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A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients C. Fonte, S. Fatigoni, F. Roila ∗ Medical Oncology, “S. Maria” Hospital, Terni, Italy Accepted 24 February 2015
Contents 1. 2. 3.
4. 5. 6. 7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for preventing chemotherapy-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Phase I–II studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Phase III studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for breakthrough chemotherapy-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for refractory emesis in terminal cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors’ contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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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. © 2015 Published by Elsevier Ireland Ltd.
Keywords: Olanzapine; Chemotherapy induced emesis; Breakthrough emesis; Emesis in terminal cancer patients
∗ Corresponding author at: Medical Oncology, “S. Maria” Hospital, Via Tristano di Joannuccio 1, 05100 Terni, Italy. Tel.: +39 0744 205410; fax: +39 0744 205631. E-mail address: [email protected] (F. Roila).
http://dx.doi.org/10.1016/j.critrevonc.2015.02.010 1040-8428/© 2015 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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1. 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 5HT3 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.
2. 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 5HT2 receptors as D2 receptors [10]. The mechanism by which olanzapine reduces chemotherapy-induced emesis is still unclear even if the antiemetic effects of antipsychotic drugs are well known in palliative medicine. The effect on dopaminergic and serotoninergic receptors, known mediators of chemotherapy-induced emesis, may explain this property [9,11]. Olanzapine could have the advantage over combinations of antiemetics for preventing chemotherapy-induced nausea and vomiting regimens to target multiple key receptors with one medication. This, associated with the once daily oral administration, could increase patient compliance. The usual dose is 5–10 mg daily, with a maximum dose of 20 mg daily [12,13]. Another potential benefit of this drug is that it is not a cytochrome P450 inhibitor and, therefore, it could have fewer
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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drug interactions [9]. Finally, but not least important, the availability of the generic drug in some countries could reduce the costs of antiemetic therapy.
3. Olanzapine for preventing chemotherapy-induced emesis 3.1. 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 emetogenic chemotherapy (regimens containing cisplatin, cyclophosphamide, irinotecan or doxorubicin) were evaluated for toxicity and activity of olanzapine during the delayed emesis phase. All patients received a standard pre-treatment antiemetic regimen consisting of dexamethasone 20 mg po or iv and granisetron 10 g/kg or 1–2 mg orally 30–60 min prior to chemotherapy administration. The 16 patients enrolled in the study were divided into 4 cohorts. Beginning two days before chemotherapy, the first cohort (3 patients) began olanzapine 5 mg daily and continued with olanzapine 5 mg on the day of chemotherapy and for 7 days following chemotherapy. The second cohort (3 patients) began olanzapine 5 mg/day 2 days before chemotherapy and subsequently received 10 mg/day on the day of chemotherapy and for 7 days following chemotherapy. The third cohort (8 patients) began olanzapine 5 mg 2 days before chemotherapy and subsequently the dose was increased to 15 mg daily on the day of chemotherapy and for 7 days following chemotherapy. The fourth cohort (2 patients) began olanzapine 10 mg/day 2 days before chemotherapy and 15 mg/day on the day of chemotherapy and for 7 days after chemotherapy. If patients had an episode of vomiting or experienced nausea or retching, a rescue dose of 5 mg of olanzapine was administrated. No grade 4 toxicity was seen; three patients experienced a dose limiting toxicity (grade 3) represented by a depressed level of consciousness. The maximum tolerated dose appeared to be 5 mg for 2 days before chemotherapy and 10 mg on the day of chemotherapy and for 7 days following chemotherapy. Interestingly, 4 of 6 patients receiving cisplatin and 9 of 9 receiving moderately emetogenic chemotherapy had no delayed emesis. Using the maximum tolerated dose of olanzapine in the phase I trial, two phase II trials were carried out by the Hoosier Oncology Group in chemotherapy naïve patients [17,18]. In the first study 30 patients were enrolled, 20 receiving moderately emetogenic chemotherapy (carboplatin, irinotecan, cyclophosphamide and doxorubicin) and 10 receiving
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(cisplatin ≥ 70 mg/m2 ) [17]. All patients were treated with olanzapine 5 mg/day for two days prior to chemotherapy and 10 mg daily on the day of chemotherapy and on days 2–4 after chemotherapy. The day of chemotherapy the patients also received granisetron 10 g/kg iv or 2 mg po and dexamethasone 20 mg iv or po Dexamethasone 8 mg bid on days 2 and 3 and 4 mg bid on day 4 was added. The primary endpoint was complete response defined as no vomiting and no rescue treatment. Complete response was observed in 100% of the patients on acute period (day 1), in 80% in delayed period (days 2–5) and in 80% in the overall period (days 1–5) in the 10 patients receiving cisplatin and, respectively, in 100%, 85% and 85% in the 20 patients receiving moderately emetogenic chemotherapy. No nausea was reported in the acute and delayed period with cisplatin, while 85% of patients on day 1 and 65% on days 2–5 and 65% days 1–5 reported no nausea with moderately emetogenic chemotherapy. There were no grade 3 or 4 toxicities and no significant disturbed sleep, memory changes, lack of appetite, dry mouth, drowsiness, mood changes, dyspnea or restlessness episodes were experienced by the patients. In the second trial 40 chemotherapy naïve patients were enrolled, 8 were submitted to cisplatin-based and 32 to moderately emetogenic chemotherapy [18]. As antiemetic prophylaxis patients received palonosetron 0.25 mg iv plus dexamethasone 8 mg iv or po for moderately emetogenic chemotherapy or 20 mg iv or po for cisplatin chemotherapy. Patients also started oral olanzapine 10 mg on the day of chemotherapy and continued for days 2–4 after chemotherapy administration. Again, in this study the primary endpoint was the rate of complete response. Complete response was 100% on day 1, 75% on day 2–5 and 75% on days 1–5 for the 8 patients receiving cisplatin and was 97%, 75% and 72%, respectively, for the 32 patients receiving moderately emetogenic chemotherapy. No nausea was reported by 100% on day 1 by 50% on days 2–5 and by 50% on days 1–5 of patients receiving cisplatin and by 100% on day 1, 78% on days 2–5 and 78% on days 1–5, respectively, in patients receiving moderately emetogenic chemotherapy. No grade 3 or 4 toxicities were reported. Therefore, it seems that the combination of olanzapine administrated for 4 days with a single dose of palonosetron and a single dose of dexamethasone, administrated on day of chemotherapy, is safe and effective in preventing acute and delayed emesis in patients receiving highly and moderately emetogenic chemotherapy. 3.2. Phase III studies The first phase III randomized study evaluated the efficacy and tolerability of azasetron, a 5-HT3 receptor antagonist, at the dose of 10 mg iv and dexamethasone 10 mg iv plus olanzapine 10 mg po on days 1 and days 2–5 versus azasetron plus dexamethasone at the same doses on day 1 and dexamethasone 10 mg iv on days 2–5 for the prevention
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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of highly and moderately emetogenic chemotherapy [19]. The study enrolled 229 patients. Complete response was the primary endpoint and was reported separately for nausea and vomiting. Complete response from acute nausea (first 24 h) (94.6% with olanzapine and 87.0% without olanzapine) and complete response from acute vomiting (91.1% versus 89.1%) in patients submitted to cisplatin and 98.5% versus 93.5% for acute nausea and 96.9% versus 96.8% for acute vomiting in patients treated with moderately emetogenic chemotherapy were not significantly different. Instead, in the delayed period, olanzapine was significantly more efficacious than dexamethasone. In particular, complete response from delayed nausea was 69.6% versus 30.4% and complete response from delayed vomiting 78.6% versus 56.5% in cisplatin treated patients and 83.1% versus 58.1% in acute and 89.2% versus 75.8% in delayed vomiting in moderately emetogenic chemotherapy. Even the quality of life was superior with olanzapine in global health status, emotional functioning, social functioning fatigue, nausea and vomiting, insomnia and appetite loss. Concerning toxicity, 73% of the patients receiving olanzapine presented sleepiness during chemotherapy, but there were no grade 3 or 4 toxicities. Unfortunately, this study was not well planned from the methodological point of view: it was not doubleblind, chemotherapies with high and moderately emetogenic potential were put together without any stratification according to the antiemetic prophylaxis, the sample size was not calculated, the patients could have received previous chemotherapy with possible previous different incidence of nausea and vomiting in the two arms and, finally, in the first 24 h patients received a different antiemetic treatment that could have influenced the results on the prevention of delayed emesis. Unfortunately considering these shortcomings we cannot draw any definitive conclusion about the efficacy of olanzapine added to a 5-HT3 antagonist and dexamethasone with respect to a 5-HT3 antagonist and dexamethasone alone in the prevention of chemotherapy-induced emesis. Another randomized phase III trial compared olanzapine to aprepitant for the prevention of chemotherapy-induced emesis in patients receiving their first administration of highly emetogenic chemotherapy (cisplatin ≥ 70 mg/m2 , cyclophosphamide ≥ 500 mg/m2 , doxorubicin ≥ 50 mg/m2 ) [20]. Patients were randomized to receive as antiemetic prophylaxis palonosetron 0.25 mg iv, dexamethasone 20 mg iv, olanzapine 10 mg po on the day of chemotherapy and subsequently olanzapine 10 mg po on days 2–4 following chemotherapy or palonosetron 0.25 mg iv, dexamethasone 12 mg iv, aprepitant 125 mg po on the day of chemotherapy and subsequently dexamethasone 4 mg po bid on day 2–4 and aprepitant 80 mg po on days 2 and 3 following chemotherapy. The primary end-point was complete response for the overall period (0–120 h following chemotherapy). Two hundred forty seven patients were enrolled in the study. During their first cycle of chemotherapy no significant differences were found between the two antiemetic regimens.
Complete response on day 1 was obtained in 97% of patients receiving olanzapine and in 87% receiving aprepitant, complete response on day 2–5 was 77% versus 73% and on day 1–5 was 77% versus 73%. On day 1 patients receiving olanzapine and aprepitant all presented the same incidence of no nausea (87%) while on days 2–5 and days 1–5 patients submitted to olanzapine achieved a significantly superior rate of no nausea with respect to aprepitant (69% versus 38%). The M.D. Anderson Symptom Inventory (MDASI) which utilizes 13 core symptom items and 6 items reflecting interference with daily life for the entire study period (i.e., pain, fatigue, disturbed sleep, distress, etc.) was used [21]. No significant difference in MDASI frequency and intensity of symptoms was demonstrated. There were no grade 3 or 4 toxicities attributable to the study drugs. Unfortunately even this study has many shortcomings: it was an open study and, therefore, unable to evaluate the impact on soft endpoint such as nausea. Due to the small sample size, the study was only powered to investigate large differences such as a 15% difference in complete response on days 1–5. It was not defined if the study was designed as a superiority, non-inferiority or equivalence study. Furthermore, an unplanned interim analysis was carried out [22] but the significance level was not modified according to Bonferroni’s inequality. Therefore, before a change in the recommendations is considered, more well-conducted double-blind studies are necessary to evaluate the role of olanzapine in the control of acute and delayed emesis in highly–moderately emetogenic chemotherapy. To report all the published phase III studies, another small (17 patients submitted to highly emetogenic chemotherapy not otherwise specified), double-blind, placebo controlled study comparing aprepitant with olanzapine containing antiemetic regimens was presented as an abstract at ASCO 2009 but has not yet been published in a peer reviewed journal [23]. The complete response on day 1 was 75% with olanzapine versus 44% with aprepitant, and on days 2–5, respectively, 63% versus 56%. Finally, a randomized, double-blind study evaluating the addition of olanzapine 5 mg day from the day before chemotherapy administration until day 5 after chemotherapy or placebo to the standard combination of antiemetics of a 5-HT3 receptor antagonist (granisetron 3–6 mg day on days 1–3, ondansetron 4 mg day on days 1 and 2, ramosetron 0.6 mg on day 1–3 or palonosetron 0.75 mg on day 1), dexamethasone (9.9 mg iv on day 1 followed by 6.6 mg iv on day 2–4) and aprepitant (125 po on day 1 and 80 mg po on days 2 and 3) in patients submitted to highly and moderately emetogenic chemotherapy was carried out [24]. The sample size (22 patients for arm) was calculated considering an increase of total control (no vomiting, no rescue treatment and maximum nausea of 5 mm on a 100 mm VAS) from 40% to 83.3% with the addition of olanzapine. Total control was significantly higher in the olanzapine group (86% versus 55% on day 1 and 64% versus 23% on days 2–5).
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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Quality of life evaluated with the FLIE (Functional Living Index of emesis) was significantly superior with olanzapine. Unfortunately, even this study has many shortcomings: patient characteristics between the two arms were different so that the olanzapine group presented more favorable prognostic factors than patients receiving placebo (more oldest and more patients receiving palonosetron); some patients (about 25%) had received a previous chemotherapy regimen of highly or moderately emetogenic potential that could possibly interfere with the final results if these were unbalanced between the two arms; both cisplatin and moderately emetogenic chemotherapy patients were enrolled but they received the same antiemetic prophylaxis in contrast with the recommendation of MASCC/ESMO and ASCO guidelines [1,2]. These shortcomings are even more important considering the very low number of patients enrolled in the study. In conclusion, the four phase III studies evaluating the role of olanzapine in association with the standard antiemetic combination or in comparison with aprepitant in cisplatin or AC–EC combination chemotherapy on breast cancer women, due to important shortcomings cannot permit us to draw firm conclusions. Therefore, more well conducted, randomized, double-blind trials are necessary to identify the role of olanzapine to prevent chemotherapy-induced acute and delayed emesis.
4. 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]. Furthermore, many experts suggest that in the presence of vomiting or severe nausea antiemetics should not be administered orally because there will be problems of absorption and sometimes even the assumption of the drug can induce vomiting episodes. Therefore, breakthrough emesis remains one of the unsolved problems of antiemetic research. A phase II study, published only as an abstract at ASCO 2011, carried out in patients submitted to highly and moderately emetogenic drugs who presented breakthrough emesis (at least one vomiting episode) despite standard antiemetic administration of ondansetron, a corticosteroid and metoclopramide received olanzapine 5 mg orally every 12 h for 2 doses [25]. In the following 24 h complete response with no vomiting was reported by 60.8% of patients and partial response with one vomiting episode by 17.4% of patients. A phase III randomized, double-blind trial was recently published to compare olanzapine to metoclopramide for the
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treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving their first dose of highly emetogenic chemotherapy (cisplatin ≥ 70 mg/m2 , cyclophosphamide ≥ 600 mg/m2 or doxorubicin ≥ 50 mg/m2 ) [26]. All 276 patients evaluated received the prophylactic antiemetic regimen on the day of chemotherapy, consisting of dexamethasone 12 mg iv, palonosetron 0.25 mg iv and fosaprepitant 150 mg iv on day 1 and dexamethasone 4 mg bid on days 2–4 after chemotherapy. After chemotherapy administration, patients were randomized to receive olanzapine 10 mg once a day (and two placebo tablets) for 72 h after chemotherapy or metoclopramide 10 mg tid for 72 h after chemotherapy. Patients were instructed to begin their breakthrough therapy within 30 min after experiencing any emesis and/or moderate to severe nausea, evaluated by greater than 3 on a visual analog scale of 0–10. At the beginning of breakthrough therapy, patients discontinued dexamethasone. The primary endpoint was the proportion of patients with no episodes of emesis in the 72 h following initiation of the study treatment. The study enrolled 276 patients; 138 randomized to olanzapine and 138 to metoclopramide. Of these, respectively, 58 and 54 developed nausea and/or vomiting during the 72 h following chemotherapy administration and 56 and 52 patients were evaluable. No emesis was reported by 70% of patients receiving olanzapine and by 31% of those receiving metoclopramide, a statistically significant difference. No nausea was reported by 68% and 23% of the patients, respectively, again a significant difference between the two groups. In this trial, the dose of olanzapine (10 mg) was not associated with significant sedation, weight gain or hyperglycemia. There were no grade 3 or 4 toxicities attributable to the treatment and there were no significant differences between olanzapine and metoclopramide regimens for any impact of the symptoms on quality of life. Are these results changing? The studies are open to some important criticisms: metoclopramide is not the standard treatment for breakthrough emesis induced by chemotherapy; the administration by oral route generally cannot be recommended for a rescue treatment; the emetogenic power and therefore, the efficacy of a rescue treatment, could be different if patients are submitted to a highly with respect to a moderately emetogenic drug; the breakthrough emesis could be different according to the type of emesis (only nausea, only vomiting, both nausea and vomiting) and the time to the start of emesis (first 24 h, day 2–5, etc.) that cannot have the same antiemetic response even if these last two points seem well balanced between the two groups of patients; the sample size calculation required a number of patients superior to those entered in the trial (133 per arm were planned instead of about 55 per arm). In conclusion, the study furnished important results but we do not think that an oral drug can resolve the problem of breakthrough emesis induced by chemotherapy. Differently from our point of view others have outlined the importance of these results suggesting olanzapine in the control of breakthrough emesis [27].
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Two other randomized studies have been published but only as abstracts and were carried out in patients submitted to non-specified moderately emetogenic chemotherapy. These are unblinded studies carried out in patients presenting breakthrough emesis despite prophylaxis with dexamethasone and a 5-HT3 antagonist. One of these compared dexamethasone 20 mg iv followed by 4 mg bid orally for 3 days (35 patients) versus metoclopramide 20 mg iv followed by 10 mg orally bid for 3 days (33 patients) versus dexamethasone 20 mg iv plus olanzapine 5 mg orally bid for 3 days (32 patients) [28]. The patients achieved complete response in 37%, 36%, and 66%, respectively. The other study compared prochlorperazine 10 mg iv followed by 10 mg orally tid for 3 days (35 patients) versus metoclopramide 10 mg iv followed by 10 mg orally bid for 3 days (33 patients) versus dexamethasone plus olanzapine as above reported (32 patients). Complete response was reported by 20%, 36% and 66% of patients, respectively [29].
5. 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 was effective in controlling opioid-induced nausea [32]. In 4 patients in palliative care with intractable nausea and vomiting (not responding to three or more antiemetics) olanzapine reduced the need for any other antiemetic medication and reduced “as needed” rescue antiemetics [33]. Finally, in a patient with brain metastasis originating from colorectal cancer presenting nausea and vomiting despite metoclopramide, granisetron and glycerol, olanzapine, at the dose of 1.25 mg every night, controlled persistent nausea and decreased the frequency of emesis [34]. An open label study of 15 patients evaluated the antiemetic activity of three dose levels of olanzapine (2.5, 5 and 10 mg) for controlling nausea in patients with cancer pain requiring opioid therapy [35]. Eligible patients were those presenting nausea in the past three days of an intensity ≥4 but not exceeding 8 on a 0–10 scale. All three dose levels were associated with significant reductions in nausea compared to baseline. Only the dose of 5 mg showed a statistically significant benefit with respect to baseline on overall well-being measured with the FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire. None of the doses of olanzapine were associated with increased extrapyramidal symptoms over baseline. Finally, a retrospective study investigated the antiemetic activity of olanzapine in 20 patients with incomplete bowel
obstruction with advanced cancer [36]. In 18 (90%) there was a reduction of the intensity of nausea. Before treatment 10 patients experienced vomiting and 8 of them presented a decrease in the frequency of vomiting. Olanzapine appears to be effective for the control of nausea in incomplete bowel obstruction without any serious adverse event. In conclusion, in palliative care it seems that olanzapine could control or reduce the intensity of nausea and vomiting refractory to standard antiemetics and reduce nausea and vomiting induced by opioids and incomplete bowel obstruction. Of course, more studies are necessary to identify the role of olanzapine in these situations. 6. 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 drowsiness [26]. All these results are in contrast with the side effects observed in patients with mental health problems receiving olanzapine daily for many years in which sedation, weight gain [37,38], increased blood glucose [39] and cholesterol, fatigue, extrapyramidal reactions such as akathisia, cardiovascular (i.e., postural hypotension, atrial fibrillation, cerebrovascular accident, congestive heart failure) respiratory (i.e., infections such as pneumonia, dyspnea), ocular (i.e., amblyopia, abnormal vision, conjunctivitis), genitourinary (i.e., urinary incontinence) and dermatologic side effects have been reported. Finally, patients presented psychiatric side effects that frequently included depression, euphoria, delusions, manic reaction and schizophrenic reaction. Obsessive–compulsive symptoms and suicide attempt have also been reported [40]. 7. 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 antagonist and dexamethasone, or with respect to placebo as an addition to the standard triple drug combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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Our conclusions are different from those reported in a recently published systematic review [41] stating that regimens including olanzapine were associated with significant improvements in chemotherapy-induced emesis with both highly and moderately emetogenic chemotherapy. Indeed, putting together randomized studies incorrectly carried out does not improve their quality and often, as in this case, the conclusions are not valid. Therefore, well-planned, randomized double-blind studies are urgently needed if we want to identify the role of olanzapine. Concerning breakthrough emesis in the only published randomized study, olanzapine appears superior to oral metoclopramide. Despite this, we think that breakthrough emesis requires a treatment with a non-oral drug because if vomiting or severe nausea occurs even the oral administration of a drug can induce vomiting. Therefore, orally administered olanzapine could be used as a rescue treatment for patients presenting mild or moderate nausea. In breakthrough emesis different formulations of olanzapine must be studied. Orally disintegrating tablets (ODT) of olanzapine produced through ZYDIS technology (Velotab) have been developed with the aim of improving patient compliance. ODT rapidly dissolves in the mouth and, therefore, patients may find it preferable to swallowing tablets. The fast oral absorption could be useful in the setting of breakthrough emesis avoiding parenteral administration of antiemetics, but at present ODT of olanzapine have not been tested in antiemetic trials [42]. Finally, in palliative care patients presenting emesis due to causes which cannot be eliminated, the use of olanzapine when other antiemetics have failed is appropriate based on various case reports and observational retrospective studies. Also in this setting it is necessary to plan randomized, double-blind studies comparing olanzapine with the currently available antiemetic drugs. Due to its action on a number of key receptor sites olanzapine is a very interesting drug with potentially important efficacy and mild to moderate toxicity (especially sedation), no QTc prolongation and reduced drug interactions with respect to other antiemetics. Furthermore, the fact that only one oral daily administration is necessary has the potential advantage of improving compliance and also the possibility of using generic pharmaceuticals in various countries. Cost could thus be significantly reduced and this should put olanzapine at the top of our research interest on antiemetics.
Conflict of interest None declared.
Role of the funding source No funding for this study.
7
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.
References [1] 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(Suppl. 5):232–43. [2] Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetic American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29:4189–98. [3] Davis MP, Hallerberg G. A systematic review of the treatment of nausea and vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manage 2010;39:756–67. [4] Bruera E, Belzile M, Neumann C, et al. A double-blind, crossover study of the controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage 2000;19:427–35. [5] Gupta M, Davis M, LeGrand S, et al. Nausea and vomiting in advanced cancer: the Cleveland Clinic protocol. J Support Oncol 2013;11:8–13. [6] European Medicines Agency recommends changes to the use of metoclopramide. Change aim mainly to reduce the risk of neurological side effects. 26 July 2013, EMA/443003/2013. [7] Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol 2014;722:67–78. [8] Hardy J, Daly S, McQuade B, et al. A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 2002;10:231–6. [9] Bymaster FP, Calligaro D, Falcone J, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:87–96. [10] Stephenson CME, Pilowsky LS. Psychopharmacology of olanzapine: a review. Br J Psychiatry 1999;174:52–8. [11] Bymaster FP, Falcone JF, Bauzon D, et al. Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol 2001;430:341–9. [12] Passik S, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 2002;23:526–32. [13] Brafford MV, Glode A. Olanzapine: an antiemetic option for chemotherapy-induced nausea and vomiting. J Adv Pract Oncol 2014;5:24–9. [14] Pirl WF, Roth AJ. Remission of chemotherapy-induced emesis with concurrent olanzapine treatment: a case report. Psychooncology 2000;9:84–7. [15] Passik SD, Kirsh KL, Theobald DE, et al. A retrospective chart review of the use of olanzapine for the prevention of delayed emesis in cancer patients. J Pain Symptom Manage 2003;25:485–9.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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[16] Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer Invest 2004;22:383–8. [17] Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 2005;13:529–34. [18] Navari RM, Einhorn LH, Loehrer PJ, et al. A phase II trial of olanzapine, dexamethasone and palonosetron for the prevention of chemotherapyinduced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 2007;15:1285–91. [19] Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 2009;28:1–7. [20] Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 2011;9:188–95. [21] Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer 1999;94:1011–5. [22] Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant in the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Clin Oncol 2010;28:641s [abstract 9020]. [23] Shumway NM, Terrazzino SE, Jones CB. A randomized pilot study comparing aprepitant to olanzapine for treatment of chemotherapyinduced nausea and vomiting. J Clin Oncol 2009;27:516s [abstract 9633]. [24] Mizukami N, Yamauchi M, Koike K, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo controlled study. J Pain Symptom Manage 2014;47:542–50. [25] Chanthawong S, Subongkot S, Sookpraseert A. Evaluation of olanzapine for breakthrough emesis in patients with cancer not responding to standard antiemetic regimen. J Clin Oncol 2011;29 [abstract e19596]. [26] Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapyinduced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013;21:1655–63. [27] Roth BJ, Krilov L, Adams S, et al. Clinical cancer advances 2012: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2013;31:131–61. [28] Navari RM, Gray S. Treatment of chemotherapy-induced breakthrough nausea and vomiting. In: 7th annual conference of the American Psychosocial Oncology Society. 2010. [29] Navari RM, Gray RE. Treatment of chemotherapy-induced breakthrough nausea and vomiting. J Clin Oncol 2009;27:e20536. [30] Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med 2003;6:251–5. [31] Srivastava M, Brito-Dellan N, Davis MP, et al. Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. J Pain Symptom Manage 2003;25:578–82. [32] Lundberg JC, Passik S. Controlling opioid-induced nausea with olanzapine. Primary Care Cancer 2000;20:35–7. [33] Atkinson SR. Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med 2014;17:503–4. [34] Suzuki M, Komuro K, Ohara K. Olanzapine and betamethasone are effective for the treatment of nausea and vomiting due to metastatic brain tumors of rectal cancer. Case Rep Gastroenterol 2014;8:13–7. [35] Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 2002;23: 526–32. [36] Kaneishi K, Kawabata M, Morita T, et al. Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage 2012;44:604–7. [37] Hale AS. Olanzapine. Br J Hosp Med 1997;58:443–5.
[38] Allison DB, Casey DF. Antipsychotic-associated weight gain: a review of the literature. J Clin Psychiatry 2001;62:22–31. [39] Goldstein LE, Sporn J, Brown S, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999;40:438–43. [40] Mahendran R, Liew E, Subramaniam M, et al. De novo emergence of obsessive–compulsive symptoms with atypical antipsychotics in Asian patients with schizophrenia or schizoaffective disorder: a retrospective, cross-sectional study. J Clin Psychiatry 2007;68:542–5. [41] Hocking CM, Kichenadasse G. Olanzapine for chemotherapy-induced nausea and vomiting: a systematic review. Support Care Cancer 2014;22:1143–51. [42] Belgamwar RB, Fenton M. Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses. Cochrane Database Syst Rev 2005;2:CD003729.
Biographies 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 cochairs 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.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients C. Fonte, S. Fatigoni, F. Roila ∗ Medical Oncology, “S. Maria” Hospital, Terni, Italy Accepted 24 February 2015
Contents 1. 2. 3.
4. 5. 6. 7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for preventing chemotherapy-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Phase I–II studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Phase III studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for breakthrough chemotherapy-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine for refractory emesis in terminal cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olanzapine toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors’ contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
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. © 2015 Published by Elsevier Ireland Ltd.
Keywords: Olanzapine; Chemotherapy induced emesis; Breakthrough emesis; Emesis in terminal cancer patients
∗ Corresponding author at: Medical Oncology, “S. Maria” Hospital, Via Tristano di Joannuccio 1, 05100 Terni, Italy. Tel.: +39 0744 205410; fax: +39 0744 205631. E-mail address: [email protected] (F. Roila).
http://dx.doi.org/10.1016/j.critrevonc.2015.02.010 1040-8428/© 2015 Published by Elsevier Ireland Ltd.
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1. 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 5HT3 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.
2. 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 5HT2 receptors as D2 receptors [10]. The mechanism by which olanzapine reduces chemotherapy-induced emesis is still unclear even if the antiemetic effects of antipsychotic drugs are well known in palliative medicine. The effect on dopaminergic and serotoninergic receptors, known mediators of chemotherapy-induced emesis, may explain this property [9,11]. Olanzapine could have the advantage over combinations of antiemetics for preventing chemotherapy-induced nausea and vomiting regimens to target multiple key receptors with one medication. This, associated with the once daily oral administration, could increase patient compliance. The usual dose is 5–10 mg daily, with a maximum dose of 20 mg daily [12,13]. Another potential benefit of this drug is that it is not a cytochrome P450 inhibitor and, therefore, it could have fewer
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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drug interactions [9]. Finally, but not least important, the availability of the generic drug in some countries could reduce the costs of antiemetic therapy.
3. Olanzapine for preventing chemotherapy-induced emesis 3.1. 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 emetogenic chemotherapy (regimens containing cisplatin, cyclophosphamide, irinotecan or doxorubicin) were evaluated for toxicity and activity of olanzapine during the delayed emesis phase. All patients received a standard pre-treatment antiemetic regimen consisting of dexamethasone 20 mg po or iv and granisetron 10 g/kg or 1–2 mg orally 30–60 min prior to chemotherapy administration. The 16 patients enrolled in the study were divided into 4 cohorts. Beginning two days before chemotherapy, the first cohort (3 patients) began olanzapine 5 mg daily and continued with olanzapine 5 mg on the day of chemotherapy and for 7 days following chemotherapy. The second cohort (3 patients) began olanzapine 5 mg/day 2 days before chemotherapy and subsequently received 10 mg/day on the day of chemotherapy and for 7 days following chemotherapy. The third cohort (8 patients) began olanzapine 5 mg 2 days before chemotherapy and subsequently the dose was increased to 15 mg daily on the day of chemotherapy and for 7 days following chemotherapy. The fourth cohort (2 patients) began olanzapine 10 mg/day 2 days before chemotherapy and 15 mg/day on the day of chemotherapy and for 7 days after chemotherapy. If patients had an episode of vomiting or experienced nausea or retching, a rescue dose of 5 mg of olanzapine was administrated. No grade 4 toxicity was seen; three patients experienced a dose limiting toxicity (grade 3) represented by a depressed level of consciousness. The maximum tolerated dose appeared to be 5 mg for 2 days before chemotherapy and 10 mg on the day of chemotherapy and for 7 days following chemotherapy. Interestingly, 4 of 6 patients receiving cisplatin and 9 of 9 receiving moderately emetogenic chemotherapy had no delayed emesis. Using the maximum tolerated dose of olanzapine in the phase I trial, two phase II trials were carried out by the Hoosier Oncology Group in chemotherapy naïve patients [17,18]. In the first study 30 patients were enrolled, 20 receiving moderately emetogenic chemotherapy (carboplatin, irinotecan, cyclophosphamide and doxorubicin) and 10 receiving
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(cisplatin ≥ 70 mg/m2 ) [17]. All patients were treated with olanzapine 5 mg/day for two days prior to chemotherapy and 10 mg daily on the day of chemotherapy and on days 2–4 after chemotherapy. The day of chemotherapy the patients also received granisetron 10 g/kg iv or 2 mg po and dexamethasone 20 mg iv or po Dexamethasone 8 mg bid on days 2 and 3 and 4 mg bid on day 4 was added. The primary endpoint was complete response defined as no vomiting and no rescue treatment. Complete response was observed in 100% of the patients on acute period (day 1), in 80% in delayed period (days 2–5) and in 80% in the overall period (days 1–5) in the 10 patients receiving cisplatin and, respectively, in 100%, 85% and 85% in the 20 patients receiving moderately emetogenic chemotherapy. No nausea was reported in the acute and delayed period with cisplatin, while 85% of patients on day 1 and 65% on days 2–5 and 65% days 1–5 reported no nausea with moderately emetogenic chemotherapy. There were no grade 3 or 4 toxicities and no significant disturbed sleep, memory changes, lack of appetite, dry mouth, drowsiness, mood changes, dyspnea or restlessness episodes were experienced by the patients. In the second trial 40 chemotherapy naïve patients were enrolled, 8 were submitted to cisplatin-based and 32 to moderately emetogenic chemotherapy [18]. As antiemetic prophylaxis patients received palonosetron 0.25 mg iv plus dexamethasone 8 mg iv or po for moderately emetogenic chemotherapy or 20 mg iv or po for cisplatin chemotherapy. Patients also started oral olanzapine 10 mg on the day of chemotherapy and continued for days 2–4 after chemotherapy administration. Again, in this study the primary endpoint was the rate of complete response. Complete response was 100% on day 1, 75% on day 2–5 and 75% on days 1–5 for the 8 patients receiving cisplatin and was 97%, 75% and 72%, respectively, for the 32 patients receiving moderately emetogenic chemotherapy. No nausea was reported by 100% on day 1 by 50% on days 2–5 and by 50% on days 1–5 of patients receiving cisplatin and by 100% on day 1, 78% on days 2–5 and 78% on days 1–5, respectively, in patients receiving moderately emetogenic chemotherapy. No grade 3 or 4 toxicities were reported. Therefore, it seems that the combination of olanzapine administrated for 4 days with a single dose of palonosetron and a single dose of dexamethasone, administrated on day of chemotherapy, is safe and effective in preventing acute and delayed emesis in patients receiving highly and moderately emetogenic chemotherapy. 3.2. Phase III studies The first phase III randomized study evaluated the efficacy and tolerability of azasetron, a 5-HT3 receptor antagonist, at the dose of 10 mg iv and dexamethasone 10 mg iv plus olanzapine 10 mg po on days 1 and days 2–5 versus azasetron plus dexamethasone at the same doses on day 1 and dexamethasone 10 mg iv on days 2–5 for the prevention
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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of highly and moderately emetogenic chemotherapy [19]. The study enrolled 229 patients. Complete response was the primary endpoint and was reported separately for nausea and vomiting. Complete response from acute nausea (first 24 h) (94.6% with olanzapine and 87.0% without olanzapine) and complete response from acute vomiting (91.1% versus 89.1%) in patients submitted to cisplatin and 98.5% versus 93.5% for acute nausea and 96.9% versus 96.8% for acute vomiting in patients treated with moderately emetogenic chemotherapy were not significantly different. Instead, in the delayed period, olanzapine was significantly more efficacious than dexamethasone. In particular, complete response from delayed nausea was 69.6% versus 30.4% and complete response from delayed vomiting 78.6% versus 56.5% in cisplatin treated patients and 83.1% versus 58.1% in acute and 89.2% versus 75.8% in delayed vomiting in moderately emetogenic chemotherapy. Even the quality of life was superior with olanzapine in global health status, emotional functioning, social functioning fatigue, nausea and vomiting, insomnia and appetite loss. Concerning toxicity, 73% of the patients receiving olanzapine presented sleepiness during chemotherapy, but there were no grade 3 or 4 toxicities. Unfortunately, this study was not well planned from the methodological point of view: it was not doubleblind, chemotherapies with high and moderately emetogenic potential were put together without any stratification according to the antiemetic prophylaxis, the sample size was not calculated, the patients could have received previous chemotherapy with possible previous different incidence of nausea and vomiting in the two arms and, finally, in the first 24 h patients received a different antiemetic treatment that could have influenced the results on the prevention of delayed emesis. Unfortunately considering these shortcomings we cannot draw any definitive conclusion about the efficacy of olanzapine added to a 5-HT3 antagonist and dexamethasone with respect to a 5-HT3 antagonist and dexamethasone alone in the prevention of chemotherapy-induced emesis. Another randomized phase III trial compared olanzapine to aprepitant for the prevention of chemotherapy-induced emesis in patients receiving their first administration of highly emetogenic chemotherapy (cisplatin ≥ 70 mg/m2 , cyclophosphamide ≥ 500 mg/m2 , doxorubicin ≥ 50 mg/m2 ) [20]. Patients were randomized to receive as antiemetic prophylaxis palonosetron 0.25 mg iv, dexamethasone 20 mg iv, olanzapine 10 mg po on the day of chemotherapy and subsequently olanzapine 10 mg po on days 2–4 following chemotherapy or palonosetron 0.25 mg iv, dexamethasone 12 mg iv, aprepitant 125 mg po on the day of chemotherapy and subsequently dexamethasone 4 mg po bid on day 2–4 and aprepitant 80 mg po on days 2 and 3 following chemotherapy. The primary end-point was complete response for the overall period (0–120 h following chemotherapy). Two hundred forty seven patients were enrolled in the study. During their first cycle of chemotherapy no significant differences were found between the two antiemetic regimens.
Complete response on day 1 was obtained in 97% of patients receiving olanzapine and in 87% receiving aprepitant, complete response on day 2–5 was 77% versus 73% and on day 1–5 was 77% versus 73%. On day 1 patients receiving olanzapine and aprepitant all presented the same incidence of no nausea (87%) while on days 2–5 and days 1–5 patients submitted to olanzapine achieved a significantly superior rate of no nausea with respect to aprepitant (69% versus 38%). The M.D. Anderson Symptom Inventory (MDASI) which utilizes 13 core symptom items and 6 items reflecting interference with daily life for the entire study period (i.e., pain, fatigue, disturbed sleep, distress, etc.) was used [21]. No significant difference in MDASI frequency and intensity of symptoms was demonstrated. There were no grade 3 or 4 toxicities attributable to the study drugs. Unfortunately even this study has many shortcomings: it was an open study and, therefore, unable to evaluate the impact on soft endpoint such as nausea. Due to the small sample size, the study was only powered to investigate large differences such as a 15% difference in complete response on days 1–5. It was not defined if the study was designed as a superiority, non-inferiority or equivalence study. Furthermore, an unplanned interim analysis was carried out [22] but the significance level was not modified according to Bonferroni’s inequality. Therefore, before a change in the recommendations is considered, more well-conducted double-blind studies are necessary to evaluate the role of olanzapine in the control of acute and delayed emesis in highly–moderately emetogenic chemotherapy. To report all the published phase III studies, another small (17 patients submitted to highly emetogenic chemotherapy not otherwise specified), double-blind, placebo controlled study comparing aprepitant with olanzapine containing antiemetic regimens was presented as an abstract at ASCO 2009 but has not yet been published in a peer reviewed journal [23]. The complete response on day 1 was 75% with olanzapine versus 44% with aprepitant, and on days 2–5, respectively, 63% versus 56%. Finally, a randomized, double-blind study evaluating the addition of olanzapine 5 mg day from the day before chemotherapy administration until day 5 after chemotherapy or placebo to the standard combination of antiemetics of a 5-HT3 receptor antagonist (granisetron 3–6 mg day on days 1–3, ondansetron 4 mg day on days 1 and 2, ramosetron 0.6 mg on day 1–3 or palonosetron 0.75 mg on day 1), dexamethasone (9.9 mg iv on day 1 followed by 6.6 mg iv on day 2–4) and aprepitant (125 po on day 1 and 80 mg po on days 2 and 3) in patients submitted to highly and moderately emetogenic chemotherapy was carried out [24]. The sample size (22 patients for arm) was calculated considering an increase of total control (no vomiting, no rescue treatment and maximum nausea of 5 mm on a 100 mm VAS) from 40% to 83.3% with the addition of olanzapine. Total control was significantly higher in the olanzapine group (86% versus 55% on day 1 and 64% versus 23% on days 2–5).
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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Quality of life evaluated with the FLIE (Functional Living Index of emesis) was significantly superior with olanzapine. Unfortunately, even this study has many shortcomings: patient characteristics between the two arms were different so that the olanzapine group presented more favorable prognostic factors than patients receiving placebo (more oldest and more patients receiving palonosetron); some patients (about 25%) had received a previous chemotherapy regimen of highly or moderately emetogenic potential that could possibly interfere with the final results if these were unbalanced between the two arms; both cisplatin and moderately emetogenic chemotherapy patients were enrolled but they received the same antiemetic prophylaxis in contrast with the recommendation of MASCC/ESMO and ASCO guidelines [1,2]. These shortcomings are even more important considering the very low number of patients enrolled in the study. In conclusion, the four phase III studies evaluating the role of olanzapine in association with the standard antiemetic combination or in comparison with aprepitant in cisplatin or AC–EC combination chemotherapy on breast cancer women, due to important shortcomings cannot permit us to draw firm conclusions. Therefore, more well conducted, randomized, double-blind trials are necessary to identify the role of olanzapine to prevent chemotherapy-induced acute and delayed emesis.
4. 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]. Furthermore, many experts suggest that in the presence of vomiting or severe nausea antiemetics should not be administered orally because there will be problems of absorption and sometimes even the assumption of the drug can induce vomiting episodes. Therefore, breakthrough emesis remains one of the unsolved problems of antiemetic research. A phase II study, published only as an abstract at ASCO 2011, carried out in patients submitted to highly and moderately emetogenic drugs who presented breakthrough emesis (at least one vomiting episode) despite standard antiemetic administration of ondansetron, a corticosteroid and metoclopramide received olanzapine 5 mg orally every 12 h for 2 doses [25]. In the following 24 h complete response with no vomiting was reported by 60.8% of patients and partial response with one vomiting episode by 17.4% of patients. A phase III randomized, double-blind trial was recently published to compare olanzapine to metoclopramide for the
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treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving their first dose of highly emetogenic chemotherapy (cisplatin ≥ 70 mg/m2 , cyclophosphamide ≥ 600 mg/m2 or doxorubicin ≥ 50 mg/m2 ) [26]. All 276 patients evaluated received the prophylactic antiemetic regimen on the day of chemotherapy, consisting of dexamethasone 12 mg iv, palonosetron 0.25 mg iv and fosaprepitant 150 mg iv on day 1 and dexamethasone 4 mg bid on days 2–4 after chemotherapy. After chemotherapy administration, patients were randomized to receive olanzapine 10 mg once a day (and two placebo tablets) for 72 h after chemotherapy or metoclopramide 10 mg tid for 72 h after chemotherapy. Patients were instructed to begin their breakthrough therapy within 30 min after experiencing any emesis and/or moderate to severe nausea, evaluated by greater than 3 on a visual analog scale of 0–10. At the beginning of breakthrough therapy, patients discontinued dexamethasone. The primary endpoint was the proportion of patients with no episodes of emesis in the 72 h following initiation of the study treatment. The study enrolled 276 patients; 138 randomized to olanzapine and 138 to metoclopramide. Of these, respectively, 58 and 54 developed nausea and/or vomiting during the 72 h following chemotherapy administration and 56 and 52 patients were evaluable. No emesis was reported by 70% of patients receiving olanzapine and by 31% of those receiving metoclopramide, a statistically significant difference. No nausea was reported by 68% and 23% of the patients, respectively, again a significant difference between the two groups. In this trial, the dose of olanzapine (10 mg) was not associated with significant sedation, weight gain or hyperglycemia. There were no grade 3 or 4 toxicities attributable to the treatment and there were no significant differences between olanzapine and metoclopramide regimens for any impact of the symptoms on quality of life. Are these results changing? The studies are open to some important criticisms: metoclopramide is not the standard treatment for breakthrough emesis induced by chemotherapy; the administration by oral route generally cannot be recommended for a rescue treatment; the emetogenic power and therefore, the efficacy of a rescue treatment, could be different if patients are submitted to a highly with respect to a moderately emetogenic drug; the breakthrough emesis could be different according to the type of emesis (only nausea, only vomiting, both nausea and vomiting) and the time to the start of emesis (first 24 h, day 2–5, etc.) that cannot have the same antiemetic response even if these last two points seem well balanced between the two groups of patients; the sample size calculation required a number of patients superior to those entered in the trial (133 per arm were planned instead of about 55 per arm). In conclusion, the study furnished important results but we do not think that an oral drug can resolve the problem of breakthrough emesis induced by chemotherapy. Differently from our point of view others have outlined the importance of these results suggesting olanzapine in the control of breakthrough emesis [27].
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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Two other randomized studies have been published but only as abstracts and were carried out in patients submitted to non-specified moderately emetogenic chemotherapy. These are unblinded studies carried out in patients presenting breakthrough emesis despite prophylaxis with dexamethasone and a 5-HT3 antagonist. One of these compared dexamethasone 20 mg iv followed by 4 mg bid orally for 3 days (35 patients) versus metoclopramide 20 mg iv followed by 10 mg orally bid for 3 days (33 patients) versus dexamethasone 20 mg iv plus olanzapine 5 mg orally bid for 3 days (32 patients) [28]. The patients achieved complete response in 37%, 36%, and 66%, respectively. The other study compared prochlorperazine 10 mg iv followed by 10 mg orally tid for 3 days (35 patients) versus metoclopramide 10 mg iv followed by 10 mg orally bid for 3 days (33 patients) versus dexamethasone plus olanzapine as above reported (32 patients). Complete response was reported by 20%, 36% and 66% of patients, respectively [29].
5. 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 was effective in controlling opioid-induced nausea [32]. In 4 patients in palliative care with intractable nausea and vomiting (not responding to three or more antiemetics) olanzapine reduced the need for any other antiemetic medication and reduced “as needed” rescue antiemetics [33]. Finally, in a patient with brain metastasis originating from colorectal cancer presenting nausea and vomiting despite metoclopramide, granisetron and glycerol, olanzapine, at the dose of 1.25 mg every night, controlled persistent nausea and decreased the frequency of emesis [34]. An open label study of 15 patients evaluated the antiemetic activity of three dose levels of olanzapine (2.5, 5 and 10 mg) for controlling nausea in patients with cancer pain requiring opioid therapy [35]. Eligible patients were those presenting nausea in the past three days of an intensity ≥4 but not exceeding 8 on a 0–10 scale. All three dose levels were associated with significant reductions in nausea compared to baseline. Only the dose of 5 mg showed a statistically significant benefit with respect to baseline on overall well-being measured with the FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire. None of the doses of olanzapine were associated with increased extrapyramidal symptoms over baseline. Finally, a retrospective study investigated the antiemetic activity of olanzapine in 20 patients with incomplete bowel
obstruction with advanced cancer [36]. In 18 (90%) there was a reduction of the intensity of nausea. Before treatment 10 patients experienced vomiting and 8 of them presented a decrease in the frequency of vomiting. Olanzapine appears to be effective for the control of nausea in incomplete bowel obstruction without any serious adverse event. In conclusion, in palliative care it seems that olanzapine could control or reduce the intensity of nausea and vomiting refractory to standard antiemetics and reduce nausea and vomiting induced by opioids and incomplete bowel obstruction. Of course, more studies are necessary to identify the role of olanzapine in these situations. 6. 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 drowsiness [26]. All these results are in contrast with the side effects observed in patients with mental health problems receiving olanzapine daily for many years in which sedation, weight gain [37,38], increased blood glucose [39] and cholesterol, fatigue, extrapyramidal reactions such as akathisia, cardiovascular (i.e., postural hypotension, atrial fibrillation, cerebrovascular accident, congestive heart failure) respiratory (i.e., infections such as pneumonia, dyspnea), ocular (i.e., amblyopia, abnormal vision, conjunctivitis), genitourinary (i.e., urinary incontinence) and dermatologic side effects have been reported. Finally, patients presented psychiatric side effects that frequently included depression, euphoria, delusions, manic reaction and schizophrenic reaction. Obsessive–compulsive symptoms and suicide attempt have also been reported [40]. 7. 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 antagonist and dexamethasone, or with respect to placebo as an addition to the standard triple drug combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
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Our conclusions are different from those reported in a recently published systematic review [41] stating that regimens including olanzapine were associated with significant improvements in chemotherapy-induced emesis with both highly and moderately emetogenic chemotherapy. Indeed, putting together randomized studies incorrectly carried out does not improve their quality and often, as in this case, the conclusions are not valid. Therefore, well-planned, randomized double-blind studies are urgently needed if we want to identify the role of olanzapine. Concerning breakthrough emesis in the only published randomized study, olanzapine appears superior to oral metoclopramide. Despite this, we think that breakthrough emesis requires a treatment with a non-oral drug because if vomiting or severe nausea occurs even the oral administration of a drug can induce vomiting. Therefore, orally administered olanzapine could be used as a rescue treatment for patients presenting mild or moderate nausea. In breakthrough emesis different formulations of olanzapine must be studied. Orally disintegrating tablets (ODT) of olanzapine produced through ZYDIS technology (Velotab) have been developed with the aim of improving patient compliance. ODT rapidly dissolves in the mouth and, therefore, patients may find it preferable to swallowing tablets. The fast oral absorption could be useful in the setting of breakthrough emesis avoiding parenteral administration of antiemetics, but at present ODT of olanzapine have not been tested in antiemetic trials [42]. Finally, in palliative care patients presenting emesis due to causes which cannot be eliminated, the use of olanzapine when other antiemetics have failed is appropriate based on various case reports and observational retrospective studies. Also in this setting it is necessary to plan randomized, double-blind studies comparing olanzapine with the currently available antiemetic drugs. Due to its action on a number of key receptor sites olanzapine is a very interesting drug with potentially important efficacy and mild to moderate toxicity (especially sedation), no QTc prolongation and reduced drug interactions with respect to other antiemetics. Furthermore, the fact that only one oral daily administration is necessary has the potential advantage of improving compliance and also the possibility of using generic pharmaceuticals in various countries. Cost could thus be significantly reduced and this should put olanzapine at the top of our research interest on antiemetics.
Conflict of interest None declared.
Role of the funding source No funding for this study.
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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.
References [1] 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(Suppl. 5):232–43. [2] Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetic American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29:4189–98. [3] Davis MP, Hallerberg G. A systematic review of the treatment of nausea and vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manage 2010;39:756–67. [4] Bruera E, Belzile M, Neumann C, et al. A double-blind, crossover study of the controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage 2000;19:427–35. [5] Gupta M, Davis M, LeGrand S, et al. Nausea and vomiting in advanced cancer: the Cleveland Clinic protocol. J Support Oncol 2013;11:8–13. [6] European Medicines Agency recommends changes to the use of metoclopramide. Change aim mainly to reduce the risk of neurological side effects. 26 July 2013, EMA/443003/2013. [7] Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol 2014;722:67–78. [8] Hardy J, Daly S, McQuade B, et al. A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 2002;10:231–6. [9] Bymaster FP, Calligaro D, Falcone J, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:87–96. [10] Stephenson CME, Pilowsky LS. Psychopharmacology of olanzapine: a review. Br J Psychiatry 1999;174:52–8. [11] Bymaster FP, Falcone JF, Bauzon D, et al. Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol 2001;430:341–9. [12] Passik S, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 2002;23:526–32. [13] Brafford MV, Glode A. Olanzapine: an antiemetic option for chemotherapy-induced nausea and vomiting. J Adv Pract Oncol 2014;5:24–9. [14] Pirl WF, Roth AJ. Remission of chemotherapy-induced emesis with concurrent olanzapine treatment: a case report. Psychooncology 2000;9:84–7. [15] Passik SD, Kirsh KL, Theobald DE, et al. A retrospective chart review of the use of olanzapine for the prevention of delayed emesis in cancer patients. J Pain Symptom Manage 2003;25:485–9.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
ONCH-1948; No. of Pages 8
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ARTICLE IN PRESS C. Fonte et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
[16] Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer Invest 2004;22:383–8. [17] Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 2005;13:529–34. [18] Navari RM, Einhorn LH, Loehrer PJ, et al. A phase II trial of olanzapine, dexamethasone and palonosetron for the prevention of chemotherapyinduced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 2007;15:1285–91. [19] Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 2009;28:1–7. [20] Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 2011;9:188–95. [21] Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer 1999;94:1011–5. [22] Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant in the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Clin Oncol 2010;28:641s [abstract 9020]. [23] Shumway NM, Terrazzino SE, Jones CB. A randomized pilot study comparing aprepitant to olanzapine for treatment of chemotherapyinduced nausea and vomiting. J Clin Oncol 2009;27:516s [abstract 9633]. [24] Mizukami N, Yamauchi M, Koike K, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo controlled study. J Pain Symptom Manage 2014;47:542–50. [25] Chanthawong S, Subongkot S, Sookpraseert A. Evaluation of olanzapine for breakthrough emesis in patients with cancer not responding to standard antiemetic regimen. J Clin Oncol 2011;29 [abstract e19596]. [26] Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapyinduced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013;21:1655–63. [27] Roth BJ, Krilov L, Adams S, et al. Clinical cancer advances 2012: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2013;31:131–61. [28] Navari RM, Gray S. Treatment of chemotherapy-induced breakthrough nausea and vomiting. In: 7th annual conference of the American Psychosocial Oncology Society. 2010. [29] Navari RM, Gray RE. Treatment of chemotherapy-induced breakthrough nausea and vomiting. J Clin Oncol 2009;27:e20536. [30] Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med 2003;6:251–5. [31] Srivastava M, Brito-Dellan N, Davis MP, et al. Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. J Pain Symptom Manage 2003;25:578–82. [32] Lundberg JC, Passik S. Controlling opioid-induced nausea with olanzapine. Primary Care Cancer 2000;20:35–7. [33] Atkinson SR. Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med 2014;17:503–4. [34] Suzuki M, Komuro K, Ohara K. Olanzapine and betamethasone are effective for the treatment of nausea and vomiting due to metastatic brain tumors of rectal cancer. Case Rep Gastroenterol 2014;8:13–7. [35] Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 2002;23: 526–32. [36] Kaneishi K, Kawabata M, Morita T, et al. Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage 2012;44:604–7. [37] Hale AS. Olanzapine. Br J Hosp Med 1997;58:443–5.
[38] Allison DB, Casey DF. Antipsychotic-associated weight gain: a review of the literature. J Clin Psychiatry 2001;62:22–31. [39] Goldstein LE, Sporn J, Brown S, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999;40:438–43. [40] Mahendran R, Liew E, Subramaniam M, et al. De novo emergence of obsessive–compulsive symptoms with atypical antipsychotics in Asian patients with schizophrenia or schizoaffective disorder: a retrospective, cross-sectional study. J Clin Psychiatry 2007;68:542–5. [41] Hocking CM, Kichenadasse G. Olanzapine for chemotherapy-induced nausea and vomiting: a systematic review. Support Care Cancer 2014;22:1143–51. [42] Belgamwar RB, Fenton M. Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses. Cochrane Database Syst Rev 2005;2:CD003729.
Biographies 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 cochairs 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.
Please cite this article in press as: Fonte C, et al. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.02.010
