Object: The appropriate use of antiemetics is important for the prevention of chemotherapy‐induced nausea and vomiting (CINV); however, little is known about the rate of concordance with antiemetic guidelines for CINV in the field of pediatric, adolescent, and young adult. Methods: Using the Diagnosis Procedure Combination system in Japan, we identified patients <30 years of age who were diagnosed with cancer between July 2010 and March 2016. We have assessed concordance with the ASCO antiemetic guidelines for each emetic risk category of chemotherapeutic drugs. Furthermore, we have assessed the risk factors of discordance with the antiemetic guidelines using a logistic regression. Results: In total, 21 106 patients who underwent chemotherapy were included. The rates of concordance with the guidelines in each emetic risk category of chemotherapeutic drugs were 51.1% in high risk, ≥18 years of age; 21.5% in high risk, <18 years of age; 32.1% in moderate risk; 52.0% in low risk; and 51.6% in minimal risk. The main reason for the discordance was underuse of antiemetics, especially steroids. The factors for discordance were younger age, use of moderate and high emetic risk chemotherapeutic drugs, hematological malignancy, and brain tumor. Conclusion: There is substantial scope to improve the antiemetic practice and reduce the risk of discordance with the antiemetic guidelines in pediatric, adolescent, and young adult patients. The risk factors are different from those in adults. Further investigations to evaluate the causes of discordance are warranted.
Keywords: adherence; administrative database; adolescent and young adult; antiemetic guideline; pediatrics
This is the first large‐scale report of adherence to antiemetic guidelines for pediatrics, adolescents, and young adult patients who have received chemotherapy. Our study demonstrated that a concordance with the antiemetic guidelines in the pediatric population is lower than that in adults.
Chemotherapy‐induced nausea and vomiting (CINV) is one of the most serious concerns for children and adolescent and young adult patients (AYA) with cancer,[
The guidelines published from different societies, such as the American Society of Clinical Oncology (ASCO),[[
Several studies conducted in the adult population have demonstrated concordance with the antiemetic guidelines, reporting a concordance rate of 70%‐90% in Japan[
On the other hand, in the pediatric patients, the Children's Oncology Group (COG), the world's largest clinical trials consortium have expressed concerns regarding discordance with the antiemetic guidelines.[
The scenario is, however, obscure in Japan. Hence, we have aimed to assess the concordance with the antiemetic guidelines in the pediatrics fields, together with adolescent, and young adult patients who are usually seen in the department of pediatrics department in Japan.
This was a retrospective observational study using the Diagnosis Procedure Combination (DPC) database, an administrative database in Japan. The data were obtained from approximately 80% of all the DPC hospitals which encompassed approximately 8 million inpatient admissions per year.[
The study was conducted after obtaining approval from the Kyoto University Graduate School and Faculty of Medicine, Kyoto University Hospital Ethics committee in accordance with the guidelines on medical and epidemiological research (No. R135). Using the DPC database, we have identified inpatients of age <30 years at the time of receiving chemotherapy from July 2010 to March 2016. In Japan, there is no official age range definition for AYA.[
All data were collected from the DPC database; demographic characteristics including age, gender, diagnosis, chemotherapeutic drugs, antiemetic drugs, body weight, height, and first date of chemotherapy were collected. The chemotherapeutic drugs were classified according to the ASCO emetic risk category.[[
We examined the prescription pattern of the prophylactic antiemetic drugs used (NK‐1RA, 5HT
The factors of discordance with the guidelines were determined by using logistic regression models. We classified the patients into the following seven age groups: 0‐2, 3‐4, 5‐9, 10‐14, 15‐19, 20‐24, and 25‐29 years of age. The independent variables were age group, gender, antiemetic risk category, and existing disease. The odds ratios (ORs) and 95% confidence intervals (CIs) for each variable were calculated. All the analyses were computed by using r statistical software (version 3.4.0) and a two‐sided significance level was fixed at 0.05.
In total, 21 106 patients who underwent chemotherapy were included. The patients were classified into the following seven age groups: 0‐2 (n = 2480), 3‐4 (n = 1417), 5‐9 (n = 2436), 10‐14 (n = 2528), 15‐19 (n = 3112), 20‐24 (n = 3513), and 25‐29 years of age (n = 5620). The median age was 16 years (range 0‐29 years) and the most common age category was 25‐29 years. The most frequent type of cancer was solid tumor (45.3%), and the most frequent emetic risk category was moderate (34.1%) (Table). The proportion of different types of cancer within each emetic risk category is shown in Table S1.
Patient characteristics (N = 21 106)
Characteristic n (%) Gender Male 11 246 (53.4) Female 9860 (46.7) Age (y) Median (range) 16 (0‐29) 0‐2 2480 (11.8) 3‐4 1417 (6.7) 5‐9 2436 (11.5) 10‐14 2528 (12.0) 15‐19 3112 (14.7) 20‐24 3513 (16.6) 25‐29 5620 (26.6) Disease Solid tumors 9562 (45.3) Hematologic 9463 (44.8) Brain tumor 2081 (9.9) Received anticancer agents High emetic risk 6661 (31.6) Moderate emetic risk 7188 (34.1) Low emetic risk 5806 (27.5) Minimal emetic risk 1451 (6.9)
The major cancer type among the patients who received moderate (42.2%), low (73.2%), or minimal (58.6%) risk category chemotherapy was hematologic malignancy, whereas the major cancer type among the patients who received chemotherapy in the high emetic risk category was solid tumor (72.4%) (Table S1). In addition, even when we analyzed only patients <18 years of age, the proportion of cancer type in each risk category was similar.
With the high emetic risk chemotherapeutic drugs, the commonly used prophylactic antiemetic drugs were a combination of NK‐1RA, 5HT
Details of prescription of each category of prophylactic antiemetic drugs and concordance with the ASCO antiemetic guidelines, 2006 and 2017
Antiemetic category (n) Combination of agents Recommendation of ASCO guidelines % (95% CI) 2006 2017 Minimal (1451) NK‐1RA + 5HT3RA + steroids D D 0.6 (0.2‐1.1) 5HT3RA + steroids D D 3.2 (2.4‐4.3) NK‐1RA + 5HT3RA D D 3.0 (2.0‐4.0) NK‐1RA D D 0.3 (0.1‐0.8) 5HT3RA D D 37.8 (35.0‐40.0) Steroids D D 3.4 (2.0‐4.0) None Concordance Concordance 51.6 (49.0‐54.2) Low (5806) NK‐1RA + 5HT3RA + steroids D D 1.5 (1.2‐1.8) 5HT3RA + steroids D D 9.4 (8.7‐10.2) NK‐1RA + 5HT3RA D D 2.6 (2.2‐3.0) NK‐1RA + steroids D D 0.2 (0.1‐0.3) NK‐1RA D D 0.2 (0.1‐0.3) 5HT3RA D Concordance 52.0 (50.7‐53.3) Steroids Concordance Concordance 5.9 (5.3‐6.6) None D D 28.3 (27.1‐29.4) Moderate (7188) NK‐1RA + 5HT3RA + steroids D D 14.0 (13.2‐14.8) NK‐1RA + steroids D D 0.1 (0.0‐0.20) NK‐1RA + 5HT3RA D D 7.3 (6.8‐8.0) Steroids + 5HT3RA Concordance Concordance 32.1 (31.0‐33.2) NK‐1RA D D 0.2 (0.1‐0.3) 5HT3RA D D 43.0 (41.9‐44.2) Steroids D D 0.4 (0.30‐0.60) None D D 2.9 (2.5‐3.3) High (≥18 y of age) (4130) NK‐1RA + 5HT3RA + steroids Concordance Concordance 51.1 (49.5‐52.6) 5HT3RA + steroids D D 20.1 (18.9‐21.4) NK‐1RA + 5HT3RA D D 9.7 (8.8‐10.7) NK‐1RA + steroids D D 0.3 (0.20‐0.50) NK‐1RA D D 0.2 (0.10‐0.30) 5HT3RA D D 17.6 (16.5‐18.8) Steroids D D 0.3 (0.2‐0.50) None D D 0.7 (0.50‐1.00) High (<18 y of age) (2531) NK‐1RA + 5HT3RA + steroids D Concordance 21.5 (19.9‐23.2) 5HT3RA + steroids Concordance D 18.2 (16.7‐19.8) NK‐1RA + 5HT3RA D D 10.2 (9.1‐11.5) NK‐1RA + steroids D D 0.2 (0.0‐0.40) NK‐1RA D D 0.2 (0.0‐0.40) 5HT3RA D D 48.2 (46.2‐50.1) Steroids D D 0.2 (0.10‐0.50) None D D 1.3 (0.90‐1.90)
1 Abbreviations: NK‐1RA, neurokinin‐1 receptor antagonists; 5HT
The concordance in each emetic risk category varied. Although up to 51.1% of the patients ≥18 years of age received the appropriate antiemetic drugs following the recommendation of the ASCO guidelines, only 21.5% patients <18 years of age received antiemetic drugs. The rate of concordance with the guidelines for moderate and minimal emetic risk chemotherapeutic drugs was 32.1% and 51.6%, respectively. The 2017 ASCO antiemetic guidelines are identical to the 2006 guidelines, except for the low emetic risk chemotherapeutic drugs. For the patients who had received low emetic risk chemotherapeutic drugs, the rate of concordance increased from 5.9% in the 2006 guidelines to 57.9% in the 2017 guidelines, reflecting the revision of the guidelines (Table). The factors of discordance were younger age, use of high and moderate emetic risk chemotherapeutic drugs, brain tumor, and hematological malignancy (Table). The reason for discordance was mainly the underuse of antiemetic drugs. In particular, steroids were less frequently prescribed to the patients who received low, moderate, and high emetic risk category chemotherapeutic drugs (Figure). The rate of overuse of NK1RA increased as age increased. In contrast, the rate of underuse of steroids increased as age decreased (Figure).
Factors of concordance with the ASCO antiemetic guidelines, 2017
Odds ratio 95% CI Gender 1.17 1.10‐1.24 <.001 Age (y) 0‐2 0.53 0.48‐0.59 <.001 3‐4 0.73 0.64‐0.83 <.001 5‐9 0.80 0.72‐0.89 .001 10‐14 0.83 0.75‐0.91 .008 15‐19 0.80 0.73‐0.84 <.001 20‐24 0.96 0.88‐1.05 .598 25‐29 1 Antiemetic category High emetic risk 0.51 0.46‐0.58 <.001 Moderate emetic risk 0.41 0.36‐0.46 <.001 Low emetic risk 1.31 1.16‐1.47 <.001 Minimal emetic risk 1 Disease Hematologic malignancy 0.69 0.62‐0.77 <.001 Brain tumor 0.80 0.75‐0.85 <.001 Solid tumors 1
This is the first study that demonstrates the concordance with the antiemetic guidelines in the pediatric population by using a large‐scale administrative database. Our study has four major findings.
First, the concordance with the antiemetic guidelines in the pediatric population was lower than that in the adults. Previous studies have shown that the rate of concordance with antiemetic guidelines was 70%‐90% in adults. We have found the concordance was approximately 20%‐60% in the pediatric population.
Second, this study clarified that the discordance was mainly caused by the underuse of antiemetics. We found that the prescription rate of steroids was low in all emetic risk categories. One reason for this was the clinicians' concerns about the adverse effects of steroids on the endocrine system and growth in the children. There is no consensus on the use of short‐term steroids for the treatment of emesis in children; hence, further research is needed. In cases of the overuse of antiemetics, we found that clinicians tended to prescribe NK1RA in the moderate risk category, or 5HT
Third, the risk factors of discordance in the pediatric population are different from those in the adults. The risk factors of discordance with antiemetic guidelines in adults were hematological malignancy, older age, and the use of low emetic risk chemotherapeutic drugs.[[
Fourth, the rate of concordance was improved by the updated 2017 ASCO antiemetic guidelines. The 2017 ASCO antiemetic guidelines recommend the use of 5HT
Recently, NK‐1RA has been recommended along with the high emetic risk chemotherapeutic drug regimens in the pediatric population. The rate of concordance with the guidelines with high emetic risk chemotherapeutic drugs was low in our study. One possible reason for this was that the use of NK‐1RA for patients under 12 years of age has only been permitted in Japan only from April 2016.
A recent Canadian study of 200 patients, evaluating the rate of prescription concordance to the CINV guidelines showed that only 29% of the prescriptions containing high and moderate emetic risk chemotherapeutic drugs were concordant with the guidelines, resulting in poor control of CINV.[
Our study has several limitations. First, our study considered only the chemotherapeutic drug‐induced acute emesis and did not consider delayed emesis. The guidelines mainly recommend the use of antiemetic drugs during acute emesis in the pediatric population. Further studies on the use of prophylactic drugs to prevent delayed emesis are needed. Second, the DPC database did not provide patients outcomes, such as vomiting rates, medical history, and laboratory results of patients. Third, the assumption that all centers used ASCO as their source guidelines for antiemetic prescribing was made. We need to interview the medical staff in the centers that treat pediatric and AYA patients with cancer to determine which guidelines were used in daily practice.
In conclusion, our study has identified a substantial scope to improve the antiemetic practice and mitigating the risk factors of discordance with the antiemetic guidelines in the pediatric, adolescent, and young adult patients. These identified risk factors were different from those in the adult population. Further studies to evaluate the causes of this discordance are warranted.
This work was supported by a Grant‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (16H02634, 19H01075; https://
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By Seiko Bun; Susumu Kunisawa; Noriko Sasaki; Kiyohide Fushimi; Kimikazu Matsumoto; Akimasa Yamatani and Yuichi Imanaka
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