- Email: [email protected]
A Retrospective Chart Review of the Use of Olanzapine for the Prevention of Delayed Emesis in Cancer Patients
Vol. 25 No. 5 May 2003
Journal of Pain and Symptom Management
485
Clinical Note
A Retrospective Chart Review of the Use of Olanzapine for the Prevention of Delayed Emesis in Cancer Patients Steven D. Passik, PhD, Kenneth L. Kirsh, PhD, Dale E. Theobald, PhD, MD, Pamela Dickerson, BA, Randall Trowbridge, MD, David Gray, MD, Megan Beaver, BS, Jessica Comparet, BA, and Justin Brown, BA Symptom Management and Palliative Care Program (S.D.P., K.L.K.), Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and Community Cancer Care, Inc. (D.E.T., P.D., R.T., D.G., M.B., J.C., J.B.), Indianapolis, Indiana, USA
Abstract Chemotherapy-induced delayed emesis (DE) affects approximately 50–70% of patients receiving moderately and highly emetogenic chemotherapy. DE most commonly occurs within the first 24–48 hours of chemotherapy administration and can persist for 2–5 days. Olanzapine, which has been used anecdotally for chronic nausea in advanced cancer patients, might be a useful treatment for the prevention of delayed emesis in chemotherapy patients. We conducted a chart review to explore this hypothesis and to plan potential studies. Using pharmacy records or an electronic medical record, we identified all patients who had received olanzapine in the oncology clinic (n 98). We reviewed these records and selected all patients (n 28) who had received olanzapine for the prevention of delayed emesis for structured review. There were 17 women (60.7%) and 11 men (39.3%). Eleven patients (39.3%) had at least one instance of nausea recorded while undergoing olanzapine treatment and seven (25%) had an episode of vomiting recorded. During 95 total cycles of chemotherapy with olanzapine (mean 3.4 cycles per patient), there were 21 incidents of nausea (22.1%) and 10 instances of vomiting (10.5%). Side effects were rarely noted. These data suggest that olanzapine was well tolerated and may reduce the incidence of delayed emesis in patients receiving moderate to highly emetogenic chemotherapy. A series of prospective trials are underway. J Pain Symptom Manage 2003;25:485–489. © 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Nausea, chemotherapy, olanzapine
Introduction
Address reprint requests to: Steven D. Passik, PhD, Symptom Management and Palliative Care Program, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0093, USA. Accepted for publication: August 30, 2002. © 2003 U.S. Cancer Pain Relief Committee Published by Elsevier. All rights reserved.
Despite the efficacy of the serotonin 3 (5HT3) receptor antagonists for the control of acute emesis caused by chemotherapy, these agents have not eliminated the problem of delayed emesis.1–3 Delayed emesis (DE) most commonly occurs within the first 24 to 48 hours after chemotherapy. Approximately 40% of pa0885-3924/03/$–see front matter doi:10.1016/S0885-3924(03)00078-2
486
Passik et al.
tients treated with chemotherapy may develop delayed emesis and it has been associated predominantly with cyclophosphamide, doxorubicin, platinum-based chemotherapies, and more recently, irinotecan-containing regimens. Nausea and vomiting (N/V) related to chemotherapy are the most feared and distressing of chemotherapy-related side effects.4 Patients who have experienced uncontrolled chemotherapy-induced N/V can become particularly wary of N/V for the remainder of their cancer treatment and become even more sensitized to these symptoms, worsening their acute, delayed, and anticipatory nausea and emesis.5 They may be unwilling to endure these side effects without major changes in their cancer treatments. Medications or combinations of medications with multiple actions may be required to relieve complex N/V symptoms.7 The polypharmacy that is often required is not without side effects, many of which can be difficult for patients to endure.8 Thus, both delayed emesis and the effort to treat it can have a major impact upon optimal treatment delivery and quality of life for patients with cancer.6 In a pilot study,9 olanzapine (Zyprexa), currently indicated for schizophrenia and bipolar mania, was efficacious in the treatment of chronic nausea related to opioids. A subsequent clinical experience suggests that it is well-tolerated and may be effective in nausea and vomiting from other sources.10 Olanzapine has actions at multiple receptor sites implicated in N/V11,12 and is a neuroleptic with relatively few side effects and minimal extrapyramidal symptoms (EPS). Common treatments for delayed emesis include corticosteroids, metoclopromide, or prochlorperazine, sometimes given with lorezapam or diphenhydramine. Side effects of these drugs include EPS, restlessness, sedation, agitation, insomnia, and depression. In an effort to improve the prevention of DE, olanzapine was used empirically in a group of cancer patients who received highly emetogenic chemotherapy. The drug usually was started 24–48 hours before chemotherapy was administered, and was then continued for days and after treatment. To explore the hypothesis that olanzapine may be useful for DE, we conducted a retrospective chart review of this experience.
Vol. 25 No. 5 May 2003
Methods The study was carried out at the following sites: Indiana Oncology Hematology Consultants (IOHC) in Indianapolis and 2 outreach sites of Community Cancer Care Inc. (CCC): Decatur County Memorial Hospital in Greensburg, IN, and Clinton County Memorial Hospital in Frankfort, IN. Using an electronic medical record in Indianapolis, and pharmacy records in the outreach sites, all oncology patients who were prescribed olanzapine were identified (n 98). Medical records of these patients were reviewed and 28 (28.6%) had received the drug specifically for the prevention of delayed emesis. Other reasons for use of olanzapine included treatment of chronic nausea, anxiety, and unclearly documented reasons. Using a standardized review form, data were collected on demographic variables, disease site, stage, chemotherapy history, relevant laboratory values, pre-chemotherapy medications, dosage of olanzapine, and adverse side effects from the drug. N/V during this period immediately after the chemotherapy were the outcomes of interest and mentions about either were similarly recorded.
Results There were 17 women (60.7%) and 11 men (39.3%), with an average age of 60.0 years (range 38–84 years). Most were white (n 25, 89.3%); three patients were AfricanAmerican (10.7%). The patients had a variety of tumors, with lung (n 7, 25%) and breast (n 5, 17.9%) cancer being most common (Table 1). Four patients had stage I cancer
Table 1 Distribution of Cancer Type Across the Sample Diagnosis
n
%
Lung Breast Prostate Colon Rectum Ovarian Esophagus Pancreas Cervical Lymphoma Bowel Stomach
7 5 4 2 2 2 1 1 1 1 1 1
25.0 17.9 14.3 7.1 7.1 7.1 3.6 3.6 3.6 3.6 3.6 3.6
Vol. 25 No. 5 May 2003
Olanzapine for Prevention of Delayed Emesis
(14.3%), 7 patients had stage II (25%), 7 patients had stage III (25%), and 9 patients had stage IV disease (32.1%). Only 1 patient (3.6%) had an unknown stage of disease. The mean weight at diagnosis was 187.1 pounds (SD 45.4). There were no significant relationships between the demographic variables and the presence of nausea and vomiting in the sample according to a series of Chi-square analyses and t -tests. Several other demographic variables were also of interest. Ten (35.7%) patients had previous psychiatric disorders, with depression (n 5), mixed anxiety and depression (n 4), and anxiety (n 1) being the specific subtypes. Seven patients (25%) were noted to drink alcohol at least on occasion (an important variable associated with lower rates of delayed emesis in the literature). Fifteen patients (53.6%) had some form of gastrointestinal problem not associated with cancer. These included peptic ulcers (n 4), gastroesophageal reflux (n 3), or hiatal hernias (n 2). Renal function was within normal limits in 100% of the sample (n 28) and liver function was within normal limits in 92.9% of the sample (n 26). Eleven patients (39.3%) were given a corticosteroid or metoclopramide, in addition to
487
olanzapine, as chemotherapy pre-medications (Table 2). These patients were also treated with 5HT3 blockers. Before olanzapine was used, most patients were treated with highly (n 12, 42.9%) or moderately (n 10, 35.7%) emetogenic chemotherapy regimens. The chemotherapy for which olanzapine was administered was also likely to be highly (n 11, 39.3%) or moderately (n 10, 35.7%) emetogenic. A series of Chi-square analyses were conducted to determine if the emetogenic potential of the chemotherapy agents (designated as high, moderate, or low) affected nausea and vomiting, but no significant differences were found. Most patients had a history of nausea (n 23, 82.1%) and vomiting (n 15, 53.6%) from prior chemotherapy noted before being started on olanzapine. The documented dosages of olanzapine used varied from patient to patient, but most were given 2.5 mg twice daily (n 18, 64.3%) or 5 mg twice daily (n 7, 25%). Seven of the 28 patients (25%) were treated with a 2-day run-in before the start of chemotherapy. No patients received extra doses of olanzapine. A Chi-square analysis failed to detect any significant differences in nausea and vomiting based on whether the subject had the 2-day run-in period.
Table 2 Chemotherapy Data for the Sample Item How emetogenic was the patient’s previous chemotherapy history? How emetogenic was the patient’s chemotherapy during olanzapine treatment? Did the patient ever have radiation therapy? Did the patient have a history of delayed emesis? Did the patient have a history of vomiting Did the patient have a history of anorexia? Did the patient receive pre-chemotherapy benzodiazepines before the current regimen? Did the patient receive pre-chemotherapy 5HT3 before the current regimen? Did the patient receive pre-chemotherapy antihistamines before the current regimen? Did the patient receive pre-chemotherapy steroids before the current regimen? Did the patient receive pre-chemotherapy neuroleptics before the current regimen?
Rating
n
%
High Moderate Low High Moderate Low Yes No Yes No Yes No Yes No Yes No
12 10 6 11 10 7 17 11 23 5 15 13 2 26 10 18
42.9 35.7 21.4 39.3 35.7 25.0 60.7 39.3 82.1 17.9 53.6 46.4 7.1 92.9 35.7 64.3
Yes No Yes No Yes No Yes No
18 10 6 22 11 17 11 17
64.3 21.4 78.6 39.3 60.7 39.3 60.7
488
Passik et al.
The rates of nausea, vomiting, and the common side effects of sedation, edema, and restlessness from olanzapine are listed in Table 3. Eleven patients (39.3%) had nausea during at least one cycle of chemotherapy with olanzapine and 7 patients (25%) had an episode of vomiting documented. Overall, 95 cycles of chemotherapy with olanzapine were noted across the 28 patients (mean 3.4 cycles per patient), with an incidence of 21 documented periods of nausea (22.1%) and 10 instances of documented vomiting (10.53%). A single patient accounted for 6 of the 21 reported instances of nausea while taking olanzapine, but all cases in the patient’s chart were reported as being “minimal.” In addition, another patient reported both nausea and vomiting for each of three cycles of chemotherapy while taking olanzapine. Thus, 2 patients accounted for 9 of the 21 (42.9%) incidents of nausea. The patient who had 6 episodes had stage II breast cancer and was undergoing a highly emetogenic chemotherapy regimen. There were no other features of this case that might help to identify why she was a conspicuous non-responder. With regard to side effects, both sedation (n 2, 7.1%) and edema (n 1, 3.6%) were rarely documented, and restlessness was never noted in the patient records. A paired-samples t-test did not show any significant weight gain between pre-olanzapine (mean 186.57, SD 46.4) and postolanzapine (mean 186.6, SD 47.4) conditions (t 0.05, P 0.96). A series of Chi-square analyses comparing a past history of nausea and vomiting secondary to chemotherapy and current nausea and vomiting (while taking olanzapine) failed to show
Vol. 25 No. 5 May 2003
significant relationship for nausea, but did indicate a link between a previous history of vomiting and current vomiting (2 8.09, P 0.007). A series of Chi-squares comparing the past and present chemotherapy regimens (rated as high, moderate, or low for emetogenesis) were all found to be non-significant to the presence of nausea or vomiting while the patient was on olanzapine.
Discussion A pilot study of olanzapine in the treatment of the chronic nausea of advanced cancer was promising9 and inspired our oncologists to examine its utility in the complicated problem of DE from chemotherapy. We found that the drug was generally well-tolerated, with sedation becoming problematic for a small number of patients. The rates of N/V were less than expected, suggesting the potential for benefit in the treatment of DE following emetogenic chemotherapy. Only 25% of the patients received a 2-day pretreatment with the drug. It is not clear if this is necessary in using the drug as an antiemetic. The potential influence of steady-state drug levels, dose adjustments, and varied durations of therapy also cannot be determined on the basis of this experience. As with any chart review, these data must be interpreted cautiously. The fact that nausea and vomiting were not noted in nearly 80% of the cycles of chemotherapy does not mean that it did not occur. Patients may have underreported these symptoms due to potential recall bias, and physicians and nurses may have failed to document them for multiple reasons,
Table 3 Rates of Nausea and Vomiting While on Olanzapine, Including Side Effect Profiles for Sedation, Edema, and Restlessness Item Was nausea noted during any cycle of chemotherapy with olanzapine? Was vomiting noted during any cycle of chemotherapy with olanzapine? Did the patient have any instance of sedation from olanzapine noted? Did the patient have any instance of edema from olanzapine noted? Did the patient have any instance of restlessness from olanzapine noted?
Rating
n
%
Yes No Yes No Yes No Yes No Yes No
11 17 7 21 2 26 1 27 0 28
39.3 60.7 25.0 75.0 7.1 92.9 3.6 96.4 0 100
Vol. 25 No. 5 May 2003
Olanzapine for Prevention of Delayed Emesis
489
especially since they did not use structured tools or protocols for generating their chart notes. In addition, there is no demographically matched comparison group of patients who did not receive olanzapine. Although it would have been of interest to examine the efficacy of olanzapine for DE compared to the efficacy of agents used in prior cycles of chemotherapy, the data on prior antiemetic regimens was not captured in the review. Therefore, these results require replication and confirmation in larger, prospective trials.
tryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 1994;268:1403–1410.
Acknowledgments
7. Sweet R, DeSensi E, Zubenko G. Reliability and applicability of movement disorders rating scales in the elderly. J Neuropsych Clin Neurosci 1993;5:56–60.
This study was supported, in part, by Eli Lilly & Co., Indianapolis, Indiana, USA.
References 1. Gobert A, Rivet J, Audinot V, et al. Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist (+) --S 14297 II. Both D2 and “silent” D3 autorecptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways. J Pharmacol Exp Ther 1995;275:899–913. 2. Meltzer H, Matsubara S, Lee J. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin 2 pK, values. J Pharmacol Exp Ther 1989;251:238–246. 3. Roth B, Craigo S, Choudary M, et al. Binding of typical and atypical psychotic agents to 5-hydroxy-
4. Passik SD, Lundberg J, Kirsh KL, Theobald DE, Donaghy KD, Holtsclaw E, Cooper M, Dugan W. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain and Symptom Management, 23:526–532. 5. Pisters K, Kris M. Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds. Principles and practice of supportive oncology. Philadelphia: Lippincott-Raven, 1998:165–177. 6. Ward SE, Goldberg N, Miller-McCauley V, et al. Patient-related barriers to management of cancer pain. Pain 1993;52:319–324.
8. Aparasu R, McCoy R, Weber C, et al. Opioidinduced emesis among hospitalized nonsurgical patients: effect on pain and quality of life. J Pain Symptom Manage 1999;18:280–288. 9. Passik SD, Kirsh KL, Rosenfeld B, McDonald M, Theobald D. The changeable nature of patients’ fears regarding chemotherapy: Implications for palliative care. J Pain and Symptom Management, 21: 113–120, 2001. 10. Pirl WF, Roth AJ. Remission of chemotherapyinduced emesis with concurrent olanzapine treatment: a case report. Psycho-oncol 2000;9:84–87. 11. Bymaster F, Calligaro D, Falcone J et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacol 1996;14:87–96. 12. Bymaster F, Falcone J, Bauzon D, et al. Potent antagonism of serotonin (5HT3) and 5HT6 receptors by olanzapine. Euro J Pharm 2001;430:341–349.
Journal of Pain and Symptom Management
485
Clinical Note
A Retrospective Chart Review of the Use of Olanzapine for the Prevention of Delayed Emesis in Cancer Patients Steven D. Passik, PhD, Kenneth L. Kirsh, PhD, Dale E. Theobald, PhD, MD, Pamela Dickerson, BA, Randall Trowbridge, MD, David Gray, MD, Megan Beaver, BS, Jessica Comparet, BA, and Justin Brown, BA Symptom Management and Palliative Care Program (S.D.P., K.L.K.), Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and Community Cancer Care, Inc. (D.E.T., P.D., R.T., D.G., M.B., J.C., J.B.), Indianapolis, Indiana, USA
Abstract Chemotherapy-induced delayed emesis (DE) affects approximately 50–70% of patients receiving moderately and highly emetogenic chemotherapy. DE most commonly occurs within the first 24–48 hours of chemotherapy administration and can persist for 2–5 days. Olanzapine, which has been used anecdotally for chronic nausea in advanced cancer patients, might be a useful treatment for the prevention of delayed emesis in chemotherapy patients. We conducted a chart review to explore this hypothesis and to plan potential studies. Using pharmacy records or an electronic medical record, we identified all patients who had received olanzapine in the oncology clinic (n 98). We reviewed these records and selected all patients (n 28) who had received olanzapine for the prevention of delayed emesis for structured review. There were 17 women (60.7%) and 11 men (39.3%). Eleven patients (39.3%) had at least one instance of nausea recorded while undergoing olanzapine treatment and seven (25%) had an episode of vomiting recorded. During 95 total cycles of chemotherapy with olanzapine (mean 3.4 cycles per patient), there were 21 incidents of nausea (22.1%) and 10 instances of vomiting (10.5%). Side effects were rarely noted. These data suggest that olanzapine was well tolerated and may reduce the incidence of delayed emesis in patients receiving moderate to highly emetogenic chemotherapy. A series of prospective trials are underway. J Pain Symptom Manage 2003;25:485–489. © 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Nausea, chemotherapy, olanzapine
Introduction
Address reprint requests to: Steven D. Passik, PhD, Symptom Management and Palliative Care Program, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0093, USA. Accepted for publication: August 30, 2002. © 2003 U.S. Cancer Pain Relief Committee Published by Elsevier. All rights reserved.
Despite the efficacy of the serotonin 3 (5HT3) receptor antagonists for the control of acute emesis caused by chemotherapy, these agents have not eliminated the problem of delayed emesis.1–3 Delayed emesis (DE) most commonly occurs within the first 24 to 48 hours after chemotherapy. Approximately 40% of pa0885-3924/03/$–see front matter doi:10.1016/S0885-3924(03)00078-2
486
Passik et al.
tients treated with chemotherapy may develop delayed emesis and it has been associated predominantly with cyclophosphamide, doxorubicin, platinum-based chemotherapies, and more recently, irinotecan-containing regimens. Nausea and vomiting (N/V) related to chemotherapy are the most feared and distressing of chemotherapy-related side effects.4 Patients who have experienced uncontrolled chemotherapy-induced N/V can become particularly wary of N/V for the remainder of their cancer treatment and become even more sensitized to these symptoms, worsening their acute, delayed, and anticipatory nausea and emesis.5 They may be unwilling to endure these side effects without major changes in their cancer treatments. Medications or combinations of medications with multiple actions may be required to relieve complex N/V symptoms.7 The polypharmacy that is often required is not without side effects, many of which can be difficult for patients to endure.8 Thus, both delayed emesis and the effort to treat it can have a major impact upon optimal treatment delivery and quality of life for patients with cancer.6 In a pilot study,9 olanzapine (Zyprexa), currently indicated for schizophrenia and bipolar mania, was efficacious in the treatment of chronic nausea related to opioids. A subsequent clinical experience suggests that it is well-tolerated and may be effective in nausea and vomiting from other sources.10 Olanzapine has actions at multiple receptor sites implicated in N/V11,12 and is a neuroleptic with relatively few side effects and minimal extrapyramidal symptoms (EPS). Common treatments for delayed emesis include corticosteroids, metoclopromide, or prochlorperazine, sometimes given with lorezapam or diphenhydramine. Side effects of these drugs include EPS, restlessness, sedation, agitation, insomnia, and depression. In an effort to improve the prevention of DE, olanzapine was used empirically in a group of cancer patients who received highly emetogenic chemotherapy. The drug usually was started 24–48 hours before chemotherapy was administered, and was then continued for days and after treatment. To explore the hypothesis that olanzapine may be useful for DE, we conducted a retrospective chart review of this experience.
Vol. 25 No. 5 May 2003
Methods The study was carried out at the following sites: Indiana Oncology Hematology Consultants (IOHC) in Indianapolis and 2 outreach sites of Community Cancer Care Inc. (CCC): Decatur County Memorial Hospital in Greensburg, IN, and Clinton County Memorial Hospital in Frankfort, IN. Using an electronic medical record in Indianapolis, and pharmacy records in the outreach sites, all oncology patients who were prescribed olanzapine were identified (n 98). Medical records of these patients were reviewed and 28 (28.6%) had received the drug specifically for the prevention of delayed emesis. Other reasons for use of olanzapine included treatment of chronic nausea, anxiety, and unclearly documented reasons. Using a standardized review form, data were collected on demographic variables, disease site, stage, chemotherapy history, relevant laboratory values, pre-chemotherapy medications, dosage of olanzapine, and adverse side effects from the drug. N/V during this period immediately after the chemotherapy were the outcomes of interest and mentions about either were similarly recorded.
Results There were 17 women (60.7%) and 11 men (39.3%), with an average age of 60.0 years (range 38–84 years). Most were white (n 25, 89.3%); three patients were AfricanAmerican (10.7%). The patients had a variety of tumors, with lung (n 7, 25%) and breast (n 5, 17.9%) cancer being most common (Table 1). Four patients had stage I cancer
Table 1 Distribution of Cancer Type Across the Sample Diagnosis
n
%
Lung Breast Prostate Colon Rectum Ovarian Esophagus Pancreas Cervical Lymphoma Bowel Stomach
7 5 4 2 2 2 1 1 1 1 1 1
25.0 17.9 14.3 7.1 7.1 7.1 3.6 3.6 3.6 3.6 3.6 3.6
Vol. 25 No. 5 May 2003
Olanzapine for Prevention of Delayed Emesis
(14.3%), 7 patients had stage II (25%), 7 patients had stage III (25%), and 9 patients had stage IV disease (32.1%). Only 1 patient (3.6%) had an unknown stage of disease. The mean weight at diagnosis was 187.1 pounds (SD 45.4). There were no significant relationships between the demographic variables and the presence of nausea and vomiting in the sample according to a series of Chi-square analyses and t -tests. Several other demographic variables were also of interest. Ten (35.7%) patients had previous psychiatric disorders, with depression (n 5), mixed anxiety and depression (n 4), and anxiety (n 1) being the specific subtypes. Seven patients (25%) were noted to drink alcohol at least on occasion (an important variable associated with lower rates of delayed emesis in the literature). Fifteen patients (53.6%) had some form of gastrointestinal problem not associated with cancer. These included peptic ulcers (n 4), gastroesophageal reflux (n 3), or hiatal hernias (n 2). Renal function was within normal limits in 100% of the sample (n 28) and liver function was within normal limits in 92.9% of the sample (n 26). Eleven patients (39.3%) were given a corticosteroid or metoclopramide, in addition to
487
olanzapine, as chemotherapy pre-medications (Table 2). These patients were also treated with 5HT3 blockers. Before olanzapine was used, most patients were treated with highly (n 12, 42.9%) or moderately (n 10, 35.7%) emetogenic chemotherapy regimens. The chemotherapy for which olanzapine was administered was also likely to be highly (n 11, 39.3%) or moderately (n 10, 35.7%) emetogenic. A series of Chi-square analyses were conducted to determine if the emetogenic potential of the chemotherapy agents (designated as high, moderate, or low) affected nausea and vomiting, but no significant differences were found. Most patients had a history of nausea (n 23, 82.1%) and vomiting (n 15, 53.6%) from prior chemotherapy noted before being started on olanzapine. The documented dosages of olanzapine used varied from patient to patient, but most were given 2.5 mg twice daily (n 18, 64.3%) or 5 mg twice daily (n 7, 25%). Seven of the 28 patients (25%) were treated with a 2-day run-in before the start of chemotherapy. No patients received extra doses of olanzapine. A Chi-square analysis failed to detect any significant differences in nausea and vomiting based on whether the subject had the 2-day run-in period.
Table 2 Chemotherapy Data for the Sample Item How emetogenic was the patient’s previous chemotherapy history? How emetogenic was the patient’s chemotherapy during olanzapine treatment? Did the patient ever have radiation therapy? Did the patient have a history of delayed emesis? Did the patient have a history of vomiting Did the patient have a history of anorexia? Did the patient receive pre-chemotherapy benzodiazepines before the current regimen? Did the patient receive pre-chemotherapy 5HT3 before the current regimen? Did the patient receive pre-chemotherapy antihistamines before the current regimen? Did the patient receive pre-chemotherapy steroids before the current regimen? Did the patient receive pre-chemotherapy neuroleptics before the current regimen?
Rating
n
%
High Moderate Low High Moderate Low Yes No Yes No Yes No Yes No Yes No
12 10 6 11 10 7 17 11 23 5 15 13 2 26 10 18
42.9 35.7 21.4 39.3 35.7 25.0 60.7 39.3 82.1 17.9 53.6 46.4 7.1 92.9 35.7 64.3
Yes No Yes No Yes No Yes No
18 10 6 22 11 17 11 17
64.3 21.4 78.6 39.3 60.7 39.3 60.7
488
Passik et al.
The rates of nausea, vomiting, and the common side effects of sedation, edema, and restlessness from olanzapine are listed in Table 3. Eleven patients (39.3%) had nausea during at least one cycle of chemotherapy with olanzapine and 7 patients (25%) had an episode of vomiting documented. Overall, 95 cycles of chemotherapy with olanzapine were noted across the 28 patients (mean 3.4 cycles per patient), with an incidence of 21 documented periods of nausea (22.1%) and 10 instances of documented vomiting (10.53%). A single patient accounted for 6 of the 21 reported instances of nausea while taking olanzapine, but all cases in the patient’s chart were reported as being “minimal.” In addition, another patient reported both nausea and vomiting for each of three cycles of chemotherapy while taking olanzapine. Thus, 2 patients accounted for 9 of the 21 (42.9%) incidents of nausea. The patient who had 6 episodes had stage II breast cancer and was undergoing a highly emetogenic chemotherapy regimen. There were no other features of this case that might help to identify why she was a conspicuous non-responder. With regard to side effects, both sedation (n 2, 7.1%) and edema (n 1, 3.6%) were rarely documented, and restlessness was never noted in the patient records. A paired-samples t-test did not show any significant weight gain between pre-olanzapine (mean 186.57, SD 46.4) and postolanzapine (mean 186.6, SD 47.4) conditions (t 0.05, P 0.96). A series of Chi-square analyses comparing a past history of nausea and vomiting secondary to chemotherapy and current nausea and vomiting (while taking olanzapine) failed to show
Vol. 25 No. 5 May 2003
significant relationship for nausea, but did indicate a link between a previous history of vomiting and current vomiting (2 8.09, P 0.007). A series of Chi-squares comparing the past and present chemotherapy regimens (rated as high, moderate, or low for emetogenesis) were all found to be non-significant to the presence of nausea or vomiting while the patient was on olanzapine.
Discussion A pilot study of olanzapine in the treatment of the chronic nausea of advanced cancer was promising9 and inspired our oncologists to examine its utility in the complicated problem of DE from chemotherapy. We found that the drug was generally well-tolerated, with sedation becoming problematic for a small number of patients. The rates of N/V were less than expected, suggesting the potential for benefit in the treatment of DE following emetogenic chemotherapy. Only 25% of the patients received a 2-day pretreatment with the drug. It is not clear if this is necessary in using the drug as an antiemetic. The potential influence of steady-state drug levels, dose adjustments, and varied durations of therapy also cannot be determined on the basis of this experience. As with any chart review, these data must be interpreted cautiously. The fact that nausea and vomiting were not noted in nearly 80% of the cycles of chemotherapy does not mean that it did not occur. Patients may have underreported these symptoms due to potential recall bias, and physicians and nurses may have failed to document them for multiple reasons,
Table 3 Rates of Nausea and Vomiting While on Olanzapine, Including Side Effect Profiles for Sedation, Edema, and Restlessness Item Was nausea noted during any cycle of chemotherapy with olanzapine? Was vomiting noted during any cycle of chemotherapy with olanzapine? Did the patient have any instance of sedation from olanzapine noted? Did the patient have any instance of edema from olanzapine noted? Did the patient have any instance of restlessness from olanzapine noted?
Rating
n
%
Yes No Yes No Yes No Yes No Yes No
11 17 7 21 2 26 1 27 0 28
39.3 60.7 25.0 75.0 7.1 92.9 3.6 96.4 0 100
Vol. 25 No. 5 May 2003
Olanzapine for Prevention of Delayed Emesis
489
especially since they did not use structured tools or protocols for generating their chart notes. In addition, there is no demographically matched comparison group of patients who did not receive olanzapine. Although it would have been of interest to examine the efficacy of olanzapine for DE compared to the efficacy of agents used in prior cycles of chemotherapy, the data on prior antiemetic regimens was not captured in the review. Therefore, these results require replication and confirmation in larger, prospective trials.
tryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 1994;268:1403–1410.
Acknowledgments
7. Sweet R, DeSensi E, Zubenko G. Reliability and applicability of movement disorders rating scales in the elderly. J Neuropsych Clin Neurosci 1993;5:56–60.
This study was supported, in part, by Eli Lilly & Co., Indianapolis, Indiana, USA.
References 1. Gobert A, Rivet J, Audinot V, et al. Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist (+) --S 14297 II. Both D2 and “silent” D3 autorecptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways. J Pharmacol Exp Ther 1995;275:899–913. 2. Meltzer H, Matsubara S, Lee J. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin 2 pK, values. J Pharmacol Exp Ther 1989;251:238–246. 3. Roth B, Craigo S, Choudary M, et al. Binding of typical and atypical psychotic agents to 5-hydroxy-
4. Passik SD, Lundberg J, Kirsh KL, Theobald DE, Donaghy KD, Holtsclaw E, Cooper M, Dugan W. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain and Symptom Management, 23:526–532. 5. Pisters K, Kris M. Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds. Principles and practice of supportive oncology. Philadelphia: Lippincott-Raven, 1998:165–177. 6. Ward SE, Goldberg N, Miller-McCauley V, et al. Patient-related barriers to management of cancer pain. Pain 1993;52:319–324.
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