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Real‐world emetic risk of chemotherapy and the corresponding antiemetic therapy in Japan: A study based on a nationwide database

Real‐world emetic risk of chemotherapy and the corresponding antiemetic therapy in Japan: A study... INTRODUCTIONChemotherapy‐induced nausea and vomiting (CINV) is a serious adverse event of chemotherapy.1–3 The frequency of CINV depends primarily on the emetic potential of the chemotherapeutic agent used. There are effective antiemetic agents for the prevention of CINV,4 which alleviate CINV significantly.5 Vomiting is observed in more than 90% of patients receiving high‐emetic‐risk chemotherapy (HEC) without prophylaxis6; this prevalence is reduced to approximately 30% when antiemetics are administered.6–8 Several guidelines of antiemetic therapy for chemotherapy recommend prescriptions based on the emetic risk of the chemotherapeutic agent used.9,10In clinical practice, chemotherapy regimens are chosen depending on the cancer type, tumour stage, patient's general state and preference.11 Most chemotherapy regimens are not highly emetic, and effective prophylaxis is available. Moreover, with an increasing number of molecular‐targeted and immunological therapies, more agents with low and minimal emetic potentials are becoming available.12However, the side effects of chemotherapy remain a major concern of patients with cancer.1,13 Some patients refuse chemotherapy14,15 for fear of its side effects.16 Previous studies have reported a chemotherapy non‐compliance rate of 5%–18%.14,17 In addition, avoidance of a treatment‐related decrease of their quality of life was the primary reason for refusal, and the fear of nausea before chemotherapy initiation was found to be a strong predictor of subsequent nausea.18 These data suggest that the patients' concern about treatment, which may be a result of their negative perception of high‐risk emetic agents and the lack of antiemetic therapy in early days, can deprive them from receiving appropriate treatment. This fear may be due to limited knowledge of CINV and chemotherapy‐specific anti‐emetic therapy.Thus, awareness of the frequency of CINV and its management may help curb patients' negative perceptions of chemotherapy and ensure a more objective treatment decision‐making. A nation‐wide survey reported good compliance with the guidelines of anti‐emetic therapy19; however, the findings did not reflect those of a real‐world setting as the registry contained clinical information of patients from selected institutions, and a detailed analysis according to cancer type was not performed.Using health utilisation data from the Hospital‐Based Cancer Registries (HBCR), this study aimed to describe the actual frequency of emetic chemotherapy use and the appropriate prophylaxis by cancer type.METHODSStudy design and data sourceThis observational study used data from the Quality Indicator project,20 which involved health utilisation data linked with the HBCR. The project was conducted to evaluate the quality of health care of patients with cancer. In brief, the National Cancer Centre collects HBCR data from designated cancer care hospitals and voluntarily participating hospitals nationwide in Japan, covering approximately 70% of all patients with newly diagnosed cancer.21 Among these hospitals, 475 hospitals participated in the Quality Indicator project. We analysed health utilisation data collected from 1 January 2016 through 31 December 2017 for patients diagnosed with cancer in 2016. Collection of health utilisation data was part of the governmental survey that assesses the effect of the introduction of the diagnosis procedure combination‐based payment system. The survey data included information equivalent to fee‐for‐service insurance claims that cover all billable health services (e.g., diagnostic tests, imaging workup, procedures, treatments, and prescribed drugs) for both in‐ and out‐patients. These data were linked to the HBCR data of each patient in the participating hospitals. The data of approximately 49% of incident cancer cases in Japan were included in this study.Patient selectionThe subjects of this study were selected as follows. First, patients with cancer who were at least 20 years old at the time of diagnosis in 2016 and who were initiated on chemotherapy (intravenous and/or oral) were included in the study. Second, information on chemotherapeutic agents and antiemetic drugs were extracted from the utilisation data. Patients who received chemotherapy with interferon‐alpha were excluded as interferon‐alpha is used in other conditions like hepatitis C virus infection. For patients who received chemotherapy more than once, data of the first chemotherapy session after diagnosis was analysed. Many chemotherapeutic agents were administered within the first 8 days in one course (e.g., for patients with gastric cancer, cisplatin was added on Day 8 after S‐1 [tegafur/gimeracil/oteracil potassium] initiation). Thus, all drugs administered within the first 8 days were systematically included in one combination regimen in the emetic risk classification. Patients in whom chemotherapy was administered on the same day as surgery, thoracic drainage, abdominal drainage, and/or pericardial drainage were excluded because the chemotherapy drugs might have been administered topically. Patients who received chemotherapy drugs requiring arterial injection were excluded. Further, patients who received haematopoietic stem cell transplantation within 3 weeks of chemotherapy were also excluded because the emetic risks and prophylactic anti‐emetic drugs are different from those for regular chemotherapy.Emetic risk classificationThe emetic risk of chemotherapy was classified using the Japan Society of Clinical Oncology guidelines (JSCO).22 The guidelines of the National Comprehensive Cancer Network (NCCN),6 American Society of Clinical Oncology (ASCO),23 and Multinational Association Supportive Care in Cancer (MASCC) were used to classify the acute emetogenicity of chemotherapy drugs.24 The major differences between the guidelines are presented in Table 1. The emetic risks of some drugs differed according to dosage. Thus, the emetic risk of these drugs was based on the average Japanese adult's body surface area of 1.48 m2.13,25 Finally, we classified cyclophosphamide administered at >1500 mg/m2 as HEC and methotrexate sodium administered at >250, 50–250, and <50 mg/m2 as HEC, MEC, and LEC, respectively.1TABLEMajor differences between the classifications of emetic risk of intravenous chemotherapy drugsJapanASCONCCNMASCC/ESMOHigh‐riskCarboplatin (AUC ≥4)Doxorubicin (≥60 mg)Epirubicine (>90 mg)Ifosfamide (≥2 g/m2 per dose)Moderate‐riskCarboplatinCarboplatinCarboplatin (AUC < 4)CarboplatinEpirubicineEpirubicineEpirubicineIfosfamideIfosfamideIfosfamideDoxorubicinDoxorubicinDoxorubicinCytarabine (>200 mg/m2)Cytarabine (>1000 mg/m2)Cytarabine (>200 mg/m2)Cytarabine (>1000 mg/m2)Methotrexate (≥250 mg/m2)Methotrexate (≥250 mg/m2)Low‐riskMethotrexate (50–250 mg/m2)MethotrexateMethotrexate (50–250 mg/m2)MethotrexateBortexomibBortexomibCetuximabCetuximabNelarabinePanitumumabPanitumumabPertuzumabMinimal‐riskBortexomibBortexomibCetuximabCetuximabNelarabineNelarabinePanitumumabPanitumumabPertuzumabPertuzumabNote: Japan: The 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis. ASCO: American Society of Clinical Oncology Antiemetics guidelines, J Clin Oncol 2020; 38:2782–2797. NCCN: National Comprehensive Cancer Network, Antiemesis guidelines, version 2.2020. MASCC: MASCC and ESMO consensus guidelines for the prevention of chemotherapy and radiotherapy‐induced nausea and vomiting: ESMO clinical practice guidelines. Ann Oncol 2016; 27:v119–v133.Some of the emetic risks were defined based on the combination of the drugs.22 That is, fluorouracil, levoholinato, oxaliplatin, and irinotecan (FOLFOXIRI) for colorectal cancer and oxaliplatin, irinotecan, fluorouracil, and levoholinato (FOLFIRINOX) for pancreatic cancer were classified as HEC; gemcitabine and S1 (GS) and gemcitabine and nab‐paclitaxel (GEM/nab‐PTX) for pancreatic cancer as MEC; ifosfamide, carboplatin, and etoposide (ICE) for malignant lymphoma as HEC; and oral etoposide, nimustine, and ranimustine for malignant lymphoma as MEC.Statistical analysisThe frequency of chemotherapy use by emetic risk was calculated in both the overall population and by cancer type. The prescription rate of the prophylactic antiemetic drugs according to the type of cancer and typical regimens in each cancer was also calculated. In general, antiemetic drugs administered on the same day as the first chemotherapy were regarded as prophylactic. For patients who received HEC after the initiation of chemotherapy with lower emetic risks (e.g., S1 + cisplatin is added on Day 8 for gastric cancer) or antiemetic drugs that were prescribed on the same day as HEC were considered prophylactic. To capture oral antiemetic drugs administered in preparation for the initiation of chemotherapy, oral drugs that were prescribed 30 days before chemotherapy initiation were also considered prophylactic. The disease stage was assessed by combining the clinical and pathological stages; the pathological stage was used for patients who underwent surgical resection, whereas the clinical stage was used for patients with unavailable data on the pathological stage of the tumour.26 All statistical analyses were performed using Stata software (ver. 15.0; Stata Corporation, Texas, USA).RESULTSIn total, 172 133 patients receiving chemotherapy were identified (Table 2), among whom 70.4% received intravenous chemotherapy. The mean age of the study population was 65.9 (standard deviation, SD 12.0) years. The oral chemotherapy group was slightly older than the intravenous chemotherapy group (68.7 vs. 64.1 years). Non‐small cell lung cancer was the most common cancer type (14.1%), followed by colorectal cancer (12.9%) and breast cancer (9.9%). A larger proportion of patients who received oral chemotherapy had gastric and colorectal cancers (57.7% and 55.3%, respectively) compared with other cancers (4.7%–36.8%). A total of 62.5% of prescribed oral chemotherapy was adjuvant chemotherapy.2TABLEPatients' characteristicsIntravenous chemotherapy groupOral chemotherapy groupTotalN121 103(%)100.0N51 030(%)100.0N172 133(%)100.0Sex, male64 07952.930 08459.094 16354.7Age (years), mean (SD)64.7(SD: 12.2)68.7(SD: 11.2)65.9(SD: 12.0)Cancer typeNon‐small cell lung15 99113.2826416.224 25514.1Colorectal99328.212 26524.022 19712.9Breast15 86113.112622.517 1239.9Gastric67725.6924618.116 0189.3Malignant lymphoma13 19010.96431.313 8338.0Pancreatic69465.740397.910 9856.4Oesophageal69225.75161.074384.3Small cell lung cancer42113.5370.142482.5Others41 27834.114 75828.956 03632.6StageStage 027242.28591.735832.1Stage I16 71713.8787015.424 58714.3Stage II20 65817.110 68720.931 34518.2Stage III29 70424.512 66224.842 36624.6Stage IV41 57634.312 22224.053 79831.3Unknown97248.0673013.216 4549.6Adjuvant chemotherapy51 14842.231 87362.583 02148.2Abbreviation: SD, standard deviation.The most prescribed chemotherapy was MEC (n = 60 528, 35.2%), followed by LEC (n = 51 645, 30.0%), and HEC (n = 46 458, 27.0%; Table 3 and Figure 1). In the intravenous chemotherapy group, 47.0% (n = 56 911) and 38.2% (n = 46 306) received MEC and HEC, respectively. Further, more than 50% of the patients who received HEC were prescribed cisplatin (n = 27 933). Meanwhile, 40.7% (n = 23 171) of the patients who received MEC were administered carboplatin. In the oral chemotherapy group, 39 446 (77.3%) patients received LEC, and approximately 50% of them (n = 18 740) received S1.3TABLEDistribution of emetic risk by antineoplastic agent and mode of administrationIntravenous chemotherapyOral chemotherapyTotalN121 103(%)100.0N51 030(%)100.0N172 133(%)100.0High emetic risk46 30638.21520.346 45827.0Cisplatin (IV)27 93360.3–27 93360.1Doxorubicin and cyclophosphamide (IV)10 14321.9–10 14321.8Epirubicine and cyclophosphamide (IV)692515.0–692514.9Procarbazine (PO)–152100.01520.3Moderate emetic risk56 91147.036177.160 52835.2Carboplatin (IV)23 17140.7–23 17138.3Oxaliplatin (IV)12 14521.3–12 14520.1Cyclophosphamide (IV) ≤1500 mg625111.0–625110.3Temozolomide (PO)–156643.315662.6Imatinib (PO)–96026.59601.6Cyclophosphamide (PO)–60616.86061.0Low emetic risk12 19910.139 44677.351 64530.0Gemcitabine (IV)314625.8–31466.1Docetaxel (IV)336027.5–33606.5Paclitaxel (IV)300624.6–30065.8Mitomycin C (IV)10648.7–10642.1Fluorouracil(IV)6675.5–6671.3S1 (tegafur/gimeracil/oteracil potassium) (PO)–18 74047.518 74036.3UFT (tegafur/uracil) (PO)–953224.2953218.5Capecitabine (PO)–532813.5532810.3Lenalidomide hydrate (PO)–10362.610362.0Afatinib maleate (PO)–9742.59741.9Dasatinib hydrate (PO)–8672.28671.7Sunitinib malate (PO)–7702.07701.5Minimal emetic risk47894.0778615.312 5757.3Bortezomib (IV)148230.9–148211.8Rituximab (IV)123025.7–12309.8Trastuzumab (IV)71715.0–7175.7Gefitinib (PO)–179823.1179814.3Methotrexate (PO)–167221.5167213.3Hydroxycarbamide (PO)–157620.2157612.5Sorafenib (PO)–137517.7137510.9Erlotinib (PO)–94612.29467.5Unknown8980.7290.19270.5Abbreviations: iv, intravenous chemotherapy; po, oral chemotherapy.1FIGUREDistribution of chemotherapy emetic risk by cancer typeThe distribution of the chemotherapy emetic risk differed with cancer type. Table 4 shows the major chemotherapy regimens. HEC was commonly used for oesophageal cancer (80.3%), malignant lymphoma (60.2%), and breast cancer (53.8%). Among the patients with oesophageal cancer who received HEC, 77.5% received 5‐fluorouracil plus cisplatin (FP). Among patients with malignant lymphoma who were administered HEC, 84.1% received CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) with or without rituximab. MEC was used for small cell lung (59.9%), pancreatic (44.2%), and colorectal cancers (40.4%). Meanwhile, LEC was administered most in patients with gastric (60.2%), colorectal (55.2%), and pancreatic (51.6%) cancers.4TABLEExamples of chemotherapy regimens and proportion of prescription for each emetic riskCancer typeChemotherapy regimenHigh riskModerate riskLow riskMinimal riskNon‐small cell lungCDDP + pemetrexed (35.3%)NP (35.6%)TC* (48.8%)UFT (53.0%)Pemetrexed (38.6%)Gefitinib (49.6%)Erlotinib (30.4%)ColorectalFOLFOXIRI (30.2%)CAPOX (58.7%)FOLFOX (22.1%)Capecitabine (38.5%)UFT + LV (36.5%)Panitumumab (17.9%)Regorafenib (14.9%)BreastFEC (43.1%)EC (31.9%)AC (24.6%)TC** (85.8%)PTX (35.0%)Trastuzumab + PTX (17.0%)DTX (12.9%)Trastuzumab (74.7%)GastricS‐1 + CDDP (64.4%)Cape + CDDP (17.7%)SOX (68.4%)S‐1 (88.7%)Nivolumab (3.9%)Ramucirumab (3.6%)Malignant lymphomaCHOP (84.1%)CPM <1500 mg (65.1%)––PancreaticFOLFIRINOX (79.8%)GEM + nab‐PTX (91.3%)S‐1 (69.6%)GEM (29.2%)–OesophagealFP (77.5%)DCF (17.6%)Nedaplatin + 5‐FU (63.8%)DTX (12.4%)–Small cell lungPE (69.0%)PI (30.3%)CBDCA + etoposide (88.8%)CBDCA+CPT11 (5.8%)CPT11 (41.3%)‐Note: This table shows the percentage of the tumours' major regimens at each emetic risk. NP, CDDP + VNR; TC*, CBDCA + PTX; FOLFOXIRI, 5‐FU + l‐LV + L‐OHP + CPT11; CAPOX, capecitabine + L‐OHP; FOLFOX, 5‐FU + l‐LV + L‐OHP; FEC, 5‐FU + EPI + CPA; EC, EPI + CPA; AC, ADM + CPA; TC**, DTX + CPA; SOX, S‐1 + L‐OHP; CHOP, CPA + ADM + VCR + PSL; FOLFIRINOX, L‐OHP + CPT‐11 + 5‐FU + l‐LV; FP, 5‐FU + CDDP; DCF, DTX + CDDP + 5‐FU; PE, CDDP + etoposide; PI, CDDP + CPT11.Abbreviations: 5‐FU, 5‐fluorouracil; ADM, doxorubicin hydrochloride; CBDCA, carboplatin; CDDP, cisplatin; CPA, cyclophosphamide; CPM, cyclophosphamide; CPT11, irinotecan hydrochloride hydrate; DTX, docetaxel hydrate; EPI, epirubicine hydrochloride; GEM, gemcitabine hydrochloride; l‐LV, levofolinate calcium; L‐OHP, oxaliplatin; LV, folinate; PSL, prednisolone; PTX, paclitaxel; S‐1, tegafur/gimeracil/oteracil potassium; UFT, tegafur/uracil; VCR, vincristine sulphate; VNR, vinorelbine ditartrate.Table 5 shows the prescription rate of the prophylactic antiemetic drugs. In the intravenous chemotherapy with HEC subgroup, 70.7% (95% confidence interval [CI], 70.3%–71.1%) of the patients were prescribed a three‐drug combination comprising an NK1 receptor antagonist, a serotonin receptor antagonist, and dexamethasone. In the intravenous chemotherapy with MEC subgroup, 59.1% (95% CI, 58.7%–59.5%) were prescribed a two‐drug combination, and 24.0% (95% CI, 23.7–24.4) were prescribed a three‐drug combination. Among the patients who received HEC, the prescription rates of antiemetic drugs differed with cancer type (Figure 2). Among the patients with small cell lung, non‐small cell lung, breast, and oesophageal cancers who were administered intravenous chemotherapy with HEC, 96.2% (95% CI, 95.1–97.1), 93.4% (95% CI, 92.7–94.1), 92.9% (95% CI, 92.4–93.4), and 91.6% (95% CI, 90.9–92.3) were prescribed a three‐drug antiemetic regimen, respectively. Meanwhile, 17.7% (95% CI, 16.8–18.5) of the patients with malignant lymphoma treated with HEC were prescribed this regimen. Antiemetic therapy according to chemotherapy regimen for each cancer type was shown in Appendix S1. More than 90% of patients who received HEC regimen were prescribed the recommended three‐drug antiemetic regimen, while 13.5% of patients with malignant lymphoma receiving CHOP were prescribed these antiemetic regimen.5TABLEPrescription of antiemetic drugsIntravenous chemotherapy (n = 121 103)Oral chemotherapy (n = 51 030)Total (n = 172 133)%, CI%, CI%, CIHigh emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea70.7 (70.3–71.1)4.6 (1.9–9.3)70.5 (70.1–70.9)Serotonin receptor antagonist + dexamethasonea24.7 (24.3–25.1)34.9 (27.3–43.0)24.7 (24.3–25.1)Serotonin receptor antagonist1.8 (1.7–2.0)10.5 (6.1–16.5)1.8 (1.7–2.0)Dexamethasone0.5 (0.4–0.6)16.4 (10.9–23.3)0.6 (0.5–0.6)None of above1.2 (1.1–1.3)32.9 (25.5–41.0)1.3 (1.2–1.4)Moderate emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea24.0 (23.7–24.4)0.0 (0.0–0.2)22.6 (22.3–22.9)Serotonin receptor antagonist + dexamethasonea59.1 (58.7–59.5)10.6 (9.6–11.6)56.2 (55.8–56.6)Serotonin receptor antagonist3.7 (3.6–3.9)13.7 (12.6–14.9)4.3 (4.2–4.5)Dexamethasone2.7 (2.6–2.8)10.6 (9.6–11.7)3.2 (3.0–3.3)None of above8.6 (8.4–8.8)64.6 (63.0–66.1)11.9 (11.7–12.2)Low emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea2.1 (1.9–2.4)0.4 (0.3–0.5)0.8 (0.8–0.9)Serotonin receptor antagonist + dexamethasonea31.6 (30.8–32.4)0.8 (0.7–0.8)8.0 (7.8–8.3)Serotonin receptor antagonist4.7 (4.3–5.0)0.6 (0.5–0.7)1.5 (1.4–1.7)Dexamethasone46.9 (46.0–47.8)3.6 (3.4–3.8)13.8 (13.5–14.1)None of above13.3 (12.7–13.9)93.8 (93.6–94.1)74.8 (74.4–75.2)Minimum emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea0.2 (0.0–0.3)0.0 (0.0–0.0)0.0 (0.0–0.1)Serotonin receptor antagonist + dexamethasonea5.0 (4.4–5.6)0.1 (0.0–0.2)2.0 (1.7–2.2)Serotonin receptor antagonist0.9 (0.7–1.2)0.2 (0.1–0.3)0.5 (0.4–0.6)Dexamethasone30.0 (28.7–31.3)2.6 (2.3–3.0)13.0 (12.4–13.6)None of above63.1 (61.7–64.5)96.8 (96.3–97.1)83.9 (83.3–84.6)Note: None: No prescription of an NK1 receptor antagonist, serotonin receptor antagonist, and dexamethasone.aAny steroid included.2FIGUREDistribution of prescription of antiemetic drugs by cancer typeIn the oral chemotherapy group, the two‐drug regimen was prescribed for 34.9% (95% CI, 27.3–43.0) and 10.6% (95% CI, 9.6–11.6) of the patients treated with HEC and MEC, respectively. The rate of use of a single serotonin receptor antagonist for HEC and MEC was 10.5% and 13.7%, respectively.DISCUSSIONThis study showed that MEC was used more than HEC, and CINV prophylaxis was widely used for HEC in a real‐world setting in Japan. The rate of prescription of HEC was dependent on the cancer type and was highest for patients with oesophageal cancer (80.3%), malignant lymphoma (60.2%), and breast cancer (53.8%). Meanwhile, MEC was prescribed mostly for patients with small cell lung (59.9%), pancreatic (44.2%), and colorectal (40.4%) cancers. For LEC, it was administered mostly for patients with gastric, colorectal, and pancreatic cancers, accounting for 50% of the patients who received chemotherapy. Further, the guidelines for antiemetic prophylaxis were used widely in 2016; meanwhile, some guidelines were revised in 2016.Patients with cancer and an indication for chemotherapy often experience pre‐treatment psychological distress.27 A previous study showed that pre‐chemotherapy education can decrease treatment‐related concerns and improve physical/psychological outcomes.28 Therefore, psychoeducational support can be an effective intervention for managing CINV.29,30 To avoid treatment refusal due to strong concerns about CINV, health care providers should establish a system to educate patients on the CINV risk of their planned chemotherapy regimen. Further, it should be emphasised that chemotherapy should be accompanied by a recommended anti‐emetic therapy. Moreover, the actual risk may depend on the patients' characteristics (cancer and treatment type, patient's age and sex),31 and thus these factors may need to be incorporated in the educational materials.A nationwide survey reported a good compliance to the guidelines for anti‐emetic therapy.19 Using the health utilisation data linked with the HBCR, this study described the actual frequency of using emetic chemotherapy and the appropriate prophylaxis by cancer type and typical regimens. The overall adherence to prophylactic antiemetic drugs for intravenous chemotherapy in this study was higher than that in previous studies in Japan.32,33 However, this study found that only 13.5% of patients with malignant lymphoma treated with CHOP received the recommended antiemetic therapy; this was consistent with a previous study.34 CHOP therapy use high dose prednisolone administration. Therefore, it may be recognised in clinical practice that many patients receiving CHOP do not suffer CINV. Aapro et al. reported that guideline‐consistent antiemetic therapy alleviates CINV significantly.5 Healthcare professionals should consider using recommendations from guidelines.Assuming that the effectiveness of the antiemetic drugs was similar to that in previous reports (i.e., in patients receiving both intravenous HEC and the recommended antiemetic, the frequency of vomiting was 30%) and that 90% of the patients received the anti‐emetic prophylaxis for HEC, the frequency of vomiting in the patients who received HEC without antiemetic prophylaxis was approximately twice that of the patients who took HEC with prophylaxis. Furthermore, considering that more than 90% of patients with non‐small cell lung, breast, and oesophageal cancers who received HEC with the recommended antiemetic treatment in 2016, the frequency of vomiting was approximately 35%. Education of patients on the risk of CINV may reduce excessive concerns about CINV.The appropriateness of antiemetic prophylaxis for oral chemotherapy could not be evaluated because the recommendations for prophylactic antiemetic drugs for oral chemotherapy vary with existing guidelines because of limited information on the emetic risk of oral chemotherapeutic agents.6,35,36 For example, the NCCN guideline recommend the use of a single serotonin receptor antagonist for patients with a high‐to‐moderate risk of CINV.8 Meanwhile, the MASCC guideline recommends a two‐drug combination of a serotonin receptor antagonist and dexamethasone for the same patients.37 This study simply describes the current status of prophylactic antiemetic drugs prescribed for patients receiving oral chemotherapy. These findings may be used for further research on the appropriate antiemetic therapy for these patients.This study had some limitations. First, this study did not measure the frequency of CINV due to unavailability of the CINV incidence data. Therefore, we estimated the frequency using data from a previous study. Second, antiemetic prophylaxis was defined based on the time of prescription recorded in the database. Although prophylactic antiemetic drugs prescribed on the same day with chemotherapy or within 30 days of oral chemotherapy were most likely prophylactic, the possibility that they were actually prescribed for therapeutic purposes could not be excluded. Third, this study examined the situation of patients diagnosed in 2016. The NCCN and ASCO antiemetic guidelines have been revised after 2016. The new guidelines also recommended additional use of olanzapine for HEC.6,23 We did not examine this recommendation. Fourth, the authors did not consider the patients' individual risk factors for CINV, such as sex, morning sickness, and comorbidities. Incorporating these factors may justify the non‐prescription of antiemetic prophylaxis in patients receiving HEC. Finally, the exact drug dosages per the body surface area of the patients were not available, because information on the patients' body surface area was not available in the claims data. Consequently, the emetic risks of patients receiving chemotherapy with agents, such as methotrexate and cytarabine, may be misclassified.33 Despite these limitations, these findings will be helpful in understanding the real‐world clinical situation of the CINV risk and prophylactic antiemetic use in Japan. Further studies should evaluate the effect of prophylactic education with/without psychoeducational support on relieving patients' concerns.CONCLUSIONOverall, HEC was less prescribed than MEC, and prophylactic antiemetic drugs were generally prescribed. Healthcare professionals should educate patients about emetic risks before chemotherapy initiation to avoid patients' concerns about CINV that may lead to treatment termination. This type of survey should be repeated to observe the improvements in compliance with recommended anti‐emetic therapy.ACKNOWLEDGMENTWe would like to appreciate the registrars of the Hospital‐Based Cancer Registries.CONFLICT OF INTERESTNarikazu Boku received funds from Ono and Takeda, and honorarium from Ono and Taiho. All the other authors declare no conflict of interest.AUTHOR CONTRIBUTIONSAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.O., T.H.; Methodology, A.O.; Investigation, A.O.; Formal Analysis, A.O; Writing—Original Draft, A.O; Writing—Review & Editing, A.O., N.B., T.H.; Supervision, N.B., T.H.; Founding, A.O.; Data Collection, T.H.ETHICS STATEMENTThis study was approved by the institutional review board of the National Cancer Centre in Japan (2018–270) and was conducted according to the Declaration of Helsinki.DATA AVAILABILITY STATEMENTOur data was permitted for use for only this research.REFERENCESCoates A, Abraham S, Kaye SB, et al. On the receiving end‐patient perception of the side‐effects of cancer chemotherapy. Eur J Cancer Clin Oncol. 1983;19(2):203‐208.de Boer‐Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side‐effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997;76(8):1055‐1061.Assi S, Barling M, Al‐Hamid A, Cheema E. Exploring the adverse effects of chemotherapeutic agents used in the treatment of cervical and ovarian cancer from the patients' perspective: a content analysis of the online discussion forums. Eur J Hosp Pharm. 2020:002162. https://doi.org/10.1136/ejhpharm-2019-002162Hesketh PJ. Chemotherapy‐induced nausea and vomiting. N Engl J Med. 2008;358(23):2482‐2494.Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline‐consistent antiemetic therapy on chemotherapy‐induced nausea and vomiting (CINV): the pan European emesis registry (PEER). Ann Oncol. 2012;23(8):1986‐1992.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Antiemesis; 2020. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed June 6, 2020.Herrstedt J, Rapoport B, Warr D, et al. Acute emesis: moderately emetogenic chemotherapy. Support Care Cancer. 2011;19(1):S15‐S23.Dranitsaris G, Leung P, Warr D. Implementing evidence based antiemetic guidelines in the oncology setting: results of a 4‐month prospective intervention study. Support Care Cancer. 2001;9(8):611‐618.Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy‐ and radiotherapy‐induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(5):v232‐v243.Takeuchi H, Saeki T, Aiba K, et al. Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary. Int J Clin Oncol. 2016;21(1):1‐12.Glaus A, Knipping C, Morant R, et al. Chemotherapy‐induced nausea and vomiting in routine practice: a European perspective. Supportive Care Cancer. 2004;12(10):708‐715.Olver I, Clark‐Snow RA, Ballatori E, Espersen BT, Bria E, Jordan K. Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential. Supportive Care Cancer. 2011;19(1):S33‐S36.Griffin AM, Butow PN, Coates AS, et al. On the receiving end. V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol. 1996;7(2):189‐195.Ma AM, Barone J, Wallis AE, et al. Noncompliance with adjuvant radiation, chemotherapy, or hormonal therapy in breast cancer patients. Am J Surg. 2008;196(4):500‐504.Landercasper J, Dietrich LL, Johnson JM. A breast center review of compliance with National Comprehensive Cancer Network Breast Cancer guidelines. Am J Surg. 2006;192(4):525‐527.Brock DW, Wartman SA. When competent patients make irrational choices. N Engl J Med. 1990;322(22):1595‐1599.Balasubramanian SP, Murrow S, Holt S, Manifold IH, Reed MW. Audit of compliance to adjuvant chemotherapy and radiotherapy guidelines in breast cancer in a cancer network. Breast. 2003;12(2):136‐141.Roscoe JA, Bushunow P, Morrow GR, et al. Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer. 2004;101(11):2701‐2708.Tamura K, Aiba K, Saeki T, 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(2):405‐412.Iwamoto M, Nakamura F, Higashi T. Monitoring and evaluating the quality of cancer care in Japan using administrative claims data. Cancer Sci. 2016;107(1):68‐75.National Cancer Center in Japan. Hospital‐Based Cancer Statistics in 2017; 2018. https://ganjoho.jp/reg_stat/statistics/brochure/hosp_c_registry.html. Accessed January 18, 2021.Aogi K, Takeuchi H, Saeki T, et al. Optimizing antiemetic treatment for chemotherapy‐induced nausea and vomiting in Japan: update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis. Int J Clin Oncol. 2021;26(1):1‐17.Hesketh P, Kris MG, Basch E, et al. Antiemetics: ASCO guideline update. J Clin Oncol. 2020;38:2782‐2797.Roila F, Mokassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy and radiotherapy‐induced nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27:v119‐v133.Manabe S, Hashimoto S. What do you think of the Japanese standard body surface area of 1.48? (in Japanese). Kensa to Gijyutu. 1999;27(11):1312.Okuyama A, Higashi T. Patterns of cancer treatment in different age groups in Japan: an analysis of hospital‐based cancer registry data, 2012‐2015. Jpn J Clin Oncol. 2018;48(5):417‐425.Passik SD, Kirsh KL, Rosenfeld B, McDonald MV, Theobald DE. The changeable nature of patients' fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage. 2001;21(2):113‐120.Aranda S, Jefford M, Yates P, et al. Impact of a novel nurse‐led prechemotherapy education intervention (ChemoEd) on patient distress, symptom burden, and treatment‐related information and support needs: results from a randomised, controlled trial. Ann Oncol. 2012;23(1):222‐231.Tipton JM, McDaniel RW, Barbour L, et al. Putting evidence into practice: evidence‐based interventions to prevent, manage, and treat chemotherapy‐induced nausea and vomiting. Clin J Oncol Nurs. 2007;11(1):69‐78.Devine EC, Reifschneider E. A meta‐analysis of the effects of psychoeducational care in adults with hypertension. Nurs Res. 1995;44(4):237‐245.Clemons M, Bouganim N, Smith S, et al. Risk model‐guided antiemetic prophylaxis vs physician's choice in patients receiving chemotherapy for early‐stage breast cancer: a randomized clinical trial. JAMA Oncol. 2016;2(2):225‐231.Okuyama A, Nakamura F, Higashi T. Prescription trends of prophylactic antiemetics for chemotherapy‐induced nausea and vomiting in Japan. Support Care Cancer. 2014;22(7):1789‐1795.Okuyama A, Nakamura F, Higashi T. Prescription of prophylactic antiemetic drugs for patients receiving chemotherapy with minimal and low emetic risk. JAMA Oncol. 2017;3(3):344‐350.Yoshida I, Tamura K, Miyamoto T, et al. Prophylactic antiemetics for haematological malignancies: prospective nationwide survey subset analysis in Japan. In Vivo. 2019;33(4):1355‐1362.Japan Society of Clinical Oncology. JSCO Clinical Practice Guidelines 2015 for Antiemesis. Tokyo, Japan: KANEHARA & Co., Ltd.; 2015.Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(28):3240‐3261.Multinational Association of Supportive Care in Cancer. MASCC/ESMO antiemetic guideline 2013. http://www.mascc.org/antiemetic-guidelines. Accessed January 18, 2021. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

Real‐world emetic risk of chemotherapy and the corresponding antiemetic therapy in Japan: A study based on a nationwide database

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Abstract

INTRODUCTIONChemotherapy‐induced nausea and vomiting (CINV) is a serious adverse event of chemotherapy.1–3 The frequency of CINV depends primarily on the emetic potential of the chemotherapeutic agent used. There are effective antiemetic agents for the prevention of CINV,4 which alleviate CINV significantly.5 Vomiting is observed in more than 90% of patients receiving high‐emetic‐risk chemotherapy (HEC) without prophylaxis6; this prevalence is reduced to approximately 30% when antiemetics are administered.6–8 Several guidelines of antiemetic therapy for chemotherapy recommend prescriptions based on the emetic risk of the chemotherapeutic agent used.9,10In clinical practice, chemotherapy regimens are chosen depending on the cancer type, tumour stage, patient's general state and preference.11 Most chemotherapy regimens are not highly emetic, and effective prophylaxis is available. Moreover, with an increasing number of molecular‐targeted and immunological therapies, more agents with low and minimal emetic potentials are becoming available.12However, the side effects of chemotherapy remain a major concern of patients with cancer.1,13 Some patients refuse chemotherapy14,15 for fear of its side effects.16 Previous studies have reported a chemotherapy non‐compliance rate of 5%–18%.14,17 In addition, avoidance of a treatment‐related decrease of their quality of life was the primary reason for refusal, and the fear of nausea before chemotherapy initiation was found to be a strong predictor of subsequent nausea.18 These data suggest that the patients' concern about treatment, which may be a result of their negative perception of high‐risk emetic agents and the lack of antiemetic therapy in early days, can deprive them from receiving appropriate treatment. This fear may be due to limited knowledge of CINV and chemotherapy‐specific anti‐emetic therapy.Thus, awareness of the frequency of CINV and its management may help curb patients' negative perceptions of chemotherapy and ensure a more objective treatment decision‐making. A nation‐wide survey reported good compliance with the guidelines of anti‐emetic therapy19; however, the findings did not reflect those of a real‐world setting as the registry contained clinical information of patients from selected institutions, and a detailed analysis according to cancer type was not performed.Using health utilisation data from the Hospital‐Based Cancer Registries (HBCR), this study aimed to describe the actual frequency of emetic chemotherapy use and the appropriate prophylaxis by cancer type.METHODSStudy design and data sourceThis observational study used data from the Quality Indicator project,20 which involved health utilisation data linked with the HBCR. The project was conducted to evaluate the quality of health care of patients with cancer. In brief, the National Cancer Centre collects HBCR data from designated cancer care hospitals and voluntarily participating hospitals nationwide in Japan, covering approximately 70% of all patients with newly diagnosed cancer.21 Among these hospitals, 475 hospitals participated in the Quality Indicator project. We analysed health utilisation data collected from 1 January 2016 through 31 December 2017 for patients diagnosed with cancer in 2016. Collection of health utilisation data was part of the governmental survey that assesses the effect of the introduction of the diagnosis procedure combination‐based payment system. The survey data included information equivalent to fee‐for‐service insurance claims that cover all billable health services (e.g., diagnostic tests, imaging workup, procedures, treatments, and prescribed drugs) for both in‐ and out‐patients. These data were linked to the HBCR data of each patient in the participating hospitals. The data of approximately 49% of incident cancer cases in Japan were included in this study.Patient selectionThe subjects of this study were selected as follows. First, patients with cancer who were at least 20 years old at the time of diagnosis in 2016 and who were initiated on chemotherapy (intravenous and/or oral) were included in the study. Second, information on chemotherapeutic agents and antiemetic drugs were extracted from the utilisation data. Patients who received chemotherapy with interferon‐alpha were excluded as interferon‐alpha is used in other conditions like hepatitis C virus infection. For patients who received chemotherapy more than once, data of the first chemotherapy session after diagnosis was analysed. Many chemotherapeutic agents were administered within the first 8 days in one course (e.g., for patients with gastric cancer, cisplatin was added on Day 8 after S‐1 [tegafur/gimeracil/oteracil potassium] initiation). Thus, all drugs administered within the first 8 days were systematically included in one combination regimen in the emetic risk classification. Patients in whom chemotherapy was administered on the same day as surgery, thoracic drainage, abdominal drainage, and/or pericardial drainage were excluded because the chemotherapy drugs might have been administered topically. Patients who received chemotherapy drugs requiring arterial injection were excluded. Further, patients who received haematopoietic stem cell transplantation within 3 weeks of chemotherapy were also excluded because the emetic risks and prophylactic anti‐emetic drugs are different from those for regular chemotherapy.Emetic risk classificationThe emetic risk of chemotherapy was classified using the Japan Society of Clinical Oncology guidelines (JSCO).22 The guidelines of the National Comprehensive Cancer Network (NCCN),6 American Society of Clinical Oncology (ASCO),23 and Multinational Association Supportive Care in Cancer (MASCC) were used to classify the acute emetogenicity of chemotherapy drugs.24 The major differences between the guidelines are presented in Table 1. The emetic risks of some drugs differed according to dosage. Thus, the emetic risk of these drugs was based on the average Japanese adult's body surface area of 1.48 m2.13,25 Finally, we classified cyclophosphamide administered at >1500 mg/m2 as HEC and methotrexate sodium administered at >250, 50–250, and <50 mg/m2 as HEC, MEC, and LEC, respectively.1TABLEMajor differences between the classifications of emetic risk of intravenous chemotherapy drugsJapanASCONCCNMASCC/ESMOHigh‐riskCarboplatin (AUC ≥4)Doxorubicin (≥60 mg)Epirubicine (>90 mg)Ifosfamide (≥2 g/m2 per dose)Moderate‐riskCarboplatinCarboplatinCarboplatin (AUC < 4)CarboplatinEpirubicineEpirubicineEpirubicineIfosfamideIfosfamideIfosfamideDoxorubicinDoxorubicinDoxorubicinCytarabine (>200 mg/m2)Cytarabine (>1000 mg/m2)Cytarabine (>200 mg/m2)Cytarabine (>1000 mg/m2)Methotrexate (≥250 mg/m2)Methotrexate (≥250 mg/m2)Low‐riskMethotrexate (50–250 mg/m2)MethotrexateMethotrexate (50–250 mg/m2)MethotrexateBortexomibBortexomibCetuximabCetuximabNelarabinePanitumumabPanitumumabPertuzumabMinimal‐riskBortexomibBortexomibCetuximabCetuximabNelarabineNelarabinePanitumumabPanitumumabPertuzumabPertuzumabNote: Japan: The 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis. ASCO: American Society of Clinical Oncology Antiemetics guidelines, J Clin Oncol 2020; 38:2782–2797. NCCN: National Comprehensive Cancer Network, Antiemesis guidelines, version 2.2020. MASCC: MASCC and ESMO consensus guidelines for the prevention of chemotherapy and radiotherapy‐induced nausea and vomiting: ESMO clinical practice guidelines. Ann Oncol 2016; 27:v119–v133.Some of the emetic risks were defined based on the combination of the drugs.22 That is, fluorouracil, levoholinato, oxaliplatin, and irinotecan (FOLFOXIRI) for colorectal cancer and oxaliplatin, irinotecan, fluorouracil, and levoholinato (FOLFIRINOX) for pancreatic cancer were classified as HEC; gemcitabine and S1 (GS) and gemcitabine and nab‐paclitaxel (GEM/nab‐PTX) for pancreatic cancer as MEC; ifosfamide, carboplatin, and etoposide (ICE) for malignant lymphoma as HEC; and oral etoposide, nimustine, and ranimustine for malignant lymphoma as MEC.Statistical analysisThe frequency of chemotherapy use by emetic risk was calculated in both the overall population and by cancer type. The prescription rate of the prophylactic antiemetic drugs according to the type of cancer and typical regimens in each cancer was also calculated. In general, antiemetic drugs administered on the same day as the first chemotherapy were regarded as prophylactic. For patients who received HEC after the initiation of chemotherapy with lower emetic risks (e.g., S1 + cisplatin is added on Day 8 for gastric cancer) or antiemetic drugs that were prescribed on the same day as HEC were considered prophylactic. To capture oral antiemetic drugs administered in preparation for the initiation of chemotherapy, oral drugs that were prescribed 30 days before chemotherapy initiation were also considered prophylactic. The disease stage was assessed by combining the clinical and pathological stages; the pathological stage was used for patients who underwent surgical resection, whereas the clinical stage was used for patients with unavailable data on the pathological stage of the tumour.26 All statistical analyses were performed using Stata software (ver. 15.0; Stata Corporation, Texas, USA).RESULTSIn total, 172 133 patients receiving chemotherapy were identified (Table 2), among whom 70.4% received intravenous chemotherapy. The mean age of the study population was 65.9 (standard deviation, SD 12.0) years. The oral chemotherapy group was slightly older than the intravenous chemotherapy group (68.7 vs. 64.1 years). Non‐small cell lung cancer was the most common cancer type (14.1%), followed by colorectal cancer (12.9%) and breast cancer (9.9%). A larger proportion of patients who received oral chemotherapy had gastric and colorectal cancers (57.7% and 55.3%, respectively) compared with other cancers (4.7%–36.8%). A total of 62.5% of prescribed oral chemotherapy was adjuvant chemotherapy.2TABLEPatients' characteristicsIntravenous chemotherapy groupOral chemotherapy groupTotalN121 103(%)100.0N51 030(%)100.0N172 133(%)100.0Sex, male64 07952.930 08459.094 16354.7Age (years), mean (SD)64.7(SD: 12.2)68.7(SD: 11.2)65.9(SD: 12.0)Cancer typeNon‐small cell lung15 99113.2826416.224 25514.1Colorectal99328.212 26524.022 19712.9Breast15 86113.112622.517 1239.9Gastric67725.6924618.116 0189.3Malignant lymphoma13 19010.96431.313 8338.0Pancreatic69465.740397.910 9856.4Oesophageal69225.75161.074384.3Small cell lung cancer42113.5370.142482.5Others41 27834.114 75828.956 03632.6StageStage 027242.28591.735832.1Stage I16 71713.8787015.424 58714.3Stage II20 65817.110 68720.931 34518.2Stage III29 70424.512 66224.842 36624.6Stage IV41 57634.312 22224.053 79831.3Unknown97248.0673013.216 4549.6Adjuvant chemotherapy51 14842.231 87362.583 02148.2Abbreviation: SD, standard deviation.The most prescribed chemotherapy was MEC (n = 60 528, 35.2%), followed by LEC (n = 51 645, 30.0%), and HEC (n = 46 458, 27.0%; Table 3 and Figure 1). In the intravenous chemotherapy group, 47.0% (n = 56 911) and 38.2% (n = 46 306) received MEC and HEC, respectively. Further, more than 50% of the patients who received HEC were prescribed cisplatin (n = 27 933). Meanwhile, 40.7% (n = 23 171) of the patients who received MEC were administered carboplatin. In the oral chemotherapy group, 39 446 (77.3%) patients received LEC, and approximately 50% of them (n = 18 740) received S1.3TABLEDistribution of emetic risk by antineoplastic agent and mode of administrationIntravenous chemotherapyOral chemotherapyTotalN121 103(%)100.0N51 030(%)100.0N172 133(%)100.0High emetic risk46 30638.21520.346 45827.0Cisplatin (IV)27 93360.3–27 93360.1Doxorubicin and cyclophosphamide (IV)10 14321.9–10 14321.8Epirubicine and cyclophosphamide (IV)692515.0–692514.9Procarbazine (PO)–152100.01520.3Moderate emetic risk56 91147.036177.160 52835.2Carboplatin (IV)23 17140.7–23 17138.3Oxaliplatin (IV)12 14521.3–12 14520.1Cyclophosphamide (IV) ≤1500 mg625111.0–625110.3Temozolomide (PO)–156643.315662.6Imatinib (PO)–96026.59601.6Cyclophosphamide (PO)–60616.86061.0Low emetic risk12 19910.139 44677.351 64530.0Gemcitabine (IV)314625.8–31466.1Docetaxel (IV)336027.5–33606.5Paclitaxel (IV)300624.6–30065.8Mitomycin C (IV)10648.7–10642.1Fluorouracil(IV)6675.5–6671.3S1 (tegafur/gimeracil/oteracil potassium) (PO)–18 74047.518 74036.3UFT (tegafur/uracil) (PO)–953224.2953218.5Capecitabine (PO)–532813.5532810.3Lenalidomide hydrate (PO)–10362.610362.0Afatinib maleate (PO)–9742.59741.9Dasatinib hydrate (PO)–8672.28671.7Sunitinib malate (PO)–7702.07701.5Minimal emetic risk47894.0778615.312 5757.3Bortezomib (IV)148230.9–148211.8Rituximab (IV)123025.7–12309.8Trastuzumab (IV)71715.0–7175.7Gefitinib (PO)–179823.1179814.3Methotrexate (PO)–167221.5167213.3Hydroxycarbamide (PO)–157620.2157612.5Sorafenib (PO)–137517.7137510.9Erlotinib (PO)–94612.29467.5Unknown8980.7290.19270.5Abbreviations: iv, intravenous chemotherapy; po, oral chemotherapy.1FIGUREDistribution of chemotherapy emetic risk by cancer typeThe distribution of the chemotherapy emetic risk differed with cancer type. Table 4 shows the major chemotherapy regimens. HEC was commonly used for oesophageal cancer (80.3%), malignant lymphoma (60.2%), and breast cancer (53.8%). Among the patients with oesophageal cancer who received HEC, 77.5% received 5‐fluorouracil plus cisplatin (FP). Among patients with malignant lymphoma who were administered HEC, 84.1% received CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) with or without rituximab. MEC was used for small cell lung (59.9%), pancreatic (44.2%), and colorectal cancers (40.4%). Meanwhile, LEC was administered most in patients with gastric (60.2%), colorectal (55.2%), and pancreatic (51.6%) cancers.4TABLEExamples of chemotherapy regimens and proportion of prescription for each emetic riskCancer typeChemotherapy regimenHigh riskModerate riskLow riskMinimal riskNon‐small cell lungCDDP + pemetrexed (35.3%)NP (35.6%)TC* (48.8%)UFT (53.0%)Pemetrexed (38.6%)Gefitinib (49.6%)Erlotinib (30.4%)ColorectalFOLFOXIRI (30.2%)CAPOX (58.7%)FOLFOX (22.1%)Capecitabine (38.5%)UFT + LV (36.5%)Panitumumab (17.9%)Regorafenib (14.9%)BreastFEC (43.1%)EC (31.9%)AC (24.6%)TC** (85.8%)PTX (35.0%)Trastuzumab + PTX (17.0%)DTX (12.9%)Trastuzumab (74.7%)GastricS‐1 + CDDP (64.4%)Cape + CDDP (17.7%)SOX (68.4%)S‐1 (88.7%)Nivolumab (3.9%)Ramucirumab (3.6%)Malignant lymphomaCHOP (84.1%)CPM <1500 mg (65.1%)––PancreaticFOLFIRINOX (79.8%)GEM + nab‐PTX (91.3%)S‐1 (69.6%)GEM (29.2%)–OesophagealFP (77.5%)DCF (17.6%)Nedaplatin + 5‐FU (63.8%)DTX (12.4%)–Small cell lungPE (69.0%)PI (30.3%)CBDCA + etoposide (88.8%)CBDCA+CPT11 (5.8%)CPT11 (41.3%)‐Note: This table shows the percentage of the tumours' major regimens at each emetic risk. NP, CDDP + VNR; TC*, CBDCA + PTX; FOLFOXIRI, 5‐FU + l‐LV + L‐OHP + CPT11; CAPOX, capecitabine + L‐OHP; FOLFOX, 5‐FU + l‐LV + L‐OHP; FEC, 5‐FU + EPI + CPA; EC, EPI + CPA; AC, ADM + CPA; TC**, DTX + CPA; SOX, S‐1 + L‐OHP; CHOP, CPA + ADM + VCR + PSL; FOLFIRINOX, L‐OHP + CPT‐11 + 5‐FU + l‐LV; FP, 5‐FU + CDDP; DCF, DTX + CDDP + 5‐FU; PE, CDDP + etoposide; PI, CDDP + CPT11.Abbreviations: 5‐FU, 5‐fluorouracil; ADM, doxorubicin hydrochloride; CBDCA, carboplatin; CDDP, cisplatin; CPA, cyclophosphamide; CPM, cyclophosphamide; CPT11, irinotecan hydrochloride hydrate; DTX, docetaxel hydrate; EPI, epirubicine hydrochloride; GEM, gemcitabine hydrochloride; l‐LV, levofolinate calcium; L‐OHP, oxaliplatin; LV, folinate; PSL, prednisolone; PTX, paclitaxel; S‐1, tegafur/gimeracil/oteracil potassium; UFT, tegafur/uracil; VCR, vincristine sulphate; VNR, vinorelbine ditartrate.Table 5 shows the prescription rate of the prophylactic antiemetic drugs. In the intravenous chemotherapy with HEC subgroup, 70.7% (95% confidence interval [CI], 70.3%–71.1%) of the patients were prescribed a three‐drug combination comprising an NK1 receptor antagonist, a serotonin receptor antagonist, and dexamethasone. In the intravenous chemotherapy with MEC subgroup, 59.1% (95% CI, 58.7%–59.5%) were prescribed a two‐drug combination, and 24.0% (95% CI, 23.7–24.4) were prescribed a three‐drug combination. Among the patients who received HEC, the prescription rates of antiemetic drugs differed with cancer type (Figure 2). Among the patients with small cell lung, non‐small cell lung, breast, and oesophageal cancers who were administered intravenous chemotherapy with HEC, 96.2% (95% CI, 95.1–97.1), 93.4% (95% CI, 92.7–94.1), 92.9% (95% CI, 92.4–93.4), and 91.6% (95% CI, 90.9–92.3) were prescribed a three‐drug antiemetic regimen, respectively. Meanwhile, 17.7% (95% CI, 16.8–18.5) of the patients with malignant lymphoma treated with HEC were prescribed this regimen. Antiemetic therapy according to chemotherapy regimen for each cancer type was shown in Appendix S1. More than 90% of patients who received HEC regimen were prescribed the recommended three‐drug antiemetic regimen, while 13.5% of patients with malignant lymphoma receiving CHOP were prescribed these antiemetic regimen.5TABLEPrescription of antiemetic drugsIntravenous chemotherapy (n = 121 103)Oral chemotherapy (n = 51 030)Total (n = 172 133)%, CI%, CI%, CIHigh emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea70.7 (70.3–71.1)4.6 (1.9–9.3)70.5 (70.1–70.9)Serotonin receptor antagonist + dexamethasonea24.7 (24.3–25.1)34.9 (27.3–43.0)24.7 (24.3–25.1)Serotonin receptor antagonist1.8 (1.7–2.0)10.5 (6.1–16.5)1.8 (1.7–2.0)Dexamethasone0.5 (0.4–0.6)16.4 (10.9–23.3)0.6 (0.5–0.6)None of above1.2 (1.1–1.3)32.9 (25.5–41.0)1.3 (1.2–1.4)Moderate emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea24.0 (23.7–24.4)0.0 (0.0–0.2)22.6 (22.3–22.9)Serotonin receptor antagonist + dexamethasonea59.1 (58.7–59.5)10.6 (9.6–11.6)56.2 (55.8–56.6)Serotonin receptor antagonist3.7 (3.6–3.9)13.7 (12.6–14.9)4.3 (4.2–4.5)Dexamethasone2.7 (2.6–2.8)10.6 (9.6–11.7)3.2 (3.0–3.3)None of above8.6 (8.4–8.8)64.6 (63.0–66.1)11.9 (11.7–12.2)Low emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea2.1 (1.9–2.4)0.4 (0.3–0.5)0.8 (0.8–0.9)Serotonin receptor antagonist + dexamethasonea31.6 (30.8–32.4)0.8 (0.7–0.8)8.0 (7.8–8.3)Serotonin receptor antagonist4.7 (4.3–5.0)0.6 (0.5–0.7)1.5 (1.4–1.7)Dexamethasone46.9 (46.0–47.8)3.6 (3.4–3.8)13.8 (13.5–14.1)None of above13.3 (12.7–13.9)93.8 (93.6–94.1)74.8 (74.4–75.2)Minimum emetic riskNK1 receptor antagonist + serotonin receptor antagonist + dexamethasonea0.2 (0.0–0.3)0.0 (0.0–0.0)0.0 (0.0–0.1)Serotonin receptor antagonist + dexamethasonea5.0 (4.4–5.6)0.1 (0.0–0.2)2.0 (1.7–2.2)Serotonin receptor antagonist0.9 (0.7–1.2)0.2 (0.1–0.3)0.5 (0.4–0.6)Dexamethasone30.0 (28.7–31.3)2.6 (2.3–3.0)13.0 (12.4–13.6)None of above63.1 (61.7–64.5)96.8 (96.3–97.1)83.9 (83.3–84.6)Note: None: No prescription of an NK1 receptor antagonist, serotonin receptor antagonist, and dexamethasone.aAny steroid included.2FIGUREDistribution of prescription of antiemetic drugs by cancer typeIn the oral chemotherapy group, the two‐drug regimen was prescribed for 34.9% (95% CI, 27.3–43.0) and 10.6% (95% CI, 9.6–11.6) of the patients treated with HEC and MEC, respectively. The rate of use of a single serotonin receptor antagonist for HEC and MEC was 10.5% and 13.7%, respectively.DISCUSSIONThis study showed that MEC was used more than HEC, and CINV prophylaxis was widely used for HEC in a real‐world setting in Japan. The rate of prescription of HEC was dependent on the cancer type and was highest for patients with oesophageal cancer (80.3%), malignant lymphoma (60.2%), and breast cancer (53.8%). Meanwhile, MEC was prescribed mostly for patients with small cell lung (59.9%), pancreatic (44.2%), and colorectal (40.4%) cancers. For LEC, it was administered mostly for patients with gastric, colorectal, and pancreatic cancers, accounting for 50% of the patients who received chemotherapy. Further, the guidelines for antiemetic prophylaxis were used widely in 2016; meanwhile, some guidelines were revised in 2016.Patients with cancer and an indication for chemotherapy often experience pre‐treatment psychological distress.27 A previous study showed that pre‐chemotherapy education can decrease treatment‐related concerns and improve physical/psychological outcomes.28 Therefore, psychoeducational support can be an effective intervention for managing CINV.29,30 To avoid treatment refusal due to strong concerns about CINV, health care providers should establish a system to educate patients on the CINV risk of their planned chemotherapy regimen. Further, it should be emphasised that chemotherapy should be accompanied by a recommended anti‐emetic therapy. Moreover, the actual risk may depend on the patients' characteristics (cancer and treatment type, patient's age and sex),31 and thus these factors may need to be incorporated in the educational materials.A nationwide survey reported a good compliance to the guidelines for anti‐emetic therapy.19 Using the health utilisation data linked with the HBCR, this study described the actual frequency of using emetic chemotherapy and the appropriate prophylaxis by cancer type and typical regimens. The overall adherence to prophylactic antiemetic drugs for intravenous chemotherapy in this study was higher than that in previous studies in Japan.32,33 However, this study found that only 13.5% of patients with malignant lymphoma treated with CHOP received the recommended antiemetic therapy; this was consistent with a previous study.34 CHOP therapy use high dose prednisolone administration. Therefore, it may be recognised in clinical practice that many patients receiving CHOP do not suffer CINV. Aapro et al. reported that guideline‐consistent antiemetic therapy alleviates CINV significantly.5 Healthcare professionals should consider using recommendations from guidelines.Assuming that the effectiveness of the antiemetic drugs was similar to that in previous reports (i.e., in patients receiving both intravenous HEC and the recommended antiemetic, the frequency of vomiting was 30%) and that 90% of the patients received the anti‐emetic prophylaxis for HEC, the frequency of vomiting in the patients who received HEC without antiemetic prophylaxis was approximately twice that of the patients who took HEC with prophylaxis. Furthermore, considering that more than 90% of patients with non‐small cell lung, breast, and oesophageal cancers who received HEC with the recommended antiemetic treatment in 2016, the frequency of vomiting was approximately 35%. Education of patients on the risk of CINV may reduce excessive concerns about CINV.The appropriateness of antiemetic prophylaxis for oral chemotherapy could not be evaluated because the recommendations for prophylactic antiemetic drugs for oral chemotherapy vary with existing guidelines because of limited information on the emetic risk of oral chemotherapeutic agents.6,35,36 For example, the NCCN guideline recommend the use of a single serotonin receptor antagonist for patients with a high‐to‐moderate risk of CINV.8 Meanwhile, the MASCC guideline recommends a two‐drug combination of a serotonin receptor antagonist and dexamethasone for the same patients.37 This study simply describes the current status of prophylactic antiemetic drugs prescribed for patients receiving oral chemotherapy. These findings may be used for further research on the appropriate antiemetic therapy for these patients.This study had some limitations. First, this study did not measure the frequency of CINV due to unavailability of the CINV incidence data. Therefore, we estimated the frequency using data from a previous study. Second, antiemetic prophylaxis was defined based on the time of prescription recorded in the database. Although prophylactic antiemetic drugs prescribed on the same day with chemotherapy or within 30 days of oral chemotherapy were most likely prophylactic, the possibility that they were actually prescribed for therapeutic purposes could not be excluded. Third, this study examined the situation of patients diagnosed in 2016. The NCCN and ASCO antiemetic guidelines have been revised after 2016. The new guidelines also recommended additional use of olanzapine for HEC.6,23 We did not examine this recommendation. Fourth, the authors did not consider the patients' individual risk factors for CINV, such as sex, morning sickness, and comorbidities. Incorporating these factors may justify the non‐prescription of antiemetic prophylaxis in patients receiving HEC. Finally, the exact drug dosages per the body surface area of the patients were not available, because information on the patients' body surface area was not available in the claims data. Consequently, the emetic risks of patients receiving chemotherapy with agents, such as methotrexate and cytarabine, may be misclassified.33 Despite these limitations, these findings will be helpful in understanding the real‐world clinical situation of the CINV risk and prophylactic antiemetic use in Japan. Further studies should evaluate the effect of prophylactic education with/without psychoeducational support on relieving patients' concerns.CONCLUSIONOverall, HEC was less prescribed than MEC, and prophylactic antiemetic drugs were generally prescribed. Healthcare professionals should educate patients about emetic risks before chemotherapy initiation to avoid patients' concerns about CINV that may lead to treatment termination. This type of survey should be repeated to observe the improvements in compliance with recommended anti‐emetic therapy.ACKNOWLEDGMENTWe would like to appreciate the registrars of the Hospital‐Based Cancer Registries.CONFLICT OF INTERESTNarikazu Boku received funds from Ono and Takeda, and honorarium from Ono and Taiho. All the other authors declare no conflict of interest.AUTHOR CONTRIBUTIONSAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 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Journal

Cancer Reports – Wiley

Published: Mar 1, 2022

Keywords: chemotherapy; nausea; neoplasms; psychological distress; registries; vomiting

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