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Acta Oncol. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Acta Oncol. 2016 June ; 55(6): 700–704. doi:10.3109/0284186X.2016.1154603.
Delayed nausea and vomiting from carboplatin doublet chemotherapy Saiama N. Waqar, MBBS, MSCI1, Janelle Mann, PharmD2, Maria Q. Baggstrom, MD1, Muhammad Atif Waqar, MBBS3, Pooja Chitneni, MD4, Kristina Williams, BS1, Feng Gao, MD, PhD5, Daniel Morgensztern, MD1, and Ramaswamy Govindan, MD1 1Division
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of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
2Department
of Pharmacy Practice, Saint Louis College of Pharmacy, St. Louis, MO
3Department
of Internal Medicine, University of Nevada School of Medicine, Reno, NV
4Department
of Hospitalist Medicine, New York Presbyterian Hospital, New York, NY
5Department
of Surgery, Washington University School of Medicine, St. Louis, MO
Abstract
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Background—Delayed nausea and vomiting following administration of carboplatin containing chemotherapy regimen remains a clinically significant problem for patients with cancer despite administration of standard antiemetic prophylaxis comprising of a 5-HT3 antagonist and dexamethasone. We performed a prospective study to define the incidence and risk factors for delayed chemotherapy induced nausea and vomiting (CINV). Methods—Previously untreated patients with newly diagnosed cancer scheduled to receive carboplatin containing chemotherapy (AUC 5 or above), but no prophylactic aprepitant were enrolled in the study. The primary endpoint was the incidence of delayed CINV after cycle 1 of chemotherapy. Secondary endpoints included the incidence of CINV with the third chemotherapy cycle and gender differences in incidence of CINV. Patients completed the Functional Living Index Emesis (FLIE) questionnaires 24, 48, 72 and 96 hours after receiving chemotherapy. Telephone interviews were conducted 24–48 hours following chemotherapy to assess the severity and need for breakthrough medications for CINV.
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Results—Between December 2006 and July 2009, 105 patients were enrolled onto this study. Delayed emesis following cycle 1 of carboplatin was observed in 30% of patients. Of these, 14.1%, 22.4% and 23.5% of patients described CINV at 48 hours, 72 hours, and 96 hours respectively. The incidence of delayed CINV following cycle 3 dropped to 12.8%, 14.6% and 16% of patients at 48 hours, 72 hours and 96 hours respectively. No differences were observed in the incidence of CINV between men and women. A total of 20% of patients required use of breakthrough antiemetics with cycle 1.
Corresponding author: Ramaswamy Govindan, M.D, Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid, Box 8056, St Louis, MO 63110, Telephone: 314 362 5737, Fax: 314 362 3895, [email protected].
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Conclusions—Without prophylactic aprepitant administration, 30% of patients receiving carboplatin containing regimen had moderate to severe delayed CINV. Keywords carboplatin; emesis; vomiting; delayed nausea; FLIE
INTRODUCTION
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Nausea and vomiting are among the most distressing side effects of chemotherapeutic agents. Inadequately controlled chemotherapy-induced nausea and vomiting (CINV) can lead to dehydration, electrolyte imbalances and malnutrition, which can jeopardize patient willingness to continue chemotherapy.(1, 2) The incidence of CINV varies by chemotherapeutic agent, with drugs such as cisplatin classified as highly emetogenic with CINV rates greater than 90%. CINV with moderately emetogenic agents can vary from 30% to 90%. Carboplatin falls in the higher range of moderately emetogenic chemotherapy. Other reported risk factors for CINV include younger age, female gender, emesis gravidarum, prior history of CINV, motion sickness, and sporadic alcohol use.(2, 3)
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CINV is described as acute if it observed within the first 24 hours following chemotherapy administration, and delayed if seen after 24 hours. Delayed CINV peaks 48–72 hours following chemotherapy and subsides over the next 2 to 3 days.(4) As a result of effective prophylactic antiemetic combinations of 5-hydroxytryptamine type 3 (5HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists and corticosteroids, CINV rates with highly emetogenic chemotherapy has dropped to 30%.(5, 6) Current guidelines support the use of 5HT3 receptor antagonists and corticosteroids for moderately emetogenic agents, plus or minus NK1 receptor antagonists, as data supporting the use of all three antiemetics together is scant. Carboplatin is a platinum salt which cross-links deoxyribose nucleic acid (DNA), and is routinely used for the treatment of solid tumors, as an alternative to cisplatin due to favorable toxicity profile. Data regarding the incidence and severity of CINV with carboplatin are limited, as is its impact on quality of life.(7, 8) Therefore the optimal prophylactic antiemetic combination for use with carboplatin remains undefined. We therefore performed a prospective observational study to determine the incidence, severity and risk factors for delayed CINV following the administration of carboplatin doublet chemotherapy.
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PATIENTS AND METHODS Patient Selection and Eligibility This study was approved by Washington University School of Medicine Institutional Review Board and all study participants provided written informed consent for participation. This study was a prospective, observational trial conducted between December 2006 and July 2009. The study population included patients over the age of 18 with newly diagnosed, histologically or cytologically proven cancer, who were scheduled to receive chemotherapy Acta Oncol. Author manuscript; available in PMC 2017 June 01.
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with carboplatin at AUC 5 or above. Eligible patients received standard antiemetic prophylaxis prior to carboplatin, defined as 5-HT3 antagonist and dexamethasone. At the time of study enrollment the standard antiemetics at our institution involved ondansetron 32 mg IV or palonosetron 0.25 mg IV in combination with dexamethasone 10 or 20 mg IV on day 1 of chemotherapy. Patients were ineligible if they received aprepitant as part of their prophylactic antiemetic regimen. Patients who had received prior cytotoxic chemotherapy within the last 5 years were also excluded, as were patients who were pregnant. Assessment of Delayed Nausea and Vomiting
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Nausea and vomiting were defined as “acute” if occurred within the first 24 hours after carboplatin administration, and “delayed” if observed after 24 hours and assessed up to 96 hours after chemotherapy. The Functional Living Index –Emesis (FLIE) standardized questionnaire was given to each patient during their scheduled clinic visit prior to their first and third cycle of carboplatin. This self-administered questionnaire captured the incidence and severity of nausea and vomiting in the preceding 24 hours. Patients completed the questionnaire 24 hours after carboplatin administration to determine symptoms of acute chemotherapy induced nausea and vomiting, and at the following time points to record incidence and severity of delayed nausea and vomiting: 48 hours, 72 hours, and 96 hours. A trained clinical research associate (CRA) explained the instructions to complete the questionnaire to the patient.
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The FLIE questionnaire has 18 questions divided into two categories: Nausea (questions 1– 9) and Vomiting (questions 10–18). Each of these questions was answered using a 100-mm (1 to 7 points) visual analog scale (VAS) with anchors to “not at all” and “a great deal” and tick-marks dividing the scale into six equal zones. Questions within the category were weighted equally and totaled to create the category score. The two category scores were then combined to create a total score. Higher scores indicated less impairment on daily life as a result of nausea or vomiting. Based on the total FLIE scores, each patient was assigned to one of the following groups: 1) severe delayed nausea and vomiting (score ≤ 45), 2) moderate delayed nausea and vomiting (score 46–99), and 3) no impact of nausea and vomiting on daily life (score ≥ 100). A FLIE score less than 100 (severe and moderate delayed nausea and vomiting) constituted an emetic episode and was used to calculate the incidence of delayed nausea.
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Patients were sent home with prescriptions for breakthrough antiemetic medications as per physician preference. Patients were also interviewed by a trained clinical research assistant or research nurse over the telephone 24–48 hours following carboplatin administration to assess the severity of delayed nausea and vomiting and to assess the need for any breakthrough antiemetic medications. Breakthrough antiemetics used as well as frequency of use were recorded. Statistical Considerations The goal of this study was to prospectively characterize the incidence and severity of delayed emesis following administration of carboplatin-containing chemotherapy regimens
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despite the appropriate administration of standard 5-HT3 receptor antagonist antiemetic prophylaxis after the first cycle and third cycle of chemotherapy. The primary endpoint was to examine the incidence of delayed nausea and vomiting following cycle 1 of carboplatin administration. Secondary endpoints included examining the incidence of delayed nausea and vomiting following cycle 3 of carboplatin, differences in incidence of emesis by gender, and patterns of use of breakthrough anti-emetic medication use. A relatively large sample size (N=100) was proposed to allow the estimation of the overall incidence of delayed emesis with a less than 5% measurement error. This allowed sufficient numbers for the possible estimations within subgroups, but the study was not powered for subgroup analysis.
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The analysis for this study was primarily descriptive. Demographic and clinical characteristics of the sample, occurrence and severity of the delayed emesis, as well as numbers of emetic episodes and time to the onset of emesis, were summarized using descriptive statistics. The incidence of the emesis (overall and by severity) were calculated for both cycle 1 and 3 at the following time points: 24, 48, 72 and 96 hours. The overall incidence of delayed nausea and vomiting was described by single patient reports during the study time periods for cycles 1 and 3. Chi-squared test was used to tabulate and compare the difference incidence of delayed nausea and vomiting between male and female participants. A multivariate logistic regression analysis was also fitted to explore the possible associations of other demographic/clinical characteristics to the overall incidence of delayed emesis.
RESULTS Patient characteristics
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Between December 2006 and July 2009, 105 patients were enrolled onto this study. Of these participants, 99 patients completed cycle 1 FLIE questionnaires, while only 50 completed cycle 3 FLIE questionnaires. The patient characteristics are listed in Table 1. Of the patients enrolled, 62 were male and 43 were female with a median age of 64.8 years. The majority of patients were Caucasian (83/105, 79%), followed by African American (19/105, 18%), Native American or Alaskan Nation (2/105, 2%), and Asian (1/105, 1%). Seventy-nine percent of the patients were diagnosed with non-small cell lung cancer. The remaining 21% of the patients had the following tumors: small cell lung cancer 6.7%, esophageal 6.7%, melanoma 1.9%, mesothelioma 4.8%, and transitional cell 1.0%. The majority of the patients had stage III and IV disease (21.6% and 72.7% respectively). In terms of smoking status, 33% of the patients were current smokers while 61% were former smokers and 6% had never smoked. Incidence of nausea and vomiting following cycle 1 of carboplatin
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The mean FLIE score for patients following cycle 1 were 118.8 (standard deviation/SD12.2), 116.6 (SD 14.9), 112.8 (SD 19.3) and 111.3 (SD 23.1) at 24, 48, 72 and 96 hours respectively. A total of 30 patients reported delayed CINV at any time point following chemotherapy up to 96 hours during cycle 1. Ten percent of patients described acute nausea and vomiting within 24 hours following carboplatin administration, which was categorized as moderate (FLIE score 46–99). None of the patients had severe (FLIE score ≥ 100) acute CINV. Delayed emesis was observed in 14.1% (moderate), 22.4% (21.4% moderate and 1%
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severe) and 23.5% (18.4% moderate and 4.1% severe) of patients at 48 hours, 72 hours, and 96 hours respectively. Incidence of nausea and vomiting following cycle 3 of carboplatin The mean FLIE score for patients following cycle 3 were 121 (SD 9.1), 115 (SD 22.7), 115.8 (SD 19.7) and 115.5 (SD 20.2) at 24, 48, 72 and 96 hours respectively. A total of 13 patients out of 50 patients described delayed CINV at any time point following chemotherapy and up to 96 hours during cycle 1. Of these, 4.1% described acute emesis within 24 hours following cycle 3 of carboplatin, which was categorized as moderate. Delayed emesis was observed in 12.8%(8.5% moderate and 4.3% severe), 12.4.% (10.4% moderate and 2% severe) and 16% (14% moderate and 2% severe) of patients at 48 hours, 72 hours and 96 hours respectively.
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Differences in Delayed Emesis by Gender and other risk factors
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Use of breakthrough medication for nausea and vomiting
Tables 2 and 3 show the incidence of acute and delayed nausea and vomiting for both men and women, at the time points 24 hours, 48 hours, 72 hours and 96 hours respectively following cycle 1 and cycle 3 of carboplatin. Based on univariate analysis, no differences were observed in the incidence of carboplatin-containing chemotherapy induced emesis between men and women (table 4). Age was not a predictor for moderate-severe emesis in our dataset. Smoking status appeared to be a predictor on univariate analysis with the incidence of chemotherapy-induced delayed moderate to severe emesis being higher in never or former smokers compared to current smokers. However this trend was no longer observed on multivariate analysis. Therefore, no significant clinical predictors for moderate-severe emesis were observed in this dataset.
Table 5 describes the frequency of breakthrough medication for nausea and vomiting in patients following cycle 1 of carboplatin containing chemotherapy. A total of 20/99 (20.2%) patients required use of breakthrough antiemetics. Prochlorperazine was the most commonly used antiemetic (15/20) either alone, or combination with other agents such as lorazepam or metoclopramide.
DISCUSSION
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This prospective study, evaluating the incidence and severity of delayed nausea and vomiting with carboplatin containing regimens, was performed prior to aprepitant being commonly used. Unlike most studies which evaluate breakthrough emesis as a dichotomous variable, we utilized the validated FLIE questionnaire to capture not only the severity of breakthrough emesis, but also its impact on the quality of life.(9–11) This emphasis on patient reported outcomes is a major strength of this study. In addition, the FLIE questionnaire was administered at several time points, and captures date pertaining to the preceding 24 hours, which reduces recall bias. The prophylactic antiemetics administered to patients in this study were uniform, based on our institutional practice.
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Investigating the incidence and severity of emesis with cycle 1 and cycle 3 provided a snapshot of the effectiveness of pharmacologic interventions to manage breakthrough emesis. The reduction in incidence of both acute and delayed emesis with cycle 3 of chemotherapy, compared to cycle 1, reflects the successful use of rescue antiemetics, given that dose reductions in carboplatin were rare. The patient dropout rate of 50% is similar to rates observed in other quality of life studies.(12, 13) It is sobering that even with breakthrough anti-emetic use, delayed emesis was observed in over 12% of patients even with cycle 3, underscoring the importance of better prophylactic antiemetic regimens.
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Following our initial report, a phase II study randomly assigned 134 chemotherapy-naïve Japanese patients with advanced non-small cell lung cancer receiving carboplatin-based chemotherapy to receive standard prophylactic antiemetics (5-HT3 receptor antagonist and corticosteroid) with or without aprepitant.(14, 15) The primary endpoint of this study was to evaluate the complete response rate, defined as no vomiting and no rescue therapy during the 120 hours post-chemotherapy. The study showed trend towards improved emesis control in the aprepitant group compared to the non-aprepitant group (complete response rate 80.3% versus 67.2%, odds ratio 0.50; 95% CI, 0.22–1.10; p = 0.085).(15) Though this benefit of aprepitant did not meet statistical significance, improvement in emesis control remains an issue of importance.
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Several patient-related risk factors for CINV have been described, including younger age, female gender, sporadic alcohol use and prior chemotherapy.(16) The association with smoking observed in our study is interesting, and needs to be explored further. While our study did not specifically aim to evaluate individual risk factors, but rather focus on quality of life measures, we did examine the role of gender, but did not find a significant relationship in our study. Recent randomized studies of aprepitant vs placebo in female Japanese patients receiving carboplatin have shown mixed results regarding efficacy. Tanioka and colleagues demonstrated a numerically higher complete response (no emesis or rescue therapy needed) in the aprepitant group, though this did not meet statistical significance.(17) Yahata and colleagues, on the other hand, did observe a statistically significant improvement in “no vomiting” in the aprepitant group compared to placebo.(18) Further studies are needed to validate the utility of aprepitant with carboplatin-based regimens in other ethnic patient subgroups. Despite the absence of compelling data favoring prophylactic aprepitant use to control emesis with carboplatin, current guidelines list its use as “an option” to help control this feared side effect of chemotherapy.(1, 19)
Acknowledgments Author Manuscript
This publication was supported by the National Cancer Institute of the National Institutes of Health (NIH), Grant Number 1K12CA167540 and the Clinical Translational Science Award (CTSA) program of the National Center for Advancing Translational Sciences at the National Institutes of Health, Grant Number UL1RR024992. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported in part by Cancer Center Support Grant P30 CA91842 and the Clinical Trials Core of the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital in St. Louis, Missouri.
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17. Tanioka M, Kitao A, Matsumoto K, Shibata N, Yamaguchi S, Fujiwara K, et al. A randomised, placebo-controlled, double-blind study of aprepitant in nondrinking women younger than 70 years receiving moderately emetogenic chemotherapy. British journal of cancer. 2013; 109(4):859–65. [PubMed: 23860530] 18. Yahata H, Kobayashi H, Sonoda K, Shimokawa M, Ohgami T, Saito T, et al. Efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin. International journal of clinical oncology. 2015 19. van der Vorst MJ, Neefjes EC, Konings IR, Verheul HM. Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 2015; 23(8):2499– 506. [PubMed: 26041480]
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Table 1
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Demographics of patients enrolled on study Variable
Total (%) N=105
Age (Median)
64.8 years
Gender Male
62 (59%)
Female
43 (41%)
Race White
83 (79%)
Black or African-American
19 (18%)
Native American or Alaskan Nation
2 (2%)
Asian
1 (1%)
Tumor Type
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Non-small cell lung
83 (79.0%)
Esophageal
7 (6.7%)
Small cell lung
7 (6.7%)
Mesothelioma
5 (4.8%)
Transitional cell
1 (1.0%)
Stage I
2 (2.3%)
II
3 (3.4%)
III
19 (21.6%)
IV
64 (72.7%)
Smoking Status
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Current
32 (33.0%)
Former
59 (60.8%)
Never
6 (6.2%)
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Table 2
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Incidence of acute and delayed nausea and vomiting in patients following cycle 1 of carboplatin containing chemotherapy according to gender Type of emesis
Time points
Overall (%)
Male (%)
Female (%)
Acute
24 hours
10 (10%)
7 (11.9%)
3 (7.3%)
Delayed
48 hours
14 (14.1%)
10 (16.9%)
4 (10%)
72 hours
22 (22.4%)
14 (24.1%)
8 (20%)
96 hours
23 (23.5%)
16 (27.1%)
7 (17.9%)
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Table 3
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Incidence of acute and delayed nausea and vomiting in patients following cycle 3 of carboplatin containing chemotherapy according to gender Type of emesis
Time points
Overall (%)
Male (%)
Female (%)
Acute
24 hours
2 (4.1%)
1 (3.6%)
1 (4.8%)
Delayed
48 hours
6 (12.8%)
4 (14.3%)
2 (10.5%)
72 hours
7 (14.6%)
4 (14.3%)
3 (15%)
96 hours
8 (16%)
5 (17.2%)
3 (14.3%)
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Author Manuscript 69 64.85 10.38
Std Dev
24 (38.71)
38 (61.29)
N
Current
N (%)
30 (43.48)
39 (56.52)
No emesis
Mean
Never/Former
N (%)
Male Female
N (%)
Level
N (%)
Statistics
9.88
64
30
5 (17.24)
24 (82.76)
10 (33.33)
20 (66.67)
Moderate-severe emesis
0.704
0.041
0.344
Parametric P-value*
The parametric p-value is calculated by ANOVA for numerical covariates and chi-square test for categorical covariates.
*
Age
Smoking status
Gender
Covariate
incidence
Risk factors for delayed nausea and vomiting following cycle 1 of carboplatin containing chemotherapy based on univariate analysis
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Table 4 Waqar et al. Page 12
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Table 5
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Breakthrough anti-emetic use among patients following cycle 1 of carboplatin containing chemotherapy Breakthrough Anti-emetic
Frequency
Cumulative frequency
Lorazepam
2
2
Lorazepam and prochlorperazine
1
3
Prochlorperazine
13
16
Prochlorperazine and metoclopramide
1
17
Metoclopramide
2
19
Dexamethasone
1
20
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Acta Oncol. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Acta Oncol. 2016 June ; 55(6): 700–704. doi:10.3109/0284186X.2016.1154603.
Delayed nausea and vomiting from carboplatin doublet chemotherapy Saiama N. Waqar, MBBS, MSCI1, Janelle Mann, PharmD2, Maria Q. Baggstrom, MD1, Muhammad Atif Waqar, MBBS3, Pooja Chitneni, MD4, Kristina Williams, BS1, Feng Gao, MD, PhD5, Daniel Morgensztern, MD1, and Ramaswamy Govindan, MD1 1Division
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of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
2Department
of Pharmacy Practice, Saint Louis College of Pharmacy, St. Louis, MO
3Department
of Internal Medicine, University of Nevada School of Medicine, Reno, NV
4Department
of Hospitalist Medicine, New York Presbyterian Hospital, New York, NY
5Department
of Surgery, Washington University School of Medicine, St. Louis, MO
Abstract
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Background—Delayed nausea and vomiting following administration of carboplatin containing chemotherapy regimen remains a clinically significant problem for patients with cancer despite administration of standard antiemetic prophylaxis comprising of a 5-HT3 antagonist and dexamethasone. We performed a prospective study to define the incidence and risk factors for delayed chemotherapy induced nausea and vomiting (CINV). Methods—Previously untreated patients with newly diagnosed cancer scheduled to receive carboplatin containing chemotherapy (AUC 5 or above), but no prophylactic aprepitant were enrolled in the study. The primary endpoint was the incidence of delayed CINV after cycle 1 of chemotherapy. Secondary endpoints included the incidence of CINV with the third chemotherapy cycle and gender differences in incidence of CINV. Patients completed the Functional Living Index Emesis (FLIE) questionnaires 24, 48, 72 and 96 hours after receiving chemotherapy. Telephone interviews were conducted 24–48 hours following chemotherapy to assess the severity and need for breakthrough medications for CINV.
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Results—Between December 2006 and July 2009, 105 patients were enrolled onto this study. Delayed emesis following cycle 1 of carboplatin was observed in 30% of patients. Of these, 14.1%, 22.4% and 23.5% of patients described CINV at 48 hours, 72 hours, and 96 hours respectively. The incidence of delayed CINV following cycle 3 dropped to 12.8%, 14.6% and 16% of patients at 48 hours, 72 hours and 96 hours respectively. No differences were observed in the incidence of CINV between men and women. A total of 20% of patients required use of breakthrough antiemetics with cycle 1.
Corresponding author: Ramaswamy Govindan, M.D, Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid, Box 8056, St Louis, MO 63110, Telephone: 314 362 5737, Fax: 314 362 3895, [email protected].
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Conclusions—Without prophylactic aprepitant administration, 30% of patients receiving carboplatin containing regimen had moderate to severe delayed CINV. Keywords carboplatin; emesis; vomiting; delayed nausea; FLIE
INTRODUCTION
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Nausea and vomiting are among the most distressing side effects of chemotherapeutic agents. Inadequately controlled chemotherapy-induced nausea and vomiting (CINV) can lead to dehydration, electrolyte imbalances and malnutrition, which can jeopardize patient willingness to continue chemotherapy.(1, 2) The incidence of CINV varies by chemotherapeutic agent, with drugs such as cisplatin classified as highly emetogenic with CINV rates greater than 90%. CINV with moderately emetogenic agents can vary from 30% to 90%. Carboplatin falls in the higher range of moderately emetogenic chemotherapy. Other reported risk factors for CINV include younger age, female gender, emesis gravidarum, prior history of CINV, motion sickness, and sporadic alcohol use.(2, 3)
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CINV is described as acute if it observed within the first 24 hours following chemotherapy administration, and delayed if seen after 24 hours. Delayed CINV peaks 48–72 hours following chemotherapy and subsides over the next 2 to 3 days.(4) As a result of effective prophylactic antiemetic combinations of 5-hydroxytryptamine type 3 (5HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists and corticosteroids, CINV rates with highly emetogenic chemotherapy has dropped to 30%.(5, 6) Current guidelines support the use of 5HT3 receptor antagonists and corticosteroids for moderately emetogenic agents, plus or minus NK1 receptor antagonists, as data supporting the use of all three antiemetics together is scant. Carboplatin is a platinum salt which cross-links deoxyribose nucleic acid (DNA), and is routinely used for the treatment of solid tumors, as an alternative to cisplatin due to favorable toxicity profile. Data regarding the incidence and severity of CINV with carboplatin are limited, as is its impact on quality of life.(7, 8) Therefore the optimal prophylactic antiemetic combination for use with carboplatin remains undefined. We therefore performed a prospective observational study to determine the incidence, severity and risk factors for delayed CINV following the administration of carboplatin doublet chemotherapy.
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PATIENTS AND METHODS Patient Selection and Eligibility This study was approved by Washington University School of Medicine Institutional Review Board and all study participants provided written informed consent for participation. This study was a prospective, observational trial conducted between December 2006 and July 2009. The study population included patients over the age of 18 with newly diagnosed, histologically or cytologically proven cancer, who were scheduled to receive chemotherapy Acta Oncol. Author manuscript; available in PMC 2017 June 01.
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with carboplatin at AUC 5 or above. Eligible patients received standard antiemetic prophylaxis prior to carboplatin, defined as 5-HT3 antagonist and dexamethasone. At the time of study enrollment the standard antiemetics at our institution involved ondansetron 32 mg IV or palonosetron 0.25 mg IV in combination with dexamethasone 10 or 20 mg IV on day 1 of chemotherapy. Patients were ineligible if they received aprepitant as part of their prophylactic antiemetic regimen. Patients who had received prior cytotoxic chemotherapy within the last 5 years were also excluded, as were patients who were pregnant. Assessment of Delayed Nausea and Vomiting
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Nausea and vomiting were defined as “acute” if occurred within the first 24 hours after carboplatin administration, and “delayed” if observed after 24 hours and assessed up to 96 hours after chemotherapy. The Functional Living Index –Emesis (FLIE) standardized questionnaire was given to each patient during their scheduled clinic visit prior to their first and third cycle of carboplatin. This self-administered questionnaire captured the incidence and severity of nausea and vomiting in the preceding 24 hours. Patients completed the questionnaire 24 hours after carboplatin administration to determine symptoms of acute chemotherapy induced nausea and vomiting, and at the following time points to record incidence and severity of delayed nausea and vomiting: 48 hours, 72 hours, and 96 hours. A trained clinical research associate (CRA) explained the instructions to complete the questionnaire to the patient.
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The FLIE questionnaire has 18 questions divided into two categories: Nausea (questions 1– 9) and Vomiting (questions 10–18). Each of these questions was answered using a 100-mm (1 to 7 points) visual analog scale (VAS) with anchors to “not at all” and “a great deal” and tick-marks dividing the scale into six equal zones. Questions within the category were weighted equally and totaled to create the category score. The two category scores were then combined to create a total score. Higher scores indicated less impairment on daily life as a result of nausea or vomiting. Based on the total FLIE scores, each patient was assigned to one of the following groups: 1) severe delayed nausea and vomiting (score ≤ 45), 2) moderate delayed nausea and vomiting (score 46–99), and 3) no impact of nausea and vomiting on daily life (score ≥ 100). A FLIE score less than 100 (severe and moderate delayed nausea and vomiting) constituted an emetic episode and was used to calculate the incidence of delayed nausea.
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Patients were sent home with prescriptions for breakthrough antiemetic medications as per physician preference. Patients were also interviewed by a trained clinical research assistant or research nurse over the telephone 24–48 hours following carboplatin administration to assess the severity of delayed nausea and vomiting and to assess the need for any breakthrough antiemetic medications. Breakthrough antiemetics used as well as frequency of use were recorded. Statistical Considerations The goal of this study was to prospectively characterize the incidence and severity of delayed emesis following administration of carboplatin-containing chemotherapy regimens
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despite the appropriate administration of standard 5-HT3 receptor antagonist antiemetic prophylaxis after the first cycle and third cycle of chemotherapy. The primary endpoint was to examine the incidence of delayed nausea and vomiting following cycle 1 of carboplatin administration. Secondary endpoints included examining the incidence of delayed nausea and vomiting following cycle 3 of carboplatin, differences in incidence of emesis by gender, and patterns of use of breakthrough anti-emetic medication use. A relatively large sample size (N=100) was proposed to allow the estimation of the overall incidence of delayed emesis with a less than 5% measurement error. This allowed sufficient numbers for the possible estimations within subgroups, but the study was not powered for subgroup analysis.
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The analysis for this study was primarily descriptive. Demographic and clinical characteristics of the sample, occurrence and severity of the delayed emesis, as well as numbers of emetic episodes and time to the onset of emesis, were summarized using descriptive statistics. The incidence of the emesis (overall and by severity) were calculated for both cycle 1 and 3 at the following time points: 24, 48, 72 and 96 hours. The overall incidence of delayed nausea and vomiting was described by single patient reports during the study time periods for cycles 1 and 3. Chi-squared test was used to tabulate and compare the difference incidence of delayed nausea and vomiting between male and female participants. A multivariate logistic regression analysis was also fitted to explore the possible associations of other demographic/clinical characteristics to the overall incidence of delayed emesis.
RESULTS Patient characteristics
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Between December 2006 and July 2009, 105 patients were enrolled onto this study. Of these participants, 99 patients completed cycle 1 FLIE questionnaires, while only 50 completed cycle 3 FLIE questionnaires. The patient characteristics are listed in Table 1. Of the patients enrolled, 62 were male and 43 were female with a median age of 64.8 years. The majority of patients were Caucasian (83/105, 79%), followed by African American (19/105, 18%), Native American or Alaskan Nation (2/105, 2%), and Asian (1/105, 1%). Seventy-nine percent of the patients were diagnosed with non-small cell lung cancer. The remaining 21% of the patients had the following tumors: small cell lung cancer 6.7%, esophageal 6.7%, melanoma 1.9%, mesothelioma 4.8%, and transitional cell 1.0%. The majority of the patients had stage III and IV disease (21.6% and 72.7% respectively). In terms of smoking status, 33% of the patients were current smokers while 61% were former smokers and 6% had never smoked. Incidence of nausea and vomiting following cycle 1 of carboplatin
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The mean FLIE score for patients following cycle 1 were 118.8 (standard deviation/SD12.2), 116.6 (SD 14.9), 112.8 (SD 19.3) and 111.3 (SD 23.1) at 24, 48, 72 and 96 hours respectively. A total of 30 patients reported delayed CINV at any time point following chemotherapy up to 96 hours during cycle 1. Ten percent of patients described acute nausea and vomiting within 24 hours following carboplatin administration, which was categorized as moderate (FLIE score 46–99). None of the patients had severe (FLIE score ≥ 100) acute CINV. Delayed emesis was observed in 14.1% (moderate), 22.4% (21.4% moderate and 1%
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severe) and 23.5% (18.4% moderate and 4.1% severe) of patients at 48 hours, 72 hours, and 96 hours respectively. Incidence of nausea and vomiting following cycle 3 of carboplatin The mean FLIE score for patients following cycle 3 were 121 (SD 9.1), 115 (SD 22.7), 115.8 (SD 19.7) and 115.5 (SD 20.2) at 24, 48, 72 and 96 hours respectively. A total of 13 patients out of 50 patients described delayed CINV at any time point following chemotherapy and up to 96 hours during cycle 1. Of these, 4.1% described acute emesis within 24 hours following cycle 3 of carboplatin, which was categorized as moderate. Delayed emesis was observed in 12.8%(8.5% moderate and 4.3% severe), 12.4.% (10.4% moderate and 2% severe) and 16% (14% moderate and 2% severe) of patients at 48 hours, 72 hours and 96 hours respectively.
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Differences in Delayed Emesis by Gender and other risk factors
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Use of breakthrough medication for nausea and vomiting
Tables 2 and 3 show the incidence of acute and delayed nausea and vomiting for both men and women, at the time points 24 hours, 48 hours, 72 hours and 96 hours respectively following cycle 1 and cycle 3 of carboplatin. Based on univariate analysis, no differences were observed in the incidence of carboplatin-containing chemotherapy induced emesis between men and women (table 4). Age was not a predictor for moderate-severe emesis in our dataset. Smoking status appeared to be a predictor on univariate analysis with the incidence of chemotherapy-induced delayed moderate to severe emesis being higher in never or former smokers compared to current smokers. However this trend was no longer observed on multivariate analysis. Therefore, no significant clinical predictors for moderate-severe emesis were observed in this dataset.
Table 5 describes the frequency of breakthrough medication for nausea and vomiting in patients following cycle 1 of carboplatin containing chemotherapy. A total of 20/99 (20.2%) patients required use of breakthrough antiemetics. Prochlorperazine was the most commonly used antiemetic (15/20) either alone, or combination with other agents such as lorazepam or metoclopramide.
DISCUSSION
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This prospective study, evaluating the incidence and severity of delayed nausea and vomiting with carboplatin containing regimens, was performed prior to aprepitant being commonly used. Unlike most studies which evaluate breakthrough emesis as a dichotomous variable, we utilized the validated FLIE questionnaire to capture not only the severity of breakthrough emesis, but also its impact on the quality of life.(9–11) This emphasis on patient reported outcomes is a major strength of this study. In addition, the FLIE questionnaire was administered at several time points, and captures date pertaining to the preceding 24 hours, which reduces recall bias. The prophylactic antiemetics administered to patients in this study were uniform, based on our institutional practice.
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Investigating the incidence and severity of emesis with cycle 1 and cycle 3 provided a snapshot of the effectiveness of pharmacologic interventions to manage breakthrough emesis. The reduction in incidence of both acute and delayed emesis with cycle 3 of chemotherapy, compared to cycle 1, reflects the successful use of rescue antiemetics, given that dose reductions in carboplatin were rare. The patient dropout rate of 50% is similar to rates observed in other quality of life studies.(12, 13) It is sobering that even with breakthrough anti-emetic use, delayed emesis was observed in over 12% of patients even with cycle 3, underscoring the importance of better prophylactic antiemetic regimens.
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Following our initial report, a phase II study randomly assigned 134 chemotherapy-naïve Japanese patients with advanced non-small cell lung cancer receiving carboplatin-based chemotherapy to receive standard prophylactic antiemetics (5-HT3 receptor antagonist and corticosteroid) with or without aprepitant.(14, 15) The primary endpoint of this study was to evaluate the complete response rate, defined as no vomiting and no rescue therapy during the 120 hours post-chemotherapy. The study showed trend towards improved emesis control in the aprepitant group compared to the non-aprepitant group (complete response rate 80.3% versus 67.2%, odds ratio 0.50; 95% CI, 0.22–1.10; p = 0.085).(15) Though this benefit of aprepitant did not meet statistical significance, improvement in emesis control remains an issue of importance.
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Several patient-related risk factors for CINV have been described, including younger age, female gender, sporadic alcohol use and prior chemotherapy.(16) The association with smoking observed in our study is interesting, and needs to be explored further. While our study did not specifically aim to evaluate individual risk factors, but rather focus on quality of life measures, we did examine the role of gender, but did not find a significant relationship in our study. Recent randomized studies of aprepitant vs placebo in female Japanese patients receiving carboplatin have shown mixed results regarding efficacy. Tanioka and colleagues demonstrated a numerically higher complete response (no emesis or rescue therapy needed) in the aprepitant group, though this did not meet statistical significance.(17) Yahata and colleagues, on the other hand, did observe a statistically significant improvement in “no vomiting” in the aprepitant group compared to placebo.(18) Further studies are needed to validate the utility of aprepitant with carboplatin-based regimens in other ethnic patient subgroups. Despite the absence of compelling data favoring prophylactic aprepitant use to control emesis with carboplatin, current guidelines list its use as “an option” to help control this feared side effect of chemotherapy.(1, 19)
Acknowledgments Author Manuscript
This publication was supported by the National Cancer Institute of the National Institutes of Health (NIH), Grant Number 1K12CA167540 and the Clinical Translational Science Award (CTSA) program of the National Center for Advancing Translational Sciences at the National Institutes of Health, Grant Number UL1RR024992. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported in part by Cancer Center Support Grant P30 CA91842 and the Clinical Trials Core of the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital in St. Louis, Missouri.
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References
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1. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. The oncologist. 2003; 8(2):187–98. [PubMed: 12697943] 2. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer journal. 2008; 14(2):85–93. 3. Navari RM. Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting--two new agents. The journal of supportive oncology. 2003; 1(2):89–103. [PubMed: 15352652] 4. Kris MG, Gralla RJ, Clark RA, Tyson LB, O’Connell JP, Wertheim MS, et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1985; 3(10): 1379–84. [PubMed: 4045527] 5. Hesketh PJ, Grunberg SM, Herrstedt J, de Wit R, Gralla RJ, Carides AD, et al. Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 2006; 14(4):354–60. [PubMed: 16450086] 6. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1997; 15(1):103–9. [PubMed: 8996130] 7. du Bois A, Vach W, Kiechle M, Cramer-Giraud U, Meerpohl HG. Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis. Oncology. 1996; 53(Suppl 1):46–50. [PubMed: 8692551] 8. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, 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. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2010; 21(Suppl 5):v232–43. [PubMed: 20555089] 9. Martin AR, Pearson JD, Cai B, Elmer M, Horgan K, Lindley C. Assessing the impact of chemotherapy-induced nausea and vomiting on patients’ daily lives: a modified version of the Functional Living Index-Emesis (FLIE) with 5-day recall. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 2003; 11(8):522–7. [PubMed: 12827483] 10. Martin AR, Carides AD, Pearson JD, Horgan K, Elmer M, Schmidt C, et al. Functional relevance of antiemetic control. Experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant. European journal of cancer. 2003; 39(10):1395–401. [PubMed: 12826042] 11. Schipper H, Clinch J, McMurray A, Levitt M. Measuring the quality of life of cancer patients: the Functional Living Index-Cancer: development and validation. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1984; 2(5):472–83. [PubMed: 6374052] 12. Vandereycken W, Pierloot R. Drop-out during in-patient treatment of anorexia nervosa: a clinical study of 133 patients. The British journal of medical psychology. 1983; 56(Pt 2):145–56. [PubMed: 6882696] 13. Morlino M, Di Pietro G, Tuccillo R, Galietta A, Bolzan M, Senatore I, et al. Drop-out rate in eating disorders: could it be a function of patient-therapist relationship? Eating and weight disorders: EWD. 2007; 12(3):e64–7. [PubMed: 17984632] 14. Waqar MA, Chitneni P, Williams K, Goodgame BW, Gao F, Govindan R, et al. A prospective study on the incidence of delayed nausea and vomiting following administration of carboplatin containing regimens for treatment of cancer without prophylactic aprepitant. ASCO Meeting Abstracts. 2008; 26(15_suppl):20626. 15. Ito Y, Karayama M, Inui N, Kuroishi S, Nakano H, Nakamura Y, et al. Aprepitant in patients with advanced non-small-cell lung cancer receiving carboplatin-based chemotherapy. Lung cancer. 2014; 84(3):259–64. [PubMed: 24746177] 16. Jordan K, Jahn F, Aapro M. Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2015; 26(6):1081–90. [PubMed: 25755107]
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17. Tanioka M, Kitao A, Matsumoto K, Shibata N, Yamaguchi S, Fujiwara K, et al. A randomised, placebo-controlled, double-blind study of aprepitant in nondrinking women younger than 70 years receiving moderately emetogenic chemotherapy. British journal of cancer. 2013; 109(4):859–65. [PubMed: 23860530] 18. Yahata H, Kobayashi H, Sonoda K, Shimokawa M, Ohgami T, Saito T, et al. Efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin. International journal of clinical oncology. 2015 19. van der Vorst MJ, Neefjes EC, Konings IR, Verheul HM. Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 2015; 23(8):2499– 506. [PubMed: 26041480]
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Table 1
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Demographics of patients enrolled on study Variable
Total (%) N=105
Age (Median)
64.8 years
Gender Male
62 (59%)
Female
43 (41%)
Race White
83 (79%)
Black or African-American
19 (18%)
Native American or Alaskan Nation
2 (2%)
Asian
1 (1%)
Tumor Type
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Non-small cell lung
83 (79.0%)
Esophageal
7 (6.7%)
Small cell lung
7 (6.7%)
Mesothelioma
5 (4.8%)
Transitional cell
1 (1.0%)
Stage I
2 (2.3%)
II
3 (3.4%)
III
19 (21.6%)
IV
64 (72.7%)
Smoking Status
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Current
32 (33.0%)
Former
59 (60.8%)
Never
6 (6.2%)
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Table 2
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Incidence of acute and delayed nausea and vomiting in patients following cycle 1 of carboplatin containing chemotherapy according to gender Type of emesis
Time points
Overall (%)
Male (%)
Female (%)
Acute
24 hours
10 (10%)
7 (11.9%)
3 (7.3%)
Delayed
48 hours
14 (14.1%)
10 (16.9%)
4 (10%)
72 hours
22 (22.4%)
14 (24.1%)
8 (20%)
96 hours
23 (23.5%)
16 (27.1%)
7 (17.9%)
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Table 3
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Incidence of acute and delayed nausea and vomiting in patients following cycle 3 of carboplatin containing chemotherapy according to gender Type of emesis
Time points
Overall (%)
Male (%)
Female (%)
Acute
24 hours
2 (4.1%)
1 (3.6%)
1 (4.8%)
Delayed
48 hours
6 (12.8%)
4 (14.3%)
2 (10.5%)
72 hours
7 (14.6%)
4 (14.3%)
3 (15%)
96 hours
8 (16%)
5 (17.2%)
3 (14.3%)
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Author Manuscript 69 64.85 10.38
Std Dev
24 (38.71)
38 (61.29)
N
Current
N (%)
30 (43.48)
39 (56.52)
No emesis
Mean
Never/Former
N (%)
Male Female
N (%)
Level
N (%)
Statistics
9.88
64
30
5 (17.24)
24 (82.76)
10 (33.33)
20 (66.67)
Moderate-severe emesis
0.704
0.041
0.344
Parametric P-value*
The parametric p-value is calculated by ANOVA for numerical covariates and chi-square test for categorical covariates.
*
Age
Smoking status
Gender
Covariate
incidence
Risk factors for delayed nausea and vomiting following cycle 1 of carboplatin containing chemotherapy based on univariate analysis
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Table 4 Waqar et al. Page 12
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Table 5
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Breakthrough anti-emetic use among patients following cycle 1 of carboplatin containing chemotherapy Breakthrough Anti-emetic
Frequency
Cumulative frequency
Lorazepam
2
2
Lorazepam and prochlorperazine
1
3
Prochlorperazine
13
16
Prochlorperazine and metoclopramide
1
17
Metoclopramide
2
19
Dexamethasone
1
20
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