The Pediatric Oncology Group of Ontario (POGO) Guideline for the Prevention and Treatment of Anticipatory Nausea and Vomiting due to Chemotherapy in Pediatric Cancer Patients was developed by health care professionals using evidence-based or best practice references available at the time of its creation. The content of the guideline will change since it will be reviewed and revised on a periodic basis. Care has been taken to ensure accuracy of the information. However, every health care professional using this guideline is responsible for providing care according to their best professional judgement and the policies and standards in place at their own institution.# Health Questions and Recommendations Strength of Recommendation & Level of Evidence
Health Question #1: What approaches are recommended to prevent the development of anticipatory chemotherapy induced nausea and vomiting (CINV) in children?
Recommendation 1.1: Control of acute and delayed CINV should be optimized for each child in order to minimize the risk of the child developing anticipatory CINV.
Remarks : This recommendation places a high value on complete control of CINV across all phases (anticipatory, acute and delayed). It is a strong recommendation because patients who experience CINV control are likely to have an improved quality of life and less distress. Furthermore, use of guideline-informed antiemetic prophylaxis is unlikely to lead to significant adverse effects.

# Strong Recommendation Low Quality Evidence
Health Question #2: What interventions are recommended to control anticipatory CINV in children who develop it?
Recommendation 2.1: We suggest that psychological interventions such as hypnosis or systematic desensitization may be offered to children with anticipatory CINV.
Remarks : This recommendation places a high value on the possible improvement in anticipatory CINV control and the lack of harm conveyed by the recommended interventions. It is a weak recommendation because of concerns regarding the lack of standard and distinct methodologies for many of these interventions, the applicability of the evidence base underpinning the recommendation in patients receiving modern guideline-consistent antiemetic prophylaxis and the additional resources required for its implementation. Systematic desensitization is recommended based on the experience in adults.

# Recommendation 2.2:
We suggest that lorazepam in a dose of 0.04 to 0.08 mg/kg/dose (maximum: 2 mg/dose) once at bedtime the night before chemotherapy and once the next day prior to administration of chemotherapy may be used to prevent or treat anticipatory CINV in children.

# Remarks Weak Recommendation
: This recommendation places a high value on the possible improvement in anticipatory CINV control and the evidence of efficacy of benzodiazepines in adult cancer patients. It is a weak recommendation because direct evidence of lorazepam efficacy at this dose and frequency in children is lacking. Furthermore, there are concerns regarding the applicability of this recommendation to patients receiving modern, guideline-consistent antiemetic prophylaxis.

# Moderate Quality of Evidence
Weak Recommendation Low Quality of Evidence Version Date: April 23,
There is no universally accepted definition of anticipatory chemotherapy-induced nausea and vomiting (CINV). In its broadest definition, it is described as nausea and/or vomiting that occurs at a time other than immediately following chemotherapy administration or during the delayed phases of CINV. Under its most narrow definition, it is described as nausea and/or vomiting that occurs within 12 to 24 hours of planned chemotherapy treatment that is triggered by a treatment-related stimulus and is not attributable to any immediate physiological or pharmacological factors.  Although not explicitly stated, the timeframe for anticipatory CINV evaluation usually ends on administration of the first chemotherapy dose of a treatment cycle. While it may be argued that patients receiving multiple day chemotherapy treatment may experience CINV in anticipation of each day of treatment, this does not seem to have been incorporated into the definition of anticipatory CINV.
Investigators seeking to describe the prevalence of anticipatory CINV have evaluated CINV during different time frames prior to chemotherapy administration; have often focused on either nausea or vomiting but not both; have evaluated patients at different time points during the entire treatment course; and have used different approaches or instruments toward measurement. This variability leads to difficulty in prevalence assessment and reported prevalence rates are wide ranging. In children, the problem is compounded by the use of parent or caregiver report of nausea and, when patient report is used, use of non-validated nausea assessment tools. Ideally, the prevalence of anticipatory CINV, defined narrowly as described above, would be determined after administration of several cycles of chemotherapy therapy given together with guideline-recommended antiemetic prophylaxis using validated nausea assessment tools appropriate for children. Unfortunately, this type of assessment has not been done in children. However, when 5-HT3 antagonists and corticosteroids were administered as antiemetic agents and anticipatory CINV was evaluated longitudinally, anticipatory chemotherapy-induced nausea (CIN) was reported in approximately one-third of adults while anticipatory chemotherapy-induced vomiting (CIV) was reported in 6 to 11%.  This evidence-based guideline for anticipatory CINV prevention and management is presented with the intention of optimizing the control of anticipatory CINV in children receiving chemotherapy. For the purpose of this guideline, optimal anticipatory CINV control is defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for anticipatory CINV prevention or treatment and no nausea-related change in the child's usual appetite and diet. This level of CINV control is to be achieved during the 24 hours prior to administration of the first antineoplastic agent of the upcoming chemotherapy block. This guideline represents the third of a series of guidelines to address the need for, and the selection of, antiemetic prophylaxis and intervention in children with cancer receiving chemotherapy. The first two guidelines, the Guideline for the Classification  The target users of this guideline are all health care providers who care for children (0 to 18 years) with cancer who are receiving chemotherapy and who are at risk of experiencing anticipatory CINV. This guideline is aimed particularly at physicians, nurse practitioners, nurses, and pharmacists working in pediatric oncology centers and satellites in Ontario, Canada where pediatric oncology patients receive care.

# Guideline Development Panel
POGO identified CINV as a key supportive care initiative in 2008 and the POGO CINV Guideline Development Group was formed in December 2008. Members were selected with a view to obtain inter-disciplinary representation from several POGO institutions as well as content expertise. Experts who had published in the area of CINV in children or who had a current research interest in CINV or supportive care in cancer were invited to join the guideline development group. After the completion of the first two POGO guidelines in the CINV series, panel members were asked to confirm their willingness to continue as members of the panel tasked with development of the third guideline in this series. Two members resigned and two new members were recruited.

# Identification and Appraisal of Existing Guidelines
A guideline was sought which could be adapted to the POGO context for the management of anticipatory CINV.
(a) Guideline Search Strategy: During August and September 2012, the POGO CINV Guideline Development Group conducted a search of bibliographic databases and the grey literature to identify existing practice guidelines for the management of anticipatory CINV in children with cancer. Computerized searches were performed with the assistance of a library scientist using the OVID search platform for the Medline and Embase databases. The search engine Google was utilized for identification of grey literature including local, provincial, national and international databases. In addition the panel members reviewed their files for potentially relevant guidelines. The search strategies are provided in Appendix A.
(b) Guideline Selection Criteria and Appraisal: Guidelines were selected for inclusion that: (i) provided recommendations for the management of anticipatory, breakthrough and/or delayed CINV; (ii) were published in 2008 or more recently; and (iii) were published in English. Financial limitations precluded translation of guidelines published in languages other than English. Guidelines were excluded if it was not clear that the guideline statements or recommendations were based on a review of evidence from the literature and/or were not based on a source that used evidence to support the guideline development process. Each guideline identified through the search was independently reviewed and scored by at least two members of the POGO CINV Guideline Development Panel using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument. The domains assessed by this instrument include: scope and purpose; stakeholder involvement; rigor; clarity and presentation; applicability, and editorial independence. The domain scores and overall assessments of each reviewer were aggregated and presented for discussion at a panel meeting held by teleconference. The Rigor of Development quality domain score was emphasized. The AGREE scores are presented in Appendix B. The suitability of each guideline for adaptation using the ADAPTE process  was discussed by the panel. ii. Selection Criteria and Appraisal: Citations were independently screened for relevancy by two reviewers. All citations identified as potentially relevant by either reviewer were included for full-text screening. Two reviewers independently evaluated the full-text papers to determine whether they met the inclusion criteria. Disagreements were resolved by discussion and consensus. Primary studies were included if they: (i) were published in a journal in full text (i.e. abstracts, letters, book chapters and dissertations were excluded); (ii) were published in English; (iii) evaluated an intervention for the prevention or treatment of anticipatory CINV; (iv) reported the proportion of patients experiencing complete control of anticipatory CINV and (v) the number of participants was > 10 per study arm for comparative studies and > 2 overall for non-comparative studies. Financial limitations precluded translation of guidelines published in languages other than English. The minimum number of required subjects in included pediatric studies was lower than that for adult studies in recognition of the smaller evidence base in pediatrics and the likelihood that pediatric studies would involve fewer patients than adult studies. Evidence summary tables were compiled and reviewed by two panel members before consideration by the panel.
(b) Prevalence of anticipatory CINV pre-post use of 5-HT3 antagonists: As several of the prominent adultfocused antiemetic guidelines recommend optimal control of acute CINV to prevent anticipatory CINV, a review of primary studies which evaluated the prevalence of anticipatory CINV in adult and pediatric patients was performed.

# Search Strategy:
The same set of citations identified by the search strategy for the prevention and treatment of anticipatory CINV systematic review was used, as a very broad search strategy was employed to identify anticipatory CINV studies. The search strategies are provided in Appendix C.
ii. Selection Criteria and Appraisal: Citations were independently screened for relevancy by two reviewers. All citations identified as potentially relevant by either reviewer were included for full-text screening. Two reviewers independently evaluated the full-text papers to determine whether they met the inclusion criteria. Disagreements were resolved by discussion and consensus. Studies were included if they were: (i) primary studies that were published in a journal in full text (i.e. abstracts, letters, book chapters and dissertations were excluded); (ii) published in English; (iii) determined the proportion of patients experiencing anticipatory CINV; (iv)the sample size per study arm was 10 subjects for pediatric studies and 20 subjects for adult only or mixed adult/pediatric studies; and (v) the study inclusion criteria did not specifically select for patients with post-chemotherapy CINV. Evidence summary tables were compiled and reviewed by two panel members before consideration by the panel. Version Date: April 23, 2014

# Decision-Making Process for Formulation of the Recommendations
Decisions were taken through panel discussions and any differences in opinion were resolved by consensus. The quality of evidence and strength of recommendations were assessed using the GRADE system  developed by Guyatt et al by one author and confirmed through discussion by the remaining panel members. Descriptions for the strength of recommendations and quality of evidence are provided in Appendix D. If consensus was unable to be reached on any matter, a decision was made by the majority of panel members by a vote.

# Identification and Appraisal of Existing Guidelines
The search for practice guidelines yielded 693 citations that were screened for inclusion. Nine guidelines  that were either developed for use in adults and/or for use in children met the inclusion criteria (Appendix B) and were assessed using the AGREE II instrument.

# Systematic Reviews of Pediatric and Adult Primary Studies
(a) Interventions to prevention and/or treatment of anticipatory CINV: A total of 1586 references were identified from the electronic database search. After removal of 818 duplicates, 768 citations were screened for relevancy. One hundred and thirteen papers were retrieved for full-text screening. Eleven studies met the inclusion criteria (refer to Flowchart 1 in Appendix C).
(b) Prevalence of anticipatory CINV pre-post use of 5-HT3 antagonists: As the search strategy employed to identify primary studies for the systematic review described under (a) was very broad, the same set of citations could be used for this systematic review. The 768 unique citations were screened for relevancy. One hundred and ten papers were retrieved for full-text screening. Fifty studies (reported in 58 papers) met the inclusion criteria (refer to Flowchart 2 in Appendix C). The evidence that informs this recommendation is summarized in Appendices E and F. This recommendation places a high value on complete control of CINV across all phases (anticipatory, acute and delayed). It is a strong recommendation because patients who experience CINV control are likely to have an improved quality of life and less distress.  Furthermore, use of guideline-informed antiemetic prophylaxis is unlikely to lead to significant adverse effects.
Anticipatory CINV appears to be a conditioned response to CINV experienced in the acute and delayed phases.  The anxiety and distress attendant to CINV may serve to reinforce the conditioned response.  It follows, therefore, that a higher rate of complete acute and delayed CINV control would result in lower rates of anticipatory CINV. Acute CINV control in children remains sub-optimal even when guideline-recommended antiemetic prophylaxis is provided.  It is therefore likely that children continue to experience anticipatory CINV. However, the available studies evaluating acute and delayed CINV control as a risk factor for anticipatory CINV in children are few and are contradictory.
In a cross-sectional study in 149 adult and pediatric cancer patients, Cohen et al evaluated the relationship between anticipatory CINV and a number of variables including nausea and vomiting that occurred during or after a chemotherapy block.  At the time of the study, patients had received an average of 16 drug treatment blocks (range: 2 to 86). Forty-two percent and 27% reported anticipatory nausea or vomiting, respectively. Anticipatory CINV was associated with poorer control of post-treatment CINV (p<0.001). On the other hand, Tyc et al found no difference in the reported severity of post-treatment CINV and anticipatory CINV in a crosssectional study of 59 children receiving chemotherapy who were from 3 to 21 months from diagnosis.  One quarter of the patients in this study experienced anticipatory nausea alone; 9% reported anticipatory vomiting alone and 66% reported both anticipatory nausea and vomiting.
Since acute CINV control has improved with the availability of 5HT3 antagonists, a comparison of the prevalence of anticipatory CINV before and after the introduction of these agents to clinical care may provide indirect evidence of a link between acute CINV control and risk of anticipatory CINV. A single study has evaluated this question. Morrow et al conducted a longitudinal study in 2 sub-groups of adults who participated in a larger study which required evaluation of nausea and vomiting severity over at least 4 chemotherapy blocks.  No patient in the first group (0/300) received 5HT3 antagonists during the acute phase while most patients in the second group (257/300; 86%) did. The frequency of acute chemotherapy-induced nausea (CIN) was identical in both groups (79%); the frequency of acute chemotherapy-induced vomiting (CIV) was lower in the group who received 5HT3 antagonists (55 vs 43%; p=0.004). The frequency of anticipatory CINV was not different between these groups (CIN: 31 vs 32%; CIV: 8 vs 6%). Since the complete antiemetic prophylaxis provided to patients in this study is not provided, it is not possible to extrapolate these results to patients who receive optimal antiemetic prophylaxis as recommended by evidence-based guidelines. Nevertheless, the authors speculate that their findings may be result of the lack of improvement in CIN control provided by 5HT3 antagonists.
Studies which evaluate the prevalence of anticipatory CINV in adult patients who received treatment before and after 5HT3 antagonists were available are summarized in Appendix F. Study design, sample size, populations and prophylactic antiemetic regimens vary widely. In addition, study endpoints and the level of acute CINV prophylaxis provided are often not explicitly stated. Thus, given the heterogeneity of studies, synthesis of these studies in a meta-analysis was not possible.
In the pre-5HT3 antagonist era, the reported prevalence of anticipatory CIN in adults ranged from 9%  to 65%  while that of anticipatory CIV ranged from 0%  to 33%.  In each study where the prevalence of both CIN and CINV were reported, the prevalence of CIN was higher than CIV. In the post-5HT3 antagonist era, Version Date: April 23, 2014
the reported prevalence of anticipatory CIN in adults ranged from 6%  to 43%  while that of anticipatory vomiting ranged from 4%  to 11%  Again, the reported prevalence of CIN was always higher than the prevalence of CIN. Thus, these studies describe widely overlapping ranges for the prevalence of anticipatory CIN and CIV in the post-5HT3 antagonist era compared to the pre-5HT3 antagonist era.
Pediatric studies which describe the prevalence of anticipatory CINV (Appendix E) vary not only in the features listed earlier with respect to adult prevalence studies but also in the methods used to evaluate the presence or severity of nausea. Of the 11 available pediatric studies, nausea severity was determined by child or parent report in 5,  child report in 4,  by child, parent or nurse report in 1  and by parent or guardian report in 1.  None of the studies where the child reported the severity of their nausea used a validated pediatric nausea assessment tool. The pediatric studies are also limited by their small sample size. The median sample size of these studies was 52 (range: 19 to 150).
One group of investigators has evaluated anticipatory CINV in children in the pre-5HT3 antagonist era. Dolgin et al reported anticipatory CIN in 29% of children (23/80) and anticipatory CIV in 20% (16/80) who had received 11 cycles of chemotherapy, on average, before evaluation.  The same investigators observed anticipatory CINV in 13% (12/94) in another group of children 7 months after diagnosis.  In the post-5HT3 era, the reported prevalence of anticipatory CIN reported in children ranged from 0%  to 59%.  Similar to observations in adult patients, the reported prevalence of CIN was always higher than that of CIV with one exception. Stockhorst et al report an equivalent prevalence (26%; 5/19) of CIN and CIV.  On review of the reported prevalence rates, it is not clear that the use of 5HT3 antagonists and the presumed resulting improvements in acute CINV control have led to improved control of anticipatory CINV. However, the inconsistent approach to measurement of anticipatory CIN and CIV and the use of unvalidated instruments preclude the comparison of results across studies. Further, these studies did not directly evaluate the relationship between acute CINV control itself and anticipatory CINV control. The applicability of the results of these studies to patients receiving modern, guideline-informed antiemetic prophylaxis is also unclear. In particular, dexamethasone was often not given to patients receiving highly emetogenic chemotherapy. The guideline development panel members were therefore unsure of the strength of the relationship between anticipatory CINV control and acute CINV control in the setting of modern, guideline-informed antiemetic prophylaxis.
Given that anticipatory CINV appears to be a conditioned response, the guideline development panel recommends that the control of acute and delayed CINV be optimized for each child to avoid exposure to the negative stimulus required for conditioning to occur. Adherence to evidence-based guideline recommendations regarding CINV prevention has been shown to substantially improve complete acute CINV control.  The guideline development panel therefore recommends that clinicians select antiemetic interventions using guidelines such as the POGO Guideline for the Prevention of Acute AINV in Children Receiving Antineoplastic Agents  for chemotherapy agent-naive patients. Once chemotherapy has been initiated, the selection of antiemetic interventions should be guided by evidence-based guidelines, the extent of CINV control experienced by the patient as well as any adverse effects associated with antiemetic agents.

# (b) Recommendations of Clinical Practice Guidelines aimed at adult cancer patients:
Our recommendation is consistent with recommendations regarding the prevention of anticipatory CINV in adult cancer patients (Table 1), which all support the application of the most effective antiemetic interventions to prevent CINV throughout all phases of CINV. None of the guidelines aimed at adult cancer patients provide a fully supported rationale for their recommendations. Use of the most active antiemetic regimens appropriate for the chemotherapy being administered to prevent acute or delayed emesis is suggested. Such regimens should be used with initial chemotherapy, rather than assessing the patient's emetic response with less effective treatment.
MASCC/ESMO Antiemetic Guideline  The best approach for anticipatory emesis is the best possible control of acute and delayed emesis.

# NCCN Antiemesis Guideline
Prevention: Use optimal antiemetic therapy during every cycle of treatment  The evidence that informs this recommendation is summarized in Appendix G. Recommendation 2.1 places a high value on the possible improvement in anticipatory CINV control and the lack of harm conveyed by the recommended interventions. It is a weak recommendation because of concerns regarding the lack of standard and distinct methodologies for many of these interventions, the applicability of the evidence base underpinning the recommendation in patients receiving modern guideline-consistent antiemetic prophylaxis and the additional resources required for its implementation. Systematic desensitization is recommended based on the experience in adults. Recommendation 2.2 places a high value on the possible improvement in anticipatory CINV control and the evidence of efficacy of benzodiazepines in adult cancer patients. It is a weak recommendation because direct Version Date: April 23, 2014

# Evidence Summary and Discussion
evidence of lorazepam efficacy at this dose and frequency in children is lacking. Furthermore, there are concerns regarding the applicability of this recommendation to patients receiving modern, guideline-consistent antiemetic prophylaxis.
Two pediatric and 9 adult studies met the inclusion criteria and were included in the evidence base that informed the recommendations formulated by the panel. In keeping with the theory that anticipatory CINV is a conditioned response to CINV experienced in the acute and delayed phases, the majority of these studies (8/11) evaluated behavioral therapies. Hypnosis was the most common behavioral intervention (4/8) evaluated.
Hypnosis: Hypnosis has been defined as an intervention that "provides suggestions for changes in sensation, perception, cognition, affect, mood, or behavior".  One small case series has described anticipatory CINV control in adult cancer patients who received hypnosis before 2 to 5 antineoplastic treatments.  Complete control of anticipatory CINV was observed in all patients when hypnosis was used.
Interestingly, the 2 randomized trials of interventions aimed at controlling anticipatory CINV were both pediatric trials and both evaluated hypnosis.  Zeltzer et al recruited 54 children aged 5 to 17 years who had reported experiencing anticipatory CIN and/or CIV in a previous study and who were about to receive at least 2 identical antineoplastic treatment courses.  On average, children were 15.8 months (range: 0.5 to 118 months) from their cancer diagnosis at the time of the study. The control group had received antineoplastic therapy for much longer than the other 2 groups (29.5 months vs 8 or 11.5 months). Although it is not possible to precisely ascertain the emetogenicity of the antineoplastic therapy that children received, it appears that most received highly emetogenic treatment as assessed by the POGO Guideline for Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients.  The antiemetic agents received for CINV prophylaxis were not reported but children's antiemetic regimens were unchanged during the trial. CINV severity was assessed during semi-structured interviews of the child. Jacknow et al  chose to evaluate hypnosis as a means of preventing anticipatory CINV in 20 children 6 to 18 years old who were naive to chemotherapy. Controls were matched for age ( 3 years) and the emetogenicity of their antineoplastic treatment. Insufficient information is available to determine the emetogenicity of the chemotherapy regimens using the POGO Guideline for classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients.  Children randomized to receive hypnosis did not receive antiemetic prophylaxis but received antiemetic agents as needed. Children in the control group received standard antiemetic prophylaxis for 4 to 6 hours after antineoplastic therapy. Standards for antiemetic prophylaxis changed over the course of the study recruitment period: ondansetron was given to more children in the control group (7/10 vs 3/10). Children randomized to receive hypnosis were taught self-hypnosis during the initial chemotherapy treatment; children in the control group spent equivalent time in conversation with a therapist. CINV was assessed by means of a daily structured interview of the child. The presence of anticipatory CINV was assessed at 1-2 months, and at 4-6 months after diagnosis.
At the time of first assessment of anticipatory CINV, children who had been taught self-hypnosis reported significantly less anticipatory CIN than did the control group although the incidence is not reported. The rate of anticipatory CIV was identical in each group (1/10). By the time of the second assessment, there was no difference in the rate of anticipatory CIN between the groups. The rate of anticipatory CIV was also similar between the groups (hypnosis: 0/10 vs control: 2/10). Version Date: April 23,
Systematic desensitization: Systematic desensitization is a strategy where the conditioned behavior is thought to be reciprocally inhibited by a state of induced progressive muscle relaxation. Three small trials (2 randomized trials) in adults who had experienced anticipatory CINV prior to study enrollment have evaluated the use of systematic desensitization in the form of counter-conditioning of the anticipatory CINV symptoms or triggers to standardized, progressive deep muscle relaxation.  In each of these studies, systematic desensitization was associated with a significantly higher rate of complete anticipatory CINV control compared to interventions such as relaxation alone, counselling or usual care.
Relaxation training: Relaxation training alone has also been evaluated as an anticipatory CINV treatment intervention in a randomized trial in adults.  Overall, relaxation training did not influence the incidence of anticipatory CIN before the third chemotherapy treatment course of the study period regardless of the coping style of the patients (distraction-oriented vs information-gathering).
Relaxation training and hypnosis: Marchioro et al have described the cases of 16 adult cancer patients with anticipatory CINV who were treated with a combination of hypnosis and relaxation training.  All patients had complete control of anticipatory CIV; no patient had more than mild nausea.
Pharmacological interventions: Pharmacological interventions that have been evaluated for the treatment of anticipatory CINV are few and are limited to benzodiazepines. No pediatric trials of the use of pharmacological treatments of anticipatory CINV that met our criteria for inclusion were identified. Three studies in adults (2 randomized trials) have evaluated the contribution of benzodiazepines as a treatment of anticipatory CINV.  Since patients who experience anticipatory CINV have been observed to be more anxious than patients who do not experience anticipatory CINV, the use of anxiolytic agents in this setting seems reasonable in this setting.  Lorazepam 2mg by mouth the night before chemotherapy treatment, the morning of treatment and at bedtime for the next 5 days or placebo was given to adult cancer patients over 180 chemotherapy treatment courses containing cisplatin.  Patients also received metoclopramide 2mg/kg/dose, clemastine and dexamethasone for antiemetic prophylaxis. At the time of randomization, approximately two-thirds of patients were naive to chemotherapy. Anticipatory CINV was defined as nausea and/or vomiting that occurs within 12 hours prior to chemotherapy or 1 hour after the start of chemotherapy. A significantly higher proportion of treatments where lorazepam was given were associated with complete anticipatory CINV control compared to the control group (52 vs 32%; p < 0.05). Few adverse effects were attributed to lorazepam; mild sedation occurred in 76% of the treatments where lorazepam was given and 32% of the control treatments. Patients were entered into this trial more than once and were randomized independently at each entry. The experience of individual patients longitudinally over time or the effect of receipt of lorazepam/placebo during previous study enrollments on study outcomes was not described.
Women with breast cancer and about to begin chemotherapy were enrolled in a double-blind, placebo-controlled trial comparing the incidence of anticipatory CINV after relaxation training plus either alprazolam (29 patients) or placebo (28 patients). Alprazolam 0.25mg was given twice daily by mouth for 6 to 12 months. Triazolam was also given on an as needed basis to patients in both study arms to manage insomnia. The proportion of patients who experienced complete control of anticipatory CIN and CIV before the fourth chemotherapy treatment was similar in both study arms (26 vs 25% and 4 vs 0%, respectively).
Diazepam 5mg twice daily was given to 29 adult cancer patients with anticipatory CINV for 3 days before each of 4 consecutive chemotherapy treatment courses.  Thirteen patients experienced complete CIV control at some time over the 4 chemotherapy treatment courses.  2) all include recommendations for the use of non-pharmacological therapy. Two guidelines include a recommendation for the use of benzodiazepines although only one guideline specifies which agents should be used and provides dosing. Again, no adult guideline provides the evidence summary upon which their recommendations are based. 1. Behavioral therapy: Behavioral therapy (relaxation/systematic desensitization, hypnosis/guide imagery, music therapy) 2. Acupuncture/acupressure 3. Alprazolam (0.5 to 2 mg PO TID beginning on the night before treatment) or lorazepam (0.5 to 2 mg PO on the night before and morning of treatment)

# Research Gaps:
The efficacy of both new and old interventions aimed at managing anticipatory CINV must be prospectively evaluated in children receiving modern, evidence-based antiemetic prophylaxis and using validated pediatric tools to evaluate nausea severity. The optimal pediatric dose and dosing schedule of lorazepam needs to be determined to ensure optimal anticipatory CINV control. Version Date: April 23,  What process was followed?
The willingness of potential content expert reviewers to review the guideline was determined by contacting them by telephone or e-mail. Once agreement was obtained, the draft guideline was sent electronically along with instructions for the reviewer to complete a survey (Appendix H).
Following the content expert review, the draft guideline was sent electronically to health care providers who practice in POGO satellites and tertiary centres together with a request to review the document using a survey (Appendix I). Reviewers returned the completed the online survey.

#  Discussion of Feedback
The survey results were discussed in detail by the POGO CINV Guideline Development Panel and a decision on each point was taken by consensus. When the decision of the panel was not unanimous, a revision was made if it was supported by at least 60% of the guideline development panel members. The comments of the expert reviewers led to revisions to the guideline as outlined in Table 3 and a summary of the expert reviewers' responses to the survey questions is provided in Table 4. This is a guideline that is very much needed. I am particularly pleased to see the inclusion of non-pharmacological approaches to therapy, although the resources required to implement this mode of therapy may prove to be a significant barrier to their implementation.
This has now been included in the Organizational Barriers and Cost Implications section.
The report illustrates the paucity of well-conducted studies regarding the assessment and prevention of anticipatory CINV and the need for research in that area. While complete control of CINV with chemotherapy seem to impact on anticipatory CINV, there are likely developmental, physiological and genetic determinants influencing its occurrence as well. These latter are poorly understood in children and adolescents, therefore making it difficult to make blanket recommendations beyond recommendation 1.1 and I do agree with the level of recommendation i.e. weak for the use of other modalities.
In regards to the use of benzodiazepines, it has been our institutional experience that the recommended dose of lorazepam is too high for the majority of our patients and has been associated with more side effects than reported in the literature. Therefore, we do not exceed 1 mg. It has also been our experience, that AYA patients smoking marijuana before their chemotherapy admission had little anticipatory CINV.
The following statement has been added to the lorazepam evidence base summary: "This dose should be titrated to the needs of each child. For example, if this dose is associated with an unacceptable degree of sedation, lower doses are recommended for subsequent chemotherapy blocks."
 Excellent set up guideline  2 things in methods; why only English literature (no language restriction would be better)  Why differences in selection of studies; in adults >20 subjects need to be included and in children >10.  Otherwise all is very clear The evidence search was limited to the English language due to financial constraints that limited our ability to translate other languages into English. When reviewing the available evidence for inclusion into the evidence summary, a lower minimum number of subjects was applied in pediatric studies compared to adult studies. This decision recognized that pediatric studies were likely to include a smaller number of patients than were adult studies. This information has been added to Methods section of the text. Version Date: April 23,

# Content Expert Reviewers' Comments
Panel Action/Decision  The report is clear and highlights the need for further research.  It may be better that paediatric and adult guidelines are combined so that at least the adult recommendations are accessible when paediatric data is poor.
The guideline development panel took the decision not to adapt an adult guideline on this subject for the reasons delineated in the text. However, the recommendations of well known and accepted adult guidelines are presented in the text for the sake of comparison.
This offers a complete review of an issue commonly accepted as "normal" by many clinicians. It offers evidence-based guidelines needed to better understand and manage CINV. I expect that dissemination of this guideline will improve the quality of life for many patients suffering from anticipatory CINV.
No action required. Note: AINV has been changed to CINV in reviewers' responses for consistency with the final guideline terminology. The rationale for developing a guideline, as stated in the "Introduction" and "Scope and Purpose" sections of the draft guideline report, is clear.
There is a need for a practice guideline on this topic. 87.5%
The literature search described in the draft report is complete (no key studies or guidelines were missed).
The evidence described in the draft report is relevant. 50.0% The results of the studies described in the report are interpreted according to my understanding of the data.
The recommendations are clear. 75.0%
I agree with the recommendations as stated. 75.0%   Institutions should evaluate evidence-based guidelines for endorsement or adaptation and should consider developing antiemetic selection order sets or the incorporation of optimal antiemetic prophylaxis into cancer therapy order sets to facilitate their clinical use.
Health care providers should carefully and frequently evaluate CINV severity across all phases (anticipatory, acute and delayed) in children receiving chemotherapy. Particular attention should be paid to determining the incidence of CINV that may occur when the child is not in the inpatient or clinic setting and its severity. These assessments are needed to guide the need for treatment of anticipatory CINV, when present, and the selection of antiemetic prophylaxis for subsequent chemotherapy treatments. Attentive response to the child's overall CINV experience on the part of health care providers will likely minimize the development of anticipatory CINV.
Members of the health care team who have expertise in the provision of the recommended non-pharmacological interventions (hypnosis, systematic desensitization) should be identified and engaged in the care of children with anticipatory CINV.

# PLAN FOR SCHEDULED REVIEW AND UPDATE GUIDELINE IMPLEMENTATION CONSIDERATIONS
20 Version Date: April 23, Meticulous attention to the overall CINV experience (anticipatory, acute and delayed phase) of children receiving chemotherapy is required. Validated screening and assessment tools must be developed to facilitate timely and efficient identification of children who do not experience complete CINV control despite receiving guidelineinformed antiemetic prophylaxis. CINV diaries (paper or electronic) should be considered to record and track the experience of patients.
Routine systematic screening of all patients about to receive chemotherapy regarding their experience of anticipatory CINV is critical to the identification of patients who warrant intervention. Each organization should ensure that clinicians accept this as a standard of care and that they have the resources to perform this screening and provide appropriate interventions.
The availability of the resources required to implement recommendation 2.1 may be limited at many institutions. Since appropriately trained staff is the primary resource required for the incorporation of non-pharmaceutical interventions to control anticipatory CINV, it is suggested that each institution review the number of available child life specialists, psychologists and nurses with the relevant expertise to deliver these therapies.
Costs related to antiemetic agents, especially those used for acute and delayed phase CINV control, may increase when evidence-based guideline recommendations are followed. These increased costs may be counter-balanced by decreased costs due to improved CINV control.
Routine monitoring and tracking of patients' level of overall CINV control (anticipatory, acute and delayed phase) would not only provide a means to respond to the needs of individual patients but would also provide very much needed information regarding the emetogenicity of chemotherapy regimens in children.
Periodic audits of adherence of antiemetic prescribing to the guideline should be performed at individual institutions. Ideally, each prescriber should receive feed-back regarding the extent of their adherence to the guideline and the rate of complete anticipatory, acute and delayed CINV control seen in their patients.

# Quality of Evidence
High Quality Further research is very unlikely to change our confidence in the estimate of effect
Moderate Quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

# Low Quality
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very Low Quality Any estimate of effect is very uncertain

# Strength of Recommendations:

# Strong Recommendation
When using GRADE, panels make strong recommendations when they are confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects.

# Weak Recommendation
Weak recommendations indicate that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but the panel is less confident.

# Strength of Recommendations Determinants:
Factor Comment Balance between desirable and undesirable effects
The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a weak recommendation is warranted Quality of evidence
The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted Values and preferences
The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a weak recommendation is warranted Costs (resource allocation)
The higher the costs of an intervention-that is, the greater the resources consumed-the lower the likelihood that a strong recommendation is warranted Version Date: April 23,