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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 92-96

Prevalence of breakthrough chemotherapy-induced nausea vomiting in patients on highly emetogenic chemotherapy: A Single-center observational study


Department of Medical Oncology, State Cancer Institute, Gauhati Medical College, Guwahati, Assam, India

Date of Submission06-Jun-2021
Date of Decision16-Jul-2021
Date of Acceptance04-Oct-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Hitesh Deka
Department of Medical Oncology, State Cancer Institute, Gauhati Medical College, Guwahati - 781 032, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_22_21

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  Abstract 


Introduction: Chemotherapy-induced nausea and vomiting (CINV) is a distressing side-effect of cancer chemotherapy which may lead to noncompliance with treatment or delay in treatment. Breakthrough nausea and vomiting is the current unmet need in the management in of CINV. Objectives: The present study was planned to determine the prevalence of breakthrough CINV in patients on highly emetogenic chemotherapy (HEC) and to evaluate the need for rescue medications in them. Materials and Methods: The present observational study was conducted on chemotherapy-naive patients, who were scheduled to receive HEC. The patients who received at least 2 cycles of HEC over a 1-year study period enrolled as a study sample. All patients were subjected to a questionnaire which consists of the demographic details, details of disease and prescribed chemotherapy, and probable risk factors for CINV. The severity of nausea vomiting was calculated using the Multinational Association of Supportive Care in Cancer antiemetic tool. The incidence of breakthrough nausea vomiting was assessed and accordingly the rescue medication was used. Results: A total of 100 patients received at least 2 cycles of HEC which consisted of breast carcinomas (n = 74), ovarian carcinoma (n = 13), lung carcinoma (n = 2), periampullary carcinoma (n = 3), sarcoma (n = 4), lymphoma (n = 3), and seminoma (n = 1). Anthracycline-cyclophosphamide combination for breast cancer was the most prescribed chemotherapy regimen. Forty-six patients developed breakthrough nausea/vomiting. Domperidone followed by olanzapine was the preferred rescue medications used. History of CINV in previous cycle and young age (<50 years) were the risk factors associated with breakthrough nausea vomiting in our study. Conclusion: Breakthrough nausea vomiting is a major challenge in patients receiving HEC regimen.

Keywords: Antiemetics, cancer chemotherapy, nausea and vomiting


How to cite this article:
Lokkur PP, Mahanta N, Kalita NK, Deka H, Kutum N, Ray A. Prevalence of breakthrough chemotherapy-induced nausea vomiting in patients on highly emetogenic chemotherapy: A Single-center observational study. Oncol J India 2021;5:92-6

How to cite this URL:
Lokkur PP, Mahanta N, Kalita NK, Deka H, Kutum N, Ray A. Prevalence of breakthrough chemotherapy-induced nausea vomiting in patients on highly emetogenic chemotherapy: A Single-center observational study. Oncol J India [serial online] 2021 [cited 2022 Jan 21];5:92-6. Available from: https://www.ojionline.org/text.asp?2021/5/3/92/332506




  Introduction Top


Nausea and vomiting are common adverse effects of many cancer chemotherapy regimens. Not only is chemotherapy-induced nausea and vomiting (CINV) a distressing side-effect of cancer chemotherapy but it also has clinical implications in the form of interruption or delay in treatment due to various complications such as dehydration, nutritional deficiencies, and electrolyte imbalances.[1],[2] Without appropriate antiemetic prophylaxis, around 70%–80% of all cancer patients experience CINV.

CINV was a source of major concern in the 1970s and 1980s due to the lack of effective antiemetics.[3] Corticosteroids were first shown to be efficacious for CINV in the 1980s, and they are now considered a mainstay of antiemetic regimens for the prevention of acute and delayed emesis.[4] Even patients with potentially curable diseases opted to discontinue chemotherapy till around 1990s and 2000s which is when 5-hydroxytryptamine-3 (5HT3) receptor antagonists and neurokinin1 (NK1) receptor antagonists were introduced into clinical practice. Ondansetron was the first US Food and Drug Administration-approved 5-HT3 antagonist in 1991 and currently, four 5-HT3 receptor antagonists are in use, for example, ondansetron, granisetron, dolasetron, and palonosetron. Palonosetron, the newest agent, was approved in 2003.[5] NK1 receptor antagonists inhibit substance P in peripheral and central emetic pathways and currently there are 3 recommended NK1 receptors antagonists in use such as aprepitant, fosaprepitant, and neutipitant.[6]

Treatment-related factors, such as the type of chemotherapy, dosage of the chemotherapeutic agents used, and scheduling and route of administration, are fundamentally responsible for the risk of developing CINV. However, patient-related risk factors, such as sex, age, prior history of CINV, emesis during pregnancy or motion sickness, alcohol use, tumor burden, anxiety, concomitant medication and medical conditions, and inadequate hydration, should not be underestimated.[1],[7] Antiemetic guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and Multinational Association for Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) classify chemotherapeutic agents as having high, moderate, low or minimal risk of inducing CINV. Without CINV prophylaxis, highly emetogenic chemotherapy (HEC) induces vomiting in >90% of patients and moderately emetogenic chemotherapy (MEC) in 30%–90%. CINV is further categorized according to timing: Acute, delayed, anticipatory and breakthrough.[2],[8],[9]

Breakthrough CINV is described as nausea and/or vomiting that occurs, despite the use of guideline-directed antiemetic prophylaxis, within 5 days of chemotherapy.[2] Guidelines currently being used in our day-to-day clinical practice give little emphasis on breakthrough CINV due to lack of evidence from large scale, prospective randomized studies.[10] The general principle of managing breakthrough CINV is to administer an additional, as-needed antiemetic agent from a drug class different from that of the agents used in the original prophylactic regimen. Intravenous fluids, as well as dexamethasone, may also be used to manage breakthrough CINV.[11]

Although the North Eastern region of India carries some of the highest burdens of cancers in the world, there is limited scientific data regarding CINV available from this region. The present study aims to determine the prevalence of breakthrough CINV in our set of patients on HEC and evaluate the need for rescue medications after routine antiemetics in patients receiving HEC.


  Materials And Methods Top


The present study was a hospital based prospective observational study carried out in a tertiary care cancer institute at Guwahati from September 2019 to August 2020. The adult patients who were scheduled to receive HEC regimen and were willing to participate in the study were evaluated. The institutional ethics committee approved the study vide letter number: SCI/ECR/2020/01. Patients who received at least 2 cycles of HEC in the current regimen, and must not have received any previous lines of chemotherapy in the past were included as study sample. Various HEC regimens were used for different types of malignancies. Anthracycline-cyclophosphamide (AC) regimen consisted of Adriamycin 60 mg/m2 plus Cyclophosphamide 600 mg/m2. EC regimen consisted of Epirubicin 100 mg/m2 plus Cyclophosphamide 600 mg/m2. FEC90 regimen consisted of 5-Flurouracil 600 mg/m2 plus Epirubicin 90 mg/m2 plus Cyclophosphamide 600 mg/m2. VAC regimen consisted of Vincristine 1.5 mg/m2 plus Doxorubicin 70 mg/m2 plus cyclophosphamide 600 mg/m2. Pacli-Carbo regimen consisted of Paclitaxel 175 mg/m2 plus Carboplatin area under curve (AUC) 5 or 6. Pem-Carbo regimen consisted of Pemetrexed 500 mg/m2 plus Carboplatin AUC 5. All these regimens were administered through intravenous route, and given on day 1 basis. Both EC, FEC90, VAC, Pacli-Carbo, and Pem-Carbo regimens were repeated at 3-weekly intervals whereas AC regimens were repeated at either 2-weekly (dose dense regimen) or 3-weekly intervals. R-CHOP regimen included intravenous administration of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 given on day 1 plus tablet prednisolone 40 mg/m2 on day 1–5 and repeated at 3-weekly intervals. Gem-Cis regimen included intravenous administration of Gemcitabine 1000 mg/m2 plus cisplatin 35 mg/m2 on day 1 and day 8 repeated at 3-weekly intervals. IA regimen included intravenous administration of Ifosfamide 1.8 g/m2 plus doxorubicin 60 mg/m2 on day 1–5 and repeated at 3-weekly intervals. EP regimen consisted of included intravenous administration of Etoposide 100 mg/m2 on day 1–3 plus cisplatin 70 mg/m2 on day 1 and repeated at 3-weekly intervals.

Patients who were expected to have Nausea/Vomiting due to other reasons like biochemical/clinical abnormalities in the form of uremia/azotemia, deranged LFT, neutropenia/sepsis, carcinoma of gall bladder and concurrent radiotherapy were excluded from the study. Carcinoma of gall bladder and concurrent radiotherapy being important cause of nausea and vomiting by itself were excluded from the study. Patients with severe cognitive compromise and known history of central nervous system disease (e.g., brain metastases or a seizure disorder) and also those on treatment with antipsychotic agents, concurrent opioid therapy, sedating or central nervous system–depressing agents were also excluded from the study.

A written informed consent was taken from each patient before enrollment into the study. Patients who attended Day-Care and were scheduled for receiving HEC were given standard 3 drug anti-emetic regimen containing NK1 receptor antagonist (capsule aprepitant 125 mg on Day 1 followed by 80 mg on Day 2 and 3 or injection fosaprepitant 150 mg on day 1) plus 5HT3 receptor antagonist (injection palonosetron 0.25 mg on day 1) plus corticosteroids (dexamethasone 12 mg intravenously on day 1 and 8 mg orally on day 2–4) as per NCCN guidelines version 2.2017 prior to the scheduled chemotherapy.[12] Patients were also given a list of rescue medicines such as ondansetron 8 mg, olanzapine 10 mg or domperidone 10 mg as per standard of care to be taken as monotherapy in case they developed any breakthrough CINV following the HEC. Patients who were subjected to the questionnaire regarding CINV must have had at least two cycles of HEC. Questionnaire consisted of the demographic details, details of disease and prescribed chemotherapy. It also consisted of questions regarding the probable risk factors for CINV like history of CINV in previous cycle and history of motion sickness. The data regarding severity of CINV was collected using MASCC Antiemesis Tool which has a scale from 1 to 10 for expressing the severity of nausea/Vomiting.[13] Patients were also questioned regarding the need for rescue medication. They were also questioned regarding the need for hospital visit/admission for intravenous medication for Nausea/Vomiting or for hydration.


  Results Top


During study period, 109 patients who satisfied inclusion criteria were willing to participate in the study. But 9 patients were excluded as further they did not come for second cycle of chemotherapy. Hence, a total of 100 patients as the study cohort were evaluated.

The study population had a mean age of 47.83 years (range 20–68 years) with a male to female ratio of 1:7.3. Our sample consisted of patients with diverse diseases with majority receiving HEC for carcinoma breast (74%) and carcinoma ovary (13%) among others [Table 1].
Table 1: Distribution of diseases

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Among our group of patients receiving HEC, 63% of them were receiving adjuvant chemotherapy while 28% were receiving neo-adjuvant chemotherapy and rest 9% were receiving pallitative chemotherapy. Breast carcinoma patients received either AC (n = 70), FEC90 (n = 3), or EC (n = 1) regimens. The ovarian carcinoma, lung carcinoma, periampullary carcinoma, and lymphoma patients received Pacli-Carbo, Pem-Carbo, Gem-Cis, and R-CHOP chemotherapy regimens, respectively. Four sarcoma patients received either VAC (n = 3) or IA (n = 1) chemotherapy regimens. One seminoma patient received EP chemotherapy regimen.

In the present study, 46 out of 100 patients receiving HEC developed breakthrough nausea/vomiting. Among these breakthrough CINV patients, 29 (63.1%) had only nausea with no vomiting as compared to 17 patients (37%) who experienced both.

Among the 46 patients with breakthrough CINV, 24 (52.2%) of them had experienced similar problems in their previous cycle indicating that history of CINV in previous cycle can be a potential predicting factor for breakthrough CINV in the subsequent cycles. However only 9 of them (19.6%) had history of motion sickness.

Analysis using Chi-square test determined that there was a statistically significant correlation between breakthrough CINV and history of CINV in previous cycle (P = 0.012). However, in our study population there was no correlation between history of motion sickness and Breakthrough CINV [Table 2].
Table 2: Correlation of breakthrough chemotherapy induced nausea and vomiting with history of chemotherapy induced nausea and vomiting in previous cycle, history of motion sickness and gender

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Other probable predicting factors like gender and age of the patient were also evaluated in the present study. 5 out of the 46 patients with breakthrough CINV were males. A Chi square test revealed no statistical significance in the correlation with gender and Breakthrough CINV (P = 0.748) [Table 2].

Further analysis revealed that 32 out of 46 patients having CINV (69.6%) were below the age of 50 years, indicating that younger age group may be associated with higher breakthrough CINV. In the univariate analysis using the logistic regression model, a statistically significant correlation was found between younger age and Breakthrough CINV (estimate = −0.056, standard error = 0.022, P = 0.011) [Table 3].
Table 3: Correlation between history of breakthrough chemotherapy induced nausea and vomiting and age

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In a multivariate logistic regression model to evaluate the correlation of risk of breakthrough CINV with various factors like age, gender, history of motion sickness and history of CINV in previous cycle, the only variable that was found significant was history of CINV in previous cycle (standard error = 0.663, P < 0.001).

The details of breakthrough CINV as obtained using the questionnaire revealed that 60.9% (n = 28) of patients developed nausea/vomiting between day 2 and 3 of chemotherapy while 21.7% (n = 10) and 17.4% (n = 8) developed breakthrough CINV on day 1 and day 4–5 respectively.

The severities of nausea as experienced by the patients were recorded on a scale for nausea ranging from 0 to 10. Among the 46 patients with breakthrough CINV, 15 of them had a score of 6–7 and 3 of them had a score of 10 indicating severe nausea [Figure 1].
Figure 1: Severity of nausea according to multinational association of supportive care in cancer antiemetic tool

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84.8% patients (n = 39) with breakthrough CINV had symptoms severe enough to warrant the need for rescue medication and Rest 7 out of 46 patients did not require rescue medication. 23.9% (n = 11) of patients even required hospital visit or admission for intravenous hydration.

The rescue medications used in our study population were domperidone (n = 18; 39.1%) followed by olanzapine (n = 16; 34.8%) and ondansetron (n = 5; 10.9%) and these medications are used as monotherapy not as combination [Table 4]. Olanzapine was used at a dose of 10 mg day 1 to day 4 however side effects of olanzapine were not studied in this study.
Table 4: Patients requiring rescue medications

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  Discussion Top


Nausea and vomiting are the most frequently reported adverse effects of antineoplastic chemotherapy and significantly affect patient's daily functioning and health-related quality of life.[14] Substantial improvements have been made in the prevention of CINV. However, despite the use of CINV prophylaxis as per standard recommendation, many patients continue to experience nausea and/o r vomiting following chemotherapy adminstration.[15] Patients who have an electrolyte imbalance or those who have recently undergone surgery or radiation therapy are at greater risk of experiencing serious complications from CINV.[16],[17]

A study conducted by the CINV Study Group of Japan showed that 943 out of the 1910 (49.4%) patients on highly emetogenic and MEC, experienced breakthrough nausea and vomiting.[10] Another study conducted by Jones et al. on 96 patients receiving HEC and MEC, reported that 41% of the patients developed breakthrough CINV requiring treatment.[18] In line with the results from the above studies, our study showed that 46% of the patients receiving HEC developed breakthrough CINV.

A study conducted in 2014 for determining potential risk factors for CINV in general showed that the key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and history of CINV in earlier cycles (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway.[19] Our study analyzed probable predictive factors for development of Breakthrough CINV and found that there was a higher probability of developing Breakthrough CINV in younger patients and those with history of CINV in previous cycle.

The study published by Tamura et al., showed that around 32% of their patients developed Breakthrough CINV on Day 1, 20% on Day 2 and 19% on Day 3 after chemotherapy.[10] The present study showed that 21.7% developed CINV on Day 1, 60.9% between Day 2 and 3 of chemotherapy.

According to Tamura et al. 44% of the patients who developed Breakthrough CINV while on HEC and MEC required rescue medications.[10] However, the present study is done only on patients receiving HEC showed that 84.8% required rescue medications and 23.9% even required hospital visit/admission for hydration.

The general principle of managing breakthrough CINV is to administer an additional, as-needed antiemetic agent from a drug class different from that of the agents used in the original prophylactic regimen.[11] Intravenous fluids, as well as dexamethasone, may also be used to manage breakthrough CINV. According to the NCCN guidelines, the choice of agent should be based on assessment of the preventive antiemetics used for the patient.[2]

In our study, the patients received either domperidone (46.2%) or olanzapine (41%) as rescue medication based on physician's advice and availability. In the study conducted by Tamura et al. in 2016, 86% received metoclopramide or domperidone and the rest received either 5HT3 receptor antagonist or antipsychotics.

A recently published comprehensive review article by Navari et al. rightly points out that only one randomized, double-blind Phase III study has been conducted to evaluate the treatment of breakthrough CINV which showed that olanzapine was more effective than metoclopramide in controlling breakthrough nausea and vomiting in patients receiving HEC.[20] The MASCC/ESMO and ASCO Guidelines recommend olanzapine for breakthrough emesis.[8],[9] The NCCN Panel recommends olanzapine (category 1; preferred) for breakthrough emesis if olanzapine was not used on days 1–4 as part of a prophylactic regimen based on the above-mentioned phase 3 trial.[12]


  Conclusion Top


With use of new anti-emetics and recent prophylactic antiemetic guidelines for the prevention of CINV in HEC, the burden of CINV has decreased. However, breakthrough CINV continues to adversely affect patient's quality of life and health care costs. In our study, 46% of the patients developed Breakthrough CINV, among whom 84.8% required rescue medications. This signifies that in spite of use of newer drug combinations like NK1RAs, 5 HT3RAs and Dexamethasone, more potent drugs may be required for prevention of Breakthrough CINV, so that the quality of life of patients undergoing HEC remain unaffected, which would indirectly affect compliance to treatment and overall treatment outcomes.

Limitation of the study

A limitation in our study is that it was conducted on a small sample size of 100 patients. Since the duration and study population was less, further studies with a large number of patients over a larger duration of period may be required.

Acknowledgement

We acknowledge Dr. Anjana Moyee Saikia, Lecturer, Department of Community Medicine, Gauhati Medical College, for helping us in the statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J 2008;14:85-93.  Back to cited text no. 1
    
2.
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Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: A meta-analysis of randomized evidence. J Clin Oncol 2000;18:3409-22.  Back to cited text no. 4
    
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Marty M, Pouillart P, Scholl S, Droz JP, Azab M, Brion N, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990;322:816-21.  Back to cited text no. 5
    
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Schmoll HJ, Aapro MS, Poli-Bigelli S, Kim HK, Park K, Jordan K, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 2006;17:1000-6.  Back to cited text no. 6
    
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Adel N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manag Care 2017;23:S259-65.  Back to cited text no. 7
    
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Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al. Antiemetics: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2017;35:3240-61.  Back to cited text no. 8
    
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Roila F, Warr D, Hesketh PJ, Gralla R, Herrstedt J, Jordan K, et al. 2016 updated MASCC/ESMO consensus recommendations: Prevention of nausea and vomiting following moderately emetogenic chemotherapy. Support Care Cancer 2017;25:289-94.  Back to cited text no. 9
    
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Tamura K, Aiba K, Saeki T, Nakanishi Y, Kamura T, Baba H, et al. Breakthrough chemotherapy-induced nausea and vomiting: Report of a nationwide survey by the CINV Study Group of Japan. Int J Clin Oncol 2017;22:405-12.  Back to cited text no. 10
    
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Navari RM, Roeland EJ. Unscheduled hydrations: Redefining complete response in chemotherapy-induced nausea and vomiting studies. Future Oncol 2020;16:1863-72.  Back to cited text no. 11
    
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Berger MJ, Ettinger DS, Aston J, Barbour S, Bergsbaken J, Bierman PJ, et al. NCCN Guidelines insights: Antiemesis, version 2.2017. J Natl Compr Canc Netw 2017;15:883-93.  Back to cited text no. 12
    
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Hilarius DL, Kloeg PH, van der Wall E, van den Heuvel JJ, Gundy CM, Aaronson NK. Chemotherapy-induced nausea and vomiting in daily clinical practice: A community hospital-based study. Support Care Cancer 2012;20:107-17.  Back to cited text no. 14
    
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Dranitsaris G, Molassiotis A, Clemons M, Roeland E, Schwartzberg L, Dielenseger P, et al. The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting. Ann Oncol 2017;28:1260-7.  Back to cited text no. 15
    
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Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and vomiting continue to reduce patients' quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol 2006;24:4472-8.  Back to cited text no. 16
    
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Navari RM. Management of chemotherapy-induced nausea and vomiting: Focus on newer agents and new uses for older agents. Drugs 2013;73:249-62.  Back to cited text no. 17
    
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Jones JM, Qin R, Bardia A, Linquist B, Wolf S, Loprinzi CL. Antiemetics for chemotherapy-induced nausea and vomiting occurring despite prophylactic antiemetic therapy. J Palliat Med 2011;14:810-4.  Back to cited text no. 18
    
19.
Molassiotis A, Aapro M, Dicato M, Gascon P, Novoa SA, Isambert N, et al. Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: Results from a European prospective observational study. J Pain Symptom Manage 2014;47:839-48.e4.  Back to cited text no. 19
    
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Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013;21:1655-63.  Back to cited text no. 20
    


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