni, Italy.

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    Carla Fonte earned her medical degree in 2007 at University of Perugia and she received her diploma in medical oncology in 2014 at University of Florence. At present she is a medical oncologist at “S. Maria” Hospital, Terni, Italy.

    Sonia Fatigoni works as medical oncologist at the Medical Oncology Division, S. Maria Hospital, Terni, Italy. She received her medical degree in 2003 and her specialization in medical oncology in 2007 from the University of Perugia. Being member of the Rare Tumors Italian Network she has dedicate herself particularly to the treatment of the rare tumors. Furthermore, she worked on supportive care, especially the prophylaxis of chemotherapy-induced emesis. She is a member of the ESMO (European Society for Medical Oncology). She participated to international clinical trials on antiemetics and sarcoma, lung cancer and colorectal cancer. She participated as speaker at the 2009 ECCO 15–34th ESMO Congress and at several Italian meetings. She has published some scientific articles in important medical journals.

    Fausto Roila is the chairman of medical oncology of “S. Maria” Hospital, Terni, Italy. He is a member of the Board of MASCC (Multinational Association for Supportive Care in Cancer) and he was the Subject Editor of ESMO clinical recommendations on supportive/palliative care from 2006 to 2012. In 1997, 2004 and 2009 he was one of the organizers of the MASCC Perugia Conference on antiemetics. The recommendations published in Annals of Oncology in 1998, 2006 and 2010 have had an important role in influencing clinical practice worldwide. He has been the chair of the MASCC antiemetic subcommittee and one of the co-chairs of the 2009 MASCC/ISOO symposium in Rome. In December 2013, with Carla Ripamonti, Paolo Bossi, Andrea Antonuzzo he founded NICSO (Network Italiano Cure di Supporto in Oncologia) which has received MASCC recognition. Finally, he is a member of the Consultant Committee for Oncological Drugs of the Italian Drug Agency (A.I.F.A.), of the Ethical Committee of the Aziende Sanitarie of Umbria and of the Committee of Hospital Therapeutic Formulary of the Umbria region.

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