The working group of JSCO clinical practice guidelines for antiemesis adopted a clinical question (CQ) form as the main guideline format and selected the following 21 CQs:
CQ1. How is the emetic risk induced by cancer chemotherapy categorized?
Recommendation (Grade A): the emetic risk induced by cancer chemotherapy is classified as high, moderate, low, and minimum according to the frequency of patient nausea and vomiting experiences, and antiemetic prophylactic treatments are prescribed in accordance with these categories.
The emetic risks of cancer chemotherapy depend on the potential emetogenicity of combined chemotherapeutic regimens. The emetic risk is evaluated on the basis of the percentage of untreated patients who experience acute emesis within 24 h of initiation and/or administration of cancer chemotherapy and is categorized as follows:
High emetic risk: 90 % or more patients experience acute emesis
Moderate emetic risk: 30–90 % of patients experience acute emesis
Low emetic risk: 10–30 % of patients experience acute emesis
Minimum emetic risk: fewer than 10 % of patients experience acute emesis
CQ2. How are intravenous chemotherapeutic agents categorized for the emetic risk?
Recommendation (Grade A): proper and sufficient antiemetic prophylaxis should be recommended in accordance with the four risk categories (Table 1).
Recommendation (Grade C1): antiemetic treatments for domestic chemotherapeutic agents developed in Japan are uncertain because of limited evidence of drug efficacy and low frequency of usage.
Emetic risks of chemotherapeutic agents are classified in Table 1 on the basis of the recommendations of existing guidelines produced with a high level of consensus, for example NCCN, MASSC, and ASCO; they were modified in consideration of particular clinical circumstances in Japan [6, 7]. Most chemotherapeutic regimens with high or moderate emetic risk include intravenous chemotherapeutic agents, and proper and flexible management of their emetic risks is essential because they are usually administered over several days and include several drugs. Although the 2009 NCCN guidelines indicate that high and low-dose cisplatin regimens have high and moderate emetic risk, respectively, the 2008 MASCC and 2006 ASCO guidelines categorized cisplatin as a drug of high emetic risk irrespective of dosage [8, 9]. Accordingly, all cisplatin regimens, including those administered over several days were regarded as regimens of high emetic risk (CQ10). However, combined regimens that include anthracycline and cyclophosphamide, for example AC, CAF, EC, and FEC, are usually regarded as having high emetogenicity. The 2009 NCCN guidelines categorized these anthracycline-containing regimens as high emetic risk similar to other monotherapeutic agents with high emetogenicity. Hence, this categorization was used for all anthracycline-containing regimens.
CQ3. How are the emetic risk categories for oral chemotherapeutic agents defined and managed?
Recommendation (Grade C1): according to clinical study protocols designed to assess efficacy as supportive co-treatments, suspension and/or dose reduction of chemotherapeutic agents should be considered to limit nausea and vomiting to grade 3 or less.
The emetic risk of oral chemotherapeutic agents is listed in Table 2. In Japan, oral fluoropyrimidine-based regimens are frequently used as adjuvant treatments with tegafur-uracil and/or leucovorin and capecitabine for colorectal cancer, S-1 for gastric cancer, and tegafur-uracil for breast and lung cancers, and several clinical trials have demonstrated efficacy is reasonable. Moreover, the Japanese clinical practice guidelines have indicated that S-1 and tegafur-uracil and/or leucovorin are efficacious treatment strategies for advanced gastric and colorectal cancers. Although these oral chemotherapeutic agents have lower emetogenicity when administered alone, adverse digestive events occur after repeated daily administration. Hence, antiemetic treatments are important to achieving higher drug adherence and to optimizing treatment.
CQ4. How should acute nausea and vomiting induced by cancer chemotherapy be prevented?
Recommendation (Grade A): a triple regimen of neurokinin 1 (NK1) receptor antagonist (aprepitant), serotonin (5-hydroxytryptamine: 5HT3) receptor antagonist, and dexamethasone is recommended for acute emesis during highly emetic cancer chemotherapy.
Recommendation (Grade A): regimens containing 5HT3 receptor antagonists and dexamethasone are basically recommended for acute emesis during moderately emetic cancer chemotherapy. For particular chemotherapeutic regimens, addition of an NK1 receptor antagonist to regimens of 5HT3 receptor antagonist and dexamethasone are considered.
Acute onset of nausea and vomiting occurs within a few minutes to several hours, and intensity generally peaks from 5 to 6 h after administration of chemotherapy and usually recovers within 24 h. Management and control of CINV are essential for successful cancer chemotherapy, because unfavorable side effects of nausea and vomiting are associated with poor treatment adherence and effects. In addition, incomplete prevention of acute emesis may lead to uncontrollable delayed emesis . Hence, according to the four emetic risk categories indicated in CQ2 and 3, appropriate and sufficient antiemetic treatments are needed from the start of chemotherapy. The standard model of antiemetic treatment regimens is detailed in the four diagrams in Fig. 1. In the high emetic risk diagram, evidence of antiemetic actions of AC regimens was taken from clinical trials of other highly emetic cancer agents, and suggests no additional effects of dexamethasone after day 2. Upon issue of the 1st guideline, oral aprepitant was the only NK1 receptor antagonist available for clinical use in Japan. Subsequently, in November 2011, the Japanese Ministry of Health, Labour, and Welfare approved the intravenous NK1 receptor antagonist, fosaprepitant. Accordingly, we immediately modified the diagram and included additional information about fosaprepitant as a minor revision of the guideline, with careful consideration of the limited evidence of its efficacy and safety.
CQ5. How should delayed nausea and vomiting after cancer chemotherapy be prevented?
Recommendation (Grade A): a combined regimen of NK1 receptor antagonist (aprepitant) and dexamethasone is recommended for treatment of delayed emesis during highly emetic cancer chemotherapy.
Recommendation (Grade A): single administration of dexamethasone is basically recommended for delayed emesis during moderately emetic cancer chemotherapy. However, regimens of NK1 antagonist and/or dexamethasone are considered.
Delayed onset of nausea and vomiting occurs later than 24 h after administration of chemotherapy. In these circumstances, control of delayed emesis is essential to maintaining patients’ quality of life and for motivating further treatment with a healthy mentality. As described in CQ4, complete prevention of acute emesis is the most important and fundamental strategy for preventing delayed emesis (Fig. 1). In specific cases in which dexamethasone should be restricted, 2–4 days of 5HT3 antagonist is recommended instead of dexamethasone.
CQ6. What kinds of serotonin (5HT3) receptor antagonist are available in Japan?
Recommendation (Grade A): 5HT3 receptor antagonists are effective treatments for prevention of nausea and vomiting during cancer chemotherapy; seven drugs are approved in Japan: granisetron, palonosetron, ramosetron, ondansetron, tropisetron, azasetron, and indisetron.
Several 5HT3 receptor antagonists are currently available in Japan, and efficacy for management of CINV has been demonstrated for all these agents, particularly under conditions of acute phase emesis. However, the efficacy of these agents for treatment of delayed emesis remains controversial because no further antiemetic effects of additional treatments have been observed after initial use of 5HT3 receptors with antagonistic agents. It has been proved that palonosetron is not inferior to granisetron in the acute phase and is superior to granisetron in the delayed phase .
CQ7. What is the recommended dose of corticosteroid for antiemetic treatment?
Recommendation (Grade A): corticosteroid is an effective antiemetic at recommended doses determined according to the emetic risk categories of chemotherapeutic regimens.
Corticosteroid has been used as an antiemetic prophylactic during cancer chemotherapy for 25 years , although its mechanism of action remains unclear compared with those of 5HT3 and NK1 antagonists, which have recently been approved with clear evidence of mechanisms. Although several classes of corticosteroid are available, dexamethasone and methylprednisolone are most frequently used as antiemetics, with strong evidence of their effects [13, 14]. In particular, oral and intravenous dexamethasone (4–20 mg/day) has been approved as antiemetic treatment during cancer chemotherapy in Japan. However, the efficacy of high-dose dexamethasone has not been compared with that of 20-mg treatments among either Western [13, 14] or Japanese populations .
CQ8. How should breakthrough nausea and vomiting be managed?
Recommendation (Grade B): fixed around-the-clock administration of a variety of drugs should be considered according to patient symptoms. In addition, antiemetic 5HT3 receptor antagonists should be replaced with another type of 5HT3 receptor antagonist.
Breakthrough emesis refers to nausea and vomiting despite prophylactic antiemetic treatment, and requires additional treatment with antiemetic agents with mechanisms of action that differ from that of the primary antiemetic agent. Among these, the dopamine antagonists metoclopramide, butyrophenone, corticosteroid, and lorazepam may be considered for breakthrough emesis, despite poor evidence of their efficacy. A systematic review of antiemetic treatments for patients with advanced cancer showed that metoclopramide is superior to placebo and equivalent to ondansetron, although responses were only 23–36 % and 18–52 % for nausea and vomiting, respectively . Moreover, a randomized clinical controlled study of 51 advanced cancer patients showed no significant effects of additional dexamethasone for nausea after failure of antiemetic response to metoclopramide .
Some reports recommend antiemetic prophylaxis using agents that are not 5HT3 receptor antagonists.
CQ9. How should acute nausea and vomiting induced by low and minimum emetic chemotherapy be managed?
Recommendation (Grade B): during low emetic chemotherapy, dexamethasone should be considered according to chemotherapeutic regimen and patient background.
Recommendation (Grade C1): routine usage of dexamethasone is not recommended for minimum emetic chemotherapy.
Prophylactic antiemetic treatment is not recommended for low or minimum emetic chemotherapy, because patients do not progress to definite nausea and vomiting. Nonetheless, some patients suffer from emesis during treatment with low or minimum emetic chemotherapy, necessitating flexible and appropriate treatment despite the absence of high-level evidence. The 2006 ASCO and 2008 MASCC guidelines recommended administration of 4–8 mg dexamethasone [13, 18], and include prochlorperazine  and metoclopramide as optional antiemetics.
CQ10. How is nausea and vomiting managed for such regimens as several cisplatin treatments daily?
Recommendation (Grade B): a triple antiemetic regimen of 5HT3 antagonist, dexamethasone, and aprepitant is recommended for acute nausea and vomiting during more typical chemotherapeutic regimens. A double regimen of dexamethasone and aprepitant is recommended for delayed nausea and vomiting, even during regimens of several cisplatin treatments daily.
It is widely accepted that cisplatin is a highly emetic chemotherapeutic agent, and it is commonly administered every 3 or 4 weeks at ≥50 mg/m2 for treatment of a variety of malignancies. However, different cisplatin regimens have been established with reasonable evidence, including several cisplatin treatments daily at <50 mg/m2 for oncologic tumors such as cholangiocarcinomas, bladder cancers, and germinomas [20, 21], and continuous cisplatin injections at 100 mg/m2 over 4 days for non-Hodgkin malignant lymphomas.
CQ11. How should anticipatory nausea and vomiting be managed?
Recommendation (Grade B): initially, complete prevention of emesis is essential during acute and delayed phases, so patients never experience nausea and vomiting.
Recommendation (Grade B): benzodiazepine is effective for anticipatory nausea and vomiting.
Recommendation (Grade B): such psychological therapy as systematic desensitization and/or behavioral treatment, relaxation therapy, and hypnotherapy for pediatric patients effectively ameliorate anticipatory nausea and vomiting.
Anticipatory nausea and vomiting occurs immediately before treatment, and reflects previous negative experiences of cancer chemotherapy [22–24], although nausea is more common than vomiting among such cases. The ideal prophylaxis for this symptom is complete prevention of emesis from the initial treatment [23–26]. Hence, appropriate antiemetic treatments are essential, and require accurate assessment of emetic risks for planned chemotherapeutic regimens. The 2009 NCCN and 2008 MASCC guidelines recommended treatments with lorazepam  for anticipatory nausea and vomiting, and alprazolam  for anticipatory nausea.
CQ12. How are emetic risks categorized for radiation therapy?
Recommendation (Grade A): emetic risks of radiation therapy are classified (Table 3) according to tissue targets and volumes for irradiation.
As for chemotherapy, antiemetic treatments for radiation therapy are critical for successful treatment. Accordingly, the 2004 MASCC and 2006 ASCO guidelines indicate the emetic risk categories for specific targeted tissues, and recommend prophylactic emetic regimens based on these risk classifications. The risk of radiation-induced nausea and vomiting is categorized according to the percentage of patients who experience emesis. Moreover, whole body and upper abdominal radiation therapy are likely to cause greater emesis, and the frequency of nausea and vomiting increases with larger total doses and target tissue volumes [29, 30].
CQ13. Do antiemetic treatments differ in equivalent regimens from those in standard regimens containing specific key agents?
Recommendation (Grade C1): the emetic risk should be assessed on the basis of the agent with the highest emetic risk, even for similar chemotherapeutic regimens that comprise several agents.
Most clinically used chemotherapeutic regimes include several drugs, although many variations of standard chemotherapeutic regimens containing similar key agents. Thus, it is important to assess the emetic risks of regimens according to the emetic risks of each agent in isolation.
CQ14. What clinical factors and patient backgrounds affect CINV?
Recommendation (Grade C1): treatment and patient factors affect the emetic risks of CINV. Treatment factors include emetogenicity and dosages of chemotherapeutic agents, and tissue targets and volumes of radiation therapy. Relevant patient factors include age, gender, and alcohol consumption.
The frequency and intensity of emesis from CINV are affected by numerous factors, including specific chemotherapeutic agents, regimens, dosages, schedules, routes of administration, and tissue targets and volumes for radiation therapy. In addition, patient factors such as age , gender [31, 32], alcohol consumption , and experience of nausea gravidarum affect the emetic effects of CINV. The NCCN guideline also suggests that bowel obstruction, vestibulopathy, brain metastasis, electrolyte dysbolism, uremia, opioid use, gastric atony, and mental disorders are potential risk factors for emesis. Accordingly, management of treatment-related emesis is well-established with consensus, whereas patient-oriented factors remain unclear.
CQ15. How should CINV be managed in pediatric patients with malignancies?
Recommendation (Grade C1): multidisciplinary management using 5HT3 receptor antagonists, corticosteroid, and other antiemetic agents control the emetic effects of CINV, even for pediatric patients.
In the last three decades, advances in cancer treatment, for example high dose methotrexate, cytarabine, cyclophosphamide, and hematinic stem cell transplantation, have led to long term prognoses for ≥70 % of pediatric patients with malignancies. However, there are only a few reports with high level evidence about antiemetic treatment in pediatric patients from western populations [34–36]. Accordingly, they are treated with modified dosage on the basis of results of clinical trials on adult patients. Proper antiemetic treatments also enable pediatric patients to receive cancer chemotherapy without decline in QOL.
CQ16. Is it possible to discriminate nausea from anorexia, pyrosis, and dyspepsia? Which diseases produce symptoms of nausea and vomiting?
Recommendation (Grade B): no definitive evidence distinguishes nausea from anorexia, pyrosis, and dyspepsia. However, proton pump inhibitors (PPI) and H2 blockers are recommended for patients with these symptoms.
Recommendation (Grade C1): antiemetic agents should be used on the basis of accurate assessment of patient conditions.
Symptoms of anorexia, pyrosis, and dyspepsia are caused by several factors related to digestive dysfunction, and are frequently accompanied with nausea and other symptoms. Therefore, nausea induced by chemotherapy has not been strictly distinguished from other symptoms of digestive dysfunction. Nonetheless, PPI and H2-blockers are recommended as optional treatments for these symptoms .
In addition to treatments for CINV, patients with malignancies may suffer from nausea and vomiting as a result of the following conditions:
Partial or complete bowel obstruction
Electrolyte dysbolism (hypercalcemia, hyponatremia, and hyperglycemia)
Other combinations of drugs, including opioids
Anticipatory nausea and vomiting
CQ17. How are different forms of agents appropriately selected and used?
Recommendation (Grade B): patients should self-manage the use of oral agents. However, in circumstances in which nausea and vomiting prevent patients from taking oral treatments, optional intravenous administration should be considered.
Antiemetic agents are available in a variety of formulations for oral, rectal, intravenous, and intramuscular administration. A meta-analysis of randomized control trials showed equivalence of oral and intravenous 5HT3 receptor antagonists . However, the cost effectiveness and convenience of administration of oral agents are superior to those of intravenous agents, particularly when administered as tablets that disintegrate orally. Nonetheless, intravenous agents may improve treatment adherence among pediatric patients.
CQ18. For which antiemetic drugs are pharmacokinetic interactions observed?
Recommendation (Grade B): it is essential that aprepitant is used carefully to avoid interactions with co-administered drugs, including some chemotherapeutic agents. Moreover, strict dose control of combined drug regimens according to patient conditions and disease backgrounds is critical.
Because aprepitant induces and inhibits the cytochrome P450 enzymes 3A4 (CYP3A4) and 2C9 (CYP2C9) it can alter plasma concentrations of co-administered drugs by interacting with these critical drug-metabolizing enzymes . Chemotherapeutic agents that are metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosphamide, imatinib, vinorelbine, vinblastine, and vincristine. Although doses were not adjusted for several chemotherapeutic agents used concurrently with aprepitant in phase III trials, these drugs should be used with caution [40, 41] because aprepitant interacts with several non-chemotherapeutic drugs, including warfarin, dexamethasone, and methylprednisolone. Concurrent use of aprepitant temporarily reduces prothrombin time–international normalized ratio (PT–INR) for patients receiving regimens that contain warfarin, necessitating anticoagulant monitoring for these patients . Aprepitant also increases AUCs of the corticosteroids dexamethasone and methylprednisolone, necessitating appropriate reductions of corticosteroid doses (CQ7) . However, to ensure anti-cancer effects, steroid doses should not be reduced in chemotherapeutic regimens for malignant lymphoma that include corticosteroid, despite concomitant use of aprepitant. Moreover, concurrent use of the CYP3A4 inhibitors ketoconazole, itraconazole, and erythromycin may increase aprepitant AUCs, whereas the CYP3A4 inducers carbamazepine, rifampicin, and phenytoin may reduce plasma levels of aprepitant.
CQ19. How are the effects of antiemetic treatment evaluated?
Recommendation (Grade A): the effects of antiemetic treatment should be assessed at every visit for outpatients, and within 24 h after administration of chemotherapy for admitted patients.
Recommendation (Grade C1): strict assessments require patients to report their conditions to medical staff by using self-reporting systems.
No definitive evidence or consensus has been published for assessment of antiemetic treatments. However, successful anticancer treatment depends on optimum patient assessments, and nausea and vomiting are observed for 31 and 20 % of cancer patients, respectively . Accordingly, the 2009 NCCN guidelines for palliative care recommend optimum screening for supportive care of all oncology patients according to their symptoms throughout the entire clinical course. Moreover, the RAND Cancer Quality-Assessing Symptoms Side Effects and Indicators of Supportive Treatment Project recommends symptom evaluations for all cancer patients, at every outpatient visit, and within 24 h of hospital admission. The 2009 NCCN Clinical Practice Guidelines for Antiemetics in Oncology suggest that prevention of nausea and vomiting is a primary objective. Hence, prophylactic treatment is mandatory for ≥4 days, because the emetic risks of CINV continue for several days under conditions of highly or moderately emetogenic cancer chemotherapy . Moreover, complete responses were reportedly not achieved for acute and delayed emesis, despite optimum prophylactic treatment .
Differential diagnosis of the causes of emesis are necessary during clinical evaluations (CQ14, 16). However, common terminology criteria for adverse events (CTCAE) may remain useful when chemotherapeutic regimens are applied, and are based on objective assessments by medical staff rather than subjective assessments by patients. Nonetheless, applicable patient directed subjective evaluations include the numerical rating scale (NRS), the visual analog scale (VAS), the verbal rating scale (VRS) and the Wong–Baker face rating scale. In addition, index of nausea, vomiting and retching (INVR) , Morrow assessment of nausea and emesis (MANE) , and functional living index-emesis (FLIE) scores  are also applicable as tools for evaluating longitudinal changes in emesis and the ensuing effects on quality of life.
CQ20. How is occlusive ileus managed in cancer patients with advanced and metastatic status, including carcinomatous peritonitis?
Recommendation (Grade A): reduction of gastrointestinal pressure using a nasogastric tube or percutaneous gastrostomy is recommended. In addition, intraperitoneal injection of octreotide is recommended as a drug therapy for carcinomatous peritonitis.
Recommendation (Grade C1): such salvage surgery as bowel bypass may also be effective for patients who are not in a critical condition and have expectations of comparatively long survival. However, endoscopic stents are recommended to resolve symptoms of simple intestinal obstruction for patients with poor prognosis.
Bowel obstruction among patients with advanced metastatic disease reduces quality of life and causes difficulty in the continuation of anticancer treatments. Conservative treatments are usually used for such patients, because of poor prognosis as a result of advanced oncological status. However, 50 % of colon cancer patients and 6–34 % of gynecologic cancer patients suffer from benign bowel obstructions , so accurate diagnoses is required.
CQ21. How are opioid-induced nausea and vomiting managed?
Recommendation (Grade B): emesis that is induced by opioid use should be managed by use of antiemetic treatments, although opioid rotation or changes in routes of administration may be considered.
Recommendation (Grade C1): prophylactic antiemetic treatments during opioid therapy may be useful despite the lack of high-level evidence of efficacy and safety.
The WHO ladder strongly recommends opioid use for oncological pain and cites high-level evidence of efficacy and safety. Moreover, three opioid receptors, the δ and κ receptors for emetogenic functions and the μ receptor for antiemetic functions, have been characterized. Patients frequently suffer from constipation, sleepiness, nausea, and vomiting on initiation of opioid therapy. However, antiemetic treatments for opioid-induced emesis are important for successful pain control among cancer patients. Moreover, differential diagnosis of other causes is important in patients suffering from emesis after opioid treatments (CQ16). Nonetheless, opioid-induced emesis is usually relieved within a few days of opioid administration.