American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006 Mark G. Kris, Paul J. Hesketh, Mark R. Somerfield, Petra Feyer, Rebecca Clark- Snow, James M. Koeller, Gary R. Morrow, Lawrence W. Chinnery, Maurice J. Chesney, Richard J. Gralla, and Steven M. Grunberg J Clin Oncol 24: ; JUNE

INTRODUCTION evidence-based clinical practice guidelines for the use of antiemetics in 1999, ASCO review on published randomized controlled trials, and systematic reviews and meta-analyses of published phase II and phase III randomized controlled trials. consensus statements from the International Antiemetic Consensus Conference, hosted by the Multinational Association of Supportive Care in Cancer (MASCC; Perugia, Italy)

2006 PRACTICE RECOMMENDATIONS

Neurotransmitter (dopamine, acetylcholine, histamine, serotonin, opiates, substance P)  serum, CSF  CTZ  vomiting center Medulla dorsolateral reticular formation Enterochromaffin cell in stomach  5HT3  5HT3 receptor in Vagal afferent neuron  vomiting center Aprepitant 5HT3 antagonist

A. VOMITING OCCURRING 0 TO 24 HOURS AFTER THERAPY (ACUTE EMESIS)

1. Emetic Risk of Antineoplastic Agents: Emetic Risk Categories Antineoplastic agents –grouped by the risk of emesis –matched to specific antiemetic regimens designed to prevent the degree of vomiting The recent MASCC consensus conference –established four emetic risk categories based on the data available –Adopted for the 2006 update of the ASCO Guideline for Antiemetics in Oncology.

2. Antiemetic Agents: Highest Therapeutic Index Three classes of agents are in this category: –the 5-HT3 serotonin receptor antagonists, –corticosteroids (dexamethasone), –the NK1receptor antagonists (aprepitant). –highly effective –few significant adverse effects when used appropriately –safely in combination. therapeutic index – 치료 지수 ( 指數 ) 《약물의 최대 내용량 ( 耐容量 ) 의 최소 치료량에 대한 비 ( 比 ) 》 유효용량에 비해서 독성용량이 큰 경우

a. 5-HT3 Serotonin Receptor Antagonists dolasetron, granisetron,ondansetron, palonosetron, tropisetron The principles of 5-HT3-receptor antagonist use – (i) use the lowest tested fully effective dose –(ii) no schedule is better than a single dose given before chemotherapy, –(iii) the antiemetic efficacy and adverse effects of these agents are comparable in controlled trials –(iv) intravenous and oral formulations are equally effective and safe; – always use in combination with dexamethasone and administer before chemotherapy literature update and discussion. –Equivalent antiemetic activity and safety. –similar adverse effect patterns

Intravenous palonosetron –became available in –longer serum half-life (about five times) –higher binding affinity to the 5-HT3 serotonin receptor. –superior to ondansetron in the prevention of acute emesis. –the palonosetron and ondansetron regimens were equivalent. –Although palonosetron outperformed ondansetron and dolasetron –no prospective trials to prove the superiority of palonosetron over any 5-HT3 antagonist –Combination with dexamethasone & aprepitant ?

b. Corticosteroids among the most frequently used antiemetics; single-agent use –appropriate in patients of low emetic risk. Dexamethasone –especially valuable in combination with 5-HT3 serotonin receptor antagonists and aprepitant in patients receiving chemotherapy of high or moderate emetic risk.

2006 literature update and discussion –recommends dexamethasone –Most extensively studied and widely available –the appropriate dose of dexamethasone administered in combination with a 5-HT3 serotonin receptor antagonist for the prevention of acute emesis  8 mg administered once before chemotherapy.

c.NK1 Receptor Antagonists : Aprepitant NK1 receptors –the binding site of the tachykinin substance P –found in the brainstem emetic center and in the GI tract. –prevent emesis caused by virtually all experimental emetic stimuli (including cisplatin).

Neurotransmitter (dopamine, acetylcholine, histamine, serotonin, opiates, substance P)  serum, CSF  CTZ  vomiting center Medulla dorsolateral reticular formation Enterochromaffin cell in stomach  5HT3  5HT3 receptor in Vagal afferent neuron  vomiting center Aprepitant 5HT3 blocker

Aprepitant –the first agent of this class available for general use. –13% improvement in the prevention of acute emesis –21% improvement in the delayed phase –No significant differences in any treatment-related adverse effect –a moderate inhibitor of Cytochrome p450 3A4 –the metabolism of corticosteroids, which are 3A4 substrates, is affected in normal volunteers –Steroid serum level increase  infection risk increase ? –use a lower dose of dexamethasone when administered as an antiemetic with aprepitant –But steroid as a chemotherapeutic agent, dose should not be reduced –Oral agent, 80mg qd

2. Antiemetic Agents: Lower Therapeutic Index Metoclopramide, Butyrophenones, Phenothiazines, and Cannabinoids Current recommendation –high emetic risk, Not appropriate as first-choice antiemetics. reserved for patients intolerant of or refractory to 3 drugs 2006 literature update and discussion –not appropriate as first-choice antiemetics.

3. Antiemetic Agents ; Adjunctive Drugs benzodiazepines [lorazepam, alprazolam], antihistamines Current recommendation –Lorazepam and diphenhydramine are useful adjuncts to antiemetic drugs –not recommended as single agents literature update –No relevant studies

4. Antiemetic Agents :Combinations of Antiemetics Current recommendation –in high emetic risk & AC regimen  3 drug combination –moderate emetic risk other than AC.  A 5-HT3 serotonin receptor antagonist + dexamethasone 2006 literature update and discussion –high emetic risk & AC chemotherapy  the combination of 3 drugs  the greatest antiemetic protection

5. Recommendations for Specific Emetic Risk Categories the primary determinant for choice of preventative therapy  intrinsic emetic risk of the chemotherapy administered.

a. High (90%) Emetic Risk Current recommendation –3-drug combination before chemotherapy 2006 literature update and discussion –3 drug combination to prevent acute emesis with these drugs as well as cisplatin.

b. Moderate Emetic Risk Current recommendation –AC regimen  3 drug combination –other chemotherapy of moderate emetic risk,  2 drug combination of a 5-HT3 receptor antagonist + dexamethasone literature update and discussion –3 drug antiemetic regimen for any chemotherapeutic regimen that includes cyclophosphamide alone –dosages and schedules of any corticosteroids not be reduced due to the aprepitant.

c. Low (10% to 30%) Emetic Risk Current recommendation –Dexamethasone 8mg is suggested –no routinely in patients without a history of nausea and vomiting (MASCC level of confidence: no confidence possible; MASCC level of consensus: high) 2006 literature update and discussion –There are no trials specifically addressing the optimal antiemetics for chemotherapies of low emetic risk.

d. Minimal (10%) Emetic Risk Current recommendation –no routine treatment before chemotherapy literature update and discussion –Few antiemetic studies were found –Use of a single dose of dexamethasone 8 mg, –as-needed prescribing of oral metoclopramide, or a phenothiazine is common.

e. Combination Chemotherapy Current recommendation. –antiemetics appropriate for the component chemotherapeutic agent of greatest emetic risk literature update. –No relevant studies were identified

f. Multiple Consecutive Days of Chemotherapy. Current recommendation –Antiemetics for each day of the chemotherapy 2006 literature update. –No relevant studies were identified

B. VOMITING OCCURRING 24 OR MORE HOURS AFTER CHEMOTHERAPY (DELAYED EMESIS)

Area Postrema Delayed emesis may involve AP Adjacent to CSF-containing ventricles Lacks a blood-brain barrier to large polar molecules Therefore, able to detect toxins in blood and CSF Projection from AP to NTS VN = vestibular nuclei AP = area postrema NTS = nucleus tractus solitarius EC = enterochromaffin cell [1-3,8] EC pons medulla VN cerebellum AP NTS v v v v v

Role of the AP in Delayed Emesis Cisplatin is able to activate the AP and the activation is not inhibited by 5-HT 3 receptor antagonists High concentrations of substance-P in the AP Antagonists of the substance-P receptor, neurokinin-1, appear to be able to prevent delayed emesis after cisplatin chemotherapy Aprepitant (Emend) – FDA approved 2003

1. Chemotherapeutic Agents Delayed emesis –Any emesis during the initial 24 hours after chemotherapy predicts a higher likelihood of emesis persisting or starting more than 24 hours after antineoplastic therapy.

2. Antiemetics to Prevent Emesis Occurring 24 or More Hours After Chemotherapy a. Dexamethasone –alone and in combination –most widely studied drug for the prevention of emesis occurring 24 or more hours after chemotherapy –typically is administered as an antiemetic for 2 to 4 days –adrenal insufficiency has not been described. –Clinically significant hyperglycemia and insomnia occur rarely. The Update Panel –dexamethasone should be part of any regimen for delayed emesis after cisplatin

b. Aprepitant Initial trials & subsequent experience testing NK1 receptor antagonists –effective in preventing delayed emesis placebo-controlled phase III trials of 1,053 –randomly assigned patients receiving cisplatin –72% of individuals receiving the combination of aprepitant and dexamethasone had no delayed vomiting or rescue compared with 51% receiving dexamethasone alone 866 patients receiving the combination of AC –55% of patients receiving aprepitant 80 mg once daily had no delayed emesis and no rescue as opposed to 49% receiving ondansetron 8 mg twice daily

c. Metoclopramide and 5-HT3 Serotonin Receptor Antagonists Metoclopramide –reported efficacy for oral metoclopramide in combination with dexamethasone. –Doses vary between 20 and 40 mg (or 0.5 mg/kg) administered two to four times per day for 3 to 4 days. 5-HT3 serotonin antagonists –conflict on the effectiveness of for the prevention of emesis 24 or more hours after chemotherapy. –palonosetron before chemotherapy improves the control of delayed vomiting better than single doses of ondansetron and dolasetron. The Update Committee –aprepitant and dexamethasone when it is necessary

3. Recommendations to Prevent Emesis Occurring 24 or More Hours After Chemotherapy a. High Emetic Risk Current recommendation –In all patients receiving cisplatin and high emetic risk  2 drug combination of dexamethasone & aprepitant 2006 literature update and discussion –2 drug superior to dexamethasone alone –2 drug superior to ondansetron and dexamethasone –The MASCCConsensus Conference and the Update Committee no longer recommend that a 5-HT3 antagonist plus dexamethasone be used to prevent delayed emesis after chemotherapy of high emetic risk.

b. Moderate Emetic Risk Current recommendation –In patients receiving AC –Aprepitant as a single agent is recommended –For all other chemotherapies of moderate emetic risk, single- agent dexamethasone or a 5-HT3 receptor antagonist is suggested for the prevention of delayed emesis literature update and discussion –AC chemotherapy.  Aprepitant alone –superiority of a 3-drug aprepitant-containing regimen over a 2- drug ondansetron plus dexamethasone regimen

c. Low and Minimal Emetic Risk Current recommendation –No routine preventive antiemetics for delayed emesis are indicated for patients receiving chemotherapeutic agents of low or minimal emetic risk literature update –No relevant studies were identified

C. SPECIAL EMETIC PROBLEMS

1. Anticipatory Emesis occurs in patients poor control of vomiting with prior chemotherapy A history of motion sickness predisposes patients to anticipatory emesis a. Prevention of Anticipatory Emesis Current recommendation. –Use of the most active antiemetic regimens appropriate for the chemotherapy –Such regimens must be used with the initial chemotherapy 2006 literature update –No relevant studies were identified

b. Treatment of Anticipatory Emesis Current recommendation –behavioral therapy with systematic desensitization is effective and is suggested literature update –No relevant studies were identified –Although many Update Committee members recommend lorazepam and alprazolam, there are no prospective trials

3. High-Dose Chemotherapy Current recommendation –5-HT3 receptor antagonist + corticosteroid The Update Committee –encourages the addition of aprepitant to the antiemetic regimens 2006 literature update. –the Update Committee urges that the use of aprepitant be considered. –But no data specifically studying aprepitant in patients –theoretical possibility for a drug interaction because aprepitant has been shown to moderately inhibit CYP3A4 in normal volunteers.

4. Vomiting and Nausea Despite Recommended Prophylaxis The Update Committee suggests (1) conduct a careful evaluation of risk, antiemetic, chemotherapy, tumor, and concurrent disease, and medication factors (2) ascertain that the best regimen is being administered for the emetic setting (3) consider adding an lorazepam or alprazolam to the regimen (4) consider substituting a high-dose intravenous metoclopramide for the 5-HT3 antagonist or adding a dopamine antagonist to the regimen.

II. RADIATION-INDUCED EMESIS A. RISK FACTORS FOR RADIATION-INDUCED EMESIS –varies with the treatment administered –Controversy exists concerning definitions of emetic risk groups. routinely or reserved as needed by individual patients. –treatment field is one of the major determinants of emetic risk. the dose of radiotherapy administered per fraction and the pattern of fractionation.

방사선치료로 인한 오심과 구토 전신조사를 시행할 때 80% 로 가장 높은 발생률 상복부에 치료하는 경우 50 ∼ 80% 에서 발생 방사선치료의 부위 이 외에도 총선량과 분할 조사선량 환자 요인으로 성별, 연령, 과거치료 시 오심과 구토가 발생했던 경력, 알코올 섭취의 정도 등이 영향 방사선치료 시 오심과 구토가 발생하는 기전 – 종양세포의 파괴로 인해 유리되는 독소, – 능동적 방어기전에서 유리되는 구토 유발 물질, – 방사선치료로 인한 염증반응의 이차적 현상 –enterochromaffin 세포에서 유리되는 세로토닌 등  상복부의 세로토닌의 농도와 세로토닌의 대사물인 5- hydroxyindoleacetic acid (5-HIAA) 의 혈중 농도가 방사선치료로 인한 오심 및 구토의 발생과 연관 대한방사선종양학회지 2001; 19(2):127 ∼ 135

II. RADIATION-INDUCED EMESIS